Brain and Behavior Lecture #1 - Introduction Page 1 of 4 Announcements: This is Brain and Behavior. Thanks for showing up. I hope you guys will come to the lecture. I’d like to keep the other lecturers happy. There is also the benefit to you as future clinicians. But I do understand that you won’t find all the lecturers equally important. For the most part, if you have questions, it is easiest to email the individual lecturers. They are very willing to answer emails. You can also send the emails to me and I can forward them on to the individual lecturers. Lecture: WHAT IS THE VALUE OF A COURSE ON CLINICAL NEUROSCIENCE FOR A MEDICAL STUDENT? ANSWER Brain disorders are the leading causes of disease and disability, and it is a growing population of chronic patients (e.g. traumatic brain injury a.k.a. TBI, stroke, and dementia). You will find that there is a correlation between brain diseases and chronic diseases. If you are not aware of it, you might miss serious consequences for the patients. So the conclusion is that learning about the brain is good! GOALS OF BB COURSE We want to integrate and extend certain information presented in neuroanatomy, as well as develop an understanding of the reciprocal relationship between body and brain in disease. Also, we want to learn about basic tools of “lab” evaluation in clinical neuroscience (e.g. neuropsychiatry), such as functional imaging and neuropsychological testing. We also want to learn about basic neurobehavioral functions e.g. memory, language, executive functions, and aspects of neurochemical and neuoanatomical substrates. So this course will provide examples of certain disorders that will integrate previous lectures as much as possible. For example, when we think of schizophrenia -- it is both a psychiatric and neurologic disease. UNTITLED SLIDE The final exam focuses primarily on material presented in lectures. I only ask the other lecturers to give one reading each. Some of the references may be useful to you for future. For example, today’s handout is useful for clinical neuropsychiatric testing. Please give feedback. If you give feedback, you are encouraged to be constructive and to give specifics and examples. And be professional. This will help me to understand how to further develop the course. I will keep copies of all comments sent to me for review purposes. I would appreciate comments e-mailed after lectures or at intervals whenever you can. READINGS FOR THIS LECTURE I put the Neuropsychiatric Exam Chapter on Blackboard. It’s a bit lengthy, but a good resource. In addition, a very good clinical resource book is: The Mental Status Exam in Neurology by Richard Strub and F. William Black -- very practical and portable. I don’t know which edition is the most recent. Good to have, but not required reading. NEUROBEHAVIORAL FUNCTIONS This just refers to the entire spectrum of cognitive, mood, and behavioral functions – for example, integrating sensory-motor function. In terms of neurobehavioral function, the brain is specialized in some ways, but much overlap exists. For example, the frontal cortex circuitry we will talk about in a later lecture EXAMPLES OF MECHANISMS OF BRAIN DYSFUNCTION Brain dysfunction can be due to structural changes including: Focal lesion-- focal damage or disease such as stroke, bleed, contusion. White or gray matter can be involved. Diffuse axonal injury ( DAI )-- can be wider spread structural damage to white matter, such as due to trauma. In addition, you can have: Electrical abnormalities — seizures and epilepsy. Abnormalities are a spectrum. Chemical/metabolic abnormalities – disturbances in neurotransmitter systems or metabolism. Such as due to substance use, medications, systemic illness. This can range from schizophrenia to stroke and brain injury.

Brain and Behavior Lecture #1 - Introduction Page 2 of 4 The thing to keep in mind is some illness or injury can be due to or result in a combination of the above. Such as TBI, stroke, delirium, seizures presenting as mental status changes, drug induced dysfunction. For example, degenerative disorders, like Alzheimer’s disease, can involve several mechanisms. So with many illnesses, several of these processes can be in play. Even in Parkinson’s disease, a number of things can contribute to the ultimate clinical features of neurobehavioral function. OVERVIEW: NEUROANATOMY AND FUNCTION We know that neurobehavioral function is dependent upon specific brain areas, but also networks of areas, and their connections (white matter tracts). So while we associate the frontal cortex with a certain function, we understand that other parts of the brain serve as part of the network for those functions. So what that means is you can get dysfunction from direct damage to the frontal lobe or dysfunction from cortical or subcortical damage. For example, in Parkinson’s disease, the frontal lobe may look fine, if it can’t connect to the cortical and subcortical areas, you can see frontal lobe dysfunctions. So functional deficits can result from dysfunction of a specific area of brain (mechanisms we discussed), as well as other parts of a network, or to the white matter tracts that connect areas of a network. RELATIONSHIP OF NEUROPATHOLOGY TO CLINICAL EFFECT The effect of any neurological damage or dysfunction is going to be determined by several factors: Obviously, size -- in general, greater area means worse deficits. Also keep in mind that location is key -- specific brain region, part of network or WM tracts involved. But remember that a strategically located smaller lesion/disease process could cause as many or more problems than a larger area of damage in another location -- so where is the damage? For example, a range of thalamic lesions can do a lot of damage. CORTEX Bottom line is that there is not area of the brain that doesn’t contribute to neurobehavioral function. CORTEX-OVERVIEW Cerebral Cortex – damage/dysfunction of different areas of cortex can result in a variety of neurobehavioral deficits: motor sensory, language, etc. For example, temporal lobe dysfunction can result in memory disorders, language problems, personality and behavior changes associated with temporal-limbic areas (e.g. types of epilepsy, trauma). Frontal cortex dysfunction can result in higher level cognitive problems, mood and behavioral disturbances, and language problems. This is one of the areas that can be a bit of an imposter sometimes. They can present with frontal cortex symptoms, but can really be due to damage elsewhere. CORTICAL-SUBCORTICAL CONNECTIONS Remember that “unplugging” cortex from subcortex can also produce cortical deficits when involving key parts of the network, or the white matter (the “cables” linking networks). So it’s not that simple in thinking that someone with frontal lobe symptoms has damage to the frontal lobe. For example, infarct of the inferior genu of the internal capsule, a strategic location, can interrupt the thalamic peduncles and cause dysfunction of ipsilateral frontal cortex. Confusion, memory loss, apathy and memory loss can result. Example: Parkinson disease can cause executive dysfunction (frontal cortex) due to disruption of cortical-subcortical connections. THALAMUS Anyone who wants to know about the thalamus can ask Dr. Gorelick about the thalamus. That’s his favorite part of the brain. THALAMUS The thalamus has multiple functions. It constitutes the main part of the diencephalon. It processes and relays sensory information (except olfactory) selectively to various parts of the cerebral cortex. Its major role is on motor systems. Thalamic nuclei have strong reciprocal connections with the cerebral cortex. Neurobehavioral function: For example, damage to anterior and dorsomedial thalamus can result in wide range of neurobehavioral dysfunction such as arousal, attention, motivation, executive function, memory deficits e.g. thalamic stroke syndromes. We’re interested in the dorsal medial thalamus. BASAL GANGLIA You don’t have to memorize the chart. The basal ganglia are also a critical part of the network. Strokes and degenerative processes in that area are not good. UNTITLED Basal ganglia are part of many networks. They play a role in movement disorders, psychiatric syndromes and cognitive deficits (including aspects of learning) e.g. Parkinson Disease, Huntington Disease, Lewy Body Disease, and vascular disease. E.g. caudate infarcts can result in cognitive and behavioral deficits. There can be impaired problem solving ability, memory problems, attentional problems, and “frontal” type deficits (remember networks, tracts).

Brain and Behavior Lecture #1 - Introduction Page 3 of 4 LIMBIC SYSTEM UNTITLED The limbic system is a complex network of areas and circuits that includes the hippocampus, cingulate , amygdala, and hypothalamus as major components. Its role is in arousal, mood, attention, learning, memory, and regulating goal driven behaviors (more in a later lecture by Dr Herbner). There are major white matter pathways- such as fornix, medial forebrain bundle- that have connections to prefrontal cortex (PFC). Disruption of either the area or the connections can cause deficits/changes. For example, seizure disorders in the limbic areas can result in primarily neurobehavioral presentations (Dr. Schrift lecture will cover neuropsychiatry seizures). So again it is another example of the brain that also has discrete function; it has major connections and damages can result in wide variety of symptoms. Presentation could be a primary psychiatric disorder, but you don’t want to miss something else medial. CEREBELLUM This area is involved in motor coordination and eye movements, but also a role in motor learning, attentional activation and other aspects of cognition. Be aware of cognitive, affective, and behavioral disturbances in assessing, treating, and rehabilitating patients with cerebellar illness. Further, it may be important to consider the possibility of cerebellar disease in patients presenting with a new onset of changes in these behavioral domains. Things to keep in mind when patients present: Think of the possibilities of lesion and disease processes. NEUROBEHAVIORAL FUNCTION AND DIAGNOSIS So all this is to stress that changes in mental function may present symptoms for psychiatric, neurological, or medical disease. Never just assume a primary psychiatric disorder – e.g. in cognitive, mood, behavioral changes, or psychotic features in delirium, vascular disease, and stroke. They may be mistaken for a primary psychosis. Particularly in the elderly and very young, delirium can result in other missed things. You can have very low level delirium. So that’s an instance where you need to have very high level of suspicion. Inappropriate behavior, poor attention, language problems can present in traumatic brain injury or types of dementia. Vascular disease may first present as changes in cognition, mood, behavior, with certain tumors or endocrine disorders. Depression or cognitive changes in cerebral vascular disease, Parkinson’s or Alzheimer’s disease NEUROPSYCHIATRIC EVALUATION -- GENERAL GUIDELINES History and exam are key points. Part of the neurologic exam looks at higher cortical functions. You can’t stop at sensory motor exams. The laboratory tests are obviously driven by the history and exam. Neuropsychological testing will be another lecture. EEG should be done as necessary, but normal EEG does not always rule out underlying seizure disorder. The same goes for imaging - CT, MRI (lecture on MRI to come). But you have to be careful because these things are costly. But sometimes you can miss things. So on EEG, if you see something, great. If you don’t, don’t rule it out. So it’s good not to be too reliant on lab tests and take it as part of the big picture. Often the clinical exam and history are still primary basis for diagnosis. MMSE Example of the Folstein MMSE- Make copies and use this! It is a good, brief, standardized way of assessing mental state. This is quite sensitive for someone developing delirium. If they get 28/30 on this, it’s likely they know what’s going on. This is a nice standardized way to check patients’ mental status. CLINICAL NEUROSCIENCE AND NEUROPSYCHIATRY: CASE EXAMPLES TO ILLUSTRATE SOME COMMON CLINICAL SITUATIONS Now what I want to do with the time left is talk about why all this matters. CASE EXAMPLE You need to ask whether there have been additional changes. If someone is not challenged on a daily basis, it’s difficult for people to remember exactly when something started. Is there anything that concerns you in this history? Alcoholism. What else? So we get more history on the next slide. NEXT SLIDE So he fell, and now he is poorly orientated and distractible. So maybe he has a chronic subdural hematoma! Acute subdural hematoma is not hard to diagnose. But chronic ones are difficult because it’s a low pressure bleed. With alcoholics, they may not remember when they fell. So this can be missed when physicians aren’t thinking about it. These can present as a mood disturbance. EXAMPLE OF SUBDURAL HEMATOMA (IMAGING) This is such a common tool. So you need to understand how to interpret it.

Brain and Behavior Lecture #1 - Introduction Page 4 of 4 CASE EXAMPLE So what other type of information would be useful? NEXT SLIDE Detailed questions reveal that the family notes personality changes- the patient seems progressively more irritable and impulsive. As for cognitive changes according to the family – they note that he has been more distractible, more forgetful. Patient has history of hypertension, hyperlipidemia, and insulin-dependent diabetes. On exam, you note mild cogwheel rigidity (generally a Parkinson’s symptom), and MMSE is 22/30. What are you considering at this point? What work-up would you request? So what jumps out at you? This might be a stroke! Based on results of your exam and history, you may order further tests: NPT (neuropsych testing) may be first, unless changes are acute. NPT shows cognitive impairments, with impairments in memory, attention and executive function. Imaging? This is not an acute problem, so you’re not going to get an emergency scan. But at some point, you might get a scan. What differential diagnoses would you be considering now? What do you want to do? NEXT SLIDE The point here is to make the point that these patients may go to clinic for depression or suffering from a mood disturbance, but there may be something else going on. CASE EXAMPLE Especially with young people, you have to ask about previous head injuries. This person actually has history of significant head injury. So this type of mood disturbance can look sociopathic. NEXT SLIDE (IMAGING) This shows 3 types of MRI structure scans. The FLAIR and GRE show abnormalities in the left frontal lobe area. CASE EXAMPLE This is another elderly person with a common problem. You are an intern on the inpatient medicine service, and an 80-year-old woman is admitted for respiratory problems and fever. She is diagnosed with pneumonia and placed on antibiotics. She seems calm and cooperative. Her fever comes down, and her infection is responding, but she is tearful at times and seems withdrawn. The family is concerned she is depressed. What kind of things do we need to worry about? This is another case of low level delirium. NEXT SLIDE You perform a detailed mental status exam (MSE), and find the patient is not oriented, is distractible, has poor short term memory, and cannot copy the picture. She becomes tearful. After you speak with her for awhile longer, she expresses concern that one of the staff is poisoning her food. She also asks you to do something about the bugs in her room. Family denies any past Psychiatric history. What’s going on? With the elderly it is not uncommon for there to be lag time between injury and onset of symptoms. DELIRIUM Encephalopathy may signal a medical emergency. This may be presentation of a serious illness. It is critical to distinguish from a diagnosis of depression or psychosis. It may be difficult to do this. The elderly are very prone to delirium, and the deficits often linger after the medical problem is treated. Serial MMSE can show some resolution of the process. This disorder is excellent example of the confluence of medicine and psychiatry. Sometimes with only a UTI, the elderly can develop delirium. CASE EXAMPLE The patient looks very manic. But what are the odds of developing bipolar after 40 years old? Not very likely. NEXT SLIDE You get a complete medical history. The family says she has no history of any psychiatric disorder. She has been relatively healthy in the past, except for a history of asthma which can be severe at times. She was recently put on a round of corticosteroids. They also worry she may have been taking more of her asthma medication, theophylline, than she should, as she forgets that she took them sometimes. SECONDARY MANIA To conclude, you just have to keep in mind that neurobehavioral problems can present as psychological problems. If you misdiagnose a medial/neurological problems as a psych problem, you will do more harm.

Brain and Behavior: MRI in Clinical and Research Neurosciences Announcements: See Blackboard for schedule changes. Readings for this lecture are not required but are for those who want to know more about the area. Lecture Content

Today we are going to talk about MRI and the role it plays in the clinical neurosciences. Let me walk you through the procedure and process of MRI. This is a big magnet that is on at all times. When you go toward the scanner you will see that there are markings on the floor so people with pacemakers, metal, etc. shouldn’t go in. The precautions are important because the bigger the magnet the bigger the risk. So if you’re going in the scanner what happens is you are being put in this large, static, magnetic field that’s always on.

What we are particularly interested in, in biological systems, is the hydrogen atom because there are a lot of them in biologic systems. They act like little magnets and have random movement and we can do a lot to them in MRI which allows us to pick up signal and look at different tissues. Different tissues are going to have different concentrations and locations of hydrogen atoms. They are positively charged and have a nuclear spin. They normally spin in random directions.

(Slide 5) The idea is that they are random so that you have a net magnetization of zero. The first thing you are trying to do in an MRI scan is get your hydrogen atoms in a more consistent state. If you want to get a measurement out of them you have to get them in order first. The hydrogen atoms in a static magnetic field are going to try to line up either parallel or anti-parallel to the field. It is easier to measure change from a more uniform state so you are setting the stage for the measurements you are going to get.

T1 is the value of time it takes for the hydrogen atoms to line up with the static field. The T1 constant is different for different tissues and we take advantage of this. When you are put in a scanner a cylindrical coil is placed around your head, the type of coil you use corresponds with what you look at and the sensitivity of it. The coil can transmit and receive signal. We transmit a radio frequency pulse to your brain that is strong enough to overcome the static field. This frequency is going to try to make those hydrogen atoms move again. They will shift and line perpendicular to the static magnetic field. So thus far you have manipulated the protons twice. Then when you turn the RF off the protons want to go back to where they were in the static field.

The time it takes them to decay (go back to align with the static field) is the constant T2 and it is also going to be different for different tissues. This is what we want to take advantage of and there are so many different sequences we can use depending on what we want to look at. Things such as water and lipid content will affect the signal. We scan an area and get a reconstructed picture that looks a lot like the real thing. In reality it is done many times, we collect the data and it is processed to develop and image.

Slide 10 is a fundamental example of T1. Basically the difference is T1 CFS looks black T2 CFS looks white. That’s just a generality because it can vary to some degree. This website whole brain atlas is a great resource to use.

Slide 11 is an example of T2, take note of the difference. Slide 13 is a picture I showed in the first talk. It was a patient we thought to have vascular dementia. Is this T1 or T2? T2. Again to jog your memory from the first lecture, what structure is this pointing to in slide 13? Hypothalamus.

It is important as a clinician to know something about the technology of MRI to know how serious to take the reports you get and how to interpret them. A lot is dependent on the scanner that’s used, the skill of the people that set it up, sequences that were used, size of the magnet, and whoever is doing the post processing. There are more steps that can make it a better tool but also leave a little more room for mistakes. For the size of the magnet in general, bigger is better but there are limitations because the larger the magnet the more concerns to worry about. It is usually measured in Tesla units. A lot of clinical scans are 1.5T. We have a 3T as well and it gives you better sensitivity and resolution. So how do we use the MRI? First and foremost we can assess structure. We can look at blood plot and get an idea about perfusion and that is routinely done clinically. It is also used to assess function, a lot of us are doing research on this but it is not yet used routinely for clinical purposes. It is used in some procedures to help guide neurosurgeons in terms of understand where viable and nonviable tissue is etc. CT is similar to an x-ray and is very useful acutely. People that come into the ER with traumatic brain injury first get a CT scan. It gives you what you need for acute triage but will not give you better sensitivity to look in more detail at more subtle aspects of injury. MRI has a lot of flexibility, CT does not have setting you can play with to look at more specifics. MRI has a number of parameters you can adjust to look at different things. Once you start looking at MRI reports, these are terms you may see. A good report is going to tell you what sequences were done. A bad report is just going to tell you this MRI is normal. If you need to look at something specific you need to ask what you should order because they may just do a general scan that won’t be helpful to you. Flair is often used to look at white matter because is helps eliminate the high signal intensity of CSF which messes up your ability to look at other structures. Gradient-recalled echo (GRE) is very sensitive to blood product. If anyone has ever had a contusion in the past, blood product never completely goes away so GRE is more sensitive to identify even a bleed from years ago. Be aware if the different sequences for different things, not all MRIs are the same and you need to know that clinically and if you go into research. Slide 18 hopefully looks familiar, this is the example I showed you in the intro lecture of a traumatic brain injury patient that I actually saw a number of years ago. This gentleman had a pretty significant injury and was comatose for a period of time. We looked at these three images and as you can tell some of them make the lesion look more identifiable. This gentleman has encephalo (inaudible) in the left frontal lobes, it is just a fancy term for dead tissue, mush, it’s gone. You can see the tissue loss in the left frontal area. It’s quite obvious on the flair you also can see some changes her in the white and gray matter. In the GRE you can see it. If you

Brain and Behavior: MRI in Clinical and Research Neurosciences Marylin F. Kraus M.D. 3/14/08 9:30 am 2 of 3

look at anther type of sequence though, an SPGR, it’s not as easy to see the injury. These are the same level, same patient, same scanning session. Let me talk about diffusion tensor imaging (DTI). The grandfather of DTI is diffusion weighted imaging. That has been around for a little while and has been useful in disorders like stroke. It takes advantage of the fact that water molecules do not diffuse the same in all directions of brain tissue. It’s going to depend on the tissue structure, how highly structured it is, what gets in the way of the water. If the molecules are left to their own devices they have random motion and tend to diffuse randomly or spherically. If there is no obstruction you will see random diffusion equally in all directions. In biologic tissue you know there is going to be restriction to that movement so we take advantage of that to reconstruct the tissue particularly the microstructure of white matter which we know is more structured than gray matter. Isotropy and anisotropy are terms that refer to the diffusion. A good example of isotropic diffusion is dropping ink into a bowl of water and it diffuses spherically because there is no restriction in any direction. The opposite is that you would have complete restriction, anisotropic. So in reality you don’t get a 0 or 1 in biologic systems, you get somewhere in the middle. In healthy tracts you have more limited directionality in healthy white matter than you do in gray matter, in other words there’s more random diffusion in gray matter. Q: what do you mean by restriction? A: Restriction means the molecule meets barriers like tissue. Diffusion tensor represents the 3-D image of diffusion in any area of the brain and it is usually elliptical.

One of the measures we use a lot is FA (fractional anisotropy). It gives you a number that tells you how restricted the diffusion is in that tissue. 1 reflects completely restricted diffusion, 0 for diffusion like ink in water. So again in reality it’s going to diffuse between 0 and 1. So white matter may be .4 and gray matter .1. There is slight variability so when we do research we use a control group to compare FA values with. You can get an FA value for a voxel or for the whole brain, which will be more of an average. It is really nice to use it to look at specific areas and specifics tracts of interest.

Another thing you can do that is sort of the “bling” here with DTI is tractography. If you take the FA values and you take a seed voxel wherever it is you want to start to look at specific tracts and where they go in the brain, statistical software grows the white matter tracts for you and you get a visual like this that actually looks very much like the real thing. We don’t really do group data this way right now, it’s more of something that gives a pretty picture.

There’s a more practical application of DTI is when you are looking at FA maps and this is an example of that. So you have an anatomical scan here, and here is an FA map. Basically what it is telling you is that the hotter areas are the denser white matter areas. So as you would expect your corpus callosum is one of your densest white matter tracts. Some of the more slender white matter tracts may not stand out as much. This is just a map generated by FA values and yet it closely resembles the anatomical scan. For many more subtle white matter dysfunctions it is not going to be adequate to just inspect the map. You will need something more quantifiable and that’s why we look at specific regions and do statistics on those and compare them to the health individual data.

So let me give you some examples. This is the paper you had in the additional reading and I want to go over it a little bit to make sense of how we use it in context. What we did is looked at chronic traumatic brain injury subjects of all severity. We had 18 healthy controls. We obtained DTI levels and neuropsychological testing which will be talked about later. Slide 27 is an example of region of interest maps. We did this by hand. This gives you an example of how we label the white matter tracts we are interested in. We color code it so we know what we are looking at. We found the moderate/severe subjects had abnormalities in all 13 regions we were interested in. They are pretty damaged. The mild traumatic brain injuries including those with concussions with or without consciousness had abnormal white matter, it was only significant in 3 of the areas we were interested in but the take home message is even without severe injury there all alterations in white matter. It has consequences and creates vulnerability even if you recover well. What we did is decide to take those 13 regions of interest and get a number. So for every subject in the study including the healthy controls we added up the number of areas in that met certain criteria of abnormality of FA (we picked a cut off point). So each person had a defined number and we called it white matter load. It was a way of getting a global measurement of white matter disorder in that individual. It was significantly different between the controls, the milds, and the severes.

I wanted to show slide 30 as an example of what we are able to do now with DTI. What we were able to do is not just look at the white matter tract; we were able to look at the relative contribution of axonal damage vs. myelin damage. This is an incredibly important tool in studying disorders like MS. The myelin integrity as well as the axonal integrity are going to make up the FA value, we think we can actually look at them separately. What we found is the moderate/severes both seemed abnormal and with the mild the myelin seemed relatively intact but there was irreversible axonal damage. A little bit about Functional MRI. This is more of a research tool as well. The big difference is that structural MRI including DTI looks at structure vs. fMRI which is an indirect way of looking at activity by looking at changes in blood flow which is affected by metabolism. Different brain regions and different networks are going to be specialized to perform different functions. When an area is activated when doing an activity obviously the area is going to have increased blood flow and metabolism. So we are using that to then end up with the information we get for fMRI. fMRI will help you localize area that are more or less activated during particular tasks. The basis of this is when neurons become more active obviously they are using more oxygen, there is increased metabolism and this if followed very quickly by increased blood flow in the area. There is a net decrease in the amount of deoxygenated hemoglobin present. It changes the magnetic quality. The BOLD technique is the way we do all of our fMRI studies. This is a schematic to show you that when you are at rest this is the amount of signal that is going. If you do a task like moving your finger there is an initial dip then a rise, it plateaus, then there’s

Brain and Behavior: MRI in Clinical and Research Neurosciences Marylin F. Kraus M.D. 3/14/08 9:30 am 3 of 3

a decay and a bit of an overshoot. This is the model we have and use. So again depending on how much oxygen is in the area at the time it changes the magnetic quality of that blood and that is what allows us to look at certain areas. Activation tasks for imaging can be anything you can do in a scanner safely. Obviously you want to choose a task depending on the area you want to look at specifically. Simple motor tasks are done most often but you can also do more complicated cognitive tasks depending on what questions you want to ask. You can have a button press and a screen the person can see. One of the tasks we do is an oculomotor task. Eye movement task are simply having a person follow a target but it is a sensitive indicator of the integrity of a lot of neural circuits that a lot of us are interested in research. This is the fMRI testing environment. Essentially we have to set op a mirror, camera, projector, there’s a lot we have to do and there are limits. This is what we might see if we had them do a basic visual saccade task. They are simply following a target but they may activate very differently depending on how their brain is working. The more intense regions are representing more activation. To end, this is once again our traumatic brain injury patient. We acquired all these different sequences. We saw the structural scans already. In the FA you can see there is some loss of symmetry and therefore loss of white matter. In the fMRI it may not be as obvious to you but take my word for it there should be more activity on this side.

Brain and Behavior 3: Prefrontal Cortex Function and Dysfunction Announcements: Just a few quick announcement before I forget. Just a reminder to check the schedule. I just had to shift a couple of lectures around to accommodate the time issue. And the last scheduled lecture, which was originally going to be Dr. Klarity (sp?), who traditionally gives a lecture in this course, he will be unable to because he will be out of town. Since that’s the last lecture, it’s just going to be cancelled. So the revised schedule is online now and it reflects that change. For those of you who were very interested in the physics of MRI and had questions that I could not answer, I did download some notes, completely optional. For some people who had good questions about T1 and T2, I don’t think I did a very good job explaining that detail. I did add an extra reading to the documents for anyone who is interested and it’s optional. Also, I just wanted to mention that in the past, some students who were particularly interested in psychiatry and in seeing some of these patients in a clinical setting, I have had them shadow me during my clinics. My clinic is mainly traumatic brain injury, the other two psychiatrists do more general practice. Just email me. That’s just extra but I have had some people ask me that question. OK, the readings for today’s lecture are again on Blackboard. Since I haven’t heard anything, I am assuming that everything off blackboard has been downloadable. In the past, it’s been a little shaky but since I haven’t heard anything, I will take it as a sign that it’s fine. The Cummings article is just a good review article about circuitry, frontal circuitry, it’s kind of based on classic work. I think it’s a good model for trying to understand the way that the frontal lobe, particularly the pre-frontal lobe, do function. The reality is that in most diseased states, this is not going to be that clean. But I do think that understanding circuits gives you a better idea of how things work. It’s a very good article and much of what I talk about is based on circuitry so that reading is directly applicable to today. I did put an extra reading online. I thought it was very well done and a very good review of frontal type epilepsy. Some of these, especially behavioral type epilepsies are hard to diagnose and hard to pin down. Sometimes it is very difficult to treat and they can masquerade as a number of different disorders, particurly other neurobehavioral disorders or psychiatric disorders. So you need to be aware of them. This is also a very good review article that talks about frontl lobe functions. In general, I think it’s very good, it’s very readable. I also think it will be very applicable to Dr. Schrift’s lecture because he will talk about the neuropsyhiatric aspects of epilepsy. Slide 2 So for today, for those of you who have had neuroanatomy, these first couple slides are just quick review. There are a couple of anatomical locations when you are just trying to figure out geographically where your frontal lobes are. The central and lateral sulcus, these are critical landmarks. And essentially, if you remember your neuroanatomy lab, you will remember looking for these landmarks. Now remember in the frontal cortex, we are looking for a region that is pre-frontal as well as areas that are more involved in motor, like the supplemental motor area, etc. So for the purpose of our talk, we are more interested in prefrontal cortex. Slide 3 Another nice picture of your brain, with nice, strange colors. But you can see that it is not very difficult to divide up the lobes. In terms of functioning, there can be some overlap there. But not very difficult to divide. Slide 4 The prefrontal cortex, that’s going to be a more anterior section. There are key areas that it’s going to be divided into. Again, remember that, to some degree, this is our attempt to provide artificial organization to the pre-frontal cortex, it doesn’t always follow our rules. But in general, we talk about dorsolateral prefrontal section, we talk about orbito-frontal, mesial-prefrontal or cingulate areas. In terms of circuitry and function, they all have something that is unique from the others. Again in many diseased states, in trauma, you don’t just affect one circuit or one pre-frontal area. You will see that in some of the examples. But again, it is a good model to try and understand how this works. [Inaudible question from the audience, something about the cingulate] Well they use them interchangeably, when they talk about circuitry. It is not totally the same per se but when you read the Cummings article, but they will kind of interchangeably talk about it. That’s why this system is useful but if you read other sources, they will even divide the prefrontal cortex into four areas. It is arbitrary but for our purposes, I am just going by the Cummings article. When they go through the circuitry, they kind of put those two together. When we talk about the function, hopefully it will hang together and make some sense. Slide 5 This is again just putting it on geographic context. The area that we are interested in is the very front area, the anterior pole of the frontal lobe. Now this is an area, the reason that I am particularly interested in it, is that in traumatic brain injury, my area of specialty, that is a particularly vulnerable area. Especially acceleration or deceleration incidents because it’s right out there, against the bone, it is easily contused. It is one of the most commonly contused areas in trauma. We will talk about that more in another lecture. The reason that it interests neuropsychiatrists is because a lot of modulatio of behavior, mood and cognition take place here. It’s a pretty critical area. Most of you allegedly have a high-functioning pre-frontal cortex that allows you to do what you do. Don’t take it for granted when you are playing rugby or butting heads or doing something like that.

Brain and Behavior 3: Prefrontal Cortex Function and Dysfunction Slide 6 So essentially, pre-frontal cortex. Some of this may overlap with neuroanatomy. I know it doesn’t go into a ton of detail but a little overlap is not so bad, it helps you to remember things. It does play a role in cognition, mood and behavior. The one thing to remember about the prefrontal cortex (PFC) is that it’s primary role is modulatory. So the functions that it handles also relies on other areas or circuitry as you will see. But the PFC is very important for modulating, fine-tuning lots of higher functions, particularly mood and behavior, as well as cognition. So planning complex behaviors, aspects of personality, although it’s not totally seeded there. We will see that people who have frontal lobes affected by trauma have very significant personality changes. Social behaviors are modulated here. If you PFC is not working as it should, you might be very inappropriate, even without alcohol. Socially inappropriate behavior is a common problem if there is injury here. So it has an integrative role, modulating is very important here. Slide 7 So executive function, I have talked about this term several times already. It really is what it sounds like. This is referring to higher-order cognitive functions. Now some of this is testable. Dr. Pliskin generally gives you his talk earlier in the year but we had some scheduling conflicts this year. But he will specifically be covering this and he will be talking about some of the tests that I am going to mention in this lecture, as well. Some of this execuetive function is directly testable. Some you will acquire by taking a good history, what a patient is doing in the real world. So for instance, if a patient comes in and there has been some changes that involve them making poor judgments at work or complaining that they can no longer multi-task at work. So in a sense, what you are getting is a history of possible execuetive dysfunction. So overall, it’s a lot of factors involved, to have a goal, to work towards it, to show good judgment in social settings, to account for possible consequences of your actions etc., to predict outcomes, to problem-solve. So all of these things that we basically take for granted because hopefully, we do these things on a pretty routine basis. All of these things are pretty heavily seeded in PFC. We rely on it being intact and functioning. Slide 8 Some of the testable functions, cognitive functions, include working memory. You will hear more about this. This is a very commonly studied phenomenon in a lot of disorders. This is the analogy that sometimes you are the chalkboard that you have got in your brain where you might quickly write down phone number and remember it long enough to dial it. Or someone gives you a bunch of numbers to add up in your head. You need working memory to retain those numbers but you really have no intention of retaining those numbers in an hour or two. Working memory can provide the template for things to go into longer memory or it can be just what it sounds like. Working memory, you are just using it like your brain’s blackboard, so to speak, and then you are losing that information. Again, something that we don’t think about but we have to use all the time. But if you have a mild impairment and you are an individual in a high functioning position, physician, attorney, somebody who multitasks or manages a business, small decrements in function here can really impair your ability to do what you need to do. So it’s really very important function because impairment affects so many broader aspects of function. Verbal and design fluency is also commonly tested and also related to PFC function. This is the ability to generate a list of words. An example of a task is I am going to give you one minute to think of all the words that begin with a “f”. Or all the animals that you can think of. This fluency, this ability to generate a list of words based on some category, is very related to PFC functions. Obviously, other areas of the brain are involved in this because this also involved language functions. This applies to design as well. They might ask you to draw as many novel designs as you can think of in one minute. That sort of thing. So maintaining and shifting from one concept to another, let’s see some examples of this, like the strue (sp?) task where you have to use one concept or idea to solve one problem and then you have to be flexible enough to decide on a new set of rules. There are examples of these things in the lab, in the neuropsychological test designs. Again, Dr. Plisken will cover that in more detail. The nice thing about neuropsychological testing is that if there is an impairment in PFC, there is a nice pattern of impairment that you will see on the testing. In some ways, this makes them more sensitive than some of our images. If testing is done well, if it is done by someone who is qualified, they can in sum, with pretty good accuracy, this is suggestive of left frontal dysfunction or right prefrontal dysfunction or there seems to be parietal components etc, there is temporal lobe dysfunction etc. So they can look at it and give you a pretty good idea of functionally mapping out the brain. Just from these tests, it’s not perfect science but it’s very good. So the PFC also has a role in focus and attention. To some extent, that’s more of a modulatory role but when your focus and attention are very impaired, obviously that’s also going to affect working memory and longer term memory etc. None of these things are very distinct but they are all interrelated and interdependent for you to function all the ways that you do. Slide 9 Now, frontal lobe syndrome is a term that is still actually used because clinically it is very useful. So they say prefrontal syndrome but they basically refer to cognition, mood and behavior dysfunction that follow damage to prefrontal cortex. And it is useful, it is a loose term, not easily quantifiable or qualifiable in some ways. But clinically, it is useful. And if I use it, I can still be more specific in what I mean. For example, if I say a patient is disinhibited or inappropriate or inattentive, I will say that. I won’t just say frontal lobe syndrome. Or I might have a patient that’s apathetic and inert, slow to start things. That’s another of PFC dysfunction. I will describe that. Slide 10 So a little bit more specific about things that could be impaired. We talked about execuetive dysfunction that you could see, the functioning that is very reliant upon PFC being intact. Behavior changes, there is quite a range that you can see with PFC dysfunction, which in some ways, leads to it being misdiagnosed or misunderstood. People can look depressed with PFC dysfunction, they can

