Block 9 Brain and Behavior - Marcus

Anxiety Disorder Treatment

*Symptomatic:* benzodiazepines (BZDs) *Preventative:* *SSRIs*, SNRIs, TCAs When starting a new medicine regimen, benzos (symptomatic) can help bridge the patient until preventive medication (SSRIs) takes action.

*DSM-V: Substance Use Disorder* -59-65k people die annually from drug OD -13k people die annually from heroin OD

*2 or more of the following over 12 months:* 1. Hazardous use 2. Social/interpersonal problems related to use 3. Neglected major roles to use 4. Withdrawal 5. Tolerance 6. Used larger amounts/longer 7. Repeated attempts to quit/control use 8. Much time spent using 9. Physical/psychological problems related to use 10. Activities given up to use 11. Craving 2-3 = mild, 4-5 = moderate, >5 = severe *ASAM Addiction Definition:* ABCDE 1. Inability to *A*bstain 2. Impairment in *B*ehavioral control 3. *C*raving 4. *D*iminished recognition of significant problems 5. Dysfunctional *E*motional response

Unmet Needs with Current Anti-Depressant Therapies

*20-40% of patients do not respond to any single antidepressant, and 50% will have side effects.* - Treatments have low long term adherence and relapses are common

Genetics of Anxiety Disorders

*30-50% heritability in anxiety disorders and OCD (panic disorders higher percentage).* 1. Genes may influence trait features that, in turn, confer risk for development of disorder (e.g., behavioral inhibition (withdraw from novelty) and neuroticism (stable tendency to experience negative emotional states)) 2. *Relatives of patients with OCD are 3-5x more likely to have OCD or OC symptoms* 3. Obsessions are more familial than compulsions, and onset of OCD before 18 is highly predictive of OCD in relatives 4. Not a single gene, and if there is one with a major effect, it has not been identified -*Serotonin transporter polymorphisms* are suspected because of serotonin's role in anxiety and OCD (S/S genotype → ↑risk for depression after early maltreatment) -*Animal* studies: *Stathmin protein* critical for the amygdala to *form fear memories* (KO mice showed less anxiety when exposed to fear-inducing stimuli) 5. Epigenetics can play a role as well

ALS vs. Subacute Combined Degeneration (B12) vs. Friedreich's Ataxia: (GAA)n Friedreich Mnemonic: Friedreich is *Frat*astic (*frat*axin): he's your favorite frat brother, always *staggering and falling* but has a *sweet*, *big heart*.

*ALS:* 1. Affects alpha motor neurons (ventral horn) and lateral corticospinal tract 2. UMN and LMN *Subacute Combined Degeneration:* B12 deficiency 1. DC-ML 2. Lateral corticospinal tract *Friedreich's Ataxia:* sensory ataxia characterized by damage to the dorsal columns 1. Expansion of an intronic GAA triplet repeat in the FXN gene (Chr. 9) 2. *↓mitochondrial protein frataxin* (deficiency) 3. *Poor coordination* (ataxic *GAAit*) 4. Scoliosis (sideways curvature of the spine) 5. *Hypertrophic cardiomyopathy (cardiac arrhythmias)* (big heart) 6. *Diabetes* (sweet) *Spinal Cord Affected in Friedreich's Ataxia:* spastic, hereditary ataxia 1. DC-ML (sensory ataxia) 2. Clark's nucleus 3. Spinocerebellar tracts (especially dorsal): proprioception 4. Distal corticospinal tract

*Psychosis Flowchart* (primary vs. secondary) Deli*rium* = altered senso*rium* (2°)

*Abnormal cognition* → Psychosis 2° to cognitive disorder (delirium/dementia) *Normal cognition* → Psychosis due to primary psychiatric syndrome ("clear sensorium") 1. Schizophrenia 2. Delusional disorder 3. Depression with psychosis 4. Bipolar disorder with psychosis 5. Schizoaffective disorder (SAD)

Dopamine Receptors (GPCRs)

*Activate Gs:* D1, D5 (direct pathway: less thalamic inhibition) *Activate Gi:* D2, D3, D4 (indirect pathway: more thalamic inhibition) Antipsychotic potency has been correlated with affinity for the D2 receptor (blocks the receptor). *Drugs Affecting Dopamine System:* 1. *Amphetamines:* cause dopamine release 2. *Cocaine:* blocks dopamine uptake

*Korsakoff's Syndrome* -B1 deficiency → mammillary body destruction -Confabulation is characteristic

*Amnesia (anterograde > retrograde)* caused by *vitamin B1 deficiency* and associated destruction of *mammillary bodies* and *dorsomedial thalamic nucleus* (episodic memory). *Disorientation to Time:* no string of memories to get a general time estimate *Cognitive Deficits:* 1. Severe anterograde amnesia for declarative info 2. Severe retrograde amnesia for declarative info with temporal gradient (recent worse than remote, possibly due to preserved semantic memory) 3. Impaired episodic memory 4. Preserved procedural memory 5. Preserved priming 6. Abulia (lack of willpower/ability to act) and other "frontal/dysexecutive" deficits

*Delirium* -*Impaired attention* is an *early* finding in *delirium*, but a *late* finding in *dementia* (test with DOW backwards) -Dementia is a risk factor for delirium -Acute confusional state (changes in sensorium) -CC: altered mental status (AMS) -AVOID benzodiazepines

*Acute (within 24-48 hours) encephalopathy*, characterized by: 1. *Rapid fluctuations ("waxing and waning") of alertness and attention* 2. Decreased concentration and coherent thought *(patient is "not themselves")* 3. Hallucinations (often visual) 4. Decreased skilled movement (motor findings) 5. Disorientation 6. Memory 7. Language 8. Irritability and agitation 9. Disturbances in sleep-wake cycles 10. Sensory findings (e.g., irritation to light touch) *Usually 2° to other illness:* 1. CNS disease 2. *Infection* (e.g., UTI) 3. Trauma 4. *Substance abuse/withdrawal* 5. *Metabolic/electrolyte disturbances* 6. Hemorrhage 7. Urinary/fecal retention 8. *New medication* (e.g., anticholinergics) Most common presentation of altered mental status (*AMS*) is in inpatient setting, especially in the ICU and with prolonged hospital stays. *Reversible.* *EEG for encephalopathy may show diffuse slowing* (the brain's electrical activity is not able to tick at the same beat it used to). *Psychiatric disorders would have normal EEGs.* *Treatment:* 1. Aimed at identifying and addressing underlying condition 2. Use antipsychotics acutely as needed 3. *Avoid benzodiazepines*

NE Receptors NE = NA = nor*adrenaline*

*Adrenergic Receptors:* 1. *Alpha:* inhibit cAMP formation 2. *Beta:* stimulate cAMP formation *Alpha-1:* vasoconstriction (↑BP) -Antagonists can lead to sedation (CNS) and orthostatic hypotension (PNS) *Alpha-2:* auto-regulation (inhibit sympathetics, ↓BP) -Agonists lead to sedation and anti-hypertension *Beta:* located in PNS (not in the brain)

Opioid Withdrawal Timeline

*After Last Dose:* 1. *6-12 hours:* start 2. *1-3 days:* peak 3. *1 week:* subside 4. Symptoms can persist for weeks, months, or even years (post-acute withdrawal syndrome)

Reponses to Toxic Stress: Executive Function

*Age:* Infant, toddler, preschooler *Working Memory:* (frontal) slow acquisition milestones *Inhibitory Control:* 1. Tantrums (frequent & severe) 2. Aggression *Cognitive Flexibility:* 1. Easily frustrated 2. Difficulty with transitions *Age:* School-age child *Working Memory:* 1. Slow acquisition of skills/learning 2. Memory loss leads to confabulation (viewed as lying) *Inhibitory Control:* 1. Fighting 2. Disrupting school *Cognitive Flexibility:* 1. Problems with organization 2. Looks like ADHD or LD, rather than trauma

*Frontotemporal Dementia (FTD) vs. Alzheimer's Disease (AD)* *More Affected:* *FTD:* behavior (early) *Alzheimers:* memory

*Alzheimer's patients will show preservation of personality and behavior, while exhibiting deficits more specific to memory function.* *FTD:* 1. *Early changes in behavior/personality* 2. Neuropsychological deficits in executive and inhibitory functions, no frank amnesia 3. Relative sparing of posterior functions (must be dissociated from dysexecutive problems) 4. Anterior atrophy (executive functions affected) *AD:* 1. *Preservation of personality & social behavior* 2. Neuropsychological *deficits in naming and construction*, with *frank amnesia after delay* 3. Relative *sparing of anterior functions* (executive functions) 4. Generalized and hippocampal atrophy Imaging: *FTD (cortical atrophy)* vs. *AD (hippocampal atrophy)*.

*Sympathomimetics* (stimulants) -Treat agitation with benzos -Avoid succinylcholine (rhabdomyolysis) 1. Amphetamine: high everything 2. Cocaine 3. Caffeine

*Amphetamines:* high everything Euphoria, grandiosity, pupillary dilation, prolonged wakefulness and attention, hypertension, tachycardia, anorexia, paranoia, fever. Skin excoriations with methamphetamine use. *Severe:* cardiovascular collapse (*cardiac arrest*), seizures *Treatment:* benzos for agitation and seizures *Cocaine:* Impaired judgment, pupillary dilation, hallucinations (including tactile), paranoid ideations, angina, sudden cardiac death. Chronic use may lead to perforated nasal septum due to vasoconstriction and resulting ischemic necrosis. *Treatment:* α-blockers, benzos. *β-blockers not recommended.* Also, avoid succinylcholine (to prevent rhabdomyolysis). *Caffeine:* Restlessness, ↑diuresis (urine), muscle twitching. *Withdrawal:* headache, difficulty concentrating, flu-like symptoms.

Hypotheses for Alzheimer's Disease Etiology

*Amyloid Hypothesis:* 1. Down Syndrome patients have ↑risk of developing AD, as APP is located on Chr. 21 (trisomy) → encourages plaque formation 2. Down Syndrome patients have shortened anteroposterior diameter and a more simplistic pattern of neuronal synapses *Cholinergic Hypothesis:* 1. *↓cholinergic cell density* in the basal nucleus of Meynert (↓ACh → ↓tropic effect on cortex, which could explain cortical atrophy) 2. *Treatment:* -*Mild to moderate cases:* AChE inhibitors (Aricept, *rivastigmine*): improve cognitive symptoms for 6-12 mo. (↑ACh), but patients succumb to the disease with time and face GI symptoms and syncope due to ACh -*Moderate to severe cases:* memantine (NMDA antagonist)

Psychodynamic Psychotherapy and Analysis

*Analysis:* patient is on the couch 4-5 days per week using free association over the course of years to try and fully understand conscious and unconscious drives -Brings the unconscious to the conscious (run out of things to talk about with frequent sessions) -Requires a patient that is cognitively intact because it is based on the patient talking freely about their experiences

*Anorectic vs. Orexigenic Circuits* 1. *Anorectic* ↓food-seeking behavior -α-MSH (melanocyte stimulating hormone) -CART (cocaine/amphetamine regulated transcript) -CCK (cholecystokinin) -Insulin -PYY (from bowel) 2. *Orexigenic* ↑food-seeking behavior -Neuropeptide Y (NPY) -AgRP (agouti-related protein) -MCH (melanin concentrating hormone) -Orexin (hypocretin) -Ghrelin (from stomach when empty)

*Anorexic Circuit:* drives satiety 1. *Leptin activates* α-MSH/CART neurons of the arcuate nucleus (hypothalamus). *Grehlin inhibits.* -The paraventricular nucleus (PVN) is stimulated to produce CRH/TRH, which ↑ energy expenditure. 2. Leptin inhibits NPY/AgR neurons of the arcuate nucleus (hypothalamus). -The lateral hypothalamus is not as activated, and ↓ feeding (↓MCH and orexin) *Orexigenic Circuit:* drives feeding 1. Less activation of α-MSH/CART neurons by reduced leptin 2. Less inhibition of NPY/AgR neurons by reduced leptin. *Grehlin excites.* -The *lateral hypothalamus is activated*, and ↑feeding (↑MCH and orexin) -The PVN is inhibited by NPY/AgR neurons, which ↓ energy expenditure.

Brain Circuitry in Panic Disorder

*Anterior cingulate cortex* (processing of stimuli) and *Amygdala* (processing of emotion) implicated

*Neurotransmitters and Anxiety Disorders* *Mnemonic:* 1. Ben*z*o: Hz (frequency) 2. Barbi*durate*: duration

*Anxiety Disorders:* 5-HT, NE, GABA *OCD:* 5-HT and GABA 1. β-agonists (albuterol) or α2-antagonists (yohimbine) → panic attacks 2. α2-agonists (clonidine) → prevent anxiety attacks 3. Serotonergic anti-depressants (e.g., SSRIs) show therapeutic effects in anxiety and OCD 4. Benzodiazepines (↑GABA channel open-frequency and ↑GABA activity at GABA-aR) *Physical symptoms* of anxiety are tied to: 1. Hypothalamus (autonomic/endocrine response) 2. Locus ceruleus (poor NE regulation → sympathetic response) 3. Reticular formation (respiratory rate) *Behavioral symptoms* of anxiety are tied to: 1. Hypothalamus (defensive) 2. Periaqueductal Gray (PAG) (defensive) *Regulatory systems* in anxiety are tied to: 1. Anterior cingulate cortex (conscious processing of stimuli) 2. Hippocampus (context/memory of stimuli) 3. Amygdala (processing of emotion)

Anxiety Disorders

*Anxiety is a normal, adaptive response that has lifesaving qualities.* An *anxiety disorder* is a *persistent* (1-6 months), inappropriate experience of *fear/worry* and its physical manifestations (anxiety) *incongruent with the magnitude of the perceived stressor*. *Symptoms interfere with daily functioning* and are not attributable to another mental disorder, medical condition, or substance abuse. *Early Onset:* progressive, persistent, or recurrent course that is predictive of problems in adulthood with work adjustment, family problems, stress, and life satisfaction *Affects 6.5% of the world's youth (age 5-19); females > males.* 28.8% lifetime prevalence in US adults. *Workup:* goal is to achieve a balance between avoiding excessive workups that delay psychiatric treatment and investigating physiological explanations (take a good history, ROS, meds, vitals). *Protective Factors:* 1. Resilience 2. Family factors 3. Coping style *Treatment:* 1. CBT 2. SSRIs 3. SNRIs

*Generalized Anxiety Disorder* (GAD) (onset in late adolescence and early adulthood)

*Anxiety lasting >6 months unrelated to a specific person, situation, or event.* Associated with restlessness, irritability, sleep disturbance, fatigue, muscle tension, difficulty concentrating. *Treatment:* 1. CBT, SSRIs, SNRIs are first line. 2. Buspirone (NDRI), TCAs, benzodiazepines are second line. *Adjustment Disorder:* emotional symptoms (anxiety, depression) that *occur within 3 months* of an identifiable psychosocial stressor (e.g., divorce, illness) *lasting <6 months* once the stressor has ended. *If symptoms persist > 6 months after stressor ends, it is GAD.* Symptoms do not meet criteria for MDD. *Treatment:* CBT, SSRIs.

*Atypical Anti-Psychotics* for Bipolar Disorder ↓DA2R + ↓5-HT2AR

*Atypical antipsychotics* can be used to *treat acute mania*, but can cause metabolic changes and adverse side effects if used for a long time. *Mechanism:* DA2R antagonism (indirect pathway inhibits thalamus → ↓motion) The *depressed* portion of bipolar disorder can be treated with *lamotrigine*, quetiapine, or lurasidone, possibly a primary antidepressant if used carefully and with a mood stabilizer *Lamotrigine inhibits release of excitatory AA (e.g., glutamate, NMDA).* -Usually well tolerated and effective in *preventing bipolar depression relapse* -Requires slow dose titration and not helpful in acute mania or mania prophylaxis -Metabolized by the P450 system (side note: valproic acid slows metabolism by 50%, carbamazepine increases it by 100%) (contraindicated/toxic with valproic acid) -*Side Effect:* rash → Stevens-Johnson syndrome (epidermal sloughing)

*Huntington's Disease (HD)* -Neurodegenerative Disease

*Autosomal dominant* trinucleotide (CAG)n repeat expansion in the *hunt*ingtin (HTT) gene on *chromosome 4* (4 letters). *Symptoms manifest between ages 20 and 50:* CAADD 1. Chorea (hyperkinesia initially) → hypokinesia (Parkinsonism later) 2. Athetosis (slow, writhing/serpentine movements) 3. Aggression 4. Depression 5. *Dementia (progressive)* *Pathology:* 1. *Striatal degeneration (caudate and putamen)* 2. Compensatory gliosis after degeneration 3. Damage first appears in the tail of the caudate (damage involving the head of the caudate suggests advanced disease) 4. Large gemistocytes (reactive astrocytes) replace neurons *Paternal anticipation* results from expansion of CAG (polyglutamine) repeats (age of onset inversely related to number of repeats), which *destroys the caudate* and putamen (striatum). *Neurotransmitter Changes:* *C*audate loses *A*Ch *G*ABA (*CAG*) 1. *↑dopamine* (SNc) (chorea) 2. *↓ACh* (basal nucleus of Meynert) (↓memory) 3. *↓GABA* (nucleus accumbens) (less inhibition = aggression) *Treatment:* No cure -Treat symptoms using *dopamine receptor antagonists* or *decrease dopamine production*

*Attachment Theory* (Margaret Mahler, John Bowlby)

*Babies need to develop a close relationship with their primary caregiver for successful socio-emotional development.* Children internalize that representation of caregiver and can soothe themselves by their memory during brief absences. This primary relationship also serves as template for future relationships.

*Sedative-Hypnotics* (GABA) (depressant) 1. Benzos: low everything 2. Barbiturates 3. Alcohol

*Barbiturates:* *Intoxication:* relief of anxiety and disinhibition *Toxidrome:* 1. Low safety margin 2. *Marked respiratory depression* 3. Bradycardia 4. Apnea and CNS depression 5. *Miosis* →*Tx:* symptom management (assisted respiration, BP) *Withdrawal:* 1. Delirium 2. *Life-threatening* cardiovascular collapse *Benzodiazepines:* *Intoxication:* relief of anxiety and disinhibition *Toxidrome:* 1. Greater safety margin 2. Ataxia 3. *Minor respiratory depression* →*Tx:* flumazenil (benzo receptor antagonist, but rarely used as it can precipitate seizures) *Withdrawal:* 1. Sleep disturbance 2. Depression 3. Rebound anxiety 4. Seizure *Alcohol:* *Intoxication:* Relief of anxiety and disinhibition *Toxidrome:* 1. Emotional lability 2. Slurred speech 3. Ataxia 4. Coma and blackouts 5. Serum γ-glutamyltransferase (GGT)—sensitive indicator of alcohol use 6. ↑LFTs: *AST* value is 2× *AL*T value ("to*AST 2* *AL*cohol") →*Tx:* IV fluids and glucose (thiamine for Wernicke's encephalopathy) *Withdrawal:* Time from last drink: 1. *3-36 hr:* tremors, insomnia, GI upset, diaphoresis, mild agitation 2. *6-48 hr:* withdrawal seizures 3. *12-48 hr:* alcoholic hallucinosis (usually visual) 4. *48-96 hr:* delirium tremens (DTs): hallucinations, autonomic instability, AMS →*Tx:* benzodiazepines →*Relapse Prevention:* naltrexone, disulfiram, topiramate, acamprosate

*Anxiety Disorders (Age of Onset)*

*Before 12:* 1. Separation Anxiety Disorder 2. Selective Mutism 3. Specific Phobia *Late childhood and adolescence:* 1. Social Anxiety Disorder (Social Phobia) 2. Obsessive-Compulsive Disorder *Late adolescence and early adulthood:* 1. Panic disorder 2. Agoraphobia 3. Generalized Anxiety Disorder

*Symptomatic Treatment of Anxiety* (immediate)

*Benzodiazepines* are good *symptomatic treatment* for exposure to a specific stressor. *Mechanism:* ↑GABA-R open frequency and ↑GABA action at GABA-aR in the CNS 1. *Shorter Acting:* alprazolam (Xanax) and *lorazepam (Ativan)* 2. *Longer Acting:* diazepam (Valium) and *clonazepam (Klonopin)* *Pros:* 1. Effective (anxiety > OCD) 2. Help people get onto SSRIs (4-6 week transition period before efficacy) *Cons:* 1. Side effects 2. Increased tolerance → abuse 3. Withdrawal (similar to alcohol)

*Bipolar Disorder (manic depression)* *Diagnosis:* *I:* do not require depression episodes *II:* requires depression episodes

*Bipolar I:* 1. *At least 1 manic episode (7 days)* ± a hypomanic or depressive episode (may be separated by any length of time). 2. *Does not require an episode of depression*, but 90% of patients have depressive episodes. 3. Does not require psychosis, but many experience mood-congruent psychosis (delusions or hallucinations whose content is entirely consistent with the typical depressive themes of personal inadequacy, guilt, disease, death, nihilism, or deserved punishment) *Bipolar II:* 1. Presence of a *hypomanic (4 days)* and *depressive* episode. 2. If a manic episode occurs → Bipolar I. 3. *Depressive episodes predominate*, so BP II can look like MDD (which requires different treatment) → need a good history to avoid prescribing anti-depressants (which can destabilize mood) *Cyclothymic Disorder:* milder form of bipolar disorder lasting *≥ 2 years*, fluctuating between mild depressive and hypomanic symptoms. *BPAD Specifiers:* 1. Patient's mood and functioning usually normalize between episodes. 2. *Rapid Cycling:* > 4 episodes per year either at similar or different poles 3. *Mixed Episode:* typically involves *depression* and *psychomotor* symptoms *Treatment:* polypharmacy common (atop a mood stabilizer = thymoleptic) 1. *Mood stabilizers* (e.g., *lithium*, valproic acid, carbamazepine, lamotrigine) 2. Atypical antipsychotics (clozapine, quetiapine) 3. Lamotrigine can be used to treat depression (inhibits GABA/glutamate) *Use of antidepressants can destabilize mood.* High suicide risk.

Peptides/Hormones and Eating Regulation

*CART* (peptide) is regulated by cocaine and amphetamines to *inhibit feeding behaviors.* *Serotonin* levels increase when anticipating food and in response to eating and can improve mood, yet *high levels decrease appetite and inhibit eating.* - Prozac (SSRI, fluoxetine) has been used to treat eating disorders by ↑serotonin availability at synapses

*Anti*cholinergic Poisoning *ANTI* = "can't" -*Can't* see (dilation) -*Can't* spit (dry mouth) -*Can't* pee (bladder sphincter not relaxed) -*Can't* shit (sphnicter not relaxed) -Hot (hyperpyrexia) -Dry (reduced salivation) -Tachycardia: ACh block of parasympathetic -Wacky (agitated; seizures; coma = CNS) -BP not affected (muscarinic)

*Can't* see, spit, pee, shit (rhyme); hot, dry, tachy, wachy. *Causes:* -Anti-histamines (Benadryl, H1 agonist) -Jimsonweed → gardener's pupil (mydriasis due to plant alkaloids) -Atropa Belladonna (atropine) (Olive Oil's eyes widen, dilation). *Mechanism:* Blocks muscarinic receptors *Treatment:* Physostigmine. -*Blocks ACh-ase to increase ACh present.* -Contraindicated for wide QRS → flatline.

Neoplastic (Encephalopathy)

*Carcinomatous Meningitis:* tumor cells infiltrating the spinal fluid, can cause a form of meningitis characterized by encephalopathy

Naltrexone (antagonist)

*Depot injection:* given in a carrier liquid that allows for slow-release and slow action for longer-lasting effects. 1. *Blocks all opiate effects* (administered 1x/month) 2. Only effective orally when adherence is assured 3. Two RCTs demonstrated improvement in treatment retention and more negative urine drug tests for opioids

*Wernicke's Encephalopathy*

*Cause:* Alcohol *Lesion:* Mammillary bodies (bilateral) *Clinical Presentation*: CAN O' beer 1. *C*onfusion 2. *A*taxic gait 3. *N*ystagmus 4. *O*pthalmoplegia (dysconjugate gaze) *Treatment:* Vitamin B1 before glucose (thiamine is a cofactor for the metabolism of carbs/sugar) *Korsakoff Syndrome:* memory loss (poor episodic, intact procedural), confabulation, personality change due to bilateral lesions to the *dorsal medial nucleus* of the thalamus

Prader-Willi Syndrome

*Cause:* Chr. 15 mutation ↑ghrelin levels (regardless of stomach state). -Begins in late childhood and causes extreme obesity by adolescence -Can be partially rescued with the normalization of ghrelin levels

Klüver-Bucy Syndrome

*Cause:* HSV-1 encephalitis or surgical bilateral amygdalectomy for refractory epilepsy or aggression *Lesion:* bilateral amygdala *Clinical Presentation:* disinhibited behavior 1. Placid 2. Hyperorality (attempt to eat non-food items) 3. Hyperphagia 4. Hypersexuality (animals may fail to recognize dominant animals, and sometimes initiate sex with other species)

Special Motor Exam Cases

*Cerebral Palsy:* fixed injury that is stable over time 1. Varies from mild to severe (can present as whatever region of the brain is injured) → complicated diagnosis 2. Causes are heterogeneous - *Hypoxic-ischemic encephalopathy* - Intracerebral Hemorrhage (ICH) - Stroke - Trauma - Kernicterus (hyperbillirubinemia moves into brain) →*Treatment:* brain cooling improves prognosis *Perventricular Leukomalacia (PVL):* perinatal vascular injury (image) 1. White matter atrophy around the ventricles due to ↓perfusion (hypotension due to low blood pressure) → scarring 2. Leg fibers run close to ventricles (vulnerable) 3. Infants may have bilateral *spastic legs (UMN) and normal upper extremity tone* (can cause cerebral palsy in survivors) *Tay Sachs:* autosomal recessive condition (HexA) 1. HexA mutation (Chr. 15) prevents breakdown of lipid derivatives (gangliosides) 2. Accumulation of lipids in neurons → cell death 3. *Disease is diffuse and cortical in nature → global development delay, epilepsy, blindness* 4. *Hypotonic* (floppy baby, head lag) due to cortical disorder (not LMN damage); does not reach for objects or track them with eyes 5. *Cherry red spot:* gangliosides build up in the ganglion cells lining the retina. This makes the fovea (area with no gangliosides) look redder.

