Fallon Higher Cereb Funct I Ii Iii 2007

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Types of neocortex by general function

and locationPrimary sensory Sensory associationMultimodal associationPrimary motorPremotorPrefrontalCingulate

…..from Cortex II lecture slides

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The surface of the cortex is divided into four lobeswhich feature key localized functions, but functionsare usually elaborated in circuits that involve at least several cortical and subcortical areas

Frontal

Temporal

Parietal

Occipital

Frontal Lobe•personality•mood•planning•judgement•motor skills•social•ethics, morality

Parietal Lobe•somatosensory•spatial•comprehension•self•language

Temporal Lobe•language•auditory processing•visual perception• memory

Occipital Lobe•visual processing

…..from Cortex II lecture slides

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Symptoms of association cortex dysfunction

See Blumenfeld text Chapter 19 for excellent coverage of higher cerebral functions

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Loss of function from lesions of

association cortices• Agnosia-”without knowledge”-the inability to perceive or create meaning to sensory input (sensory association and multimodal cortices)-A normal perception stripped of meaning

• Aphasia-language disorder, inability to understand or express words as symbols (sensory association,multimodal, prefrontal)

• Amnesia-memory loss (association, prefrontal, limbic, hippocampal types)

• Apraxia

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Agnosias-examples for posteriorassociation cortex in parietal andtemporal lobes

Acalculia-impaired arithmetic calculationFinger agnosia-can’t name individual fingersRight-left disorientationParacusis-hear a sound, keep hearing it over and overEcholalia-repeating sounds heard over and overAllesthesia-report localization of stimuli on wrong side of the bodyHemi-neglect-sensory, motor, combined, conceptual typesAnosognosia-lack of awareness of the illnessAnosodiaphoria-aware of severe deficits but don’t care (Chicago Cubs fan syndrome)Hemiasomatognosia-Denial that the left half of body belongs to them

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Visual Agnosias,illusions-examples

Simultagnosia-cannot see visual scene as a whole, items jump around randomly.Dorsal type stops movement intermittentlyMicropsia, macropsia-visual objects wrong sizeMetamorphosia-distorted shape and size, Alice in Wonderland syndromePalinopsia-previously viewed object reappears sporadicallyPolyopia-see two or more images of the same objectErythropsia-unnatural coloring of the visual fieldProsopagnosia-can’t recognize people by face, but can by voice, touch

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Agnosias

Gerstmann’s syndrome-lower 7/39on left side-dysgraphia, dyscalcula,right left confusionfinger agnosia, dyslexia

Prosopagnosia-20/21(inferior temporal):Inability to recognizefaces

Dyslexia

Auditory agnosia

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Agnosias Sensory neglect-; superior parietalEspecially on non dom hem- get a right para-sylvian area syndrome-dressing apraxia, constructional apraxia, anosognosia (inability torecognize contra body, disease denial)

QuickTime™ and aTIFF (LZW) decompressor

are needed to see this picture.

Unilateral neglect

Non-dominant hem superior parietal strokes can causeneglect, even of visual memories. Patientswill describe only the right side of theirhome town square, mall. Asked to imaginethe same scene when turned 180o, they describethe other half, still neglecting their left visual field

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A broadly distributed networkof nearly half of cortex

Aoccdrnig to a rscheearch at Cmabrigde Uinervtisy, it deosn't mttaer in waht oredr the ltteers in a wrod are, the olny iprmoatnt tihng is that the frist and lsat ltteer be in the rghit pclae. The rset can be a taotl mses and you can sitll raed it wouthit a porbelm. Tihs is bcuseae the huamn mnid deos not raed ervey lteter by istlef, but the wrod as a wlohe.

FallonThompson 2001

Is the capacity for language predominantly genetically orenvironmentally determined? - twin study

Areas in red show high genetic impact- note dominant hemisphereWernicke and Broca areas

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Ideationalspeech area

Wernicke’sspeech area

Broca’s area

Semanticspeech area

Fallon Blumenfeld 2002

PrimaryLanguage Areas

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40

3922

43

47

4544 Visual

Somatosensory

Auditory

Ideational speech area of inferior parietal lobule influenced by sensory association areas-impact on reading/writing/speech

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Functional localization in

association cortices• Agnosia-”without knowledge”-the inability to perceive or create meaning to sensory input (sensory association and multimodal cortices) A normal percept stripped of meaning

• Aphasia-language disorder, inability to understand or express words as symbols (sensory association, multimodal, prefrontal)


• Apraxia

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Language related cortices-for dominant hemisphere

