Ressler KJ, et al. PPT.ppt

8/14/2019 Ressler KJ, et al. PPT.ppt

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Targeting abnormal neural circuits

in mood and anxiety disorders:

from the laboratory to the clinic

Kerry J Ressler & Helen S Mayberg

VOLUME 10 NUMBER 9

SEPTEMBER 2007

1116-1124

NATURE NEUROSCIENCE 14.805, for 2006; 4th of 341 neuroscience journals

http://www.nature.com.libaccess.lib.mcmaster.ca/neuro/index.html


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Kerry J. Ressler MD, Ph.D

Assistant Professor of Psychiatry and Behavioral

Sciences

1- Department of Psychiatry and Behavioral Sciences, Emory University, School

of Medicine, Atlanta, Georgia

2- Yerkes National Primate Research Center

http://userwww.service.emory.edu/~kressle/

http://userwww.service.emory.edu/~kressle/kerry.htm
http://userwww.service.emory.edu/~kressle/http://userwww.service.emory.edu/~kressle/kerry.htmhttp://userwww.service.emory.edu/~kressle/kerry.htmhttp://userwww.service.emory.edu/~kressle/


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B.S. in molecular biology@ M.I.T.

PhD (1995) Department of Neurobiology, Harvard University

M.D. (1997) Harvard School of Medicine

Residency in Psychiatry at Emory University School of Medicine

Research fellow with Dr. Michael Davis at Emory

studying behavioral neuroscience


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Dr. Ressler's lab at Yerkes Research Center is focused onthe molecular and cellular mechanisms of fear learning

and the process of extinction of fear in mouse models. He

hopes that by understanding how fear works in the brain,

it will improve our understanding of and advancetreatments for fear-based disorders, such as PTSD and

Panic Disorder.


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The goal of my laboratory is to create a program whichutilizes the enormous power of molecular biology to

approach difficult and important questions in systems

neuroscience.

I use genes known to be involved in synaptic plasticity to

examine plasticity in the amygdala and regions whichconnect with it during the consolidation phase of fear

memory formation.

http://www.emory.edu/NEUROSCIENCE/facultyprofiles_Z.html


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I am also initiating a program to create transgenic animal

models for visualizing the amygdala neurons, some of its

sensory inputs and the neuromodulatory projections which

together mediate some of the important behavioralresponses of fear and stress.


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During his clinical time, Dr. Ressler is co-director

with Dr. Ann Schwartz of the newly created Post-traumatic Stress Disorders Clinic at the Adult

Outpatient Psychiatry Clinic at Grady Memorial

Hospital.

Dr. Ressler was recently nominated as an Investigatorwith the Howard Hughes Medical Institute.


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Helen S Mayberg M.D., FRCPC

Professor of Psychiatry & Neurology

http://en.wikipedia.org/wiki/Helen_S._Mayberg

http://neurology.emory.edu/Faculty/Mayberg.htm

1- Department of Psychiatry and Behavioral Sciences, Emory University,School of Medicine, Atlanta, Georgia

2- Department of Neurology, Emory University, School of Medicine, Atlanta,

Georgia

She is also affiliated with Rotman Research Institute at Baycrest Centre and the

Departments of Psychiatry and Neurology, University of Toronto
http://en.wikipedia.org/wiki/Helen_S._Mayberghttp://neurology.emory.edu/Faculty/Mayberg.htmhttp://neurology.emory.edu/Faculty/Mayberg.htmhttp://en.wikipedia.org/wiki/Helen_S._Mayberg


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Born in 1956 in California

B.A. (1976) Psychobiology @ UCLA

M.D. (1981) University of Southern California

University of California, Irvine Graduate studies: Departmentof Radiological Sciences

Residency (1985) @ Columbia Universitys Neurological

Institute in New York City

Research fellowship (1987) at Johns Hopkins Universitys PET

facility from


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Research Focus

My research concerns the characterization of neural

systems mediating mood and emotions in health anddisease using functional neuroimaging.

Defining brain mechanisms underlying major

depression is the primary goal, with an emphasis on

development of algorithms that will discriminatepatient subgroups, optimize treatment selection, and

provide markers of disease vulnerability.


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INTRODUCTIONMajor depressive disorder (MDD) is the most common of allpsychiatric disorders.

MDD ranks among the top causes of worldwide diseaseburden and disability, with lifetime risk of 712% in menand 2025% in women.

20% completely fail to SSRIs, 60% may not achieveadequate response.