*Thought Process (Mental Status Exam)* -*Normal:* coherent and goal-oriented

*Circumstantial:* organized but overly inclusive, eventually gets to the point, but in a painstakingly slow manner *Tangential:* Occasional lapses in organization such that the patient suddenly changes the subject and never returns to it -- if a question is asked, it isn't answered *Flight of Ideas:* Flow of thoughts is extremely rapid but connections remain intact *Loosening of Associations:* Frequent lapses in connection between thoughts, disorganized *Word Salad:* Incomprehensible speech due to lapses in connections even within a single sentence; incoherent, a "tossed salad" of ideas *Blocking:* Patient loses his or her train of thought; by definition, the patient should confirm the subjective experience of being blocked; the term should not be based on the interviewer's observation alone *Neologism:* A created word with an idiosyncratic meaning

Obsessive-Compulsive Disorder

*Clinical Presentation:* 1. Recurrent unwanted, intrusive thoughts (obsessions) that cause anxiety 2. Anxiety is relieved to some extent by performing repetitive actions (compulsions). *Mechanism:* overactivity in frontal:subcortical circuits (interrupted by refractory surgery) *Treatment:* CBT, SSRIs, venlafaxine (SNRI), and clomipramine (TCA)

*Autism (behaviorally-defined syndrome)* *Characteristics:* 1. *Must present in early childhood.* 2. More common in boys. 3. Associated with head/brain size. 4. May be accompanied by intellectual disability 5. Rarely accompanied by unusual abilities (savants) 6. Non-verbal IQ correlates with better outcomes *Short Test:* 1. *Pointing:* way of sharing a social experience 2. *Prosody:* rhythm of speech, understanding sarcasm

*Clinical Presentation:* defined by *behavior* 1. Poor social interactions (impaired empathy, sociability, and insight into other minds) 2. Social communication deficits (verbal and non-verbal) 3. Repetitive/ritualized behaviors (stereotypic, perseverative) 4. Restricted interests (desire for sameness, rigidity) While formal testing and scales may place a child on the autism spectrum, *a simple test of pointing and prosody can help identify if a child is autistic*. Pointing is an important form of communication (a way to share a social experience), and if a child is *not pointing to indicate interest by the age of 1*, they likely have impaired joint attention. Similarly, evaluating a child's prosody or rhythm of speech can be useful. Children with autism tend to have either a *flat or sing-song speech* and often *cannot understand sarcasm* which relies on *prosody*. *Essential Autism vs. Complex Autism:* 1. Essential (probably a genetic mechanism) 2. Complex (also presents with a neurological problem) (probably a neurological injury model)

*Pre-motor Cortex* -Broadmann Area 6 -Intermediate Neurons -*Coordination of complex movements* (integrates sensory and motor information)

*Components:* 1. *Supplementary Motor Area (SMA):* program complex movement 2. *Frontal Eye Fields (FEF):* contralateral eye movements 3. *Broca's Area:* speech formation *Function:* involved in *integration of sensory and motor information* to coordinate complex movements (praxis). *Input:* 1. Secondary somatosensory area/posterior parietal cortex (integrates somatosensory and visual input) 2. *Ventral anterior thalamic nucleus* (a relay nucleus with projections from the basal ganglia, which modulates motor activity) *Output:* 1. Motor Cortex (M1) 2. Contralateral premotor area (via corpus callosum) *Dysfunction:* 1. *Apraxia:* inability to carry out learned tasks (but without paralysis) 2. *Preserved postural praxis* (basal ganglia) 3. Deficits in contralateral fine motor control 4. Difficulty using sensory feedback for control/performance of movements.

*Self Development* (Kohut)

*Development of the Self:* 1. Self-Concept (who am I?) 2. Self-Esteem (what am I good at?) 3. Academics 4. Identity Formation 5. Knowing about Others 6. "Self Psychology" Development of self happens properly when one's needs (including sense of worth and well-being) are met in relationship with others (primarily mother). The mother is like a mirror. When she looks at her baby and smiles, it shows the baby that he/she is beautiful and worthy of love and esteem.

Physiological Pathways of Eating Disorders

*Cortical-Striatal Taste Pathway:* when food is presented in front of a person: -The *ventral system (hedonic)* involves the salience (reward) of the food and whether or not it is good to eat (endogenous opioids, cannabinoids, DA) -The *dorsal system (self-regulatory)* gives executive control over the consumption of the food (5-HT, NE, DA) 1. *Anorexia:* ↑dorsal inhibition ↓ventral reward -Restricting food intake is more rewarding than eating (anxiolytic effect) 2. *Bulimia:* Loss of control in the dorsal pathway, and an inability to not be rewarded by food Dysfunctional pathways do not change with recovery, so those with anorexia still do not find food rewarding and other reinforcements need to be used. *Hypothalamic-Pituitary-Gonadal (HPG) Axis:* low weight causes low FSH and LH, leading to *low estrogen and progesterone*. This causes *amenorrhea* in anorexia, but is *reversible*.

*PTSD Requirements for Diagnosis* (Hartselle) (EXAM) *Criterion A:* 1 required (exposed to threat) *Criterion B:* 1 required (re-experience) *Criterion C:* 1 required (avoidance) *Criterion D:* 2 required (negative thoughts) *Criterion E:* 1 required (irritability, insomnia, poor concentration)

*Criterion A (one required):* threat exposure via: 1. Direct exposure to the trauma 2. Witnessing the trauma 3. Learning about a loved one experiencing a trauma 4. Indirect exposure to the trauma in learning the details (first responders, medical personnel, fire fighters, police officers, military personnel) *Criterion B (one required):* persistent re-experiencing of the trauma 1. Nightmares 2. Flashbacks (distorting reality at times) 3. Unwanted upsetting memories 4. Emotional distress post reminder (anger) 5. Physiological distress post reminder (heart rate) *Criterion C (one required):* avoidance 1. Trauma related thoughts or feelings 2. Trauma related reminders *Criterion D (two required):* negative thoughts or feelings that began or worsened with the trauma 1. Inability to recall details of trauma 2. Overly negative cognitions 3. Exaggerated self blame or blame of others for trauma 4. Negative affect (down, irritable) 5. Decreased interest in activities 6. Feeling isolated 7. Difficulty experiencing positive emotions *Criterion E (one required):* 1. Irritability or aggression 2. Risky or destructive behavior 3. Hypervigilance 4. Heightened startle response 5. Poor concentration 6. Insomnia

Thought Content (Mental Status Exam)

*Delusion:* A firmly held, false belief not shared by members of the patient's culture (by definition, reality testing is not intact, i.e., the patient is unable to consider the possibility that the belief is incorrect) *Obsession:* An idea that is intrusive and ego-dystonic (by definition, reality testing is preserved, i.e., the patient will readily acknowledge that the obsession makes no sense); should not be confused with ruminations, which are ego-syntonic, or delusion *Paranoid Ideation:* Specific type of overvalued idea characterized by suspiciousness about others' motives *Ideas of Reference:* Specific type of overvalued idea characterized by misinterpretation of external events as having a particular meaning for the individual

Dementia vs. Age-Related Memory Loss vs. MCI

*Dementia:* a *progressive* deterioration in intellectual function and other cognitive skills, leading to a *decline in the ability to perform activities of daily living*, in the *absence of delirium* (no "waxing and waning" consciousness or decreased attention span) (deli*rium* = changes in senso*rium*). *Who is affected by dementia?* 1. 1% of people aged 60 to 64 2. 30-50% of those over 85 3. Prevalence doubles every 5 years after age 60, until about age 90. *Dementia vs. Age-Related Changes (ARC) in Memory:* 1. ARCs are *milder* and *not as progressive* 2. ARCs *do not impair daily functioning* (unimpaired higher cortical function if given extra time). 3. ARC patients learn new/recall previously learned information more slowly and less efficiently. *Dementia vs. MCI:* 1. *MCI:* cognitive loss (memory) not severe enough to meet dementia criteria, but *beyond normal*. 2. Up to 50% of patients with MCI that affects memory → *dementia within 3 years*.

*Huntington's Disease* 1. Progressive dementia 2. Neostriatal (caudate) atrophy 3. ↓ACh, ↓GABA, ↑DA

*Disease Markers:* memory 1. Chorea 2. Progressive dementia 3. Atrophy of neostriatum (procedural) *Impaired central executive system: moderate anterograde amnesia* 1. Impaired retrieval 2. Impaired temporal order judgments 3. Impaired source judgments 4. Impaired metamemory judgments 5. Moderate, flat retrograde amnesia 6. *Intact semantic memory:* intact fund of knowledge (temporo-parietal association) 7. *Impaired procedural memory:* impaired skill learning (basal ganglia)

*Psychosis* 1. *Primary psychiatric:* -Primary psychotic disorders -Mood disorders with psychotic features (depressive or manic phase of BPAD) 2 *Secondary medical-neurologic:* -Medical -Cognitive -Substances and medications

*Distorted perception of reality characterized by delusions, hallucinations, and/or disorganized thought/speech.* Can occur in patients with medical illness, psychiatric illness, or both. *Characterized by:* positive symptoms (easier to treat) 1. *Delusions:* unique, *false*, *fixed*, *idiosyncratic beliefs* that persist despite the facts and are not typical of a patient's culture or religion (e.g., thinking aliens are communicating with you). Can include *ideas of reference* (over-interpretation of innocuous events or mere coincidences). - *Types* of delusions: *erotomanic* (someone is in love with me → pursue), *grandiose* (religious, special relationships), *jealous* (Othello Syndrome), *persecutory* (paranoid), *somatic* (I have cancer, infestation, etc.), *mixed*, and unspecified. 2. *Disorganized thoughts:* speech may be incoherent ("word salad"), tangential, or derailed ("loose associations"). 3. *Hallucinations:* misperceptions in the *absence of external stimuli* (e.g., seeing a light that is not actually present). Contrast with *illusions*, which are *misperceptions of real external stimuli*. Misprocessing of sensory information at unimodal or heteromodal association cortex level. 4. *Disorganized behavior:* isolation, impoverished behavior (stick to self), agitation and aggression, purposeless/repetitive activities, wandering, catatonia) *Types of Hallucinations:* auditory (commands/running commentary) is most common 1. *Visual:* medical illness (e.g., substance abuse) > psychiatric illness. 2. *Auditory:* psychiatric illness (e.g., schizophrenia) > medical illness. 3. *Olfactory:* aura of temporal lobe epilepsy (burning rubber); brain tumors. 4. *Gustatory:* rare, but seen in patients with epilepsy 5. *Tactile:* common in alcohol withdrawal and stimulant use (e.g., cocaine, amphetamines), delusional parasitosis, *"cocaine crawlies*" (formication) 6. Hypna*go*gic: occurs while *go*ing to sleep. Sometimes seen in narcolepsy. 7. Hypno*pomp*ic: occurs while waking from sleep ("*pompous* upon awakening"). Sometimes seen in narcolepsy.

*Executive Functions of Pre-Frontal Cortex* -Granular neurons

*Dorsolateral:* managing functions -Holding, manipulating, planning, executing, shifting, problem solving *Orbital:* regulation of emotions and behavior (personality) 1. Initiating, timing, sustaining, modulating, inhibiting 2. *Good angel:* regulates compulsions, impulses, and drives 3. *Personality* *Anterior Cingulate:* evaluation of one's own behavior 1. Monitoring, gauging, inhibiting, shifting 2. Selective *attention* (dorsal) 3. Emotions depression/anxiety (ventral) *Ventromedial PFC:* emotional processing

*Pseudotumor Cerebri* (Idiopathic Intracranial Hypertension, IIH) -Neurodegenerative Disease *Risk Factors:* female TOAD -Tetracyclines (antibiotics) -Obesity -A (vitamin A) excess (acne meds) -Danazol (steroid for endometriosis) Treatment: *carbonic anhydrase inhibitors and weight loss*

*Elevated ICP* with *no mass* present on imaging. If untreated, could cause loss of vision. *Disease Characteristics:* 1. *Papilledema (↑ICP)* with no apparent cause 2. Positional headache (worse when lying) 3. Diplopia with lateral gaze (*CN VI palsy*) 4. No change in mental status 5. *Enlarged blind spot* and peripheral constriction *Risk Factors:* female TOAD -*T*etracyclines (antibiotics) -*O*besity -*A* (vitamin A) excess (acne meds) -*D*anazol (steroid that treats endometriosis) *Treatment:* 1. *Weight loss* 2. *Carbonic anhydrase inhibitor* (acetazolamide and *topiramate*): *↓CSF* 3. CSF shunt placement 4. Optic nerve sheath fenestration surgery (for visual loss)

*Emotional Development* 1. Emotional expression 2. Emotion regulation 3. Understanding of emotion

*Empathy:* the ability to experience the same emotions that someone else is experiencing. *Social referencing:* the use of others' emotional expressions to infer the meaning of otherwise ambiguous situations (how should I be reacting to something based on response from others around me).

*Toxic-Metabolic Encephalopathy* -Think: old lady with a UTI -*Risk factors:* elderly and cognitively impaired -*Inattention* occurs EARLY

*Encephalopathy:* 1. The *inability to carry out a coherent plan of thought or action* (brain + disease) 2. Potentially reversible (if not chronic traumatic encephalopathy (CTE) seen in football players, which is seen as static and progressive). 3. *Global problem:* localizes to *bilateral cerebral hemispheres* A *diffuse disturbance of cortical function*, which affects speed of processing, clarity, and coherence. *Causes:* 1. Toxins (endogenous or external) 2. Liver (processes toxins) or kidney (cleans blood) dysfunction *Treatment:* first, identify the cause! 1. Thiamine for Wernicke's Encephalopathy 2. Narcan (Naloxone) for opiate overdoses 3. Hydration, electrolytes

Behavior Therapy (ERP)

*Exposure and Response Prevention (ERP):* involves incremental exposure (obsession) and response prevention (no compulsion, ritual) 1. ERP is evidence-based to treat OCD (ego-dystonic). 2. Moderate to severe OCD: ERP and medication may be necessary In moderate-severe OCD, the *frontal lobe and limbic system are always on*. The frontal lobe rationalizes that something is not dangerous, but the limbic system maintains that it is. There is no negative feedback here.

Eating Disorders

*Fairburn's Transdiagnostic Model:* the central cognitive disturbance in ED is *over-evaluation of eating, shape, weight*, and one's control over them.

*Antipsychotic Agents (Overview)* -Pay attention to high and low risk drugs (EXAM)

*First generation antipsychotic (FGA):* 1. Potent D2 blockade 2. Nigrostriatal (NS) side effects 3. *EPS prone* 4. High potency (more EPS prone; Haldol) vs low potency (less EPS prone; thioridizine) *Second generation antipsychotic (SGA):* atypical antipsychotics 1. Less potent D2 blockade (D1,D4 blockade > D2) 2. Mesolimbic and mesocortical (ML-MC) occup > nigrostriatal (NS) 3. 5-HT 2A antagonism 4. Dynamic receptor occupancy 5. *Less EPS* 6. *More metabolic adverse effects* *Serotonin neurons inhibit DA transmission:* 1. Can drive EPS (SSRIs) 2. Therefore, molecule with 5-HT antagonism disinhibit DA transmission → less EPS

*Delusional Disorder* -Delusions in isolation for *>1 month* *Crush:* 1. Delusions are *not bizarre* (like in schizophrenia) 2. Delusions are *plausible, but unwavering* (e.g., nothing you say can make the patient shake his belief that members of the CIA are following him every time he leaves his house)

*Fixed, persistent, false belief system lasting >1 month.* Functioning otherwise not impaired. No thought disorder, disorganized behavior, negative symptoms (preservation of affect), or neurocognitive impairments. Less marked impairment. Can be shared by individuals in close relationships (*folie à deux*). *Subtypes:* 1. Persecutory (paranoid) 2. Grandiose (religious connection) 3. Jealous (Othello syndrome) 4. Erotoromantic (stalker) 5. Nihilism (Cotard Syndrome: dead and don't exist) 6. Somatic (cancer, infestation, rotting) *Multiple subtypes of misidentification syndromes:* 1. *Capgras:* friend, family, or spouse replaced by monster 2. *Fregoli:* different people are actually a single person who changes appearance 3. *Reduplicative Paramnesia:* place, people, and objects have been duplicated and removed Misidentification syndromes are associated with *right temporo-parietal cortex dysfunction* that can be seen on imaging (disturbance in visual perceptual systems).

Schizophrenia Associations and Prevalence

*Frequent cannabis use in teens is associated with psychosis/schizophrenia.* *Lifetime prevalence:* 1.5% (males > females, African Americans = Caucasians). Presents *earlier in men* (late teens to early 20s vs late 20s to early 30s in women). Patients are at risk for *suicide* (*20% attempt*; 5-6% complete), especially when experiencing command hallucinations, co-morbid depressive symptoms, or substance abuse. *Most patients die due to cardiovascular disease.*

Goals of EtOH Treatment

*Frontal Lobe:* 1. Improve emotional control 2. Improve decision making 3. Reduce impulsivity *Basal Ganglia:* 1. Reduce reward from drugs 2. Decrease stress and distress

Fronto-Temporal Dementia (FTD)

*Frontal subtype* 1. Early changes in *behavior/personality* 2. Dysexecutive and inhibitory deficits on neuropsych testing 3. "Frontal" memory impairment, *no frank amnesia as in AD* 4. Relative sparing of posterior functions (must be dissociated from dysexecutive problems) *Primary progressive aphasia subtype* 1. *Language deficits progressing to mutism* -Non-fluent (Broca's) progressive aphasia -Logopenic progressive aphasia (trouble with confrontation word meaning; trouble coming up with a word to use that you want) 2. *Semantic dementia (loss of individual word knowledge and meaning)*

*Frontal Eye Fields*

*Function:* volitional eye movements in the contralateral visual field for processes such as active visual search. *Dysfunction:* 1. Deficits in voluntary eye movement to the contralateral visual field (active visual search deficits) (*look towards lesion*) 2. Preserved passive eye movement ("follow my finger").

Opioid Receptors

*GPCRs (metabotropic):* 1. Inhibit adenylate cyclase (↓cAMP), 2. Decrease conductance of voltage-gated Ca2+ channels, or 3. Open inward flowing K+ channels *Overall:* ↓neuronal activity (depressing affect) *Major Classes:* 1. *Mu (μ)* - *μ1:* analgesia (supra-spinal/spinal), euphoria, low abuse potential, bradycardia - *μ2:* analgesia (spinal), respiratory depression, physical dependence, constipation 2. *Kappa (κ)* (analgesia-both, dysphoria, sedation) 3. *Delta (δ)* (analgesia-both, respiratory depression, physical dependence) Reminder: buprenorphine is a partial agonist of the μ receptor (less risk of respiratory depression)

*Opioids* (depressant) -Concurrent *benzo* use can lead to *death* -Also avoid benzos in delirium 1. Heroin, morphine, methadone, oxycodone, hydromorphine 2. Salvia

*Heroin, morphine, etc.* *Intoxication:* euphoria *Toxidrome:* 1. Respiratory depression and bradycardia 2. CNS depression 3. ↓gag reflex and slurred speech 4. Pupillary constriction (*miosis* = pinpoint pupils) 5. Seizures (overdose) *Salvia:* *Intoxication:* 1. Trance-like state 2. Hallucinations 3. Synesthesia 4. Extra-bodily experiences 5. Elevated mood *Toxidrome:* 1. Tachycardia and hypertension 2. Depersonalization 3. Anxiety, confusion, fear 4. Headaches, drowsiness *Withdrawal:* 1. Mild hypertension and tachycardia 2. Anxiety, irritability, agitation 3. Restlessness, tremor 4. *Mydriasis* 5. *GI Symptoms:* cramps, diarrhea, nausea 6. *Flu-like symptoms:* lacrimation, rhinorrhea, diaphoresis (sweating), shivering *Treatment:* 1. *Intoxication:* naloxone (short half life → must continually dose) 2. *Withdrawal:* long-term support, methadone, buprenorphine

*Epigenetic (Michael Meany's Rats)* 1. *Negative feedback* on the HPA axis is *normal* (cortisol binds glucocorticoid receptors of the hypothalamus and anterior pituitary). 2. Trauma/stress can impact methylation of glucocorticoid receptors (↓receptors → ↑cortisol / stress) 3. Prolonged ↑cortisol (due to early trauma and neglect) can biologically re-program a circuit (which can last a lifetime)

*High licking of pups:* highly nurtured, resilient 1. Stress-resistant 2. Bold, relaxed 3. Licking activates NGFI-A (nerve growth factor initiator), reducing methylation of GR gene in hippocampus of pups (turns gene on) 4. High GR concentration in hippocampus 5. Negative feedback HPA *Low licking of pups:* low nurtured, neglected 1. Stress-sensitive 2. Anxious 3. GR gene in hippocampus remains methylated (turned off) without mom's licking 4. Low GR concentration in hippocampus 5. Exaggerated HPA responses

*First Generation Antipsychotics* 1. *Mechanism:* Block DA2R (↑cAMP) 2. *Clinical Use:* Schizophrenia (positive symptoms), psychosis, BPAD, delirium, Tourette syndrome, HD, and OCD. 3. Used over 2nd generation to avoid bad metabolic side-effects. *Anticholinergic Effects:* low potency *Can't* see, spit, pee, shit; hot, dry, tachy, wachy. *For dystonia caused by high potency APs (haloperidol/fluphenazine), treat with an IM anticholinergic (benztropine) to combat the decreased dopamine (motor symptoms) and balance ACh/DA in the basal ganglia.*

*High potency (2mg):* *T*ry to *F*ly *H*igh 1. *T*rifluoperazine 2. *F*luphenazine (Prolixin) 3. *H*aloperidol (*Haldol*) *Side Effects:* EPS (due to ACh > DA), but low anticholinergic 1. High risk for neurologic side effects (extrapyramidal symptoms) 2. Lowest risk for sedative, hypotensive, and anticholinergic effects 3. High potency means the drug binds the DA2R more tightly and causes more motor side effects. *Intermediate Potency (8mg):* 1. Perphenazine (Trilafon) 2. Thiothixene (Navane) *Low potency (100mg):* *C*heating *T*hieves are *low* 1. *C*hlorpromazine (Thorazine): sedating and orthostatic hypotension 2. *T*hioridazine (Mellaril): prolonged QT; retinitis pigmentosa *Side Effects:* anticholinergic, but low EPS risk (D2 blockage by anticholinergics) 1. More anticholinergic (dry mouth, constipation, blurry vision), antihistamine (sedation and weight gain), α1-blockade effects (orthostatic hypotension and dizziness) 2. *Lowest risk for extra pyramidal symptoms (motor symptoms); anticholinergic effects attenuate the D2 blockade* 3. Low potency means the drug binds the DA2R less tightly and causes fewer motor side effects (but still more than atypical AP). *Overview:* mesolimbic → tuberinfundibular → nigrostriatal (spillover order) 1. Blocking 65% of DA2Rs in the NAcc and associative striatum causes a decrease in psychotic (*positive*) symptoms via the *mesolimbic* pathway 2. Blocking 72% of DA2Rs causes *hyperprolactinemia* via the *tuberoinfundibular* pathway -Hyperprolactinemia causes hypogonadism, ↓libido, galactorrhea, infertility, and ↓bone density 3. Blocking 80% of DA2Rs causes *extrapyramidal symptoms* via the *nigrostriatal* pathway (i.e., if patient has rigidity, then 80% of DA2Rs are blocked in NS pathway) *ADAPT (acute dystonia, akathisia, parkinsonism, tardive):* Extra-Pyramidal Symptoms 1. *Acute:* *A*cute *D*ystonia (hours), *A*kathisia (days), *P*arkinsonism (weeks) 2. *T*ardive: *late onset* (months to years) of dyskinesia (hyperkinetic), akathisia, and Parkinsonism from upregulated D2 receptors and hypersensitivity to dopamine -*Dystonia* is acute spasms of the neck, back, tongue, eyes, or larynx -*Akathisia* is a subjective feeling of restlessness in the lower extremities (can't sit still) -*Dyskinesia* is involuntary movements of the face, trunk, or extremities -Adaptation of the system increases response to dopamine with time (hypersensitivity), causing *hyperkinetic* instead of hypokinetic symptoms *Neuroleptic Malignant Syndrome:* 10-20% mortality *Malignant FEVER:* high-potency primary antipsychotics (e.g., Haldol) and genetic predisposition 1. *M*yoglobinuria 2. *F*ever (*↑WBC*) 3. *E*ncephalopathy 4. *V*itals unstable (autonomic instability) 5. ↑*E*nzymes (↑CPK due to rhabdomyolysis) 6. *R*igidity of muscles ("lead pipe") *Treatment:* cessation of the antipsychotic; supportive treatment

Perception (Mental Status Exam)

*Illusion:* Misinterpretation of a sensory stimulus that can occur in any sensory modality (e.g., misperceiving billowing curtains in a darkened room to be an intruder) *Hallucination:* Perceiving a sound, sight, taste, smell, or touch in the absence of external sensory stimulation that seems indistinguishable from such an experience in reality

*Immature Ego Defences:* -Mental processes (unconscious or conscious) used to resolve conflict and prevent undesirable feelings (eg, anxiety, depression). -The goal of psychotherapy to help person become aware of what defense they're using, how effective they are, and how to use less primitive defense mechanisms

*Immature Defences:* 1. *Acting out:* Expressing unacceptable feelings and thoughts through actions. (A young boy throws a temper tantrum when he does not get the toy he wants.) 2. *Denial:* Avoiding the awareness of some painful reality. (A patient with cancer plans a full-time work schedule despite being warned of significant fatigue during chemotherapy.) 3. *Displacement:* Redirection of emotions or impulses to a neutral person or object (vs projection). (A teacher is yelled at by the principal. Instead of confronting the principal directly, the teacher goes home and criticizes her husband's dinner selection.) 4. *Dissociation:* Temporary, drastic change in personality, memory, consciousness, or motor behavior to avoid emotional stress. Patient has incomplete or no memory of traumatic event. (A victim of sexual abuse suddenly appears numb and detached when she is exposed to her abuser.) 5. *Fixation:* Partially remaining at a more childish level of development voluntarily (vs regression). (A surgeon throws a tantrum in the operating room because the last case ran very late.) 6. *Idealization:* Expressing extremely positive thoughts of self and others while ignoring negative thoughts. (A patient boasts about his physician and his accomplishments while ignoring any flaws.) 7. *Identification:* Largely unconscious assumption of the characteristics, qualities, or traits of another person or group. (A resident starts putting his stethoscope in his pocket like his favorite attending, instead of wearing it around his neck like before.) 8. *Intellectualization:* Using facts and logic to emotionally distance oneself from a stressful situation. (In a therapy session, patient diagnosed with cancer focuses only on rates of survival.) 9. *Isolation (of affect):* Separating feelings from ideas and events. (Describing murder in graphic detail with no emotional response.) 10. *Passive aggression:* Demonstrating hostile feelings in a nonconfrontational manner; showing indirect opposition. (Disgruntled employee is repeatedly late to work, but won't admit it is a way to get back at the manager.) 11. *Projection:* Attributing an unacceptable internal impulse to an external source (vs displacement). (A man who wants to cheat on his wife accuses his wife of being unfaithful.) 12. *Rationalization:* Proclaiming logical reasons for actions actually performed for other reasons, usually to avoid self-blame. (After getting fired, claiming that the job was not important anyway.) 13. *Reaction Formation:* Replacing a warded-off idea or feeling with an (unconsciously derived) emphasis on its opposite (vs sublimation). (A patient with lustful thoughts enters a monastery.) 14. *Regression:* turning back the maturational clock and going back to earlier modes of dealing with the world (involuntary) (vs fixation). (Seen in children under stress such as illness, punishment, or birth of a new sibling (eg, bedwetting in a previously toilet-trained child).) 15. *Repression:* withholding an idea or feeling from conscious awareness (involuntarily) (vs suppression). (A 20-year-old does not remember going to counseling during his parents' divorce 10 years earlier.) 16. *Splitting:* Believing that people are either all good or all bad at different times due to intolerance of ambiguity. Commonly seen in borderline personality disorder. (A patient says that all the nurses are cold and insensitive but that the doctors are warm and friendly.)

*Amnesic Syndrome* -*Affected:* medial temporal lobe or diencephalon -*Type of Memory Impaired:* episodic -*Amnesia:* severe anterograde

*Impaired episodic memory:* severe anterograde amnesia 1. Consolidation deficit (of episodic memories within neocortex by gradually binding together the multiple, geographically separate cortical regions that together store memory for a whole event) 2. Rapid forgetting 3. Temporally-graded retrograde amnesia 4. *Intact semantic memory:* intact fund of knowledge 5. *Intact procedural memory:* intact skill learning *A*nterograde Amnesia: inability to remember things that occurred *a*fter a CNS insult (acquisition of new memory).