Brain and Behavior 3: Prefrontal Cortex Function and Dysfunction look manicky or hypo-manic. From the first lecture, we talked about one of the great pretenders of patients who come in with manic behavior. It can represent so many different things, not necessarily a primary psychiatric disorder of bipolar. Certainly, in the differential but there is a number of different things that can masquerade as that. PFC dysfunction is one of those things. But you can see that there is a range here. You can have someone who is distractable, disinhibited, irritable, manicky but you can also have someone who is very apathetic, slow to respond, inert. They can almost look depressed, they go so slow. That’s where the different circuitry comes into the PFC. Mood disorders also. We know that the PFC plays a significant role here. It’s probably not studied as well as it should be, compared to primary mood disorders. But we do know that there is a strong connection here. We do know that if there is PFC dysfunction, it can either aggravate or cause a type of mood disturbance or you can see a mood dysregulation, where a person is almost going back to like when you were two years old, where you react first and you think second. So for instance, you are not as good at filtering things out. The environment affects you very strongly. Something good happens and you jump up and down. Something bad happens and you won’t come out of your room for a week. Sometimes, responses can be very extreme with this dysregulation because all those abilities that we have built up in our frontal lobes that allow us to temper our responses to our environment. So we don’t have all these extremes, we don’t feel like a human yo-yo. This can happen if we have disruption of function here. [inaudible question] To some degree, yes. That’s usually picked up on the cognitive testing and I am going to get to that. But we are going to focus on talking more about circuitry right now. Slide 11 What are the causes of PFC dysfunction? Again, going back to previous lecture. How can you have dysfunction in the brain in general. You can have direct lesions or indirect dysfunction due to damage in other parts of the circuit. You can also have dysfunction due to damage in the circuitry itself. In other words, white matter or tracts are damaged. You can have electrical abnormalities such as seizure disorders. Actually we take it for granted that when we think of seizures, you always think of convulsive or motor seizures. But if you think about the brain and how much of the brain manages non-motor behavior and how much of the brain is dedicated to neurobehavioral function. The fact is those areas of the brain also tend to more sensitive to things such as oxygen deprivation or types of trauma or strokes. Then it starts to make sense. Your seizure disorders could present as neurobehavioral changes. We are more used to thinking of motor seizures but really not the significant bulk of seizure types that we see. Neurobehavioral seizures are harder to pin down, harder to diagnose and unfortunately, sometimes harder to treat. Slide 12 There are certain neurotransmitters (NTs) that we know are key to PFC dysfunction. So this kind of gets into chemical, metabolic ways that the brain might become dysfunctional. Perhaps, pathologically, it looks intact but if you have disruption of NTs, you will see certain types of dysfunction. And that’s what we think of in certain types of disorders. There is not only structural damage, there is also a disruption of NT systems, they don’t function the way that they should. They are either hyperactive or hypoactive. In different diseased states and in trauma, such as TBI, generally involves several of these mechanisms. There can be structural damage, there can be dysfunction chemically or neuro-transmitter wise and all of this can be contributing to the clinical picture. And all of these aspects, understanding all of them, gives you a rationale for where you want to target when you treat the patient. So if you have an understanding that something looks frontal, and you think about the things that cause that, it’s going to lend itself to making rational decisions about treatment or give you research ideas about treatment. It’s an intervetion point. So if you think there is a disruption in a NT system, hypo-dominageric states, at times can lead to symptoms that look rather pre-frontal. You might think why don’t I enhance dopamine. It’s sort of a simple example but it does lend you to making rational decisions about possible treatments or interventions that you might want to study. We will talk about this in another lecture as well. But I wanted to talk about it here because it is a critical component of proper functioning of PFC. Slide 14 Key points again. Circuitry is a good model for understanding neuroanatomy functional relationships but you have to keep in mind, it’s a nice model, I think it’s a good way to understand the trees before the forest, so you get a good sense of things. But again, I always stress that many disorders will affect a number of different aspects, that ultimately show you that the PFC is dysfunctional. Rarely, do you get a disorder where you can say this is just a dorsolateral PFC dysfunction. We have nothing that specific. But again it is a good model for understanding how it works and how it overlaps and how all the different subsections complement each other. Slide 15 So the cummings article. It’s based on work that a number of other authors have contributed to. It’s very elegant work that looked at all of these circuits. This is relatively new work. It wasn’t that long ago that we used to think that if you damage the cortex, you get the dysfunction. Before we used to think of the brain as discrete areas and damage in these discrete areas causes dysfunction, which it can. But now we think more in terms of networks. Much more than we will say this is a parietal function, we will say this is a parieto-occipital circuit. This is very elegant work that was done. They described essentially five frontal-subcortical circuits. They are parallel but they are independent and they are closed. They are loops, so to speak. They are named after their function or their site of origin in the cortex. Two of these are motor circuits that arise from the supplemental motor area. They are heavily involved in oculomotor testing. And if anyone remembers some of the slides that I showed, fMRI. I showed a fMRI image of using oculomotor

Brain and Behavior 3: Prefrontal Cortex Function and Dysfunction testing as a way of probing PFC. We are not going talk about the motor circuits but just be aware of them. We are going to focus on the neurobehavior circuits. Basically, there are three, the dorsolateral prefrontal, orbital frontal and the medial frontal circuit, which is also interchangeable with anterior cingulate. You will see how they have some commonalities and some differences. Slide 16 The common features of these circuits. So for all of these circuits, damaging common areas can damage circuits in all of them. Basically all these circuits originate in the frontal lobe area. They have specific projections to striatal areas, from there to globus pallidus, to the thalamus and then back to the prefrontal area of origin. This creates a closed loop. There are also open loops that we are not going to talk about in great detail. But these are other types of pathways or circuits that modulate these systems that are open. In other words, they are not closed systems. Slide 17 This is a schematic for these common model, these closed circuits. Frontal cortex, striatum, globus pallidus, substantia nigra in that area, the thalamus, back to the frontal cortex. So again back to what I mentioned in an earlier lecture. Remember I talked about strategic placed lesions. Location, location, location. So if you have a lesion in a certain area of the thalamus, like the dorsomedial thalamus, for example, because that has a lot of connections to the pre-frontal cortex, you will see frontal cortex like symptoms. There doesn’t have to be direct damage to PFC but if you have damage or dysfunction in a key area, the patient can have that type of presentation. Slide 18 We won’t spend a lot of time here. I just want to make the point here that there are some open connections. For instance, dorso-lateral PFC has some connections with the parietal lobe etc. , things that moderate the function. These things work together and they allow proper functioning of that circuit. Slide 19 So here are the circuits for our purposes. Dorsolateral prefrontal cotex, this circuit is one that we classically refer to as being cognitive. None of these circuits are exclusively cognition, exclusively mood or exclusively behavior. So This is very easily tested, as someone like Dr. Plisken will do. Very heavily cognitive, you can see some behavioral and mood changes here. In contrast to that, lateral orbital or orbitofrontal cortex, we think of this as having more behavioral or mood consequences when there is damage or dysfunction here. The model that is often used or the expression often used is that you will talk about patients who are pseudopsychopathic or psychopathic or look anti-social. A number of terms apply. The reason that is used is that these are patients that seem to have significant changes in personality and behavior, inappropriate social behavior, difficulty understanding consequences for their actions. So they look a bit sociopathic. But it is due to some lesion or dysfunction as opposed to someone who have might have been like this their whole life, which in psychiatry, they refer to this as character disorder. And it’s hard to know what the involvement of this is, in long term character disorders because there are so many similarities to people with acquired lesions here. It can look like these long-standing anti-social personality types. You just wonder how people developed those character disorders in the first place. So lesion models, at least allow you to pinpoint if the person was functioning fine beforehand. It allows you to make some assumptions about neuroanatomy functional relationships. The other circuit, medial frontal, or sometimes referred to as anterior cingulate cortex circuit, is more involved with apathy, motivation and drive. So patients with damage or dysfunction here can look very apathetic and amotivational. At the most extreme, patients seem akinetic or mute, waking and alert but not really responding well, not doing too much, sometimes referred to pseudo-depression. These patients can seem very slow, psycho-motor retarded and they will look depressed. But interestingly, they may not report depressed mood. They may not feel sad but they have all the other features that can make them appear depressed. And the treatment can be different so it might be difficult, not to be confused with the fact that young patients and elderly patients sometimes don’t acknowledge that primary depression is a sad mood. That just makes things a little complex. So sometimes, this can get a little tricky. People with genuine depression may not acknowledge sad mood. But all these other features are here to suggest depression. For young children who are depressed, not uncommonly instead of crying and telling you that they are sad, they will act out. So if you are going into child psychiatry, you will have your hands full trying to figure that business out. And sometimes, I think medically ill or elderly patients, there can be a depression that they may not acknowledge as a sad mood. So, it can get a little difficult to sort out. Slide 20 So, dorsolateral PFC syndrome. What would you expect to see if your primary dysfunction is in this area. Based on what I have said, you would see a lot of cognitive execuetive dysfunction, that is usually very testable. So these people are not very hard to sort out, to get the appropriate evaluation. A lot of problems with impaired reasoning, mental flexibility, maintaining and redirecting attention. You can see attentional problems with PFC dysfunction. Examples of tests that test classic PFC tasks are Wisconsin Card Sorting, you will hear more about it, and Trail B, again you will hear more about it. It is not so important to rememeber how you do these tests or how to score these but just to remember that these are classic tests that are generally associated with PFC function. But the reality is that it can get a little dirty. There is really no such thing as as a pure PFC test. However, we know from studies that have been done, lesions, model etc., that the PFC is very heavily involved in these tests. So when there is an impairment here, we are relatively safe in saying that there is a PFC dysfunction. Other parts of the brain may be involved. The bottom line is these tests are very heavily

Brain and Behavior 3: Prefrontal Cortex Function and Dysfunction weighed towards PFC function. Verbal and design fluency, again this is something that is not too difficult to test, and it reflects dysfunction here. Slide 21 Conversely, orbitofrontal syndrome patients may not look so bad on cognitive testing. That’s one of the key things to keep in mind here. PFC syndromes don’t look all the same and you don’t evaluate them all the same. So some of these patients may not show deficits on some of these classical tests that we do. Their behavioral disturbances are the key features here. Disinhibition, for example. Emotional disability. The classic case of Phineas Gage is an example. We will talk about that a little bit later. Damage here can cause significant personality changes. And if you didn’t know how a person was originally, you might assume that they are very difficult and annoying and irritating. Since these are being videotapes or audiotaped, I have to be very careful of what I am saying. But very difficult people here, if you didn’t know how they were functioning before the injury or the diseased state. So unlike dorsolateral lesions, they may be able to do the card sorting, they may be able to do the Wisconsin card sorting. So these are the patients that I think can be mistakenly diagnosed with other disorders, like primary psych disorders. Because they can look disinhibited, they can look hypo-manic. But if you take a good history, you are not going to make a mistake. But I have seen some of my head patients mislabelled as bipolar. The problem is that if they get mislabelled, sometimes the treatment is not appropriate. So they may have features in common with it but it’s not the same thing. And you have to be careful to make that distinction. Or at least, know when to consult someone who can tell the difference. So if you have a high index of suspicion and you are looking at other possibilities, you are going to pursue other avenues. You are not just going to accept that if a patient comes to the emergency room, they are psychiatric when they are not. Slide 22 Anterior cingulate are the mesial type syndrome. The cingulate has been studied a lot in regards to apathy and motivation, that sort of thing. This is an important part of the PFC circuitry here. One of the primary behavior manifestations is lack of motivation. Patients that have dysfunction here can look very amotivated. And everything exists on a spectrum, from mildly impaired to greatly impaired. In this syndrome, the extreme version is the akinetic mute. This is rare in reality, you would need bilateral lesions of the system. They can look wakeful but they are indifferent, apathetic, they are not very responsive. The milder version of this, what I often see with my TBI patients, is they don’t care about things too much anymore, they will tell you that. Again, you need to be careful here because you might think they are depressed. They might be but we also know that PFC dysfunction will cause them to lose motivation and drive in varying degrees while at work or school, they might just be labeled as being difficult or not trying hard enough. You might see how on the mild end of the spectrum, we might just brush this off as and think that the patient has more control over it than they actually do. Neuroyschological deficits you may see here. They are more subtle as well. I am going to defer to Dr. Plisken and ask him to make sure and cover this. But again, history and behavioral and mood disturbances will help you to make the diagnosis. These patients can show some impairment under psych testing but again not going to be the classic signs that you see with dorsolateral PFC. There are go/no-go tests that test response inhibition. They may do poorly on those. Overall, broad difficulty understanding new thoughts, participating in creatve thought processes. This is not very easily testable. Again, you might get in the history that this person had a change in function that is consistent with this. You might have family members or someone else to tell you how they were like before. Very important that you get this history beforehand to make sure that you are not missing anything. And apathy does occur in wide variety of disorders. By itself, it doesn’t help you to localize the lesion. People have tried to work directly with apathy. My feeling is that is too broad. Because you can have apathy with somebody being primarily depressed, someone with PFC dysfunction, they can look apathetic. There are certain subcortical diseases that make people seem apathetic, again because of that construction of cortical-subcortical circuitry. Parkinson’s, Huntington’s Disease, diseases that we think of as subcortical processes, can look frontal because these circuits depend on various subcortical aras of the brain. Slide 23 So some specific causes, to make this clinically practical. Stroke, either directly involved in the PFC or indirectly by involving the circuitry. Examples we use are basal ganglia or thalamic infarct and cause certain types of cognitive impairments and they can look prefrontal. But the good news about these thalamic cognitive syndromes is that there is often very good recovery, if that is the only area involved. Tumors and AVMs, depending on where they are located and where they are impairing structurally, can present this way. Degnerative diseases, we will talk about these a little more because I think they are a good example of someone presenting clinically where you may make mistakes about what is initially going on with them. TBIs, another good example of patients who can look personality altered, mood dysregulated etc. so that unless you have a good history of the injury, you can miss. We will go over that more in another lecture. [inaudible question]. Oh, I am sorry, arterio-venous malformations, just so you see some abbreviations. Also, PFC dysfunction is studied in regards to its role in primary psychiatric disorders. That makes a lot of sense right? It makes sense that people with schizophrenia, obsessive-compulsive disorder may have some dysfunction in these regions, in these circuits, although it may be because of developmental or genetic reasons. These areas make sense as targets for a number of different disorders. These acquired disorders actually allow us to study them more clearly. People who were functioning fine getting strokes ot traumas in these regions and then you can kind of look at before and after and say this makes sense in light of the regions where we the lesion or the dysfunction. And seizure disorders, last but not least, the great imitators in the way that they present. And Dr. Schrift will talk about those in greater detail. Slide 24

Brain and Behavior 3: Prefrontal Cortex Function and Dysfunction Brain injury in general can disrupt circuits. Brain injury can be due to a number of causes, that’s just a loose term. Stroke is a type of brain injury, right? TBI, usually from an external source such as you are struck in head with bat or during car accident. Slide 25 Let me talk a little bit about dementia. Extremely common disorder. You will see this unless you go into Peds and then you will see parents or grandparents with this. Very hard to avoid this. These are patients that you are going to see clinically, in a variety of different settings. Primarily for a dementia work-up or they are being seen for other medical problems or surgeries and they have an early type or already diagnosed type of early dementia. And depending on how these things present, they can represent different degnerative processes. It can show you clinically how it looks to have varying degrees of PFC involvement. Alzheimer’s disease, Fronto-temporal dementias, there are different classification systems for those. For fronto-temporal dementias, we don’t need to go into great detail but I think the primary concept is that this is a group of dementias where the primary feature is that the frontal cortex is more involved or where the fronto-temporal cortex is more involved. Vascular dementia, that’s going to have a variable presentation depending on where the primary location is. If it is a multi-infarct dementia, it’s going to depend on where the infarct is. The more gradual type of vascular dementia, that is going to occur over time if you have hypertension or diabetes and you don’t have an identified stroke but you have an ischemic changes over time. As a result, there can be mood or behavioral changes. We used an example in a past lecture where someone may present looking weepy, depressed and distractable as a manifestation of them having a type of vascular dementia. Slide 26 Subcortical dementia. We think of Parkinson’s Disease or Huntington’s Disease as primarily subcortical diseases. Certainly, motor manifestations are subcortical. But these patietnts, either early on or eventually, will show some degree of PFC dysfunction. It is not unusual for Parkinson to have as one its earlier presentations either a mood disorder or some mild behavioral changes etc. And you have to be an alert clinician as you examine your patients. You might miss the early cogwheeling if you see the mood disorder or depression present. For a number of these neurodegenerative processes, they can present neuro-behaviorally. You need to think of it as all part of a neurological exam and you have to consider all of this when you are localizing the lesion. It just gets more difficult as you talk about higher functions, like neurobehavioral functions. But it’s no less important than demonstrating that they have right side hemiparesis, that’s just easier. You are not going to miss that but people are going to miss the neurobehavioral manifestations of these disorders. Slide 28 So let me give you some case examples. The classic case, the one that everyone has heard of, is Gage. The interesting thing about this case is that allowed scientists, at that time, to study a discrete lesion that was more mesial and orbito-frontal of the PFC, that behavioral and personality part that I talked about. The guy lived, God knows how, with the instances of infection. This was a rod that went through his head and he was completely different afterwards. We don’t see these projectile lesions very much these days, it’s very rare. With all of our TBIs now, most of them are very diffuse or dirty injuries, acceleration, deceleration accidents, motor vehicle accidents, falls etc., the occasional gunshot wound. Very rarely, do we actually see a projectory so that we can actually look at the path of whatever damaged the brain and make some conclusions. So, Gage inadvertently became a type of case report but people learned a lot from studying him. It’s just really amazing that he lived. But his primary features were his behavioral and personality changes. He became very difficult. I have heard different stories about what happened long term. He was no longer Gage. One of the things that you will hear from family members of patients who have this type of PFC involvement, irregardless of whether it’s due to dementia or TBI or tumor or AVM, is that they will tell you that the patient is no longer the same person. I hear this so often in my TBI clinic, even with post-concussive syndromes, allegedly mild injuries. So you see again that with strategic lesions, it doesn’t have to be a big or grand lesion, but when you disrupt key functions of PFC, you can alter the basics, the way that some people come across to other people, personality. These families will say, “they don’t seem like the same person” and that’s always a red flag. Of course, they could be sustance abusing as well. You don’t rule out other things that alter presentation and behavior but that’s really one of the things that you hear and it clues you into the things that could be going on. Slide 29 Here is a picture that I found of the trajectory. And the rod that was driven through his skull came out clean the other side. And the guy lived. But like I said, given the area, there was more of a behavioral and personality presentation. This was a historic case example. Slide 30 Now what we see are usually diffuse injuries of the PFC and also in other areas of the brain. So it’s never this neat. So here is an example that should sound a little similar to some the ones that we have talked about. A 60 year old gentleman comes in, he has a history of progressive change over several years, we are not talking about anything abrupt. But the family has noticed that he has become more disinhibited, he swears now, he throws things and they say, the classic thing, “he is not like how he used to be, he is different now”. And at times, he is socially inappropriate, sometimes he seems apathetic and unmotivated. Very significant mood and behavioral changes are the family’s key concerns here. They are not coming in and saying: “Gee, his working memory doesn’t seem like how it was before”.

Brain and Behavior 3: Prefrontal Cortex Function and Dysfunction Slide 31 So you send them to someone like Dr. Plisken, who does cognitive testing and it shows that he is relatively intact, in terms of his memory. Visual and spatial abilities seem OK but he is kind of slow, he is kind of perserverative. This is very common in the presentation of some prefrontal patients, they get very stuck in set, very perserverative, have difficulty getting off or letting go of things, getting stuck on things. Perserveration, although it can be due to a number of things, is not uncommon in PFC dysfunction. He also has a short fuse, gets very impatient when you try and test him. This is a patient that you would expect to be very difficult after four or five hours of testing. … Slide 32 This can be a case of fronto-temporal dementia [49:44]. These are people who present with more than behavioral mood alterations. So you might be thinking, this is an older gentleman, he is getting difficult, maybe he is just depressed. And he might get better with medication, he might look better. Maybe you sprinkled a little water on the fire but you didn’t make the correct diagnosis. This is pretty classic and very extreme where there is this selective fronto-temporal involvement on this MRI where this is getting back to your normal aging brain. And the asymmetry here, almost nobody looks really straight. There is almost always a little tilt, you will see a little asymmetry. So this normal person really doesn’t these terribly asymmetric ventricles, they are just a little rotated. This is classic, it is relatively extreme but it’s classic. It shows you that there is clearly this predilection for involvement in the fronto-temporal area, as opposed to other areas of the brain. Is this T1 or T2? T2. Slide 33 So as I mentioned, in fronto-temporal dementia, there is a lot of different sub-categories of people to look at. So in the olden days, we used to just talk about Pick’s Disease, because there were certain types of inclusion bodies that you were able to see. But for our purposes, it is just important to know that this is a type of dementia and once you have identified it, you can figure out which one it is, whether it is fronto-temporal dementia or something else. Many of the specific diagnoses can’t be made until you do a pathological exam. But you can diagnose a fronto-temporal or frontal type of dementia. And this is probably estimated to upwards of 20% of degenerative dementias. Maybe more, because as I said, these patients can be misdiagnosed initially, it’s not always pickes up on. Slide 35 And this is just re-iterating what we covered. And just to make the point again that neuropsychological testing results in fronto-temporal dementia are going to be variable. If you catch someone early on, they might not look so bad on testing but their behavior during the testing may be more obvious. You know, they are irritable, they are impatient, they are amotivational, they don’t do what you want them to do. For example, if they show some memory problems but you cue them by giving them a list of words that they can recognize, they may do better with that. Whereas in an Alzheimer’s patient, they just don’t remember it, they don’t store it. So even if you cue them, theoretically it shouldn’t help them that much. Frontal-type or these subcortical type dementias, sometimes will show these modifications of memory impairment, something Dr. Plisken will talk about a little more. Slide 36/37/38 Let me just move through some of these other examples. 72 year old woman with relatively negative past medical history, she is pretty healthy. The family brings her in and the primary complaint is gradual onset of problems with memory. Again, these are examples that are relatively clean and obvious. If you are lucky in your clinical careers, you will see one or two classic cases. Everything is usually complicated by so many other things. But again, she has this gradual onset of memory problems, trouble with names, where she put things etc. So this wouldn’t be so hard if this person was brought in. So the primary complaint is that she has memory problems so lots of people will be thinking, “oh she has alzheimer’s”. But they are denying that she has changed in other ways, she might be a little sad, she is really still herself. So relatively classic Alzheimer’s. If you look at the parietal sulci, they look widened. But here is the point that I am making, the PFC doesn’t look so bad. There is some atrophy there but as opposed to the fronto-temporal dementia slide that I showed you earlier, the pathology here involves more other areas. So this is a relative sparing of the frontal areas and it’s more this inferior parietal lobule, which you will see in the imaging of some Alzheimer’s patients. Now when this disorder progresses far enough, everything gets involved. As the disease spreads, it is going to affect circuits. But early on, relative sparing of frontal type features. So this is the type of dementia that you are not going to be so suspicious that it’s there because they present with memory complaints. So two examples of degenerative diseases, both involve PFC but at different points in the disease process, which makes it important to be aware of this, so you don’t miss early manifestations of frontal type dementias. Also be aware that Alzheimer’s, at certain points, can look relatively frontal when it’s more impaired. Slide 39 This is another case that I mentioned before. Remember the young man with the TBI and remember that I showed you that MRI scan. He nearly had some left frontal involvement. I will talk about it later. But again, a good example to keep in mind because these patients are going to come to the ER or they are going to wind up in a neurology or psychology clinic because of behavioral and mood changes.

Brain and Behavior: Traumatic Brain Injury Announcements: Lecture Content So today we get to talk about the topic that is nearest and dearest to my heart. It has been my area of expertise for at least 20 years now, traumatic brain injury. There are a couple reasons why it is useful for you to know about this, not only is it a very common problem it is also a good model for understanding neuroanatomy functional relationships. Much of what we talk about in terms of treatment in chronic TBI and behavioral disorders will also generalize to patients with disorders due to stroke, other types of trauma, and even some disease states. The reading I suggest for this is a book chapter so it is pretty thick but it is very good and very up to date. Also some of these slides have been updated since yesterday so make sure you have the updated ones. When I talk about traumatic brain injury I’m talking about a non-degenerative, non-congenital injury that’s due to external force. Classic example would be a motor vehicle accident or a baseball bat to the head. There’s different categories like closed head injury and penetrating head injuries. Most cases are closed head injury; even severe injuries can still be closed head. There is no breech of the skull and the injury occurs from the mechanical trauma that occurs.

Clinical severity of TBI. This is what you will see being used in an acute triage situation to discern which injuries are most important early on. You want to sort out who is a medical and neurological emergency. If it is followed by a decreased loss of consciousness, decreased respirations or a bleed then it is more of an emergency. Very few mild head injuries are emergencies, it doesn’t mean they don’t have consequence but we just don’t treat them as emergencies. The rough scale that is used is based on several factors. You will see the Glascow coma scale (GCS) in all trauma patients when you rotate through the emergency room. It is just a rough scale designed to measure level of alertness, so if they are in a coma, how deep is the coma. There is a copy of the scale on the next slide if you're interested but the general take home from this is that it is a scale up to 15 with 15 being most of us in this room, fully conscious. Then depending on certain tests of eye opening, motor response, response to verbal cues, if you call their name do they respond etc. It is a nice scale to use acutely and also to monitor someone's progression overtime. It really isn't used for chronic patients obviously. There is a general breakdown, most of the time they consider milder injuries those where the GCS is 13 to 15. The trouble with the GCS is it depends on who administers it and when they administer it. Early on it if you get to someone in the field who has a traumatic brain injury they may not have become unconscious yet; similarly, if you don't measure them until they come into the emergency room they could be worse or better than they were initially. It is still good for acute patients. Posttraumatic amnesia is a bit tricky because most clinical settings don't do a formal measurement and what they're talking about for PTA is anterograde amnesia, so if you got knocked on the head and you were out of it for 15 minutes and you look back and you don't remember much from the 15 minutes, and during the 15 minutes you may have been repeating yourself and asking where you are etc. You were in posttraumatic amnesia. So you are awake but you're not able to store new memories. Or you are just not able to keep track of things. So the rough guideline is when somebody comes out of that state PTA is resolved. Obviously if someone is comatose you can’t really include that in the duration of PTA, and that is where it becomes a little tricky. Also in hindsight with most mild injuries nobody was around you can't get an estimate of PTA, they may not even be able to tell you if they lost consciousness or not. If you are off by yourself riding a bike on a trail and go over the handlebars and you come to you have fallen and you hit your head, you might not be sure if you were really knocked out or just dazed etc. So these measurements are good but they're not always perfect and they are difficult to obtain. In general the old rule of thumb was that a mild injury did not have findings on a standard clinical imaging exam. When they did CT scans acutely in an emergency room and they saw something on CT a mild head injury was bumped up a grade. They were trying to base severity on acute image findings. Now we know imaging varies so much from center to center. But in general the rule of thumb is if you find something on a scan acutely it is more severe than just an uncomplicated mild injury. This modifies overtime as imaging does improve. If you remember from previous lecture of DTI, even mild head injuries showed decrease in white matter. So it is not that they don't have changes it is just that imaging used in emergency protocol may not pick up these changes. So this is just a copy of the GCS for your own reference.

What is a mild DTI? This is one of the areas that I think is most tricky. This is by far the most common group, it accounts

for 80% of all traumatic brain injuries. It is probably under reported because a lot of people in sports or other activities can actually be concussed but they think they are ok so it never gets reported. Even if you’ve had an uncomplicated mild head injury you probably recovered very well with no residual effects, but like I said that doesn’t mean there weren’t changes. So this makes it difficult to diagnose because if you look at this criteria it actually sort of fits everyone here because you are basically saying it is manifested by any period of loss of consciousness, any loss of memory of events, any alteration of mental status, you can have a normal neurological exam with a mild injury, etc. There’s other criterion for mild head injury. Some research studies will require a documented loss of consciousness just to have some kind of clear cut off but if you remember what I said some times it is difficult to determine if there was a loss of consciousness and how long it was. So these papers that I read look at chronic TBI subjects and report that they know the average loss of consciousness, my question is always where they get this info. That’s something to keep in mind. So this is why clinically mild head injury has been difficult. We don’t know where the cut off for no head injury and enough head injury to sustain change and enough head injury to sustain clinically observable change is. You can have neuropathology with no loss of consciousness. We are trying to sort out where the threshold is when that neuropathology can be clinically observed.

Brain and Behavior: Traumatic Brain Injury Traumatic brain injury is a huge public heath problem and very common. It can be a problem in how it is approached

medically because it falls in so many different domains. The majority of these injuries falls in the mild category and is often overlooked. It is a significant cause of long term disability because the population most affected is generally younger people, otherwise healthy. If you suffer a head injury you can go living a long life but with persistent disability. There are of lot of specialties that deal with TBI, I’m a little bit rare in that I am a neuropsychiatrist who focuses on traumatic brain injury, but it tends to be a bit scattered. When an individual wants to seek treatment for consistent problems, they are not sure where to go initially.

Again mild head injury is by far the most common problem. Even though it is called mild it can leave you with some

permanent neuropathic changes that can predispose you to future difficulties or problems. Repeat head injuries, like in a number of athletes who have just been “dinged”, but a number of times to point where they don’t remember their wife’s name or they have to become sports broadcasters because they can’t play ball anymore. It’s very common and this is the first time I have seen where athletes will actually admit to that. As an athlete you are not going to say you felt funny after an injury, you are going to say you are fine because your goal is to get back into the game, they have anti-malingering problems so the bias is the other way. But sports injuries are coming to the forefront now and are given more importance as they should be.

Also another problem we have now that we have completely created is blast injuries. It is something that would not occur in

nature unless you were near a volcano that erupted, so they are sadly a human created form of injury and it is causing a huge problem. Mostly what I see are motor vehicle accidents but I am getting more calls and emails from family and from veterans that are coming back and have persistent problems consistent with head injury. Be aware of these because this is something that I think is going to be persistent, long-term residual because blast injuries can be more severe. So they feel that 25% of bomb blast survivors are suffering from TBI, it is not well studied so this is probably the tip of the iceberg. These IEDs are to blame and part of the issue now is body armor is much improved so rather than dying from blast injuries you can protect the body but not the brain. They are trying to study this in animal research because it seems to have things in common with civilian head injuries like motor vehicle accidents, but there are some differences that will need to be considered with treatment. It is this primary blast injury that seems to be the difference, that’s the injury that seems to be the direct result of this wave induced change in atmospheric pressure, we are just starting to understand and do research on that. Secondary and tertiary blast injuries are when something flies and hits your head or you are tossed and you hit your head. That type is the type you see similar to motor vehicle accidents. It has been something newer in the news, but that’s sad because it has been around for a while. You’d be surprised how much media and popularity plays in getting funding for research. So Bob Woodruff suffered a blast injury and now there is a Bob Woodruff family traumatic brain injury fund.

Another case that probably helped get exposure was probably Andre Waters, former pro football player, had multiple head

injuries. In his forties he had a lot of problems with depression and probably other problems as well. He was having a lot of difficulties and he ended up committing suicide. I don’t think at the time anyone really related it to the injuries but Chris Nowinski who was a former Harvard football player and had a number of concussions went on to do wrestling and he understood very well the issue of sports concussions went under recognized. He had himself had problems from his injuries. He went to the family of Waters and asked that an autopsy be done. He looked at Andre Waters’s brain and it did not look like the brain of a 40yr old man, it had significant evidence and pathology of multiple past brain injuries. They also saw the same type of plaques from Alzheimer’s in Waters brain from TBI. This is one of the reasons they talk about brain injury being a risk factor for degenerative diseases. So it was seen as an important problem and now there are requests for research proposals to fund this.

When we talk about the neuropathology of TBI we talk about primary and secondary injuries. Primary injuries are as a direct

result of mechanical trauma like if you contuse an area of your brain. Diffuse neuronal injury like I showed you in the DTI lecture is a very common finding in TBI. That is also considered a primary injury because it is a process initiated by the injury or mechanical trauma. The part of the brain most vulnerable is the anterior frontal lobes of the brain and the anterior temporal cortex. Those two areas of the brain are sitting against bony prominences so if there is an acceleration/deceleration course they are very likely to strike the skull. If you remember the last lecture where I talk about neurobehavioral problems, dysfunction of prefrontal cortex and anterior temporal lobes underlie a lot of disturbances in mood, behavior, cognition, regulation of mood, features of temperament, personality, etc. Often these patients are ok and walking around with no observable lesion but the primary problems are the neurobehavioral deficits.

Just to clarify a couple definitions. A concussion is a physiologic process that occurs with the blow that produces this

observable altered level of consciousness. This is a physiologic, metabolic type disturbance, it can be transient, and it is due to the blow. It is an event that produces something observable. So it’s not a lesion you see. The contusion is something you can pathologically see, like a bruise of the brain. You can get coup and contrecoup-contusions. What it is saying is that you don’t just get a contusion at the site of impact; you can get a contusion opposite that. It has to do with the biomechanics of the injury.

Just to reinforce this, this is what an acute contusion looks like and obviously this person didn’t do so well. As you can see

there’s blood and a lesion, so it is observable damage. Although significant, what is more significant as far as I am concerned, or can be more overlooked is the effect of diffuse axonal injury on a person’s outcome after TBI. It is also called traumatic axonal injury. It’s talking about the mechanical force from the impact setting up a process in the bundles of white matter that leads to degeneration and destruction that translates into abnormalities we can pick up on DTI from the previous lecture. You don’t need direct impact to the

Brain and Behavior: Traumatic Brain Injury head; for example shaken baby syndrome. If severe enough it can result in death. In general the model that is used is with severity the involvement gets deeper. So we expect more superficial or more cortical effects with milder injury. We think severer injuries involve structures as deep as brain stem, in general. It’s a result of a progressive process and less likely to be a mechanical sheering of the white matter. This acceleration/deceleration process on the axon actually induces a number of changes to disturb it metabolically, there’s calcium influx etc. this process can occur over short or long periods of time and the final result can take some time to complete. What this tells us is there are a number of points where we can potentially intervene. In terms of research we can use this. It’s a process.

The disturbance is set up by the initial trauma but it can take hours to days for the damage to occur. Not all the white matter

tracts respond the same; some will degenerate and become dysfunctional others will actually show some repair processes. Different axons are at different stages of this process. One of the basic things we know about cell death is that calcium influx is bad and this can occur secondary to mechanical trauma. Again diffuse axonal injury is important because it may be one of the few pathological findings in mild head injury. It also may not be visible in standard scanning may need to use something like DTI to really assess white matter changes. Like I said if you interrupt the cables and connections you can have problems even if the primary areas aren't damaged or contused.

Secondary mechanisms are possible if injury is at a point where we may be able to intervene. Once someone has had the trauma you can’t go back and reverse that, but the trauma sets up a number of events. So in some ways the axonal injury gives you a cascade of events and therefore an opportunity to intervene. There are also things set in place secondary to the trauma that also contribute to the amount of injury you end up with, so if you intervene you can stop some damage. One of the better studied aspects of this is excitatory amino acids. Glutamate and Aspartate serve a normal role under normal circumstances, but in trauma for whatever reason, they are released in excess and become neurotoxic producing damage. This occurs in stroke as well. Also they think low level excitatory levels play a role in neurodegenerative damage like Alzheimer's. I won't talk about all of these but again there is a variety of events that still occur so it's not a done deal with the trauma itself. Acetylcholine seems to be elevated after trauma and appears to be neurotoxic as well. You can have intercranial pressure and edema that causes secondary tissue damage. Also bleeds, subdural hematomas are not uncommon in TBI.

I sort of covered this but again this area is of interest because it is a potential step we can intervene at. There has been a lot of work trying to look at the possibility of using glutamate type receptors to use agents that might block of modify, thinking that it may reduce secondary causes of damage

I’ve mentioned that these bleeds can be a significant source of the trauma before. Subdural hematomas can either be acute and be a medical emergency, or not noticed early and gradual, and even some cases a chronic subdural hematoma. Here is picture showing you a very obvious subdural hematoma and pointing out where that occurs.

Let me spend a little time talking about the neurobehavioral sequelae of TBI. There is the issue of acute treatment. If someone comes in they are going to need to be evaluated to see if they need acute care. More of the severe injuries are going to need to be admitted to the hospital and can be very complicated. Milder injuries, if they come to the emergency room are rarely kept in the emergency room. We are more interested in what happens after the acute event and the problems that arise. We talked about the changes with disturbances in frontal and temporal lobes but also white matter disruption can aggregate frontal dysfunction. That’s why the disabilities you see after TBI are not going to be the motor complaints like after stoke. Very often the complaints are going to be from the neurobehavioral sequelae. TBI is very weighted on the side of prefrontal cortex function. Memory and attention can also be affected and the more severe the injury the more global the cognitive deficits. In the milder injury there is more selectivity across cognitive domains and more equal deficit in severe injury. Behavioral changes can often be devastating. Mood disorders are common, there’s a lot of vulnerability for depression and mood disregulation. Somatic symptoms and disorders are very critical in this population. These patients often have chronic pain issues like head ache, back and neck pain. Chronic pain in itself becomes an overriding factor in itself. All of these things have to be addressed. Seizure disorders are more common than we think in TBI and can present more as neurobehavioral defects. He brain can be disrupted structurally, chemically, electrically, etc. Most people come in with more that one impairment.

It can be complicated because a lot of symptoms of PTSD (post traumatic stress disorder) look like TBI. People often refer to the effects of litigation and malingering in TBI. I have a clinic full of patients who I don’t think are faking but I think are made worse because they’ve had years of litigation and people looking at them and saying “you’re malingering aren’t you?” So the natural response of people feeling like they are not being listened to is to embellish and get worse.

Mood disorders generally respond well to treatment, cognitive disorders only do so so. Bottom line is what ever they come in for you have to assess everything not just their chief complaint. You need to get the full picture to get the appropriate treatment plan .Depression after TBI is probably underestimated and it is probably due to its presentation. Sometimes the depression results in difficult behavior, poor ability to respond to rehabilitation, apathetic, non compliant, etc.

Brain and Behavior: Traumatic Brain Injury Evaluate everything. Neuropsych testing can be invaluable. If someone comes in complaining of neurobehavioral problems

your history should include questions about past TBI. Someone with past injuries may be more likely to show psychiatric type disturbances. It is important to know that even milder injuries can present with problems unseen so that you can give the right treatment and not tell the patient they are malingering or something. Lab workup for this is as needed. Imaging is going to be used in a severe patients based on what you suspect could be wrong.

We use a lot of medications to treat these patients like antidepressants, psycho stimulants, pain medications, epileptic

medications and mood stabilizers. They are not FDA approved for TBI but it is ok to use medications off label as long as you document it, the proof is in the research. It has been suggested that the Alzheimer’s medications (cholinesterase inhibitors) can be good for brain disorders that have cognitive problems. Based on the etiology of TBI choosing those drugs makes sense. Two areas are important. Acute treatments geared toward the secondary injuries. I see acute patients who are more chronic. Even patients years out from injury can get help. Even if this is not the field you want to go into, knowing when to consult is the key. Rational pharmacology means we treat patients based on what we think needs to be addressed. For example if we think prefrontal cortex is dysfunctional we think dopamine. There is also a symptom approach for example if they look depressed or irritable putting them on an SSRI. So it is not all etiologically driven. Brain injury patients of any cause are more sensitive to side effects and you have to be extremely cautious no matter what you give them especially those that might effect their mood or cognition. Remember the somatic symptoms; you can’t just treat one thing you have to treat all symptoms. If they are in pain or not sleeping it worsens everything. Consider a sleep study. This is a list of different medications we may use with TBI. Each clinician tends to have his/her own library.