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The different anxiety disorders, including panic disorder,

post-traumatic stress disorder (PTSD) and phobias, are

also extremely common, with a combined lifetimeprevalence of over 28%, and with a similar societal cost-

burden with similar rates of failure to respond to

treatment with that in MDD.


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In this review, MDD and anxiety disorders will be

considered together:

1- comorbidity

2- a significant problem of diagnostic classificationwith highly overlapping symptom criteria

3- similar involved brain circuits

4- similar treatments (e.g., SSRIs, CBT)

Current clinical descriptions are probably not

identifying the phenotypic clusters of disorders

that may be most useful from a neurobiological

and treatment perspective.

Problem in current clinical descriptions!


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There are several circuits within the limbic-cortical

system that mediate

-Stress responsiveness

- Mood and emotional regulation.

Disorders of mood and anxiety represent brain-baseddisorders that lead to dysregulation of these circuits.


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New neurostimulatory therapiesbased on progress inunderstanding emotion circuitryand new

pharmacological therapiesbased on understandingemotional learningare likely to provide more rapid androbust methodologies for treating MDD and anxietydisorders.


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1- Abnormal circuit modulation in mood and

anxiety disorders

PET and fMRI studies have examined differences in

brain regional activation in depressed and anxious

subjects relative to controls and in patients before

and after treatment.


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Many brain areas may underlie some of the differentsymptom clusters of depression.

nucleus accumbensalong with other areasinvolved in reward processing, are also likely to beinvolved in the anhedonic components ofdepression.

http://en.wikipedia.org/wiki/Nucleus_accumbens

http://www.biopsychiatry.com/nucleus-accumbens.htm
http://en.wikipedia.org/wiki/Nucleus_accumbenshttp://www.biopsychiatry.com/nucleus-accumbens.htmhttp://www.biopsychiatry.com/nucleus-accumbens.htmhttp://www.biopsychiatry.com/nucleus-accumbens.htmhttp://www.biopsychiatry.com/nucleus-accumbens.htmhttp://en.wikipedia.org/wiki/Nucleus_accumbens


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The areas most reproducibly found to be dysregulated in

common emotional disorders are the prefrontal cortex(PFC) and subgenual cingulate cortex (Cg25), whichseem to be involved in emotion experience andprocessing,

as well as

the hippocampusandamygdala, which are involved inemotional memory formationand memory retrieval.


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Review focuses on:

role of Cg25 in emotion regulation and processing, therole of the amygdala in emotional memory formation and

expression.

1 = BA25 (subcallosal gyrus),

2 = BA24sg (SGPFC)

3 = BA32 (paracingulate gyrus)


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Cg25 is involved in the production of sad

emotions and in antidepressant treatment

response.

activated during transient sadness

Decreased activity in Cg25 after treatment, even after

placebo. Also in social phobia.

Activity in Cg25 before treatment predicts treatment

response with CBT.


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A- Transient sadness in healthy

volunteers increases activity in Cg25

measured by PET

B- Decreased Cg25 activity with chronic

fluoxetine treatment for MDD.

C- Cg25 decrease in recovery with chronic

fluoxetine from Parkinsons disease

related depression.

D- Natural recovery with decreased Cg25

activity in patients treated with placebo.

E- Predictors of response in subjects

responding to CBT for depression included

low pretreatment Cg25 activity.

F- Subgenual cortical decreased activity

was common in responders compared with

nonresponders for those responding both

to citalopram and CBT for social phobia.


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Overactivation of the amygdala is also implicated indepression and anxiety.

Amygdala activation decreases with recovery frommood symptoms.

Studies that implicate Cg25 also find significantamygdala decreases with response to CBT treatment forsocial phobia.

http://www.psycheducation.org/emotion/amygdala.htm
http://www.psycheducation.org/emotion/amygdala.htmhttp://www.psycheducation.org/emotion/amygdala.htm


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A genetic polymorphism has repeatedly beenimplicated in gene by environment interactions fordisorders of emotional dysregulation: the serotonin

promoter polymorphism 5-HTTLPR.


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Takahashi T, Suzuki M, Kawasaki Y, Hagino H, Yamashita I, Nohara S, Nakamura K, Seto H, Kurachi M.Biol Psychiatry.

Perigenual cingulate gyrus volume in patients with schizophrenia: a magnetic resonance imaging study. 2003;53:593-600.

