16 Neurological and Psychiatric Disorders Cognitive Neuroscience David

16: Neurological and Psychiatric Disorders Cognitive Neuroscience David Eagleman Jonathan Downar

Chapter Outline Alzheimer’s Disease: Burning Out with Age? n Frontotemporal Dementia: Like a Cancer of the Soul n Huntington’s Disease: A Genetic Rarity, in Two Senses n Tourette Syndrome: A Case of Involuntary Volition? n 2

Chapter Outline Obsessive-Compulsive Disorder: Neurological or Psychiatric? n Schizophrenia: A Dementia of the Young n Bipolar Disorder n Depression: A Global Burden n 3

Alzheimer’s Disease: Burning Out with Age? Dementias are neurologic disorders characterized by slow deterioration of higher cognitive functions. n Such functions include language, memory, judgement, and emotion. n Alzheimer’s disease or Alzheimer’s dementia is thought to affect about 24 million people world-wide. n 4

Alzheimer’s Disease: Burning Out with Age? 5

Alzheimer’s Disease: Burning Out with Age? The major deficit of Alzheimer’s is the loss of episodic memory. n Executive functions decline throughout Alzheimer’s disease. n Biological markers of Alzheimer’s disease include amyloid-beta plaques and neurofibrillary tau tangles. n 6

Alzheimer’s Disease: Burning Out with Age? 7

Alzheimer’s Disease: Burning Out with Age? 8

Alzheimer’s Disease: Burning Out with Age? Most cases of Alzheimer’s disease occur in individuals over age 60. n The epsilon 4 variant of the apolipoprotein E (Apo. E 4) gene seems to increase the risk of developing the disease. n Genetic forms of Alzheimer’s disease account for only a small percentage of cases. n 9

Alzheimer’s Disease: Burning Out with Age? 10

Alzheimer’s Disease: Burning Out with Age? n Treatment of Alzheimer’s disease ¨ There are currently no cures for Alzheimer’s disease. ¨ No medications significantly slow down or reverse the progression of the disease. ¨ Acetylcholinesterase inhibitors and NMDA glutamate receptor antagonists sometimes slow the progression of the disease. 11

Alzheimer’s Disease: Burning Out with Age? A potential treatment uses the immune system to remove plaques, but this has not resulted in any clinical improvement. n Social, mental, and physical activity can decrease the risk and severity of Alzheimer’s disease. n 12

Frontotemporal Dementia: Like a Cancer of the Soul This dementia results from progressive atrophy of the brain. n This is most common in the inferior frontal lobes and anterior temporal lobe. n The age of onset is typically about 40 – 50 years of age. n Personality and social behaviors change significantly. n 13

Frontotemporal Dementia: Like a Cancer of the Soul 14

Frontotemporal Dementia: Like a Cancer of the Soul Behavioral variant frontotemporal dementia (bv. FTD) is most common. n This is characterized by progressive semantic dementia, personality changes and loss of empathy. n Frontotemporal dementia is sometimes associated with an increase in creativity. n 15

Frontotemporal Dementia: Like a Cancer of the Soul 16

Huntington’s Disease: A Genetic Rarity, in Two Senses Patients perform restless involuntary movements of the face, trunk, and limbs. n It commonly also includes psychiatric symptoms such as depression, apathy, anxiety, delusions, and hallucinations. n The biological cause is degeneration of the anterior caudate nucleus of the striatum. n 17

Huntington’s Disease: A Genetic Rarity, in Two Senses 18

Huntington’s Disease: A Genetic Rarity, in Two Senses 19

Huntington’s Disease: A Genetic Rarity, in Two Senses Huntington’s disease is caused by the mutation of an autosomal dominant gene. n This mutation encodes the inclusion of a trinucleotide repeat of the sequence CAG in the final protein. n ¨ Most people have fewer than 28 CAG repeats, and this results in no issues. ¨ Individuals with more than 35 repeats are at an increased risk of developing the disease. 20

Huntington’s Disease: A Genetic Rarity, in Two Senses Risk factors for Huntington’s disease include both genetic and environmental factors. n Treatment for Huntington’s disease involves dopamine receptor antagonists. n These relieve some of the motor and psychiatric symptoms. n 21

Huntington’s Disease: A Genetic Rarity, in Two Senses 22

Tourette Syndrome: A Case of Involuntary Volition? In Tourette syndrome, the individual repeats purposeless movements of the face, head, shoulders, or hands. n There also verbal tics, which are purposeless noises like throat-clearing and snorting or meaningless phrases. n 23

