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Prefrontal Cortex: Disease Processes and Aging

Prefrontal Cortex: Disease Processes and Aging. Amy F.T. Arnsten, Ph.D. Professor of Neurobiology amy.arnsten@yale.edu. The PFC: Our Mental Sketch Pad Our Central Executive (Daeyeol’s lecture). Human PFC. Left Generative Lesions: Impaired initiative, depression. Right

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Prefrontal Cortex: Disease Processes and Aging

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  1. Prefrontal Cortex: • Disease Processes and Aging Amy F.T. Arnsten, Ph.D. Professor of Neurobiology amy.arnsten@yale.edu

  2. The PFC: Our Mental Sketch Pad Our Central Executive (Daeyeol’s lecture)

  3. Human PFC Left Generative Lesions: Impaired initiative, depression Right Inhibitory Lesions: impulsive mania, sociopathy

  4. PFC NETWORKS: TOP-DOWN CONTROL

  5. THE PFC HAS EXTENSIVE, HIGHLY ORGANIZED CONNECTIONS

  6. PFC INPUTS: PARALLEL PROCESSING STREAMS Dorsal- Space Feature visuo-spatial auditory-spatial auditory-feature visuo-feature emotion Ventral- Emotion The work of Patricia Goldman-Rakic

  7. PFC OUTPUTS: GUIDE THOUGHT AND ATTENTION posterior sensory and association cortices

  8. Example: PFC to Superior Temporal Cortex Enhance: PFC input onto glutamatergic pyramidal cell spine PFC projections are positioned to enhance or suppress stimulus processing The work of Helen Barbas Medalla M et al. Cereb. Cortex 2007;17:i136-i150 Suppress: PFC input onto GABAergic interneuron dendrite

  9. PFC OUTPUTS: GUIDE MOVEMENTS/BEHAVIORS Premotor cortices Motor cortices Frontal eye fields Caudate and Subthalamic nuc. Cerebellum via pons The right inferior PFC and dorsomedial PFC are especially important for inhibition of movements (Aron et al 2004)

  10. Example: PFC to Subthalamic Nucleus The work of Adam Aron CORTEX Including PFC R inf PFC STRIATUM Hyper-direct pathway Rapid, crude inhibition Direct Pathway Inhibits Thal-Cort Indirect Pathway Excites Thal-Cort THALAMUS GPe Gpi/SNr SubTh

  11. PFC OUTPUTS: VENTROMEDIAL PFC GUIDES EMOTION nuc. accumbens hypothalamus Brainstem e.g. PAG amygdala

  12. Example: PFC to Amygdala GABAergic interneurons Glutamatergic neurons Inhibit emotional processing Enhance emotional processing Ghashghaei and Barbas (2002) Neuroscience 115: 1261-79

  13. PARALLEL DISTRIBUTED NETWORKS FOR VISUAL SPATIAL PROCESSING: CORTICAL CONNECTIONS parietal association cortex visuo-spatial prefrontal association cortex

  14. PARALLEL DISTRIBUTED NETWORKS FOR VISUAL SPATIAL PROCESSING: CORTICAL CONNECTIONS Selemon and Goldman-Rakic, J. Neurosci 8:4049-68,1988

  15. PARALLEL DISTRIBUTED NETWORKS FOR VISUAL SPATIAL PROCESSING: CORTICAL CONNECTIONS Parahippocampal Gyrus Retrosplenial Ctx Posterior Cingulate Anterior Cingulate Areas 7m &19 SMA premotor insula Superior Temporal Sulcus Orbital PFC Selemon and Goldman-Rakic, J. Neurosci 8:4049-68,1988

  16. PARALLEL DISTRIBUTED NETWORKS FOR VISUAL SPATIAL PROCESSING: CORTICAL CONNECTIONS Parahippocampal Gyrus Memory (connect to hippocampus) Retrosplenial Ctx Error correction Posterior Cingulate Anterior Cingulate Areas 7m &19 SMA Top-down regulation of earlier stages of visual processing Motor planning Motor planning premotor insula Coordination with representations of internal state Coordination with auditory information Superior Temporal Sulcus Orbital PFC Coordination with emotional response e.g. reward for correct response Selemon and Goldman-Rakic, J. Neurosci 8:4049-68,1988

  17. PARALLEL DISTRIBUTED NETWORKS: STRIATUM Selemon and Goldman-Rakic, J. Neurosci 5: 776-94,1985

  18. PFC to Striatum: Dorsal vs. Ventral Pathways The Dorsolateral PFC Projects to Dorsal Parts of Striatum, and the Ventromedial PFC Projects To Ventral Parts of Striatum (accumbens) Selemon and Goldman-Rakic, J. Neurosci 5: 776-94,1985

  19. DISORDERS THAT AFFLICT PFC NETWORKS

  20. PARALLEL CORTICAL BASAL GANGLIA LOOPS

  21. Cognitive symptoms of: Normal aging

  22. Cognitive symptoms of: ADHD Tourettes Autism Schizophrenia Neurodevelopmental disorders

  23. Cognitive symptoms of: Parkinson’s Disease Huntington’s Disease Alzheimer’s Disease Frontotemporal Dementia Neurodegeneration in aged

  24. Emotional symptoms of: PTSD Bipolar disorder, Major Depression Conduct disorder (sociopathy) OCD Drug abuse

  25. Emotional symptoms of: PTSD Bipolar disorder, Major Depression Conduct disorder (sociopathy) OCD Drug abuse

  26. Depression • Gray matter loss • Increased fMRI activity • Decreased 5HT1A binding (may be related to polymorphism in the promoter region) Also increased activity in the amygdala to negative stimuli (related to the 5HT transporter genotype) Altered ventromedial PFC in depression Savitz and Drevets, 2009