Carriers of the risk-conferring 5-HTTLPR

polymorphism have reduced gray matter volume

in the perigenulate regionsurrounding Cg25 aswell as in the amygdala.


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prefrontal-limbic circuits, the Cg25 and amygdala

areas in particular, may be critically involved in

emotional processing and regulation in mood and

anxiety disorders.


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2- Neurostimulation therapies modulate

dysregulated circuits

Several somatic therapies, available or under

investigation, may modulate the disrupted circuit activity.Vagus nerve stimulation therapy(VNS)

Transcranial magnetic stimulation(TMS)

Magnetic seizure therapy (MST)

Deep brain stimulation (DBS)

Deep Brain Stimulation for Treatment-Resistant Depression: An ExpertInterview With Helen S. Mayberg, MD@http://www.medscape.com/viewarticle/520659

Posted 01/05/2006


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VNSapproved by the FDA for treatment of medication-resistant

depression and was approved earlier for the treatment ofepilepsy.

Promising but long-term efficacy in refractory patients stillremains to be demonstrated.

Mechanism: may help correct dysfunctionalneurotransmitter modulatory circuits in patients withdepression.

the nucleus of the tractus solitarius


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Functional imaging suggests that VNS leads to acute

changes in hypothalamus, orbitofrontal cortex,amygdala,hippocampus, insula, medial prefrontalcortexand cingulate cortex.

Chronic VNS treatment leads to significant

ventromedial prefrontal cortex deactivation, similarlyto other approaches to depression treatment.

Low rates of relapse, well-tolerated

VNS may be an important adjunct for

refractory depression.


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TMS

Repetitive transcranial magnetic stimulation (rTMS) andelectroconvulsive therapy (ECT) are both somatic

treatments relying upon altering local and distant neural

circuits within the brain.

rTMS is also potentially useful as a probe for

understanding brain activity changes with response to

treatment with rTMS and ECT.


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When PET and TMS combined it was seen that,

Baseline hypometabolism responds better to high-

frequency stimulation that seems to enhance excitability,

Baseline hypermetabolism responds better to low-

frequency stimulation that seems to dampen excitability.


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In preclinical studies, rTMS modulates neuralcircuits and neurotransmitter systems thought to beinvolved with mood regulation.

rTMS modulates cortical -adrenergic receptors,

serotonergic receptors in frontal cortex, and increasesNMDA receptors in hypothalamus and basolateral

amygdala.

Furthermore, rTMS at 10 Hz in a rat model of depressionleads to enhanced hippocampal plasticity after stress.

rTMS acutely modulates dopamine and serotonin levels.


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MST

involves the induction of relatively focal seizureactivityusing focused magnetic stimulation.

MST seems to offer greater control of intracerebralcurrent intensity than is possible with ECT and thus

may result in fewer cognitive side effects.

.

Relatively new May 2000. in Switzerland. But yetpromising as it has the ability to focally stimulate

cortical areas. It will provide a new tool to dissectthe critical circuitry involved in recovery fromdepression.


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DBS

Parkinsons disease

DBS may also modulate disorders of emotion, in

addition to its known role in treating disorders of

motion.

DBS targeting the left caudate may lead to recovery

from depressive symptoms.


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BA25 has been investigated in treatment-resistant

depressive patients more extensively.

DBS can reduce elevated BA25 activity. Distal effects on

remote cortical and brainstem areas might arise from

indirectly from BA25 or directly from the WM tractspassing through the field of stimulation.

Early data on DBS suggest that it might be a

powerful tool to specifically target dysregulatedneural circuits.


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3- Pharmacological therapies to modulate

emotional learning

3a-Enhancing extinction of fear

3b- Preventing consolidation of traumatic

memories

3c-Preventing reconsolidation of traumatic

memories


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3a- Enhancing extinction of fear

From an operational perspective,

Extinction may thus be defined as

a reduction in the strength or probability of a

conditioned fear response as a consequence ofrepeated presentation of the conditioned stimulusin the absence of the UCS.


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Extinction is a form of learning and not unlearning or

the forgetting of a conditioned association so why not

enhance the neurotranmission of NMDA receptors

the D-Cycloserine(DCS) partial NMDA agonist, used in

the treatment of tuberculosis, potential use in facilitating

extinction-based therapies for human anxiety disorders.

Subjects receiving DCS (one dose) showed greater decreases

in physiological measure of anxiety. Placebo-compared

trials also showed promising results in favor of DCS in

patients with anxiety.