Intellectual Disability (formerly "Mental Retardation")

*Impairment in mental ability* that impacts adaptive functioning in 3 domains: 1. Conceptual 2. Social 3. Practical *Onset:* during developmental period 1. Severity specifiers 2. No longer based on IQ or specific age 18 *Intelligence quotient (IQ):* cognitive development (Piaget) 1. Perceptual reasoning 2. Working memory 3. Verbal comprehension 4. Processing speed

Depressive Episodes (not disorders)

*Individual Symptoms:* 1. Anemia (anergia) 2. Malignancy (weight loss) *Secondary to:* 1. Fuller Syndrome (hyperthyroidism) 2. Medications

*Episodic Memory* -Personally experienced events -Hippocampus, medial temporal lobe, neocortex -Stored in the posterior parietal cortex via entorhinal cortex

*Information that is remembered within a particular temporal and/or spatial context.* The acquisition and retention of episodic memories are critically dependent upon the *medial temporal lobe* (i.e., hippocampus, amygdala, entorhinal cortex, and parahippocampal cortex) and related *diencephalon* (i.e., DM thalamus and hypothalamic mammillary bodies). *Permanent storage:* posterior parietal cortex via entorhinal cortex For example, remembering what you had for breakfast this morning or when you last saw a physician would require retrieval from episodic memory. Recalling what Bill did in Boston rather than in New York.

*Orbitofrontal/Ventromedial Cortex* -Broadmann Areas 10-14 *Orbital:* regulation of emotions and behavior 1. Initiating, timing, sustaining, modulating, inhibiting 2. *Good angel:* regulates compulsions, impulses, and drives 3. *Personality* *Ventromedial PFC:* emotional processing

*Input:* 1. Limbic system 2. Olfactory system 3. Inferotemporal lobe areas (memory formation) 4. Ventral visual pathways (analysis of form and color of visual input) *Output:* 1. Autonomic musculature 2. Basal forebrain cholinergic system (nucleus of Meynert) *Function:* 1. Modulation of affective, social behavior (good angel) 2. Working memory for feature recognition 3. Recognize emotional valence (bad or good) of a situation based on memory 4. Smell discrimination *Dysfunction:* 1. *Behavioral disinhibition, socially inappropriate actions* (bad angel) 2. Anosmia (an inability to discriminate smells) 3. Confabulation when asked to recall things 4. Failure on feature working memory tasks *Testing:* 1. Drawing tasks may show *disinhibition and intrusion* in the construction of figures and shapes (begin drawing a +, but get distracted and draws a truck, a stimulus-bound intrusion) 2. *"Go/No-Go"* task requires patients to make a response to a "go" signal and withhold a response to a "no-go" signal. The reverse is also conducted to test for *difficulty inhibiting behavior*. 3. UPSIT (smell ID test) 4. FrSBe (historical social behavioral test) 5. Iowa Gambling Test (ability to make intelligent decisions)

*Cognitive Development (Jean Piaget)* -How do we think about things? *Stages:* 1. Sensorimotor (birth to 2-3 yo) 2. Pre-operational Thought (3 to 6-7 yo) 3. Concrete Operations (7 to 10-11 yo) 4. Formal Operations (11 yo and above)

*Intellectual functions form the core of personality.* Progression through "stages" relies on nervous system maturation and life experiences. 1. *Sensorimotor (birth-2 years):* Infants learn through sensory observation by activity, exploration, and manipulation of their environment. - *Object permanence:* By 7-9 months, infant begins to comprehend that objects continue to exist even when they are outside of the child's visual field. - *Symbolic thought:* By 18 to 24 months, toddlers start using pretend play and reasoning. 2. *Pre-operational Thought (2-7 years):* Children begin analyzing their environment by using mental symbols (words and images). At this stage, children lack the ability to do cognitive operations like mental math. (Think of same soda in different sized cups.) - *Egocentrism:* child believes he or she is the center of the universe, finds it difficult to take other people's perspectives. 3. *Concrete Operations (7-11 years):* At this age, children begin to use cognitive operations. They focus on concrete, real, and perceivable objects and events, and are prone to take the literal meaning of proverbs and sarcasm. They develop the ability to understand concepts of conservation (amount doesn't always change with size) and reversibility (e.g. ice and water). - *Operational thought:* child can see things from other's perspective. 4. *Formal Operations (11 years to end of adolescence):* In this final stage of cognitive development, adolescents are able to think more rationally and systematically about abstract ideas and hypothetical events.

Stimulants (Symptoms)

*Intoxication:* mood elevation, psychomotor agitation, insomnia, cardiac arrhythmias, tachycardia, anxiety. *Withdrawal:* post-use "crash," including depression, lethargy, appetite, sleep disturbance, vivid nightmares.

Depressants (Symptoms)

*Intoxication:* mood elevation, ↓anxiety, sedation, behavioral disinhibition, respiratory depression. *Withdrawal:* anxiety, tremor, seizures, insomnia.

Biogenic Amine Neurotransmitters

*Location of Synthesis:* 1. *ACh:* basal forebrain nucleus of Meynert (septal nuclei) 2. *Dopamine (DA):* ventral tegmentum (SNc) 3. *Serotonin (5-HT):* Raphé nucleus in midbrain (rostral to cerebrum, caudal to cerebellum) 4. *NE:* locus ceruleus (pons) Once these neurotransmitters are synthesized in a nucleus of neurons, axons project throughout the brain to reach terminal sites.

*Cingulate Cortex/Supplementary Motor Area (SMA)* -Broadmann Areas 24, 32 *ACC:* evaluation of one's own behavior 1. Monitoring, gauging, inhibiting, shifting 2. Selective attention (dorsal) 3. Emotions depression/anxiety (ventral)

*Location:* 1. *Anterior Cingulate Cortex:* medial portion of the cortex just superior to the corpus callosum 2. *SMA:* medial to the premotor cortex just anterior to M1 (receives input from ACC, VL thalamus, and PFC → output to motor/pre-motor) *Function:* evaluation of one's own behavior 1. *Drive and motivated behavior* 2. *Environmental exploration* (cingulate initiates, SMA inhibits in danger) 3. *Complex attention* (dorsal) 4. *Procedural memory* Connections with deep limbic structures of the brain (i.e., basal forebrain structures such as the nucleus accumbens). *Dysfunction:* uniquely bizarre characteristics 1. Apathy (anterior cingulate) 2. Akinetic mutism (loss of drive and motivation); ACC = no initiation. 3. Complex attentional deficits 4. Delayed habituation to external stimuli 5. *Alien Hand Syndrome:* (SMA) patients experience a loss of conscious control over the movements and actions of their hand, which proceeds to "explore" the surrounding environment.

*Dorsolateral Prefrontal Cortex (DLPFC)* -Broadmann Areas 45-49 -Associative Cortex *Functions:* executive 1. Spatial working memory 2. Persistence (set) 3. Integrates sensory information

*Location:* rostral to the FEFs and superior to orbitofrontal cortex *Input:* 1. *Ventral anterior and mediodorsal nuclei* of the thalamus (VA/MD) 2. *Dorsal* pathway: *where* something happened 3. *Ventral* pathway: *what* happened *Output:* caudate nucleus (dorsolateral head) → GP → VA/MD → DLPFC *Executive Functions:* managing functions (problem solving, analysis) 1. Integration of multimodal sensory information (i.e., visual/auditory) 2. Generation of alternative responses 3. Selection of appropriate response 4. Persistence (maintainance of "set") 5. Set shifting (flexibility) 6. Spatial working memory *Dysfunction:* 1. *Difficulty integrating sensory information* 2. Generation of few, stereotyped response alternatives 3. *Poor judgement* in response selections (choose most salient idea, not best for long-term) 4. *Crossed-task perseveration* (continue repeating last task when given a new one) 5. Lesions will have downstream effects (clock drawing, memory)

Alchohol Overview (Crush) *Delirium tremens:* hallucinations, altered mental state, and autonomic instability (sympathetic)

*Low doses:* 1. EtOH ↑GABA signaling → relaxing and sedating effects 2. Patients experience impaired fine motor control, coordination, and judgment *Higher doses:* EtOH permeates the inner ear and changes endolymph density → vertigo *Even larger doses:* Coma and respiratory depression (potentially fatal) *Chronic alcohol use upregulates glutamate and downregulates GABA*, causing seizures, tremors, and general hyperactivity during withdrawal *Acute Treatment for EtOH Overconsumption:* 1. Supportive care (intubation and IV fluid) 2. The liver will eventually metabolize the EtOH, but large quantities will take quite some time because of alcohol's zero-order kinetics (process not sped up with ↑alcohol; constant rate) . *Medicine for Alcohol Dependence:* 1. *Naltrexone:* opioid antagonist (binds to opioid receptors, blocking alcohol reward pathways); 380mg reduces heavy drinking days by 26%. *Vivitrol (sustained release form given 1x monthly).* 2. *Acamprosate:* glutamate receptor-NDMA antagonist (↓glutamate release and post-synaptic effect on NDMA receptors) and GABA agonist that helps reduce withdrawal symptoms 3. *Disulfiram:* blocks acetaldehyde dehyrdogenase → patient feels sick (*helpful if taken*) *Withdrawal:* ↑glutamate pathways with heavy use (without GABA → hyper- symptoms) 1. *6-12 hours:* minor symptoms (tremors, anxiety, headache, palpitations, diaphoresis, and insomnia) 2. *12-48 hours:* alcoholic *hallucinosis (visual, auditory, or tactile hallucinations)* (e.g., formication: the sensation of bugs crawling on the skin). 3. *24-48 hours:* a *minority of patients* develop *seizures* because of the loss of GABA-ergic signaling in the brain (due to hyperexcited glutamatergic state) 4. *48-72 hours:* a small percentage of patients develop *delirium tremens*, which includes hallucinations (typically visual, such as seeing rats or snakes), altered mental status, and autonomic instability (*tachycardia, hypertension, tremor, fever, and diaphoresis (sweat)*). *Delirium tremens symptoms peak at 5 days after the last drink.* Mortality for delirium tremens is 5% to 15%. *EtOH Detox Medications:* CIWA = symptom-triggered dosing 1. *Benzodiazepines:* GABA-ergic -Long-acting: diazepam, chlordiazepoxide -Short-acting: lorazepam, oxazepam 2. *Anti-convulsants:* carbamazepine, valproic acid, phenobarbital, gabapentin, *topiramate (reduces heavy drinking days)* 3. *Adrenergic blockers:* treat sympathetic hyperactivity (atenolol, propranolol, clonidine) 4. *Adjunctive agents:* -Neuroleptics (for psychosis) -Hypnotics (for sleep) -Vitamins (thiamine, folate, Mg2+)

*Primary Motor Cortex (M1)* -Broadmann Area 4 -Pyramidal Neurons

*M1* is the source of *cortical (pyramidal) neurons* that will project to the brainstem and spinal cord to activate neurons involved in the *control of voluntary, fine motor movements*. *Input:* 1. Primary somatosensory area (S1) 2. Premotor cortex 3. *Ventral lateral nucleus* of the thalamus These inputs modulate the output of M1 by providing information about the positioning, timing, and coordination of voluntary movements. *Output:* 1. *Internal capsule* 2. Synapses in the brainstem (corticobulbar) or the spinal cord (corticospinal). *Damage:* contralateral *motor deficits* (initially *flaccid* hemiplegia / hemiparesis → *spastic* hemiplegia / hemiparesis). *LMN → UMN.* Depending on the extent of cortical damage, these deficits may be localized to a specific region of the body or can be more widespread.

*Mild Cognitive Impairment (MCI) and AD on MRI* -Hippocampal Atrophy

*MCI:* gliosis present, hippocampal shrinking, larger lateral ventricles *AD:* lateral ventricles are much wider due to parenchymal atrophy; hippocampal shrinkage more pronounced

*Cannabinoids* 1. Marijuana 2. Synthetic cannabinoids (K2, "spice"): don't show up on tox screen *Use benzos for agitation*

*Marijuana:* *Intoxication:* 1. Euphoria 2. Anxiety 3. Paranoid delusions (brighter colors, music more vivid) 4. Perception of slowed time 5. Impaired judgment 6. Social withdrawal 7. Appetite 8. Dry mouth 9. Conjunctival injection 10. Hallucinations *Withdrawal:* 1. Irritability 2. Anxiety 3. Depression 4. *Insomnia* 5. Restlessness 6. ↓appetite (weight loss)

*Prevention of Anxiety* (long term)

*Mechanism:* 1. Indirect modulation of 5-HT ± NE (i.e., SSRI or SNRI/TCA) 2. Inhibits reuptake of NT back into the neuron (↑synaptic concentration) *Treatment Order:* 1. *SSRIs* (first line) -Fluoxetine (Prozac): longer half-life (good for missed doses) -Sertraline (Zoloft): GI side effects -Escitalopram (Lexapro) -Citalopram (Celexa): set max dose (can't go over) 2. *SNRIs:* -Venlafaxine (Effexor): useful in OCD -Duloxetine (Cymbalta): helps with neuropathic pain 3. *TCAs* -Amitriptyline (more likely to have anti-cholinergic effects: see, spit, pee, shit; H,D,T,W) *Pros:* 1. Effective prevention 2. No tolerance or abuse 3. Minimal withdrawal (when not abrupt) *Cons:* 1. Side effects (GI, CNS, sexual): reminder that 80% of 5-HTR are in the gut 2. Require daily dose 3. Do not work immediately (4-6 weeks)

*Lithium (Li)* for Bipolar Disorder *LiTHIUM:* narrow therapeutic window 1. *L*ow *T*hyroid (hypothyroidism) 2. *H*eart (Ebstein anomaly) 3. *I*nsipidus (diabetes insipidus) 4. *U*nwanted *M*ovements (tremor) ↓DA ↓cAMP

*Mechanism:* mood stabilizer 1. ↑5-HT and ACh function 2. ↓DA function 3. ↓adenylate cyclase activity (↓cAMP) 4. Regulates G protein and PKC activity *Dose:* 600-2400 mg/day (0.5-1.2 mmol/L) *Pros:* 1. Efficacy in mania established 2. Known response *Cons:* 1. Often poorly tolerated due to its *narrow therapeutic index* 2. Can cause tremor, weight gain, *renal toxicity*, nausea, acne, and hypothyroidism 3. Impaired concentration/lethargy/weakness → impaired consciousness/ataxia/convulsions 4. *Contraindicated with NSAIDs or diuretics* (interferes with renal tubules / clearance)

*Divalproex* (Valproate) for Bipolar Disorder -Valproic Acid ↑GABA

*Mechanism:* mood stabilizer 1. ↑GABA synthesis and release 2. ↓GABA catabolism 3. ↑GABA effects at receptor 4. Regulation of PKC *Dose:* 750-2500 mg/day (50-125ug/ml) *Pros:* 1. Efficacy in mania established (through GABA) 2. *Better than lithium in mixed states and rapid cyclers* 3. Well tolerated *Cons:* 1. Weight gain, nausea, hair loss, tremor 2. ↓platelets, liver and pancreas toxicity, polycystic ovary disease

*Carbamazepine* for Bipolar Disorder ↓DA ↓cAMP ↑GABA

*Mechanism:* mood stabilizer 1.↓NE, ↓DA, ↓adenylate cyclase activity (↓cAMP) 2. ↑GABA function *Pro:* Usually well tolerated and effective *Con:* May cause ataxia, neurocognitive effects, weight gain, nausea, hair loss, leukopenia, *hyponatremia*, and hepatotoxicity

*Medications for OCD*

*Medications:* 1. *Symptomatic:* benzos (not as helpful for OCD as for anxiety) 2. *Preventative:* *SSRIs*, SNRIs (venlafaxine), TCAs *Psychotherapy:* CBT *Coping model:* strategies employed to reduce physiological arousal -Deep breathing, limiting catastrophic thinking *Exposure model:* repeated confrontation of feared stimulus (habituation) -*Exposure with Response Prevention (ERP)* prevents ritualizing and negative reinforcement (by escape/quick relief) after exposure to feared stimuli. This allows for habituation rather than a return to obsession/climbing anxiety that leads to compulsion. *Start treatment with SSRIs*. *For moderate-severe OCD, antipsychotics are used off-label.* Poor insight, rigid thinking, treatment-resistenant depression, and/or tics make these compelling. 1. Haloperidol (Haldol) 2. Risperidone (Risperdal) 3. Aripiprazole (Abilify)

*Mature Ego Defences:* SASH -Mental processes (unconscious or conscious) used to resolve conflict and prevent undesirable feelings (eg, anxiety, depression). -The goal of psychotherapy to help person become aware of what defense they're using, how effective they are, and how to use less primitive defense mechanisms

*Mnemonic:* *Mature* adults wear a *SASH* 1. *Sublimation:* Replacing an unacceptable wish with a course of action that is similar to the wish but socially acceptable (vs reaction formation). (Teenager's aggressive urges toward his parents' high expectations are channeled into excelling in sports.) 2. *Altruism:* Alleviating negative feelings via unsolicited generosity, which provides gratification. (Mafia boss makes large donation to charity.) 3. *Suppression:* withholding an idea or feeling from conscious awareness (intentionally) (vs repression); temporary. (Choosing to not worry about the big game until it is time to play.) 4. *Humor:* Appreciating the amusing nature of an anxiety-provoking or adverse situation. (Nervous medical student jokes about the boards.)

*Post-Traumatic Stress Disorder* (First Aid) *PTSD is HARD:* 1. *H*yperarousal (persistent) 2. *A*voidance of trauma-related stimuli 3. *R*e-experiencing of the event 4. *D*istress *Two Subtypes:* 1. *Delayed Subtype:* Criteria are not met until six months after the trauma 2. *Dissociative Subtype:* High levels of de-realization (not feeling grounded in your body) or de-personalization (hovering above yourself)

*Mnemonic:* PTSD is HARD Experiencing a potentially life-threatening situation (e.g., serious injury, rape, witnessing death) → 1. *H*yperarousal (persistent): irritable or aggressive behavior, sleep disturbance 2. *A*voidance of distressing trauma-related stimuli 3. *R*e-experiencing of the event (intrusive nightmares, flashbacks) 4. *D*istress (changes in cognition and mood; self blame, fear, horror, anger) *Disturbance lasts > 1 month* with significant distress or impaired social-occupational functioning. Otherwise *acute stress disorder* (3 days-1 month) → Treatment: CBT; pharmacotherapy is usually not indicated. *Treatment:* 1. *CBT, SSRIs* (sertraline, paroxetine), and venlafaxine (SNRI) are first line. 2. *Prazosin can reduce nightmares (α1 antagonist)*.

Causes of Encephalopathy

*Mnemonic:* VIITTAMIN *V*ascular *I*nflammatory *I*nfectious *T*raumatic *T*oxic *A*utoimmune *M*etabolic *I*diopathic/Genetic *N*eoplastic

*Mood vs. Affect (Mental Status Exam)* -*Normal Mood:* euthymic -*Normal Affect:* full range

*Mood:* Subjective* feeling state of the individual sustained over much of the interview (expansive, euphoric, sad, depressed) *Affect:* Objective* description of the individual's emotional state as observed by the clinician (blunted, constricted, flat, inappropriate, labile)

Brain Development (Myelination)

*Motor and sensory:* muscles, vision, etc. 1. Begins before birth 2. Completed by the first birthday *Prefrontal cortex:* (Executive Function: attention, organization, impulse control) 1. *Not fully myelinated until early adulthood*

Developmental Milestones: Newborn

*Motor:* gross and fine 1. *Symmetric tone & movements* 2. Flexed posture (not hypotonic) 3. Complete head lag 4. Reflexic grasp (26 neonatal reflexes) *Sensory/Language:* 1. Alerts to sound (bell or voice) 2. Fixates on face or object; follows briefly 3. Optimal focal distance 8-12 inches *Social/Cognitive:* 1. Sucking organizes attention 2. Recognizes maternal voice and smell

Cholinergic Receptors

*Muscarinic:* sweat glands (sympathetic) and smooth muscle, cardiac cells, nerve terminals (parasympathetic) 1. M1-M5 (metabotropic) 2. Antagonized by *atropine* (treats bradycardia/ophthalmic applications) and anti-cholinergic drugs *Nicotinic:* ionotropic receptors made up of 4 subunits 1. NN (found in autonomic ganglia, adrenal medulla) 2. NM (found in neuromuscular junction of skeletal muscle)

Motor Exam to Localize Source of Delay

*Muscle Bulk:* 1. *Thin calf muscles:* CMT or other peripheral nerve disorders 2. *Sunken thenar eminences (hands):* carpal tunnel or another median nerve entrapment disorder 3. *Pseudohypertrophic calves:* apparent excess muscle bulk found in DMD *Tone:* 1. *Spasticity:* UMN injury (release of spinal cord reflexes) → increased tone during action 2. *Dystonia:* shift in resting posture (*extrapyramidal*/basal ganglia lesions) 3. *Hypotonia:* decreased muscle tone (head lag) → often indicative of a peripheral (*NMJ or muscle*) problem *Strength:* *Gower's Sign:* proximal muscle weakness (when seated on the ground, children are unable to get up without using their hands or nearby objects) *Reflexes:* more sensitive to nerve function than muscle 1. *Neuropathic:* reflex is diminished disproportionately to the degree of muscle strength 2. *Muscle:* reflex loss and loss of strength are equal

*Anti-Psychotic Treatment Effects* -DA Receptor = *DA2R*

*Normal State:* Equal relative tone (DA and ACh in balance) *Psychosis:* Hyper-DA (ML-MC) *Parkinson's:* Hypo-DA (NS) = hypokinetic 1. L-DOPA therapeutic goal is to achieve DA baseline (↑DA) 2. L-DOPA overshoots → hyper-DA (NS) = hyperkinetic (L-DOPA dyskinesia) 3. L-DOPA enters other circuit → hyper-DA (ML-MC) = psychosis *Treated Psychosis:* hyper DA (ML-MC) 1. Antipsychotic therapeutic goal is to achieve DA baseline (↓DA) 2. Overshoot → hypo-DA (NS) = parkinsonism 3. Overshoot → hypo-DA (ML-MC) = cognitive-affect slowing (negative symptoms) *Tardive Dyskinesia:* hyper DA (ML-MC) = psychosis 1. Antipsychotic therapeutic goal is to achieve DA baseline (↓DA) 2. Overshoot → hypo-DA (NS) = parkinsonism 3. Chronically blocked DA state → hyperkinetic state (see below) 4. DA receptor (NS) up-regulation and supersensitivity

*Autism Spectrum Disorder*

*Must present in early childhood.* More common in boys. Associated with head/brain size. May be accompanied by intellectual disability; rarely accompanied by unusual abilities (savants). *Clinical Presentation:* 1. Poor social interactions 2. Social communication deficits 3. Repetitive/ritualized behaviors 4. Restricted interests *Deficits in Social Interaction:* 1. Nonverbal communication: eye contact, facial expression, body postures, gestures 2. Peer relationships not appropriate to developmental level 3. Lack of spontaneous sharing of enjoyment, interests, achievements 4. Impaired social & emotional reciprocity (can play alone for hours) *Deficits in Social Communication:* 1. Delayed or absent speech 2. If adequate speech, marked impairment to initiate or sustain conversation 3. Language is stereotyped, repetitive, or idiosyncratic 4. Lack of imaginative play (pay more attention to mechanics) *Restricted, Repetitive, Behaviors, Interests, & Activities:* 1. Restricted pattern of interest abnormal in intensity or focus 2. Inflexible adherence to nonfunctional routines and rituals 3. Stereotyped and repetitive motor mannerisms 4. Preoccupation with parts of objects (e.g., toy car parts) *Treatment:* multifactorial 1. *Behavioral interventions* - *Applied behavior analysis:* go into child's home and teach them how to do what they don't know how to do 2. Special education services 3. Family psychoeducation & support 4. Medication to treat irritability: *Risperidone and Aripiprazole* (atypical antipsychotics)

*Noradrenergic Receptor Drugs* -Used to treat depression

*NE Reuptake Blockers:* 1. TCAs (serotonin/NE reuptake inhibitors; block ACh) 2. SNRIs (serotonin/NE reuptake inhibitors) 3. Bupropion (NE/dopamine reuptake inhibitor) *MAO-inhibitors (MAOIs):* prevent NE degradation by MAO

Glutamate Receptors

*NMDA-R:* 1. Allow entry of Ca2+ 2. Ligand gated 3. Bind glutamate 4. *Requires agonist binding (glutamate and glycine) and voltage activation to remove Mg2+* *AMPA-R and Kainate-R:* 1. Allow entry of Na+ 2. Ligand gated 3. Bind glutamate

*Cognition Changes with Aging* (Pure Aging)

*Neuroanatomy Changes:* 1. Brain size peaks round age 20 and *shrinks by around 10% by age 85*, with no clinical relevance other than increasing risk for subdural hematoma 2. *High education is protective against Alzheimer's*, but is also correlated with increased mass loss with age 3. *Number of neurons lost is greatest in the hippocampus, STG (superior temporal gyrus), entorhinal cortex, and NBM (nucleus basalis of Meynert)* while the brainstem, and supra-optic and paraventricular nuclei remain intact 4. *Plaques and tangles naturally accumulate*, but are far fewer than in Alzheimer's and not concentrated in the same loci 5. *Cerebral blood flow decreases proportional to brain size*, especially in the prefrontal and gray matter *Cognitive Changes:* 1. *Crystallized Intelligence* (learned): ↑over time (especially when well educated) 2. *Fluid/Native Intelligence:* problem-solving, reasoning about unfamiliar, process and learn new information, executive function, processing speed, memory (↓after peak in 20s) 3. *Attention:* ↓over time beginning in 60s; also, ↓multi-tasking 4. *Long Term (Secondary) Memory:* - Semantic (facts, meanings): ↑ or no change - Procedural (ride bike, play music): no change - *Episodic (dates, times, place): ↓*

Alzheimer's Disease Risk Factors

*Risk Factors FOR AD:* 1. Age 2. Positive family history 3. ApoE4 (homo > hetero) 4. Hypertension 5. Obesity 6. Diabetes 7. Inactivity 8. Smoking 9. Depression 10. Low education 11. Down syndrome *Risk Factors AGAINST AD:* 1. Absence of Box 1 2. ApoE2 3. High education 4. Cognitive engagement 5. *Physical activity* 6. Mediterranean diet 7. High social supports

Olivopontocerebellar Degeneration vs. Friedreich's Ataxia

*Olivopontocerebellar Degeneration:* 1. *Degeneration of the inferior olive → transsynaptic degeneration of Purkinje cells* (due to loss of input from climbing fibers) 2. Purkinje degeration → dying axons (*torpedoes*) 3. Caused by disturbances in Chr. 10 *Regions affected:* 1. Pons 2. Inferior olive 3. Middle cerebellar peduncles. *Clinical Presentation:* ataxia, usually beginning in the legs (cerebellum) *Friedrich's ataxia* results from damage to Chr. 9 and differs from olivopontocerebellar degeneration in that it is a *sensory ataxia* characterized by damage to the *dorsal columns*.