Let me just end on an interesting story. Someone did a post mortem assessment of the Red Baron. Turns out he had a very

significant brain injury and part of the reason he went down behind enemy lines may be because he had poor judgment and showed symptoms of TBI which altered his ability and put him at harm. So being whacked in the head is not good.

Brain and Behavior 5: Language 1 of 3

Announcements: It was a hard decision to make but I chose to spare the reader from the estimated 500 “you knows” expressed in this language lecture. I hope you don’t mind. Usually about 10% of the population is believed to be left-handed. Other numbers say a little bit differently, but as a summary, right-handers are by far the majority in normal relations. So the left hemisphere is more the rule than the exception, but again, you have to recognize that left-handers that have language in both hemispheres, but still 67% have their dominant language hemisphere as the left hemisphere so it’s more variable in left-handers. How is this represented in the brain? There is a post-mortem study that shows that 65% of individuals have an enlarged planum temporale on their left side, which is basically the area of the brain where your primary auditory cortex is; so this study is not related to handedness but it gives you a clue as to the function of that region. And the other thing to have in mind is that many of these functions, specialized, lateralized functions have a lot of plasticity in the early years of development; so full lateralization of the brain won’t happen until after childhood. A little bit more clinical here. When you evaluate handedness, one way to do it is to ask the patient which hand they use for writing. They have to remember that handedness goes beyond that; writing is one thing, but many left-handers because they are exposed to a majority of people who are right-handers might use their right hand to write but really use their left for most manipulation of the world. So it is always useful to ask them what hand they use to hold a cup of coffee, to throw a ball or hold a knife. Writing is one of them, but may not be specific. This also tends to run in families. Q: If you’re ambidextrous, does that refer to the ability to use both hands with the same task or depending on the tasks, it varies? A: Again, ambidextrous have bilateral representation so you might be able to do different things, but there might be a preference to do it with one or the other. When you are evaluating patient’s language, there are 6 basic elements that you always have to remember. I have them here in color. One of them is fluency. It’s basically determined by the number of words that the patient can use per phrase or the number of words that can be said in a minute. One classical test is the Animal naming test where you ask the patient to tell you as many animals as they can in minute…or the FAS test, where the patient has to tell you as many words that start with the letters F, A, or S in a minute. So that basically determines the fluency. Comprehension is important also especially for what people know as Wernicke’s aphasias; where you ask the patient basically to point to objects (e.g. a chair). You also ask the patient yes or no questions so you can gauge whether or not the patient understands you. One important aspect of comprehension is that it’s not only about understanding what an object or where an object is; sometimes there are syntax-dependent meanings sometimes that need to be evaluated and that would actually be affecting more the fluent aphasias or the broca’s aphasias. If I give you the phrase: “the lion was killed by the tiger” and then I ask: Who killed the tiger? Because the syntax-dependent will allow you through the syntax to be able to sort out the meaning. People with problems with syntax-forming might have difficulty differentiating how this phrase was formed. Repetition is also important to evaluate this patient and you’d basically ask the patient to repeat after you and you’d make it more difficult as you. You’d start with single phrases and become more and more elaborated. Naming is important also, more specifically for Wernicke’s aphasia when you want to evaluate the patients’ ability to name different things. Visual confrontation- you show them an object in the room and ask them what it is; it’s important to ask objects from different categories, because if you ask for objects that aren’t so used, low-frequency words basically, that might detect the difference in language disorders. Reading and writing are other forms of evaluating language. The evaluation of language won’t only be oral or verbal but also includes written material. So, going more into the neuroanatomy. You heard me make references about Broca and Wernicke and where these sites are in the brain. Paul Broca described patients with language disorders with lesions in this part here of the inferior frontal gyrus. Brodman areas 44 and 45. Wernicke described patients with lesions in the superior temporal gyrus, but over the years, it was found that patients with different lesions would present differently in terms of the language disorders they had. The classification of the aphasias and dysphasias basically, you have basically two main types: an expressive aphasia which will be located in the Broca’s area- the problem here is basically the fluency of language (the amount of words that they could use in a minute), and repetition could also be affected, especially in Broca’s aphasia. Receptive aphasias differently have problems with repetition, but also comprehension and this sets it apart. I will show you a diagram that will make it easier for you to see. This is Broca’s aphasia, which basically is also called non-fluent aphasia and they have difficulty putting a sentence together, but the sentence has some meaning; when they form a sentence, there’s more nouns than verbs- what it means is that there’s a comprehension there but they can’t put it together correctly. It’s described as telegraphic basically and you can see Broca’s area there. Now because this also affects an area connecting Broca’s area which is called the Arcuate fasciculus, it will also affect repetition. So this is Broca’s aphasia. Now, sometimes the lesion might not be specifically in Broca’s area but in a more frontal area that is adjacent to it that may not touch the arcuate fasciculus, that is called transcortical motor aphasia, that is basically Broca’s aphasia but repetition is preserved. So comprehension is preserved and repetition is also preserved here. The same can be said with Wernicke’s aphasia, but the other side. The main thing with Wernicke’s is comprehension, ok? Basically here, the difference is that they can say phrases, sentences, but the sentences lack meaning- the opposite of Broca’s aphasia- in Broca’s you had telegraphic speech where patients are saying a lot of nouns trying to convey meaning but they can’t form sentences. Here, the problem is not in forming the sentences; they can form sentences that are syntactically correct but they lack meaning. Sometimes

Brain and Behavior 5: Language 2 of 3 what happens with these patients is that they use paraphasias or paraphasic errors, where they substitute certain words for other

words and there’s a classification for paraphasias so patients can substitute one word for another that has a similar meaning; for instance, you can use ink instead of pen, because they’re semantically connected (semantic paraphasia). Phonemic paraphasias will happen when the substituted words are similar in sound (phonetically); so instead of using pen, you use pet. They’re similar in sound and so you replace a word with the other. And you could also see patients using neologisms where the substitution is one in which the words may be used without any connection either semantically or phonetically with the intended word. But the idea for you to keep here is the two main types of aphasias- the more non-fluent aphasias (Broca’s) where the meaning is preserved but the patient can’t form sentences and Wernicke’s when the patient can form sentences but they lack meaning. As you remember, there was a transcortical motor aphasia, right? If the lesion was in front of Broca’s area, you’d still see the same symptoms but repetition would be preserved because it wouldn’t affect the Arcuate fasciculus. Same goes for Wernicke’s- if the lesion is here (above Wernicke’s area in the parietal cortex), the presentation would be very similar to Wernicke’s but repetition would be preserved, so the transcortical sensory aphasia is basically a sensory aphasia where repetition is preserved. You heard me talk about the Arcuate fasciculus which is a bunch of white fiber tracts connecting the Wernicke’s area to Broca’s. And basically what these tracts allow us to do is to repeat (upon hearing a word, being able to repeat it). A lesion in this white matter tract causes conduction aphasia where all elements of language are preserved but repetition. Was it clear the difference between the aphasias? There’s a lot of synonymous use in the literature about the aphasias, Broca’s for instance can also be called motor, non-fluent or expressive aphasias. Wernicke’s can be called sensory, receptive or fluent aphasia (because fluency is preserved since they only have problems with comprehension). Those are always used interchangeably. Now, clinically speaking, what causes someone to have aphasic syndromes or language disorder? By far the most common reason is ischemic or hemorrhagic vascular accidents. There are other causes, for example ictal or post-ictal deficits with focal seizures (but these are usually temporary). And there are other types of lesions; usually though the ones that are affecting the brain more globally would present with problems beyond the aphasia. The ones that result in the aphasia only are usually vascular events. When we talk about vascular events, we’re talking about the Middle Cerebral artery being one of the main arteries that could be affected in aphasic syndromes. A lesion here would more likely cause Broca’s and a lesion here would more likely cause Wernicke’s. As we can see here, these are the territories that are strategically covering language functions that are supplied by the MCA. The other thing to have in mind is that we’re describing these as disorders of the cortex, but you have to remember that these areas are also connected to subcortical areas like the thalamus or the basal ganglia. So, sometimes, lesions in subcortical regions will also present with similar problems. You heard me talk about the transcortical aphasias and they are like the subforms of aphasias. Specifically, as I said MCA infarctions are usually the cause for the main type of aphasias, but for transcortical are usually problems involving the watershed areas: for transcortical mortor aphasia, we’re talking about the MCA-ACA watershed area, and for the transcortical sensory aphasia, we’re talking more about the MCA-PCA watershed. So, trying to leave now the classification of aphasias…As we talked before, language is one of the few functions that still can be said to have very clear lateralization. What happens if we have lesion in a similar region that we saw before but now in right or the non-dominant hemisphere? Besides the components of meaning, and syntax, there’s also an affective or emotional component of language which also contains emotion to whatever we want to say. The disorders of prosody are called aprosodias, and the affected area is the comprehension of emotional intonations of language, where the comprehension of the meaning is intact but one can’t understand the affective aspect of language. There’s a whole literature looking at the classification of aprosodias. (Inaudible) I’m going to talk about some of the more specific disorders of language processing. One is Agraphia which is basically impairment in writing caused by deficits in central language processing and not by simple sensory or motor deficits. That’s really important. The same goes for language disorders, again, when you’re evaluating a patient, you have to make sure that it’s not that the patient can’t speak, but you have to evaluate all aspects including writing and verbal communication. Agraphia is impairment in writing not because the patient’s arm can’t write-that would be a motor deficit- but because of central language processing. But all patients with aphasia present with some level of agraphia because it usually affects all modalities of language. But basically, agraphia without aphasia can occur. And it’s usually seen in lesions in the inferior parietal lobule of the dominant hemisphere and mostly on the left side. It’s rarely seen in isolation, but also is accompanied by acalculia, R-L disorientation, finger agnosia (Gerstmann’s syndrome). The same can be said about Alexia, which was discovered by the French Neurologist Dejerines. Basically, alexia is impairment in reading also caused by central language processing like we said for agraphia, and it has also has to be distinguished from visual problems (which would be simple motor deficits). There alexia with agraphia and alexia without agraphia. Alexia without agraphia involves a lesion in the dominant side of the primary visual cortex and extends into the splenium of the corpus collosum and what’s happening here is that the visual information coming from the left hemispheres cannot cross to the respective right structures, and vice-versa. So, these patients in part can see because they do get vision on the right side on their visual cortex, but they can’t apply meaning because the info would have to cross towards the contralateral Wernicke’s side. (Inaudible) And these are usually due to PCA infarcts or hemorrhagic and are usually accompanied by right homonymous hemianopsia because of the primary visual cortex that is affected. Alexia can also occur with agraphia and here the lesion will be more downstream in terms of the flow of information from the visual cortex, as I said, the info needs to go to Wernicke’s where you know the meaning is given to whatever symbol the person is looking at; the same goes for auditory (from primary auditory cortex directly to Wernicke’s). In alexia with agraphia, what happens is that the lesion affects the angular gyrus, which is this area here in green, and the angular gyrus has implications in cross-modal visual-auditory association and so one of the hypotheses as to what the angular gyrus does is that it changes the modality to be

Brain and Behavior 5: Language 3 of 3 able to go from visual to auditory, so info can go into Wernicke’s area. But basically the lesion is in the dominant inferior

parietal lobe. A few words about developmental dyslexias… Most of the disorders that we talked about today were acquired disorders; disorders that occur usually because there were lesions in the brain, but people had normal developments. But it also happens that people have difficulty actually learning to read despite having great intelligence and educational opportunities. It is estimated that dyslexias affect anywhere from 5-10% of school children and it’s more common in boys than in girls. Some studies in the 80’s state that there is a loss of planum temporale asymmetry. If you recall in the beginning of the lecture, we said that there is some asymmetry in a post-mortem study that the planum temporale was larger in the left vs. the right in 65% of people. So that asymmetry is lost in people with developmental dyslexia and probably because of that, people have more difficulty in processing language; that would be a speculation at this point, but that’s the finding. Obviously with this developmental disorder, we’re not talking about a specific lesion that can be traced like an infarct, but more on neuronal ectopias and architectonic dysplasias that also have been seen in the left perisylvian zone. So, again, we’re talking about a neuro-developmental problem here that the specific cause can’t be traced at this point yet, but it’s important to differentiate or consider, when evaluating language, the person’s development as well as events that happened throughout their life. Naming as I said is actually affected in all these types of aphasias, so naming doesn’t give you any specific clue about what type of aphasia you’re facing. But there are people who just have anomia and the rest of the language is pretty well preserved; especially when you present to them objects that they use very frequently. It has a very poor localizing value, unlike Broca’s or Wernicke’s. One very intriguing finding is that certain categories of words are represented in distinct areas of the left hemisphere, so we don’t have one specific “dictionary” area of the cortex. There might be parts of our brain that represent different groups of things, and that might differ from person to person. But anomia is a common finding, and it could be the only thing the person presents with, but these patients should be followed over time, because anomia could also be the first symptom of others that will characterize a degenerative disease. One thing that I’d like to add before ending the lecture here is that…moving from…we talk about auditory input, verbal sound that you hear that goes into the primary auditory cortex then to Wernicke’s to be sorted out… But there are specific disorders that can occur between the primary aud. Cortex and Wernicke’s. Obviously, if the lesion is in the primary auditory cortex, it’ll render deafness, right? But if the lesion is between that area and Wernicke’s, the info doesn’t arrive there, and the syndrome specifically for words is called pure-word deafness which is a form of auditory-verbal agnosia, ie the inability to recognize/differentiate words and their meaning and this is not a language disorder but a pre-language disorder because when you talk about a language disorder, you’re assuming intact arrival of the sensory input into the language areas and the problems start there, but this would be a pre-language disorder. And clinically, it might be very difficult to distinguish because the presentation might be quite similar. The same can be said about the post-language disorder, where the problem is not so much forming a sentence or understanding; the person might be able to form a sentence but may not be able to articulate or move their motor apparatus so that it can be said appropriately, which is called aphemia (bucco-facial apraxia). This should be differentiated from dysarthria which is the inability to move your motor apparatus appropriately. So, this will be a post-language disorder because you’re assuming that the formation of the sentence is intact, but the problem happens after the sentence has been formed (consciously). So those are things that you have to keep in mind when you’re evaluating a patient with a language disorder. Another thing, we’ve talked about this differentiation between these aphasias, but patients can also present with what is called a global aphasia which means that they might present not only with comprehension or fluency problems but also other problems, and it could start with one of them and develop into a more global aphasic disorder. They might start with a little aphasia, develop into Broca’s, and then only have anomia for instance. So, it’s not so black and white or as clear-cut as Broca’s or Wernicke’s, but there are many aspects of language that overlap. Q: Is there a way to clinically distinguish between aphemia and motor aphasia? A: When you’re in doubt, and you might be, you can always use more sophisticated language tests. Aphemia patients have problems writing, but Broca’s patients may also show contralateral hemiparesis and thus writing impairment as well, so it can be hard to differentiate the two. Q: Where exactly is the lesion for aphemia? A: It’s an apraxia syndrome, which can be very difficult to localize; we don’t have a specific site in the brain for our lexicon, but basically Wernicke’s has the function of applying meaning. The same happens with motor programs, but it’s very hard to localize, but probably somewhere between Broca’s (where the formation of the sentence should begin) and the respective motor area responsible to articulate the muscles; somewhere in there, but there’s no specific tract. So, I think that’s it for today. Thank you!

Page 1 of 8 Brain and Behavior 6: Physiological Monitoring and Biofeedback Training Slide 2: My name is Eric Prensky and I’m here to talk about biofeedback and physiological monitoring. I’m in the department of psychiatry and I’m going to talk about biofeedback today. I don’t know how much experience anyone has with this, but basically what I’m going to do today is talk a bit about the mind-body interaction initially, a little bit about what it is. I’ll talk about the biopsychosocial model, and then I’m going to talk about the definition of biofeedback, talk about some of the equipment, modalities, how we use it and what we use it for. Towards the end, it’s going to be what we use biofeedback for, the efficacy of biofeedback in general, and some of the disorders you can use it to treat. I have a couple brief video clips in here, so you’ll have to bear with me as we go through to make sure it works. Slide 3: A huge percentage of visits to heathcare professionals – between 60 and 90% - are related to stress and other mind-body interaction problems. There are these inseparable links between the mind and the body, as people probably already know. Physical symptoms are influenced by one’s thoughts, feelings, and behaviors, and vise-versa. In addition to all these problems, these stress-related disorders take a huge toll economically on our system. Some research indicates that stress-related disorders account for as much as 17 billion dollars a year in lost productivity. Beyond that, some old research from the 70s said that approximately 60 billion dollars per year is lost overall due to stress-related illnesses. They take a huge toll on us, on our system and on people. Slide 4: Just a quick review: this is the biopsychosocial model. You can see how all these things interact: biological and cellular processes interacting with psychological processes and social processes and context. Slide 5: Out of this biopsychosocial model came the idea of disease versus illness. This is kind of where the first idea for biopsychosocial model came from, the distinction between disease and illness. Disease is this objective biological event, which is probably what most of you guys are studying, but illness is the subjective experience or this self-attribution. What is the attitude of the person going through? How do they experience it? How does it affect them personally and individually? That’s an important part of this. Slide 6: A quick review of what stress does, as you guys probably know already. Some of the things it can do lead to sympathetic activation, cortisol release, among others. It leads to things like hypertension, immunosuppression, insulin resistance, and other things. It ultimately leads to poor clinical health, which is probably why you’re going to end up seeing these patients. So we need some techniques to manage stress for patients, so stress won’t take as big an effect on their lives. We also want to avoid some of the negative psychophysiological consequences of stress on our bodies over time. Stress itself has been shown to have a big behavioral and psychological link to illness. As you can tell here, the decreased immune function is one of the biggest things you’re going to see. Slide 7: The whole idea of applied psychophysiology, which is where biofeedback falls under, came out of this idea that initially we thought that only voluntary muscular skeletal system was responsive to operant conditioning. The autonomic nervous system was thought to function kind of automatically, beyond voluntary control, so there was really no need to do anything like biofeedback. Things like circulation may not be affected by this self-regulatory learning was the initial belief. However, some work in the 70s with humans and animals showed that with some training, as people worked on these things and practices, that they could have increases and decreases in bodily responses, in things like skin conductance and blood pressure. If they focused on it and if they worked on it, they could make these changes. So that was quite revolutionary. You can see the new technology as well has lead to biofeedback having kind of resurgence. It can be quite interesting and complex with the screens and computers that we use these days, as you’ll see in a few moments. Slide 8: This ultimately led to what biofeedback, and that’s the definition here. It’s the use of real-time information about one’s psychophysiological responses to help an individual learn how to consciously bring involuntary processes under control. So they’re learning these techniques in real time. Slide 9: One of the big byproducts of this process is that they learn about mind-body interaction. That’s one of the biggest things that people are going to learn doing biofeedback. An example of this would be a patient who may have something like chronic pain. So someone has a lot of chronic pain. Because they have all this pain, they then frequently breathe from their chest, activating the sympathetic nervous system, which may then increase their anxiety level, which is then going to increase their pain level. So you have this vicious cycle that people are going to continue to go through until they can learn about the mind-body connection, learn how to be more sensitive to their body, and how to decrease this arousal.

Page 2 of 8 Brain and Behavior 6: Physiological Monitoring and Biofeedback Training Slide 10: Biofeedback itself can be used in a lot of different ways. We can use electronic or computer information to aid the process, but it’s not necessary. You can go the physician and you can use the blood pressure, or even just taking your temperature, can give some information in terms of biofeedback about your body. You can learn how to control some of that. It’s usually non-invasive. It’s painless. We’re just measuring things that your body gives off normally. With the advances in technology, we can now utilize audio and visual feedback, which is pretty cool to show some screens to people and increase the changes that they are able to make through treatment. Slide 11: So here are some of the modalities we typically use in treatment. For the elctromyography (EMG), there are 2 different placements. The frontalis of the forehead or trapezius placement are the 2 most common we use but you can use it in all different areas of the body. Maybe an arm or leg, depending on where you need it. These are measured in microvolts, and 2 or 3 microvolts is what we ideally want. Less than 2 microvolts is a relaxed muscle, and less than 3 is kind of a non-tense muscle. What we’re measuring here is the electrical aspect of the muscle contraction. We’re not measuring the muscle contraction itself. It’s the skin above the muscle, of course. Also, we have skin conductance or sweat gland activity. This measures changes on the skin through electrical conductance, the salts on the skin surface. If you see the lie detector test, this is one of the main things they’re going to be using, the skin conductance. It’s measured in micro-ohms, and similar to the EMG, we want to have less than 2. It’s a pretty good indicator of someone who has pretty low skin conductance. Slide 12: Next we have peripheral skin temperature. Of course, we’re not doing the internal body temperature like we would normally do with a patient in the hospital. We’re doing what’s given off on the outside of the body. A thermoster is what is used to measure this. It’s correlated to peripheral vasoconstriction. As people are breathing from their chest, using the autonomic nervous system, blood flow is going to be constricted in their fingers, which is where we usually measure it, and the temperature will go down. As we increase the parasympathetic nervous system activation, it’s going to increase the blood flow and increase the temperature. So a higher temperature is associated with this vasodilation, which is usually what we want. Then we have respiration rate. We have abdominal and thoracic breathing. A normal, healthy should breathe around 12-20 breaths per minute, and the depth should be similar between breaths. So we’re looking to make some consistency with these people so they have a similar depth between their breaths. Slide 13: The next is heart rate and blood pulse volume. It’s measured with a photoplethysmograph. You see that often in the hospital with patient. The relative amplitude of the blood volume is what we’re looking at here. It’s variable with each pulse. The average heart rate for adult males is about 72. For adult females, it’s between 76 and 80. Slide 14: The last area we have is EEG or neurofeedback. This is not an area that I practice, but it’s another one that’s sort of burgeoning these days. There’s a lot of controversy in terms of whether this is effective, what it means. The research is kind of mixed in terms neurofeedback. We’re looking at EEG (alpha and theta waves). It’s used for a lot of different disorders, as you’ll see in a little bit, but some of them include ADHD, learning disability, seizures, traumatic brain injuries, and maybe anxiety. Again, this is much more controversial. I don’t think there’s great evidence saying that neurofeedback is the right way to go, but it’s still being researched. It’s pretty popular. Slides 15,16: This is an example of the equipment that I have. It’s called the NeXus-10. This box is the encoder box. It’s wireless, as you can see. We have the sensors that are attached to the patient from here, and there’s no other wire to the computer. It sends it wirelessly to the Bluetooth which then goes to the computer. You can see it in real time on the computer screen. This is an example of a screen you might see. We’ll look at a few more in a moment. So this is great. It’s very portable. In some cases, you could actually think of doing it in the hospital, although it’s not something we’re doing right now, but we can take it between different floors in our outpatient clinics. It allows a lot of flexibility for us. This is an example of the equipment hookup. Question: How much does it cost? Good question. Mine was probably about $5,000 total for everything. Then you need a laptop, probably, and we have an additional screen like this. You could probably get away with 7 or 8 thousand for the whole thing. So this is the hookup for the equipment. Here you can see on the patient’s fingers, we have all the different equipment hooked up. Here is the photoplethysmograph on these 2 fingers here. We have the skin conductance, and here is where the temperature is measured. Here we have the EMG on the forehead (frontalis placement) and we have the respiration belt right here. That’s typically what it will look like for patients when they are hooked up to this. Here’s the encoder box I was talking about before; it wirelessly

Page 3 of 8 Brain and Behavior 6: Physiological Monitoring and Biofeedback Training sends the information to the computer. Here’s an example of what you might see. I am going to talk about the psychophysiological stress profile in a minute. This is what you might see on the screen during that. This is just to test the signal. As you can tell, we have all this information. Heart rate. Skin temperature which is 74, a little bit low. Skin conductance (we said we wanted it to be about 2) is high, and the EMG is high as well. To some extent, you expect these to be a little bit high when you’re seeing someone for the first time. They’ve never been hooked up to these things. It’s kind of foreign and they may be a little bit nervous. We have respiration right here. Slide 17: Let’s talk a little bit about what we do in these sessions, what it involves and characteristics of the patients and what we’re looking for. We try to do this as a short term course in biofeedback. We don’t really want it to be an ongoing treatment that’s going on forever. It’s great to have 8-15 visits. That gives us enough time to really focus in on the referral question and really make some good treatment in that time. If needed, people can come back in for some booster sessions afterwards, maybe once a month or once every couple months as needed. However, the real goal in biofeedback is to give patients some skills so they can go home and use these. The goal is not to be dependent on the visits but to give them some skills so they can implement these things on their own. The motivation to make changes here is really important, because, again, the gains are going to be made between the visits not just during the time people are here to see us. So we want them to learn some things, take them home, and practice every day. You may come in once a week for 45 minutes. That may not be enough time to make significant changes. Slide 18: In the initial visit, what do we do? Usually we do the typical intake. We focus on the chief complaint of why they are coming to see us, what exacerbates or alleviates the chief complaint, whether it’s pain or something like that. We talk about sleep, get some other health behaviors like appetite, stress, caffeine intake (which can make them more anxious), and experience with relaxation training, if they’ve had any or not. Then, if there’s time, we can do this Psychophysiological Stress Profile (PSP), which we’ll talk about more in a minute. If not, when they come back fro the 2nd visit, that’s what we’ll usually do. The idea with the PSP is to get the patient’s response to minor stressors, that’s the focus of it. We also want to see which modalities, like EMG or skin conductance, are elevated and how they can recover after stress. If EMG, like we saw in the other one was high consistently, that might be an area that we might want to focus on later in treatment. That gives us an idea where we want to go with things. Slide 19: Usually this takes about 20 minutes or so. The various signals are recorded: respiration rate (diaphragmatic breathing), heart rate, muscle tension. Usually we do frontalis placement, but you can do the trapezius as well, depending on their chief complaint and their report of where their tension is held. We do skin conductance and peripheral skin temperature. Slide 20: This what the profile involves. We have a resting baseline of 2 minutes, just to get acclimated to the equipment, what it feels like. We do a Stroop color word task for 2 minutes. Then we have a recovery period. We’re seeing how they respond to relaxation afterwards, They don’t have any skills at this point. They’re just doing it themselves. Then we do serial 7s starting at 1084, which for some people is quite challenging, for 2 minutes. Then we do recovery period for 2 minutes. Then they do a talk stressor. They come up with an idea in their minds of something that’s been stressful recently and they talk about it. We see how they respond. Then another recovery period and then we discuss the results. The Stroop color word task is that you’re given a word that’s in different colors. The word brown could be written in blue. You don’t say the word but just name the color. It’s an interference. The interference would be the word brown. For the word brown written in blue, you’re just supposed to name blue. There’s a whole cycle of these and it goes quite quickly. It’s just to kind of increase stress, but it’s something used in neuropsychological testing for more executive function. The serial 7s is to count back from 1084 by 7s. You just keep going. It’s part of the mini-mental status exam, as you’ll see. Slide 21: Here’s a clinical case example. A 35 year old woman is referred by a psychiatrist for recurring, tension-type headaches. The person had a history of migraines as a child. It was treated with Imitrex successfully. The patient now has daily headaches that begin upon arising. There’s muscle tension in the shoulder and back area and trouble falling asleep, in addition to stress in multiple different areas of this person’s life, professional and personal. Prvious treatments that this person has used include physical therapy, exercise, hot and cold compresses, and massage. Slide 22: This is the PSP example. Here’s the minimum and maximum during the baseline period. We get an aggregate of the baseline, the stress periods, and the relaxation periods, which we’re going to go through here so you can see what it might look like. As you can see here, for the respiration rate, there’s quite a big range which is not abnormal, but it’s a little bit high for a baseline, not too bad. The skin conductance is 6.2, which is a little high as well. We wanted it to be around 2. The temperature and heart rate are pretty good. The EMG is pretty high, indicating that it will probably be an area of focus as well in the future.

Page 4 of 8 Brain and Behavior 6: Physiological Monitoring and Biofeedback Training Slide 23: Then we do the stressor phase. This is an aggregate of that data. You can see here how the respiration rate changed from 12.8 to 27.3. During the stressor, there was much more rapid and shallow breathing, indicating they’re breathing from their chest. Skin conductance increases as well, from 6.2 to 13.8, a big increase there. Temperature decreases, as you would expect. During the stressor, that vasoconstriction is happening. Heart rate goes up as you would expect, and EMG goes up. The average is pretty high, 25.4. That is fairly significant. That’s something we really want to focus on here. Slide 24: We can look then how this person recovers from the stressor during these relaxation phases. You can see they’re doing a good job with bringing the breathing back to a fairly good rate when they’re trying to relax. The skin conductance remains pretty high, even higher than the baseline. The temperature came back pretty well. That’s a good sign as well. It’s probably related to the breathing. Heart rate came back pretty well, but you can see the muscle tension is still very high, which is consistent with their presenting problem of tension headaches. It is related to this muscle tension. That would indicate to me that the areas we want to work on in future treatments are skin conductance and muscle tension. Slides 25, 26: This is an example of what we might get as an output from the overview of the PSP. You can see here up top we have the skin conductance. You can see how, during the stressor, it goes up. It kind of comes down a little bit during these relaxation phases, goes back up during the stressor, and then down during relaxation. It’s the same for the temperature where it will go down during the stressor and then it will go back up during the relaxation phases. Here’s the blood-pulse volume. For the respiration rate, during relaxation phases it’s a little more consistent, but you can see during the stressors, it’s a lot more erratic. Then you can see here the muscle tension is off the chart, particularly during the talk stressor. It’s very high with all these stressors. The computer allows us to zoom in and look more specifically at these areas, and that’s where you can see even more data on the stressor. Slide 27: That gives us some initial data on what to do with the patient, but then we have to figure out how to treat them, what do we do. With these additional sessions, we want to teach the patient how to breathe diaphragmatically. That’s usually the first thing that I try to do. We use some visual feedback. They will get to look at their breathing rate on the screen, and get the data back for themselves. What we want to try and do is make the waves similar between each breath, deep and not shallow. We may try out some different ways of breathing during the session. They can inhale for a count of 4, then exhale for a count of 4. Inhale for a count of 4, exhale for a count of 6,7, or 8. The idea with this breathing is to extend your exhalation. You want to make the exhalation nearly twice as long as your inhalation. If you do it the other way, you’re going to start hyperventilating. So we really want these patients to practice. For the example here, she did a count of 4 inhaling and a count of 7 exhaling. This is what she liked. That is then given to her for homework. She’s expected to practice that every day, 2 times a day for about 10-15 minutes. What we also do, depending on the case, is give them a SUDS (subjective units of distress) sheet. They will take this scale home with them and they can then monitor their stress level (anxiety related), muscle tension, and pain. They rate these things from 0 to 100 before and after they practice relaxation. The goal is for them to understand that when they practice their deep breathing, they can see an association with pain going down or muscle tension going down. They can learn that this really is working. When they come back, you can operationalize this for them and discuss how the practice went. In this case, her distress level before practicing was a 42. It went down to a 29. These are all self-rated. There’s no right or wrong answer. The muscle tension went from a 62 to a 45. The pain went from a 59 to a 57. That’s not a really big change, but not atypical in the beginning when the patient isn’t really used to practicing. This is foreign to them. Over time, hopefully they will give a bigger response for the pain. Slide 28: In terms of future sessions, we often teach some more in-depth relaxation techniques in addition to using the feedback that we’re going to see on the screen. In some cases, depending on the referral question, you can do a specific protocol, like a migraine headache treatment. The patient can apply the skills they’ve learned along with the auditory and visual feedback. We’ll teach them something to take with them. There are kind of 2 ways you can decide you want to go. Slide 29: One of the biggest in the success of biofeedback is self-efficacy. The patients really have to believe they are able to make changes and feel that they are learning a skill and understanding it. It’s a really important factor. Some data, that was done a while ago in the 80s, found that high success biofeedback of patients who were getting a lot of success, regardless of what was actually learned, showed improvements in headache activity by 53% more than only moderate success, which was 26%. Question: How much of this is due to the placebo effect?

That’s what a lot of people are looking at and trying to figure out how much placebo is related to this. Sometimes, I think, depends on the referral question. I think a lot of it is based on the self-efficacy and if you have a specific referral question you’re looking at, if

Page 5 of 8 Brain and Behavior 6: Physiological Monitoring and Biofeedback Training people are having a reduction in their headaches and they’re relaxing, then that is effective. Maybe spending some time focusing on these things can be effective. That’s a good question. There’s some research looking at it. One of the main things that you try to want to work on with patients is to reinforce when they’ve had success so they can really get this self-efficacy experience. Slide 30: Passive attitude is also an important approach. For many of the people that come through trying to teach them how to take a passive attitude is foreign. It’s not something they’re used to. Maybe they are really high achievers. They’re used to not focusing on their attitude at all. Relaxation can be difficult. We want to tell them that it takes time to learn. It’s not something you’re going to get immediately. Maybe they’ve picked things up quickly before, and this is something that they feel they should understand quickly as well. That’s not always the case. The opposite reaction often occurs in the beginning. That’s something you can tell patients and teach them, to expect this opposite reaction. You provide yourself with a win-win situation. If it happens, then you say, well I told you this might happen. If it doesn’t happen you can say, look you made some good gains and you did a great job. It isn’t uncommon though when people are trying to learn this that they try too hard. We want to let things happen and take a more passive approach to relaxation. That’s what relaxation is. Slide 31: Some other important data looks at the role of coaching and what impact that has. Does the patient want to be coached or not? To some extent, we’re going to be in the room with the patient so we have to do some coaching. Why not just ask them? How much do you want from me? Should I be constantly telling you what you’re doing or do you want me to just tell you after the end of the session or towards the end? A small percentage want constant coaching so that’s also important. I was talking about the different strategies we can use. We’re going to talk about 7 different possible strategies. We talked about deep breathing already. You can also add in repeating the word “calm” or “relax” when exhaling. You want to do about 6-8 breaths per minute, really slowing down the breathing. You want to exhale longer than you inhale, as we said before. We also have relaxing imagery, like visualization, putting yourself in a relaxing place, trying to stimulate all 5 senses, and really putting yourself in that situation and imagine as much as you can. We also have relaxing or autogenic phrases, where you repeat a specific phrase maybe 50-100 times. An example could be: “My mind is quiet. My arms and legs are heavy and warm.” It’s shown to be very effective for people who have things like cognitive anxiety where they’re really focused on what’s going on in their heads. You want to try to get them to relax and calm those thoughts down. The last 4 are awareness of sensation. For some people this can be useful, just understanding what the sensations are in their body. Some sort of passive relaxation. It’s a little bit more difficult. Doing some mental games like focusing on a color (a warm or earth color like yellow or green) can be useful. Concentrating on auditory feedback can also be useful for some patients. There’s some screens with peripheral skin temperature. They can just try to make the music play as they increase their temperature. Also, nothingness, some meditation is pretty difficult for people to do. Allowing your mind to go blank is pretty difficult. Less than 2% of people can achieve that. Some of these are more advanced and some are more straightforward and basic. Slides 34, 35: Here’s an example of the peripheral skin temperature screen I was saying before. Here we have on the left the temperature. The patient wants to keep the sun up in the air. As their temperature goes down, the sun will go down as well. You can’t see it on the screen but there’s a threshold you can set up (we’ll see it in a minute with the EMG screen) and they have to constantly be working to achieve that threshold. Once they achieve that threshold, the music will play. You can do it the opposite way also where the music will go off when they achieve it. I am going to show an example of an EMG screen. It gives you some good data. Slide 36: This is just an example of what you might do for someone with chronic headaches, depending if they are tension or migraine headaches. You do the clinical interview we did before. There is a headache log they can take with them. They can monitor their headaches and how they change over time and any triggers to the headaches. Developing awareness of the over-arousal and tension, trying to understand things in the 2nd visit. Maybe do some diaphragmatic breathing. Might do the progressive muscle relaxation, which is systematically tensing and relaxing muscles, which is a great thing for headaches. Home practice with audio tapes. They can either take home tapes or a list of the muscle groups they want to focus on, and do this every day. We don’t want them to become dependent on the audio tapes. So we ask them to maybe once a day or once every day to listen to the tape and then do it without the tapes on their own so they don’t become dependent on using that as the only way they can relax. Then they might come in for the 3rd visit and do some EMG biofeedback. They’ve practiced this progressive muscle relaxation and now they can work on learning how to relax their muscles with the feedback. We can do then presentation of a passive relaxation technique, maybe autogenic phrases, maybe just visual imagery, something like that.