Seromycin

http://www.coccyx.org/treatmen/cycloser.htm
http://www.coccyx.org/treatmen/cycloser.htmhttp://www.coccyx.org/treatmen/cycloser.htm


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3b- Preventing consolidation of traumatic

memories

With certain disorders, notably PTSD, the time of the

insult that created the disorder is knownit is when

the initiating trauma occurred.

Memories do not immediately become permanent atthe time of the initial experience.

Instead they exist in a labile state for at least hours

and possibly days, during which they becomeconsolidated into a more permanent memory.

There is a host of in vitro and in vivo data in


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There is a host of in vitro and in vivo data in

animals outlining the molecular, synaptic,

neurotransmitter and systems-level changes that

may occur during this consolidation process.

TraumaLabile memoriesConsolidation of memories (after

hours/days)Labile again when recalled = Reconsolidation

(following retrieval)


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Differential memory systems are encoding differentaspects of a memory in parallel.

Declarative memory systems [hippocampal-corticalpathways]

are likely to be encoding the what, when and where ofan event,

in parallel

amygdala-cortical pathways are encoding the emotional

salience and aversiveness of the memory.


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Therefore, agents that block the emotionaloverconsolidation of a traumatic memory perhaps

could preserve the declarative aspects of the samememory. This idealized approach would not render thepatient fully amnestic, but would potentially preventPTSD.


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Fear consolidation is blocked after training by anantagonist of noradrenergic activation.

Propranolol, a common -blocker used for

hypertensioncan block central 1 and 2 adrenergic

receptors.


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Patients after a trauma (motorcyle accident) tookpropranolol and placebo for 10 days.

After 1 month; patients who were on propranolol

PTSD measures trended lower, as well as

physiological symptoms of PTSD.


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Another consolidation-blockade approach is basedon the findings that lower cortisol levels after

trauma predict subsequent PTSD.

Glucocorticoids are involved in emotional memoryencoding and retrieval and high doses ofglucocorticoids decrease the catecholamine.

Early data with small # of subjects support thatwhen cortisol given after the trauma it decreasesthe number of subjects with PTSD.


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Every memory recall event is accompanied by

competition between molecular events that strengthen

the original memory (reconsolidation) and those thatinhibit that memory (extinction).

By differentially enhancing or inhibiting these

processes, opposing effects on the state of the existingfear memories may be obtained.


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Other neuromodulators including dopamine andglutamate-NMDA receptor activation are

implicated in the consolidation of fear memories.This work remains in its early stages, but there isroom for optimism.

In emergency rooms, in the future, on the battlefield orafter a disaster the early routine medical interventionsin later PTSD prevention may be as important as theones we do after stroke and MI today.


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3c- Preventing reconsolidation of traumatic

memories

Memories remain labile and associative when they arerecalled.

Reactivated memories are also sensitive to

pharmacological disruption.

Local infusion of protein synthesis inhibitors into discretebrain regions prevents the reconsolidation of the memory,but do not cross the blood-brain barrier easily, so unlikely

to be used in humans.


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More benign drugs, given in animals acutely with

recall of fear memories, may also act to reduce

later memory expression, possibly through

inhibiting reconsolidation mechanisms.

NMDA receptor agonists

-adrenergic antagonists timolol or propranolol

block reconsolidation, and thus may serve as

useful agents in future human studies of

reconsolidation.


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Reconsolidation occurs for recently learned memories

but not distant memories.

Propranololhas not been reported to block

reconsolidation in humans, as the initial report about

animals was a decade ago but it is safe to try in humans

as well.


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Disrupting the remote memories from chronic PTSD maynot be possible using reconsolidation-impairing

approaches.

Extinction of fearmay eventually be optimal in more

chronic cases.


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Conclusions

This is a very exciting time in the fields of learningand memory and psychiatry, because the growingliterature on the differential processes involved inmemory formation are now increasingly amenable to

translational human studies.

This review has focused on recent developments in

understanding the neural circuit processes

underlying mood and anxiety disorders.


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It is hoped that recent progress in understanding theneurobiology of emotional regulation anddysregulationwill lead to powerful and exciting new

treatments for mood and anxiety disorders.

New experimental treatments may alleviate symptomsthrough the correction of dysregulated circuitactivityas well as prevent overlearning or enhance

extinction learningin circuits mediating negativeemotional memories.

CREDITS


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Casting

Margaret

McKinnon

PhD

Title

Page

Margaret

McKinnon

PhD

Cathy

Preete

Speakers

hairsytyle

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