*DSM-IV: Substance Abuse* -Patient lives a "normal life"

*One or more of the following in a 12-month period:* 1. Recurrent substance use → failure to fulfill major role obligations at work, school, or home 2. Recurrent substance-related legal problems 3. Recurrent substance use in situations in which it is physically hazardous 4. Continued substance use despite persistent or recurrent social or interpersonal problems caused or exacerbated by the effects of the substance

Addiction Medications

*Opioids:* 1. *Methadone* (agonist, long half life) 2. *Buprenorphine* (partial agonist) 3. *Naltrexone* (antagonist) - Patient must be opioid-free 7-10 days or Naltrexone will cause withdrawal *Alcohol:* 1. *Naltrexone:* antagonist (blocks alcohol reward pathways); Vivitrol is a sustained release form 2. *Acamprosate:* amino acid with anti-glutamate activity that blocks release and postsynaptic ion channel activity to fight the hyperglutamatergic nature of alcohol abuse (poor bioavailability → multiple daily doses) 3. *Disulfiram:* blocks acetaldehyde dehyrdogenase → patient feels sick 4. Antiepileptics (carbamazepine, valproic acid, gabapentin, *topiramate*) can be used off label to treat alcohol dependence *Cocaine:* None *Marijuana:* None

Idiopathic/Genetic (Encephalopathy)

*Ornithine transcarbamoylase (OTC) deficiency:* can't process NH3 into urea for excretion in the kidneys → buildup

*Separation Anxiety Disorder* (onset before age 12)

*Overwhelming fear of separation from home or primary attachment figures lasting ≥ 4 weeks* (beyond first month of school). Can be normal behavior up to age 3-4. May lead to factitious physical complaints to avoid school (somatic complaints). *Treatment:* CBT, play therapy, family therapy.

*HPA Axis Derangement in PTSD* -↑susceptibility to GR activation (which ↓HPA) -↑suppression of HPA axis (↑negative feedback due to hypersensitivity of GR)

*PTSD Patients:* chronically high levels of cortisol (stress) produces hypersensitive HPA system → when dexamethasone is administered, the hypothalamus and anterior pituitary overact to the glucocorticoid, resulting in an overly strong negative feedback (over suppression) → much less cortisol release (= increased cortisol suppression)

*Reactive Attachment Disorder* -Trauma disorder

*Pathogenic care is responsible for the disturbed behavior.* *History of pathogenic care, with at least one of the following:* 1. Persistent disregard of the child's basic emotional needs for comfort, stimulation, and affection 2. Persistent disregard of the child's basic physical needs (first 1.5 years of life) 3. Repeated changes of primary caregiver that prevent formation of stable attachments (e.g., frequent changes in foster care) *Clinical Presentation:* 1. Consistent pattern of *inhibited, emotionally withdrawn behaviors toward adult caregivers*: - Rarely or minimally seeks comfort when distressed - Rarely or minimally responds to comfort offered when distressed 2. Persistent *social and emotional disturbance* characterized by at least 2 of the following: - Minimal social and emotional responsiveness - Limited positive affect - Episodes of unexplained irritability, sadness, or fearfulness evident during nonthreatening interactions with adult caregivers *Treatment:* 1. Identify stable attachment figure 2. Psychotherapy (dyadic therapy between child & caregiver) 3. Medications to treat co-morbidities or specific symptoms (aggression, sleep disturbance, hyperactivity/impulsivity, etc.) 4. *Do not use physical restraint or coercion* or "rework" trauma (e.g. "Therapeutic Holding", "Compression Holding", "Rebirthing Therapy")

*Alzheimer's Disease (AD)* -Most common cause of dementia in elderly *Image:* *B:* normal cortex (hippocampus) *C:* Alzheimer's cortex (hippocampus) *D:* senile plaques (extracellular β-amyloid) *E:* neurofibrillary tangles (intracellular, hyperphosphorylated tau)

*Pathology:* 1. *Cortical atrophy:* especially in the hippocampus and centers of higher cognition (association cortices, e.g., temporo-parietal = semantic memory) -Narrowing of gyri -Widening of sulci 2. *Neurofibrillary tangles (NFT's):* intracellular, hyperphosphorylated tau protein (insoluble microtubule-associated elements) -The number of tangles correlates with degree of dementia 3. *Senile plaques (SP's):* extracellular β-amyloid (can cause CAA ICH) -Usually first appears in the *hippocampus*, entorhinal cortex, and amygdala -Central core (β-amyloid) surrounded by neurites, astrocytes, and microglia 4. *Hirano bodies* (actin aggregates) and *granulovacuolar degeneration* (tubulin aggregates; halo with a bird's eyes dotting the cytoplasm) 5. *↓ACh* (loss of cholinergic neurons in the nucleus basalis of Meynert) 6. *CSF:* ↓β-amyloid (in plaques) and ↑tau (leaks out of plaques) *Genetic Associations:* majority sporadic 1. *ApoE-2:* ↓risk of *sporadic* form 2. *ApoE-4:* ↑risk of *sporadic* form (Chr. 19) -Homozygous ApoE-4:↑risk of early-onset by 60% 3. *APP:* precursor → β-amyloid (Chr. 21): *familial* form with early onset 4. *Presenilin-1* (Chr. 14), *Presenilin-2* (Chr. 1): *familial* form with early onset 5. *β-catenin:* late-onset, *sporadic* AD (Chr. 10) *Clinical Presentation:* 5 As 1. *Amnesia:* memory loss 2. *Anomia:* inability to remember names 3. *Apraxia:* misuse of objects because of failure to identify them 4. *Agnosia:* inability to recognize familiar objects, tastes, sounds, etc. 5. *Aphasia:* inability to express oneself through speech *Treatment:* 1. AChE inhibitors (*rivastigmine*) -- think cholinergic hypothesis 2. Memantine (NDMA antagonist);↓glutamate signaling in more severe cases 3. Aducanumab (↑microglial clearance of β-amyloid)

*Parkinson's Disease* -Neurodegenerative Disease

*Pathology:* 1. *Loss of dopaminergic neurons* (i.e., depigmentation) of substantia nigra pars compacta (SNc). 2. *Lewy bodies:* composed of α-synuclein (intracellular, eosinophilic inclusions with surrounding halos) (*in SNc*, not cortex) Note: MPTP, a contaminant in illegal drugs, is metabolized to MPP+, which is toxic to substantia nigra. Parkinson *TRAPS* your body: *T*remor (pill-rolling tremor at rest) *R*igidity (cogwheel) *A*kinesia (or bradykinesia) *P*ostural instability *S*huffling gait

Perinatal and Developmental History for Motor Delay

*Perinatal History:* pregnancy, labor, delivery *Pregnancy:* 1. Fetal movements 2. Complications - Infections - Medication - Medical illnesses *Labor:* - How long? - Fetal heart rate/distress *Delivery:* - C-section or vaginal - Need for vacuum assistance - Birth weight - Apgar (newborn screen) - Discharged to home with mother? or need to stay longer? *Developmental History:* gross and fine motor, cognition, and social *Gross Motor:* - Head control - Rolling over - Moving all extremities equally *Fine Motor:* - Reaching (symmetric or asymmetric) - Hands together - Pincer *Cognition:* - Language (cooing, babbling) *Social:* - Smiling - Laughing - Pat-a-cake - Imitate sounds

*Selective Mutism* (onset before age 12)

*Persistent failure to speak in specific social situations* where speaking is expected despite speaking in other situations. Shyness or fear of embarrassment, and social withdrawal are common. *Must last ≥ 1 month* (after 1st month of school). May be a precursor to social phobia.

*Why people use EtOH and drugs:* phases

*Phase 1.* Reward/Incentive-Salience -Alcohol stimulates dopamine neurons (inhibits the inhibitor) in the VTA of the brain, which makes the body feel rewarded, reinforcing the behavior *Phase 2.* Relief/Negative Affect -*Relief:* alcohol ↓DA2R activity (less activity in basal ganglia on PET) -Many people start as *reward drinkers*, then become *relief drinkers* to not shake *Phase 3.* Impaired control/Preoccupation/Anticipation -Chronic alcoholism *↑stress hormones (CRF, NE) and ↓anti-stress hormones (NPY, 5-HT)*, requiring alcohol to function normally -*↑dynorphin/κ-opioid signaling (↑impulsivity and dysphoria)* -↑anti-reward signaling from habenula -Loss of inhibitory glutamine receptors (mGluR2) in the frontal cortex causing hyperglutamatergic state; loss of NAcc inhibition = loss of control *Overall:* Alcohol eventually causes impaired control over drinking behavior and increased impulsivity with time.

*Hallucinogens / Serotinergic Drugs* -Patient at risk for *Serotonin Syndrome* -Autonomic instability (BP↑↓↑↓) -*Treatment:* supportive care and *benzos*; *avoid succinylcholine* (due to risk of exacerbating rhabdomyolysis-associated hyperkalemia) -LSD, ecstacy (MDMA), PCP, mescaline -"Molly": stimulant + hallucinogen + anti-depressant: causes hyponatremia (confusion, seizures, brain swelling, brain herniation)

*Phencyclidine (PCP):* vertical nystagmus Violence, impulsivity, psychomotor agitation, nystagmus, tachycardia, hypertension, analgesia, psychosis, delirium, seizures. Trauma is most common complication. *Lysergic Acid Diethylamide (LSD):* Perceptual distortion (visual, auditory), depersonalization, anxiety, paranoia, psychosis, possible flashbacks. *MDMA (ecstasy):* *Hallucinogenic stimulant:* euphoria, disinhibition, hyperactivity, distorted sensory and time perception, teeth clenching. *Life-threatening* effects include hypertension, tachycardia, hyperthermia, hyponatremia, *serotonin syndrome*. *Serotonin Syndrome:* 3 A's 1. *A*ctivity (neuromuscular hyperactivity) 2. *A*utonomic stimulation 3. *A*gitation →*Withdrawal:* Depression, fatigue, change in appetite (cravings), difficulty concentrating, anxiety.

Types of Stress

*Positive:* vaccination, first day at preschool 1. A mild-normative degree of adversity or threat 2. Caring and responsive adult helps the child cope 3. Brief increase HR, mild elevation stress hormone 4. Once they conquer the stress, they learn how to do it again in the future (healthy social-emotional development) *Tolerable:* death, terrorism, divorce 1. Greater degree of adversity or threat 2. Serious, more intense stress response 3. *Tolerable only if protective, caring adult relationships* are available to facilitate coping *Toxic:* abuse, neglect, violence, financial hardship, parental mental illness or substance abuse 1. Serious prolonged or frequent adversity 2. Chronic activation of the body's stress system 3. Prolonged because of lack of protective, supportive adult relationships 4. Changes brain architecture → root of chronic stress-related physical & mental illness

Workup for Encephalopathy (Altered Mental Status)

*Primary:* vitals first 1. Careful history 2. Physical and neuro exam to look for *focal findings* 3. *ABCs (vital signs, BP, HR, fever, O2)* 4. Lab Testing -*Complete blood count* (infection, anemia) -*Basic metabolic profile* (BMP) or Chem 10: electrolytes, kidney function, glucose -*Liver function tests* (LFTs): liver function -Ammonia -Tox screen (drug abuse, prescription meds) *Secondary:* head CT first here 1. If focal findings → *head CT* or MRI 2. If fever → *urinalysis*, chest x-ray, *spinal tap (LP)* to check for infection 3. *Thyroid function tests:* thyroid dysfunction? 4. If hypoxic → check arterial blood gas 5. *MRI* to rule out structural lesion 6. *EEG* to rule out nonconvulsive status epilepticus and evaluate severity of encephalopathy

Adverse Childhood Experiences (ACE) Model

*Progression:* 1. Adverse Childhood Experiences 2. Social, Emotional, & Cognitive Impairment 3. Adoption of Health Risk Behaviors 4. Disease, Disability, & Social Problems 5. Early Death As *ACE Score (childhood stress) increases*, the risk of the following *health problems increases* in a strong and graded fashion: 1. Alcoholism/alcohol abuse 2. COPD 3. Ischemic heart disease 4. Depression 5. Fetal death 6. Health related QOL 7. Liver disease 8. Smoking 9. Unintended pregnancy 10. Suicide attempts 11. Intimate partner violence 12. STDs Even by elementary school, 3+ ACEs lead to increased academic failure, severe attendance problems, severe school behavior concerns, and frequent reported poor health.

*Creutzfeldt-Jakob Disease (CJD)* -Neurodegenerative Disease

*Rapidly progressive* (weeks to months) dementia that presents with: 1. *Myoclonus* (brief, involuntary muscle twitch) 2. *Ataxia* *EEG:* periodic sharp waves *CSF Findings:* ↑14-3-3 protein *Pathology:* spongiform cortex affected (*spongiform change*) 1. Prions (PrPc→PrPsc sheet [*β -pleated sheet* resistant to proteases]) 2. Parenchymal vacuolization (*champagne bubbles* = prion protein aggregates)

*Obsessive-Compulsive Disorder (OCD)* 1. *Obsessions:* unwanted and intrusive thoughts, images, or impulses that cause marked distress 2. *Compulsions:* excessive, repetitive behaviors and/or mental acts that are performed in order to prevent or reduce anxiety/distress Lifetime prevalence: 2.5% (males = females)

*Recurring intrusive thoughts*, feelings, or sensations (*obsessions*) that cause severe distress; relieved in part by the performance of *repetitive actions or rituals (compulsions)*. *Ego-dystonic:* behavior inconsistent with one's own beliefs and attitudes (vs obsessive-compulsive personality disorder). Note that *insight varies* (e.g., one person may believe that touching a surface gives them a 50% chance of getting sick, while another might think their chance is 100%). *Treatment:* CBT, SSRIs, venlafaxine, and clomipramine (worse side effects) are first line. *Body dysmorphic disorder:* preoccupation with minor or imagined defect in appearance → significant emotional distress or impaired functioning; patients often repeatedly seek cosmetic treatment. *Treatment:* CBT

*Epileptic Disorders of Childhood* -*Acquired epileptic aphasias:* usually more common if patient *regresses* after 18 months (after appearing seemingly normal until then) vs. autism seen at much earlier ages (but still only seen in 1% of patients that have regressed).

*Rolandic Epilepsy:* Benign Childhood Epilepsy 1. *Centrotemporal spikes* (not mid- or anterior-temporal) may explain why *expressive language* (Broca) as opposed to perceptive language is preferentially affected. (*Spikes in speech areas.*) 2. Rarely involves language delay, but can occasionally lead to expressive language delays similar to those in patients with Wernicke's Aphasia (wordy, non-sensical speech). *Landau-Kleffner Syndrome:* 1. Results in a *severe language disorder affecting comprehension* (Wernicke). 2. The *EEG abnormalities* in these children are *localized to one or both temporal lobes* and can thus *impair verbal and auditory recognition*. *Continuous Spikes and Waves during slow sleep (CSWS):* 1. Diagnosis based on EEG 2. Usually transitory, but can last for several months 3. Children experience *spike and wave discharges during 85% of non-REM sleep.* 4. *Continuous epileptic activity* → neuropsychological deficits (e.g., language disorders) 5. Prognosis of the epilepsy is usually good

Diagnostic Symptoms for Depression

*SIG E CAPS:* 5 for at least 2 weeks 1. *Depressed mood* (can present as *irritability in children*) 2. *S*leep disturbance (insomnia or hypersomnia) 3. Loss of *I*nterest (anhedonia) 4. *G*uilt or feelings of worthlessness 5. *E*nergy loss and fatigue (anergia) 6. *C*oncentration problems (slowed thinking) 7. *A*ppetite/weight changes 8. *P*sychomotor retardation or agitation (restless, anxious, mute, catatonic) 9. *S*uicidal ideations *Vegetative Sx:* energy, appetite, sleep, libido, concentration (biologic) *Psychological Sx:* low mood, low interest, anhedonia, poor self-esteem, hopelessness *Depression is commonly masked by somatic symptoms (pain).* ↓5-HT. 1. NE and 5-HT ascend from brainstem to cortex (affect mood) 2. NE and 5-HT descend from brainstem (normally inhibit upcoming pain information)

Treatment of PTSD

*SSRIs FDA Approved to treat PTSD:* 1. Sertraline (Zoloft) 2. Paroxetine (Paxil) *SSRIs Off Label but used:* 1. Citalopram (Celexa) 2. Escitalopram (Lexapro) 3. Fluoxetine (Prozac) 4. Fluvoxamine *Mechanism:* ↑serotoninergic activity (5-HT) by decreasing reuptake pump action by 60-80% (calming). Downstream effects likely also involved that are neuroprotective or promote plasticity. *SNRIs* are also used, blocking presynaptic serotonin and norepinephrine transporter proteins, increasing stimulation of postsynaptic receptors. *Prazosin for nightmares (off label):* competitively inhibits alpha-1 adrenergic receptors. *↑NREM sleep* (reduces dreams of REM). ↓cortisol response. *Novel Treatments:* not on EXAM 1. *D-Cycloserine:* potential for increasing neuroplasticity (also used before ERP) 2. *NMDA partial agonists:* neuroplasticity 3. *MDMA:* recently approved by FDA for "Breakthrough Therapy" easing the way for clinical trials. (Potential mechanisms: ↑oxytocin; improves dysregulation of amygdala/mPFC feedback loop.)

Depression Due to a Medical Condition

*Secondary depression* with a relationship between the medical illness and the depression. *Causes:* 1. Hypothyroidism (↓T3 ↓BMR) 2. Adrenal insufficiency 3. Hyperparathyroidism (hypercalcemia: stones, bones, groans, moans/physic overtones) 4. Epilepsy 5. Stroke 6. B12 deficiency 7. Infection, encephalitis 8. Lupus (NP-SLE) 9. Hormone imbalances and brain injuries/diseases

*GABA, Glutamate, and 5-HT* in Schizophrenia *↑5-HT:* aberrant salience (ideas of reference and paranoia) *↓GABA:* neurocognitive symptoms 1. ↓GABA neurons (PVBC) 2. ↓γ-oscillation synchronization (leads to hyper- and hypo-excitability in different parts of the brain) 3. Perceptual distortions and failures of cognitive integration *↓NMDA-R:* negative symptoms 1.↓NMDA receptor functioning on GABAergic interneurons 2. Disinhibition of glutamatergic projections onto midbrain dopaminergic neurons 3. ↑DA activation → ↑pyramidal excitability

*Serotonin (5-HT):* positive symptoms? 1. Salience is how an object stands out compared to its neighbors (influenced by serotonin). 2. *↑5-HT could cause aberrant salience* seen in ideas of reference and paranoia. *Glutamate and GABA pathways:* negative symptoms 1. *↓NMDA (glutamate) receptors* is believed to be the cause of the *negative symptoms* of schizophrenia (glutamate is involved in *synaptic plasticity*) 2. *↓GABA neurons (parvalbumin basket cells, PVBC) associated with ↓cognitive abilities* -Synchronized PVBC facilitates the creation of γ-oscillations. When these neurons are impaired (schizophrenia), *cortical circuitry cannot synchronize properly → perceptual distortions and failures of cognitive integration*. Schizophrenic patients have difficulty mobilizing network activity in the prefrontal and premotor cortex 3. *↓NMDA receptor functioning on GABAergic interneurons causes disinhibition of glutamatergic projections onto midbrain dopamine neurons, increasing activation → ↑pyramidal excitability.*

Substance or Medication Induced *Psychosis (2°)*

*Substances (intoxication):* psychotomimetic 1. Cocaine (sympathomimetic) 2. Methamphetamines 3. Psychostimulants (abuse) 4. Hallucinogens 5. PCP 6. Bath salts 7. Cannabis 8. Synthetic cannabinoids *Substances (withdrawal):* killer Bs 1. Booze (alcohol) 2. Barbiturates 3. Benzos *Medications:* 1. Steroids 2. Interferons 3. Chemotherapy agents 4. Antibiotics (quinolones) 5. Antimalarial (mefloquin) 6. Anti-Parkinson's dopaminergic agents (DA spills into behavioral tracts from NS motor) 7. Anticholinergic agents ("wacky")

*Specific Phobia* (onset before age 12)

*Severe, persistent (≥ 6 months) fear or anxiety* due to presence or anticipation of a specific object or situation. Person often recognizes fear is excessive. Avoids or endures with intense anxiety. Can be *treated with systematic desensitization*. *Social Anxiety Disorder:* exaggerated fear of embarrassment in social situations where the person is exposed to scrutiny by others (e.g., public speaking, using public restrooms). *Treatment:* 1. CBT, SSRIs, venlafaxine (Effexor=SNRI). 2. For *performance type* (e.g., anxiety restricted to public speaking), use β-blockers (e.g., *propranolol*) or benzodiazepines as needed. *Agoraphobia:* irrational fear/anxiety while facing or anticipating *≥ 2 specific situations* (e.g., open/ closed spaces, lines, crowds, public transport). If severe, patients may refuse to leave their homes. Associated with panic disorder. *Treatment:* CBT, SSRIs.

*Lewy Body Diseases* 1. *Shy-Drager (MSA):* sympathetic autonomic ganglia → orthostatic hypertension 2. *DLB:* Lewy bodies not seen in SNc (seen in cortex) 3. *PSP:* Lewy bodies not seen in SNc; NFT in SNc → disturbances of vertical gaze

*Shy-Drager Syndrome:* aka Multiple System Atrophy (MSA) 1. Lewy bodies in *sympathetic* autonomic ganglia 2. Resulting damage → body cannot respond to postural changes (*orthostatic hypotension*) 3. Parkinsonian features and autonomic dysfunction *Diffuse Lewy body disease:* 1. Lewy bodies appear diffusely 2. However, Lewy bodies are not usually seen in the SNc 3. Dementia develops over time 4. Second leading cause of dementia in the United States (second to AD) 5. Frequently a comorbidity with AD *Progressive Supranuclear Palsy (PSP):* 1. Neurofibrillary tangles → damage to the brainstem → *disturbances of vertical gaze* 2. *Lewy bodies* seen in the *brainstem*, but *not in the SNc* 3. *SNc depigmentation* and neurofibrillary tangles are \ present

*Regulatory Reponses to Unrelenting, Unbuffered Toxic Stress*

*Sleep:* stimulation of reticular activating system (ARAS) 1. Insomnia 2. Night waking 3. Nightmares *Eating:* anxiety; inhibition of satiety center 1. Overeating 2. Hoarding food 3. Loss of appetite *Toileting:* ↑sympathetic tone (↑catecholamines) 1. Constipation 2. Encopresis: diarrhea in potty-trained children 3. Enuresis: wetting the bed (involuntary)

Brain Imaging in Response to Psychotherapy

*Social Phobias:* 1. Undergo CBT and citalopram (Celexa) treatment 2. ↓limbic activity (amygdala, hippocampus, and adjacent temporal cortex) *Panic Disorder:* 1. Undergo CBT 2. ↓inferior frontal gyrus activity (↓negative cognition such as increased harm expectancy or attention to threat -- related to frontal cortex) *OCD:* overactivity in frontal:subcortical circuits 1. Undergo ERP or SSRI treatment 2. ↓metabolism in the caudate nucleus *Depression:* 1. Undergo CBT or venlafaxine (SNRI) 2. *CBT:* ↓cortico-limbic connectivity 3. *Venlafaxine:* ↑cortical and striatal engagement

Other Primary Psychiatric Disorders 1. *Brief psychotic disorder:* < 1month 2. *Schizophreniform disorder:* 1-6 months 3. *Schizoaffective disorder:* schizophrenia + mood

*Symptoms Reminder:* 1. Delusions 2. Hallucinations—often auditory 3. Disorganized speech 4. Disorganized or catatonic behavior 5. Negative symptoms (affective flattening, avolition, anhedonia, asociality, alogia) 1. *Brief psychotic disorder:* ≥ 1 positive symptom(s) lasting < 1 month, usually stress related. Can be postpartum. 2. *Schizophreniform disorder:* ≥ 2 symptoms (meets Criterion A), lasting 1-6 months (less than 6). *Placeholder* between brief psychotic disorder and schizophrenia. 3. *Schizoaffective disorder:* Meets criteria for *schizophrenia in addition to major mood disorder* (major depressive or bipolar). To differentiate from a major mood disorder with psychotic features, patient must have *>2 weeks of psychotic symptoms without major mood episode*. -Unlike schizophrenia, have frequent mood episodes of mania or depression -Unlike mood disorders, the psychosis persists when euthymic

Acetylcholine (ACh)

*Synthesis:* Choline + Acetyl CoA → ACh *Function:* 1. Neurotransmitter at NMJ (depolarizes motor end plate) and *parasympathetic* nervous system 2. Plays a role in *arousal, attention, memory, and motivation* *Cholinergic Pathways:* 1. Nucleus basalis of Meynert → cerebral *cortex* and limbic system 2. Pedunculopontine nucleus (PPN) of ARAS → *thalamus* *Termination:* 1. ACh is rapidly broken down in the synaptic cleft by AChE 2. Choline is transported back into the axon terminal to make more ACh

Peptide Neurotransmitters

*Synthesis:* Made in the cell bodies of neurons and stored in synaptic vesicles. *Termination:* peptidases *Receptors:* metabotropic (GPCRs)

*Serotonin (5-HT)* 1. *Sero:* found in serum 2. *Tonin:* ↑vessel tone

*Synthesis:* Tryptophan → 5-HTP → 5-HT (in the brain, Trp is rate-limiting; affected by diet) *Enzyme 1:* tryptophan hydroxylase (RLS); add -OH *Enzyme 2:* 5-HTP decarboxylase; remove -CO2 *Overall:* ↑Trp ↑5-HT (contributes to feelings of well-being and happiness) *Termination:* 1. Re-uptake by 5-HT transporter 2. Metabolism by *MAO-A* → 5-HIAA 3. 5-HTTLPR (serotonin transporter-linked polymorphic region → variation in transporter amount between individuals) *Location:* 1. *Raphé nucleus* (upper pons and midbrain) → basal ganglia, limbic system, and cerebral cortex 2. *Enterochromaffin cells in the GI tract and platelets* (this is why anxiety causes nausea) *Receptors:* 1. 5-HT3: ionotropic (Na+/K+) and excitatory 2. All other 5-HT receptors (1,2,4,5,6,7) are metabotropic (with prolonged activity) 3. 5-HT1A (presynaptic); 5-HT2A (postsynaptic) *Disorders Related to Serotonin:* 1. Depression 2. Anxiety 3. OCD 4. Schizophrenia 5. Migraines

Histamine

*Synthesis:* histidine → histamine (L-histidine decarboxylase) *Location:* *Tuberomammillary nucleus of posterior hypothalamus* to cerebral cortex, limbic system, and thalamus *Function:* Histamine is involved in *allergic reactions* in the periphery. *Receptors:* H1, H2, H3 1. H1-R: densely clustered in the *hypothalamus* 2. Histamine *increases wakefulness and inhibits appetite via H1* (H1-R inhibitors are used for allergy, motion sickness, and as sleep aids) 3. *Histamine R antagonism is a psychotropic medication side-effect that leads to sedation, weight gain, and hypotension.*

*DSM-IV: Substance Dependence* -Patient spends most of his/her time obtaining, using, and recovering from substance

*Three or more of the following in a 12-month period:* 1. Withdrawal 2. Tolerance 3. Using larger amounts / longer 4. Repeated attempts to quit or control use 5. Much time spent using 6. Physical/psychological problems related to use 7. Activities given up due to use

Transferance vs. Counter-Transferance (Freud)

*Transferance:* Patient projects feelings about formative or other important persons onto physician (e.g., psychiatrist is seen as parent). *Counter-transferance:* Doctor projects feelings about formative or other important persons onto patient (e.g., patient reminds physician of younger sibling).