40 39

22

43

47

45 44

8

38

Ideationalspeech area-39, 40

Wernicke’sspeech area-22+39+40

Broca’s area-44+45

Semanticspeech area

-Speech apraxia orBroca’s aphasia-44/45

-Pure word deafness-22

-Pure word blindness-39/37 boundary

-Fluent aphasia or Wernicke’s aphasia-22/39/40-Conduction aphasia-43/underlying arcuate bundle-Agraphia-39/40-Anomia-nouns-38

37

FallonLeft side is dominant in 95% of righties, 60% of lefties

Basic distribution of cortical speech pathology

“Anterior aphasia”“Frontal”“Expressive”“Motor”“Non-fluent”(phrase length,content vsfunction words)

“Posterior”“Temporo-Parietal”“Receptive”“Sensory”“Fluent”

Broca’s Aphasia Wernicke’s Aphasia

Dominant side(usually left)

Non-dominant side(usually right)

SyntaxGrammar

ProsodyEmotional expression

FallonBlumenfeld

Blood supply of language cortices

Fallon Blumenfeld

Types of aphasia and their primary localization

Aphasia

Fluent?

Comprehends?

Repeats?

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Broca’s aphasia-

Damage to Broca’s Area (BA 44,45) in dominant (left) hemisphere. Decreased premotor and motor aspects of speech.

Fluency is diminished, with phrase length less than 5 or 6 words, increased ratio of content words (nouns)to function words (articles, prepositions, syntax modifiers);agrammatism, telegraphic speech)

Poorer naming of items, and repetition of words is impaired.

Understanding/comprehension is intact, except for syntactically dependent structures (Dog bites man or man bites dog??)

Writing and reading is also slow, laborious (Broca’s Patient gets frustrated when being examined )

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Wernicke’s Aphasia

Damage to posterior superior temporal gyrus (BA 22) and adjacent inferior parietal (BA39) and temporo-occipital cortex (BA 37) in dominant hemisphere.Impaired comprehension of speechFluent aphasiaFull of nonsense words, empty speech, neologisms, paraphasia (jumbled, unintelligible speech)Impaired repetitonAnoganosia-unaware of their deficitAngry, paranoidCan have contralateral field loss, esp upper right quadrantWriting and reading also severely impaired (Examiner gets frustrated with Wernicke’s patients)*

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Fluent aphasia lesion-CT

R L

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Language/Speech Agnosias-examplesAlexia- loss of reading abilityAgraphia- loss of writing abilityAnomia-can’t name objects, various lesionsParaphasia- inappropriate word substitution. Semantic type substitute “water” for “jacuzzi”. Phonemic type substitutes “trap” for “flap” Global-impaired fluency, comprehension,repetition (full MCA infarct)Conduction-impaired repetition, normal fluency, comprehension. Lesion of arcuate fasciculus, overlying cx Transcortical- impaired fluency, comprehension,repetition is spared. Follows a watershed lesion or basal ganglia/thalamus lesionAprosodosia- Flat speech. Lesion of nondominant inf frontal

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AlexiawithoutAgraphialesion

(PCA infarct ofdominant occipital cortex andcorpus callosum)Blumenfeld 2002

Can write normallybut can’t read, eventheir own writing

Alexia with agraphiawith lesion ofdominant angulargyrus

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AlexiawithoutAgraphialesion

Blumenfeld 2002

Can write normallybut can’t read, eventheir own writing

Left visual field

Can have an emotional responseto what is seen, read (Right Wernicke connection OK)

Can’t understandwhat is read

(Motor cortexconnection OK)

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Alexia without agraphia lesion-MRI T2

R L

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But what’s worse, not remembering,or never being able to forget?

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Functional localization in

association cortices• Agnosia-”without knowledge”-the inability to perceive or create meaning to sensory input (sensory assoc, multimodal cortices)

A normal percept stripped of meaning• Aphasia-language disorder, inability to understand or express words as symbols (sensory association,multimodal, prefrontal)


• Apraxia-

FallonMemory

Acquisition ofnew, non-emotionalmemories-declarative

Hippocampal area

Precuneus-31episodic

Dorsal lateral prefrontal cortex-46Executive/short term memory

Amygdala-emotional memoryorganizer

Striatum-procedural

Cerebellum-Motor/procedural

Long term-everywhereGenetic-orbital/ant temp

Faces

FallonConvergence onto the final common pathway on the PFC pyramidal neuron..and its loops

Fallon et al 2003

Optional slide

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DARPP-rememberingPP-1-forgetting

Optional slide

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Functional localization in association cortices

• Agnosia-”without knowledge”-the inability to perceive or create meaning to sensory input (sensory assoc, multimodal cortices) A normal percept stripped of meaning