Tourette Syndrome: A Case of Involuntary Volition? Tourette syndrome is typically a disorder of childhood. n Studies suggest there is a genetic basis to Tourette syndrome, but no gene has been isolated. n 24

Tourette Syndrome: A Case of Involuntary Volition? n Pediatric Autoimmune Neuropsychiatric Disorder Associated with group A Streptococcal infection (PANDAS) ¨ This is characterized by the tics of Tourette syndrome or the intrusive thoughts and behaviors of obsessive compulsive disorder. ¨ Sometimes occurs in patients shortly after they have had a throat infection caused by the bacteria Group A streptococcus. 25

Tourette Syndrome: A Case of Involuntary Volition? Patients have a decrease in gray matter in the caudate nucleus and lateral motor and premotor cortex. n Gray matter is thinner in medial motor areas. n 26

Tourette Syndrome: A Case of Involuntary Volition? 27

Tourette Syndrome: A Case of Involuntary Volition? Therapy for Tourette syndrome includes education and acceptance. n Neurolepic medications are prescribed for the most severe cases, where the tics interfere significantly with daily life. n 28

Obsessive-Compulsive Disorder: Neurological of Psychiatric? “Neurological” disorders and “psychiatric” disorders are grouped based on the nature of the condition. n Conditions with an observable brain abnormality were considered neurological. n 29

Obsessive-Compulsive Disorder: Neurological of Psychiatric? n A more modern criteria based on the symptoms. ¨ Psychiatric conditions impact emotion, motivation, social behaviors, personality, or reality testing. ¨ Neurological conditions impact strength, movement, sensory perception, memory, attention, or level of consciousness. 30

Obsessive-Compulsive Disorder: Neurological of Psychiatric? 31

Obsessive-Compulsive Disorder: Neurological of Psychiatric? Obsessive-compulsive disorder is a psychiatric disorder that affects about 2 – 3% of the population. n Symptoms include obsessions (intrusive, disturbing thoughts) and compulsions (stereotyped, ritualized behaviors). n 32

Obsessive-Compulsive Disorder: Neurological of Psychiatric? Obsessions include contamination, fear of committing inappropriate acts, symmetry and number, and hoarding. n The most common age of onset for symptoms of obsessive-compulsive disorder is either about age 11 or 23. n 33

Obsessive-Compulsive Disorder: Neurological of Psychiatric? 34

Obsessive-Compulsive Disorder: Neurological of Psychiatric? There is increased activity in the circuits connecting the basal ganglia to the orbitofrontal, anterior cingulate, and dorsomedial prefrontal cortex. n The pattern of activity differs depending on the types of obsession. n 35

Obsessive-Compulsive Disorder: Neurological of Psychiatric? 36

Obsessive-Compulsive Disorder: Neurological of Psychiatric? Cognitive behavioral therapy addresses cognitive distortions and decreases anxiety. n Medications than increase serotonin reduce the obsessions, compulsions, and anxiety. n Neuroleptics are sometime prescribed for severe cases. n 37

Schizophrenia: A Dementia of the Young Schizophrenia is characterized by loss of contact with reality. n The age of onset is typically around early adulthood. n Schizophrenia affects about 1% of the world’s population. n 38

Schizophrenia: A Dementia of the Young n Positive symptoms include hallucinations and delusions. ¨ Delusions include paranoid delusions, delusions of reference, delusions of passivity, and somatic delusions. n Negative symptoms include poverty of speech, apathy, social withdrawal, and loss of emotion. 39

Schizophrenia: A Dementia of the Young 40

Schizophrenia: A Dementia of the Young Antipsychotic medications treat the positive symptoms, but do not treat the negative symptoms. n Such medications often cause unwanted side effects. n Second-generation antipsychotic medications are no better at treating the negative symptoms. n 41

Schizophrenia: A Dementia of the Young There is a genetic basis to schizophrenia, but no specific genes have been identified. n Environmental factors during fetal development or early life seem important in the incidence of schizophrenia. n 42

Schizophrenia: A Dementia of the Young 43

Schizophrenia: A Dementia of the Young n Neurodevelopmental factors ¨ Abnormal pruning of neurons ¨ Smaller cell bodies of neurons ¨ Decreased functioning of inhibitory GABA interneurons in the cortex 44

Schizophrenia: A Dementia of the Young 45

Schizophrenia: A Dementia of the Young 46

Schizophrenia: A Dementia of the Young n Dopamine hypothesis ¨ There is too much dopamine signaling or the dopamine receptors are oversensitive. ¨ The first-generation antipsychotic drugs were dopamine D 2 receptor antagonists. ¨ Drugs that increase dopamine, such as amphetamines and cocaine, can mimic the positive symptoms of schizophrenia. 47