Traumatic/Toxic (Encephalopathy)

*Trauma:* diffuse axonal injury (DAI) from MVA *Toxins:* 1. Street drugs (intoxication or overdose) 2. *Prescription medications* - *Overdose* - Antibiotics (*fluouroquinolones* like ciprofloxacin) in the elderly - Anti-cholinergic drugs (*diphenhydramine*) and sedating drugs (*lorazepam*) in the elderly - Transplant medications 3. Real toxins (poisons) like organic solvents, heavy metals, poisons, biotoxins like snake venom. 4. *Serotonin Syndrome* (overabundance of 5-HT) can result from mixing a few serotonergic drugs (antidepressants/migraine medications): *3 A's:* (1) Activity, (2) Autonomic stimulation, (3) Agitation 5. Alcohol - Intoxication (euphoria → ataxia → confusion → coma → death) - Withdrawal (*delirium tremens*: tremor, hallucinations, confusion, *sympathetic hyperactivity*)

*Tricyclics (TCAs)* -Tertiary amines (amitriptyline)

*Tricyclics* work by *blocking pre-synaptic transporters* with varying degrees of specificity. -*Block* both *5-HT* and *NE* re-uptake (like SNRIs) -Effective in 60-70% of patients and helpful in neuropathic pain (*analgesic effects*) -Can interfere with cholinergic, histaminic, and adrenergic (α1) receptors -3° TCAs (amitriptyline) have more anticholinergic effects than 2° TCAs (nortriptyline). -*Side Effects:* dry mouth, urinary hesitance, constipation, blurred vision, sedation, and ↑weight (can't see spit pee shit; hot dry tacky wacky) *Tri-C's:* 1. *C*onvulsions 2. *C*oma 3. *C*ardiotoxicity (arrhythmia due to Na+ channel inhibition). *Very lethal in overdose* *Can prolong QT interval.*

*Types of Attachment* (Bowlby)

*Types (Secure vs. Insecure):* 1. *Secure:* uses caregiver as secure base from which to explore the environment 2. *Resistant:* insecure bond, strong separation protest, remains near but resists contact with caregiver 3. *Avoidant:* insecure bond, little separation protest, avoidance, or ignoring of caregiver 4. *Disorganized/disoriented:* insecure bond, tends to first seek then abruptly avoid caregiver

*Antipsychotic Effects on Mesolimbic System* -↓positive symptoms

*Typical antipsychotics that block DA2R reduce psychotic (positive) symptoms.* Overall, antipsychotics are good at fixing positive symptoms and mood disturbance, but not so good at fixing negative symptoms (synaptic plasticity) or cognitive impairment (GABA neuron asynchronous γ-oscillations). *Positive Symptoms:* 1. Hallucinations 2. Delusions 3. Disorganized thoughts and behavior

Dopamine

*Tyrosine→Dopa→Dopamine*→NE→E. *Enzyme 1:* tyrosine dehydrogenase (*RLS*) *Enzyme 2:* L-aromatic AA decarboxylase *Enzyme 3:* dopamine β-hydroxylase *Enzyme 4:* PNMT Note: L-Dopa can be given to get around the rate-limiting step *Termination:* 1. Re-uptake 2. Metabolized by MAO-B → homovanillic acid *Disorders Related to Dopamine:* 1. Parkinson's Disease 2. ADHD (treatment: Clonidine, an α2-agonist) 3. Drug addiction 4. Psychosis (Schizophrenia) Note: 1. MAO: mono-amine oxidase 2. COMT: catechol-O-methyl transferase (degrades NE, E, and dopamine)

*Motor Exam Findings*

*UMN:* "high" everything *Bulk:* normal *Tone:* hypertonic (spastic) *Strength:* 1. Upper extremity extensor weakness (not reaching) 2. Lower extremity flexor weakness *Reflexes:* hyperreflexic, brisk, clonus *LMN:* "low" everything (HAFAH, weakness) *Bulk:* reduced bulk, wasting, fasciculations *Tone:* hypotonic *Strength:* reduced (in distribution of affected nerves) *Reflexes:* absent or reduced *NMJ:* *Bulk:* normal *Tone:* normal or hypotonic *Strength:* fatigable weakness *Reflexes:* normal or absent *Muscle:* *Bulk:* increased, normal, or reduced (cause dependent) *Tone:* hypotonic *Strength:* reduced (often proximal > distal) (depends on tone) *Reflexes:* reduced (in proportion to strength) *Extrapyramidal:* *Bulk:* normal (rarely increased) *Tone:* hypertonic, rigid (*sometimes fluctuating with hypotonia*) *Strength:* normal (rarely increased) *Reflexes:* normal

Different Types of Memory

*Working Memory (short term):* prefrontal cortex *Long-Term Memory:* posterior association cortexes of the temporal and parietal lobe *Long term:* includes declarative (episodic, semantic) and procedural memory *Declarative Memory:* - *Episodic Memory:* medial temporal lobe and hippocampus - *Semantic Memory:* temporo-parietal association cortex *Procedural Memory:* basal ganglia

Cholinergic System

1. *AChE inhibitors:* treat dementia 2. Striatal ACh > DA → EPS. Treat with anti-cholinergics to ↓ACh and balance. 3. *Anti-cholinergic medication:* treat delirium

Preferred Medications for Psychiatric Conditions

1. *ADHD:* stimulants (methylphenidate, amphetamines) 2. *Alcohol withdrawal:* benzodiazepines (eg, chlordiazepoxide, lorazepam, diazepam) 3. *Bipolar disorder:* Lithium, valproic acid, carbamazepine, lamotrigine (negative symptoms), atypical antipsychotics 4. *Bulimia nervosa:* SSRIs and CBT (NO bupropion) 5. *Depression:* SSRIs 6. *Generalized anxiety disorder:* SSRIs, SNRIs (buspirone: stimulates 5-HT1A receptors) 7. *OCD:* SSRIs, venlafaxine, clomipramine 8. *Panic disorder:* SSRIs, venlafaxine, benzodiazepines 9. *PTSD:* SSRIs, venlafaxine 10. *Schizophrenia:* atypical antipsychotics 11. *Social anxiety disorder:* SSRIs, venlafaxine; for performance only: β-blockers, benzodiazepines 12. *Tourette syndrome:* antipsychotics (fluphenazine, risperidone), tetrabenazine

GABA-ergic Drugs

1. *Alcohol:* acute use potentiates channel activity; *chronic use down-regulates GABA system* 2. *Benzodiazepines:* ↑affinity of GABA-aR for GABA and ↑channel opening Hz (*requires GABA*) (alprazolam, lorazepam-short acting, clonazepam-long acting) 3. *Barbiturates:* allosteric modulator at low doses and direct agonist at high doses (*GABA not required*) (-barbital) 4. *Flumazenil:* benzodiazepine antagonist (competes at benzo site on GABA receptor); *used in benzo overdoses*

*Experiential Factors and Mood* -5-HTR has unique polymorphisms that can influence depression likelihood in response to adverse life events

1. *Early life stressors include neglect and abuse (inadequate nurturance)* 2. Adult life stressors involve object loss (abandonment, isolation, despair) and failure (reduced self-esteem, worthlessness, guilt) 3. *Serotonin receptor (5-HTR) genetics can play a role in the ability to respond to stress and susceptibility to depression as a result of stress* 4. Epigenetic methylation changes based around early life experiences can outweigh pure genetic factors (cross-fostering studies) - *5-HTR gene promotor remains methylated with early stress* (↓5-HTR for 5-HT binding) - *S/S form increases likelihood of depression after severe maltreatment* - L/L form does not increase likelihood of depression after severe maltreatment 5. Stressors are known to increase risk, and can sometimes be primary to pathogenesis, but are often secondary - *Nonspecific stress reduction is usually ineffective treatment*; instead, decrease the subjective experience of stress - *Stress can ↓BDNF expression and dendritic arborization of hippocampal neurons* - Anti-depressants ↑BDNF expression and dendritic arborization of hippocampal neurons 6. Complex relationships between neuroplasticity, experiences, genetics, physiological changes, and disease course

*Dementia Etiology* (Roth) -Associations

1. *Alzheimer's Disease* - Senile plaques (extracellular β-amyloid) - Neurofibrillary tangles (intracellular, hyperphosphorylated tau) 2. Associated with *tau protein or ubiquitinated TDP-43 abnormalities:* - FTD, FTD-ALS, corticobasal ganglionic degeneration, progressive supranuclear palsy 3. Associated with *Lewy bodies*: -Dementia with Lewy bodies (cortical Lewy bodies; only in SNc in Parkinson's) -Parkinson's-associated dementia (if motor findings are first and more severe) 4. *Vascular:* step-wise progression of dementia due to infarcts over time - Lacunar state (Bingswanger's disease) - Multi-infarct dementia - Strategic infarct dementia (on memory centers) 4. *Alcohol, drugs, or toxins:* damage over the long term - Alcohol-associated dementia - Dementia due to exposure of heavy metals 5. *Infection:* -*Fungal:* cryptococcosis -*Spirochetal:* neurosyphilis or Lyme disease -*Viral:* *HIV* (↓CD4+ count ↑risk); infection predisposes patient to PML (progressive multifocal leukoencephalopathy) by JC virus infection 6. *Prions:* CJD / Kuru (spongiform change) 7. Due to *structural brain disorders:* - Brain tumor - Chronic subdural hematoma (rare) - *Normal pressure hydrocephalus:* TRIAD in patients with enlarged brain ventricles and ↑CSF pressure (due to defect in CSF resorption by arachnoid granulations): *(1) gait disturbance (magnetic), (2) urinary incontinence, (3) dementia (executive function and attention)* 8. Due to other *potentially reversible disorders:* - Depression - Hypothyroidism (fatigue, weight gain, lethargy)(thyroid hormones ↑BMR) - Vitamin B-12 deficiency

Major Neurotransmitter Types

1. *Amino Acids* (>70% of neurons): Glutamate, aspartate, D-serine, GABA, glycine 2. *Biogenic amines:* Catecholamines (dopamine, NE, E), indolamines (5-HT, melatonin), ACh, H 3. *Peptides* (~200 identified): Endogenous opioids

Divisions of the Limbic System

1. *Archicortical Division:* centered around the *hippocampus*, including the *cingulate gyrus and Papez circuit*, and is responsible for *sensory processing, encoding, and attention* 2. *Paleocortical Division:* centered around the *amygdala* and involves the *orbitofrontal cortex*, basal forbrain, hypothalamus, and autonomic nervous system.

Treatment of EtOH Addiction

1. *Assessment and Diagnosis* 2. *Intervention:* start treatment 3. *Detoxification:* remove EtOH from body and treat withdrawal 4. *Rehabilitation:* medical, psychological, and social measures to help avoid the use of substances in the future (rebalance the limbic drive and cortical thinking)

Other Specified Eating Disorder

1. *Atypical Anorexia Nervosa:* despite significant weight loss, weight remains within or above normal weight range 2. Bulimia or binge eating disorder of low frequency or limited duration 3. *Purging Disorder:* recurrent purging to influence weight or shape without binge eating 4. *Night Eating Syndrome:* recurrent episodes of large night eating with recall of the episode

*GABA-B Receptor Drugs* -GABA-B is metabotropic

1. *Baclofen:* GABA-B agonist that relaxes skeletal muscle to treat spasticity, hypertonia, and MS 2. *γ-hydroxybutyrate (GHB):* weak agonist that treats narcolepsy

Bulimia Nervosa (BN)

1. *Binge eating with recurrent inappropriate compensatory behaviors* (self-induced vomiting, using laxatives or diuretics, fasting, excessive exercise) 2. Occurs weekly for at least *3 months* 3. *Overvaluation of body image* (self-evaluation is unduly influenced by body shape/weight) 4. Body weight often maintained within normal range *Clinical Symptoms:* 1. Parotitis (swollen parotid gland) 2. Enamel erosion 3. Electrolyte disturbances (hypokalemia, hypochloremia) 4. Metabolic alkalosis 5. Dorsal hand calluses from induced vomiting (Russell sign). *Psychology:* 1. Depression and anxiety 2. Co-morbid *substance abuse* (1/3 of patients) 3. Impulsivity (ventral-limbic network is under-inhibited) *Treatment:* 1. *Psychotherapy* (CBT is first line) 2. Nutritional rehabilitation 3. Antidepressants (SSRIs): fluoxetine (Prozac), 60 mg/day 4. *Topiramate:* reduce binge-eating and weight 5. *Bupropion (Wellbutrin) is contraindicated due to seizure risk* (NDRI)

How is Psychiatric Diagnosis in Children Different?

1. *Biopsychosocial formulation* (every patient comes with biology, thoughts, and world around them) 2. Multiple data sources (pediatrician, parents, teachers) 3. Relationship with the patient (need to build rapport for child to share) 4. Interview style 5. Reliability of historian 6. Developmental context

Basic Motor Milestones

1. *Birth:* equal movements 2. *2-3 months:* grasps objects, bears weight on legs 3. *3-4 months:* rolls over, hands to midline (grasp own bottle) 4. *4-6 months:* sits without support, transfers objects across midline 5. *6-9 months:* pulls to stand, bangs two objects, pincer grasp, stands alone 6. *1 year:* WALKS (and first words), scribbles 7. *15 months:* runs 8. *18 months:* jumps up, towers of cubes 9. *2-3 years:* balance on one foot, multiword sentences 10. *5-6 years:* hop on one foot

Adrenergic Receptor Drugs

1. *Clonidine:* α2-agonist -↓NE production and release (↓sympathetic overflow) -Treats: ADHD and opioid withdrawal (sedative and anti-hypertensive) 2. *Propranolol:* β-blocker -↓heart rate and output -Treats: *performance anxiety*, akathisia (inability to sit still, an EPS), and Li-induced tremor

Dementia (Clinical Syndrome Symptoms)

1. *Deficit in memory* (trouble remembering that's that have happened recently) 2. *Impairment in ≥1 other cognitive function:* - Language - Skilled motor activities - Recognition of objects - Executive function

*Mimics of Delirium/Encephalopathy* *Reminder:* encephalopathy on EEG appears as diffuse slowing

1. *Dementia with Lewy Bodies (DLB):* - Visual hallucinations ("ha*Lewy*cinations"), dementia with fluctuating cognition/alertness) - Cognitive and motor symptom onset < 1 year apart - Lewy bodies in *cortex* 2. *REM Sleep Behavior Disorder:* parasomnia with abnormal behavior in REM sleep 3. Wernicke's Aphasia: wordy, nonsensical speech 4. Psychosis, mania, depression (*psychosis = NORMAL EEG*) 5. Non-convulsive status epilepticus (nonstop seizure state) → differentiated with EEG (*encephalopathy = diffusely slow*) - An EEG in a patient with *NCSE* would show continuous, rhythmic electrical discharges - sometimes called *"sharp waves,"* "sharp and slow wave discharges," or "spike and slow wave discharges."

Metabolic (Encephalopathy)

1. *Endocrine Disorders* -Glucose (hypo/hyper-glycemia) -Hypo/hyper-thyroidism -Hyperparathyroidism (high Ca2+) 2. *Nutritional Deficiencies* (B12, B1, B6) 3. Dehydration 4. *Electrolytes* -Sodium (hypo/hyper-natremia) -Calcium (hypercalcemia) 5. *Respiratory* -High CO2, low O2 (hypoxia) 6. *Organ Failure* -Uremia (kidney disease) → buildup of urea and other metabolites -Hyperammonemia (liver disease) → excess NH3

Pharmacodynamics of EtOH

1. *Ethanol is both hydrophilic and hydrophobic*, with no single mechanism of action (i.e., no one receptor or active site) 2. High doses non-specifically *disrupt membrane functioning* ("fluidization"). 3. *Low doses act on many membrane proteins*, (receptors, transporters, ion channels, second messengers, etc.), binding to hydrophobic pockets and/or displacing water.

Neurobiology of Mood Disorders (Price Lecture)

1. *Euthymia* is a maintenance of normal mood state, dependent on the interaction of *cortical-limbic and cortico-striatal pathways*. 2. The *limbic system* includes the cingulate cortex, hippocampus, and amygdala - Mediates *coordination of emotional, cognitive, vegetative, autonomic, and motor processes* - *↓hippocampal volume* is associated with longer periods of untreated depression 3. *Vascular Depression Hypothesis* → small *white matter hyperintensities* may be seen on MRI, resulting from pathways involving inflammation, perfusion deficits, focal tract disruption, altered connectivity, and depression (helps explain late-onset depression) 4. *Limbic-Cortical Model of Mood Regulation:* the dorsal cortex mediates attention, cognition, motor, and executive functions; the subcortex mediates gating and monitoring (interactions between other compartments); and the limbic system (ventral) mediates autonomic, vegetative, and somatic (pain) symptoms - Different therapeutic interventions target different areas (e.g., CBT for cortex (self pathway) and drugs/surgery for limbic (reward pathway)) 5. Unclear whether the mood disorder is due to structural abnormalities (e.g., hippocampus), or the cause of the abnormalities 6. Biological treatments have been associated with functional brain changes (and mood regulation), but it is unknown if these treatments result in structural changes 7. The *serotonin system* originates from the *rostral raphe nuclei* and widely distributes to higher cortical areas - There is ↓5-HTR and ↓5-HT binding in depression - Different types of receptors (5-HT1 through 7); no specific one is highly implicated in depression - 5-HT is created from tryptophan by tryptophan hydroxylase (TPH) - Mutation in TPH-2 or depletion of Tryptophan can cause relapse of depression 8. The *norepinephrine (NE) pathway* originates from the *locus ceruleus* and has similar projections - NE is created through the tyrosine pathway by tyrosine hydroxylase (TH) - *Inhibition of TH enzyme can cause relapse of depression* 9. Other implicated neurotransmitters include *↓DA*, *↓ACh*, *↓GABA*, and ↑glutamate 10. Complicated structural and dysfunctional changes in cortex, receptor functioning, downstream pathways, and NTs are related to mood disorders - Unknown if this is cause of depression or reflective of depression, although NTs are hypothesized to be central to pathogenesis - Effective treatments for mood disorders have been associated with changes to neuropeptide systems, although these are believed to be secondary to pathogenesis - Primary intervention is under investigation 11. *↑cortisol or dysfunctional regulation of the HPA axis* (hypothalamic-pituitary-adrenal): ↓T3, ↓GH, gonadotropins, and endogenous opioids are also implicated in depression - *Anti-glucocorticoids (anti-cortisol) may have clinical antidepressant activity* - Unknown if changes in neuropeptides are primary or secondary to pathogenesis - Changes to these systems following treatment are believed to be secondary 12. *Cytokines* ↑HPA axis → depression; especially *IL-1b, IL-2 IL-6, and TNF* 13. *Growth factors* (VEGF and BDNF, brain-derived neurotropic factor) role implicated - *BDNF appears to be enhanced by almost all antidepressive treatment* - Again, unsure if primary or secondary pathogenesis, changes seen with treatment, but believed to be secondary 14. *Genetics* are a risk factor for mood disorders, more so for bipolar disorder than depression - Genetics are central for pathogenesis - Identified genes are highly multifactorial and influenced by experience - Determining genetic influence on treatment options is experimental, and currently more linked to issues with tolerance than successfulness

Language Delay (Potential Causes)

1. *Hearing disorder:* can be correctible if caught early (cochlear implant by 3 years). Negative test → refer to neurologist 2. *Motor disorder:* oro-motor disorders -Cerebral Palsy (static, congenital) -Infarct, tumor, lesion (acquired) → *localizing exams* and neuroimaging. 3. *Cognitive disorders:* decreased capacity for language -Intellectual disability (static deficit) -Degenerative disease (progressive deficit; regression) 4. *Social disorders:* -*Normal neurological exam (EEG):* social and psychological evaluation to rule out conditions such as speech disorders, elective mutism, depression, and autism -*EEG abnormal (seizures):* treat with anti-epileptic drugs

Vascular (Encephalopathy)

1. *Hypertensive encephalopathy* (fluid can leak out of vessels) 2. *Global hypoxic-ischemic injury* (from cardiac arrest) -The brain does not get perfused in a global manner, and exhibits cortical and subcortical dysfunction. Severe anoxic damage can cause coma, recurrent seizures, or myoclonus. 3. Scattered *small ischemic strokes in both hemispheres* (i.e., from cardiac thrombus)

Mood Terminology

1. *Hyperthymia:* exceptionally positive mood and disposition 2. *Euthymia:* maintenance of normal mood state (dependent on cortical, limbic, and striatal interactions) 3. *Dysthymia:* depressed mood

Neurobiology of EtOH Addiction

1. *Incentive salience:* (reward) a cognitive process that confers a "desire" or "want" attribute, which includes a motivational component, to a rewarding stimulus. 2. Binge intoxication 3. Withdrawal/Negative affect 4. Preoccupation/anticipation *Mechanism:* *Alcohol enhances GABA signaling in the brain*, accounting for its relaxing and sedating effects. Because neurons grow accustomed to this exogenous GABA enhancement, they *compensate by decreasing GABA receptor responses* to bring signaling back to baseline. When alcohol is removed, the patient is left with less GABA signaling than normal (*global neuronal excitability can cause seizures*). Additionally, the NMDA-glutamate receptor is inhibited by acute alcohol and up-regulated (supersensitive) during alcohol withdrawal. Overall, *chronic alcohol use upregulates glutamate and downregulates GABA*, causing seizures, tremors, and general hyperactivity during withdrawal.

Glutamatergic Drugs

1. *Ketamine:* NMDA receptor antagonist (anti-depressant) 2. *Memantine:* NMDA receptor antagonist (Alzheimer's) 3. *PCP:* NMDA receptor antagonist 4. *Dextromethorphan (Dayquil):* NMDA receptor antagonist for pseudobulbar affect treatment (used along with quinidine to prolong half-life)

*Dopaminergic Tracts of the CNS* -Commonly altered by drugs (e.g., antipsychotics) and movement disorders (e.g., Parkinson's). -Antipsychotic drugs block dopamine receptors (DA2R) 1. *Nigrostriatal:* movement 2. *Mesolimbic/Mesocortical:* behavior 3. *Tuberoinfundibular:* prolactin

1. *Nigrostriatal Tract:* SNc → striatum (basal ganglia). *Treatment:* ↓DA (below normal) → extrapyramidal symptoms (e.g., acute dystonia, akathisia, parkinsonism, tardive dyskinesia).* 2. *Mesolimbic tract:* VTA → limbic forebrain (*reward*, emotion) *Mechanism:*↑activity → *positive symptoms* (e.g., delusions, hallucinations). *Treatment:* ↓DA (to normal) → ↓positive symptoms. 3. *Mesocortical tract:* VTA → prefrontal cortex (*motivation, planning*) *Mechanism:* ↓DA → *negative symptoms* (e.g., anergia, apathy) *Treatment:* ↓DA → exacerbated negative symptoms 4. *Tuberoinfundibular tract:* arcuate nucleus of hypothalamus → infundibulum and anterior pituitary *Treatment:* ↓DA → ↑prolactin (DA normally blocks prolactin release) → ↓libido, sexual dysfunction, galactorrhea, gynecomastia (in men).

*Dopamine in Schizophrenia* *DA without Antipsychotics:* 1. *Nigrostriatal:* motor control (normal DA) 2. *Mesolimbic/Mesocortical:* behavior -*Mesolimbic:* emotional learning, long-term memory, goal-oriented behavior, motivation and reward (↑DA) -*Mesocortical:* attention, short-term memory, future planning, set-shifting (executive functions) (↓DA) (*↓NMDA receptors = neg symptoms*) 3. *Tuberoinfundibular:* prolactin (normal DA) *DA with Antipsychotics:* 1. *Nigrostriatal:* ↓DA: EPS 2. *Mesolimbic/Mesocortical:* behavior -*Mesolimbic:* normal DA -*Mesocortical:* normal to ↓DA (impaired motivation and cognition, negative symptoms are difficult to treat) 3. *Tuberoinfundibular:* prolactin (↓DA): galactorrhea

1. *Nigrostriatal Tract:* SNc → striatum (motor control). -Impaired in Parkinson's disease -Blocking with medications (DA2R) will cause EPS (motor symptoms) 2. *Mesolimbic tract:* involved in the *positive symptoms* of schizophrenia passing from the VTA to the associated striatum and the nucleus accumbens -Involved in emotional learning, long term memory, goal-orientated behavior, and motivation/reward -*↑synthesis and release of dopamine from the VTA in schizophrenia* -Present in those who are prodromal and progress to psychosis, but not in those who do not progress -Dopamine levels in the mesolimbic tract are predictive of treatment success (↑DA → respond better to DA2R blockers) -This is the pathway *intended to be blocked by anti-dopaminergic medications* 3. *Mesocortical tract:* involved in the cognitive and *negative symptoms* passing from the ventral tegmental area to the prefrontal cortex -*Involved in attention, short-term memory, future planning, and set shifting* -*Dopamine levels decrease in this pathway with schizophrenia* -Decreased size and branching in the prefrontal cortex, but this is not the cause of negative symptoms (thought to be due to ↓NMDA receptors and loss of synaptic plasticity) -Blocking with medications will cause *impaired motivation and cognition* 4. *Tuberoinfundibular tract:* involved in pituitary control passing from the hypothalamus to the anterior pituitary -Blocking with medications with cause hyperprolactinemia (*galactorrhea*)

OCD vs. OCPD

1. *OCPD is ego-syntonic* (Cluster C: worried) -Rigid, orderly personality style that does not include actual obsessions and compulsions -"I wash my hands 200x/day and everyone else should too" 2. *OCD is ego-dystonic* -"I know this is weird, but I was my hands 200x/day"

Methadone (opioid agonist)

1. *µ-opioid receptor agonist* 2. *Long half-life allows for 1x/day dosing* 3. Reduces opioid craving, prevents symptoms of opioid withdrawal, and reduces the effects of shorter-acting opioids such as heroin (less euphoric high) 4. Normalizes daily functioning of opioid addicts 5. Highly effective in retaining patients in treatment and reducing opioid use 6. Decreased mortality, HIV transmission 7. Restricted to licensed opioid treatment programs (can be stigmatizing) 8. Long-term treatment often necessary

Serotonergic System Drugs

1. Anti-depressants 2. Hallucinogenics (LSD, psilocybin) 3. Anxiolytics (buspirone) 4. Atypical anti-psychotics (5-HT2AR block + DA2R block) 5. Antiemetics (-setrons) 6. Antimigraines (-triptans): agonist for 5-HTR; constricts blood vessels in the brain

*Human Development* -Psychosexual Stages (Freud)

1. *Oral (birth to 12-18 mo):* centered on mouth, tongue. Babies put everything in mouth to get pleasure, relieve pain and frustration (feeding, tasting, soothing). 2. *Anal (1-3 years):* focused on achieving sphincter control and voluntary control of bowel movements; this stage is marked by a shift from passivity to activity along with struggles to achieve separation and independence. Toilet training is the major conflict. *Too lenient → anal explosive; Too strict (say no) → anal retentive.* 3. *Phallic (3-5 years):* focused on genitals. Oedipus complex: wanting love from opposite sex parent but viewing same sex parent as rival. Oedipal Conflict resolved by identification with the same sex parent and marks formation of superego. Sets stage for gender identity, character organization, and future genito-sexual orientation. 4. *Latency (5-6 to 11-13 years):* libido is channeled into other (non-sexual) areas such as play, exploration, intellectual pursuits, and social interactions. 6. *Genital (11-13 years to adulthood):* starts with the onset of puberty and lasts throughout life. Libidinal drive focused on genitals. In contrast to earlier stages (entirely focused on self), individual takes interest in well-being of others. Goal is to love, work, and play.

