Neuroscience Exploring the Brain 4 e Chapter 22

Introduction • Neurology – Branch of medicine concerned with the diagnosis and treatment of nervous system disorders • Neurological disorders – Ranging from multiple sclerosis to aphasia – Help illustrate the role of physiological processes in normal brain function Copyright © 2016 Wolters Kluwer • All Rights Reserved

Introduction—(cont. ) • Psychiatry – Branch of medicine concerned with the diagnosis and treatment of disorders that affect the mind or psyche • Psychiatric disorders – Anxiety disorders – Affective disorders – Schizophrenia Copyright © 2016 Wolters Kluwer • All Rights Reserved

Mental Illness and the Brain • Human behavior – Product of brain activity • Brain – Product of two mutually interacting factors • Heredity • Environment • DNA determines individualism. • Health and illness along continuum of bodily function Copyright © 2016 Wolters Kluwer • All Rights Reserved

Mental Illness and the Brain—(cont. ) • Mental illness – Diagnosable disorder of thought, mood, or behavior that causes distress or impaired functioning • Earlier belief – Disorders of the body – Disorders of the mind • Current belief – Most disorders of mood, thought, and behavior have biological explanations. Copyright © 2016 Wolters Kluwer • All Rights Reserved

Psychosocial Approaches to Mental Illness • Freud’s theory: mental illness: unconscious and conscious elements of psyche come into conflict – Treat by unearthing hidden secrets of unconscious • Skinner: Many behaviors are learned maladaptive responses to the environment. – Treat by “unlearning” through behavior modification • Psychosocial approaches to mental illness have sound neurobiological basis. • Psychotherapy Copyright © 2016 Wolters Kluwer • All Rights Reserved

Biological Approaches to Mental Illness • Former major disorder: general paresis of the insane – Symptoms: mania, cognitive deterioration – Cause: infection with Treponema pallidum (syphilis) – Paul Ehrlich (1910) discovered treatment. – Penicillin (1928) treatment • Other mental illnesses traced directly to biological causes. – Examples: vitamin deficiency, HIV in brain, autoimmune response Copyright © 2016 Wolters Kluwer • All Rights Reserved

Molecular Medicine in Psychiatry • Using genetic information to develop treatment • Discovery of pathophysiology—may suggest biological processes – Target with drug therapy • Unique challenges of brain diseases – Same diagnosis may arise from many causes. – Genetic complexity • New approach: study the pathophysiology of neurons Copyright © 2016 Wolters Kluwer • All Rights Reserved

Molecular Medicine Copyright © 2016 Wolters Kluwer • All Rights Reserved

Anxiety Disorders • Fear – Adaptive response to threatening situations – Many fears innate and species-specific. – Other fears learned • Anxiety disorders – Caused by inappropriate expression of fear – Most common of psychiatric disorders Copyright © 2016 Wolters Kluwer • All Rights Reserved

Common Anxiety Disorders • Panic disorder • Agoraphobia • Generalized anxiety disorder; severe anxiety >6 months • Specific phobias • Social phobia Copyright © 2016 Wolters Kluwer • All Rights Reserved

Other Disorders Characterized by Increased Anxiety • Post-traumatic stress disorder – Symptoms • Increased anxiety • Intrusive memories, dreams, or flashbacks • Irritability, emotional numbness • Obsessive-compulsive disorder – Obsessions: recurrent, intrusive thoughts, images, ideas, or impulses – Compulsions: repetitive behaviors to reduce anxiety – Equally affects males and females unlike other emotional disorders Copyright © 2016 Wolters Kluwer • All Rights Reserved

Biological Bases of Anxiety Disorders • Genetic predisposition for many anxiety disorders • Fear evoked by threatening stimulus: stressor – Manifested by stress response – Stimulus–response relationship strengthened (or weakened) by experience • Stress response – Humoral response: corticotropin-releasing hormone (CRH) adrenocorticotropic hormone (ACTH) cortisol Copyright © 2016 Wolters Kluwer • All Rights Reserved

Hypothalamic. Pituitary-Adrenal Axis Copyright © 2016 Wolters Kluwer • All Rights Reserved

Regulation of the HPA Axis by the Amygdala and Hippocampus • Both regulate CRH neurons. – Amygdala projects to bed nucleus of the stria terminalis, which activates the HPA axis. – Hippocampus deactivates the HPA axis. • Glucocorticoid receptors • Feedback loop • Push–pull regulation Copyright © 2016 Wolters Kluwer • All Rights Reserved

Location of Amygdala and Hippocampus Copyright © 2016 Wolters Kluwer • All Rights Reserved

Push–Pull Regulation of the HPA Axis Copyright © 2016 Wolters Kluwer • All Rights

Treatments for Anxiety Disorders • Psychotherapy • Anxiolytic medications – Role of GABA – Benzodiazepines – Serotonin-selective reuptake inhibitors (SSRIs); via chronic and adaptive changes • Target for new drugs: CRH receptors Copyright © 2016 Wolters Kluwer • All Rights Reserved

The Action of Benzodiazepine Copyright © 2016 Wolters Kluwer • All Rights Reserved

Diminished binding of BDZ in a patient with panic disorder (PET) Copyright © 2016