Schizophrenia: A Dementia of the Young 48

Schizophrenia: A Dementia of the Young n Glutamate hypothesis ¨ Schizophrenia is caused by too little glutamate neurotransmission. ¨ NMDA receptor antagonists, like ketamine, can mimic both the positive and negative symptoms of schizophrenia. ¨ Many of the genes associated with schizophrenia affect NMDA glutamate receptors. 49

Schizophrenia: A Dementia of the Young 50

Bipolar Disorder Normal mood alternates with periods of depression and mania. n This affects 1% of the population and a milder form may affect as much as 4 -5% of the population. n The age of onset is about 20 years of age. n There is a genetic basis to the condition, but no specific genes have been identified. n 51

Bipolar Disorder 52

Bipolar Disorder n Individuals with bipolar disorder show thinner gray matter in the ¨ Bilateral ventrolateral frontal cortex ¨ Bilateral anterior insula Dorsomedial prefrontal cortex ¨ Subgenual cingulate cortex n Some of these regions are also affected in unipolar depression. 53

Bipolar Disorder 54

Bipolar Disorder n Common treatments include ¨ Mood-stabilizing drugs, such as lithium ¨ Anti-dpileptic drugs 55

Bipolar Disorder 56

Depression: A Global Burden Impact of Depression n Causes of Depression n Neurochemical Effects of Depression on Brain n Functional Effect of Depression on the Brain n Treatment of Depression n 57

Impact of Depression is characterized by a low mood that makes it difficult to carry out the functions necessary for daily life. n Individuals with depression do not take pleasure in typical activities, lack motivation and energy, and have altered sleep patterns and appetite. n 58

Impact of Depression 59

Impact of Depression The worldwide incidence of depression is 5% at any one time. n In the United States, the incidence is 5% for men and 10% for women. n Lifetime incidence is roughly double the one-time incidence rates. n The cost of depression is estimated to be about $80 billion per year in the U. S. n 60

Impact of Depression 61

Causes of Depression Mood disorders run in families, suggesting a genetic basis. n Depression may be an evolutionary adaptation to suffering a trauma or defeat n Depression causes the individual to stay away from opponents and predators while waiting for better times. n 62

Causes of Depression 63

Neurochemical Effects of Depression on Brain n Monoamine hypothesis of depression ¨ There is a shortage of the monoamine neurotransmitters. ¨ By inhibiting the enzyme monoamine oxidase, which breaks down these transmitters, mood will be improved. 64

Neurochemical Effects of Depression on Brain n Serotonin hypothesis ¨ More specific than the monoamine hypothesis. ¨ There is, specifically, a shortage of serotonin. ¨ Selective serotonin reuptake inhibitors specifically affect serotonin levels. 65

Neurochemical Effects of Depression on Brain n Other biological theories ¨ There abnormalities with glutamate neurotransmission. ¨ There are low levels of the neuronal growth factor brain-derived neurotrophic factor (BDNF). 66

Neurochemical Effects of Depression on Brain 67

Functional Effect of Depression on the Brain n Networks of brain areas are under- and over-activated in individuals with depression. ¨ The subgenual cingulate cortex is consistently hyperactive. ¨ This hyperactivity returns to normal following successful treatment of depression. ¨ The dorsolateral and dorsomedial prefrontal cortex tend to be less active. 68

Functional Effect of Depression on the Brain 69

Functional Effect of Depression on the Brain The pattern of hyper- and hypo-active brain regions differs across individuals. n Current research is examining the interactions between different brain regions. n 70

Treatment of Depression n Three major treatments are used for individuals with depression ¨ Psychotherapy ¨ Pharmacotherapy ¨ Somatic therapy 71

Treatment of Depression In psychotherapy, the patient interacts with a clinician to work through the causes of their depression. n Cognitive therapy is about as effective as pharmacotherapy n The effects seem to persist for a longer time than the medication does. n 72

Treatment of Depression 73

Treatment of Depression n Anti-depressant medications include ¨ Monoamine oxidase inhibitors (MAOIs) ¨ Tricyclic antidepressants (TCAs) ¨ Selective serotonin reuptake inhibitors (SSRIs) All of these are about equally effective. n Different medications are more or less effective for different individuals. n 74

Treatment of Depression 75

Treatment of Depression Somatic therapies are more invasive. n These include n ¨ Repetitive transcranial magnetic stimulation ¨ Electroconvulsive therapy ¨ Deep brain stimulation 76