Buprenorphine (partial agonist)

1. *Partial µ-opioid receptor agonist* 2. Approved for office-based settings 3. Most commonly taken sublingually and includes naloxone, which has poor bioavailability (designed to discourage injection) 4. High receptor affinity, acts as opioid blocker 5. Partially activates receptor - reduces craving and withdrawal, ceiling reduces risk of overdose 6. As effective as methadone in reducing opioid use (but with fewer drug-drug interactions)

*Trait vs. Type vs. Disorder* (Personality)

1. *Personality Traits:* stable (not flares), recurring patterns of human behavior, can change slowly over time as a result of growth, trauma, or successes 2. *Personality Types:* an enduring, repetitive pattern of perceiving, relating to, and thinking about the environment and oneself. 3. *Personality Disorder:* inflexible, maladaptive, and rigidly pervasive pattern of behavior causing subjective *distress and/or impaired functioning*; person is usually not aware of problem (*ego-syntonic*). Usually presents by early adulthood. *Personality Disorder Presentation:* 1. *Medical settings:* noncompliance and difficulty coping with medical situations 2. *Family setting:* marital conflicts, sexual dysfunction, child rearing difficulties, and domestic violence 3. *Within the individual:* High comorbidity with anxiety, depression, substance use, and psychosis 4. Often leads to divorce, job loss, and legal troubles *Diagnosis:* 1. Personality disorders should be *diagnosed longitudinally over time* (not in ER settings), taking into consideration the person at their best and worst times. 2. Typically not formally diagnosed until *adulthood* 3. Diagnosis usually requires collateral sources of information to understand patient baseline 4. Family history can provide information regarding social and developmental history (*maladaptive traits* to survive dysfunctional family upbringings) *Treatment:* psychotherapy 1. Acute symptom focus: DBT (especially for BPD) 2. Fundamental: focused on changing personality through long-term psychotherapy 3. Typically poor response, partially due to rigorous treatment and tendency towards *noncompliance* (due to mistrust of doctors)

Language Acquisition

1. *Phonology:* the ability to discriminate and produce the specific sounds of a given language 2. Babies start discriminating phonemes during first few months of life and they produce them soon after 3. *Phonological receptivity is pluripotential at birth but it starts to decay at around 10 months*, reaching a general inability to acquire native phonology by pre-adolescence (e.g., accenting "H"anukkah) 4. *Prosody* (got the keys? vs. got the keys!) and *stress* are aspects of phonology 5. *Language acquisition (semantics = vocabulary)* is greatly affected by the environment (bed time stories, dinner conversations, schooling, SES) and maximally acquired during *year 3 and 4*. 6. *Pragmatics:* social use of language (turn taking, politeness) (high cognitive function)

*Stages of Attachment* -Emotional relationship between child and caregiver

1. *Pre-attachment (birth to 8-10 wks):* orients to caregiver but does not discriminate 2. *Attachment in the Making (8-10 wks to 6 mos):* attaches to one or more figures, if needs met → no separation anxiety (doesn't matter which primary caregiver is meeting needs) 3. *Clear-Cut Attachment (6 mos and beyond):* distress upon separation (keep baby in parent's lap during well-child exam)

Primary vs. Secondary Mood Disorder

1. *Primary* psychiatric: requires *functional impairment and long-lasting symptoms*. 2. Cannot be better explained by another different psych disorder, a separate medical or neurological condition, or a substance or medication effect (*secondary mood disorders*) 3. Neuropsychiatric status exists on a *spectrum* or normal to pathologic

Psychological Theories of Anxiety Disorders

1. *Psychoanalytic (Freudian):* anxiety is the observable symptom that signifies an unconscious conflict, and the goal of treatment is to rectify underlying conflict (and increase capacity to tolerate and experience anxiety) -*Amygdala activity (anxiety)* associated with the *unconscious processing* of fearful faces, as opposed to being given time to consciously observe and process the faces. 2. *Existential:* anxiety is the response to the perceived void in existence and meaning in life -Goal of therapy is more about self-acceptance 3. *Behavioral:* a. *Classical Conditioning:* anxiety is a conditioned response to a specific, neutral environmental stimulus (Pavlov's dogs; Little Albert: loud sound around white, fluffy objects) b. *Operant Conditioning:* negative reinforcement maintains anxiety as removing yourself or avoiding the stimulus results in the reduction of stress, reinforcing this behavior

Anorexia Nervosa (AN)

1. *Restriction of energy intake* relative to requirements causing a significantly low body weight 2. *Intense fear of gaining weight or becoming fat*, even though at a significantly low weight 3. *Body image distortion* and a disturbance in the way one's body weight or shape is experienced *Two Types:* 1. *Restricting Type (90%):* weight loss accomplished primarily by dieting, fasting, and/or excessive exercise without recurrent episodes of binging and purging 2. *Binge-Eating/Purging Type (10%):* accomplished by recurrent episodes of binging and purging via vomiting, laxatives, diuretics or enemas -Distinct from bulimia nervosa based on weight (these patients are underweight) -BMI of 18.5 is bar for underweight, 17.5 is anorexic (extreme is <15) *Associated Symptoms:* slow heart, low BP, dry skin, bones break 1. Bradycardia 2. Hypotension 3. Risk of sudden death 4. Dry skin, lanugo (fine, soft) hair 5. Amenorrhea, infertility 6. Electrolyte and other lab abnormalities 7. Gastric dilation and constipation upon re-eating 8. ↓bone density (often irreversible) 9. Anemia *Mortality:* 5% mortality rate, usually cardiac events (1/5 due to suicide) *Psychology:* 1. Tend to be perfectionists 2. Compulsive 3. Emotionally inhibited (dorsal cognitive network, self regulation) 4. Need for order or symmetry *Treatment:* 1. *Weight restoration* is first line 2. Psychotherapy (family-based) 3. SSRIs for comorbid anxiety and/or depression (not effective) 4. Fluoxetine (Prozac acts on 5-HT in dorsal system/self-regulation; FDA approved, but similar to placebo for weight-restoration) With chronic malnutrition, AN patients are in a *chronic hypometabolic state*. Re-feeding increases utilization of phosphate, and the resulting hypophosphatemia can lead to Refeeding Syndrome. *Refeeding Syndrome:* ↑insulin at onset → hypophosphatemia, hypokalemia, hypomagnesemia → cardiac complications (arrhythmia), respiratory failure, rhabdomyolysis, seizures

5 Rs of Early Childhood Education

1. *Routines* help children know what to expect of us and what is expected of them 2. *Reading* together daily 3. *Rhyming*, playing, and cuddling 4. *Rewards* for everyday successes (*praise*) 5. *Relationships*, reciprocal and nurturing (foundation of healthy child development)

Inflammatory/Infectious (Encephalopathy)

1. *UTIs in the elderly* 2. Infection of the CNS (encephalitis)

Frontal Lobe Dysfunction (indicators)

1. *Working Memory Impairment:* spatial and feature 2. *Reflexes:* release signs reappear (present in infancy): snout, suck, glabellar, and grasp 3. *Dystonia:* gegenhalten (↑resistance to movement of a limb throughout flexion and extension) 4. *Gait abnormalities:* magnetic gait (difficulty picking up feet when ambulating)

*Frontal Lobe Overview* 1. *Orbitofrontal deficits:* behavioral disinhibition 2. *Cingulate deficits:* apathy 3. *Dorsolateral deficits:* executive function problems 4. *Temporal lesions:* amygdala (emotional processing and social behavior) or left temporal lobe (language: aphasia, semantic dementia).

1. 33% of cortical surface areas in humans, part of what makes us human (personality) 2. *Normal function* includes organizing incoming information, response selection, working memory, maintenance of goals, behavioral flexibility, impulse control, and initiation/drive 3. *Leukotomy/lobotomy* was initially used to treat mental illnesses and involved nonspecific cutting of white matter tracts connecting the frontal lobes to other cortical areas 4. *Lesions* to the frontal lobe will cause *difficulty completing spatial and object alternation tasks* -*Spatial Tasks:* learning food is under tray on right, not tray on left, then switching rules and seeing how long it takes to adjust (dorsolateral lesions specifically) -*Object Tasks:* learning food is under cylinder, not cube, then switching rules and seeing how long it takes to adjust (orbital lesions specifically) 5. *Frontal lobe function decreases with age* (pure aging)

PTSD Comorbidities

1. 3x increase in substance use disorders 2. 4x increase in panic disorders 3. 16x increase in depressive disorders 4. Higher rates of eating disorders, esp bulimia 5. Chronic fatigue syndrome, IBS, HAs, GERD, heart/liver/pulm, and autoimmune disorders 6. 20% attempt suicide

Basic principles of antidepressant use

1. Achieve adequate dosing (gradual titration) 2. Treat for adequate duration (*4-6 week acute trial at effective dose determined by FDA*) 3. Assess adequacy of response 4. Ensure adherence (avoid complex dosing, and make sure the medication is affordable)

Treatment Effectiveness for Opioid Addiction

1. Addiction is a chronic disease: - *40-60% who receive addiction treatment are continuously abstinent at 1-year follow-up* - Treatment is effective, but access to treatment is low 2. Opioid maintenance treatment reduces opioid use, mortality risk, risk of HIV, criminal behavior 3. Most effective treatment (gold standard) is a *combination of medication and psychosocial supports* → medication-assisted treatment (MAT) can at least double the rate of opioid abstinence in those patients with a psychological dependence

Treatments for Bipolar Disorder

1. Anti-Manics 2. Anti-Depressants 3. Thymoleptics (mood stabilizers)

Neurotransmitter Requirements

1. Be stored in a presynaptic neuron (within vesicles) 2. Released via depolarization of the presynaptic neuron (Ca2+ channel-mediated) 3. Able to bind a specific receptor on a nearby post-synaptic neuron 4. Inactivated by enzymes or active re-uptake

Myelination Development

1. Begins *early in 3rd trimester* with most rapid myelination in the first 2 years of life (most rapid motor/cognitive development) 2. *Continues through 20s (frontal lobes last)* 3. Myelination starts at proximal portion of axon and shortest axons myelinate first (brainstem) 4. Then upper extremity axons and trunk 5. Then longer lower extremity axons myelinate (distal legs) 6. This pattern correlates with head-to-toe developmental milestone acquisition *Progression Rules:* 1. Central to peripheral 2. Caudal to rostral 3. Dorsal to ventral 4. Sensory then motor *At term birth:* brainstem, cerebellum, posterior limb of internal capsule, visual tract, perirolandic *2 months:* anterior limb of internal capsule *3 months:* splenium of corpus callosum (caudal) *6 months:* genu of corpus callosum (rostral)

Complex Subcellular Effects of Drugs

1. Causes increased release of opioid peptides 2. Affects G-protein signal transduction 3. Affects protein kinases 4. Affects translocation from cytoplasm to nucleus 5. Influences ion channel phosphorylation 6. Affects a variety of nuclear transcription factors 7. Affects receptor cross-talk 8. Affects control of protein kinases 9. Affects receptor subunit composition 10. Affects gene expression, histone methylation

*Memory in PD, DLB, and VaD* -Parkinsons (PD) -Lewy Body Dementia (DLB) -Vascular Dementia (VaD): small vessels affecting deep, subcortical structures

1. Damage to fronto-subcortical circuits 2. Inefficient encoding and retrieval 3. Improvement with cueing/recognition 4. Absence of dense amnesia (which usually requires a larger brain injury)

*Changes in Senses* (Pure Aging)

1. Decline in accommodation, low contrast acuity, adaptation, and color discrimination 2. *>50% of patients >80 years old will have hearing loss* (threshold >25dB) - Hearing handicap inventory for elders is a set of questions to determine hearing loss 3. Number of taste buds does not change, but *ability to taste salt declines while bitter increases* - Saliva volume and quality decreases - May result in loss of interest in food, causing malnutrition

Age-Related Structural Brain Changes

1. Enlarged subdural space (predisposition to subdural hematoma) -Bridging veins are under stretch -↓elasticity (cross-linked elastin/collagen) 2. Narrower gyri 3. Wider sulci 4. Enlarged ventricles (due to less brain mass maintaining shape)

*Schizophrenia Neurobiology* (Halt) *Stage I:* risk (<12 years) *Stage II:* prodrome (12-18 years) *Stage III:* psychosis (18-24 years) *Stage IV:* chronic disability (>24 years) *Mechanism:* 1. Stress, trauma, maternal infection, maternal malnutrition → 2. Synaptic pruning → 3. *↓glutamate synaptic plasticity*

1. Heterogeneity of the disease limits the ability to understand its neurobiology 2. Current developments are trying to find clinical biomarkers that can distinguish different subtypes of schizophrenia 3. *Strong heritable component* (2nd highest behind bipolar) with room for environmental impact - *Genes implicated:* NMDA receptor signaling, immune function (MHC locus), Ca2+ signaling, post-synaptic density, miR137 (regulates gene expression) - *Maternal influenza* during the first trimester causes a *7x risk* in schizophrenia, similarly with malnutrition or adverse life events - *Cannabis use, immigration, minority status, and urban living can be adolescent stressors* - Multi-hit hypothesis of priming glial cells when young, followed by another trauma later 4. *During adolescence, the GABA system is not developing as strongly as intended, the glutamate system is excessively pruning neurons (↓glutamate synaptic plasticity), and the myelination system is impaired* - Cognitive problems (age 13-16) can precede psychotic symptoms (dopamine-induced) - *Trauma is present in 85% of patients* with psychotic disorders and is associated with increased severity of hallucinations and delusions, mood symptom severity, earlier onset, number of hospital admissions, and dose response - *Can treat psychosis* (antipsychotics block dopamine signaling at D2 receptors), but *tough to treat cognitive symptoms* 5. *Early* onset associated with increased *genetic risk factors* causing more *negative* and *cognitive* symptoms (worse prognosis) 6. *Later* onset associated more with *paranoia*, fewer birth complications, migrant status, and *stressful life events* 7. Course is variable in severity and recurrence, and prognosis is tough to determine on initial encounter

*Schizophrenia Neurobiology* (Crush) 1. ↑DA in mesolimbic → positive symptoms 2. ↓DA in mesocortical → negative symptoms (cortex = PFC = executive)

1. Excess dopaminergic signaling in the meso-limbic pathway (midbrain to limbic system) (positive symptoms) 2. Decreased dopaminergic signaling in the mesocortical pathway (midbrain to frontal cortex) (negative symptoms) *Dopamine Hypothesis Evidence:* Drugs that block D2 receptors reduce psychotic symptoms; dopamine agonists (e.g., amphetamines) worsen symptoms.

*Symptoms of Opioid Withdrawal* -Feels like the "worst flu of your life"

1. Fatigue 2. Muscle aches or restlessness 3. Rhinorrhea 4. GI upset, nausea/vomiting/diarrhea 5. Dysphoria, irritability, anxiety 6. Insomnia 7. Yawning 8. Tachycardia, hypertension

Dorsolateral Cortex Deficit Testing

1. Figural fluency tasks (perseveration) 2. Luria's alternating figures test 3. Visual organization test 4. Copy/free recall tests (ability to replicate figure and hand movement patterns is diminished)

Satiety Signals

1. Gastric and gut distention (vagal activation) 2. Release of CCK (vagal activation) 3. ↑blood insulin (inhibits orexigenic pathway) 4. ↑blood glucose

*Alzheimer's Dementia* 1. Progressive dementia 2. Cortical atrophy and neuronal loss - *Medial temporal lobe structures* (episodic) - *Temporo-parietal association cortices* (semantic) 3. Neurofibrillary tangles and neuritic plaques 4. ↓ACh and ↓NE

1. Gradual, insidious onset 2. Neurologic exam generally normal (early) 3. Neuroimaging reveals diffuse cortical and subcortical atrophy, *hippocampal atrophy* 4. Neuropsychological abnormalities in: - Naming - Construction - Memory (rapid forgetting) *Memory Deficits:* 1. Hippocampal and basal frontal degeneration 2. Relatively intact initial encoding in early stages 3. Rapid forgetting after a delay (inability to acquire and retain new information and experiences) 4. Minimal benefit from cueing or recognition *Memory Findings:* 1. *Impaired episodic memory:* due to medial temporal degeneration 2. *Impaired semantic memory:* impaired fund of knowledge (temporo-parietal association) 3. *Intact procedural memory:* intact skill learning (basal ganglia) *Amnesia:* 1. *Anterograde:* severe 2. *Retrograde:* temporally-graded (recent memories are more impaired than remote memories)

*Limbic Emotional Circuit (Paleocortical)* -Amygdala processes emotional memories -Modulates fear responses -*NE enhances emotional memory in the amygdala* -Integrates affect, drives, and object associations -Autonomic control -Olfaction

1. Important for *fear response and emotional memory* 2. *Amygdala* is anterior and medial to the head of the hippocampus -*Attaches affective color and social meaning to sensory information* -*Involved in the startle reflex and can generate fight-or-flight responses* -Receives *input* directly from the *olfactory tracts* via *olfactory stria* -Sends *output* via the *stria terminalis* to the *basal forebrain* (cholinergic septal nuclei) -Sends *output* via the *ventral amygdalofugal pathway* to the *hypothalamus* (associative learning) 3. The hypothalamus has 2 main nuclei: -*Lateral:* aggressive, voracious, hypersexual behavior // feeding center -*Ventromedial:* placid behavior // early satiety 4. Auras from partial seizures involving the amygdala cause feelings of fear, GI disturbances, and altered perceptions of smell (burning rubber) or sight

Leptin

1. Produced by fat cells (adipocytes) 2. Blood levels ∝ body fat mass (↑fat ↑leptin) 3. Leptin receptors are located especially in the *arcuate nucleus* of the hypothalamus.

Alcoholic Population Heterogeneity and EtOH Dependence

50% genetic, 50% environment. *Protect:* ALDH2*2, CN1, OPRMI (mu opioid receptor that binds β-endorphin more avidly → ↑stimulation to IV EtOH) *Promote:* GABRA2, TAS2R16, ↓plasma β-endorphin (an opioid peptide) There is a high co-morbidity of addiction in certain psychiatric disorders (e.g., schizophrenia, bipolar, PBD, panic disorder, PTSD, social phobia).

Memory Encoding, Storage, and Retrieval

1. Information is initially *encoded*, tagged in either a temporal or spatial context, and organized in the working memory. - Frontal lobe lesions lead to poor organization and clustering, exaggerated primary and recency effects, shallow learning curve, and poor temporal tagging 2. Information can then be *stored* permanently by the *hippocampus in posterior association cortexes* of the temporal and parietal lobe - Frontal lobe lesions will not likely affect encoding which is done by the hippocampus 3. *Retrieval* is mediated by the *frontal lobe* through selection/elimination of alternatives - Metamemory is judgements made about the memories retrieved (I'm 99% confident) - Frontal lobe lesions lead to perseverative (repeating) and intrusion (wrong memory due to faulty retrieval) errors, difficulty establishing temporal/spatial context (i.e., knowing when and where you heard something, not just that you heard it), great disturbances to metamemory, and will be able to recognize much better than recall (priming).

GABA

1. Inhibitory (↓brain activation) 2. Roles in sleep, pain, anxiolysis, catatonia, and seizure suppression *GABA Receptors:* 1. GABA-A (ionotropic): GABA binds outside of central *Cl- pore* (α1/β2); benzodiazepines binds between α1/γ2 2. GABA-B (metabotropic)

Mood vs. Mood Disorders (Distinguishing Features)

1. Intensity and severity of symptoms (large amplitude sine wave) 2. Duration of symptoms 3. Associated functional impairment

Two Major Neurotransmitter Receptors

1. Ligand-gated (ionotropic) 2. GPCR (metabotropic)

Autoimmune (Encephalopathy)

1. Lupus cerebritis 2. Rare paraneoplastic syndromes or autoimmune encephalitis (e.g., anti-NMDA receptor encephalitis due to ovarian teratoma)

*Changes in Motor Systems and Balance* (Pure Aging)

1. Major causes of muscle loss are disuse and disease 2. *Muscle mass and strength do decline, but not much (~15%) if resistance training is maintained (slow twitch less resistant)* - *Reflexes are diminished and the cerebellum shrinks, affecting balance, gait, tone, and motion* - Balance declines substantially, more so in women than in men - Otolith and vestibular portion of CN VIII degenerate and may cause positional vertigo 3. Proprioception decreases, and can be complicated by peripheral nerve diseases

*Glycine* (inhibitory) -Spinal cord and brainstem

1. Mandatory adjunct neurotransmitter that acts on the NMDA receptor along with glutamate (excitatory) 2. Inhibitory by binding to "strychnine-sensitive glycine receptor" in the spinal cord and brainstem 3. Has been studied as possible treatment for schizophrenia

Trauma-Induced Epigenetic Changes

1. Methylation or histone acetylation of DNA promoters or inhibitors during early trauma or neglect 2. Down-regulation of GRs in the hippocampus (remain methylated) → decreased inhibition of stress response/HPA axis (no longer say "ok, calm down, we've got it")

Glutamate

1. Most common NT 2. *Excitatory* 3. Involved everywhere (*learning and memory*, excitotoxicity, plasticity) *Glutamate Receptors:* 1. NMDA (ionotropic, Ca2+) 2. AMPA (ionotropic, Na+) 3. Kainate (ionotropic, Na+) 4. mGluR (GPCR)

Parental Stress Impact on Children

1. Mothers' stress levels during their child's 1st year correlated with methylation of 139 DNA sites in their teens 2. Fathers' stress in their child's preschool years correlated with methylation of 31 DNA sites in their teens

How is Psychiatric Treatment in Children Different?

1. Multi-disciplinary, team-oriented approach 2. Family and school involvement 3. Always some type of therapy (not just meds) 4. Developmental context 5. Importance of the milieu culture (patients can return to drugs in old environment post treatment) 6. Compliance (medications) 7. Informed consent/assent (including black box warnings and paucity of data for meds): anti-depressants increase the risk of suicidal thinking and behavior in children and adolescents

Ligand-Gated Receptor (ionotropic)

1. Multiple subunits with central pore 2. Neurotransmitter binding site which gates central pore 3. Allow passage of ions (Na+, K+, Ca2+, Cl-) 4. *Fast effect* (milliseconds)

*Antipsychotic Effects on Mesocortical System*

1. Negative symptoms persist (affective flattening, avolition, anhedonia, asociality, alogia) 2. ↓working memory (due to ACh > DA imbalance)

*Persistent Depressive Disorder (PDD)* -Primary depressive disorder

1. Often milder than MDD (dysthymia), but chronic 2. *≥ 2* depressive symptoms *lasting ≥ 2 years*, with *no more than 2 months without symptoms*

*Psychosis Prevention*

1. Only 35% of patients in an *at-risk mental state* (ARMS) convert to psychosis in 2 years. 2. Early interventions with CBT can reduce transition rates by 54%. - Psychoeducation and normalization (↓stress) - Challenging and "reality testing" of delusional thoughts - Enhancing coping strategies - Encouraging self-monitoring of symptoms After a first episode (acute phase), medical treatment is best when combined with therapy, family interventions, case management, and work support. Overall, the *duration of untreated psychosis (DUP) is an important predictor of schizophrenia outcome*. Patients with intervention (regular medication and wrap-around care services) *before 74 weeks* have *better outcomes*.

Other Monotherapies for Mood Disorders

1. Psychosocial treatment involving behavioral therapy, mindfulness, self-management, and interpersonal/family/marital relationships can be beneficial 2. Occasionally, *lithium*, *anticonvulsants* (valproic acid, carbamazepine, and lamotrigine), and *atypical antipsychotics* (quetiapine) are used to treat mood disorders 3. *Stimulants may be used if other options fail first*, but have ↑dependency and side effect risks 4. *Combination therapies involving any of these methods with a primary antidepressant* 5. *Electroconvulsive therapies (ECTs)* pass electrical pulses through the scalp to produce seizures in an anesthetized patient (gold standard for severe depression) - 6-12 treatments at 2-3 treatments per week - Contraindicated for brain lesions or heart problems, and can cause cognitive side effects 6. Less frequently used strategies include transcranial magnetic stimulation, vagus nerve stimulation, magnetic induced seizure therapy, and deep brain stimulation

Aberrant Medication-Taking Behavior

1. Requests for specific medication by name, "brand name only" 2. Non-adherence with other recommended therapies (e.g., PT) 3. Requests for dose increase 4. Running out early (i.e., unsanctioned dose escalation) 5. Resistance to change therapy despite adverse effect (e.g., over-sedation) 6. Deterioration in function at home and work 7. Non-adherence with monitoring (e.g. pill counts, urine drug tests) 8. Multiple "lost" or "stolen" prescriptions 9. Illegal activities: forging scripts, selling prescriptions

*Primary Anti-Depressants* -Look at pharmacology chart

1. SSRIs 2. Mixed MARIs (e.g., SNRIs, NDRI) 3. Monoamine receptor antagonists 4. TCAs 5. MAOIs

G Protein Coupled Receptors (metabotropic)

1. Single subunit with 7 transmembrane regions 2. Linked to membrane proteins (G proteins) 3. Binding of neurotransmitter leads to intracellular response 4. *Slower*, modulatory/dampening/enhancing, and *more sustained*

*HPA Axis* 1. Negative feedback on the HPA axis is normal (cortisol binds glucocorticoid receptors of the hypothalamus and anterior pituitary). 2. Trauma/stress can impact methylation of glucocorticoid receptors (↓receptors → ↑cortisol / stress) 3. Prolonged ↑cortisol (due to early trauma and neglect) can biologically re-program a circuit (which can last a lifetime)

1. Stress and inflammatory cytokines activate the hypothalamus. 2. Hypothalamus releases CRH (corticotropin-releasing hormone). 3. CRH acts on the corticotrope cells of the anterior pituitary (ACTH) and the locus ceruleus (NE → sympathetic response) 4. The anterior pituitary releases ACTH into the bloodstream, which travels to the adrenal glands. 5. The adrenal cortex secretes mineralocorticoids (aldosterone) and glucocorticoids (cortisol). 6. Cortisol has *negative feedback* on the hypothalamus and anterior pituitary. *Cortisol Action:* 1. ↑BP and blood volume 2. ↑blood sugar (gluconeogenesis) 3. ↓immune system 4. ↑metabolism of fat, protein, and carbohydrates. 5. ↓GH and ↓T3 *Michael Meany's Rats:* 1. Rodent pups receiving low levels of maternal licking and grooming (from birth mother or foster mother) developed into fearful adults with heightened startle responses & intense adrenocortical responses to stress 2. Differences in adrenocortical responses to stress were linked to differential synthesis of hippocampal receptors (↑GRs → ↑negative HPA feedback → ↓stress) 3. Receptor synthesis was regulated by genes whose rates of expression were in turn modified by epigenetic variation (histone methylation and deacetylation) induced by normally occurring levels of maternal behaviors (heavy licking → ↓pre-set methylation of GR promotor genes → ↑GR → ↑neg feedback → ↓stress) 4. The adrenocortical changes could be reversed by specifically blocking these epigenetic modifications

Resilience

1. Stress-innoculation: provide children a scaffold (boundaries and a role in the household) 2. Neuropeptide Y (NYY) → ↑neuroplasticity

Pediatric Manifestations of PTSD

1. Temper tantrums 2. Decreased participation in play 3. Play reenactment, symbolic play 4. Frightening dreams 5. Oppositional Defiant Disorder (ODD)

*Limbic Memory Circuit* (Archicortical) -*Hippocampus* involved in *episodic memory*. Sensory processing, encoding information, attention *Components:* -*Hippocampus:* short-term memory formation, spatial memory and orientation, attention, regulation of mood -*Entorhinal cortex:* processing new information for coding (atrophy)

1. The hippocampus receives input from the entorhinal cortex via the perforant pathway on the medial temporal lobe. - *Entorhinal cortex:* most common area beginning of AD degeneration, leading to difficulty encoding information (names, faces, facts) → *episodic memory loss* - *Episodic memory:* hippocampus activation; parietal (precuneus) deactivation - *Verbal information is encoded by the left hippocampus, and spatial information is encoded by the right hippocampus (words vs faces)* 2. Sends output through the *subiculum* back to the entorhinal cortex and associated areas 3. The subiculum gives rise to the *fornix*, and the hippocampi are allowed to communicate via the hippocampal commissure of the fornix 4. The fornix has main projections to the mammillary bodies of the hypothalamus, and a smaller projection to the *septal nuclei* (cholinergic neurons) of the frontal lobe (degenerates early in AD) - DBS near the fornix and hypothalamus causes better memory (currently being tested as treatment for AD) 5. Mammillary bodies → *mammilo-thalamic tract* → anterior nucleus of the thalamus → internal capsule → cingulate gyrus - A lesion in the *anterior nucleus* of the thalamus (PCA small perforator infarct) can produce *amnesia* - The *cingulate gyrus* is involved in attention, drive motivation, and initiation of speech → bilateral injury causes *akinetic mutism* 6. The *cingulate gyrus* has many cortical connections involved in processing information, and connects back to the *hippocampus* via an underlying *cingulum bundle* white matter tract 7. *Damage to any aspect of this system can cause difficulties with memory or behavior* 8. *H.M.* was a patient who had both anterolateral temporal lobes removed to treat epilepsy - Treatment was successful, but he was unable to learn anything new (episodic memory) following the surgery due to bilateral hippocampal removal - Motor learning was intact (basal ganglia), but he was unaware that he had learned the motor task 9. *Mesial Temporal Sclerosis:* unilateral neuronal loss in the hippocampus, possibly due to infection, that can cause seizures - If a clear focus is found and the patient does not respond to treatment, may be cured surgically if language and memory function are conserved in the other hemisphere - *WADA Test:* inject a barbiturate into one carotid only, teach a task, and see if task/communication is conserved with only one active hemisphere, repeat on other side

Key Strategies Against Opioids

1. Treatment 2. Rescue (↑Naloxone = Narcan) 3. Prevention (↑prescription monitoring) 4. Recovery (expansion of peer supports)

*Neurocognitive Symptoms of Psychosis* -Less effective treatment

1. Working memory 2. Executive function 3. Verbal memory 4. Processing speed

Addiction Risk Factors

1. Young age 2. Personal history of substance abuse (illicit, prescription, alcohol, nicotine) 3. Family history of substance abuse 4. Legal history (DUI, incarceration) 5. Mental health problems 6. Trauma to the limbic system or frontal lobe

Fronto-Temporal Lobar Degeneration (FTD)

A *degenerative disorder* of the cerebral cortex that *preferentially affects the frontal and temporal lobes* of the brain. *Clinical Presentation:* 1. *Orbitofrontal deficits:* behavioral disinhibition (bad angel) 2. *Cingulate deficits:* apathy and lack of motivation (SMA inhibits exploration) 3. *Dorsolateral deficits:* executive function problems 4. *Temporal lobe lesions:* amygdala (emotional processing and social behavior) or left temporal lobe (language: aphasia, semantic dementia = naming objects).

