Psyc 211 - All the things that can go wrong (in the brain)

Genetic basis of disease, Schizophrenia & Autism, Mood disorders, Anxiety disorders

Most psychological disorders are [not/highly] heritable, [are/aren’t] Polygenic, and are [localized/brain-wide]

Highly heritable - go from parent to offspring

Are polygenic - many genes involved

Brain-wide - not localized to one region

Genetic risk: rare mutations vs common varients

Rare genetic mutations have a big affect on risk and are often linked to multiple disorders, but there are also common genetic variants that have small individual affects (not necessarily bad) across many genes, that when added up, can increase risk of mental disorders

Effects of environment on risk of mental disorders

A genetic predisposition = a vulnerability, but the environment influences if the disorder actually develops

Ex: prenatal stress/infection/nutrition, birth complications, childhood trauma

What does it mean when a gene has gone to fixation?

The gene mutation clearly boosts reproductive success and its prevalence increases across generations until everyone gets it

Mostly neutral vs completely neutral gene mutations

Mostly neutral genes can be neutral in almost all contexts, but if slightly bad for some people in some contexts, it’s ultimately considered bad

Completely neutral genes exist and are common → they spread by chance. These mutations CAN become bad due to environment change (gene environment interaction)

Diagnostic categories in the DSM are based on what?

Symptoms bc genetic factors can have overlapping risk across many disorders - categories might not reflect true biological boundaries

Genes guide (2 things) and so mutations can disrupt (3 things), but the effects of these mutations are (2 things)

1. Brain development + neural connectivity

2. Migration + Synapse formation + network balance

3. Subtle + distributed (not localized

Development is usually (r___) but mutations can increase (___ ___)

Robust, developmental instability

What are some indications of developmental instability?

Minor physical abnormalities, reduced symmetry (subtle anatomical differences)

Autism:

• Characterized as?

• Prevalence in world population?

• Genetic disorder?

• When are symptoms noticed?

• Challenges with social interaction & communication + restricted & repetitive behavior

• Nearly 2% of world population

• Mainly genetic - gene mutations associated with brain development

• First noticed in first 2-3 years of child’s life

Autism Symptoms: Social interaction/communication issues (3)

Difficulty communicating: abnormal or nonexistent speech (few words, echoing, 3rd person self reference)

Social awareness issues: struggle with social cue interpretation (“reading the room”/tone of voice/body language)

Sensory processing issues: sensory overload impacts interactions (room to bright/sound too loud)

Autism Symptoms: restricted/repetitive behavior

Repetitive Movements: simple motor actions like rocking back and forth

Ritualistic behavior: compulsive need for routine

Extreme narrow interests: interest in very specific subjucts- know everything abt that subject

Autism: Comorbidities

Intelectual disability, Seizure disorder, ADHD, OCD, Depression, Anxiety

Autism: Brain Development/Function abnormalities

• Brain growth slightly above average: age 2-3ish = brain volume 10% larget than average - falls back to normal range in adulthood

• Reduced activity in the fusiform gyrus (area for faces)

Autism: Treatments

• Goals

• Therapy?

• Medication?

• Goal = lessen impact of associated deficits + increase functional independence & quality of life

• Special education programs + behavioral therapy to achieve goals

• Meds don’t usually address core symptoms but reduce associated comorbidity symptoms

Gene-Environment “Paradox” - Schizophrenia + Autism

Regarding mental disorders, gene variants can be either protective or increase risk (or do nothing).

Prevalence of most common disorders fluctuates across cultures/history because of Gene-Environment interaction - NOT THE CASE FOR Schizophrenia and Autism

Even though they aer primarily genetic disorder, natural selection hasn’t eliminated these bad genes because they are combinations of smaller gene variants that only have negative effects when all together - these gene variants also increase risk of developing other disorders

Schizophrenia: Genetic heritability

• What kind of disorder?

• Affects % of population? that changes to _% if __also has it

  • Identical twin

  • Both parents

  • One parent

  • Sibling

• Primarily a genetic disorder (environmental factors have only a small influence - mainly genetic predisposition)

• Affects 1% of population

  • Identical twin: 50%

  • Both parents: 50%

  • One parent: 13%

  • Sibling: 8%

Schizophrenia: Environmental Factors

Mostly relate to developing embryos

• Pregnancy “issues” like nutrition/stress/infections

• Birth month - higher rates in Feb-May

  • Theory = higher viral infection rates affect embryo more and therefore brain development

• Raised in city - 3x more prevalent than in rural areas (virus spreads easier in more densely populated areas)

Also can be result of

• Prenatal hypoxia/brain damage

• Childhood trauma

• Social isolation

Schizophrenia Symptoms:

• Negative

• Cognitive

• Positive

Negative = absence of wanted behaviors

• Social withdrawal; reduced emotional expression, speech, & motivation

Cognitive = disorganized & irrational thinking

• Learning & memory deficits; poor abstract thinking & problem solving

Positive = presence of unwanted behaviors

• Delusions (persecution, grandeur, control)

• Hallucinations (perception of stimuli that’s not actually there, often auditory