Page 6 of 8 Brain and Behavior 6: Physiological Monitoring and Biofeedback Training Slide 37: Then in the next few sessions, we might do something more specific toward the tension headaches. We might do EMG feedback until they’re able to decrease their tension by about 50% in the neck, face, and shoulder area. Generalizing relaxation through frequent, short relaxation exercises, learning how to implement this to make it more portable. You can do it if you’re in the grocery store line, if you’re out at the mall. We want this to be utilized as much as you can. We want to utilize them at the earliest point at which you think you’re getting a headache. Then you can begin to taper the frequency of the sessions so they can come in less frequently. Slide 38: In terms of generalizing to the real world, that’s really important. The hardest thing for many people is trying to figure out how they get it at home. They don’t have the equipment or the stuff. How do they do it? So we want to try to prepare the patients as we complete treatment for them to be able to do this on their own. We want to utilize self-control treatment. One idea would be to hook them to it and you don’t let them see the screen where the feedback is. You tell them to try to relax and you can get some data. How are they doing? Are they doing well or poorly? That’s something you can do consistently at the beginning of the session. You can also present a specific stressor before treatment and after treatment and see how they react. Are they better at doing this stress profile after rather than before? Attempt to have the office resemble a real world situation. So, maybe they go from a comfortable chair to a less comfortable chair to standing up. They’re using the feedback during these sessions. You’re kind of progressively trying to move them towards being able to do this on their own without having to be in treatment. Slide 39: That’s sort of the general overview of biofeedback and what we do and what we might do in a specific protocol. I’m going to finish up the talk by talking about some specific disorders that we might treat. We talked about pain a little bit already. This is a quick overview of the difference between efficacy and clinical effectiveness. You might already understand this. Slides 40, 41: The AAPB, which is the psychophysiology group, set some criteria and they looked at a bunch of different disorders and asked which disorder meets which criteria. We have these 5 different levels from not empirically supported to efficacious and specific. There’s even more criteria I wasn’t able to list. Basically, if it’s efficacious and specific the investigational treatment is statistically superior to a credible sham therapy, medication or alterative bona fide treatment in 2 or more independent research settings. Slide 42: Here’s a list of ones that meet these different criteria, 5th being the highest level. Urinary incontinence in females is the most specific one. It’s not something I do, but it’s something a physical therapist or occupational therapist can do. At the 4th level, we have anxiety, ADHD (neurofeedback), headache, hypertension, temporomandibular disorder, and urinary incontinence in males. Slide 44: These are some that are not really empirically supported as of yet. It probably won’t be very useful for autism, maybe for some anxiety with the autism. Probably not very useful for eating disorders, multiple sclerosis, spinal cord injuries. Question: What about addiction, like people trying to quit smoking? Would this be something that would be applicable to them? Peripherally, yes. I wouldn’t do it as a 1st line treatment, but if someone is addicted to smoking or drinking and anxiety is a big problem related to that, then yes it might be a good idea to help learn these skills so they can substitute these behaviors. I would be hesitant to say just use biofeedback to treat an addiction. To be clear, when I implement this, I don’t just use biofeedback. I always add in some cognitive and behavioral components of CBT in addition to this. It’s not going to be an isolated thing. I like to add in these other techniques so they can really get a better picture, and I can feel like I’m providing more global treatment. Question: How do patients get referred to you? Do they find you or go through docs? Both. It’s on the UI website for the hospital. Some people can find us that way and they’ll call up and self-refer. We get a lot of referrals in psychiatry, but some coming from neurology right now. Those are the main couple sources. This is still pretty new. I’ve only been doing it here for a year and a half. Slide 45: So just some quick information on some of these disorders and what can be useful. Arthritis. Some research has shown that thermal and EMG biofeedback used to teach relaxation techniques with chronic arthritis are very effective. Meta-analysis of 25 randomized control studies indicated significant pooled effected sizes post-intervention for pain, functional disability, psychological status, coping, and self-efficacy. So it’s pretty effective for things like arthritis pain. Slide 46:

Page 7 of 8 Brain and Behavior 6: Physiological Monitoring and Biofeedback Training Chronic pain in general. A recent meta-analysis was just in 2007. Meta-analysis of 22 randomized controlled trials of chronic low back pain found that self-regulation therapy such as biofeedback or relaxation training had large positive effect sizes on pain intensity and in the reduction of depression even following treatment, even though CBT didn’t reduce depression significantly. It’s kind of interesting that it has an effect on their mood. It indicates how much someone’s mood is going to be tied to their pain as well. Alleviating the pain may also help alleviate some of their depression. Slide 47: The goal here with chronic pain is to help patient identify potential underlying processes that are maintaining or at the root of the pain. Biofeedback-based interventions for chronic pain can be efficacious for selected disorders. Stress and anxiety responses are going to increase the patient’s experience of pain, which is really the focus of what we’re trying to do here, decrease the stress and increase the ability to cope with it and manage it more effectively. Slide 48: EMG biofeedback was compared with cognitive therapy and found to have similar positive effects and these were sustained in 6 month follow-ups. In terms of TMJ pain, it was found to be relieved by EMG biofeedback. Results were significant in 24 month follow-up. Slide 49: I think the article you guys had was on headaches so we’re going to talk about that a little bit as well. It’s efficacious for adults. Headache pain is one of the most common problems seen in medical clinics, so you might see that a lot. Behavioral interventions resulted in a 35-50% reduction in migraine and tension-type headache activity. Some techniques we can use are relaxation training, thermal biofeedback with relaxation training, EMG biofeedback, and CBT. These are considered the best treatment options for migraines. Slide 50: In terms of that study you guys had online, the prevalence rate of headaches in North America (indicated one or more attacks per year) is about 18% of women and 7% of men. Medical contraindications may include someone who’s pregnant and can’t take the medication. Or they may have poor tolerance of the medication. Or some people just don’t want to take the medication. Previous meta-analyses indicated improvement rates around 40% with biofeedback. Clinical reduction in migraine activity is similar to pharmacotherapy. Slide 51: This meta-analysis for migraine headaches looked at 55 studies randomized control trials and pre-post trials. The number of sessions for these patients ranged from 3-24. The average was 11 sessions. In 11 visits, they really can gain a lot of control. The ones that were found to be most effective were peripheral skin temperature, blood-volume pulse, and EMG biofeedback. Biofeedback yielded significant medium effect size. The weight list control has small to medium effect size. Treatment effect was more than ½ the standard deviation, which is very significant. It was stabilized over an average follow-up of over one year. These are really some positive effects they showed over time. Patients have to continue to maintain and practice these things. That’s where you’re going to see the biggest benefits. Slide 52: In terms of outcomes, for psychological barriers (we talked about self-efficacy and depression a little bit) there was a significant medium to large effect sizes here, small to medium effect sizes with anxiety, and significant reductions in headache frequency. Duration compared to medication-intake condition, of the ones who took medication. Slide 53: In terms of the outcome again, BVP, EMG, or temperature alone or in combination are found to be about equally effective. Biofeedback in combination with home training had the biggest impact. That’s one of the biggest results of the study you read. 20% higher effect sizes than outpatient alone. That really points to the importance of practicing things on a frequent basis, and really ingraining these skills into your life. Slide 54: In terms of some of the clinical implications of the study, biofeedback was recommended as an efficacious, non-medical treatment alternative for patients with chronic migraines. It helps in the long-term prevention of migraine attacks as well. That’s really the goal here: to prevent these headaches from occurring. Once they’ve occurred and you’re already in the middle of it, they’re not going to be so effective. Slide 55:

Page 8 of 8 Brain and Behavior 6: Physiological Monitoring and Biofeedback Training For tension-type headaches. EMG biofeedback and some form of relaxation training were used. Often progressive muscle relaxation is used. Some reviews have found that 50% of tension headache sufferers were improved both statistically and clinically. That’s a 50% or greater reduction in headache activity through either activity. Randomized control trials found positive results and excellent maintenance of improvements over a 2 year period with EMG in 287 patients. It’s pretty useful. Slide 56: In terms of hypertension, it’s found to be efficacious at level 4 as well. Meta-analysis indicated that biofeedback significantly reduced systolic and diastolic blood pressure compared to non-intervention controls. Differences between biofeedback and other behavioral interventions were not significant however. This is often the case that you’re seeing. It gets to a little bit of the placebo effect. Is biofeedback so much different than relaxation training? Sometimes it is, sometimes it isn’t, depending on the disorder. What it can be useful for is people who clearly don’t get relaxation training. It’s hard for them to implement. That’s when biofeedback can be nice. They can really see some more effects. A variety of modalities have been used with hypertension between looking at blood pressure specifically, but you can also use thermal biofeedback (the temperature), EMG, heart rate. People who are found to benefit the most here are those with low skin temperature, high heart rate, and high blood pressure. Slide 57: The take-home message here is that biofeedback is a non-invasive treatment modality, typically utilized as an adjunct to other regiments already in place. Like I said, individual therapy or medication management can be a nice adjunct to using biofeedback. Specific patient characteristics are important to achieving success. Someone who is motivated, someone who is adherent and wants to come in and make these changes, is really going to see the most effect. The key is really practicing.

Brain and Behavior 7 – Learning and Memory NOTE: Dr. Deborah Little jumped around in her slides and did not finish all the slides in the lecture. She mentioned that we would only be tested on what is covered in class. Intro: Dr. Little talks about how learning and memory is traditionally seen as a topic in psychology and as such does not receive much attention from the medical community. However, many of the learning and memory related diseases are based on interesting biochemical basis. There is a huge focus on imaging. Slide 5 (page 3) Dr. Little asks for two volunteers and asks them what they were doing on September 11, 2001 (the slide mistakenly says 2006). The students remember where they were and what they were doing. She asks the class why they remember. ‘Associations’ is mentioned. Dr. Little responds that associations do not persist. “So why doe we remember the salient things? People from our parent’s generation remember where they were when JFK was assassinated, people remember where they were when Elivs died. Why do you remember those things – these emotionally salient events? Emotionally salient things even hold through things like amnesia, head injury, stroke, and severe CNS damage. It is actually pretty straightforward. Slide 10 (page 5) It makes sense because the amygdala is involved in processing anything related to your own instincts. It is not just involved in emotions, not just involved in the processing of negative emotions. It is involved in anything where your survival instinct as a human kicks in. This instinct kicks in if there is anything relevant to your own survival or if there is a terrifying or extremely happy event. It makes sense when you think about the anatomy and where the amygdala is in relation to the hippocampus, hypothalamus, and the thalamus. All of these structures have feedback and feed-forward mechanisms in them. This is why the psychology of learning and memory will never explain the patient end of learning and memory because those of us with training – like I do – like to localize everything to a specific section of the brain. For example: memory is the hippocampus, emotion is the amygdala - it is all a bunch of crap. We like to localize because before we only went by lesion studies. So if there was damage to the amygdala was damaged and the patient had these different emotional responses to things – we concluded that emotion was localized in the amygdala. When ‘H.M.’ had temporal lobe damage to the hippocampus – we came to conclude that the hippocampus is involved in memory. However we have moved beyond that. Slide 6 (page 3) Something we may never do is understand the reference between the two of those. We need to remember where those connections are and why they matter. There are some key chemicals in the brain that affect your ability to learn and have an effect upon learning. A classical definition of learning is: “the ability to adapt to environmental demand”. So if you walk out onto Wood & Taylor without paying attention, and you get hit by a car - the next time you are in that situation you will look twice at the street because you have this nice classical conditioning model. Learning is simply an adaptation on what the environment demands. In classical studies of learning we like to talk about how people learn to differentiate between a poisonous snake/plant and a non-poisonous one. The same goes for stereotyping. The biology of learning is entirely dependent upon memory. That is why all of these lectures end up with memory. So in the behavioral model of learning we talk about an increase in performance accuracy with a decrease in time taken to respond to the target. So if you’re trying to categorize meaningless shapes, over time you will get more accurate categorization and do it faster. This is the classic learning curve. All the curve represents is an increase in accuracy and a decrease in latency as people become better at doing something.

Brain and Behavior 7 – Learning and Memory So what does this mean for the brain? This topic is based on how you ask the question and the type of patient you are looking at. In healthy controls it is really easy to apply this model of Hebbian learning. Donald Hebb came up with this great theory that when you have an event that has the same time course in the brain the connections in between the regions involved in the activities get synchronized with each other. So what happens when you see a poisonous snake? You have the amygdala that fires, areas of the hippocampus that fire, areas of the visual cortex, and areas of the parietal lobe that all fire at the same time. So there are chemicals released in certain areas of the brain – one of those is dopamine. When dopamine is released – it reinforces the connections between these neurons. As such, learning is the best example in terms of plasticity in humans and animals. The reality is that although this may be the case for us (rational, healthy individuals) it is difficult in patients. As soon as you break down this system – it impacts this learning process. Once this system is compromised – our theories of learning/memory do not operate. We have no idea how the brain adapts to the environment – for a variety of a reasons.: First because we don’t have the methods to look at it directly, and secondly because humans are very ‘messy’ and there is a lot of discrepancy and genetic variability between humans. Slide 9 (page 5) So in a very long winded-way – we cannot learn without memory. Learning is the association to adapt to numerous times. However, if we cannot remember what happened at time 1 – how do you associate anything with it? The topic of learning and memory go hand to hand. If you are successful at learning you will reinforce memory – if not you won’t. I will talk about 3 of the major neuro-chemicals involved in learning and memory. My favorite thing on earth is dopamine, but if you read the NY Times you have probably heard that glutamate is considered the ‘holy grail’ for many psychiatric patients. Glutamate is a hot field of research today and thought to outperform dopamine in treatment of every disorder. Acetylcholine is the third neuro-chemical in this list. Slide 12 (page 6) So when you talk about memory there is a difference between talking about memory for humans and memory in mice/rats. In mice and rats, frontally based and medial-temporally based memory is treated the same. In humans we differentiate between memory coming out of the medial-temporal lobes and hippocampal structures and memory that is coming out of the frontal lobes. We can get very different disorders in memory with lesions in each location. The classic test for these hippocampal structures is to give someone a list of numbers or letters and have them repeat that list back. The classic bedside memory test is to give the patient three words to remember and repeat them later. I have never been able to pass that because I cannot pay attention – I assume that means that I have no hippocampus (joke). The frontally based areas put off more complex functions (in humans). So if I give you a list of words and have you repeat them back in alphabetical order – it requires that you do some processing of that information. When we look at the hippocampus and he medial-temporal lobe structures we see there are direct connections to other medial temporal lobe structures and there are direct connections through the thalamus to the frontal lobes and sensory areas. What does this mean? It means that you don’t necessarily have to be consciously aware of an event to respond to it – this is that fight or flight. You can actually respond to something without having awareness and planning of a response. So when you back away from something and you don’t know why – it is generally because you negatively associate something with that to pull yourself back. We almost never do that with positive emotions – we do it mostly with negative emotions. There are also feedback and feed-forward connections with all of the cortical regions. The likelihood is high that in all of these areas where we think there is only feed-forward connections – we just haven’t found the feedback connections. This is because as we’ve found many white matter tracts and these go both ways.

Brain and Behavior 7 – Learning and Memory Slide 13 (page 7) One of the limiting factors for looking at memory is that memory has to be evoked in order to see things. We cannot look the relationship between volume and memory if the patient is dead. The problem is is that the hippocampus is not a homogenous structure – there are 5 parts that are all cellular defined. We cannot see this in vivo. If you are aware of the fact that we have the largest MR magnets in the world a few blocks away that can give you a great amount of detail and we may be able to see the connections between areas better. Slide 14 (page 7) This is a 7 tesla MR from ohio state and I would argue that this would rival the amount of detail of anything you could see in a gross anatomy cross-section. Imagine being able to impose these functional tasks with the influence of medication upon them. We are down to about ¼ mm of resolution. That allows us to look better at the hippocampus. Slide 17 (page 9) So HM is this classic case. With HM, due to a severe seizure disorder, the only solution they could find to save his life was a bilateral dissection of the hippocampus. He is still alive – he’s a great guy. He has a wonderful personality, but is difficult to work with because all of these emotional salient connections are difficult to hold onto. He will mention that he has to go to the bathroom, but he will forget this idea with time (although his need to urinate does not diminish). This is what the resection looked like – you will probably never do this unless there was a very rare bilateral tumor. The HM studies show us that you can have learning in the absence of the hippocampus – this is the important part. Slide 18 (Page 9) So how do we study learning in the absence of memory? This is a very common neuropsychological test used to study learning in very compromised patients. You first show the star to them and then have them draw that start with their dominant hand and then their non-dominant hand. When you use your dominant hand you become very accurate about drawing the star – it takes a lot longer for the non-dominant. In healthy controls this gap gets corrected with time. This is HM’s data here. It was a three-day experiment and there is a dramatic decrease in the number of errors. HM can learn this – he was faster on each sequential memory. Slide 19 (Page 10) This is possible because we have multiple memory systems. This is one of the biggest advances in neuropsychiatry that we have and it continues to be differentiated. If you look at the left side of the graph – this gets back to the 3 word bedside test – explicit, fact-learning type of tasks. To this day if you introduce yourself to HM a thousand times over- he will not remember who you are – he has damage to the explicit learning tasks. However, he does have memory in the implicit parts of the brain (the right side of the diagram). So what is included in these implicit tasks? Anything like hand-drawing - which is a motor task - over time appears to be entirely independent of the hippocampus. So even with HM if you show him a list of words over and over again and then show him a word from that list he will recognize it. So although he cannot explicitly state the list of words, there is evidence that learning is taking place. Most of your amnesia patients lose various paths of these implicit functions. So when we talk about these implicit paths of learning: skills, task priming, (if you are presented a list of words and then asked to identify it later on), the emotional responses (where were you on 9/11?) & some basic stuff (how you house train a dog) that are both associated with the amygdala and the cerebellum. The cerebellum is involved in a lot of these classical conditioning tasks. What you end up with is

Brain and Behavior 7 – Learning and Memory that only these explicit memories are dependent on the hippocampus. Everything else you have nice cortical and sub-cortical involved from the striatum to the amygdala. More evidence for this – specifically in the amygdala – comes from pet studies done in the early 1990s. It turns out that the amygdala and the hippocampus both light up if you are presented with something you have never seen before. They are both active when presented with a novel stimulus. This makes a lot of sense in terms of how we survive in the world. If you’re familiar with something it shouldn’t take as much effort or time – if its novel you want to be able to react to it as soon as possible. What you will notice here is that there is no cerebellar activity. There is also really limited higher cortex activity. So what does this tell you about HM? Do you think HM would respond this way? HM has no ability to tell you about what is new and what is old. Even though he can respond to things because he is familiar they are old - he does not know they are old. It’s a wicked little disassociation. Slide 21 & 22 (page 11) When you look at the classic tests for neurological function – those bedside tests for memory – you are only looking at the hippocampus. If you remember nothing other than that I will be happy. Declarative memory is almost all hippocampal and it is supported by lesion studies like HM and by thousands of imaging studies. The interesting thing is that the hippocampus does not just respond when you’re trying to remember things. It turns out that the hippocampus can predict how well you are going to remember things later on. There was a beautiful study done - and I was unable to get the images from it – showing that activity in the hippocampus when you are learning something completely predicts how well you are going to remember it later on. So how do you actually look at this in vivo? Unfortunately, it turns out children with seizure disorders are the best population to study learning and memory. There is a large-scale center in Boston where they do cranial mapping in the median temporal lobes prior to surgical resection or a procedure. They put like 5000 electrodes around hippocampal structures and medial temporal structures. The kids wait until they have had enough seizures so that they know exactly where the seizure is coming from. As you can imagine, the kids get kind of bored as it may be quite a long time between seizures and so they become the perfect sample to look at memory space. So anyone who works with memory in Boston will end up working with these kids because we have this beautiful in vivo cranial mapping of very complex functions. Turns out that if you have a certain frequency of neuronal spiking happening it can predict to an accuracy of 89% whether that is going to be remembered. It is interesting because the frequency of that oscillation is right around 7-9Hz. If any of you took psychology in college you may remember the ‘magic number’ of 7 +/- 2. So 90% of people, if you give them a list of words, they will remember 7 plus or minus 2 words. It is a very classic short-term memory test. I don’t care how good your memory is, if you are within 90% of the population you will only remember 5 to 9 words. It is this classic response, and the nice part is that it corresponds to this oscillation rate for the hippocampus. This was published in Science a few years ago and the paper is worth looking up in your free time. So why is this important? It turns out that those people that remember a given number of items have a spiking oscillation that corresponds to it. So if you remember 5 items – you have an oscillation of 5Hz. If you can remember 9 items, you have an oscillation of 9Hz. In terms of explicit or implicit memory, and that is what this graph is showing hippocampal oscillation in terms of Alzheimer’s patients, how your hippocampus functions entirely predicts your explicit memory. I don’t think I’ve seen any better evidence in my life showing that the hippocampus is directly involved in explicit memory.

Brain and Behavior 7 – Learning and Memory Slide 23 (page 12) Student Question: ‘How long do you give them to remember the list of words?’ Answer: “it really doesn’t matter. In some of the learning studies they found that if they did enough repetition of these lists you would remember these things for about 5 years.” Student Question: “So does this mean that if you are firing at 7Hz you will remember better than someone firing at 5Hz?” Answer: “Yes – during encoding. However, this does not reflect your baseline hippocampal-firing rate. Also you can do thing to mess up the process. So what happens when you are stressed? You will release cortisol, and where do we know cortisol has a direct effect? Cortisol directly affects the hippocampus. So if you are like me and you are worried about grant funding all the time – you will eventually have no memory. This is because cortisol will eat away at your hippocampus over time.” So the firing rate of the hippocampus during encoding predicts recall. The volume of the hippocampus predicts behavior. So you have the volume predicting how well you are going to remember and the firing rate predicting how well you are going to remember as well. So when we look at disorders of the brain like Alzheimer’s where you have atrophy of the hippocampus in contrast to other diseases where you have atrophy in parts of the brain that are less crucial you will have a direct effect not only on the firing rate but on this volume. Slide 26 (page 13) So we’re going to look at the frontal lobe a little bit because it is fascinating. So we have so far covered only a very little part of learning, everything else we do in daily life falls into the (inaudible). You guys have an odd little environment here because this is what you do all day – you’re learning new things, you’re memorizing – so you are relating them back. Everyone else has learning and falls that falls into the right of this branch of that diagram, and that covers the rest of the brain. The frontal lobe is very relevant and interacts with the hippocampus very well. Similar to the hippocampus, if you look at certain areas in the frontal lobe you can predict later performance. The idea is top-down information like attention and executive functions interact with the hippocampus. So if you’re a little ADD and your attention isn’t directed 1% of the time – you can make up for not remembering as much. You can make up for hippocampal firing rate and volume by paying extra attention to a task – that is entirely frontally mediated. So if you’re like me and have a extremely small hippocampus – you can make up for it by attending to things more. When you pay more attention you increase your firing rate. If anyone tells you that you can have the same benefit of studying while listening to music – it is not true because you’re attention is divided even if you are not trying to attend to the music. Our brain processes everything – doesn’t matter if you’re trying or not. So if you attend to things better you increase the hippocampal firing rate – you respond to things better. That being said, when you learn things – because of this interaction with the frontal lobe – you want to study the way you will be tested. So if you have a couple drinks before you study, then you might want to consider having a few drinks before you take the test. Not that I’m recommending either of those things. The idea is that the state you study in is directly related to the way you recall that information. There is this beautiful study about a patient with a frontal lobe lesion. They couldn’t figure it because during memory testing the patient did horribly but was doing so well in all other neuropsychiatric tests. They kept bringing him back in, but yet he couldn’t perform well in the memory function test consistently. One day he would the horrible, then horrible again the next day, but the third day his memory function would be perfect. It turns out that every time they were in the same room to do testing the patient did great. This is an example of a frontal lobe lesion that really screwed with this state-test line. The frontal lobe is really responsible for modulating the environment you are in while you’re learning. Student Question: What is about classical music and learning? Answer: This is an interesting situation because it brings up the idea of expertise. This is where the amygdala comes in and it brings us to where I am now with the caudate and the basal ganglia. There were these studies

Brain and Behavior 7 – Learning and Memory that showed that people who listened to classical music while studying increased their firing rates -with these kids with the electrodes. It turns out that most of these kids actually had parents that played classical music for them in utero. It comes down to how you look at this. The argument is that if people grow up in an environment with this as a part of their familiarity it actually becomes something that helps them reference things and so you see this increased firing rate. Student Question: Would this hold true for parents that play punk-rock music in utero? Answer: I would presume so, but I’m not sure what means for development later on (joke). Slide 27 (page 14) So with the Amygdala anything that has that emotional content is found there. Classical music is an example of something that is very emotionally salient with most people. I haven’t quite figured this out yet because when I listen to classical music I fall asleep. However, the amygdala lights up when listening to classical music for most people. Slide 28 (page 14) I want to move a little further on and talk about procedural learning. So how do you ride a bike? Things like riding a bike, tying your shoes, text messaging - this are all basal ganglia dependent. Believe it or not, text messaging on the phone is an example of a straital learning task. What that mean about how the brain works? It means that these are in a dopaminergic system. Procedural learning only works because dopamine is being released while you are doing these things and organizing a motor response. So you do something, many neurons are firing at once, dopamine is being released, the neural connections are reinforced, and viola – you have procedural learning that lasts for time. You have deficits in procedural learning in patients with schizophrenia, and that makes sense because you have dopaminergic and serotinergic effects involved. Slide 42 and some 43 (page 21/22) Ok, I’m going to end with this one. This is the stuff that is important. Of course, I am only going to test you on what we covered in class. Everything that is retained in memory whether it is emotionally salient, whether it is dopaminergic reinforcement, whether it is state-test learning, whether it is the amount of cortisol in your system – all of these things feed into long term potentiation. That what we talk about when we refer to some type of increase in local electrical activity that affects behavior later on. All we talk about when we refer to LTP is some time of massive organization of neurons firing. You can think about it like a symphony. All it is, is an increase in electrical activity. The neat part is, when you ask someone to recall things later you don’t have a gradual increase in electrical activity again. So you have an increase in activity and an increase in accuracy occurs. If you call on someone to do things that they are now an expert on, they don’t have this gradual increase in electrical activity. They go from 0 to high levels immediately. Learning allows you to remove the build up to the electrical activity. That’s about it. Thank you guys.

Brain and Behavior 8: An Introduction to the Neuropharmacology of Cognition Slide 2 Good morning. Today is the last formal lecture that I will give to you guys. The last several lectures will be given by other faculty members. Today is a very large topic. I want to give you an overview into the mechanisms and concerns about how drugs affect cognition, whether positive or negative. The other important thing is that cognition cannot really be teased out in terms of a separate part of the nervous system. We look at it that way, but the drugs I will talk about today will have many neurobehavioral effects and other effects. It’s not that clean to just target only cognition. I think what will be helpful is that I made this lecture somewhat generalized, so you will have a good understanding. No matter what field you go into, the drugs you are prescribing will have effects on neurobehavior, mood, cognition etc. Some say that beta-blockers and hypertensive medications can cause depression. Sometimes patients will get hyper on steroid treatments. So, you really need to be sensitive to what effects your drugs can have on the CNS regardless as to what division of medicine you go into. Slide 3 So first off, a little background on neurotransmitters. Neurotransmitters are important to understand because they are the ligands, and the drugs can work as these ligands as well. The definition of a neurotransmitter is a substance that’s released in response to stimulation of a specific neural pathway and that is sufficient to result in a measurable post synaptic response, electrophysiologic or biochemical. The criteria includes a localizable response to presynaptic terminals (or in some cases to dendrites or somas) in specific neural pathways. The release results in a specific response. If you apply the substance or a similar substance exogenously, you can mimic the response. Our list has really grown in terms of what we consider a neurotransmitter. We also have to consider what is a neurotransmitter and what is a neuromodulator. For example, we primarily think of dopamine as a neurotransmitter, but a key part of its function is as a neuromodulator. So things are fluid definitions. This isn’t a problem as long as you have an idea what underlies it. We are trying to understand a system that is very hard to understand. The nomenclature we apply is kind of arbitrary, and this can change in the future with continued research. Slide 4 We can discuss general classes. For example, amino acid NT like glutamate (primary excitatory NT), GABA (primary inhibitory NT), and glycine. Amine neurotransmitters include acetylcholine, dopamine, norepinephrine, epinephrine, histamine, serotonin. There is also a very large class of peptides. Also, diffusible gases, primarily nitric oxide. This has gotten more attention recently. There are also nucleosides like adenosine. This is how caffeine works in your system. Slide 5 A few definitions. First, transduction is a basic process in molecular cell biology involving the conversion of a signal from outside the cell to a functional change within the cell. This is a very generic definition. We will talk about signal transduction. Ligand is any substance that binds to the receptor, such as either the NT or a drug. Potency talks about the strength of binding to the site. Efficacy is the term used to talk about the biologic effect drug exerts because of the binding. This is usually referring to the clinical effect. Remember things can be very potent and bind to a site and not really do much of a difference in terms of efficacy. Allosteric regulation is something you hear about with a lot of drugs. It is when drugs work at a site nearby, the allosteric site, but not the primary active site. There are some complexes like NMDA that can get quite complicated. One example is memantine, which is a cholinesterase inhibitor that we use for Alzheimers. It is marketed because it has a modulatory effect on nicotinic receptors. There are so many ways you can target a specific problem because there are all complex interactions and pathways that drug companies look at and try to impact. Slide 6 Synaptic transmission is a signal transduction process that begins with the action potential, which leads to the release of the NT from a presynaptic terminal. Then in the postsynaptic membrane you can do a few things to change the cell. You can have an ion-gated receptor, a secondary messenger, a G-protein that activates a secondary messenger, a G protein that activates another receptor, enzymes, transcription factors, genes and gene products. If the normal process of neurotransmitters produce a certain effect, then it is possible that putting drugs in can cause many side effects. So the NT is released and binds to post synaptic receptors and activates them, modifying the electrical and biochemical properties. There can be simple (just an ion channel) or complex (G protein activates secondary messenger which activates a protein, which activates transcription) pathways. Also there are presynaptic receptors that respond to the NT released by the terminal. This is a way to regulate itself. It is feedback. So these autoreceptors, if sensitive to the NT, can be sensitive to the drug. So while the post synaptic receptor is doing one thing, there is also a signal back to the original cell to dampen the neurotransmitter release, synthesis, etc. But this also makes it difficult when you consider how drugs work. There is a limit to selectivity. We will talk about that. A drug or a NT often can’t affect just the post-synaptic receptor. Given that, the clinical response we get is often not easily explained. There are so many mechanisms that could be affected by the same drug.

Brain and Behavior 8: An Introduction to the Neuropharmacology of Cognition Slide 7 There are least least 100 types of receptors. There are many types of receptors, but in general they are classified as ligand gated ion channels or G protein- coupled receptors. This is based on the signal transduction mechanism. The ligand-gated ion channel is something like the nicotinic receptor at the neuromuscular junction. In that case, it is acetylcholine. These channels happen extremely quickly. The channels work better when you want an really rapid response. However, this can even get complicated. For example, the glutamate NMDA receptor is definitely an ion channel but it has a lot of other components to it. The G-protein-coupled receptors are often associated with more complicated functions because they allow for more detail. They often work through second messengers. This is usually a longer-acting response. So neurobehaviorists are often interested in these longer-acting responses. Slide 8 So in this basic schematic of an ion channel receptor, you can appreciate how simple these receptors can be. When you want a rapid response, you want this very simple receptor. Slide 9 G proteins-coupled receptors are much more elaborate. They are called metabotropic receptors because we originally thought they only affected metabolic processes, but they can also affect ion channels. The name just stuck. Whatever binds to the site must trigger a conformational change in the receptor that allows it to interact with its G protein subunit, which allows other things to occur. This can be like modifying the ion channel, interacting with a secondary messenger, and more complicated. Slide 10 Second messengers, such as cAMP and calcium, may serve directly as effectors and directly gate ion channels. Calcium itself can be a second messenger, including in processes like cell death. This can be good in development, but when considering stroke or trauma, calcium is not good. Second messengers are more complicated. They often work through enzymes that phosphorylate or dephosphorylate proteins. This can lead to a dampening of the neurotransmitter system, affect the receptor itself, affect ion channels, or change the synthesis of neurotransmitters. Ultimately, they alter the biochemical state of a cell in a way that is necessary for cell survival. Signal transduction, including the final step of gene expression if it occurs, is critical for cell survival, development, maintenance, and also cell response to stress. That will affect how they respond to drugs as well. Slide 11 The other important area we can target for drugs if we are attempting to affect neurobehavior, including cognition, is at the level of NT recovery and degradation. We know that the neurotransmitter acts at the synapse, but it can’t be left there. It is either recycled or taken back up by transporter proteins. There are also a number of enzymes that can break them down. Individual neurotransmitters have a variety of places that drugs can have an impact. A common example would be the cholinesterase inhibitors. They act by inhibiting the enzyme that breaks down acetylcholine. So a drug can act in any number of places. Many drugs have multiple mechanisms also. Slide 12 So there are a number of ways that drugs can affect cognition. When I say cognition, the neurotransmitters involved don’t just affect cognition, but they have wider effects as well. Just keep this in mind. It is not just a clean function. Certain neurotransmitters are generally associated with certain cognitive functions, but interrelationships between NT systems are complex. Transmitters like glutamate and GABA are widely used throughout the CNS for functions including cognition. You can’t really associate them with any one function because they seem to affect so many. Dopamine (executive function) and acetylcholine (attention and memory) are associated with more discrete functions. However, even in this case, it is generally a group of NT that have to interact to get a function to occur. It is not as simple of saying enhancing acetylcholine will enhance memory. There are too many factors. Sometimes you have to think simplistically to design research, but in life, it is very complex. We also associate certain regions of the brain and networks with certain NT and cognitive functions. We talked about the prefrontal cortex, and we know that dopamine and certain NT are involved in that circuitry. We know that dopamine, glutamate, and acetylcholine are all important for this circuitry. We can look at this through a number of different ways. Drugs have multiple mechanisms, so you have to consider what you are giving your patients and how it can affect the CNS and cognition. This can be good sometimes. You can give a patient who has trouble sleeping a drug to help them sleep. However, if you another person that medication, they will say that they can’t focus at work because it is making them inattentive and sedated. There is a very complex interplay of NTs. They tend to have a checks and balances with each other. If you affect one neurotransmitter system, you will affect other systems like feedback systems and others. So if you give someone a drug to affect serotonin, you have to know that other systems are being affected. This is not just because the drug has multiple mechanisms but also because all of these neurotransmitters are connected. So what you expected can be far from what you actually see in clinical outcome.