Substance/Medication-Induced Depressive Disorder

A *secondary* prominent and persistent depressed mood that has a temporal relationship with the substance (lasts beyond detox period, but not long enough to become major depressive disorder). If due to a substance, you must distinguish if the depression is due to intoxication or withdrawal phase only (hours to days), or if it persists beyond typical physiological effects of intoxication or withdrawal (days to weeks). If the symptoms last *weeks to months* after discontinuance of the substance, then the illness is probably a *primary* mood disorder.

Korsakoff's Dementia

A disorder caused by *prolonged deficiency of vitamin B1* (thiamine), which often occurs in chronic alcoholics (since alcohol serves as a substitute for foods with essential nutrients). *Clinical Presentation:* 1. Severe amnesia (*anterograde* > retrograde) 2. Confabulations 3. Intrusions and disinhibition *Pathology:* 1. Degeneration of the medial thalamus (left) and mamillary bodies 2. Cerebral atrophy in regions such as the frontal lobes (right) Patients with Korsakoff's dementia often exhibit many of the same neuropsychological deficits that are seen in other frontal patients.

Aphasia

A language disorder that affects the ability to understand and express spoken or written language. *While it is uncommon in children, certain childhood epileptic syndromes are associated with aphasia.* *Reminder:* *Broca's aphasia:* trouble speaking fluently, but preserved comprehension. Non-fluent or expressive aphasia. Individuals with this type of aphasia may be able to read, but are limited in writing. *Wernicke's aphasia:* the ability to grasp the meaning of spoken words and sentences is impaired, while the ease of producing connected speech is not very affected. Fluent or receptive. Reading and writing are often severely impaired.

*Working (Short-Term) Memory* -Pre-frontal cortex

A limited-capacity (i.e., able to hold only about *seven recognizable items*) system that is capable of storing and manipulating information for short periods of time (i.e., about *20 to 30 seconds*) without rehearsal. *With rehearsal, information can be maintained in working memory indefinitely.* Working memory can be subjectively viewed as *the information one is immediately thinking about or working on*, and more formally viewed as the currently active subset of long-term memory. Working memory consists primarily of a *central executive system* that is aided by two subsidiary slave buffer systems: 1. *Visuospatial scratchpad:* holds visuospatial information 2. *Phonological loop:* holds speech-based information

*Schizophrenia* 1. Continuous signs or symptom disturbance for *at least 6 months* 2. ≥ 1 month of active Criterion A 3. *Can include prodromal and residual attenuated symptoms* (low level of suspiciousness, overvalued ideas, role failure, decline in social competence)

A psychiatric disorder characterized by *periods of psychosis* (loss of touch with reality) and *bizarre behavior* interspersed with periods of "negative" symptoms. *Psychosis occurs in a clear sensorium.* Patients do well on the MMSE and MoCA (as schizophrenia is *not* a cognitive disorder). *Associated with ↑dopaminergic activity* (miso-limbic system) and ↓dendritic branching. Also associated with abnormal structure and function in the dorsolateral prefrontal cortex (executive function), language cortex, thalamus, and cerebellum. Diagnosis requires *≥ 2 Criterion A symptoms for ≥ 1 month* (≥1 of bolded) *and a decline in function* (work, school, etc.). *Criterion A Symptoms:* 1. *Delusions* 2. *Hallucinations (often auditory)* 3. *Disorganized speech* 4. Disorganized or catatonic behavior 5. ((Negative symptoms)) *Negative symptoms:* ↓meso-cortical DA *↓neural activity in dorsolateral prefrontal (executive) circuits* 1. *A*logia (poverty of speech) 2. *A*pathy (anhedonia) 3. *A*volition (↓initiative) 4. *A*ffective flattening 5. *A*sociality (withdrawal) *Neurobiologic Mechanism:* ↑DA signaling in the meso-limbic and ↓DA signaling in the mesocortical pathways of the brain. *Imaging:* ventriculomegaly *Treatment:* atypical antipsychotics (e.g., *risperidone*). Negative symptoms often persist after treatment, despite resolution of positive symptoms. As such, neurocognitive and negative symptoms are best predictors of a poor outcome. *Downward Drift:* schizophrenia is not more common in those with low SES; however, it is debilitating enough to cause low SES.

Clusters of Personality Disorders

A: Weird B: Wild C: Worried

Neurocircuitry Changes in Addiction

In the addicted brain, the *pre-frontal cortex is impaired*, leading to a greater driver for "go."

Age Changes in the Neurologic Exam

Abnormalities in 20-50% of elderly, but *not pure aging* (doesn't happen to everyone): 1. *Frontal release (primitive reflexes):* snout, palmar-mental, root, suck, grasp reflexes are found in 10-35% of patients with normal cognition (can no longer be used to identify dementia) 2. *Ankle jerks more difficult to elicit* in all patients, absent in 10% (due to stiffness of tendons; ↑risk of rupture especially with fluoroquinolones) 3. *Vibration loss* in toes is common, but position sense is unimpaired *Pure Aging:* 1. ↓arm swing, ↑tone (due to ↓DA neurons) 2. ↓gag reflex 3. ↓ability to prevent postural sway 4. ↓ability to prevent orthostatic hypotension 5. ↓baro-reflex sensitivity 6. ↓hand- and foot-tapping speed 7. Restricted upward gaze

*Second Generation Antipsychotics* 1. *Block DA2R (↑cAMP) and 5-HT2AR* 2. *Clinical Use:* Schizophrenia—both positive and negative symptoms. Also used for bipolar disorder, OCD, anxiety disorder, depression, mania, Tourette syndrome. 3. Use *clozapine for treatment-resistant schizophrenia* or schizoaffective disorder and for suicidality in schizophrenia. Also useful for patients who have a history of Parkinson's or Lewy body dementia (sensitive to motor side effects) *Don't often require an anticholinergic as well to combat motor symptoms.*

Addition of the *serotonin blockade reduces its ability to inhibit dopamine release* (disinhibition) → ↓DA blockade effects (↑DA=↓EPS). 1. *Highest Risk for EPS:* risperidone (hyperprolactinemia), paliperidone, lurasidone 2. *Medium Risk for EPS:* olanzapine (obese), aripirazole 3. *Low Risk for EPS:* clozapine (agranulocytosis), quetiapine (sleepy) *Clozapine* is effective in some treatment-resistant patients, typically requiring 2 other failed medications to be tried first. *Minimal risk of EPS and tardive dyskinesia, reduces hostility, aggression, and suicidality.* ((↑metabolic syndrome.)) *Metabolic Syndrome:* weight gain, increased appetite, elevated cholesterol, high blood pressure, insulin resistance, prothrombotic and proinflammatory state 1. *Clozapine*, zotepine, and *olanzapine* are the most efficacious and have the highest risk of *metabolic syndrome* 2. *Ziprasidone (Geodon), lurasidone (Latuda), and aripiprazole (Abilify) are less efficacious, but have lower risk of metabolic syndrome* 3. Paliperidone has the highest risk for hyperprolactinemia *Adverse Affects for All Second Generation Antipsychotics:* 1. Prolonged QT interval 2. Fewer EPS side effects than typical antipsychotics 3. Fewer anticholinergic side effects than typical antipsychotics *Specific Symptoms:* 1. "-pines"—metabolic syndrome (weight gain, diabetes, hyperlipidemia). 2. *Clozapine:* agranulocytosis (monitor WBCs frequently), seizures (dose related), DVT, and constipation (↓GI motility). Low risk for EPS, and reduces hostility, aggression, and suicidality. 3. *Risperidone (Risperdal):* hyperprolactinemia (amenorrhea, galactorrhea, gynecomastia) and EPS (akathisia and parkinsonism), but only medium risk for weight gain. *Mnemonics:* 1. *O*lanzapine, cl*O*zapine → *O*besity 2. Must watch bone marrow *cloz*ely with *clozapine* (agranulocytosis)

Dialectical Behavior Therapy (DBT)

Aims to help with *borderline personality disorder (BPD)* by *working on defense mechanisms* and *objectively evaluating people* using a team to address the problem from multiple angles. Psychotherapy that combines behavior therapy with *acceptance and mindfulness*. DBT has also been used to *treat mood disorders* as well as those who need to change patterns of behavior that are not helpful, such as self-harm, suicidal ideation, and substance abuse. This approach works towards helping people *increase their emotional and cognitive regulation* by *learning about the triggers* that lead to reactive states and helping to assess which *coping skills* to apply in the sequence of events, thoughts, feelings, and behaviors to help avoid undesired reactions.

GABA/Dopamine/Opioid Interactions in Alcoholism

Alcohol releases opioid peptides (e.g., β-endorphin) that facilitates dopamine release. *β-endorphin inhibits inhibitors (GABA)*, resulting in disinhibition of SNc in the ventral tegmental area, which releases *more dopamine*.

Trauma

An inescapably stressful event that overwhelms one's coping mechanisms. *Examples:* 1. Combat exposure 2. Sexual assault 3. Child abuse/neglect 4. Cultural trauma/genocide 5. Natural disasters 6. Accidents, medical emergencies

*Procedural Memory* -Knowing how... -Motor and cognitive skills -*Stored:* Striatum (basal ganglia), cerebellum, M1

An *unconscious form of remembering* that is expressed only through the *performance of the specific operations comprising a particular task* (i.e., the performance of newly acquired motor, perceptual, or cognitive skills). *Storage:* basal ganglia (caudate/putamen)

*D-Cycloserine (DCS) and ERP* -Synthesis of medicine and psychotherapy

An antibiotic for tuberculosis that *partially agonizes NDMA receptors* involved in fear-extinction learning, but hasn't been implicated in clinical practice yet. In animal studies, administration of DCS results in *learned fears* being *extinguished more rapidly*. DCS administered 30-60 min before an exposure can facilitate learning (fear extinction) that occurs during an exposure. Preliminary trials show more rapid treatment for specific phobias, social anxiety, and panic disorder, with mixed results for OCD.

*Anxious Cluster (C) Personality Disorders* *Cluster C:* worried 1. *C*owardly: avoidant 2. *C*ompulsive: OCPD 3. *C*lingy: dependent

Anxious or fearful; genetic association with anxiety disorders. *"Worried."* 1. *Avoidant:* hypersensitive to rejection, socially inhibited, timid, feelings of inadequacy, *desires relationships with others* (vs schizoid) but fears shame. (*C*owardly.) 2. *Obsessive-Compuslive:* preoccupation with order, perfectionism, and control; zero flexibility; will not turn in assignments if not perfect; *ego-syntonic*: behavior consistent with one's own beliefs and attitudes (vs OCD); inflexibility in morality, ethics, values. (*C*ompulsive.) 3. *Dependent:* excessive need for support, low self-confidence, cannot make a decision without reassurance. Often get stuck in abusive relationships. (Submissive and *C*lingy.)

Relapse in Recovering Alcoholics

Approximately *60% of patients relapse within 3 months (90 days)*, leaving 40% of patients abstinent. Those that make it past 3 months are generally in the clear, with approximately 35% of total patients remaining abstinent at 1 year.

Bipolar Disorder due to Substance or Medication

Bipolar disorders can be secondary to substances, medications, and illnesses as with depression. *Causes:* -Cocaine, methamphetamine, PCP, bath salts -Steroids, clarithromycin, anti-Parkinson's medications (DA), stimulants (abuse) -Hyperthyroidism, Cushing's disease (↑cortisol), HIV, *R hemisphere stroke/TBI*, epilepsy, MS, frontal AD If an *anti-depressant* is the cause of a manic episode, it is a *true indicator* of BP I or II (unmasked primary mood disorder).

Traumatic Brain Injury

Blows to the head are especially likely to affect the *orbitofrontal poles* of the brain, sometimes causing such a patient to exhibit *behavioral disinhibition and inappropriate actions* (bad angel).

Glutamate Receptors in Learning and Memory

Ca2+ flows into the post-synaptic cell via NDMA receptors, leading to an enhancement of signaling at the synapse by *recruiting more receptors* to the synapse and *stabilizing* them.

Melatonin (↓with age)

Circadian rhythm controls nocturnal release of ACTH, prolactin, melatonin, NE: SCN → NE release → pineal gland → melatonin. SCN is regulated by environment (e.g., light, which suppresses melatonin production)

Limbic System

Collection of neural structures involved in emotion, long-term memory, olfaction, behavior modulation, and autonomic function. *Structures:* 1. Hippocampi 2. Amygdalae 3. Mammillary bodies 4. Anterior thalamic nuclei (relays input from the fornix to the cingulate gyrus as part of the Papez circuit; this plays a role in learning and memory.) 5. Cingulate gyrus (anterior) 6. Entorhinal cortex *Responsible for the 5 Fs:* 1. Feeding 2. Fleeing 3. Fighting 4. Feeling 5. Fornication

*Mother-Infant Duality* (Margaret Mahler)

Different stages of the separation-individuation process (ages 0 - 3 years): 1. *Normal autistic phase (birth - 4 wks)* 2. *Normal symbiotic phase (3-4 wks to 4-5 mos)* 3. *Differentiation (5 - 10 mos):* I'm different than mom 4. *Practicing (10 - 16 mos):* know that I'm different and doing different things, but staying around 5. *Rapprochement (16 - 24 mos):* mother goes to bathroom, but child knows that she'll return 6. *Consolidation and object constancy* (24 - 36 mos)

Manic Episode (7 days)

Distinct period of *abnormal and persistently elevated*, expansive, or irritable *mood* or *energy* lasting *≥ 1 week* (7 days). Often disturbing to patient and causes marked functional impairment and oftentimes hospitalization. Diagnosis requires hospitalization or *at least 3* of the following (*manics DIG FAST*): 1. *D*istractibility 2. *I*mpulsivity/*I*ndiscretion: seeks pleasure without regard to consequences (hedonistic) 3. *G*randiosity: inflated self-esteem 4. *F*light of ideas: racing thoughts 5. ↑goal-directed *A*ctivity/psychomotor *A*gitation 6. ↓need for *S*leep (vegetative activation) 7. *T*alkativeness or pressured speech (and clang associations/rhyming)

Hypomanic Episode (4 days)

Distinct period of abnormally and persistently elevated, expansive, or irritable mood AND persistently increased goal-directed activity or energy. Similar to a manic episode except *mood disturbance is not severe enough to cause marked impairment in social and/or occupational functioning or to necessitate hospitalization*. No psychotic features. *Lasts ≥ 4 consecutive days*

*Dramatic Cluster (B) Personality Disorders* *Cluster B:* wild 1. *B*ad: antisocial (sociopath) 2. *B*orderline: BPD 3. Flam*B*oyant: histrionic 4. *B*est: narcissistic

Dramatic, emotional, or erratic; genetic association with mood disorders and substance abuse. *"Wild."* 1. *Antisocial:* disregard for and violation of rights of others without remorse, criminality, impulsivity; males > females; must be ≥ 18 years old and have history of conduct disorder before age 15. *Conduct disorder if < 18 years old.* Frontal cortex and amygdala are out of balance. (*Bad.*) 2. *Borderline:* unstable mood and interpersonal relationships, impulsivity, self-mutilation, suicidality, sense of emptiness; females > males; splitting is a major defense mechanism. -*Treatment:* dialectical behavior therapy (DBT) 3. *Histrionic:* excessive emotionality and excitability, *attention seeking* (need to be center of attention), sexually provocative, overly concerned with appearance. (Flam*B*oyant.) 4. *Narcissistic:* grandiosity (unrealistic sense of superiority), sense of entitlement; lacks empathy and requires excessive admiration; often demands the "best" and reacts to criticism with rage; tends to be functional (MD/JD/MBA); narcissism used to cover up deep self-esteem issues. (Must be the *B*est.)

*Pick's Disease and Fronto-Temporal Dementias (FTD)* -Neurodegenerative Disease

Early changes in *personality and behavior* (behavioral variant), or *aphasia* (primary progressive aphasia). Memory may be relatively spared. *Onset:* presents in middle to later life (men > women) with rapid progression *Pathology:* 1. *"Knife-blade" atrophy* of the frontotemporal regions of the brain (picket-fence on CT/MRI) 2. Spherical argyrophillic intracellular inclusions (*Pick bodies*) = tau 3. *Ubiquitinated TDP-43* 4. *Atrophy of frontal lobes* (reminder that AD is more diffuse) 5. Posterior 1/3 of superior temporal gyrus is usually spared (memory) 6. *"Balloon" cells* *Clinical Presentation:* early deficits in personality (due to FTD), while higher cognition often remains intact

Importance of Early Childhood

Early childhood is a *sensitive, not critical* time in a child's life when experiences directly mold neuronal circuits (brain architecture) and influence that child's developmental trajectory - their life course. 1. Language acquisition (due to parental words/hr): 30 million word gap by elementary school 2. Parent *non-business talkativeness* (i.e., extra chit chat, praise, restatements, active listening, reciprocal) (*not SES or race*) predicted IQ and vocabulary 3. *Maternal support* in early childhood predicts *larger hippocampal volumes* at school age (even if the child was depressed vs. not depressed) 4. Early childhood stimulation benefits adult competence and reduces violent behavior 5. Household routines play a big part in health: 4 yo with <2 hr/day TV, family dinner >5x/week, sleep >10.5 hr/night → 40% less likely to be obese 6. *It takes less time, intensity, and repetition to organize developing neural systems* than to reorganize the developed neural systems

*Oppositional Defiant Disorder (ODD)*

Enduring pattern of hostile, defiant behavior toward authority figures in the absence of serious violations of social norms (refuses to follow rules). *Symptoms:* 1. Angry, irritable mood 2. Argumentative, defiant behavior 3. Vindictiveness *Treatment:* psychotherapy such as CBT. -Medication can be used to treat co-morbidities (ADHD, anxiety, irritability)

*Major Depressive Disorder (MDD)* -Primary depressive disorder -*Mood congruent* -*Catatonia*

Episodes characterized by *at least 5* of the 9 diagnostic (SIG E CAPS) symptoms lasting *≥ 2 weeks* (symptoms must include *depressed mood or anhedonia*). Screen for history of manic episodes to rule out bipolar disorder. *Treatment:* 1. CBT and SSRIs are first line. 2. SNRIs, mirtazapine (used for sleep and weight gain in elderly patients), bupropion (NDRI) can also be considered. 3. Electroconvulsive therapy (ECT) in treatment-resistant patients. Patients with depression typically have the *changes in their sleep stages:* 1. ↓slow-wave (restful) sleep 2. ↓REM latency 3. ↑REM early in sleep cycle 4. ↑total REM sleep 5. Repeated nighttime awakenings 6. Early-morning awakening (terminal insomnia) *MDD with Seasonal Pattern:* formerly SAD. Lasting *≥ 2 years* with *≥ 2 major depressive episodes* associated with *seasonal pattern* (usually winter) and absence of nonseasonal depressive episodes. Atypical symptoms common (e.g., hypersomnia, hyperphagia, leaden paralysis).

Harm Reduction vs. Abstinence

Evidence suggests that for alcohol, *both abstinence and reduced alcohol consumption during treatment are effective outcomes* and each predicts ↓drinking and ↓alcohol problems more than a year after treatment ends.

Frontotemporal Dementia (FTD) on MRI

FTD largely affects the frontal lobes (wider sulci, smaller gyri). AD largely affects the hippocampus (medial temporal lobe).

*Developmental Milestones* -Look at First Aid (pg. 616) *Infancy:* motor *Toddlers:* language, socialization, cognitive development

Failure to attain these milestones by critical time suggests potential life-long problems including moderate to severe intellectual disability, genetic anomalies, significant deprivation, sensory deficits, Cerebral Palsy, and other severe acquired or inherited disabilities *Milestones to Be Reached:* infancy 1. *Newborn:* symmetric tone and movements 2. *2 mo:* regards face/object attentively, peak crying 3. *4 mo:* good head control in sitting, coos responsively (vowels) 4. *6 mo:* reaches with raking grasp (both hands) 5. *9 mo:* sits well alone, waves bye-bye (imitation) 6. *1 year:* takes a few steps, jabbers, points to indicate wants 7. *15 mo:* walks well, stands alone, Mama/Dada, plays ball Failure to attain milestones by critical times suggests mild to moderate intellectual disability, autistic spectrum disorders (PDD), and behavioral and language disorders *Milestones to Be Reached:* toddler 1. *18 mo:* walks well *independently*, points to desired object, 6 words (+ Mama/Dada) 2. *2 years:* combines 2 words, kicks ball, jumps 3. *3 years:* speech is >50% intelligible, knows simple adjectives (cold, tired) 4. *4 years:* asks questions (why? when? how?), speech is fully intelligible 5. *5 years:* able to separate from parents for several hours at a time (school readiness)

Freudian Drives

Freud's structural model explains people's impulses and the actions they take. 1. *Id* is the part of a person's personality that drives what you want to do; it consists of *hedonistic*, impulsive urges such as seeking food and sex. 2. *Superego* is like the angel that sits on your other shoulder, opposite the devilish id; it contains one's *morals* and what you should do. 3. *Ego* is the *mediator* between the two, the source of a person's balance that determines the difference between right and wrong and what you want to do and what you should do. According to Freud's psychoanalytic theory, the ego has ways to cope with life's stressors unconsciously. Some of these ego defenses are mature and more sophisticated, whereas others are immature and more primitive.

*Frontal Lobe Amnesia* -*Affected:* central executive (frontal lobe) -*Type of Memory Impaired:* working -*Amnesia:* mild anterograde

Frontal lobe lesions lead to *perseverative* (repeating) and* intrusion errors* (wrong memories). *Impaired central executive system:* 1. Impaired coding and retrieval 2. Impaired temporal order judgments 3. Impaired source judgments 4. Impaired metamemory judgments (feeling-of-knowing) 5. *Intact semantic memory:* intact fund of knowledge (temporo-parietal association cortex) 6. *Intact procedural memory:* intact skill learning (basal ganglia)

GABA Synthesis -Location: nucleus accumbens

Glutamate → GABA via *glutamic acid decarboxylase* (GAD). As shown in the image, GABA can bind to *inhibitory (Cl-)* or excitatory (Na+) ionotropic receptors.

Brain Development (Synaptogenesis)

Highest density & number of synapses are at 1 year of age (i.e., those synapses that are not used are pruned). 1. *Visual areas* (peak at 4 mo → decline until preschool) -If newborn has blocked vision (e.g., congenital cataract or ptosis), it must be repaired within a few months. If not, the child will never have normal binocular vision due to altered connections. 2. *Prefrontal cortex* (peak at 1 year → decline stabilizes in adolescence or early adulthood) *Synapses:* 1. At birth: 50 trillion 2. At 1 year: 1000 trillion *Pruning:* 3. At age 20: 500 trillion

Metabolic Homeostasis

In an encephalopathy, the brain loses function in a "global" manner, through *impaired cellular and homeostatic mechanisms in bilateral cerebral hemispheres and brainstem*. Normal CNS function depends on homeostatic mechanisms for regulating circulating electrolytes, blood sugar, oxygen, hormones, as well as renal and hepatic mechanisms for detoxifying toxic products of metabolism such as ammonia. Small changes in metabolic parameters do not usually produce clinical symptoms, but in a "sensitive brain," smaller variations are enough to cause dysfunction. Wide variations up or down can cause behavior change, incoordination, ataxia, confusion, seizures, stupor, and coma in a dose-related fashion, as seen with alcohol. There may be a lag in recovery of CNS symptoms after the metabolic problem is corrected. Therefore, the major causes of encephalopathy would be anything that alters these homeostatic mechanisms or factors.

Neurotypical vs. PTSD

In neurotypical brains, the mPFC (pre-frontal cortex) and the amygdala reciprocally inhibit one another. *Functions:* 1. *mPFC:* short-term memory and decision making (location, context, adaptive response, retrieval) 2. *Amygdala:* integral to the limbic system, emotions, fear/aversion and reward, memory (usually wins; more primitive) In patients with PTSD, this reciprocal inhibition is disrupted. The *fear version (amygdala) wins.* *Normal Response to stress:* Limbic System Activation 1. Raise HR 2. Increase startle reflex 3. Engage hyper-arousal 4. Secrete cortisol 5. Suppress medial pre-frontal cortex ("we're leaving!") 6. Threat Averted 7. Feedback to the HPA 8. Inhibition of HPA 9. mPFC back online

Lateral hypothalamus responsible for...

Initiation of feeding (feeding center)

*Classical Conditioning* -Usually deals with involuntary responses

Learning in which a natural response (salivation) is elicited by a conditioned, or learned, stimulus (bell) that previously was presented in conjunction with an unconditioned stimulus (food). *Example:* Pavlov's classical experiments with dogs: ringing the bell provoked salivation.