  27. Bipolar Disorder DEPRESSION R L

  28. Bipolar Disorder MANIA MANIA R L DEPRESSION R L Blumberg et al., Arch Gen Psychiatry, 156:1986-8, 1999 Blumberg et al., Arch Gen Psychiatry, 60:599-607, 2003

  29. Bipolar Disorder Proper medication normalizes vPFC gray matter and function VPFC Response Bipolar Disorder Lithium Treatment Healthy Participants Bipolar Disorder without Treatment (Blumberg et al., Psychopharmacology, 2005) (Blumberg et al., Biol Psychiatry, 2006)

  30. Bipolar Disorder Right Prefrontal Cortex Dysfunction in Mania Impaired inhibition of inappropriate thoughts, feelings and actions Regulation of action Regulation of thought Regulation of emotion Blumberg et al., Arch Gen Psychiatry, 156:1986-8. 1999

  31. Bipolar Disorder Right Prefrontal Cortex Dysfunction in Mania Impaired inhibition of inappropriate thoughts, feelings and actions Regulation of action Regulation of thought Impaired maturation in ADHD Regulation of emotion Blumberg et al., Arch Gen Psychiatry, 156:1986-8. 1999

  32. Normal Development: Right Inferior PFC Grows Larger Shaw et al. (2009) Arch Gen Psych

  33. ADHD: Inferior PFC Laterality Unchanged (stays left) Shaw et al. (2009) Arch Gen Psych

  34. Normal Aging

  35. Fronto-Temporal Dementia Spindle cell (Von Economo Neurons) Pyramidal cell Found in dorsolateral PFC, insular cortex and anterior cingulate of humans, great apes, whales, elephants Heterogeneous presentation (e.g. very apathetic or very disinhibited, likely related to sites of degeneration within the PFC, and heterogeneous pathological causes, e.g. mutation in tau Early target of degeneration in FTD

  36. Schizophrenia Work of Tyrone D. Cannon, UCLA

  37. Impaired Cognition in Schizophrenia and Normal Aging: Focus on dlPFC

  38. Spatial Working Memory: Model System

  39. Spatial Working Memory: Model System Layer III Microcircuits Mental Representation of Visual Space

  40. Monkeys- Automated: Oculomotor Delayed Response Task Cue 0° 90° 45° 315° 45° 180° 0° 270° 90° 315° 135° 225° 135° 270° 180° Delay Respond Representation of spatial location needed during delay period SPATIAL WORKING MEMORY TASKS

  41. Cue 0° 90° 45° 315° 45° 180° 0° 270° 90° 315° 135° 225° 135° 270° 180° Delay VISUOSPATIAL INPUTS TO AREA 46 The work of Patricia Goldman-Rakic Respond Representation of spatial location needed during delay period

  42. Cue 0° 90° 45° 315° 45° 180° 0° 270° 90° 315° 135° 225° 135° 270° 180° Delay LESION IMPAIRS SPATIAL WORKING MEMORY The work of Patricia Goldman-Rakic Respond Representation of spatial location needed during delay period

  43. Cue 0° 90° 45° 315° 45° 180° 0° 270° 90° 315° 135° 225° 135° 270° 180° Delay RECORDING /IONTOPHORESIS SITE Site of recording and iontophoresis The work of Patricia Goldman-Rakic Respond Representation of spatial location needed during delay period

  44. Cue 0° 90° 45° 315° 45° 180° 0° 270° 90° 315° 135° 225° 135° 270° 180° Delay DELAY CELLS: SPATIALLY TUNED, PERSISTENT FIRING 0° 315° 45° 270° 90° 225° 135° 180° Spatially-tuned Delay Cell Respond Representation of spatial location needed during delay period

  45. Cue 0° 90° 45° 315° 45° 180° 0° 270° 90° 315° 135° 225° 135° 270° 180° Delay DELAY CELLS: SPATIALLY TUNED, PERSISTENT FIRING 0° 315° 45° 270° 90° 225° 135° 180° Spatially-tuned Delay Cell Respond Representation of spatial location needed during delay period

  46. Cue 0° 90° 45° 315° 45° 180° 0° 270° 90° 315° 135° 225° 135° 270° 180° Delay DELAY CELLS: SPATIALLY TUNED, PERSISTENT FIRING 0° 315° 45° 270° 90° 225° 135° 180° Respond Representation of spatial location needed during delay period

  47. Cue 0° 90° 45° 315° 45° 180° 0° 270° 90° 315° 135° 225° 135° 270° 180° Delay DELAY CELLS: SPATIALLY TUNED, PERSISTENT FIRING Persistent Firing Spatial Tuning 0° 315° 45° 270° 90° 225° 135° 180° Respond Representation of spatial location needed during delay period

  48. Cue 0° 90° 45° 315° 45° 180° 0° 270° 90° 315° 135° 225° 135° 270° 180° Delay DELAY CELLS: SPATIALLY TUNED, PERSISTENT FIRING Persistent Firing Spatial Tuning 0° 315° 45° 270° 90° 225° 135° 180° Recurrent excitatory microcircuits underlying persistent firing Respond Representation of spatial location needed during delay period

  49. Working Memory Microcircuits Are Located in Deep Layer III A. Kritzer and Goldman-Rakic, 1995

  50. Cue stimulation at 270º Information from area 7A Cue stimulation at 90º Information from area 7A Receive Visuo-Spatial Information from Parietal Cortex 90º 270º 90º 270º GABA 90º 270º

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