Brain and Behavior 8: An Introduction to the Neuropharmacology of Cognition Slide 13 So this slide uses dopamine as an example to show that by intervening with dopamine, you get all sorts of effects on other neurotransmitters like glutamate, norepinephrine, GABA, acetylcholine, and serotonin. All of these neurotransmitters interact with each other in ways necessary for normal function. This can also explain the indirect and direct results of drugs acting on these systems. Slide 14 Here are more basics to keep in mind. It is not just a direct relationship. We used to think that serotonin would just help people that were depressed because they are deficient in serotonin. It is not that simple. What we know now is that in neurobehavioral problems, whether it is depression or manic or whatever, there may be hypoactivity in the system, or there may be hyperactivity in the system. The response to the neurotransmitter is usually more of a U curve, meaning there is an optimal level of neurotransmitter to help the individual function well. You can get similar symptoms from underactive and overactive systems. Now that is true in the case of dopamine 1 receptors when we are talking about working memory. I will show you that example later. You need to know something about the baseline of the system before you add a drug to it. You can get negative effects if you are giving a drug to a person with a fairly normal level of neurotransmitter. You are disrupting what is already in normal balance. However, if you give dopamine to someone whose levels are not normal, say a Parkinson’s patient, you will get a favorable response. If you have somebody who is overactivating a system, say using speed and hyped up their dopaminergic system, then if you give them a dopaminergic agent, you will see a lot of negative side effects. Everything depends on the baseline level of the system and whether it is healthy or diseased and whether the person is hypoactive or hyperactive. Slide 15 So having gone over general neurotransmission principles, this allows you to think in terms of how drugs may act on the system and what areas they might intervene in. So the drug can act like a neurotransmitter - can bind the receptor, initiate a signaling cascade, and trigger second messengers system. The clinical effects that we see however are often the longer term effects on the cell instead of this initial action of the drug acting like a neurotransmitter. Slide 16 So what are the ways that drugs might affect the neurotransmitter system? We will use dopamine as an example here. It is a clean example because there are many drugs that affect dopamine. If you want to affect the neurotransmitter indirectly, you can affect the synthesis of it (like giving the precursor l-dopa to Parkinson’s patients), the release of dopamine (enhance release with amantadine, amphetamine, methylphenidate, other psychostimulants), the reuptake of dopamine (affect transporters like in the case of anti-depressants), or the metabolism (interfere with enzymes that are breaking it down to keep it around longer). Cholinesterase inhibitors allow acetylcholine to stay around longer. You can also directly affect the receptor. Many drugs work through a variety of ways, including different agonists and antagonists. They mimic or interfere with the neurotransmitter at the receptor level. Simple examples of this would be haldol, an old drug that indiscriminately blocks dopamine receptors. Haldol had a nice antipsychotic effect but also unfortunately blocked a lot of things we needed like motor functions etc. Bromocriptine is a dopamine agonist so it acts similarly to dopamine at the receptor. So these are both ways that you can have this primary or initial effect on the neurotransmitter level. Slide 17 You can have an initial fast response (Slide 16). You give a drug and you don’t wait weeks - you see a response very quickly. This is from acute effects on neurotransmitters. You can also have secondary effects over time. There is an effect of drugs on neural plasticity. You can affect the drugs in a good way (therapeutic) or a bad way (seizure disorders). Plasticity is not always good and can result in a disorder. So neural plasticity is the idea of ultimately altering the genetics of the cell. We think this explains a lot of the longer term effects of the drugs we use in neurobehavior. Slide 18 We can talk about the drugs at work at the receptor. They work in a variety of ways. The agonists are going to work like the neurotransmitters at the receptor. They mimic the neurotransmitter. The antagonists don’t have a function on their own really, but they bind to the receptor to interfere with the ligand. Partial agonists at low doses act as mild agonists, but at high doses act not only as mild agonists but also as antagonists. They are also called mixed agonists-antagonists. A number of agents work like way like buprenorphine. They show this range of activity and stress again the importance of dose to the response. Inverse agonists actively have the opposite biological effect of the agonist. So if the agonist opens a channel, the inverse agonist closes it. Very few drugs are in one category, and neurotransmitters themselves are not as simple as to categorize them like that. The important thing to remember is that all drugs exist on a spectrum more or less. Slide 19 I think an important concept to get used to early on is that drugs are advertised to doctors with a hook as a really selective drug for a specific purpose. However, the reality is that most drugs are not that selective. Some are more selective than

Brain and Behavior 8: An Introduction to the Neuropharmacology of Cognition others. But you have to keep in mind that the clinical effect is often due to the fact that the drug has multiple mechanisms. So selectivity isn’t always that good. In neuropsychiatry, some of the most effective drugs we use are quite dirty. You want to avoid negative side effects of course, but don’t buy into the hype that selective is better. It really depends on what you want to accomplish. You can make a really selective drug but then they have to take it for awhile, and the end result can be a number of things. So the result you end up with is not that selective. Slide 20 In SSRIs that are marketed as selective can be very useful for depression and mood disturbances (moodiness, irritability). They can say they are ten times more selective for serotonin than norepinephrine, but the reality is that selectivity is not a pure quality of any of these drugs. They can be marketed as specific, but some of their clinical effects can actually be a result of their impact on other neurotransmitter systems. Slide 21 So lets talk about some specific neurotransmitters and drugs that target them. We think about them in terms of certain aspects of cognitive function, but again they have a range of functions in different parts of neurobehavior. Acetylcholine was the first substance to be identified in the 1950s as a neurotransmitter by Carlsson. The cell bodies are restricted to a rather small number of nuclei, but axons project widely. Acetylcholine has a number of functions, from motor to neurobehavioral functions. We are most interested in its role in neurobehavior. There is a tendency to say that acetylcholine is the memory neurotransmitter, but again it’s not that simple. There are certain aspects of attention, and it affects dopamine and thus prefrontal cortex function. It is a very important point of intervention. Slide 22 There are various ways we can affect acetylcholine. We can affect synthesis and release. The research shows that giving dietary choline doesn’t work very well (say for like Alzheimers patients). What seems to work better clinically is to use the acetylcholinesterase inhibitors. These are the only clinically available drugs that have a significant effect in enhancing the acetylcholine system. This is by blocking the enzyme that breaks it down. It is an indirect way to enhance neurotransmitters. Slide 23 There are a handful of cholinesterase inhibitors available clinically. Let me make another point about FDA usage. You must be aware of the FDA and what it approves and what it does not approve. However, as a physician you will find that you are always using things off-label. If you are good, you will be doing this all the time. By the time that evidence-based medicine and FDA approval catch up with something, then physicians who know what they are doing have already been doing it for years. None of the drugs I use for traumatic brain injury have specific indications for traumatic brain injury. You have to keep this in mind. I think some people get uncomfortable using things off-label, but the bulk of really good medicine is using things off-label. It is driven by clinical experience and research. FDA approval only comes about if the drug company pursues it. Generic drugs are never going to get FDA approval because who cares. Nobody is ever going to make any money off it. So you have to be weary of it. So cholinesterase inhibitors are marketed as Alzheimers drugs, but they really are just drugs that enhance acetylcholine. Traumatic brain injury patients can have problems with acetylcholine, so they can benefit from these drugs. Studies suggest that to a degree people benefit from these drugs when they are not Alzheimers patients. You are going to think of the mechanism of the drug and figure out what the problems are with the patient, and put them together in a rational way. In general, the research literature may be there. Uncontrolled trials or small case studies may be there initially. Large scale clinical trials are extremely expensive, so just because it is not done does not mean its not useful for certain patients. You can justify off-label use. They have even used cholinesterase inhibitors with Autism patients. Slide 24 Neuroprotection is another important part of clinical neurobehavior that we are interested in. Many of the drugs I use with traumatic brain injury patients have been shown to contribute neuroprotection. Neuroprotection agents, if given early on in the stroke or neurodegenerative disorder, can act to alter the course of the disorder beneficially. This is a controversial area, but there are some animal studies that show cholinesterase inhibitors to have a neuroprotective effect. Galantamine may prevent apoptotic cell death by inducing neuroprotection through a mechanism related to activation of nAChRs. So it makes sense that if you have a neurodegenerative disorder, you want to find something that can alter the course of the disease through neuroprotection. This is an incredibly interesting area. A number of drugs that we have may be working this way, and we aren’t even aware of it. Slide 25 Glutamate is another example of an important neurotransmitter for behavioral people. Glutamate is one of the most important excitatory neurotransmitters. It is involved a broad range of cognitive processes. It is very prominent in the cortex and has a close relationship with dopamine. Any dysfunction can result in a variety of cognitive disorders..

Brain and Behavior 8: An Introduction to the Neuropharmacology of Cognition Slide 26 What is interesting about glutamate is the type of receptors we have here. There are two general types of receptors, those working at the ion channel (ionotropic) and those working through G proteins. Well glutamate has both classes of receptors. The ionotropic receptors are the AMPA( alpha –amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid) , kainate and NMDA receptors [N-methyl-D-aspartate]. They are named after the synthetic ligands that activate them. You want to keep these simple. You don’t want a lot of stuff there because you want to it to work quickly. These are fast-acting synapses. G protein-coupled receptors (metabotropic) are very complex and this is important for their function. You wouldn’t see these at fast-acting synapses. Slide 27 Let me talk about NMDA receptors. It is the focus of a lot of research. It is essentially an ion-channel-type receptor. Activation does open an ion channel. What is different here is that there are so many complications to it. It has more permeability to calcium than any other receptor. It also requires a co-agonist binding of glycine in order to effectively activate it. So you have some complexity here. It is voltage-dependent so it is only activated if a certain potential is reached. We think it has a role in neural plasticity and neural toxicity. So this can do both a very desirable effect and very undesirable effect. Slide 28 So this schematic can demonstrate how the NMDA receptor is more complicated than a normal ion channel. It is much more complex. Magnesium involvement is critical to the functioning of this channel. It has to have a co-agonist binding. You are not expected to memory this picture, but understand the complexity. Slide 29 So let me talk about synaptic plasticity as an example of what the role of NMDA receptors are. There is a lot of research here. What we think is going on is that many of these drugs may affect long-term plasticity. The activation of NMDA receptors can be associated with long-term potentiation (LTP) and long-term depression (LTD). These are processes that underlie neural plasticity and are terms that may be familiar. LTP refers to enhancing synaptic transmission and thus improves communication between presynaptic and postsynaptic membranes. It is basically strengthening the signal. LTD is the weakening of the neuronal synapse. It is not necessarily a bad thing. LTP and LTD are in a checks and balance system. It is the balance between LTD and LTP that plays a role in synaptic plasticity. The NMDA receptor plays a significant role here. Now on the other hand, activation of NMDA receptors allows calcium in. Calcium activates a number of necessary proteins, and all of these good things can result. One of the good things is neural plasticity. Slide 30 However, if this process is extreme, if the NMDA receptor is damaged, if the system is dysfunctional, if there is too much glutamate, which can happen in TBI, it can result in an excessive amount of glutamate. Due to this, you can overwhelm the cell and have too much calcium released which can overwhelm the cell and cause cell death. So glutamate in excess ends up acting as a neurotoxin. It is the same receptor type but it just depends on what happens and how it functions in cell death. A lot of research has gone into NMDA receptor antagonists as a possible way of blocking secondary mechanisms of damage. When I talk about TBI and secondary mechanisms of damage, one of the things I talk about is this glutaminergic toxicity. Research into this has had very mixed results. If you get a good antagonist of the NMDA receptor, then you can’t really tolerate it in terms of normal functioning of the cell. Slide 31 It just not so simple as more or less is better. So in the case of NMDA receptor antagonists, you can see that some of the most effective drugs are the moderate, reversible ones. That includes memantine and amantadine. These block NMDA receptors in a more fluid way so they can have therapeutic effects while still allowing normal cell processing to continue. They are middle-of-the-road agents. MK801 was one that did not do well in clinical trials because it did what it did too well. It was too effective at blocking NMDA receptors. There were a lot of side effects and negative effects there. Examples of things that function at this receptor include phenylcyclidine (PCP) with which low doses can mimic some sort of psychiatric or psychotic symptoms. Ketamine has similar effects at low doses. At higher doses, it can act as a dissociative anesthetic. Again, remember that there is a very important dose response curve acting here. Memantine and amantadine are effective because they are moderate and reversible. However, they are also probably dirty and have a lot of side effects. MK801 was great in animal models but people just couldn’t tolerate it in clinical trials. Slide 32 Alzheimers is a good example of hypoactivity and hyperactivity playing a role in disease. There is evidence of hyperactivity of glutamate leading to Alzheimers but also a theory of hypoactivity as well. There is this theory of glutamate toxicity in Alzheimers, which makes perhaps memantine useful. It all matters how you are looking at it. It doesn’t mean anyone is

Brain and Behavior 8: An Introduction to the Neuropharmacology of Cognition right or wrong. Perhaps everyone is right to an extent. So it is most likely that hyperactivity and hypoactivity both play some role here. So you have to figure out how to collectively intervene. Slides 33 I wanted to go over dopamine in more detail especially because of its roles in cognition and interacting with other neurotransmitters. I’ll go through the important things to remember about this. The slides are online and are pretty clear. When I talked about prefrontal cortex, I talked about dopamine. I also talked about dopaminergic agents in TBI. We think that dopamine is very critical to the functioning of the prefrontal cortex. Obviously, it has roles in motor activity etc, but we are very interested in the neurobehavior aspects. Slide 34 Abnormal dopaminergic transmission has been tied to a lot of disorders. It may be the main system disturbed but of course others are disturbed as well. Parkinsons is thought of as a dopamine disorder, but there are clearly other neurotransmitters disturbed. In general, it has been tied to Huntington’s, Tourette’s, TBI, bipolar, schizophrenia, autism etc. It plays a broad role in a number of disorders. Slide 35 Inactivation of dopamine is an example of where we might be able to intervene. There is an enzyme COMT, which is the primary way that dopamine is inactivated in the cortex. What is interesting is that we now know that there is genetic variation. Some people have a more active form of the enzyme, and some people have a less active form of the enzyme. So already this gets back to the baseline state that I talked about. If some people metabolize dopamine faster, they may be more vulnerable to hypodopaminergic disorders. Knowing what the individual’s genotype is could help make designer treatments when targeting enzymes like COMT. Based on that person’s genotype, you may be able to more appropriately pick medications. We are definitely moving in that direction. Slide 36 The receptors are similar to the ones I talked about before. Dopamine is primarily G-protein-linked receptors. There are two main classes, D1 and D2. Slide 37 This slide is to again demonstrate the importance of autoreceptors. These are presynaptically located receptors. They modulate the system. In the case of dopamine, it is thought that these autoreceptors are more sensitive to dopamine than the post-synaptic dopaminergic receptors. So there are all sorts of questions how drugs affect the system based on this. Slide 38 I want to talk about D1 receptors and memory. Slide 39 It is easiest to talk about it here. This is a nice example of a U-shaped dose response curve and how giving a drug, agonist, or antagonist would interact with a person’s baseline state. You can see on the left people who might be hypodopaminergic (Parkinsons, TBI). If they have working memory impairments (which involves dopamine) because dopamine is low, then giving them an agonist will facilitate working memory. Here is the optimum level here in the middle. This is a normal healthy individual in a normal range. They shouldn’t need dopamine. They are already in the optimum range, so giving them the drug could have bad effects for them. There are also people who have hyperactivity like people under a lot of stress and people with psychosis from psychostimulants. Now this person might look distractible and inattentive, just like the person with hypodopaminergic activity. So you have to know what you are doing. Hypodopaminergic and hyperdopaminergic can look the same but if you give an agonist to the latter, they will get worse. They need an antagonist probably. This is very well-known data. It is very generalizable. Slide 40 Here is just a list of dopamine agents, which can work in a variety of places. Parkinson’s also uses COMT inhibitors. Slide 41 I’ll end with a quote I really like by Carlsson.

Brain and Behavior Lecture 9 1 of 5 Schizophrenia Schizophrenia is a biological disorder, not something that happens because your parents were mean to you or that you have a weak constitution, unless you consider bad genes as weak constitution. We need to think of it as a genetic neurodevelopmental disorder. It is very prevalent, occurring in 1 out of every 100 people, across all cultures around the globe. It occurs equally in both genders and as of today we really have no way of stopping or curing it. What is schizophrenia? Schizophrenia is probably one of the most severe mental illnesses that we have. It causes chronic dysfunction when you have it, and its severity waxes and wanes but typically when you have it, it really disrupts your ability to function. It is a bimodal psychotic disorder. Psychosis is really a “lost touch with reality.” The diagnostic criteria of schizophrenia is that you have to have either something out of #1 or something out of #2. #1 is this category called Positive Symptoms, which is the presence of something abnormal. #2 is Negative Symptoms which is the absence of something normal. Positive symptoms include hallucinations (false sensory experiences, involves any of the five senses), delusions (false beliefs), disorganized behavior or speech. Negative symptoms include catatonia or avolition, anhedonia (lack of pleasurable experiences, unable to experience positive feelings) or flat affect (no emotional expressiveness). You also need to have a decline in functioning (i.e. role of a student, role of a mother) or decline in self-care where you stop showering, stop eating, etc. You would have to exhibit all this for at least 6 months to get a diagnosis of schizophrenia. Psychosis Psychosis appears in a lot of different scenarios. It typically occurs in different categories in psychiatry. Schizoaffective disorder is very similar to schizophrenia but there are a lot of emotional aspects like depression. Brief psychotic disorder looks like schizophrenia but resolves in less than six months. In fact, it’s about a month long. There’s also psychosis in mood disorders so people with bipolar disorder (manic depressive disorder) can present with psychotic features particularly during the manic phase (i.e. moving 100 miles/hour, spending a ton of money, being very promiscuous, start having self delusional thoughts about their powers). Someone with major depression can also start having a lot of delusions that become psychotic. It’s usually something called mood congruent when you have psychotic depression. People with dementia (Alzheimer’s, Parkinson’s, vascular dementias) can end up with a psychotic presentation of some nature whether hallucination or delusion because of the pathology of the brain being eaten away at cortex or whatever it could be. You can also get substance-induced psychotic presentations. Delirium for whatever medical condition can look like psychosis. Impact of Schizophrenia Schizophrenia onset occurs around adolescence/early adulthood between the ages of 15-29. When the family comes to terms with it, it usually occurs with some terrible event like the police getting involved and taking the schizophrenic to the ER. That is very frequently how somebody winds up for their first presentation for care in schizophrenia. It’s a top 10 cause of disability worldwide according to the W.H.O. There is high co-morbidity of depression, suicide, and substance abuse. In the 1950’s half the hospital beds in the country housed schizophrenic patient and then in the 1970’s there was this movement where they shut down all the big institutions and sent them to care in the communities, closer to home. It was a nice idea but it wasn’t funded well and for various reasons it fell apart. So now, instead of people being warehoused, they’re on the streets so probably 1/3 of homeless people you see probably have schizophrenia. There’s a massive cost associated with care of these people. History of Schizophrenia Taxonomy Late 1800s/early 1900s it was called Dementia Praecox which literally means “early dementia.” So diagnosticians at the time saw people with manic depression and people with schizophrenia as the same thing until they paid attention to the fact that people with dementia praecox seemed to have cognitive impairment while the manic depressed did not have cognitive impairment. Then they decided that it wasn’t dementia because it wasn’t deteriorating over time like in Alzheimer’s in terms of intellectual capacity. In Alzheimer’s, memory gets worse and a lot of cognitive function seems to go down, too. People with schizophrenia do have impairment but it’s flat impairment because it doesn’t change in time very much. So they stopped calling it dementia and someone came up with the term “schizophrenia.” Schizophrenia literally means “split mind” and this creates confusion with multiple personality disorders, which is a completely different diagnostic category and certainly controversial as to whether that’s a true diagnosis. Natural History of Schizophrenia Onset is usually between 15-29 years during early adulthood. Prodromal phase is when their function starts to slightly decline. Something will happen like they’ll stop getting good grades or stop making friends. There will be a crash and then they’ll get a mix of treatment, getting a little better and then get off treatment and crash again, and so on. But it doesn’t continue to go way down like dementia. Patients Usually Suffer Symptoms for One Year of More Prior to Receiving Treatment Patients usually take one year or two years for symptoms to present. In different studies in the 1990s, earlier studies with small samples show people with less duration of untreated illness. Later larger studies show that some patients can live up to 350 days [note:

Brain and Behavior Lecture 9 2 of 5 Professor said “days” although lecture handouts have “weeks”] living with this disorder without treatment. We’re working hard to intervene earlier but it’s hard because there’s a lot of stigma involved. The socioeconomic factor of schizophrenia is controversial. The Status of Our Understanding of Schizophrenia Schizophrenia is a brain disorder, not because you got beat as a child. There are lots of biochemical systems involved, it’s very complex. There are two journals called Schizophrenia Bulletin and Schizophrenia Research and then there at least three others that are involved in just psychosis. Treatment is palliative and works for 1/3 people who don’t really get symptoms, it doesn’t help in another 1/3, and there’s another 1/3 that’s in between. The newer medications, the antispsychotic medications, is new medication being developed but recently large epidemiological studies done in the US and UK suggest that the new medications that we’ve invested in the last couple of decades really aren’t any better than the older ones that we had in the 1950’s and 1960’s. The key thing they’ve all done is dopamine antagonism. They’re not doing much in terms of treatment efficacy although they’re reducing side effects. Nature and Nurture If you take monozygotic twins, there are about 50% concordance rates. There are numerous biomarkers and one of the articles I have you guys read covers a lot of them. First degree relatives of people with schizophrenia show a lot of the same traits of the disorder which include a lot psychological markers and may be schizotypic--funny little behaviors, exhibiting odd beliefs, whatever it may be. There is certainly a package of subclinical signs and symptoms that you can kind of see in some family members. There’s certainly a lot of evidence for environmental impacts that may bring on the disorder so you may have some sort of genetic predisposition and then some other thing has to happen in the environment to make you express the disease. Some evidence for that is that there seems to be increased risks of being diagnosed for schizophrenia if your mother had some prenatal complication (flu, rubella, pre-eclampsia, STD, etc). The mechanism behind that is not clear but those have been pieces that have been determined by epidemiological studies. Something very new is if they have used marijuana. Smoking marijuana actually enhances the possibility of you being truly psychotic, it seems to be bringing on the diagnosis sooner. Here are good examples of environmental factors: If you are born to a schizophrenic mother but get adopted into another family, your risk is much lower in having the disease. “Expressed emotion” is another environmental thing where patients who have family members who are high in expressed emotion are more likely to be diagnosed. That means in the household there’s a lot more expressiveness of particularly negative emotions. But that’s different than being abused as a child. It’s not that simple. The unhappy environment is strongly correlated with having more episodes over time. Pathogenesis of Schizophrenia and Related Psychotic Disorders It’s a complicated pathway to getting diagnosed. There’s initially a set of genes (and there have been multiple genes identified) that put people at risk for the disorder. Cells are functioning in a funky way because of how they’re programmed which results in the brain not functioning quite right. Brain connectivity is messed up and some parts just aren’t as effective as they should be and on the outside you get psychotic disturbances. Symptoms as a guide for chasing down the pathophysiology: Hallucinations Try to think of how these symptoms can lead to schizophrenia. One of the big hallmarks is hallucinations which is having sensory experiences giving you inaccurate information. There’s definitely some evidence that it could be due to having an overactive or dysfunctional sensory cortex. For example, when you’re hearing voices maybe your auditory cortex in your temporary lobe is overactive or dysfunctional. There are definitely fMRI studies that have suggested that. There’s also evidence that when patients hear voices they’re “subvocalizing.” There’s a little recording that correspond to the voices in their head so some kind of physiological mechanism is occurring where they’re actually speaking what they think they’re hearing. What about the fact that these patients are all hearing similar things? They hear one or multiple voices but they’re frequent and threatening although sometimes the voices are nice. Some voices are muttering or whispering and they can’t tell what they are. Often what happens is that the voice is a running commentary on everything they’re doing. So if I’m sitting here giving this lecture then there’s a voice telling that: I’m making no sense and nobody out there understands me and in fact they hate me and one of you probably has a gun and about ready to shoot me…this really does happen that someone with schizophrenia has a brain that works like that. Symptoms as a guide for chasing down pathophsyiology: Delusions Classic delusions in schizophrenia are: the FBI/aliens/neighbors are after me or I am in psychic contact with God/The Pope/name your celebrity or that they ARE the celebrity. In Christian cultures you’ll have people believe that they’re Jesus and in Islamic cultures they will believe that they are Muhammad. Another common delusion is that people can hear their thoughts. The themes themselves are tied to culture in terms of the specifics but the paranoid nature of them is common across all cultures. Symptoms as a guide for chasing down pathophsyiology: Disorganized/Negative Symptoms Inappropriate affect: giggling while talking about recent death or parent or crying when hearing that your family has plans to go on vacation. This is expressed emotion when the context doesn’t make any sense. Another disorganized symptom is catatonia: no talking, not bathing, hardly eating, hardly moving at all. Disorganized speech includes tangentiality, speaking off topic, and something called word salad where you’ll hear word after word that just aren’t connected nor grammatically accurate. Derailment is a less severe form of that: “My dog has a red collar from Petsmart and it’s only used on days the comic book in the bottom of that stack is my brother’s.” So their minds just completely shift mid-sentence. There’s a real disorganization to their language processing there. What common

Brain and Behavior Lecture 9 3 of 5 mechanism could underlie the above kinds of things along with seeing like dead bodies lying around one’s house (hallucinations) or believing that the CIA is implanting surveillance device in your brain (delusions)? The chase is over: the pathology is probably not localized, but is SYSTEMIC We don’t know but it’s not a local problem or a particular problem, it’s systemic in the brain to have a widespread effect. That helps us explain why patients will have different presentations. Not everybody has delusions or hallucinations who are schizophrenic. Not everybody has negative symptoms of schizophrenia. It’s a complete mix of everything. The medications impact dopamine which is a neurotransmitter system which effects multiple systems in the brain itself. The cognitive impairment is across the board. They aren’t just bad at verbal or visual stuff, they’re bad at everything when it comes to intellectual functioning. Partial Summary of Known Loci of Pathology This is part of a review paper that sums up everything that we think is wrong with schizophrenia and some authors mapped out everywhere in the brain that seems to have something to do with schizophrenia. It’s massive and a crazy endeavor to try to comprehend all of these things. Dopamine Hypothesis of Schizophrenia Antipsychotics seems to work best because they are antagonists at D2 receptors. When you have dopamine agonists in the system seems to exhibit psychotic symptoms. So when people take levadopa for Parkinson’s disease and up their doses, they start to hallucinate. Amphetamines also result in psychotic behavior. But it’s not that simple to say that schizophrenics have too much dopamine floating around in their brain. We know that they synapse too much in the basal ganglia, where D2 receptors are most dense. But they also seem to have not enough dopamine in the prefrontal cortex, where D1 receptors are. It’s still not as simple as to say that there’s too much here and not enough there because at resting state both those areas seem to be functioning too low. Dopamine Hypothesis of Schizophrenia (2) This is from a study which evaluated how effective different antipsychotics work at treating the disorder. There is old antipsychotics that are called typicals or first generation and the new ones are atypicals or second generation. This study used one of each and they showed how much binding occurred in the striatum (basal ganglia) versus the temporal cortex. In the cortex, both of the drugs occupied very well. In striatum, the new drug occupied less well than the old one. That means that both drugs are good at doing something in the cortex and in striatum the new drug is efficacious in terms of sticking in there but that actually is good because the old drugs caused lots of extra side effects like shaking and dyskinesia since it’s messing around in the basal ganglia. Both old and new drugs are pretty equally good at treating the symptoms. This is not a curable disease. The drugs can’t stop all of the symptoms. They stop some of the symptoms, particularly the positive symptoms, but they do nothing really for the negative symptoms and cognitive impairment. Dopamine is a piece of the puzzle. Brief History of Antipsychotic Medication Skipped. Hospitalization for Exacerbation of Schizophrenia in the CATIE study Old and new drugs are about the same in terms of how well they worked. Perphanizine is the old drug, the rest are new drugs. Patients ended up back in the hospital at about equal measure on whatever drug they were on. It was slightly lower in olanzapine but it has the highest side effect profile: overweight and diabetes. So it turns out that old and new drugs really aren’t that different. Comparison of Dopamine in Cortico-Striatal-Thalamo-Cortical Loops Schizophrenia probably has more to do with dorsal lateral prefrontal cortex and the whole dorsal circuits. We see three of them here: sensory/motor functioning, dorsal prefrontal cortex, and the orbital circuit. The circuit is from cortex down to the basal ganglia to the thalamus. Dopamine probably affects the dorsal prefrontal circuit more than the others. The black line represents how much dopamine is relevant to that circuit and the circles are bigger for the dorsal versus the sensory/motor. There are big circles in the orbital but there’s all this extra stuff from the amygdale and the limbic system that helps to regulate the circuit better which dorsal prefrontal doesn’t have. So the dorsal prefrontal system is most vulnerable to dopaminergic instability. Neurocognitive Deficits in Schizophrenia: Current Treatment Target Antipsychotics are good at alleviating positive symptoms. Cognitive Dysfunction and Adaptive Dysfunction Cognitive deficits are the new targets of how we need to target the development of drugs to help patients. People who get this disorder don’t start out stupid in life. They actually can be pretty good students and as they enter that prodromal zone, then their school functioning and IQ starts to lower. The amount of cognitive impairments somebody has really predetermines how their life is going to be. It’s not how bad their hallucinations or delusions are but it’s how bad their cognitive impairments are. Again, understand that medications do very little right now. Imaging Structure and Morphology

Brain and Behavior Lecture 9 4 of 5 Approach to looking at what part of the brain is affected. Brain volume changes in first-episode schizophrenia: a 1 year follow-up study This was done on patients who have never been exposed to manic medications. They were scanned, had an MRI when they first presented for treatment, and then they were scanned a year later. Their brain volumes was measured, total amounts of gray and white matter. And they partitioned up the gray matter and talked about how big the lateral ventricles were. The ventricle size was hugely larger after a year and the gray matter was smaller. Change of Whole Brain Gray Matter Volume Patients who were on olanzapine, one of the newer drugs, had less loss than people on the old drug, haloperidol. So it’s somewhat been accepted that the old drugs had something to do with losing brain volume. Commentary of Brain Volumetrics In addition to gray matter loss, it might be more specific to frontal lobes and the temporal lobes (specifically hippocampus). But this is not diagnostic. You can scan for a tumor that can cause psychotic symptoms. Gray matter loss is evidence that this is a neurodegenerative disease. Loss of gray matter is not really correlated with getting worse cognitively. People are bad cognitively but they don’t get worse over time although they are losing some brain. It’s also unclear if medication is having an impact on that. Diffusion Tensor Imaging People are looking at white matter in different ways. Rather than just looking at the volume of white matter, they’re also looking at the function using diffusion tensor imaging. Diffusion tensor imaging gives you the capacity to find out how organized white matter tracts are in the brain, if water can get through them the way they’re supposed to. Some studies coming out are showing that there are some abnormalities in white matter MR Spectroscopic Imaging Skipped. 9.4 Tesla at UIC With this we can actually follow molecules around like sodium, potassium, calcium, etc. Whereas the imaging we’re using right now, we’re just using the magnetic properties of water. The clinical neuropsychology approach to assessing treatment effects on cognition It’s about assessing how the brain works. It’s a bunch of standardized tests and tells you what part of the brain is not working well. The idea is to test them out before medication and then after to see if there are any changes. How bad is cognitive impairment? You’ll see two distributions. This is a test of generation functioning and RBANS which assesses a number of things like attention, memory, language functioning. Healthy individuals have an average of about 92. Schizophrenia patients are much lower, functioning the mildly impaired to severely impaired range. Improvement in Cognitive Test Performance Here’s how well drugs fix that. This is across cognitive domains. These are not really impressive and these studies have been done without great design in terms of accounting for practice effects (doing that test twice), adverse comparator effects (taking new drug and comparing with old drug, not really a fair comparison), or switching somebody from that drug to a new drug (different dosing where it might not mean that they’re doing well, just that they’re released from the sedation). z-Score vs. Assessment Time study These are four cognitive domains. Health controls are the circles, patients are the triangles. Everybody was measured at a baseline point so for the patients it was when they were first presented for treatment, they’ve never been on medication. They are doing worse than the controls on everything. Over time, you see that the controls are doing better on everything—there’s the practice effect. Patients have a practice effect on some of these things too, so you don’t know if they’re improving entirely on medications. A complex neuropathology: Thalamo-Prefrontal Circuitry Abnormalities in Schizophrenia This just shows you how much research is going on and what genes are associated with which abnormalities. It’s very complicated. From molecular missteps to psychotic symptoms The brain continues to mature until ages 15-29 and the last place to mature is the prefrontal cortex. So if in that developmental process, something clicks in the genetic code or something happens in the environment that makes things go wrong, that’s when you might get psychotic symptoms.

Brain and Behavior Lecture 9 5 of 5 Laboratory Environment for Eye Movement Studies Professor went through the next few slides quickly and went back and forth on them We’re doing a lot of eye movement studies here at UIC to get cognition. Eye movement studies tap into many parts of the brain from the frontal part, back part, brainstem, cerebellum, so on. Just looking at their eye movements, saccades, first episode (before treatment) patients are fast relative to controls. But after treatment, they slow down. fMRI Study of Visually-Guided Saccades in First Episode Schizophrenia: Pre-treatment This does the same thing. Many parts of the brain in the controls lighten up and they should because they control these movements. In patients these areas aren’t lighting up. These are controlled areas that are exerting control lower down in the brainstem. For patients’ there is no control on these reflexive variants and that’s why their saccades are faster. There’s not as much top down control. Oculomotor Delayed-Response Task Skipped. fMRI + Patients show inaccurate saccade There’s also evidence that antipsychotics are making memory worse. When patients are asked to remember something before treatment, they are pretty good although it gets worse for longer periods of time. They’re worst at 8 seconds. But after they treat them (open triangles), they’re worse compared to baseline. Dorsal prefrontal cortex is in charge of this working memory. Dorsal prefrontal cortex circuit is really key to understanding why treatment is NOT helpful for cognitive impairment and in fact might be doing damage. Inverted U-Shaped Relationship Between D1 Receptor Activation in Prefrontal Cortex and Working Memory D1 receptors in the prefrontal cortex mediate working memory. There is a sweet spot for optimum normal range. Too little and too much performs poorly. Academia and Industry This is the thought pattern that people like me are going through for this disorder. I think we are stuck here at “measurement tools.”

Brain and Behavior Lecture #10 The Limbic System Readers Note: As you know if you went to this class the professor had a really soft voice and it was hard to hear her at times, I did the best that I could given her vocal abilities. In addition she had trouble with the sound system. She also just for the most part read straight off the slides. I am Ellen Herberner from the department of Psychiatry at UIC. I am going to be talking about the Limbic System. Have you guys covered the Limbic system yet and what parts of it? Answer: yes all of it. I am only going to cover certain parts of it, because I am going to assume that others will cover the rest of it. I am focusing more on emotional components and how that relates to psychiatric disorders. The first thing I want to point out is that people think amygdala is the sensor of all emotional experience, that’s not the case. As an example this is a Meta analysis of studies using fMRI to look at what parts of the brain are active during certain emotions. What you see here is that you certainly get parts of the amydala activation, but you also get a lot of activation in other regions; orbital frontal cortex, insula. You get different activation of different parts when you have different emotions, you do not need to memorize every emotion and its activation, this is just to give you a sense that its not just one regions its many. Emotional face perception is involved with the amygdala; goal related activity is related to a lot more brain areas, as you already know from the article I assigned. First I want to give you some sense about what parts of the brain I am talking about, the amydala is not really shown here but it would be in this region here. Retro-splenium cortex which is involved in memory functioning and geographical memory functioning is found here, that maybe because its associated with many other regions like the fusiform gyrus, the amgdala and hippocampus as well as temporal visual regions. The insula found here is kind of on the inside between the temporal pole and the orbital frontal cortex where they meet, it has been associated with disgust and internally generated emotions like frustration or feeling guilty (intrinsically generated not something external). There are a number of different parts of the anterior prefrontal cortex; the orbital prefrontal cortex here (right next to the eyes shown here in green), it’s a convergence zone for a lot of accessory motor association information and limbic regions. It’s involved in the reward value in stimulation, and reward centers for payoffs when you learn. The ventromedial prefrontal cortex, here in the red, is involved in reward stimulation in autobiographical memory. At this point specific roles for these regions are not really clear people are studying them and get different involvements than other studies. The temporal pole shown here is the end of the ventral stream of vision so it has very complicated emotional social meaning, and has some auditory and olfactory autobiographical memories (visual emotional autobiographical memory. Finally the anterior cingulate is typically considered to be involved in monitoring or evaluating decision making and so it tells you what to do instead and can facilitate attention. These are rather broad ideas about what these sections do, and over time we will be able to refine and get to understand them better. The parts I am going to be focusing on is going to be the amygdala the temporal poles and these parts of the prefrontal cortex, because you can see they are very strongly connected to each other. You will get a hippocampus lecture from someone else. There is such a strong association between the amydala and the temporal pole and these medial prefrontal cortex region that have a lot to do with emotional decision making and evaluating different stimuli. First to start with the amydala, at this point people believe it’s responsive to different emotional intensity like arousal and extreme valence but not really positive but low arousal. Picture a nice landscape, its nice, but its not going to get the amygdela going. It influences other brain regions such as the hippocampus and prefrontal cortex. What I want to talk about is its effects on different kinds of learning, specifically episodic memory. McGaugh, Cahill and his colleagues at UC Irvine had human subjects watch negative emotional films and neutral films during a PET scan, and rated how emotional each film was. Three weeks later they called the subjects and asked them to recall as many films as they could, what they found was that the subjects could recall the emotional films a lot better than the neutral films. This makes intuitive sense; people remember things that are more emotional. What they did find is that the number emotional films recalled was correlated with the activity of the amydala at the time of film viewing. The higher the amydala activity during the initial screening the better recall of that film. This was not true to the neutral film, so it’s only specific to emotional experiences. Through animal studies they were able to deduce how this happened. Basically activity in response to emotional stimuli initiates noradrenergic activity, which starts glucocorticoid activity, which influences hippocampal function and impact long term memory. Medications such as Beta-adrenergic blockers (propanalol) selectively impair memory for emotional stimuli. Another aspect of the amydala is learning stimulus-reward associations, these are essential sometimes for survival, if you see a tiger you run because the stimulus tells you to run. Specifically the amygdela is the location where this learning occurs, in contrast to episodic learning where the amygdala influences hippocampus learning, associative learning changes happen within the structure. I will tell you about a few studies before I get to the clinicals.