Schizophrenia: Onset

Gradual symptom onset beginning in young adulthood - typically earlier in men

Negative symptoms first, then cognitive, then positive

most common onset of symptoms = periods of change both inside (puberty, menopause) and outside body (moving, new job)

Schizophrenia: Treatment

• In general…

• Control of dopamine signaling

No full cure - main treatment = medication + psychological/social support that’s focused on alleviating symptoms

• Too much dopamine in basal ganglia = positive symptoms

• Too little dopamine in prefrontal cortex = negative symptoms

Atypical antipsychotic medication helps with balancing this out, typically affecting multiple NT receptors

• Aripiprazol acts as a partial agonist at Dopamine D2/D3 & Serotonin 1A receptors

Schizophrenia treatment: Dopamine hypothesis

Excessive dopamine D2 receptor activity in basal ganglia underlies positive symptoms

• antipsychotics & neuroleptic drugs primarily work by blocking dopamine D2 receptors, relieving positive symptoms but not negative symptoms

Decreased activity in dorsolateral PFC could relate to hypoactivity of local dopamine D1 receptors (not enough dopamine in PFC)

Schizophrenia Treatment: Partial Agonists (PA)

• summary

• In Basal Ganglia

• in PFC

Partial agonists binding to receptor = receptor partially activated

Basal Ganglia: PA reduces dopamine receptor activity when bound, alleviating positive symptoms

PFC: PA increases receptor activity when bound, alleviating negative symptoms

ADHD:

• Characterized as?

• When are symptoms noticed?

• % Heritable?

• Prevalence in world population?

• Problems paying attention & controlling behavior (age appropriate), hyperactivity

• Usually first identified in classroom before age 12

• 75-90%

• 1-10% of population - 3x more in boys; >5% in N.A are treated

ADHD: Neurobiological Differences

• Fronto-striatal network differences (PFC + BG) = affect executive functioning

• Reduced activation in prefrontal regions during tasks that need attention and planning

• Altered Dopamine and Norepinephrine signaling → affect reward sensitivity, motivation, sustained attention

• Delayed Cortical maturation - particularly in the PFC

• Default Mode Network dysregulation → difficulty “turning off” internal thoughts when focusing

ADHD: Treatments

Counseling (either individual or group therapy) + Medication (stimulants and sometimes antidepressants)

• Meds can have side affects like sleeping or eating too much or too little

Bipolar Disorder:

• Characterized as?

• Prevalence in world population?

• Risk Factors?

• Cyclical periods of mania and depression

• 1% of population

• 80% risk attributed to genetics

Bipolar disorder: mania vs depression

Mania = sense of euphoria that’s not justified by the circumstances, impulsive/reckless behavior, nonstop speech and motor activity lasting days or weeks

Depression = loss of interest and pleasure in most activities, sad and hopeless

Bipolar Disorder: treatment

Lithium - used as a mood stabilizer, most effective for treating mania

• Once mania is eliminated, depression usually does’t follow

Don’t rly understand how it works but it could be decreasing presynaptic dopamine activity to reduce excitatory neurotransmission in the brai

Major Depressive Disorder (MDD):

• Characterized as?

• Prevalence in world population?

• Risk factors?

• low mood for at least 2 weeks, most of the day, every day + feelings of hopelessness, unworthiness, guilt + high risk of self-harm and suicide

• Affects abt 7% of women & 3% of men

• 40% risk attributed to genetics; environment plays a big role (like a traumatic/abusive childhood)

MDD Treatments: Medication

SSRIs = serotonin-specific reuptake inhibitors

SNRIs = Serotonin & norepinephrine reuptake inhibitors

NDRIs = Norepinephrine & dopamine reuptake inhibitors (also affect other neurotransmitters)

Tricyclic antidepressants = Serotonin, norepinephrine, & dopamine reuptake inhibitors

Monoamine oxidase inhibitors (MAOi) = reduce the enzymatic breakdown of all 3 monoamines in respective axon terminals

NMDA Glutamate receptor agonists (like ketamine) = reduce symptoms within hours

• 2-3 sessions per week for first few weeks then 1 session per month as maintenance phase

MDD Treatments: Bright-light therapy + electrical stimulation of the brain

Light therapy = for seasonal affective disorder (SAD)

DBS = deep brain stimulation

TMS = Transcranial magnetic stimulation

VNS = Vagal nerve stimulation

ECT = Electroconvulsive therapy - most rappid and effective treatment for severe depression and bipolar disorder

• People 1st given muscle relaxants + put under general anesthesia, then brief electrical shocks are applied to the head to induce a seizure

• 2-3 ECT sessions per week for 2-4 weeks then maintenance phase

• more than 50% of people experience complete remission for some amount of time

Depression: Monoamine Hypothesis

“depression is caused by low levels of monoamine signaling”

There is clearly not a 1-to-1 connection between monoamine signaling and depression though - so there are issues with this theory

Depression: Role of PFC

Very few correlations exist but we found that one area of the anterior cingulate cortex becomes less active after successful treatments