1. Types of neocortex by general function and location Primary sensory Sensory association Multimodal association Primary motor Premotor Prefrontal Cingulate … ..from Cortex II lecture slides

3. Agnosias Symptoms of association cortex dysfunction See Blumenfeld text Chapter 19 for excellent coverage of higher cerebral functions

5. Agnosias-examples for posterior association cortex in parietal and temporal lobes Acalculia -impaired arithmetic calculation Finger agnosia -can’t name individual fingers Right-left disorientation Paracusis -hear a sound, keep hearing it over and over Echolalia -repeating sounds heard over and over Allesthesia -report localization of stimuli on wrong side of the body Hemi-neglect -sensory, motor, combined, conceptual types Anosognosia -lack of awareness of the illness Anosodiaphoria -aware of severe deficits but don’t care (Chicago Cubs fan syndrome) Hemiasomatognosia -Denial that the left half of body belongs to them

6. Visual Agnosias, illusions-examples Simultagnosia -cannot see visual scene as a whole, items jump around randomly.Dorsal type stops movement intermittently Micropsia, macropsia -visual objects wrong size Metamorphosia -distorted shape and size, Alice in Wonderland syndrome Palinopsia -previously viewed object reappears sporadically Polyopia -see two or more images of the same object Erythropsia -unnatural coloring of the visual field Prosopagnosia -can’t recognize people by face, but can by voice, touch

7. Agnosias Gerstmann’s syndrome-lower 7/39 on left side-dysgraphia, dyscalcula, right left confusion finger agnosia, dyslexia Prosopagnosia-20/21 (inferior temporal): Inability to recognize faces Dyslexia Auditory agnosia

8. Agnosias Sensory neglect-; superior parietal Especially on non dom hem- get a right para-sylvian area syndrome-dressing apraxia, constructional apraxia, anosognosia (inability to recognize contra body, disease denial) Unilateral neglect Non-dominant hem superior parietal strokes can cause neglect, even of visual memories. Patients will describe only the right side of their home town square, mall. Asked to imagine the same scene when turned 180 o , they describe the other half, still neglecting their left visual field

9. Language A broadly distributed network of 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.

10. Thompson 2001 Is the capacity for language predominantly genetically or environmentally determined? - twin study Areas in red show high genetic impact- note dominant hemisphere Wernicke and Broca areas

11. Ideational speech area Wernicke’s speech area Broca’s area Semantic speech area

12. Blumenfeld 2002 Primary Language Areas

13. 40 39 22 43 47 45 44 Visual Somatosensory Auditory Ideational speech area of inferior parietal lobule influenced by sensory association areas-impact on reading/writing/speech

15. Language related cortices- for dominant hemisphere 40 39 22 43 47 45 44 8 38 Ideational speech area-39, 40 Wernicke’s speech area- 22+39+40 Broca’s area-44+45 Semantic speech area -Speech apraxia or Broca’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

16. Left 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 vs function words) “ Posterior” “ Temporo- Parietal” “ Receptive” “ Sensory” “ Fluent” Broca’s Aphasia Wernicke’s Aphasia Dominant side (usually left) Non-dominant side (usually right) Syntax Grammar Prosody Emotional expression

17. Blumenfeld Blood supply of language cortices

18. Blumenfeld Types of aphasia and their primary localization Aphasia Fluent? Comprehends? Repeats?

19. 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 )

20. 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 speech Fluent aphasia Full of nonsense words, empty speech, neologisms, paraphasia (jumbled, unintelligible speech) Impaired repetiton Anoganosia-unaware of their deficit Angry, paranoid Can have contralateral field loss, esp upper right quadrant Writing and reading also severely impaired ( Examiner gets frustrated with Wernicke’s patients) *

21. Fluent aphasia lesion-CT R L

22. Language/Speech Agnosias-examples Alexia- loss of reading ability Agraphia- loss of writing ability Anomia- can’t name objects, various lesions Paraphasia- 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 lesion Aprosodosia- Flat speech. Lesion of nondominant inf frontal

23. Alexia without Agraphia lesion (PCA infarct of dominant occipital cortex and corpus callosum) Blumenfeld 2002 Can write normally but can’t read, even their own writing Alexia with agraphia with lesion of dominant angular gyrus

24. Alexia without Agraphia lesion Blumenfeld 2002 Can write normally but can’t read, even their own writing Left visual field Can have an emotional response to what is seen, read (Right Wernicke connection OK) Can’t understand what is read (Motor cortex connection OK)

25. Alexia without agraphia lesion-MRI T2 R L

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

28. Memory Acquisition of new, non-emotional memories-declarative Hippocampal area Precuneus-31 episodic Dorsal lateral prefrontal cortex-46 Executive/short term memory Amygdala- emotional memory organizer Striatum- procedural Cerebellum- Motor/procedural Long term-everywhere Genetic-orbital/ant temp Faces

29. Convergence onto the final common pathway on the PFC pyramidal neuron..and its loops Fallon et al 2003 Optional slide

30. DARPP-remembering PP-1-forgetting Optional slide

32. Prefrontal Cortex

34. Blumenfeld 2002 Neuroanatomy through Clinical Cases Sectors of the Frontal Lobe

35. Blumenfeld 2002 Neuroanatomy through Clinical Cases Sectors of the Frontal Lobe

37. 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’t do that” Risk/Reward Decisions Behavioral Inhibition Ethics and Morality Extraversion/Introversion

38. 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.

39. 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.