• Aphasia-language disorder, inability to understand or express words as symbols (sensory association,multimodal, prefrontal)


• Apraxia-Ideomotor type-inability to carry out actions in response to verbal commands, cannot formulate correct movement sequence. Also, there are dressing, gait, constructional, etc-poor localization in cortex, in dominant (skilled) hemisphere-esp premotor cortex BA 6

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Prefrontal cortex functions:(If comic Steven Wright was a neurologist)

•A clear conscience is usually the sign of a bad memory

•A fool and his money are soon partying

•Hard work pays off in the future. Laziness pays off now

•A conscience is what hurts when all your other parts feel good

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Blumenfeld 2002Neuroanatomy throughClinical Cases

Sectors of theFrontal Lobe

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Blumenfeld 2002Neuroanatomy throughClinical Cases

Sectors of theFrontal Lobe

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Frontal Lobe FunctionFrontal Lobe FunctionFUNCTIONFUNCTION DYSFUNCTIONDYSFUNCTION

Emotional ExpressionEmotional Expression Inaccurate ExpressionInaccurate Expression

EmpathyEmpathy Lack of ConcernLack of Concern

Ambition/DriveAmbition/Drive Apathy/IndifferenceApathy/Indifference

Social AwarenessSocial Awareness Pride and AppearancePride and Appearance

Planning and SequencingPlanning and SequencingLoss of FutureLoss of Future

Flexible AttentionFlexible Attention Don’t Learn from MistakesDon’t Learn from Mistakes

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Functions of the Prefrontal Cortex: “Memory of the Future”Or “How would I look back on what I’m about to do”

“maybe I shouldn’tdo that”

Risk/Reward DecisionsBehavioral InhibitionEthics and MoralityExtraversion/Introversion

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Functions of the Prefrontal Cortex: “Memory of the Future”Or “How would I look back on what I’m about to do”

D.T.L.H.

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Progression of Myelination: Axons

For all the cortical layers, myelination starts in primary cortices, then spreads to their association cortices, proximally to distally. The last area to myelinate is the frontal pole.

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Progression of dopamine innervationof the prefrontal cortex:The last system in the brain to mature

The lamination of DAinput to the prefrontal cortexis not complete until about18 years of age. This is typicallywhen the “dopamine” disorderslike schizophrenia reallybecome obvious

Fallon Thompson 2004

Optional slide

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Onset of adaptive behaviors in infants and children-Pt 2

Onset of 1st phase: 10-12 moNarcissism, grandiosity, self, hyperactivity,exploratory, learning to deal with mother

Hedonic dopamine phase in right orbital cortex, Onset of 2nd phase: 16-18 moDevelopment of “shame” as parents give child disapproving looks, hyper, elated behavior, becomes inhibited, urine and feces provoke disgust response, learning to deal with father

Inhibition of dopamine loops, norepinephrine increases, cortisol up, endorphins down as right orbital cortex matures-

Optional slide

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Gene-environment-lesion interactions:

A quadrillion unique humans are possible

And

Examples from psychopathology

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Genetic impact on brain and behavior:

A quadrillion unique humans are possible basedon genetics alone

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MonoaminesCatecholamines Serotonin

COMT (frontal cortex)

MAO-A

MAO-A, MAO-B

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‘vv’ - high COMT activity

LOW synaptic dopamine

Arnsten and Arnsten and Goldman-Rakic, 1986Goldman-Rakic, 1986Arnsten et al., 1994Arnsten et al., 1994Murphy et al., 1994, Murphy et al., 1994, 1996 a,b, 19971996 a,b, 1997Williams andWilliams and Goldman-Rakic, 1995Goldman-Rakic, 1995Verma and Verma and Moghaddam, 1996Moghaddam, 1996

‘vm’ – intermediate

‘mm’ – low activity

HIGH synaptic dopamine

Predicted relative effects of COMT Predicted relative effects of COMT genotype on prefrontal cortical functiongenotype on prefrontal cortical function

______Optimal________

Optional slide

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D1 Receptors:Inverted U-Shaped Curve

Low DA High DA

Greatest dopamine effectsin Frontal Lobe

Normal behavior

Schiz,ManiaOCD

SchizADHD

Depression

Low, Noisy output High Output of PFC

But uncoupled from ext.

(Cf Yerkes-Dodson law) Fallon

Optional slide

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= SNP(Single Nucleotide Polymorphism)

... A C T T T G A ...