Affective Disorders • “Mood” disorders • Recurrent depression – Major depression – Dysthymia (Persistent depressive disorder (PDD); less severe but long-lasting) • Bipolar disorder, or manic-depressive disorder – Recurrent, repeated episodes • Type I: mania • Type II: hypomania Copyright © 2016 Wolters Kluwer • All Rights Reserved

Biological Bases of Affective Disorders • The monoamine hypothesis – Deficit in central diffuse modulatory systems – Studied by effects of drugs • Reserpine (inhibit VMAT 2; ves MA [5 -HT/NE/DA. . ] transporter) • Monoamine oxidase (MAO) inhibitors • Imipramine (inhibit reuptake of 5 -HT and NE) • Monoamine hypothesis of mood disorders – Treatment focus on central serotonergic and/or noradrenergic synapses Copyright © 2016 Wolters Kluwer • All Rights Reserved

Diffuse Modulatory Systems Implicated in Affective Disorders Copyright © 2016 Wolters Kluwer • All

Biological Bases of Affective Disorders—(cont. ) • The diathesis-stress hypothesis – Genetic predisposition (diathesis), other stress factors – Role of HPA axis – Impact of CRH – HPA function becomes hyperactive. – Glucocorticoid receptor gene expression regulated by early experience. Copyright © 2016 Wolters Kluwer • All Rights Reserved

Anterior Cingulate Cortex Dysfunction • Resting-state metabolic activity in anterior cingulate cortex increased in

Treatments for Affective Disorders • Electroconvulsive therapy (ECT): localized electrical stimulation – Unknown mechanism in relieving depression – Affects temporal lobe – Advantage: quick relief of depression, mania – Adverse effect: loss of prior memories, impaired storage of new information • Psychotherapy: Help patients overcome negative views. – Effective for mild to moderate depression Copyright © 2016 Wolters Kluwer • All Rights Reserved

Treatments for Affective Disorders—(cont. ) • Antidepressants: MAO inhibitors, tricyclics, and SSRIs Copyright ©

Treatments for Affective Disorders—(cont. ) • Lithium treatment for bipolar disorder • Lithium Blocks

Deep Brain Stimulation • When severe depression fails to respond to other treatment (severe treatment-resistant depression [TRD] and OCD) • Electrode implanted deep in the brain – Region of anterior cingulate cortex (Brodmann’s area 25) • Electrical stimulation decrease activity in brain circuits that are chronically overactive – Immediate relief from depression – Preliminary findings, brain surgery a treatment of last resort Copyright © 2016 Wolters Kluwer • All Rights Reserved

Schizophrenia • Severe mental disorder—loss of contact with reality • Positive symptoms – Delusions, hallucinations – Disorganized speech – Grossly disorganized or catatonic behavior • Negative symptoms – Reduced expression of emotion, poverty of speech – Difficulty initiating goal-directed behavior – Memory impairment Copyright © 2016 Wolters Kluwer • All Rights Reserved

Biological Bases of Schizophrenia • Primarily a genetic disorder – Faulty genes vulnerability to environmental factors • Associated with physical changes in the brain – Larger ventricle-to-brain size ratio – Other important physical changes in brain • The dopamine hypothesis: psychotic episodes triggered by activation of dopamine receptors – Neuroleptic drugs—potent blockers of dopamine receptors Copyright © 2016 Wolters Kluwer • All Rights Reserved

Familial nature of Schizophrenia Copyright © 2016 Wolters Kluwer • All Rights Reserved

Enlarged lateral ventricles in Schizophrenia Copyright © 2016 Wolters Kluwer • All Rights Reserved

Loss of cortical gray matter in Schizophrenia Copyright © 2016 Wolters Kluwer • All

Dopaminergic Diffuse Modulatory Systems of the Brain Copyright © 2016 Wolters Kluwer • All

Neuroleptics and D 2 receptors Copyright © 2016 Wolters Kluwer • All Rights Reserved

Biological Bases of Schizophrenia—(cont. ) • The glutamate hypothesis – Observed behavioral effects of phencyclidine (PCP) and ketamine • Neither affects dopaminergic transmission. • Both affect synapses that use glutamate as a neurotransmitter. • Inhibit NMDA receptors • Hypothesis: Schizophrenia reflects diminished activation of NMDA receptors in the brain. Copyright © 2016 Wolters Kluwer • All Rights Reserved

Blocking of the NMDA Receptor by PCP Copyright © 2016 Wolters Kluwer • All

Social withdrawal in NMDAR/Glu. N 1 mutant mice Copyright © 2016 Wolters Kluwer •

Treatments for Schizophrenia • Drug therapy combined with psychosocial support • Conventional neuroleptics, such as chlorpromazine and haloperidol, act at D 2 receptors – Reduce the positive symptoms of schizophrenia – Numerous side effects • Like symptoms of Parkinson’s disease • Tardive dyskinesia (involuntary, repetitive body movements) • Newest focus of drug research NMDA receptor Copyright © 2016 Wolters Kluwer • All Rights Reserved

Concluding Remarks • Impact of neuroscience on psychiatry • Mental illness recognized as pathologic modifications of the brain • Genes and environment play an important role, causes not fully understood. • Chemical synaptic transmission is affected by drugs. – Unclear why therapeutic drug effects take weeks. • Less known about how psychosocial treatments act on the brain. Copyright © 2016 Wolters Kluwer • All Rights Reserved