40. Progression of dopamine innervation of the prefrontal cortex: The last system in the brain to mature The lamination of DA input to the prefrontal cortex is not complete until about 18 years of age. This is typically when the “dopamine” disorders like schizophrenia really become obvious

41. Thompson 2004 Optional slide

42. Onset of adaptive behaviors in infants and children-Pt 2 Onset of 1st phase: 10-12 mo Narcissism, grandiosity, self, hyperactivity,exploratory, learning to deal with mother Hedonic dopamine phase in right orbital cortex , Onset of 2nd phase: 16-18 mo Development 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

43. Gene-environment-lesion interactions: A quadrillion unique humans are possible And Examples from psychopathology

44. Genetic impact on brain and behavior: A quadrillion unique humans are possible based on genetics alone

45. Monoamines Catecholamines Serotonin COMT (frontal cortex) MAO-A MAO-A , MAO-B

46. ‘ vv ’ - high COMT activity LOW synaptic dopamine Arnsten and Goldman-Rakic, 1986 Arnsten et al., 1994 Murphy et al., 1994, 1996 a,b, 1997 Williams and Goldman-Rakic, 1995 Verma and Moghaddam, 1996 ‘ vm ’ – intermediate ‘ mm ’ – low activity HIGH synaptic dopamine Predicted relative effects of COMT genotype on prefrontal cortical function ______ Optimal________ Optional slide

47. D1 Receptors: Inverted U-Shaped Curve Low DA High DA Greatest dopamine effects in Frontal Lobe Normal behavior Schiz, Mania OCD Schiz ADHD Depression Low, Noisy output High Output of PFC But uncoupled from ext. (Cf Yerkes-Dodson law) Fallon Optional slide

48. = 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 SNPs--millions-- have been detected within the general population and can change quickly in human evolution The presence of millions of SNPs leads to multiple trillions of individual human beings based on genetic variability alone

49. Person A Person B Person C High risk Allele/SNP Low risk Allele/SNP High risk Allele/SNP Low risk Allele/SNP High risk Allele/SNP Low risk Allele/SNP GENE LOADS

50. Person A Person B Person C High risk allele Low risk allele High risk allele Low risk allele High risk allele Low risk allele Serotonin Transporter Long Serotonin Transporter Short Serotonin Transporter Long Serotonin Transporter Short Serotonin Transporter Long Serotonin Transporter Short MAO-A High active MAO-A Low active MAO-A High active MAO-A Low active MAO-A High active MAO-A Low active COMT High active COMT Low active COMT High active COMT Low active COMT High active COMT Low active Low Hostility Average Hostility High Hostility

51. Person A Person B Person C High risk allele Low risk allele High risk allele Low risk allele High risk allele Low risk allele Serotonin Transporter Long Serotonin Transporter Short Serotonin Transporter Long Serotonin Transporter Short Serotonin Transporter Long Serotonin Transporter Short MAO-A High active MAO-A Low active MAO-A High active MAO-A Low active MAO-A High active MAO-A Low active COMT High active COMT Low active COMT High active COMT Low active COMT High active COMT Low active Low Hostility Average Hostility High Hostility These are variants of genes in the normal population. These are not mutants. So what makes one a “ reasonable person”?

52. Gene-environment-lesion interactions: A quadrillion unique humans are possible And Examples from psychopathology

53. David Berkowitz Aileen Wuornos Ted Bundy Albert Fish John Gacy Charles Manson Beltway Snipers

54. Palpatine: Darth Sidious aka His Imperial Majesty Emperor Palpatine of the Galactic Empire Movie characters inspiring real killers

55. 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

56. Tommy (Joe Pesci) In “ Goodfellas” Excellent portrayal of a psychopathic killer Frank Booth (Dennis Hopper) in ‘ Blue Velvet’

57. The sociopath-born or made? Low cortisol in boys-correlations with cruelty to animals, violence, forcing sexual acts, weapon use

59. Anderson/ Damasio 1999 Damage at 16 months age Adult lack of moral reasoning

60. Psychopathic murderer Amen 2004

61. Normal 40 yo Normal 80 yo Adult murderer Teenaged murderer AT AT ORB AT AT ORB ORB AT ORB Orbital cortex (ORB) and anterior temporal cortex (AT)

62. Brain areas most likely to be damaged or altered in psychopaths Orbital cortex Anterior cingulate Frontal pole Ventromedial Anterior medial temporal and amygdala

63. There is one major group of single nucleotide polymorphisms (SNPs) in the MAO-A gene ; A combination in one group results is low MAO-A activity and very high serotonin levels, and is associated with High Risk for 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).

64. Monoamines Catecholamines Serotonin COMT (frontal cortex) MAO-A MAO-A , MAO-B

65. Structural data: MAOA Low vs High MAO-A expression Meyer-Lindenberg et al 2006 PNAS Low MAO-A activity, high serotonin levels, hyper-reactive amygdala High Risk, Females show no effect of genotype Male at high risk have Increased orbital volumes Optional slide

66. Meyer-Lindenberg et al 2006 PNAS Emotional memory scores- response in left amygdala in Males is higher in high risk (MAO-AL) individuals Hyper-responsive left amygdala in High Risk males Optional slide

67. Caspi and colleagues (2002) also found that the high risk genotype (ie low levels of MAO-A; high levels of serotonin) affects responses to harsh environmental stressors. The genetically high risk adolescents and adults who were also maltreated as children were much more likely to develop conduct disorder, antisocial personality disorder, and to be convicted for violent crimes. Gene-Environment Interactions

68. Dorsal PFC Orbital Cortex Amygdala Nucleus Accumbens DA DA _ _ Competition among prefrontal and limbic cortices for control of DA influence in nucleus accumbens Dorsal Anterior Cingulate Ventral Anterior Cingulate CRH VTA Dopamine Net Motor Output, i.e., Behavior: Do it or Don’t Do it? GO DON’T GO