Brain and Behavior Lecture #10 The Limbic System This study published in Nature Neuroscience in 2004, had two tasks; looking at a target face and a non-target face. These were sometimes paired with a scent and sometimes they were not, some negative smells. Two neutral faces (CS+) were repetitively paired with two different unpleasant odors (UCS). One-half of all CS+ presentations were coupled to the UCS, resulting in paired (CS+p) and unpaired (CS+u) trials. Immediately after conditioning, subjects underwent UCS inflation, whereby the Tgt UCS (at increased odor intensity) and nTgt UCS (at baseline intensity) were presented in the absence of the CS+, in order to enhance Tgt UCS aversiveness. What they found was that the region of integrating was the orbital frontal cortex and the amygdala. During extinction it’s interesting that you also get orbital frontal cortex and amygdala but different aspects of it. It’s not changing the initial learning, (she umms and pauses then just goes on). LTP is a process in where calcium enters the cell via NMDA receptors; basically it depends on gene transcription. Through voltage-gated calcium channels. This can help us to intervene with anxiety disorders; there are a number of different anxiety disorders that are based on this type of learning. For example panic disorder, 5% of the population has it, it involves recurrent and unexpected attacks that last for 10-15 minuets then just go away. Symptoms are distressing, SOB, heart palpitations, chest pains, chills, nauseas, trembling, fear of dying and numbness etc. People having this for the first time think they are having a heart attack until you see them in the ER, and there is nothing wrong with them. The problem is the sudden onset, they were walking down the street and all of a sudden this happened. We believe it is probably because there are some cues in the environment that they are not aware of that triggers this. If people are having these symptoms in response to a stressful situation, then its not panic disorder its something else. This can happen several times a day, a few times a month variable onset. This is based on a conditioning model. Any questions? Ok Social anxiety disorder is a lot more common, it’s a persistent fear of showing anxiety symptoms when exposed to unfamiliar situations or people and potential scrutiny, which result in humiliation and avoidance. This is different from shyness, because it gets in the way of your life. Post traumatic stress disorder, with war veterans this has been increasing, it’s a stress disorder induced by witnessing or experiencing a traumatic event in which the person feels a threat to his or her life is in danger or life of others. They can re-experience the traumatic event in their dreams and have nightmares. They engage in avoidance of stimuli associated with the initial trauma such as impaired recall of events related to the trauma, anhedonia, restricted affect. Also they have increased autonomic reactivity; hypervigilance, irritability, insomnia and heightened startle response. This follows the conditioned model because they experience a response to a condition stimulus. Finally Specific phobias which are to specific objects or situations, there are a number of types; animal types, natural environments (like fear of heights), blood injection, and situational (like elevators). People are not really phobic until it gets in the way of your life, like if you’re scared of a dog that’s not a phobia, but if you can go to work because you see dogs in the street then that’s a phobia. You can see how the idea of conditioning apply to these anxiety disorders, some of the treatments that people have looked at is extinction. Psychology uses exposure to induce extinction. Where people are shown the stimulus that is originally paired with a negative emotional response, and with positive feedback and help we can help people un-pair the stimulus to the response. There is also a mechanism behind extinction you can use medication that work on NMDA receptors, you can give a patient an NMDA antagonist that blocks the receptor an illicit extinction, or you can actually give them a partial NMDA agonist that helps facilitate extinction. This only works as your going through a behavioral change, you have to put them in these situations and give them the drug, not just give them the drug. Exposure is the first line of many types of therapies that are used for these different disorders, over time with more exposure you get less negative behavior and eventually you get extinction. There is another way you can solve this, as people are recalling things from the past, as its retrieved it is becoming more unstable and requires reconsolidation before it can be restored. So as they are reconsolidating you can administer NMDA receptor antagonist, beta receptor antagonists, Ca blockers all these different things can alter memory reconsolidation. Question: inaudible Well there is a study with an acute trauma victim that is given an antagonist 6 hours post trauma, and continues for 10 days everyday. The victim had less sever symptoms than regular victims. That’s kinda my summary about the amydala and the points that we covered. We are going to move on and speak about the orbital frontal cortex. This is a study they paired a stimulus to a positive smell, like pizza or chocolate and this again paired only half the time. Then you have stimulus that is never paired with smell. During these pairing you get these activations from the orbital frontal cortex and the amgdala, and then you take subjects out of the scanner and have them eat as much pizza as they want, then put them back in the scanner. So now they no longer want the pizza and you are looking at how did that change given that your internal context has been modified, but do you want chocolate? Yes. Results is satiation for pizza, and therefore devaluation of the Target CS+ smell, however satiation for Target CS+ does not effect response to nonTarget CS+ chocolate. The amydala activity for pizza goes down, but is unchanged for the chocolate. The body is able to modulate its attention and how much it needs things on the basis of how much it has, which is very important. One of the illness associated with this is Obsessive Compulsive Disorder OCD, if you think of it as reversal learning, first you learn that one thins is valuable, then the next thing is that you learn that pizza is not valuable. You have to decide what is important at that moment, and be able to change that.

Brain and Behavior Lecture #10 The Limbic System The switching is the key, and you can assess orbital frontal cortex while a person is switching. Shown here is an experiment that compares FMRI form healthy vs. OCD patients during shifting indicates greater activity in orbital frontal cortex and in the insula in normal individuals that OCD patients. Any questions on that? So basically orbital frontal cortex is involved in indicating the value of the stimuli and modulating its value based on changes in internal and external environment, so the reward contingencies. This is impaired in OCD. Anterior prefrontal cortex, also known as rostral or ventral prefrontal cortex or Broadmens area 10, you can see how it’s very confusing in the literature because you can refer to it in many ways. It is the largest identifiable region of the Prefrontal cortex, and usually when it’s injured it’s hard to tell what is wrong, the injury is neuropsychologically and neurologically silent, they do not cause impairments easily elicited during the standard neurological or neuropsychological consultation. A good example of this was shown in the case of EVR. EVR had surgical removal of a large bilateral frontal meningioma, and was doing quite well. He lost his job, went bankrupt and divorced his wife, while maintaining superior IQ. What researchers found was that he had trouble with perspective memory; it was as if he forgot to remember short- and intermediate-term goals. To understand what that means this is a description from Paul Vergus that I found pretty good. Multi-tasking and prospective memory requirements involve many tasks and require interleaving, you need to only do one task at one time, and targets are self determined no immediate feedback. Sounds pretty complicated but we do this everyday, like preparing a dinner, there are many dishes you have to prepare things in order. Physical constraints in the kitchen make you only do one thing at a time. There are interruptions like early guests arrival, and you need to return to task without someone telling you to. There is no right or wrong way to serve the meal, and mistakes like forgetting an ingredient are not directly signaled at the time they occur. This is quite complex and is not reflected in an IQ test. Shallice and Burgess devised an experiment with a shopping task utilizing subjects with these kinds of impairments, multi tasking. They go into the same store more than once, they did not complete the tasks that they had previously learnt that they needed to do, and they are very forgetful. They are not able to keep their priorities straight. There are some emotional parts to it, you have to prioritize which is emotional, and you have to have an idea of goals. It’s not completely an emotional task, but emotion plays a role. Any questions? Insula, this is an area that has connections with tons of other areas, it is strongly related to everything and a lot of information is converging there. The insular cortex is involved in the processing of visceral sensory, vestibular function, attention, pain, emotion, verbal, motor, and musical information in addition to gustatory, olfactory, visual, auditory and tactile data. What does it do? It has all this information going in, therefore its hard to say what it does in particular. A number of studies suggest that emotions are recalled; recall-generated sadness had greater activity in the anterior insular cortex. What is interesting is when you compare recall versus visual recall, when you are recalling a past emotion you get the greatest insular activity rather than when you see an image that helps you recall. When its internally generated the insula is involved more so than when you have externally generated recall. We see that the insula has decreased activity when you are depressed, something called decreased rumination. In panic disorder, if you have lactate induced panic then we see increased insula activity along with increased temporal activity. Lactate induced means that it was induced by internal aspects. Schizophrenia there is a lot of data about decreased insula volume, and suggests that it has an effect in auditory and visual hallucinations in individuals with schizophrenia. Again this is internally generated. Temporal pole, is closely related with the amygdala and the prefrontal cortex, it’s often described as the association cortex because of its inner connections. It has been suggested that its part of the system that modulates visceral emotional functions in response to emotionally external perceptual stimuli, also it’s active with emotions that are perceived or imagined (so internal emotions).

Based on theoretical hypotheses, damage to the TP should cause a decoupling of high-level perception with visceral emotional experience. Several studies have reports interesting suggestions, one study found that right temporal lobectomy lost all emotional attachments to his family members, although he could recognize them. It has also been reported that a patient with a large right TP lesion extending posterior in the fusiform gyrus believed that her family had been replaced by imposters, possibly due to a decoupling between neural face recognition systems and emotion systems. Also monkeys with bilateral TP ablations lose normal emotional attachments to their infants and to peer monkeys. You are more likely to encounter temporal pole atrophy due to temporal variant of temporal pole dementia. For example a study of patient JT, JT changed from an extraverted, highly empathic individual to a somewhat introverted and cold individual, lacking in empathy. She lost her social dominance and became neurotic and demanding. She had indiscriminate eating behaviors; she would eat large quantities of floral table decorations and large quantities of butter, oil and jam by themselves.

Brain and Behavior Lecture #10 The Limbic System This is a table comparing monkeys to humans with temporal variants of frontal temporal dementia; they show very similar symptoms especially in social settings and having hyper sexuality and loss of extraversion. This is the final summary, the understanding of specific roles of different regions of limbic system still developing, and it’s clear that rarely is only one aspect of the system involved in any particular task. Our understanding is most advanced in terms of functions of the amygdala in emotional learning, and has supported the development of some useful clinical interventions particularly for anxiety disorders. As we increase our understanding of mechanisms underlying the influence of specific brain regions on functional abnormalities this helps us in ways we can intervene. As we begin to understand what the mechanisms are we can come up with ways to intervene such as in conditioning. Changes in assessment of value, goal related those kinds of things which may be important in particular illnesses such as schizophrenia where they have a decreases sense of goal related behavior. Any questions?

Brain and Behavior 11: The Neuropsychological Evaluation Good morning. My name is Dr. Neil Pliskin. I am the director of neuropsychology. I am here to talk to you about neuropsychological assessment. I am often asked if you are going to be asked about all of these tests on the exam. The answer is no. Today’s talk is about when you have those patients who have MRIs that say scattered, periventricular, white matter abnormalities of unknown significance and clinical correlation suggested. So you are looking at the clinical correlation part of it. What I want to do today is talk to you about what the neuropsychological evaluation consists of. The coordinators of this course thought it was important for you to know what the neuropsychological evaluation is and when to consider it. I am a clinical psychologist. I have specialty training in the neurosciences. So that means that I got my PhD, and I had to do 3 more years to learn how to diagnose people with known or suspected neurosystem dysfunctions with both paper/pencil and computer evaluations. Neuropsychologists see a huge range of people, from the age of 3 up. Most of what I do is evaluate and, to some extent, treat patients who have suffered a behavioral or emotional disruption as a result of damage to their CNS. Now I am not talking about a mini-mental state exam. Physicians and others consult with neuropsychologists on a wide range of patients, including those dealing with stroke, dementia, head trauma, ADHD, learning disability, workplace accidents, toxic exposures, known conditions, and medical issues (in which questions arise about what their cognitive status is and what we can do to help them). Ten years ago, when I would talk to physicians, they would say, why do I send my patient to you for 6 hours of testing when they have an early state of dementia because in a year or so, I’m going to know anyway. Why should I put my patient through this? If you look at the drug development and studies in the last decade, you will see that cognition is increasingly recognized as an important outcome and endpoint in treatment and quality of life assessments of people who have had insults to their CNS. Finally people figured out that if you can’t learn and remember or you can’t figure out how to use the coffee pot, then you may have a decreased quality of life. So drugs have been developed, cognitive-enhancing agents (especially for patients in the early stage of dementia), that have been purported to slow the rate of cognitive decline. As a result, there has been an increased emphasis on early detection and diagnosis of patients with dementia. Also, I evaluate patients who these lines of dementia and abnormality have become extremely blurred. An example is a 43-year-old female who is stopped at a stop sign and has someone slam into her from behind. She has a momentary alteration of consciousness and confusion, but by the time the ambulance comes, she is alert. The policeman asks her if she wants to go to the hospital. She says either no or she goes to the hospital. So even if she goes to the hospital, she is evaluated for acute bleeds and if there aren’t any, are declared to have a concussion and discharged home. The doctor will just tell her she may be sore for a few days, she should take Tylenol, and she should call her family doctor. Well it turns out that some patients actually who have these mild injuries do in fact have changes in their thinking abilities. So she goes back to work in 2 days as a book-keeper and tax time comes. So she has decreased ability to retrieve information and has slowed thinking, so she starts to make mistakes. She is in trouble with her boss, starts to believe she may have brain damage, and she becomes depressed and disabled as a result of this. So she is having an emotional problem as a result of this acceleration/deceleration head injury. So the neuropsychologist can help you figure out what results are based in direct dysfunction of the CNS and what results are more in reaction to the case. So this evaluation that I am talking about is portable. It is done at the bedside. It is done in the outpatient lab. This is what I want you to remember. This is how a neuropsychological evaluation goes and how it is different from a simple bedside evaluation. It is objectively scored, standardized, valid, and reliable. Here is what I mean. If my 43-year-old patient is referred to me, then I give her tests that measure memory, thinking speed, and problem solving skills. I am going to give those instructions during the test exactly the same way each and every time. That is because that’s how the tests were given to hundreds of individuals who are healthy and did not have any psychiatric or neurological issues. By sticking to this script and giving these tests in a standard way, it allows me to take my 43-year-old with 16 years of education and compare her performance with other patients in their 40s with 16 years of education. If you have these subtle or even not so subtle cognitive deficits in your patients, you can compare their performance with others so that you can declare something like, ‘her performance is below average.’ This is not subjective. It is a quantitative process in that it is given in a standard way. It is often however, qualitative. You spend 5 hours with them in a room, and you can see how they perform on the test so it is in this sense qualitative. Let’s talk about other types of patients of mine. One individual, who suffers from depression, in a compulsive moment rams her car into a tree. This happened two years ago. She is referred because over the last two years, she has had changes in her memory that has affected her job performance. Does she have a problem that is situated in the CNS as a result of the TBI? Or is she depressed and that is her basis for cognitive impairment? If she injured her back in the accident, and now at night she is awoken by pain, then can her cognitive deficits be from sleep deprivation? She is taking vicodin to treat her pain and xanax for her anxiety (about having cognitive impairment), and are these medications the reason for her complaints? How do you sort this out in 30 minutes? So you can try to cut down on her medications to see if it makes a difference, but then they won’t be able to sleep because of the pain. Maybe the real problem is depression, and because

Brain and Behavior 11: The Neuropsychological Evaluation they are depressed, they become hyper-aware of nuances in their body and pay too much attention to how they think they are doing. They become distracted and can’t perform well. This is where neuropsychologists are useful because we are both mental health professionals and clinical neuroscientists. As you are going to see when I show you these tests, they are highly biased. If you were not born or educated in the US or English is not your first language, you will have more difficulty performing these tests. That is why every PhD clinical psychologist is not a neuropsychologist. In 49 states of the US, you get licensed as a clinical psychologist. There is no licensing for neuropsychology beyond board-certification, which is voluntary. So any psychologist can use neuropsychological tests. You need to be trained to figure out how to diagnose cognitive impairment. It is a statistical process. So why do you consult a neuropsychologist? These are some of the more common reasons. Does my person really have a dementia? Are they having cognitive problems after a TBI? What strengths and weaknesses does my patient with multiple sclerosis have?...do these work with the kind of work they do?...what accommodations do they need? A patient with new onset epilepsy and cognitive impairment that is now stable on anti-convulsive medications…you want a baseline cognitive assessment so that when the patient comes back 3 months later, you can see how they are doing in comparison to baseline. Usually when I am called to the bedside (20% of what I do), I am asked, ‘Can this person live independently?’ Can this person operate a car? Do they need to be supervised? Does their work or school need to be modified? Because they have an arterio-venous malformation and they have refused the embolization treatment because they want to go back to work, are they making an informed cognitive decision? Do they have the ability to make an informed cognitive decision? So this kind of evaluation provides you with quantitative back-up to make these calls. Let me give you a quick tour of this. When we talk about a neuropsychological evaluation, we are talking about a broad range of abilities. Because I am also a mental health professional, personality and emotional functions is a core part of the evaluation. So here is a common scenario. A patient will become aggravated because they say, ‘We have never met before! And you think that you can tell me that I am no longer safe to operate a car? You are telling me that I have suffered a decline in my thinking abilities? We have never met before. How would you know that?’ This is a legitimate question. To lose one’s ability to operate a car is to lose one’s independence. So family members will be telling you there are dents on the car and this person isn’t fit to drive, and the patient is talking fine and acting fine. This is where the neuropsychological evaluation is good to help you make this call. Even though we have only met the patient one time, we have the ability to estimate their pre-morbid capabilities. In nursing homes, you will see very deteriorated patients who can’t recognize family members but can carry a normal (albeit content-free) social conversation. Their word usage is intact because verbal abilities are the most resistant to acute brain changes (unless of course you have a stroke or a lesion in the verbal pathways). We look at verbal abilities as an index into somebody’s optimal intelligence. For example, the National Adult Reading Test is comprised of words that cannot be phonetically sounded out correctly. If English is your second language, then this will be very difficult. But even if English is your first language, if you haven’t been exposed to the correct pronunciation of words like hyperbole, then how do you pronounce it? The more exposure you have had to these kinds of words, the more you will be able to pronounce them. This kind of test was given to a large group of healthy people who were also given a standardized IQ test. It was found that people who usually get say 40 out of 50 words correct, then they will have an IQ of a certain range. The idea is that if you want to know if somebody has declined, then you can use this verbal test to approximate their IQ range capability and then compare it to their current measured intelligence. That is how we make these distinctions. We also have standard IQ test. They are relatively insensitive. The common adult IQ test is the Wechsler Adult Intelligence Scale. The common child one is the Wechsler Intelligence Scale for Children. These measure a range of abilities. He shows tests:

- A few are figuring out what is wrong with a picture (footsteps in sand missing behind a person etc) - Another is block design - so you are given blocks with a different arrangement of colors on each side and have to

recreate a colored design in a picture using the blocks. - Visual abstract reasoning tests - test visual abilities, abstract reasoning, attention

So we have memory function tests. People can come in and say they have a memory problem, and this may or may not be true. So I ask these patients to give me an example. This is important. So they will say they say they can’t remember phone numbers or find their keys or forget to turn off stove etc. But it is important to figure out if the person actually paid attention to where they put the keys (were distracted when the did it) or do they actually forget it. If they never learned or encoded where they put their keys, then they haven’t really forgotten where they put their keys because they didn’t pay attention to it in first place. People with attention problems can present like they have memory problems.

Brain and Behavior 11: The Neuropsychological Evaluation He shows memory tests:

- Learn a list of words and then repeat them - Show them a figure and have them reproduce it from memory after say a 10 second exposure…do they learn if you

show them it again? This can show a problem with memory organization - have all of the components of the picture but can’t put them together correctly (like from a problem in the frontal lobe)

- Show them pictures and ask questions about them You can have memory problems from actual forgetting, lack of attention, or lack of organization. Patients who are sleep-deprived, have Alzheimers, have depression, or have frontal systems dysfunction will have problems spontaneously recalling information but they can recognize the information. You can help them by altering their environment with cues to help them facilitate their memory. Patients with Parkinson’s Disease can have spatial deficits and a problem recalling figures because they are poorly organized. Attention tests can be something like look at this screen and press the button every time you see a number 9 for a 10 minutes straight. You have to be able to focus and ignore distracters. You can make a statistical conclusion based on others that have taken this test. It is a quantitative measure of attention span. A test of problem-solving and executive function can look for individuals that are suitable for independent living. I was asked by neurosurgeons once to see a patient with a bifrontal glioma that was removed successfully. The patient woke up, had good motor function, could recognize family members, had no aphasia, and was sent home. Patient goes back to his small business, and the doctors find out a month later that he was arrested for sexual indecency with his long-time secretary. Also, he had been giving out money to whoever asked for it. He had impaired judgment and executive abilities as a result of his surgery. Frontal abilities include problem-solving, planning, organization, and judgment. So when you ask a patient close-ended questions, you can’t test for these functions. So you can instead give patients tests that require judgment and problem-solving. One such test is the Wisconsin Card Sorting Test. You have four key cards and the patient is asked to take a card off the deck and put it next to the one that they think it matches of the four key cards. The person giving the test says that they can’t tell the patient how to match them but only will say if the patient is right or wrong. So the patient matches the cards based on shape and is told they are wrong. So next they match by color and are told it is correct. So they do 10 of these matching by color, but on the 11th card, they are told it is wrong. So the person will then try matching by shape or something. They go to trial-and-error and other problem-solving techniques. A person with frontal lobe dysfunction will often just keep matching to the first way they got it right (by color) and say, ‘I know this is wrong, but…’ This test looks at executive function. Visual discrimination tests let you look at a figure and then look directly below and say which of four figures is identical to the one above. Spatial abilities can be evaluated by telling them to draw a clock - can they make the numbers evenly spaced? Neuropsychological evaluation is a tool that is available to you. It provides detailed information of cognitive abilities and emotional functioning. A neuropsychological evaluation is only as good as its recommendation. You don’t use it if you want to know if they have a structural lesion - you get an MRI in this case. However, if you want to know about their functioning, what you can expect from them on a daily basis, and what the best treatment plan for them is, then neuropsychologists can be very useful.

Brain and Behavior 12 – Autonomic Nervous System and Behavior Announcements: None Slide 1/ 2 The talk today will be a little different from what you are used to hearing about the autonomic nervous system (ANS). We want to understand the ANS from a phylogenetic perspective and understand why certain physiological functions serve the body’s need. They may not serve your needs at the time but they serve your body’s needs. The perspective that I use is a ‘polyvagal’ perspective and the theory I came up with is the ‘polyvagal theory’. The polyvagal theory shows the phylogenetic shifts in the ANS and reminds you that you have more than one vagal system. Slide 3 Of course you have to deal with metaphors in anatomy, physiology, etc.. So we’re going to reach down and grasp the metaphor from “Calvin & Hobbes”: “Calvin wakes up one morning to find he no longer exists in the third dimension – he is in 2D. Someone is coming! Calvin quickly stands up straight. Turning perfectly sideways, he is a nearly invisible vertical line – no one will notice!” Slide 4 The reason why I bring this up is because we’re going to be talking about things in physiology that are in the 3rd dimension that were usually shown in 2 dimensions. We study these things on simple levels but when we apply them in real-life we find out they exist in more than 2 dimensions. So its not that you learned things that were wrong, but that you learned things that were limited. For example, you learned that the ANS was an antagonistic system with the sympathetics in this ‘mortal battle’ with the parasympathetics that help in restoration, growth, and health. This is true in general words, but it is not true completely. This is because the parasympathetic nervous system can kill you – very rapidly. Those of you going into ob/gyn, neonataology, and exercise physiology will hear about sudden death, clinical bradycardia, and exercise-induced bradycardia. We all know about people who have died from fear, or people who have been scared ‘shit-less’ – you’ll find out that this is a vagal response. The vagus and parasympathetic nervous system is usually a very health positive system but it can kill you also. So don’t think about the ANS as an antagonistic system, but as a system that is far more organized. Those of you interested in the history of science – there is a website with all of the Nobel Prize speeches. One interesting one is from Walter Hess in 1949. In 1949 he received the prize for central control of peripheral viscera – brain regulation of ANS. It was a revolutionary talk because he basically argued that we need brain feedback to control the ANS. In 1921 Langley figured he would codify the ANS and stripped it from the brain. Even Darwin knew earlier that the brain is connected to the viscera, and the vagus is one of the primary bidirectional pathways. Langley made 2 mistakes. 1) he threw away all the ANS connections to the brain and 2) he cut out all of the sensory afferents coming back. So it couldn’t be a true ‘system’ without inputs, outputs, and central regulators. What you learn in the textbooks is limited, but I won’t say they are wrong. However, you need to realize that these textbooks are based on assumptions and theories developed in the 1920’s Slide 5 The important thing to realize about this theory is that evolution provides an important organizing principle to understand neural regulation in the ANS. Through evolution we have three major phylogenetic transitions in the regulation of the ANS. Such that we mammals now have 3 neural circuits that are hierarchically ordered based on phylogeny to adapt to a behaviors in a life-threatening environment. This means that we start with our safe

Brain and Behavior 12 – Autonomic Nervous System and Behavior response, if that doesn’t work we go to your fight-or-flight danger response, and if that doesn’t work we go to our ancient circuit that serves reptiles very well but happens to be possibly life-threatening – the immobilization response. The mechanism by which our nervous know there’s something dangerous – we do not know. However, it does find a way to understand danger and elicits responses. However, these are not cognitive responses – they are not voluntary. There are some of you out there that have a fear of public speaking. If I were to call you in front of the class we could see whether or not you faint in public. Now why would you faint in public? Why are you afraid of public speaking? Why should your body go through a potentially life-threatening vaso-vagal pass out? Somehow your nervous system is detecting a life-threat and your body is appropriately responding as if there is a life-threat. It is inappropriate if there is a mismatch between sensation and response. We will talk about people exposed to trauma and how their nervous system doesn’t work right. They may feel threatened in a normal environment. Neuroception is a construct where we try to find the featured effectors in the triggering of neural circuits. A neural circuit can be socially engaging – which would follow a feeling of safety, a neural circuit could be fight-flight which you do when faced with danger, and a neural circuit of shutting down/disappearing/feigning death when under life-threat. By understanding these circuits we can develop models, methods, and treatments to reverse-engineer to trigger people from these shutdown. Slide 6 Why are we interested in this? We want to understand the mechanisms of disorders related to this and remove myth. It is necessary in medicine that people don’t see this as ‘magic illness’ with a ‘magic cure’ – there is an underlying mechanism for the disease. If we understand the underlying neurophysiology about various states of being – we can build better assessments. Instead of just asking how they ‘feel’ we can look for a neurophysiological response. Finally, when we understand the neuroregulation of these circuits we could trigger these circuits to improve the behavior of issue. Slide 7/8 So the metaphor is that our nervous system or physiological state being regulated by our nervous system puts us in three different types of states. The state determines the reaction to the stimulus. If we are in a safe state (green light), we are safe with friends/family (baby interacting with mother), it is calming and we feel good. It is all these issues of comfort. If we are in a fight-flight state – hypervigilent, sensing danger, or if someone is walking behind us - our whole physiology shifts and our reaction to the same stimulus that we were positively engaging with will either be irrelevant or will produce a different reaction. Finally in our state of shut-down – our sensory thresholds are being raised, our pain thresholds are raised, and we are basically no longer there. This state is extraordinarily adapted for transitioning people from life to death. I want you to think about in a positive way as I emphasize this model a little bit more. Slide 9 Our nervous system is evaluating both internal and external stimuli. If it detects no risk – for example: people who have animated faces, they are making good eye contact, their heart rates are under control, have a good myelinated vagus, are calm, digestion is under control – are people that you want to engage in. As very insightful individuals – as is everyone from medical school – you can tell if someone is having a bad day by looking at their face and listening to their voice. Their face will be blank and their voice will not have intonation – very flat. Intonation is what gives your voice different frequencies – making it almost melodic. So, of course, the characteristic of a university professor is NOT to use reciprocity, NOT to make eye contact, and NOT to use

Brain and Behavior 12 – Autonomic Nervous System and Behavior facial expressivity. When that occurs, you know how you feel physiologically – what your nervous system is picking up. Your nervous system is picking up disinterest, arrogance, and you just turn off. In situations where you are being evaluated as students and you are going to talk to the professor but the professor just turns and walks by you without engaging you – how do you feel? Your nervous system reacts to this because it expects this social engagement. You respond, using this wonderful cortex we have developed, by interpreting what it means. You think, “I guess I’m not good, I guess I’m not that important”. You never really think, “I guess this person doesn’t have good social skills”. It’s not really social skills, but rather physiological state that enables people to be social. If you’re on a treadmill and you feel your heart rate going up, and some important person in your life walks up to you and wants to tell you something very pressing – you are not going to be appropriately responsive. An ex-colleague of mine has been placing married couples on treadmills and seeing how they resolve arguments. He never published the study because what he found was that people got extraordinarily angry at each other. The physiological state of fight-flight isn’t what you use to reconcile. Slide 10/11/12 The first point I want to say is that you have this physiological state that supports social engagement. It includes the normal regulation of the striated muscles of the face and head. In your neuroanatomy class these are called special visceral efferents (SVE) that come off of the branchial arches and they regulate the striated muscles of the face and head. Through evolution, through our phylogenetic development, the nucleus that is responsible for these muscles interacts in the brainstem with the myelinated vagus. This is a new vagal system that is a vagal system of calming. When we use our oral motors when we suckle, eat, or even smoke – we are using a neural circuit of social engagement. We are using a neural circuit of self-soothing and calming. When we listen to human voices in a safe environment, our middle ear muscles are at work. Our middle ear muscles are in the same circuit. When we talk to people and we see that they are interested, it is because the orbicularis oculi (the sphincter around the eye) open up. When you meet someone doing that in a bar you think, “someone’s interested”. But it is the same system in place, and it is picking up, “I feel safe”. This regulation works with fluid mobility and dynamic interactions – it regulates visceral state – it makes people feel safe. When the nervous system senses danger it pulls off this new myelinated vagus and enables the sympathetic nervous system to support the striated muscles of the trunk and limbs to support fight-flight behavior. This gets the mobilization systems working. If that doesn’t work, if people are in a closed environment and a life-threat occurs when they know they can’t get away – what happens? Has anyone seen a cat and a mouse with a mouse ‘playing dead’? Do you think it is actually the mouse ‘playing’ dead? It is actually this ancient physiological system - this old unmyelinated vagal system – that comes to mammals from reptiles. That is actually the primary adaptive response by reptiles - immobilization. A few weeks ago I was watching CNN about an airplane that was having a little difficulty landing. When they interviewed a passenger about her experience before the landing she said, “I passed out”. She was like the mouse in the cat’s paw. Her nervous system did the right thing. She had no escape; she thought she was going to die, so she ‘disappeared’. There was an increase in the pain threshold so that there would be an easy transition from life to death. The problem occurs when these people don’t die – are there long-term consequences? This is where these individuals who deal with post-traumatic-stress-disorder (PTSD) come in. You will be hearing more and more about this as more people start coming back from Iraq and many of them will have symptoms of PTSD. There are no pharmaceutical treatments for PTSD – people have to learn to deal with it on their own level to try to figure out the mechanisms. Part of the mechanisms has to be related to this old adaptive, protective circuit.

Brain and Behavior 12 – Autonomic Nervous System and Behavior Slide 11/12 Neuroception is the important interaction among physiological and emotional stages. Let’s talk about examples and consequences about how our nervous system detects safety. We want to make people feel safe so that the physiological shifts circuits as to promote health, growth, and restoration. Slide 13/14 Let’s look at this. Do we feel good when we see this? (yes) Bodies embracing, With this one there is great proximity, eye to eye contact. Slide 15 Now what about this picture? Does this picture make you feel good? There is a violation of your expectation. Not only are the people not looking at each other, their faces are covered. So the face expression triggers the visceral state. Slide 16 What about this one? What is the president of Brazil doing? He is pulling away. What is the person on the left doing? He is hugging, but what is he doing wrong? He is not engaging the person. You should look at the person before you hug the person. If you hug the person without look at them what will happen? Just like with any of you, if a person comes up behind you and grabs you – it wouldn’t feel right. It may be called abuse or battery (joke). It is an uninvited touch. Slide 17 What about this one? It is two people that look like they like each other and are more comfortable with each other. (no slide – CNN ‘love doll’ video) Now this is another clip from CNN and it shows how we are moving in our culture from dealing with face to face interactions. (shows Love Dolls video – the video describes a Japanese man who purchases tons of life-size female dolls and uses them as companions. He feels he can trust these dolls over real females because he know they won’t cheat on him. He mentions that it makes him feel ‘safe’. ) The point I want to make is that to be a human being you have to interact with others. Physiologically this is a violation of how people should relate and our culture is moving more and more towards a disconnect between face-to-face interaction. As technology develops and there is less face-to-face interaction, the level of nervous system involvement shifts so that even with the telephone you can start to tell how the other person feels because of the intonation in his/her voice. Slide 18 With Autistic individuals, the middle ear muscles do not work. As such they have an advantage of hearing low-frequency sounds, but it overwhelms their ability to hear voices. That gives them difficulty in crowds. A lot of clinical pathologies don’t like noisy environments because they can’t hear what people are saying. We are going to go through those mechanisms. The theory is there are phylogenetic shifts in the neural regulation of “state”, adaptive function of negotiating “safety” in a high-risk environment – what are the consequences of these defensive strategies on our body?

Brain and Behavior 12 – Autonomic Nervous System and Behavior Slide 19 This is a little bit of a heavy slide for you to think about. It is a picture of phylogenetic development. It is there to remind you to think about evolution in a different way. We don’t want to use the words ‘new’ and ‘old’, but talk about the phylogenetic history of mammals. Within vertebrates, mammals follow an interesting phylogenetic story which changed the neuroregulation of their heart. We will articulate this as we go along. CHM is chromaffin tissue - it is tissue that stains for catecholamines. DMX is dorsal motor nucleus of the vagus. Sympathetic (SNS) is the spinal-sympathetic nervous system. This is adrenal medualla (AD/m). NA is an area known as nucleus ambiguous. NA is very important. Cyclostomes are the jawless fish and the only way they can regulate the heart is though the release of catecholamines in the heart tissue. Elasmobranchs are cartilaginous fish like sharks and rays. They have an unmyelinated vagus that originates at the dorsal motor nucleus to slow the heart rate. If the water is cold or O2 levels are less – they can reduce the metabolic demands. Amphibia and Teleosts are the bony fish. They have a spinal sympathetic nervous system and this enables them to mobilize and dart around rapidly. Reptiles have another source of mobilization. They have an adrenal medulla that produces more catecholamines and enables them to mobilize. In some parts of the world, reptiles are at the top of the food chain (Komodo dragon) and this enables them to run quickly after and capture small mammals. Mammals have a new vagal system that comes from the nucleus ambiguous and it is myelinated. Nucleus ambiguous is also the source nucleus of CN 9, 10, and 11 – the striated parts which are glossopharyngeal, vagus, and accessory. The major inputs into that area are actually trigeminal and facial nerves. This system is intimately related. It is a column in the brain stem that leaves through 5 cranial nerves. The myelinated vagus affects the regulation of the heart, but the nerves in that area also control all the striated muscles of the face and head. Slide 20 How many have heard of John Hughlings Jackson? Jackson was a neurologist at the turn of the previous century and he came up with the concept ‘dissolution’ – which is evolution in reverse. It basically states, “The higher nervous arrangements inhibit (or control) the lower, and thus, when the higher are suddenly rendered functionless, the lower rise in activity”. As we remover higher parts of the brain – newer parts – we dis-inhibit older parts of the brain. This was done as a model for the brain to explain brain damage and various neural diseases. I apply dissolution to the brain’s regulation of the ANS. When newer autonomic circuits fail to make us feel ‘safe’ – we use older ones. These are not cognitive decisions. Slide 21 The polyvagal theory states that polyvagal response strategies are based in the phyloeny of the vertebrate ANS. Slide 22 The first one is that we remove this ventro-vagal-complex – which is they newer, myelinated vagus – from the nucleus ambiguous. When we talk about the complex not only the autonomics but also the neuroregulation of the face. Your first reaction to a threat is to take that vagal ‘brake’ off of the heart. If you block the neural imput to the heart your heart would intrinsically beat between 90-110 beats per minute. Most of you have a heart rate significantly lower – due to the chronic influence of the myelinated vagal ‘brake’. When you are startled, the vagal ‘brake’ is removed, and the heart rate increases but the neural tone to the face goes away as well. So when the face goes flat, you can tell about the physiology. The next step is an increase in sympathetic activity (tone) that enables you to mobilize. Finally, if you can’t get away – this old vagus kicks in. This is the same thing as being ‘scared to death’ or having vaso-vagal syncope (passing out) or being scared shit-less.

Brain and Behavior 12 – Autonomic Nervous System and Behavior Slide 23 You can think of this as 3 phylogenetic stages. The newest one being the myelinated vagus with functions in social communication, self-soothing and calming, and it actively inhibits sympathetic-adrenal influences. It also dampens the HPA axis so it is a positive system to calm us down. This is seen when there is a child hurt or in pain, what do we do? We don’t reprimand them; we first try to calm them down. I want you think about the mismatch between calming somebody down and bringing him or her into an emergency room. It is a mismatch because it is not calming or supportive. When I give talks to people that work in trauma – I tell them that the medical community has not done enough to calm people down. Once you calm them down, you can recruit their nervous system as an aid in their healing. If one does not have a myelinated vagus, then the sympathetic-adrenal system kicks in that supports mobilization. Finally, there is this unmyelinated vagus that is from reptilians that supports feigning death and shutting down. This unmyelinated vagus originates in the dorsal motor nuclei (DMX) of the vagus, the myelinated vagus originates at the nucleus ambiguous (NA). In embryology you can actually see the cells migrating from the DMX to the NA in mammals. Slide 24 The polyvagal theory proposes a hierarchy of response strategies. In the first one, we use our head and our heart for the function of social communication. If that doesn’t work we use our limbs for mobilization – fight-flight. Finally, if fight-flight doesn’t move us to a safe environment, we will shut down. Slide 25 This again is the system. Slide 26 This is your anatomy lesson. So the DMX is the origin for the old vagus, and it regulates the viscera. This is what it still does in us. It has some input on the heart but it is primarily the gut. The phylogenetic hierarchy of the gut is that first the old vagus came in, and then the sympathetics. The sympathetics are inhibitory to the vagus in the gut, but at the level of the heart you have the old vagus, then the sympatheics, and then the new vagus. So the new vagus is inhibitory to the sympathetics in the heart – sort of a paradox. When you run, what happens to digestion? It gets turned off. However, in order to get it that metabolic output out to run, you have to withdraw that vagus. Slide 27 Vasovagal syncope can produce fainting behaviors. This is the ‘old’ vagus. Slide 28 It can induce bradycardias and apneas. I am sure there are some of you interested in neonatology. Infants born before 32 weeks of age do not have a functionally myelinated vagus, so their defense mechanisms do not have a functional myelinated vagus. As such, their defenses are bradycardias and apneas. When they get older they have the ‘new’ vagus which is protective. Then you can touch them without getting those reactions. This brings up issues about how to treat pre-term babies. They are not miniature adults, their nervous system is different and we have to understand that.