*Operant Conditioning* -Usually deals with voluntary responses

Learning in which a particular action is elicited because it produces a punishment or reward. *Three Types:* 1. *Reinforcement:* target behavior (response) is followed by desired reward (positive reinforcement) or removal of aversive stimulus (negative reinforcement). 2. *Extinction:* discontinuation of reinforcement (positive or negative) eventually eliminates behavior. Can occur in operant or classical conditioning. 3. *Punishment:* repeated application of aversive stimulus (positive punishment) or removal of desired reward (negative punishment) to extinguish unwanted behavior. *Negative:* avoid or escape situation that reminds you of traumatic event

*Lewy Body Dementia* -Neurodegenerative Disease -25% of dementia cases -*Cortical* Lewy bodies -*Visuospatial* findings (executive function; can't draw clock)

Lewy body dementia requires that *cognitive and motor symptom (parkinsonism) onset is < 1 year apart*, otherwise LBD is considered dementia 2° to Parkinson disease. If Parkinsonism appears first and motor symptoms are more severe than cognitive impairment, Parkinson's-associated dementia is usually diagnosed. *Clinical Manifestations:* 2 of 3 bold for Dx 1. *Visual hallucinations* ("ha*Lewy*cinations") 2. *Fluctuating cognition* (visuospatial and visuoconstructional) 3. *Parkinsonism* 4. Fluctuations in alertness 5. REM sleep behavior disorder (acting out dreams; eyes and muscles both active without normal paralysis) 6. Complex, bizarre delusions (50-60%) 7. Memory impairment is mainly from deficits in alertness/attention than from deficits in memory acquisition 8. Falls due to syncope (autonomic dysregulation) *Pathology:* Lewy bodies (eosinophilic intracytoplasmic neuronal inclusions of α-synuclein) primarily in *cortex* *Treatment:* 1. *AChE inhibitors* for dementia (e.g., rivastigmine) 2. Dopaminergic drugs (*L-Dopa*) for parkinsonism 3. *AVOID antipsychotics* which can lead to severe EPS (even worse parkinsonism) 4. Clonazepam (benzo) for sleep episodes

*Thalamo-Cortical Connections*

MD → dorsolateral, ACC, orbital prefrontal VA → premotor VL → motor VPL/VPM → sensory

*Cognitive Behavioral Therapy (CBT)* -Focuses on distortions in thoughts, emotions, and behaviors and approaches them with facts to help eliminate them to decrease depressive or anxious symptoms

Mainstream CBT assumes that changing maladaptive thinking leads to change in behavior and affect, but recent variants emphasize changes in one's relationship to maladaptive thinking rather than changes in thinking itself. The goal of cognitive behavioral therapy is not to diagnose a person with a particular disease, but to look at the person as a whole and decide what needs to be fixed. The basic steps in a cognitive-behavioral assessment include: *Step 1:* Identify critical behaviors *Step 2:* Determine whether critical behaviors are excesses or deficits *Step 3:* Evaluate critical behaviors for frequency, duration, or intensity (obtain a baseline) *Step 4:* If excess, attempt to decrease frequency, duration, or intensity of behaviors; if deficits, attempt to increase behaviors. *Critical Behaviors = Cognitive Distortions:* 1. *All or Nothing Thinking:* using absolute terms like always, every, or never 2. *Overgeneralization:* taking isolated cases and using them to make wide generalizations 3. *Disqualifying the Positive:* shooting down positive experiences 4. *Catastrophizing:* extrapolating to unlikely negative outcomes 5. *Emotional Reasoning:* if you feel inadequate, you are inadequate (imposter syndrome)

*Mixed Monoamine Re-uptake Inhibitors (MARIs)* 1. Inhibit NE/DA re-uptake (Bupropion) 2. Inhibit NE/5-HT re-uptake (Venlafaxine/Duloxetine) *Trade Names:* 1. Bupropion = Wellbutrin (NDRI) 2. Venlafaxine = Effexor (SNRI) 3. Duloxetine = Cymblata (SNRI)

Mixed monoamine reuptake inhibitors are either norepinephrine/dopamine reuptake inhibitors or norepinephrine/serotonin reuptake inhibitors. 1. *Bupropion* (Wellbutrin) is a weak *NE/DA* reuptake inhibitor (NDRI) -*Fewer sexual and GI side effects*; efficacy similar to SSRIs, and effective in *smoking cessation* -May cause stimulant effects (tachycardia, insomnia), asthenia, nausea, *increased seizures* (contraindicated in bulimia), and has a high potential for drug/drug interactions -*Treats:* general anxiety disorder (GAD) 2. *Venlafaxine* (Effexor) is a *5-HT* reuptake inhibitor that also acts on *NE* at high doses (SNRI) -May have higher remission rates -Can cause nausea, sweating, orgasmic dysfunction, hypertension, insomnia, tachycardia, tremor, or discontinuation syndrome (flu-like symptoms and disturbances in sleep, mood, and thinking following cessation of SSRI or SNRIs) -Requires dose titration and can be expensive -*Treats:* social anxiety disorder, panic disorder, PTSD, OCD. 3. *Duloxetine* (Cymbalta) is a *5-HT and NE* reuptake inhibitor (SNRI) -Has higher remission rates, is effective in some pain syndromes (*neuropathic*), and does not increase blood pressure -Can cause stimulant effects (tachycardia, insomnia), asthenia, nausea, and urinary retention -*Treats:* fibromyalgia, neuropathic pain

*Monoamine Oxidase Inhibitors (MAOIs)* -*Lethal with opioids*, so often avoided

Monoamine oxidase inhibitors (MAOIs) *impact mitochondrial enzymes responsible for breaking down neurotransmitters (NE/5-HT/DA) within the presynaptic cell*, allowing more release. *Action:* irreversibly inhibit MAO-A and MAO-B -Classified either as hydrazines or non-hydrazines -Useful in patients with *atypical depression* -Involves a diet restrictive in monoamines -Can cause orthostatic hypotension, weight gain, and sexual dysfunction -*Potentially lethal interactions with opiates*, SSRIs, sympathomimetics, and linezolid

*Monoamine Receptor Antagonists* (Atypical Antidepressants) 1. *Trazodone:* insomnia 2. *Mirtazapine:* weight gain and sleep in the elderly 3. *Varenicline:* smoking cessation

Monoamine receptor antagonists either act on serotonin or norepinephrine. 1. *Trazodone* (Desyrel) is a 5-HT2, α1-adrenergic, and H1 receptor antagonist -*Used for insomnia* vs SSRIs (high doses needed for anti-depressant action), *no anti-cholinergeic side effects*, fewer sexual side effects, and is fairly safe in overdose -Can cause sedation (sleepy/drowsy), dizziness, hypotension, priapism (persistent and painful erection of the penis), and cardiac dysrhythmia, and requires slow dose titration -Called tra*ZZZ*o*bone* due to *sedative* and *male-specific side effects*. 2. *Mirtazapine* is an α2-antagonist (↓release of NE and 5-HT), potent 5-HT2 and 5-HT3 receptor antagonist, and H1 antagonist. -Has a unique pharmacology with an easier dosing strategy, lower rates or orgasmic dysfunction, and can be combined with SSRIs -Can cause *somnolence or weight gain*, which makes mirtazapine *desirable for use in the elderly* 3. *Varenicline (Chantix):* Nicotinic ACh receptor partial agonist (helps *ni*cotine cravings de*cline*) -Used for *smoking cessation*. -*Toxicity:* sleep disturbance, may depress mood.

*Moral Development* (Kohlberg, Gilligan)

Moral reasoning (basis for ethical behavior) has six distinct stages of moral development (not linked to specific ages). *Progression to higher stages occurs when new ideas and moral conflicts highlight limitations of current stage* *Preconventional:* obedience to parents 1. How to avoid punishment 2. What's in it for me? *Conventional:* treat others how you want to be treated 3. Social norm conformity 4. Follow law and order *Post-Conventional:* follow moral principles 5. Social contract: consider the greater good 6. Universal ethical principles: follow laws grounded in justice and disobey unjust ones "Heinz's Dilemma" Scenario (steal cancer drug to save dying wife?) used to elicit responses that demonstrated how a person's thought process led to determining what was right or wrong.

*Odd Cluster (A) Personality Disorders* *Cluster A:* weird 1. *A*ccusatory: paranoid 2. *A*loof: schizoid 3. *A*wkward: schizotypal

Odd or eccentric; inability to develop meaningful social relationships. No psychosis; genetic association with schizophrenia. *"Weird."* 1. *Paranoid:* pervasive distrust (*A*ccusatory) and suspiciousness of others and a profoundly cynical view of the world. Concerned about partner's fidelity and interprets others' motives as malevolent. 2. *Schizoid:* voluntary social withdrawal (*A*loof), limited emotional expression, content with social isolation (vs avoidant). Similar to autism, but *without perseverations or fixations*. 3. *Schizotypal:* eccentric appearance, odd beliefs or magical thinking (clairvoyance, superstitions), ideas of reference (innocuous events have a more personal significance), interpersonal *A*wkwardness. Pronounce schiz*o-type*-al: *odd-type thoughts*.

Psychodynamic Psychotherapy

One on one talk therapy focusing on patterns, relationships, and interactions with the world. The therapist is meant to be blank objective slate to observe patterns while developing a relationship. *Psychiatric Disorder Treatment:* *Mild-Moderate:* psychotherapy *Severe:* psychotherapy and medication

*Semantic Memory* -Facts and general knowledge -Lateral/anterior temporal cortex, prefrontal cortex -*Stored:* temporo-parietal association cortex

One's fund of general knowledge that is not dependent upon contextual cues for its retrieval (e.g., knowing that a cat is an animal with four legs). Specific information can be retrieved without recalling the particular episode in which that information was acquired. *Storage:* Semantic memory is most likely stored in the *temporo-parietal association cortex* as a network of inter-related categories, concepts, and attributes. Semantic memory has been proposed to exist as a representation of knowledge based on an organized network of inter-related categories (*associations*), concepts, and attributes.

*Attention-Deficit/Hyperactivity Disorder (ADHD)* -Neurodevelopmental disorder

Onset before age 12 (DSM-V). *At least 6 months of limited attention span and/or poor impulse control.* *Clinical Presentation:* 1. *Hyperactivity:* restlessness, often characterized by an inability to sit still, fidgeting, squirminess, climbing on things, restless sleep 2. *Impulsivity:* acting before thinking of consequences, jumping from one activity to another, disorganization, tendency to interrupt during conversations 3. *Inattention in multiple (2+) settings* (school, home, places of worship, etc): easily distracted, zoning out, not finishing work, difficulty listening 4. Normal intelligence, but commonly coexists with difficulties in school (often persists into adulthood) *Treatment:* 1. *Stimulants:* used for inattention - Methylphenidate (Ritalin) ± CBT 2. Alternatives: hyperactivity - Guanfacine and *Clonidine* (α2 agonists: sedatives) - Atomoxetine (serotinergic)

Control of Feeding

Over the long haul, body weight is controlling feeding and not vice-versa. Body weight seems to tell the brain how to regulate feeding, returning us to a "desired" body weight upon fluctuations.

Brain Circuitry in OCD

Over-synchronization of the *fronto-striato-thalamo-frontal* circuit. Neuroimaging shows abnormalities in OFC (orbitofrontal)/ACC (anterior cingulate cortex)-basal ganglia-thalamic circuitry that is central to pathphysiology and response to treatment. *Findings:* 1. Heightened activity in OFC and caudate nuclei (PET) 2. Lateral OFC hyperactivity prior to treatment predicts response to SSRIs (less hyperactivity, better response) 3. Lateral and medial OFC are dysfunctional in OCD and play different roles 4. *Dorsal anterior cingulate cortex (dACC) has been implicated in processing both the detection and appraisal of social processes, including social exclusion.* 5. OCD ↓dACC gray matter volume in patients 6.* dACC lesions (anterior cingulotomy) can significantly reduce OCD symptoms in patients with severe, treatment-refractory illness* 7. Successful treatment of OCD with SSRIs ↓ACC metabolism *OCD Treatment:* CBT, SSRIs, venlafaxine, and clomipramine are first line.

*Luria's Alternating Figures Test* (dorsolateral testing) -Perseveration -Impersistence -Cannot generate appropriate response

Patients are asked to copy a sequence of alternating +'s and 0's and then to continue the pattern across the page (top image). *Dorsolateral Dysfunction:* Patients persist in drawing only +'s or only 0's (*perseveration*), or they may change the task entirely and begin drawing x's (exhibiting *impersistence* in completion of the appropriate task; *regresses to habitual response*). The drawing of different patterns of peaks and valleys can also be used.

*Figural Fluency Tasks* (dorsolateral testing) -Perseveration

Patients are asked to draw as many different shapes as possible within a limited time period. *Dorsolateral Dysfunction:* Patients might get "stuck" on one shape and continue to draw either the same figure or something very similar (*perseveration*). The patient has difficulty generating multiple response alternatives.

*Copy/Free Recall Test* (dorsolateral testing)

Patients are presented with a figure that is first to be copied (left) and then later to be drawn from recall (right). *Dorsolateral Dysfunction:* Patients drawing from recall will remember to draw certain details of the figure without regard for the general shape and organization of the figure as a whole. *This deficit reflects poor organization of learning and recall in these patients.*

*Visual Organization Test* (dorsolateral testing)

Patients are presented with pictures of common objects that have been cut apart and rearranged on the page like a puzzle. *Dorsolateral Dysfunction:* A patient will not be able to "piece" back together the cut-apart object, instead focusing on a single aspect of one of the shapes on the page. *Difficulties in integration of sensory information are especially apparent.*

*Socio-Emotional Development* -Pyschosocial Stages (Erikson) *Early Childhood:* 1. Trust vs. Mistrust (birth to 1 yo) 2. Autonomy vs. Shame & Doubt (1 to 3 yo) 3. Initiative vs. Guilt (3 to 5 yo) *Middle Childhood-Adolescence:* 4. Industry vs. Inferiority (5 to 11 yo) 5. Ego Identity vs. Role Diffusion (11 to 21 yo) *Adulthood:* 6. Intimacy vs. Isolation (21 to 40 yo) 7. Generativity vs. Stagnation (40 to 60 yo) 8. Ego Integrity vs. Despair (60 yo+)

People move through eight stages across the lifespan, with each stage representing a conflict (between a healthy vs. unhealthy outcome). Development (movement to the next stage) depends on the resolution of each conflict. Under extreme stress, people might even regress back to a previous stage. (Regression: *involuntarily* turning back the maturational clock and going back to earlier modes of dealing with the world) *Focus on the ego (rather than id):* 1. *Trust vs. Mistrust (birth to 1 year):* Infants depend on caregivers to meet their basic needs. *If needs are met consistently and responsively, infants will learn to trust their environment* and the people in it. If not, infant may view the world as dangerous and unreliable. 2. *Autonomy vs. Shame/Doubt (1-3 years):* Toddlers learn to *explore and do things for themselves*. Their self-control, self-confidence, and independence begin to develop at this stage, (e.g. standing alone, feeding themselves, development of language - esp. "me", "mine", "no"). Warmth and reassurance from caregivers despite mistakes will help foster autonomy, while rigid and critical parenting leads to feeling ashamed and doubtful of one's choices. 3. *Initiative vs. Guilt (3-5 years):* Preschoolers are *eager to engage in adventure and play*, while learning to control their impulsive behavior. Success leads to feeling capable and able to lead, while failure leads to paralyzing guilt and lack of initiative. 4. *Competence/Industry vs. Inferiority (5-11 years):* School-age children learn to master basic social and academic skills. Now, in addition to parents, teachers and peers play a major role in their development (support). *Children begin to compare themselves with peers* and their perception of how they measure up may impact their self esteem by making them feel either industrious or inferior. 5. *Ego Identity vs. Role Confusion (11-21 years):* As adolescents strive for independence from parents and family, they are faced with the challenge of identity: *Who am I?* What is my purpose? They tend to identify with groups, cliques and crowds until they develop their own sense of self and become comfortable with that. 6. *Intimacy vs. Isolation (21-40 years):* Young adults develop close, *committed relationships* that pave the way for intimate relationships. Less stable relationships may result in loneliness and isolation. 7. *Generativity vs. Stagnation (40-65 years):* At this age, the focus is on caring for others both within the family and at work. *Success* leads to a sense of contribution, while *failure* leads to feeling unproductive. 8. *Ego Integrity vs. Despair (65 and above):* During this stage, people *reflect back on their accomplishments and challenges*. Perceived success leads to a sense of fulfillment and satisfaction, while perceived failure may lead to regret and despair.

*Negative Symptoms of Psychosis* -Less effective treatments -*↓meso-cortical* (can't plan)

Positive *and* negative symptoms are seen in *primary* psychotic disorders (schizophrenia). *Negative Symptom Deficits:* 5 A's 1. *A*logia (poverty of speech) 2. *A*pathy (anhedonia) 3. *A*volition (↓initiative) 4. *A*ffective flattening 5. *A*sociality (withdrawal)

*Serotonin Syndrome* *Manifestation:* 3 A's (hyper everything) 1. *Activity* (neuromuscular hyperactivity) 2. *Autonomic stimulation* (hypertensive) 3. *Agitation*

Psychiatric emergency due to *too much serotonin*. *Cause:* Any drug that ↑5-HT. 1. *Psychiatric drugs:* MAOIs, SSRIs, SNRIs, TCAs, vilazodone, vortioxetine 2. *Nonpsychiatric drugs:* tramadol, ondansetron, triptans, linezolid, MDMA, dextromethorphan (Dayquil), meperidine, St. John's wort Symptoms of *neuromuscular hyperactivity* include clonus, hyperreflexia, hypertonia, tremor, seizure Symptoms of *autonomic stimulation* include hyperthermia, diaphoresis, diarrhea, tachycardia, mydriasis *Treatment:* 1. STOP serotonin medications (SSRIs and sumatriptan) 2. Cyproheptadine (5-HT2 receptor antagonist on post-synaptic membrane)

*Panic Disorder* (no trigger) (onset in late adolescence and early adulthood)

Recurrent unexpected *panic attacks without a known trigger* (not cued). Periods of intense fear and discomfort peak in 10 minutes with *at least 4* of the following: *PANICS:* systemic manifestations of fear 1. *P*alpitations, *P*aresthesias, de*P*ersonalization or derealization 2. *A*bdominal distress 3. *N*ausea 4. *I*ntense fear of dying, *I*ntense fear of losing control or "going crazy," l*I*ght-headedness 5. *C*hest pain, *C*hills, *C*hoking 6. *S*weating, *S*haking, *S*hortness of breath Strong *genetic* component. *↑risk of suicide.* *Diagnosis* requires attack followed by *≥ 1 month of ≥ 1 of the following*: 1. Persistent concern of additional attacks 2. Worrying about consequences of attack 3. Behavioral change related to attacks *Treatment:* 1. CBT, SSRIs, and venlafaxine are first line. 2. Benzodiazepines occasionally used in acute setting.

*Declarative Memory* (Explicit Memory) -Knowing that...

Refers to *knowledge of episodes and facts* that can be consciously recalled and related (i.e., declared) by the rememberer (includes memory for the words on a recently presented list and knowledge that a cat is an animal). *Two Types:* 1. Episodic 2. Semantic

Binge Eating Disorder (BED)

Regular episodes of excessive, uncontrollable eating *without inappropriate compensatory behaviors*. *Clinical Presentation:* 1. Patients are usually overweight (40% obese) 2. Present in 30% of patients seeking obesity treatment 3. *↑ risk of diabetes* *Treatment:* 1. Psychotherapy such as CBT is first line 2. SSRIs and topiramate 3. *Lisdexamfetamine* (Vyvanse): a stimulant that acts on DA in the ventral hedonistic system; does not help weight loss

*Conduct Disorder (before age 18)* -After age 18 → antisocial personality disorder

Repetitive and pervasive behavior violating the basic rights of others or societal norms (e.g., aggression to people and animals, destruction of property, theft). *Lack of empathy.* Callous and unemotional traits. *After age 18, often reclassified as antisocial personality disorder.* *Treatment for both:* psychotherapy such as CBT. -Medication can be used to treat co-morbidities (ADHD, anxiety, irritability)

Ventromedial hypothalamus responsible for....

Satiety (high leptin receptors)

*Selective serotonin reuptake inhibitors (SSRIs)* 1. Down-regulation of pre-synpatic 5-HTR 2. Inhibition of 5-HT re-uptake transporter

Selective serotonin reuptake inhibitors (SSRIs). *Mechanism:* block serotonin reuptake at pre-synaptic membrane *Common SSRIs:* 1. Fluoxetine (Prozac) 2. Sertraline (Zoloft) 3. Paroxetine (Paxil) 4. Fluvoxamine (Luvox) 5. Citalopram (Celexa) 6. Escitalopram (Lexapro) 7. Vilazodone (Viibryd) 8. Vortioxetine (Trintellix) *Action:* 1. Very effective (60-70%) with broad comorbidity coverage (e.g., anxiety); safer in overdose 2. *Commonly cause nausea and headaches, decreased libido, weight gain, abnormal bleeding.* 3. Interacts with tryptophan, MAOIs, and fenfluramine (appetite suppressant)

*Temperament* (Thomas and Chess)

Set of attributes/behavioral dimensions that compile an underlying character structure *Most people (65%) fall under these three categories:* 1. *Easy (40%):* even-tempered, positive mood, open and adaptable to new experiences 2. *Difficult (10%):* active, irritable, irregular in habits, strong reaction to change in routine 3. *Slow-to-Warm-up (15%):* moody, slow to adapt to new people/situations *Goodness-of-Fit:* children to parent match

*Disruptive Mood Dysregulation Disorder* (DMDD) -Mood disorder (not bipolar disorder)

Severe and recurrent temper outbursts out of proportion to situation (≥3/week) (reaction is bigger than you'd expect for something minor). Child is constantly angry and irritable between outbursts. Onset before age 10 (symptoms must persist for at least 1 year). Treatment: stimulants, antipsychotics, CBT.

Diagnosis of Mood Disorders

The DSM characterizes *cross sectional mood episodes* (depression, mania, and hypomania), *syndromes* as clusters of these signs and symptoms, and *disorders* according to *longitudinal course and causes* of these syndromes (primary psych, secondary medical/neurologic).

*Frontal-Subcortical Connections*

The frontal cortex has connections to subcortical structures such as the thalamus and basal ganglia that function in *regulation of behavior*. In a very general sense, the frontal:subcortical:frontal circuits may be thought of a *"filter" that serves to modulate the output of the frontal cortices to regions of the brain involved in motor control of behavior.* Small subcortical lesions that affect any one of these circuits can mimic large cortical lesions.

Depression Neurobiological Mechanism

The neurotransmitter abnormalities in depression are less clear than those in schizophrenia. For this reason, drugs that increase signaling in these pathways tend to improve patients' symptoms. *Association:* 1. ↓5-HT 2. ↓NE 3. ↓DA

Perinatal and Developmental History Importance

The perinatal history is useful for identifying *potential complications during pregnancy, labor, and delivery that may have contributed to the delay*. An important clinical score that assesses the overall health of a *newborn* immediately following birth is the *Apgar score* (appearance, pulse, grimace, activity, respiration). The *developmental history focuses on assessment of motor, cognitive, and social milestones.* Pediatricians will often use the *Denver Developmental Screen* to gage whether or not a child is developing appropriately and meeting these milestones. This screen *does not cover asymmetry,* so a child presenting with a focal stroke who is weak on one side could be missed.

*Antipsychotic Effects on Nigrostriatal System* -↑EPS (motor findings) -*Cause:* *ACh > DA* in basal ganglia

Typical antipsychotics also block D2 receptors in the striatum. This leads to a risk of developing *parkinsonism and other EPS* (extra-pyramidal symptoms). *Symptoms:* *ACh > DA* in basal ganglia (ADAPT) 1. *A*cute *D*ystonia (continuous spasms and muscle contractions) 2. *A*kathisia (motor restlessness) → treat with β-blockers or benzos 3. *P*arkinsonism (characteristic symptoms such as rigidity) 4. *T*ardive dyskinesia (irregular, jerky movements such as tongue darting out of the corner of the mouth or lip smacking) 5. Bradykinesia (slowness of movement) 6. Tremor

*Positive Symptoms of Psychosis* -Easier to treat -*↑meso-limbic*

Typically associated with *secondary* psychotic syndromes (e.g., due to substance abuse). *Presence of:* 1. Hallucinations 2. Delusions 3. Disorganized thoughts and behavior

Norepinephrine (NE)

Tyrosine→Dopa→*Dopamine→NE*→E. *Enzyme 1:* tyrosine dehydrogenase (*RLS*) *Enzyme 2:* L-aromatic AA decarboxylase *Enzyme 3:* dopamine β-hydroxylase *Enzyme 4:* PNMT *Location:* NE cell bodies in the locus ceruleus (pons) sends axons to: 1. Cerebral cortex 2. Limbic system 3. Thalamus 4. Hypothalamus *Termination:* 1. Re-uptake 2. Metabolism by MAO-A and COMT Note: 1. MAO: mono-amine oxidase 2. COMT: catechol-O-methyl transferase (degrades NE, E, and dopamine)

*Epinephrine (E)* E=adrenaline

Tyrosine→Dopa→Dopamine→*NE→E*. *Enzyme 1:* tyrosine dehydrogenase (*RLS*) *Enzyme 2:* L-aromatic AA decarboxylase *Enzyme 3:* dopamine β-hydroxylase *Enzyme 4:* PNMT (phenylethanolamine N-methyltransferase) *Function:* 1. *Fight-or-Flight* (↓saliva, pupils dilate, skin blood vessels constrict, ↑heart rate, ↑breathing, ↓stomach digestive enzymes, *↑BP as major vessels dilate*) 2. NOT psychoactive

*Vascular Dementia* -Neurodegenerative Disease -10-30% of dementia cases

Vascular dementia *patients tend to be younger* than those with neurodegenerative conditions. *Patterns:* 1. *Classic Multi-Infarct Dementia:* -Multiple major cerebral infarcts in the ACA, MCA, or PCA territories. 2. *Strategic Infarct Dementia:* -Single infarct in an area of the brain crucial to memory function (e.g., angular gyrus, thalamus) 3. *Lacunar States:* -Accumulation of multiple small infarcts in the subcortical nuclei and white matter. *Classic Presentation:* (not strategic infarct) 1. *Stepwise cognitive decline*, each step driven by an ischemic insult and sometimes followed by partial cognitive recovery. 2. *Lacunar state or ischemic injury:* steps may be so small that they are clinically indistinguishable and appear gradual. 3. *Late-onset memory impairment* 4. *Visuospatial* deficits are common 5. Patients tend to be *more aware of their deficits* than patients with AD, and the *prevalence of depression may be higher*. 6. Death tends to occur earlier than in AD because patients often have diffuse vascular disorders that affect other organs and tissues (e.g., aorta, coronary arteries, peripheral arteries). *Risk Factors:* 1. Common in patients with transient ischemic attacks (TIAs) or strokes 2. Hypertension 3. Diabetes 4. Stroke risk factors (CAD, PAD, valvular heart disease, AFib, hyperlipidemia, smoker) *Imaging:* MRI or CT shows multiple cortical and/or subcortical infarcts. Periventricular and white-matter abnormalities are also common. *Diagnosis:* 1. Clinical history (abrupt or *gradual onset*; family history) 2. *Focal* neurologic findings 3. Evidence of *strokes* (lacunar or larger) on CT/MRI *Treatment:* Stroke prevention (↓BP, ↓ lipids, ↓weight, healthy diet)

Frontal Lobe Function in Drug Abusers

fMRI shows drug abuser's brains are hypo-functioning, leading to impaired impulse control and judgement.

Neurotransmitters Implicated in Distress and Relief

↑Dynorphin - "dysphoria" and impulsivity ↑CRF (corticotrophin release factor) - stress ↑NE - stress ↑Glutamate - distress ↓Dopamine - "dysphoria" ↓Serotonin (5-HT) - "dysphoria" ↓GABA - anxiety, panic ↓NPY (Neuropeptide Y) - anti-stress