... A T T T T G A ...

general population

genomic sequences

An extremely large number of An extremely large number of SNPs--millions-- have been SNPs--millions-- have been detected within the general detected within the general population and can change population and can change quickly in human evolutionquickly in human evolution

The presence of millions of SNPs leads to multiple trillionsof individual human beings based on genetic variability alone

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Person A Person B Person C

High riskAllele/SNP

Low riskAllele/SNP

High riskAllele/SNP

Low riskAllele/SNP

High riskAllele/SNP

Low riskAllele/SNP

GENE LOADS

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High riskallele

Low riskallele

High riskallele

Low riskallele

High riskallele

Low riskallele

SerotoninTransporterLong

SerotoninTransporterShort





MAO-AHigh active

MAO-ALow active

MAO-AHigh active

MAO-ALow active

MAO-AHigh active

MAO-ALow active

COMTHigh active

COMTLow active

COMTHigh active

COMTLow active

COMTHigh active

COMTLow active

Low Hostility Average Hostility High Hostility

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High riskallele

Low riskallele

High riskallele

Low riskallele

High riskallele

Low riskallele







MAO-AHigh active

MAO-ALow active

MAO-AHigh active

MAO-ALow active

MAO-AHigh active

MAO-ALow active

COMTHigh active

COMTLow active

COMTHigh active

COMTLow active

COMTHigh active

COMTLow active

Low Hostility Average Hostility High Hostility

These are variants of genesin the normal population.These are not mutants.So what makes one a“reasonable person”?

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Gene-environment-lesion interactions:

A quadrillion unique humans are possible

And

Examples from psychopathology

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David Berkowitz

Aileen Wuornos Ted Bundy

Albert FishJohn Gacy

Charles MansonBeltway Snipers

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Palpatine: Darth Sidiousaka His Imperial Majesty Emperor Palpatine of the Galactic Empire

Movie characters inspiring real killers

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Issei Sagawa

Hannibal Lecter

Albert Fish

HAL 9000

Ed Gein*

*Ed Gein inspired Psycho, The Texas Chainsaw Massacre, The Silence of the Lambs

Real killers inspiring movie characters

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Tommy(Joe Pesci)

In “Goodfellas”

Excellent portrayal of a psychopathic killer

Frank Booth(Dennis Hopper)

in‘Blue Velvet’

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The sociopath-born or made?

Low cortisol in boys-correlations with cruelty to animals,violence, forcing sexual acts, weapon use

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FallonAnderson/ Damasio 1999

Damage at 16 months age

Adult lack of moralreasoning

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Psychopathic murderer

Amen 2004

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Normal40 yo

Normal 80 yo

Adultmurderer

Teenagedmurderer

AT

AT

ORBATAT

ORB ORBAT

ORB

Orbital cortex (ORB) and anterior temporal cortex (AT)

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Brain areas most likely to be damaged or altered in psychopaths

Orbital cortex

Anterior cingulate

Frontalpole

Ventromedial

Anterior medial temporal

and amygdala

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There is one major group of single nucleotide polymorphisms (SNPs) in the MAO-A gene; A combination in onegroup results is low MAO-A activityand very high serotonin levels,and is associated with High Riskfor violence and aggression

In humans, a Dutch kindred with a missense mutation in the MAO-A gene was described : hemizygous males, representing functional gene knockouts, exhibited a pattern of impulsively violent criminal behaviour for generations (Brunner 1993).

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MonoaminesCatecholamines Serotonin

COMT (frontal cortex)

MAO-A

MAO-A, MAO-B

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Structural data: MAOA Low vs High MAO-A expression

Meyer-Lindenberg et al 2006 PNAS

Low MAO-Aactivity, highserotonin levels,hyper-reactive amygdala High Risk,

Femalesshow noeffect ofgenotype

Male at high risk haveIncreased orbital volumes

Optional slide

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Meyer-Lindenberg et al 2006 PNAS

Emotional memory scores- response in left amygdala in Males is higher in high risk (MAO-AL) individuals

Hyper-responsiveleft amygdalain High Riskmales

Optional slide

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Caspi and colleagues (2002) also found that the highrisk genotype (ie low levels of MAO-A; high levels ofserotonin) affects responses to harsh environmentalstressors. The genetically high risk adolescents and adultswho were also maltreated as children were much morelikely to develop conduct disorder, antisocial personalitydisorder, and to be convicted for violent crimes.

Gene-Environment Interactions

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DorsalPFC

OrbitalCortex

Amygdala

NucleusAccumbens

DA

DA

_

_Competition among

prefrontal and limbic cortices for control

of DA influencein nucleus accumbens

DorsalAnteriorCingulate

VentralAnteriorCingulate

CRH VTADopamine

Net Motor Output, i.e., Behavior:Do it or Don’t Do it?

GO DON’T GO

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