Brain and Behavior 12 – Autonomic Nervous System and Behavior Slide 29 Remember this guy? He had an episode of eating a pretzel and he passed out. His father had a similar episode in Japan eating Japanese food. They both experienced a vaso-vagal-syncope. They both have this old vagal circuit easily released. Slide 30 The sympathetic nervous system is mapped on the motor cortex and cells of origin in the spinal cord. This produces fight-flight behavior. Slide 32 Look at the hands up. This is from netter. In rage. Slide 33 This is a street child from Bulgaria. Look at the hands. Slide 34 This is the German chancellor at one of those meetings in Europe. I want you to go through the sequence with what you’ve learned. So the gentleman is walking by and he sees a woman engaged in dialogue with a person. He goes behind her, doesn’t make eye contact, and he touches her. What is her response? (she gets frightened). Then he walks away without engaging her or diffusing it. What is the behavior that most people do? They look at someone, they touch them, and then they walk away. If they touched them and then they walk away – they also do some social referencing. You can see her response very similar to that street child in Bulgaria. These are defensive responses that are not planned. Slide 35 Here is a crying baby –see the hands in the same position? Slide 36 Then we have this newer circuit that has cortical representation and corticobulbar pathways that monosynaptically regulate the striated muscles of the neck and head. So we can voluntarily nod and smile, we can change the pitch of our voice and sing, and we can control those cranial nerves very actively. It is also linked to the vagus and the heart. And it actually makes us feel good – not only does it look good, but when we see these things we also feel good also. It is a system that is not very often taught. Slide 37 I call this the social-engagement system and its linkage vagus. Slide 38/39 We see this system is in place at birth and they are there to help the individual calm down, self-regulate, and self-soothe.

Brain and Behavior 12 – Autonomic Nervous System and Behavior Slide 40 So a cranial nerve is only a conduit - a pipe. Unfortunately, even when I learned neuroanatomy we memorized them without thinking about where the wires came from. The wires come from special different areas but also from a common area. This area regulates the muscles of the face and neck – they are called special visceral efferents. They regulate the muscles of mastication through the trigeminal nerve, muscles of the middle ear through the facial nerve and the trigeminal, facial expressivity by the facial nerve, and the larynx and pharynx (tonal qualities of one’s voice) by the vagus and glossopharyngeal. Head turning and nodding comes through the accessory nerve (CN XI). Also this is linked to the regulation of the bronchi and heart through the myelinated vagus. This is a package about how we enagage with the world and how we relax. Slide 41 I started looking at heart rate activity many years ago. We found that heart rate goes up and down and is coincident/synchronous with breathing. I asked why we were getting these oscillations of heart rate with breathing that led me to the physiology – that it was being controlled by the vagus. Then when I started moving more into neuroanatomy, I found it was not only the vagus nerve but also pathways related to the striated muscles of the face and head. Always be careful about the questions you ask – it can lead you down a long pathway. Slide 42 This is an old picture about an article published in Sweden. It shows that if you mechanically lift your eyelids, you are tensing the middle ear muscles. When the middle ear muscles tense, the eardrums can’t vibrate as much – it’s like pulling a rubber band. Psychologically when we meet people whose eyes are opened wide we think they are listening to us, and they probably are. We teachers scan the class to see if eyes are open to assess if they are listening to us. Parents do this with their kids. People who have eyelids drooping or gaze aversion – people treat them as if they are inattentive. These cues are based on real physiology. Slide 43 This is from Scientific American and it shows how the middle ear muscles alter our perception of human voice. So the high frequency oscillation is human voice (oscillation with smaller wavelength) and the background rumble in all our environments (oscillation with larger wavelength). If the middle ear muscles are inactive, the background rumble overcomes the voice and it is lost. However, if the middle ear muscles are tense, they attenuate the background slow frequency noise so we can hear the human voice. Student Question: I love looking at eyes, but I know that not all cultures think it’s socially appropriate. How does this work? Answer: It works the same. In some cultures eye contact with a stranger is the worst thing to do. This is because eye contact is personal and it is considered reserved for intimates. It is sort of like privacy. So when a culture says that making eye contact is not acceptable, it is saying that your personal life is private. In America we are really a eye contact culture. Slide 44 When we talk about autistic individuals. We find that approximately 60% of autistic individuals have auditory hypersensitivity. They have difficulty hearing human voice from background sound. We have been doing research about how to change physiological state to support middle ear muscle function. I’m not going to talk about that.

Brain and Behavior 12 – Autonomic Nervous System and Behavior Slide 45 The face is a critical part of social interaction. At birth, the mammalian nervous system needs a ‘caregiver’ to survive and signals the caregiver via the muscles of the face and head. This is critical when we talk about why some parents have difficulties accepting severely pre-term babies. If they are severely pre-term, are in the hospital for a long period of time, and the parents don’t come to visit often – the babies are often abandoned. It is the development of the relationship that is missing because the pre-term baby doesn’t have that flexibility of the face. I often ask what is common between the parents of fussy difficult babies, the parents of pre-term babies, and the parents of autistic children. The common connection is that the parents often feel that the child doesn’t love them. What they really mean is that my child doesn’t look at me, doesn’t listen, and is non-contingent with me. They are picking up these cues. Just like when you’re talking to someone and they walk away from you - you don’t feel good. The parents are going through this on a daily basis. This is because the nervous system is not in that physiological state to promote social interaction. Slide 46 Even at birth, newborns know the different between direct eye-gaze and eye-gaze to the side. If given two pictures: one with the eyes looking forward and another with the eyes looking to the side; the newborn infant will prefer the eyes facing forward. Slide 47 In terms of modeling this social engagement system we see that this system is compromised in many psychiatric disorders. They show: lack of prosody – an inability to speak with intonation., gaze-aversion, blank facial expressivity, issues in their mood or affect – with state regulation issues. This is seen even with head posture, how people use their head when they are engaging and not engaging. I was giving a talk at Columbia once and presenting data, and someone in the back was nodding. So I focused the talk towards this individual, thinking he knew what I was talking about. When I finished my talk, he kept nodding – it was a tick. The important point was what I was picking up. I was interpreting the head nodding to mean that he was engaged in what I had to say. Slide 48 Faces don’t work in everyone. If we look at an autistic child in a textbook (left) and a painting (right) from the Rembrandt museum called ‘The Sick Child’. Notice the low muscle tone and flat facial affect. This is being ill. Now look at this child from my lab (center) that is autistic – do you see the similarity? So mental and physical illness often produce the same flatness of the face and lack of affect. Slide 49 Now look at the faces of people who have been abused. This is a abused adolescent (left), a survivor from the Holocaust (top right), and firefighters at a funeral after 911 (bottom right). We can see that these two (the back two firefighters) have facial animation (albeit not positive) but this one (front with mustache) has a flat facial tone. This is the type of face (flat) we would be most concerned about. Slide 50 Of course if your face is not working, we are in the age of modern medicine, we have choices. This is an exuberant middle-aged woman who gets botox and then looks autistic. See the flatness? People are taking away the cues because of a misunderstanding of what beauty and attractiveness is. The attractiveness is from the

Brain and Behavior 12 – Autonomic Nervous System and Behavior dynamics of the eyes moving in interaction. In face, when you talk to parents of autistic adults they often say, “my son, not a wrinkle on his face – looks extremely young for his age”. This is occurring because there is no muscle tone to those facial muscles. Slide 51 Here are autistic individuals with eyes open, eyes drooping, but no dynamic aspect. Slide 52 It has hit popular culture now. There are very few articles – if any good ones – that people are not reading their emotions properly (people who have had botox). Slide 53 Person to person interaction is important because the mammal did not evolve as a single – the mammal cannot survive without care giving. Embedded in our ability to regulate our physiology is our interaction with another person. Slide 54 How does neuroception work, how does our nervous system detect safety or danger? Slide 55 We speculate that under life threat there is an area of our amygdala called the central nucleus that interacts with an area called the periaqueductal gray – there is a component called the ventrolateral part – that literally has the behavioral and autonomic components for immobilization. It shuts us down. Slide 56 There are also areas of the central nucleus of the amygdala going to different parts of the periaqueductal gray – one for fight behavior and one for flight. Both require increased mobilization, so they result in similar autonomic activity. Slide 57/58/59 The interesting one is what turns off these defense mechanisms. We go back to the model of dissolution. Our brain evolves by putting newer and newer stages on it. We have these limbic defensive systems that we share with other organisms, but how do we turn them off? There is an area of the temporal cortex known as the superior temporal sulcus and an area known as the fusiform gyrus (or fusiform face area). These areas of the cortex detect biological movement and intentionality. So they detect the movement of hands, voice, and face. It has been misunderstood because people thought it was a face area for familiar faces, but it is actually detects biological intentionality. If the intentionality is safe then it will turn off these other structures. These areas turn off the limbic defensive systems and enable this circuit to occur and enabling us to be happier and healthier. There are individuals with borderline personalities that show in research that their physiology shifts when they are in the presence of another person.

Brain and Behavior 12 – Autonomic Nervous System and Behavior Slide 60-65 I want to leave you with some pictures to show you that mobilization is not always a bad thing. For example: play. Playing is a sport of mobilization. Here is a dog and a polar bear. What do you think is going to occur? There is something common in the pictures – they are maintaining eye contact. We see this in basketball. If you get hit in the face and the person who hit you doesn’t look back – it’s a fight. However, if he turns and diffuses the situation (says sorry) – it is fine. We mobilize in play but take part of social engagement system with it to make sure it is not true flight-or-fight. Slide 66/67 We can also talk about how we can kill individuals. In 1942 Walter Cannon wrote a paper called “voodoo death” – basically being ‘scared to death’. Cannon said that all stress is defined by the sympathetic adrenals. He figured that if someone died from voodoo death it had to be a sympathetic death. Slide 68 Karl Richter tested this theory in 1957 at Hopkins. He put rats in individual turbulent beakers and he wanted to find out how long until they would drown. What he found was that rats swam for 60 hours before dying of exhaustion, but a couple rats just swam to the bottom and died in 2 minutes. He did autopsies and found that the hearts were engorged not constricted – suggesting parasympathetic not sympathetic. Then he put electrodes on and found that as the rats fell deeper and deeper – their heart rates slowed till stopping– so it was parasympathetic. Then he got some real rats from the dumpsters in Baltimore, cut their vibrissa off (whiskers), and did the same thing. This time, virtually every rat fell down immediately and died. This is because their nervous system was not prepared for this environment. They thought they were truly life-threatened and died. The white lab rate is a working animal whose nervous system was better prepared. Slide 69 This is what Richter said. Human victims and rats die a parasympathetic death - not a sympathetic one. Slide 70 Dr. Sue Carter will lecture tomorrow about immobilization without fear – she doesn’t know that’s what she’s talking about, but she is. She will be talking about oxytocin and neuropeptides of love and social bonding. Oxytocin is a neuropeptide that literally coops these immobilization systems. The DMX and even the periaqueductal gray involved in shutting down behaviors are oxytocin sensitivity. They enable ritual behaviors and birth and parturition to occur without the individual dropping dead. I see oxytocin as a neurpeptide as a modulator of the ANS, she sees it as a modulator of behavior. Take the perspective, while she is talking, how this peptide could change visceral state and be very protective. Slide 76 We have social enagagement, mobilization with fear, mobilization without fear (the bear and dog), immobilization with fear (richter), and tomorrow you will have immobilization without fear. Slide 77 Finally, there are behaviors that are not social that are good, but that is not what we are talking about today.

Brain and Behavior Lecture 13 1 of 3 Note: Handouts on Blackboard are an abbreviated version of the actual Powerpoint Professor used during lecture. The field I come from is heavily based on certain organizing principles. One is evolution—the idea that the processes found in humans are evolved processes. They didn’t just spring up overnight or even 5000 years ago. It probably took a bit longer than that. The other principle important is development/ontogeny and I tend to focus on a physiological and anatomical approach as well. There are two kinds of causation. There are proximate causes like physiology and development and then there is ultimate causation meaning evolutionary processes that lead to what we see today. Most of those tend to revolve around reproductive fitness. Day to day principles that I am going to talk about is fear and anxiety versus safety and feeling calm. Most of information that you read in textbooks is data based on the individual. It does not take into account the social context and the history of the individual. This is especially true in physiological and anatomical studies. The biological fact is that organisms, especially mammals, cannot survive or reproduce alone. The mammalian nervous system is designed to work in a social environment. When it separates from that social environment, that homeostatic mechanism no longer works in the same way. In the absence of appropriate social interactions and social bonds (isolations), substitutions may occur. Those substitutions are going to make work for you because people substitute drugs, food, even mental dysfunction. What we’re trying to understand is the biology of human emotion and how natural factors such as social support contribute to human health and wellbeing. Social support and social bonds translate into a sense of safety. The person may not be there at the moment but they are there in a perceived sense or conceptually. Some people call it mental representation. At the heart of successful therapies is a perceived sense of safety, allowing the body to heal more successful. You cannot be in the healing mode at the same time as the aroused/activated/ “let’s get out of here” mode. What are the causes and consequences of social bonds and social support? It’s based on an ancient molecule, oxytocin. Social support and social bonds are hard to define. We know when it’s gone. Over the last roughly twenty years, epidemiology started discovering social support by accident through asking questions like, “How many people do you live with? How many people are there to help you?” The answer was a bigger predictor of outcome for every disorder except genetics. If you don’t like someone, you’ll do anything you can to move away. Proximity is an indicator. In fact, the farther away, the better. In the Berkman, et al. study, it showed who lived and who died within six months of a heart attack. The people who lived were younger (younger than 75 in a study for 65< yrs), women, and importantly, people who lived with other people. If they were over 75 and living alone, almost 75% died. If they were over 75 and had 2 or more people living with them supporting them, the death rate was 25%. That’s bigger than any of the drugs that were trying to cure them. We can also ask, when do social bonds form? Pregnancy and birth, postpartum period during parental interaction, sexual behavior and love. Sometimes social bonds even occur with people that don’t exist either at the moment or will never be in your life (i.e. Brad Pitt, Angelina Jolie). Those relationships that matter are reciprocal and there when we need them. We tend to form social bonds when we need them, such as during 9/11 when you might have gone looking for someone to be near that you cared about and made you feel safer. What are some common features of experiences that yield social bonds? There are “need state” or “need reduction” where you’re in a state of wanting or needing something or “stress” followed by “stress reduction.” We can use other people to make us feel good or more secure. We can have an increased sense of trust so we can go on and memorize all those things in the books that we’ve been given. One of the events that seems to be associated with reducing fear is the release of oxytocin. Many studies have shown that oxytocin is evolved. Gonadal steroids are things like testosterone and estrogen. Adrenal steroids are usually corticosterone in rodents, cortisol in humans. Neuropeptides are oxytocin and vasopressin or CRF corticotrophin releasing factor. Sometimes these are taught as part of the HPA or stress axis. Neurotransmitters are things like dopamine, norepinephrine, and serotonin. A neurotransmitter goes across the synapse. Most neuropeptide effects are not synaptic, they’re actually neuromodulatory. It doesn’t simply go from one side to another. It’s a very broad effect. What is oxytocin? It’s a hormone involved in birth and lactation and released during sexual behavior. It’s made of 9 amino acids with a ring and a tail and cys-cys bond. If the tail itself is cleaved off, it is analgesic and blocks pain. Probably the reason why we’re here on the planet with our huge heads is due to oxytocin which gets the baby from the inside of the mom to the outside.

Brain and Behavior Lecture 13 2 of 3 It is made primarily in the brain in the hypothalamus and then it’s released to the blood supply in the posterior pituitary. It’s also released into the brain itself. Magnocellular neurons were the largest cells in the brain discovered and contained oxytocin, vasopressin, and other chemicals. They go down from the brain to the posterior pituitary where it hooks up to the blood stream and is dumped into the blood supply in vast quantities. At least based on mRNA, oxytocin is the most abundant chemical in the brain. Not only does it play a role in lactation, it reduces fear of anxiety, downregulates the HPA (hypothalamic pituitary axis), it’s analgesic, somehow permits and encourages social behavior, and allows organisms to hold still and long enough to be social to give birth and nurse babies. Without those, mammals cannot exist. It also plays a role in development and reprograms the nervous system, probably giving information about the sense of safety in later life. Women who nurse their babies may be giving them by contact from the baby because there’s oxytocin in human milk, giving them a dose of security. Oxytocin in early life seems to facilitate the effects of oxytocin in later life. Oxytocin receptors are high in the prefrontal cortex in prairie vole pups but only in areas associated with social behavior and social thinking and social emotions. Oxytocin counterbalances other chemicals. If you get a lot of norepinephrine, vasopressin, etc. the body at the same time release oxytocin to put this thing back in balance because you don’t want to stay perpetually activated or emotionally aroused. You can’t engage in normal social behavior. Mammals are breast feeders and also give birth to their babies (if non egg-layers). The mother provides extra food and safety, protection, and so forth through oxytocin. After WWII it became trendy not to feed your baby human milk and formulas were made by companies. Formulas are pretty sophisticated now but what they don’t do is provide the mother with the experience of lactation and that matters. The mother herself is affected by whether or not she’s nursing. Bottle feeding women have higher levels of norepinephrine (so-called “stress” chemical), higher blood pressure, and higher basal heart rate than breast feeding women. These are not controlled studies. Cortisol is more elevated not before a stressor but after. In this case, exercise. The women who bottle fed had a bigger effect. Lactation is a mechanism that allows new mothers to manage stress more effectively. Even though this is a down regulated system, it’s not turned off, just simply under modulatory control. Lactation is a buffer between the physiological state of pregnancy and postpartum period. A good massage makes you feel more relaxed by safe touch. There’s a small increase in oxytocin blood levels after massage. Another study, they got a group to sit quietly and read a nonsexual National Geographic and the results were about the same as the group who got a massage. There have been some studies in Europe, where you can still buy intranasal oxytocin spray, and they looked at the effects of intranasal oxytocin. People were told to bring someone that made them feel safe (social support) and engage in a stress test. They were either given a saline control spray or oxytocin spray and were not told which one they got. The cortisol saliva levels produced were almost half in the group with the social support and oxytocin. Neither one alone was as good as the combination. This study was done in men. There has been a myth that oxytocin was a female hormone. There is no such thing as a male or female hormone. There may be relative differences in quantity. Oxytocin in the blood is not very dimorphic at all. Men and women have about the same amount. A study done in Zurich showed that the brain also regulates economics, not just models done on paper. There is one economy in Switzerland and that is money. Here they did a computer game where they had a bunch of men who were given real money and they were allowed to either keep them or give them away. If they give them away, the other person either doubles it or triples it or keeps it or gives it back. The more you trust, the more you get is the bottomline. Those who were sprayed with oxytocin trusted twice as much and got twice as much back in the end. Zak, et al., did a similar study where he gave people either a trust signal before hand or gave a random draw. Those with the trust signal had significantly more oxytocin than those with the random draw. Another study had people looking at the eyes of others, where most of our trust information comes from, with or without oxytocin. When they gave them very easy eyes to read, they got about 85% correct no matter if they got oxytocin or not. But if the eye was considered difficult to interpret, the people with oxytocin did significantly better. This means that when there are subtle cues, oxytocin may help. Oyxtocin reduces amygdala activity to fearful stimuli. People who looked at faces with oxytocin weren’t as upset as those with placebo, even when those faces were theoretically scary.

Brain and Behavior Lecture 13 3 of 3 Goldman, et al., is trying to figure out if there are different kinds of schizophrenia. He believes that there are differences because there’s a subset (~15% or less) of schizophrenics who also have polydipsia (drinking excess water). In fact, you can drink so much water that you get hyponatremia (low sodium). Oxytocin levels differs in the hyponatremia polydipsics than those that are just polydipsic versus normal controls or schizophrenics with normal water balance. Those people with polydipsia had another way of managing stress. People with low oxytocin are more reactive to stressors. The stressor here was putting their hands in cold water (seen in the next Goldman slide where a vertical dotted line is). ACTH is significantly elevated in people who were polydipsic and schizophrenic during the time they had their hands in the cold water. They also took longer to recover from the stress. This supports the notion that oxytocin is a kind of anti-stress molecule. The body filters all this external information according to your emotional state. If you feel scared, the world is more scary. Feeling frightened is not just a cortical process but an emotional process coming out of this old autonomic nervous system and the hormonal cocktail coming out of your brains that interprets how this reaction from the body and viscera is interpreted. Goldman even found that oxytocin was associated with the size of the anterior hippocampal area. This part of the hippocampus is where some of the feedback loops are that determine how reactive the body is and people with higher levels of oxytocin have bigger hippocampuses. No one understands why but people with schizophrenia have a shrinkage of the hippocampus, resulting in worse prognosis. Oxytocin has a partner in crime. It is similar except for two amino acids. One is in the ring and the other in the tail. This is arginine vasopressin. They’re using a lot of vasopressin right now in the ER to deal with shock and preventing people from going into shock. It’s a really ancient molecule. Oxytocin’s ancestral form appeared before the split between invertebrates and vertebrates. It’s the most abundant peptide in the hypothalamus, based on mRNA. It’s unusual in that there is only one known receptor. Everything else you’ll learn has more. Even vasopressin has three receptors—the one in the kidney is different than the one in the brain. By the way, the one in the brain is the one that affects blood pressure and is probably related to the system involved in shock. Serotonin has 15-22 receptor subtypes. Drug companies make their living working on subtypes of receptor compounds and they really like it when there are a lot of subtypes so they can target a drug to one of those types or multiple types and by so doing, hopefully keeping from affecting everything. Oxytocin is a special challenge because it affects everything, which is good if you don’t do harm. In a chapter by Porges, oxytocin may be a metaphor for safety. Working on part of the cortex and coming from the hypothalamus to other parts of the brain like the NTS, a relay station for visceral sensory information. Oxytocin is bathing in information coming from the gut and internal organs and helps to determine how that information is interpreted. There are also oxytocin receptors in the gut and they’re probably determining things like irritable bowel disease and Crohn’s disease. It’s also acting on an old part of the nervous system—the dorsal motor nucleus of the vagus. The dorsal motor nucleus of the vagus is part of the ancient vagus that slows the heart. It causes brachycardia. It has the highest concentrations of oxytocin receptors than any part of the brain. Vasopressin is a very similar molecule. In unsafe environments, vasopressin may be a part of the system that gives a different message to sensory regions like the NTS. The autonomic nervous system is one of the main targets of oxytocin. The whole axis, called the HPA axis, is downregulated by oxytocin. Part of the message that tells the body that “I’m ok, it’s safe” involves oxytocin. It also involves other not so relaxing molecules like vasopressin and CRF. CRF and vasopressin are usually considered components of the sympathetic nervous system and HPA axis and associated with mobilization, vigilance, and emotional reactions. Vasopressin is more abundant in males in the extended amygdala. You don’t have to know this but there’s a particular axis in the brain—the amygdala-septal axis—that is loaded with vasopressin and is probably like a filter for information and reads that as “be careful, be vigilant.” So what is oxytocin? Oxytocin put into cultures will differentiate into cardiomyocytes and can possibly go in after a heart attack and literally heal the heart. (Note: Professor did not have time to go over many of the slides at the end.)

Brain and Behavior Lecture #14 Epilepsy My name is Michael J. Schrift and I am going to talk about epilepsy, I am the medical director of the neurobehavioral program Center for Cognitive Medicine here at UIC. Before I start how many know of someone or has a family member who has epilepsy? Ok well as you can it’s a very common disorder, and it can be morbid. We will start off with a video, and hopefully its working and we have sound. It from a PBS special. (Plays a 10 minute video) So umm as you can see epilepsy can present with behavioral manners, doesn’t look like someone is having a full blown convulsion but they fall on the floor and shake their arms, some retain consciousness but a lot don’t. Hopefully after today you can realize there are a whole lot of manifestations of epilepsy, from subtle brief moments of lapses of consciousness all the way to schizophrenia like illnesses that could be chronic and everything in between. Question about child in video. Answer: he did well he had a hemisphere-ectimy, and he did well he recovered well. The other side of the brain takes over and he did well. Let’s talk about some definitions, the term epilepsy is derived from the Greek meaning take hold of, and the ancient Egyptians use the term taking hold of or being possessed in the same way. You can imagine when a person is foaming at the mouth on the ground and shaking it does look like they are possessed by something, something is controlling them. It is one of the most prevalent and serious neurological disorders that affect 1% of the population, and it have a variety of behavioral presentations as I mentioned before. There are many historical figures that had epilepsy, many of the spells that are describe in the history of these individuals suggests that were epileptic, as you see the list here for your self. I just want to go to the next slide, its hard for me to see but for example St. Paul was described as seeing a bright light and falling to the ground and hearing the voice of Jesus, blindness for 3 days with the inability to eat or drink and he had ecostatic visions (special vision) I can go down the list here but you can read it for your self. Again many of the spells that are described, if you think about them today in neurological terms they are describing epilepsy. Some of the behaviors observed in epileptic patients are a direct manifestation of the epileptic cerebral discharge, whereas others may be related to brain damage, the existence of a lesion giving rise to both the epilepsy and the behavior change. Wherever that brain damage is, where it’s located you experience certain kinds of behaviors as part of the seizures. Also another effect is the over use of medication, some of the drugs used to treat epilepsy are CNS depressants, that impair cognitive functions, so there is psychological cognitive consequences. For example phnobarabtol (?) for example it causes irritability and depression, newer drugs however have less side effects. A seizure results from an imbalance between excitatory and inhibitory brain systems. There are seizures that mainly effect excitatory systems and others that mainly effect inhibitory systems. An example of an excitatory is a generalized tonic seizure, or a gran mal seizure, that’s the one you guys are most familiar with, you fall down you foam at the mouth you shake uncontrollably, that’s a seizure of the excitatory system. A seizure of the inhibitory system would be an apsonic seizure, it’s just a brief lapse of consciousness, really brief mostly unnoticed. Different types of seizures are mediated by different physiologic mechanisms and affect different areas of the brain. We will talk briefly about that. Many of the seizures now, are manly now thought of as disorders of ion channels. As you guys have learned about the action potential neurons, there are genetic disorders that affect these transmembrane proteins that affect the flow of Ca or sodium or chloride down the concentration gradient. If you have a distribution in the flow, and it’s in a lot of neurons and its synchronized then you have a seizure.

Brain and Behavior Lecture #14 Epilepsy Some antiepileptic medications enhance inhibitory influences in the central nervous system by facilitating GABA neurotransmission like benzodiapahine (spelling?); others reduce excitatory input by inhibiting glutamic acid activity. Also some drugs inhibit calcium channels as well; this decreases the likely hood of having an action potential and increases the threshold that you need to overcome to get an AP. A seizure is a sudden, stereotyped episode meaning that you will get the same manifestation every time, with a change in motor activity, sensation, behavior, or consciousness that is due to abnormal electrical and also synchronous discharge in the brain. So if one neuron was abnormal it’s not a seizure, but if it’s a whole bunch at the same time you have a seizure. Epilepsy is a condition of recurrent, spontaneous seizures. Having one seizure in your life does not mean that you have epilepsy, they have to be recurrent, nor are a series if they are reciprocated by something. For example let’s say that you’re an alcoholic, and you get to a point that every time you drink you get a seizure, it’s mediated by the alcohol so it’s not spontaneous. That’s called alcohol induced epilepsy, there is also hyponatremia epilepsy caused by diuretics. Therefore, a seizure is the event and epilepsy is the disorder. The manifestations of a seizures depend on several factors, one of the most important being the site in the brain where the abnormal electrical discharge originates. Again it’s an abnormal synonyms firing of a whole bunch of neurons, depending on their locations you get a certain manifestation. You guys all remember the homonculous, if you go down the motor strip here the legs are medial, hands are more lateral. If you have a seizure beginning here, in the left parasagital motor region it will start out with your leg jerking and the if its spreads down the motor strip, it will move up your leg etc. When it spreads from one side to the other side, the seizure is called the Jacksonian march. It looks like a person is marching (He stomps hard with one foot, then the other). That’s for motor seizures, its just localizing the seizure to one part of the brain, it’s called a local seizure or a focal seizer, and I don’t like the term focal seizer. When focal seizers move to other parts you get what we call generalized seizure. Similarly you can have these seizers in sensory systems, it can begin here where it feels like a funny sensation in the legs, an indescribably sensation, that can rise up to your arms, face and lips. They say it feels cold tingly etc. If it effects language area, you may stop understanding or speaking. If it affects visual you may hallucinate a little. If it effects the auditory you may hear things or nothing at all. If it affects emotional centers you may have altered emotions. For example if it affects the amygdala you can get a fearful effect which is actually very common. As you know it’s in the medial part of the temporal lobe, and it’s evolved in the fear cycle and if it is activated you get an anxiety attack which can be a behavioral form of epilepsy. The classification of epilepsy, if it originates in one place it’s called a partial seizures or a focal seizure. That is further classified into sensory, motor, sensory/motor, psychic ones that has abnormal thoughts, perception (visual auditory), or ANS like a gastro intestinal rush you may experience. With these you don’t have memory loss, you do not become comatose, and you can go to the doctor and describe what is happening to you. “Doc I am hearing things, I am seeing things, smelling things, my hand is shaking, and my hand is tingling”. Seizers that have an impaired effect on memory or consciousness is called a complex seizure, they can be complex focal seizers and partial seizers. What kind of structures are in the temporal lobe? Amygdala, hippocampus, so if it effects hippocampus it can effect memory and emotion and still have a focal part, so you can have a complex focal seizure without an Ora(?) any one know what an Ora is? It’s a hint that a person is going to have a seizure, but in actuality it’s a seizure in itself it’s a simple partial seizer as in the primarily generalization. But as it spreads to parts of the amygdala and hippocampus you loose memory. You can have an Ora you may have a hand shakiness and all of a sudden you move like this (stomps) then you loose memory, the Ora was the hand shaking and the complex focal seizer is the loose of memory. Most of what we do is motor and we don’t think about it, like walking it doesn’t take much brain function to do that, so what is happening in seizers however that is its abnormal

Brain and Behavior Lecture #14 Epilepsy triggering of these unconscious motor systems in an un coordinated way. So you get the stomping and sometimes uncontrolled jumping etc, things that are usually unconscious motor but now are abnormal in coordination. Focal can spread and involve the whole brain and now you have a secondarily generalized seizure. From the hand, then you get generalized the whole brain. Then you have primary generalized where the whole brain is activated all at once. It may start as a tonic-clonic seizures beginning with a sudden loss of consciousness and stiffening, which is tonic activity of the limbs, then followed by rhythmic jerking, clonic activity of the limbs (at this point of jerking its called a myotonic generalized seizure). During this time phase you are often not breathing, and you have a sudden loss of consciousness. Sometimes you hear a cry, because you’re in the middle of inspiration, followed by a tonic contraction of your whole body including your diaphragm which pushed the air out and makes a high pitch cry. It is not an emotional cry; it’s because of your diaphragm. The seizure lasts from 1-3 minutes, after which the patient is poetical, which is characterized by sluggishness, sleepiness, and confusion, for hours. Focal seizures can spread throughout the brain, in which they cause a tonic-clonic seizure ensues. It is important, however, to distinguish true grand mal seizures, which are generalized from the start; from those that start focally and then develop secondarily into a grand mal seizure because different drugs are used to treat primarily tonic-clonic than are used for secondarily generalized tonic-clonic seizures. Because if it starts at one point it maybe because of a tumor or head injury or just pathology to one part of the brain. It’s important not to miss that because someone may have a brain tumor, you think they have primary generalize and miss the tumor. Atonic seizures are the ones in which the patient suddenly become limp and may fall to the ground, they often have to wear helmets. Myocolnic seizures have this unattained jerking activity as I mentioned before. Any of these can become status epileptics, where it is a recurring series of seizures, without intervening return of normal function that persists for at least 30 minutes. They can all become this, epileptically partialis continue of the hand, you have that focal hand jerkyness that lasts for hours or days. The most dangerous is status generalized epilpeticus, where you are going back and forth from generalized seizures and it’s a medical emergency. There is also partial simple status is known as eplilepsia partialis continua, whereas complex partial and absence status are known by several names, including nonconvulsive status, spike-wave stupor, absence status, epileptic twilight state. Or you can have one that starts as one type and blends into another is called mixed or progressive, a simple one going to a complex parial seizure and then generalizes and you have secondarily generalized. In some cases, antiepileptic medications enhance the ability of the brain to limit the spread of a seizure. He plays videos of people with these disorders. Absence movie- She is in a seizure and it’s in the frontal lobe, so it impairs cognitive and you can tell this because she is talking to you. Complex partial- The video talks about Ora, the very beginning on the seizure that is still conscious. Answers to inaudible questions after the movie? That one was an actor. They can fracture their bones, fall down get hematomas, and really injure themselves. Petite-mal can start in children because of genetic factors and can develop into gran mal form or stay petite mal. It may be the diaphragm contracting or relaxing whatever is making you produces sounds. You should clear the airway if they are vomiting, tilt them, and get hazardous things out of the way.

Brain and Behavior Lecture #14 Epilepsy (Plays another video) Tell me what you think this is? Any thoughts? (People are guessing and commenting on the video, he answers their questions but the questions and comments are inaudible) He says that he will get back at this later in the lecture. I am running out of time. In adults the most common type of seizures are complex it accounts for about 40%, simple 20%, primary generalized tonic-clonic seizures in 20%, absence in 10%, and other seizure types in 10%. In the pediatric population absence seizures are more prevalent than in adults. Just quickly going through the epileptic behavioral syndrome, for every stage of epilepsy you can have alterations occurring. Days, weeks, hours before you have built up of irritability. Post they are confused tired etc. Between seizures you have a full array, personality disorders, you feel like a machine is controlling you, dissociate, multiple personalities, feud states a period of wild behavior with no memory. Sometimes you may become toxic to some of the medications, and you may go through psychosis. Depression, can be a behavioral effect of an seizure, an out come, cause from medication, socially consequence etc. Social issues, patients want to talk about driving or employment. Really quickly some states require the driver to report that they have the condition, here in this state that’s the case. Others require the physicians to report. Occupation if you work a dangerous job like a construction site, it may not be safe for you to work there, but because of the Americans disability act some employees must make accommodations for the patients. Pregnancies its best to be treated by one drug for those patients so they don’t have birth effects, you have to out weigh the positives with the negatives, the need of the patient and the child’s best interest. You must also supplement with folic acid. Sorry I ran out of time.

Brain and Behavior 15: Substance abuse 1 of 8

Announcements: Good morning, everybody. I will be talking today about substance use, its effect on neurobehavioral functioning, and addiction in general. This is the Brain and Behavior course, so a lot of the focus will be on the role of the brain in addiction, and how drugs of abuse primarily affect brain functioning. Why should you care? As soon-to-be physicians, if everything goes well, I know you guys are just starting started, and you guys have a lot of plans, and some of you are trying to decide in what you’re going to do in the future and addiction may not be a part of it…some of you may not even be thinking about psychiatry in your future. I know family medicine is a popular choice among many physicians-to-be and a lot of people use drugs. What I’m showing here is a list of prevalence rates of drug use in the US, from 2005. And as you can see here, if you take all of the illicit drugs together (not including alcohol), you have about ½ of the individuals ever used an illicit substance. So, if we assume that you guys are a relative representative portion of the population (which would be erroneous on my part), at least one of the people sitting next to you has tried an illegal drug at some point in time. WOW! Don’t freak out; don’t shy away from the person next to you. As you can see, the primary drug that’s used the most is marijuana, followed by (in terms of the non-prescription drugs) is cocaine…but of particular relevance for you guys is looking at the fact that non-medical use of drugs that are typically prescribed in the clinical setting are actually the second group of drugs that are abused, used without a prescription. So, let’s talk about what my goals are today. First of all, I’m going to start by defining addiction and I’m going to introduce you to diagnostic criteria for substance use disorders. Last year was the first year I was teaching this lecture and I was very interested in receiving feedback from the students so I can try to adapt and modify things to figure out what your needs are…I’m not a physician; my research is primarily in HIV and addiction and their behavior on neurobehavioral functioning so the things I tend to find are the most interesting may not be the things that you find interesting. But I remember in grad school that early on, there are things that you tend to be interested in, and some things that you’re not interested in at all…and probably a lot of you guys are getting sick of the fact that you’re not getting a lot of treatment education…you all want to be physicians, you want to help people, you want to know what to do with people who come into your clinic. I’m sorry to say that I’m going to touch on those things a little bit, I am going to mention them, but for those of you who are interested in these things at all, you’ll get a lot more education on treatment down the road in different rotations that you’ll do particularly in addiction medicine or psychiatry. But I’m not going to ignore things that are relevant or practical from a non-academic sense with you guys. Defining addiction is very important; defining addiction to a large extent will dictate how you see, view and potentially treat patients that come into your setting at some point that may have substance use disorders. You need to know what to look for; you need to know what may be a problem and what is not a problem. Some underlying biases that we may have about addiction; about what it is or what it means, will very much affect what you do to a patient that comes into your clinic with a substance disorder. So we’ll talk about different ways to define addiction and some diagnostic criteria for addiction. Then comes what I believe is the meat of the talk, which is why this is the Brain and Behavior course, and is describing the neural systems that underlie drug addiction (I will spend a lot of time on that). Then, I’ll talk a bit about some of the effects that specific drugs of abuse have on brain functioning, on neuro-cognitive abilities. Do they damage the brain? How do they damage the brain? What are the behavioral manifestations of some of the damage that these specific drugs do? And finally, I’m going to talk a little more about implications for clinical care; I’m not going to teach how to treat addiction (that’d be way beyond the scope of this lecture) but hopefully you take something out of this that you find relevant for you future practice in general. How do we define drug addiction? For a very long time, addiction was seen (and it still is)… I’m still shocked at how many people out there providing services still define people with addictions as this: societal victims, people with addictive personalities, a moral defect (people who become addicted to drugs are just amoral), and it’s just a behavior problem. These are choices that people make and these choices have consequences and people endure them. If somebody is an addict, it’s because of a personal failing of theirs, some kind of moral defect, some lack of willpower, if you will. All of those things may be true-to some extent, it is a moral judgment on someone’s part-but to another extent, the story is a lot deeper than that. If an individual comes into your clinic and they have a substance use disorder, and this is the way that you view them, then the way you’re going to treat them, will be different. If you view it as a moral defect, the appropriate thing to do would then be to refer them to a priest, a community leader or somebody else, their treatment will definitely not be on your domain. This is an official definition that’s currently used to identify substance use disorders (from the DSM-IV). You all probably have been exposed to what the DSM-IV is- it’s the manual that contains diagnostic criteria to label people with different psychiatric illnesses. Substance use disorders are in there. There are two types: dependence and abuse. For dependence, this is what you need. (SLIDE 5) You need a maladaptive pattern of use that leads to clinically significant impairments or distress (there has to be a problem) and it has to be also manifested by 3 or 4 these large set of symptoms and these 3 would have to occur within a 12-month period. One is tolerance (the drug doesn’t have the same effect that it used to, to a certain extent-it’s a physiological process that can be measured). Withdrawal, after the drug is removed…In previous editions of the DSM, withdrawal and tolerance were both necessary for someone to be called addicted to a certain drug. Now, things have changed with DSM-IV. Now, you need just three of these things; you can

Brain and Behavior 15: Substance abuse 2 of 8 call someone dependent to a drug without them having tolerance or withdrawal. They could’ve just taken in larger amounts than

they intended to repeatedly: “Oh, I’m only going to have one drink (or smoke one joint)” and before the night is done, they’ve gone through the whole bag that was supposed to last a month. Persistence desire or unsuccessful attempts to control the use: “Oh, I’ve got it under control” or realizing “Hey, I need to stop”, and you don’t quite stop, you keep doing it, and using it, and you say “Oh, someday, I’ll get around to it”. And you’re unsuccessful when you try, although you may rationalize it after the fact. Spending a lot of time trying to obtain the drug, using the drug, recovering from the drug use… Of course, impact in your life very negative ways occupationally, socially, recreationally…and of course, using the drug despite the knowledge that there are negative consequences for using these drugs. So, you have any three of these, you have dependence. And dependence applies to all sorts of different substances: cannabis, nicotine, cocaine, other stimulants… Abuse is a little different. Abuse is like, you’ve been a little naughty. You’ve done things that maybe you shouldn’t have, when you’ve used these substances. This is just ONE of any of these… (From SLIDE 6) that occurs during a 12-month period. You don’t meet dependence, but because of recurrent use, you haven’t fulfilled a major role obligation (attending M1 lecture for instance)…Also, using in situations in hazardous situations, like drinking and driving; if you’re intoxicated and you got in a car, that’s problematic. Having a legal problem due to substance use; and again, continued use despite these problems that we talked about. You have one of these; you meet the criteria for substance abuse. That’s what the DSM says dependence and abuse are for drugs; this is the proxy for drug addiction, based on the DSM. What are some of the general behaviors that one can look for and ask that have been found to be associated with substance use problems?

1. Do you use the substance alone? 2. Have you substituted one drug for another? “Oh, my drinking got really bad so I decided to stop drinking and started to

smoke pot…” Or the reverse… 3. Have you ever lied to a doctor to get a particular prescription? 4. Have you ever used a drug without knowing what it was or what it would do to you?

These are questions that you can ask individuals that are associated, correlated with a chance of having dependence. Ok, here’s the definition that I like, this is the one that I’ll push; here’s the one that I wish everyone in this room would leave with, or at least be convinced to some extent that this is a way that one should at least entertain what a drug addiction is. This primarily comes from the Leshner article, which was one of the two articles that were assigned to you. It’s a 2-page article and I highly recommend that everyone read it. It wasn’t necessarily a paradigm-shifting article but one that kind of demarcated a new time for substance use research altogether. It basically said that addiction is a brain disease: it’s uncontrollable, compulsive, drug seeking and use, even in the face of negative health and social consequences. As you can see, this can accommodate the substance dependence criteria of the DSM. Also, Volkow and Li more recently have just expanded on this a bit; they said that it’s an intense desire for the drug with an impaired ability to control the urges to take the drug, even at the expense of serious adverse consequences. So, again, we’re talking about the inability to stop doing something that has become bad for you. Because of course, even for the DSM, there has to be some sort of clinical impairment or problem for it to be considered addiction. Another important thing to keep in mind from the Leshner article is that addiction is a chronic relapsing disease; sort of like diabetes or HTN; where you can’t necessarily completely cure it, but you can treat it, and it involves compulsive drug seeking and use, despite knowing that this is bad for you and that it’s causing problems for you. Now, I’m not going to talk about addiction all around. I’m basically going to focus on drug addiction, but it’s important to keep in mind that some of the underlying neurological processes on drug addiction are not specific to drug addiction. A lot of other types of addictions, some of the problems that I’ll show you in certain brain systems have also been implicated in gambling, overeating, internet addiction (some of you may have heard of internet addiction, and some of you may be contemplating if you have internet addiction). For the next DSM, they’re thinking about including it, and particularly in S. Korea, with the RPG’s, there’s a lot of addiction clinics that have gone up, because people are playing World of Warcraft instead of doing anything else in their lives. I’m sure none of you, well…some of you may be struggling with some of those problems yourself…there’s definitely a transition from undergrad to being a medical student, where some of the things you found very pleasurable and engaged in, need to be curtailed in order for some things to happen in your life. So, what are some of the neural systems that underlie the addictive process? The primary neurotransmitter that has been the focus of addiction most of the time has been dopamine. And a lot of other neurotransmitters are important as well, but dopamine is the important one for you to keep in mind. There are two primary pathways. There’s the nigrostriatal pathway that starts in the substantia nigra and goes up into the striatum, the caudate and putamen; and then there’s the mesolimbic-mesocortical pathway, that starts down here and makes it way into limbic structures (nucleus accumbens, amygdale, hippocampus) and then up into PFC. Honestly, I’m not sure what you’ve learned in the other lectures so some of the things I may say may be a little redundant because you’ve already learned about these these structures. But striatum, caudate in particular, is important in voluntary movements and planning actions and control, and it’s also important in attributing reward value to objects. And the PFC is thought to be important in planning, inhibiting behaviors, and of course the limbic structures are important in integrating emotional information in your decision-making, and also for putting down memories. I’ll talk about all those a bit more. All drugs of abuse exert some effect in these two pathways that I mentioned. So the addictive process is driven by both cortical and subcortical pathways, since structures along both these pathways cover both cortical and subcortical. This is just a little picture from a classic experiment…if you’ve taken a psych class, or if you’ve read a random magazine, you heard about these experiments that were done in the 40’s-60’s, when they’d put electrodes in rat’s brains that stimulated these pathways that I’ve just mentioned and rats are given a choice between eating and giving themselves a little shock to get that dopamine going. The rats start doing a little bit of

Brain and Behavior 15: Substance abuse 3 of 8 both, but as time goes on, the rats start just giving themselves these shocks (not shocks, but stimulation of reward pathway) and

they keep doing this until the point that they die from starvation. This pathway is very important for ascribing the reward value of objects in your environment. For a long time, it was thought that dopamine was the pleasure molecule. Dopamine is released and it makes you feel good; it makes you feel that there’s pleasure, that there’s something that feels really great, and that’s why people go after this, this kind of hedonic response. But much more recently, over the last 10 years, the story got a lot more complicated. As an organism moving through the environment, you approach an object, and you have some sort of interaction with that object, and your brain needs to encode whether this is something you should have more of, or this is something that you should stay away from. So, eating food, having sex, these are pleasurable things, stimulate these pathways, and let your brain know: “Hey, you want more of this; this feels better than what you normally expect”. So, this discrepancy between your expected reward value of something and what you get, tells your brain to go and get more of that thing. Same thing happens when something is negative and unpleasant. So, drug use and a lot of drugs specifically affect these systems. I want to talk a little bit about some of the neuropathophysiology of drug addiction and some of the structures but also the behavioral concepts that map on some of these brain regions. This is from Goldstein and Volkow (SLIDE 15), which is an article that I included in last year, but not this year. Basically, it shows a schematic of some of the key players of different brain structures involved in the process of developing an addiction. Again, you see that these are the structures involved in the mesolimbic and nigrostriatal pathways. You have the ventral tegmental area which is rich in dopamine and dopaminergic efference; nucleus accumbens, amygdala and hippocampus, limbic structures, thalamus (kind of a relay structure) but these two structures (amygdala and hippocampus) are going to do a lot in encoding memories, valence of things, and from an emotional sense, guide what behavior is going to be. And the Prefrontal Cortex (PFC), which I’m going to spend a lot of time on, is involved in a lot of different, and I’m just going to focus on the actions of these structures that pertain to drug addiction. And the PFC is particularly important, in terms of drug addiction, in putting the brakes on behavior. Because a lot of you guys may want to do things and you don’t do them because you know it’s going to be bad for you, even if you have the urges, and you inhibit; and it’s thought that a lot of human behavior is primarily driven by inhibition and the ability to inhibit. There are a lot of investigators in this area. Also, there are a lot of neuro-philosophers in this area as well that, this concept of addiction maps onto the question of freewill and what constitutes freewill, but for this system it appears that the issue is not so much freewill but freewon’t and ability to put on the brakes on the processes that start. So, let me give you an example. Here, we have marijuana, and these are some sorts of behavioral concepts that map onto the brain systems that I’ve mentioned. For any of this stuff to happen, you have to have had contact with the object before. If you’ve never tried a drug before, you’re not going to ever become addicted; that’s a given. So, you have to have tried it before. You’ve done marijuana before and let’s say you had a pleasant experience, you tried and liked it; it was a particularly good party, the music was great, you ate some good food, and marijuana is something you consider positive. So, you’ve got this memory, and then the salience of this drug is positive; it’s something that your brain (because of the positive experience) says that you should have more of it, because it’s a positive thing. So, that triggers drive. So, there’s the motor output to go ahead and use this substance, so all of a sudden you go ahead and…there’s a control system on the top that can intervene and prevent this drive from carrying out into actually using this substance, so here’s when you have this PFC working to inhibit this drive. So, you basically have systems in opposition to each other. One is telling you to go do this and get this, and another one telling you not to, and is inhibiting you from actually going out and doing this. If control is weak and you’ve had this experience (you’ve used this substance), but there’s a problem in the brain structures that put on the brakes, the outcomes will be very different. Do drug addicts have problems or deficiencies in the brain structures that are involved in inhibitory control? The answer is yes. Here’s glucose metabolism in a brain of healthy control and here’s glucose metabolism in an individual that has drug addiction. And you can see (SLIDE 17) the difference in the prefrontal, orbitofrontal cortex, there’s a lot less metabolism in these areas, suggesting that these structures are not functioning as well in these individuals. Now, back to the concept of a brain disease, this is part of the data that should help you think about addiction as…there are underlying processes and changes that are going on in these brain regions that are taking place that are making individuals vulnerable to repeated use, more drug abuse. Inaudible question by student regarding imaging studies and whether those differences were there prior to the drug abuse or they happened as a direct consequence of the drug itself. That’s an excellent question, and the problem is that it’s likely two things: this is probably a result of the drug itself, and it depends on the drug but I’m glad you brought that up because I’ll come back to this system…marijuana is a little bit different…but let’s say it was cocaine or methamphetamine, that the drug itself regardless of the fact that it feels good and it makes you go after it, the drug itself stimulates dopamine release so just the fact that you used the drug, even if you hated it, the brain systems are activated that will encode that use of that drug as something that you need to have more of. And this is something you’re going to see when individuals suffer from drug addiction: “It doesn’t even get me high anymore, I don’t like it, I want to quit, I’m trying to quit”, and they keep falling into these patterns of drug use. So, there may be some pre-morbid, prior to any drug use, differences in brain structures that would make some individuals more vulnerable to drug addiction, but once drug use starts, there are changes that take place in brain structures, particularly for some drugs, that then make the individual even more vulnerable to continue using and getting more addicted; so you’ve got kind of a feed-forward loop that makes addicts particularly vulnerable to more drug addiction. Yes, absolutely, nicotine addiction is…there’s some arbitrary branching in substance use research that occurs, and I’m not a nicotine researcher…What ends up happening is that nicotine research is a completely different branch, just like alcohol research…Nicotine is very addictive, and I’ll mention it later, but the same kinds of things happen, it’s enjoyable…but the questions are…the things that may make an individual more vulnerable to become more addicted to one drug rather than another may be slightly different: it may be reduction of dopamine transporter density in certain brain region, or problems

Brain and Behavior 15: Substance abuse 4 of 8 with glutamate and nicotinic receptors, so what I’m talking about here applies to addiction in general including nicotine, but

there are a lot of slight differences to consider. So, down here, again, is metabolism and you see a healthy heart and a heart after a heart attack. So, why would you think about the brain any differently than you would about this heart; if there’s clear physiological evidence that there is damage that’s taken place from something, why would you treat one thing and not the other? And some of you may be sitting there and thinking: “I wonder why Dr. Gonzalez is harping on this” and working with other substance use researchers and being in this field, I take it for granted that I see drug addiction as a brain disease. A friend of mine, who I grew up, decided that he wanted to go into paramedics, and he was doing his rides, and we were on the phone catching up on things. This was in Miami, and he was telling me about a situation where his mentor who he was riding with…they go into this guy’s house, and there’s a gentleman who’s complaining of a heart attack and he’s clearly in a lot of distress. My friend was telling me this story and very flippedly said that he was clearly drunk and immediately the way that this individual was treated changed dramatically. Because he was drunk, everything he now said was meaningless and unimportant; because he was drunk, now these individuals who are supposed to be health care providers are seeing him as a nuisance, are seeing him as somebody who is dialing 911 when they’re not supposed to. Now, this is an opportunity for treatment; if this is somebody who is an addict, an alcoholic, why not take him to see a psychiatrist? This individual may have been suffering from a panic attack; he may have an anxiety disorder. If he wasn’t drunk, the treatment would’ve been very differently. This is happening now, this is happening today. Last year, one of the comments that I got back from one of the medical students was that I should recognize that drug use is a behavioral choice and they also didn’t like some of the funny pictures that I put up and that my use of those pictures was also behavioral choice like addiction. Again, I’m very grateful for a comment like that because it reminds me that some of the things that I take for granted, I shouldn’t take for granted. So, you know, obviously can think about people’s morality in many different ways but to deny the fact that there are clear changes in brain functioning that take place from drug use that have clear behavioral manifestations, would be turning your back on facts. I showed you a study showing metabolism affecting the prefrontal structures. Now, that’s the brake system; remember, it’s the system that’s going to inhibit. You also see activation in the regions that attribute saliency, that’s going to get you the drive to do something, among addicts. Here you have people addicted to cocaine watching a nature video, and here you have a healthy brain watching the same video. You show a video where cocaine is being used by individuals and see that the amount of activation in these frontal regions is a lot less in the individual that has a history of cocaine addiction than the individual that does not. However, you see increase activation in anterior cingulate and structures that are important in attributing value of something. So, somebody who’s a cocaine addict is getting the structures that trigger drive and use, they’re all getting worked up pushing that drive system to GET, GET, GET, but the brake system is dysfunctional, problematic. Now, are these permanent changes that take place? No, there’s change that happens over time. Again, here you’re seeing some metabolism (usually glucose) of normal healthy controls, and here are cocaine abusers 10 days after they stop using, and here’s 100 days after they stop using. Even after 100 days, the brains don’t look quite the same, but you can see that there are improvements in metabolism in a variety of regions compared to the 10 day users. And you can see, this area up here, this PFC/orbitofrontal cortex, is practically silent compared to the healthy controls. Ok, I’m going to change gears just a little bit and talk about the neuro-cognitive problems that are associated with long-term use of a variety of substances. Everything that I’ve talked about until now are common underlying issues, or differences in brain functioning, among people who are drug addicts versus those who are not. Well, I’m going to talk about that in a bit, I’m not going to get ahead of myself. So, now I’m just going to talk about: If you use a drug, does it cause brain damage? Are there changes that take place in brain structures, and the neuro-toxicities associated with the use of these substances? And if there is, what are some of the neuro-cognitive abilities that will become problematic? Before I do that, it’s also important for you to recognize as future M.D.’s that people who are substance users typically tend to have high co-morbidity of other problems. So you get also more history of head trauma particularly with alcoholics. People who are high all the time tend to hit their heads a lot. Also, ADHD is more common among substance use disorders and with ADHD, you can probably see how there might be this underlying inhibitory problem that may be common to both of these disorders. So this common problem of inhibition may provide a liability for both ADHD and for substance use disorders, which are also more common with people with ADHD. Malnutrition, particularly with alcohol; with IV drug use, you see more HIV and hepatitis C, each which confers its own neurocognitive problems; lots of psychopathology; also polydrug use, it’s rare to find individuals who use one substance alone, they usually use a lot of different things. And then, the chicken or the egg problem; which is what was brought up here in the front row: what are things that make someone vulnerable to addiction that occurs before drug use, and what are things that happen afterwards? Ok, so I’m just going to go through a bunch of substances, the primary neurotransmitters these work on, and talk a bit about some of their effects; to make sure you guys know about these things. I focused on the common pathways that affect all drugs, but I don’t want to ignore some of the unique differences in all these drugs. So, up top we got cannabis. Cannabis is unique in that the primary neurotransmitter that THC binds to and affects is CB1, which is cannabinoid receptor, densely distributed throughout the brain, particularly in basal ganglia, cerebellum, PFC and the limbic system. Raise your hand if the endocannabinoid system has been discussed in any class before? It’s ok if you did not; it’s just going to dictate if I’ll talk about it a bit more. This is an important system that you’ll be hearing more and more as medical students because it’s probably one of the ones that have been least exploited as far as medication use, and of course, the pharmaceutical companies want to make sure that they get these medications going, and we got this relatively new neurotransmitter system that hasn’t been exploited at all, and we’re learning more and more about the behaviors that it’s implicated in. So, we know about two CB receptors, CB1 is in the

Brain and Behavior 15: Substance abuse 5 of 8 brain, and CB2 is primarily located in the immune cells throughout the periphery. So, THC binds to CB1 and we have our own

endogenous cannabinoids, because we didn’t evolve cannabinoid receptors so we could smoke pot! We have our own cannabinoid system that’s thought to be important in nursing, feeding, anxiety, pain, and there is lot of medications that are now in clinical trials; a few have been approved…Marinol is the only one that’s actually just THC and is given orally, and THC is not good to be given orally; the body has a hard time processing it; it has all sorts of erratic absorptions, it reaches peak concentrations at different times…so it’s really not a good delivery system for THC to the body, that’s why it’s not a commonly used drug. But, there’s rimonabant which is trying to be used both for weight loss and for addiction. I think it was actually approved in Europe for weight loss. So, this is a cannabinoid receptor antagonist. So, if you think about it…what happens to someone whey they smoke pot, they get the munchies, they get hungry…so this system is important in feeding behaviors, so when you block it, people stop eating. But what ended up happening (why the FDA didn’t approve it) is that people were also freaking out, they were getting really, really anxious. This system is also important to keep you calm to a certain extent. So you start blocking it, yeah, you’re not eating too much, but you’re also now much more anxious…and also they found out that it didn’t make that much of a difference in eating. But a very promising avenue for a cannabinoid agonist is for multiple sclerosis, muscle spasms and pain, also for patients who are undergoing chemotherapy because it also has anti-nausea effects. So, you’ll see a lot more of this endocannabinoid signaling system being used in pharmaceuticals. Also, it’s very important for addiction in general. This system is important, although the kinks are still being worked out, in ascribing value to different things in the environment. So, they were also trying to use rimonabant for smoking cessation as well. But the problem is of delivery; this oral delivery is not very good so they’re experimenting with all sorts of things because no doctor is going to feel comfortable telling people to smoke something, no matter what it is, so they’re doing sublingual prepartions to help the absorption of it. Also, with marijuana use, if you get individuals who are very light user, very heavy users and non-users…you don’t tend to see too many differences in neurocognitive functioning between those that are light users and non-users, but among very heavy users, you see primarily problems in learning and memory. But if you make these people abstinent, most studies show that usually by 28 days out, they’re back to normal. However, in imaging studies, you still see some differences…but the question of course is people who become dependent on marijuana, just like most drugs, are probably not representative of the general population. I’ll talk a bit more about that later. Methamphetamine, big problem! Particularly in the Midwest and in the west coast. I did my graduate work out in California and meth is just…a big scourge out there. Methamphetamine primarily works through NE, dopamine and serotonin; very addictive, because it pushes for a lot of dopamine release, so even if you hate meth, if you do it, your brain is going to encode now, do more of this, even if you’re saying “I hate this.” Meth, I don’t know how common the use is here in Chicago, but like I said, it was very common in California. And a lot of that is that it was actually frequently used during WWII, as a stimulant to keep people awake, keep them working. It was heavily used in Japan, and after WWII, there was huge surplus of meth all over the place. Japan had a huge meth problem, started to export it…making its was into the Pacific Islands, then to Hawaii (if you’ve seen Dog the Bountyhunter knows that Hawaii has a big meth problem) and then it reached the west coast, and then it’s slowly moving its way into the Midwest, primarily ‘cause it’s cheap and easy to make and people like the way it feels, obviously. With meth, you get all sorts of neuro-cognitive problems: verbal memory, executive dysfunction, speed, psychomotor, attention. Most studies show that they persist for a couple months; some say they linger for longer. MDMA, this is ecstasy. A problem with MDMA is that rarely people using ecstasy are getting only MDMA, because it gets mixed with all sorts of stuff: MDA, MDE, caffeine, etc… MDMA in and of itself primarily acts through serotonin, but also through NE and dopamine. The literature on this is very complex because most people who use MDMA use very little of it, and use it rarely. But you have a bunch of people, who don’t; who use it heavily and use it all the time, and these individuals also have a lot of other co-morbidities, psychiatric problems, all sorts of stuff. So when you start doing these studies and start comparing heavy MDMA users with normal controls and other drug users, you have these problems with these confounds, in terms of interpreting, what in fact is an effect of MDMA and what is not. There were some very seminal studies with primates that showed that administration of MDMA cause damage to serotonergic terminals that last for a very long time, and then it came out a few years ago, that the lab had totally screwed up; that they were giving the monkeys meth instead of MDMA, it was like a lab mistake. This was a paper that was published in Science magazine, and they had to retract it. It was rather embarrassing. But, there is some evidence for nerurotoxicity for MDMA, and other people argue against it. It’s hard to say, but with light users, you don’t tend to see any differences, but with heavy users, you see all kinds of problems: verbal and non-verbal memory, attention, psychomotor, speed, executive functions. Cocaine whose primary neurotransmitter is dopamine presents problems with attention, exec function, psychomotor, speed and memory and these tend to persist for months. Now, I’m talking about the behavioral manifestations of these drugs. The changes that you still see in brain structures, as far as metabolism and activation across a variety of tasks, may be different and still persist. Heroin primarily works through the opioid system in the brain. With heroin users, you tend to see executive dysfunctions, attention problems and psychomotor problems and these disappear with abstinence. Benzodiazapines is something that I’ll talk about a bit more because benzodiazapines are likely to be prescribed by you guys in some way or another. Now, you may remember from that first chart that I put up, in terms of substance abuse, that after marijuana, the non-therapeutic use of prescription medications; and that’s a big problem. And it’s a growing problem. For your classmates who didn’t attend the lectures, these slides have the incorrect neurotransmitter for benzodiazepine, but it’s GABA. I’m not going to test you on

Brain and Behavior 15: Substance abuse 6 of 8 this, but I just didn’t want you guys to walk out of here with wrong information. Neuro-cognitive deficits from benzodiazapines

(a laundry list compared to these other ones): problems with sensory processing, non-verbal memory, attention, concentration, working memory, psychomotor, speed, visual/spatial, problem solving, verbal reasoning, motor control. Most of these may persist for as much as three months. They’ve done some really good studies, longitudinal investigations, and meta-analyses of the effects of these drugs, and some of these differences compared to controls persist for up to 2 years. In these studies, primarily we’re looking at therapeutic doses of benzodiazapines; these are not heavy abusers, you know, people who are out in the streets popping out tons of valium just for fun; these are long-term therapeutic use. The more you use, the worse the problem. These studies were done by Australians and I think that the Australian Psychiatric society or another big medical group has put out strong statements saying that benzodiazapines are drugs that should be prescribed ONLY when necessary, in the LOWEST dose possible, for the LEAST amount of time possible, mainly because of these problems but also because of the potential for abuse and addiction. Most of my time I spend on research but once a week I see patients in the neuro-psychology clinic here on campus. And it’s such a commonly prescribed thing, particularly among like, little old ladies, who are potentially suffering from dementia, and they’re given drugs for long-term use for anxiety that causes all these additional problems. Just something to keep in mind. All right, now I’m going to switch back to talking about inhibitory control. This is an area that’s very interesting to me; it’s where most of my research takes place. The question is: is the inhibitory control problem in decision making common to all types of addiction? And from what I’ve already shown you earlier, the answer appears to be “YES”. So, what are we talking about when we talk about decision-making and inhibitory control? There’s lots of different ways to talk about it but one interesting way to look at it is: It’s an ability to make choices in the present that lead to the best outcomes in the future. This is a very human thing to do and one that involves very high-order processing. You’ve got this immediate environment around and somehow you brain has to trick itself so that you’re told that the best thing for you to do now is not the best for you long-term. This is happening to you all the time and your brain is constantly doing all these calculations and making these things happen. So, you may choose the less attractive option now to ensure that you have the best outcome in the future. The brain structures that are thought to be important in allowing this process to take place are the PFC, the orbitofrontal cortex (the area of the brain that sits right above the orbits of the eyes) and the ventromedial PFC. An example, as medical students, you have a test…do you go out and party? Do you sleep instead of studying? Do you spend time with your significant other? Do you go out on a date? What do you do? I’m sure most people here substitute these activities that you find pleasurable day in and day out…there’s a lot of other things that I’m sure you guys would rather be doing than sitting here listening to me (or reading me in coops, right?) or studying or doing many of the things that you do now. Even though there are so many other pleasant things that you’d rather be doing, why do you do these things? Why do you suffer? (giggles). You suffer today, so that you may graduate down the road! This system is disrupted among addicts. So, I’m going to talk about some of the tests that we use to measure inhibitory control, and I’m going to go quickly because I think I’ll run out of time. The Iowa Gambling task is one of the tasks that we use. Here, individuals see one of these screens on a computer. And they have 4 decks of cards, and they’re told to make a choice from one of the decks. They pick a card and may win some money and may also lose some. Their goal is to win as much money as possible. What these people don’t know is that some cards give you really high wins, but once in a while, give you even larger losses. And then other decks, give you small wins, but the losses are even smaller. So, what ends up happening over time is that…here what you’re seeing (in the graph) is the number of picks from bad decks (they get to pick 100 cards); you get to see how many choices they’ve made over blocks of 20 cards each, from the bad decks. At the beginning, normal healthy controls and individuals with substance use disorders start picking from the deck that is giving them the big bucks. As time goes on, normal healthy controls start reducing the number of choices that they make from the bad decks; they start switching to these other decks that have smaller rewards but they make more money over time. The individuals with substance use disorders don’t make the shift; they keep picking from these decks with the high wins and the huge losses and they’re broke at the end. That’s one of the tests. Here’s another task. This is called Delay discouting. Delay discounting has been known for a very long time; economists have examined it, and it’s basically this function that appears to take place in our brain (but not just humans, mammals in general and even pigeons are shown to have this function as well). What happens is, let’s say you make a graph of a line where you have how much value you ascribe to something (say, money) at this present moment in time. So 100-dollar bill, how much value do you ascribe to it right now? You probably would say 100 dollars. But what happens is, if I give you that bill further along in time, the value that you ascribe to that item starts going down in a hyperbolic fashion as the delay kicks in. So, here’s the function…here’s the present value that you’ve given to the reward, and here’s the actual value of the reward, and as you can see, as the delay goes out, the value is going to go down. You can figure out how individual differences in how steeply different individuals discount value of a reward as it goes out in time. Different individuals may do this more or less. And as you see here…here you have heroin users and here you have healthy controls…and when it comes to money, what you see is that…here’s how over time, normal healthy controls devalue a reward as it’s given to them further away in time, and here you see that individuals who are heroin addicts have a much steeper discounting curve. So, the further away in time some reward will be for them, the more steeply that they discounted in the present. And of course, if you guys are thinking this through, you can see how this ties back to the making a choice now that may not be the most pleasant choice, but it’s good for the long-term outcome. Now, say you don’t use money, but now you do the same the same test but you say “bags of heroin”, today versus so many bags of heroin down the road. Here’s the discounting function for heroin; much more profoundly discounted than that for money. I failed to mention this before, but basically one of the questionnaires that we use to assess this is this questionnaire that basically just asks people: would you prefer this amount of money today or this much so many

Brain and Behavior 15: Substance abuse 7 of 8 days from now? Would you prefer 54 dollars or 55 dollars in 117 days? 55 today or 75 dollars in 61 days? People do a whole

bunch of these questions then you can figure out what k is, which is the discounting rate. Here’s another task. This task is very unique and basically asks an individual to inhibit a behavior that they already started. It’s called the Stop signal task. Individuals are told that when they’re shown a certain symbol, they need to respond as quickly as possible. And that’s just your reaction time. Whenever you see an X on the screen, hit the space bar as quickly as possible. Individuals are told that sometimes when you see the X, it may be followed by a beep or a 0 on the screen; basically a stimulus upon which you need to not respond. So, you got the GO signal, now you get a STOP signal. So, you’re responding, but when another stimulus comes up, you need to stop that response. What that lets you know on this task is how much time, warning, somebody needs to be able to inhibit a response they’ve already started. Individuals with substance use disorders, with ADHD and other problems of inhibitory control need more of a heads-up to stop a behavior they’ve already initiated. So, again, we’re talking about this common deficit in inhibitory control and you can see how all this maps onto this model I showed you earlier on that involves memory, salience and drive and the ability to inhibit that drive. Here’s another unique task. This is the Balloon analog risk task (BART). Here individuals see this balloon on the screen, and they’re told the balloon is going to grow with each click. Every time you hit the space bar, the balloon is going to grow a little bit and you’ll earn 5 cents in the pot. Now, the balloon could pop in the first time you inflate or maybe you could fill the balloon to fill the entire screen until it pops. What you have to do is to decide when you want to stop pumping it up and just kind of cash out. When you cash out of that trial, the money you’ve accumulated will go onto your pot, and then you go on to the next trial. You don’t earn any money until you hit collect; if the balloon pops, you’ve lost all the money that had accumulated up to that point. Now, here’s what the individuals don’t know: there’s a fixed probability that the balloon is going to pop, it’s 1/128 on the first click, 1/127 on the second, 1/126, so with each successive click, the probability that the balloon is going to explode increases. And what’s interesting here is that the amount of money that you’ll potentially earn, it doesn’t go up, it’s still 5 cents; so with each click, the probability that balloon will explode goes up, and the amount of money that you’re making as a proportion of the amount of money that you’ve collected, starts going down. And on that task, you see that individuals with substance use disorders have a lot more popped balloons than the individuals without the substance use disorders. I’m going to talk now a little bit about some treatment related things. So, prevalence of substance use disorders... Now, I’ve showed you just use in general. What percentage of the population meets the criteria for substance use disorder on any given year? In terms of illicit drugs, it’s only 2.8% of the population. For marijuana, it’s 1.7% and as you can see, that’s the highest. That’s the drug that most people…that has the highest prevalence of being addicted to. And you can see that it’s less than 1% for most other substances; again, followed up by non-therapeutic use of prescription drugs. So, the question comes up of course…if you’re interested in the research on this…Most people who use drugs or who have ever tried drugs does not become addicted to drugs. It’s a very small subset of the people that tried drugs that has actually developed a substance use disorder. And I’ve tried to convince that there are differences in the brain of these individuals from the drug use and they may have some pre-morbid vulnerabilities as well that are worthy of giving these individuals treatment. Seeing this graph/table right here, I’m going to ask which drugs do you think people have the highest likelihood of being addicted to? I’m going to give you alcohol, heroin, cocaine, and nicotine. Raise your hand if you think it’s marijuana? Nicotine? Heroin? Cocaine? Ok, good; there’s a lot of variability in the responses. This is not to test how smart you are or how much you know; this is just to keep you guys engaged and also to make you care a little about this next slide. There’s another way to look at substance dependence that’s called conditional dependence: what are the chances that you’ll develop a substance use disorder in the future if you’ve ever tried a drug? So, of all the people who ever tried marijuana about 9.1% develop dependence, for alcohol, 15.4%, for cocaine, it’s 16.7%, for heroin, it’s 23.1%, and for nicotine, it’s 31.9%. So, as you can see, some drugs are more addictive than others, although they all work on the same underlying pathways. So, are substance use disorders a public health concern? Absolutely. You can see what the total economic burden is when you add up all the days off from work, arrests, health care costs…Another thing to keep in mind is, what good is it going to do to you as a health care provider, to be prescribing to individuals who have an active substance use disorder without treating their underlying substance use disorder or referring them for appropriate treatment. Do you think individuals in the midst of addiction are going to take their meds as prescribed, follow up on their appointments, and take care of their health? Well, as I’ve shown you, individuals that suffer from these problems will have a hard time doing that, because of their inability to not do the best thing now so you could have the best in the future. It’s about NOW, NOW, NOW, and not about the future. And this is something to keep in mind when you’re treating people with these problems. So, you’re going to see impulsive decisions in the clinic. These individuals don’t necessarily plan well for the future (I’m generalizing and I don’t want anybody to think that I’m saying that drug addicts can’t plan…that’s absolutely not what I’m trying to say)…What I’m saying is that some individuals have an increased risk for certain and individuals that have a history of substance use disorders have some of these problems that I showed, more so than the general populatioin. So, the second article that I’ve posted, Volkow & Li, if you’re interested in some treatment related information, I highly recommend you read that article. At the end, it talks a bit about some treatments that have been found to be beneficial for individuals with substance use disorders and has a laundry list of different medications that are being approved for the same. And most of these meds have to do with making the individual feel bad about the drug, or blocking the rewards to try and make the brain hijack itself in terms of the behaviors that they engage in. So, what can be done? Well, better training in addiction medicine. Your primary care physician is going to be the person that will the most people with substance use disorders. If they don’t recognize them and they don’t refer

Brain and Behavior 15: Substance abuse 8 of 8 them; not only does that mean that individuals aren’t going to get treatment for problems they have, but also that whatever

treatment that physician is trying to give will be less effective. So, it’s important to just be aware of these sorts of issues. Having clinics where individuals can get substance use treatment along with other medical care, so there doesn’t have be juggling with multiple visits, places, appointments. Communication with the other providers is also important; as individuals are referred to psychiatrists or other issues, it’s important to talk with the providers. 12 step programs, cognitve-behavioral therapy, and all sorts of treatments for substance use disorders. Now, another thing is…if somebody enters into your clinic and you’re like “oh, this person looks like a druggie”, you have to assess this thing with everybody, you never know who’s going to have a substance use disorder. Not everybody fits these stereotypes we have in our minds. 8-12% of physicians will develop a substance use problem during their careers; most of physicians who abuse substances continue to function quite well even when their problems are advanced. You’re high-functioning person; you know how to cope with adversity, and you can have this disorder and continue practicing… Here are the relative risks by specialty to develop a substance use disorder. Those of you who are going into emergency medicine are particularly vulnerable, there’s a 3X risk of developing a substance use disorder. And of course, anesthesiologists have an issue of access. Then, it starts going down…as you can see, pathology…no one wants to get high if they’re doing pathology. (giggles) So, just to summarize a bit…Addictive processes are mediated through brain circuits including limbic and prefrontal cortical regions; drug addiction involves cognitive-behavioral issues that are mediated by the PFC; drugs of abuse exert common effects on neuro-psychological functioning and these behaviors affect daily care. And finally, I just want to make a plug that in our research team (the HIV and addiction neuroscience team), every year, we have at least a couple of med students join us to do research with us over the summer, and sometimes even extend it through the year. I know you guys probably don’t talk a lot from class to class, but last year we had Oliver Chang, and Kara working with us; they’re not with us now because they’re studying for Boards. So, if someone’s interested in getting some experience in this, feel free to contact me. You can find my email address on the psychiatry website: www.psych.uic.edu . If anybody has any questions, I’m more than happy to answer them. (applause)