Exam 2 Flashcards

Question

Symptoms/criteria of Major Depression

Answer 1

At least 5 symptoms incl one of: Sad, Anhedonia, Insomnia (poor sleep), Lethargy – agitation, Poor appetite ? Weight loss, Loss energy/ Fatigue, Negative self view/guilt/low self-worth, Indecisiveness & poor cognition, Thoughts of death/suicide When do they occur? - All day, nearly every day, at least 2 weeks - distressing & leading to impairment in functioning - Not due to drug/alcohol/other medical

Answer 2

Elevated and irritable mood, And 4 of: * Increased activity level * Rapidity (e.g. of speech) * Flight of ideas – “racing” * Less sleep “needed” * Inflated self-esteem * Distractible * Recklessness/risk taking Symptoms present: * For at least 1 week * Not due to drug/alcohol/other medical Recurrence High > 50% = 4 or more episodes

Answer 3

Point prevalence (at any given moment): 5% Lifetime prevalence: between 10-20% > By the age of 18, ~20% will have had depression > Suicide rates (5-10%) in depressed individuals

Answer 4

Gender, age, stress > age 25-45 > F > M > Psychological stress is the trigger for 1st episode > Recurrence (50%: 1st episode develops into 2nd, 70% 2nd episode into 3rd, 90% etc) Anxiety > 80 to 90% of MDD have anxiety symptoms > 30% of MDD have anxiety disorder Eating disorder > Often patients develop MDD Drug abuse > drugs worsen MDD (depression as cause of drugs is not “MDD”) > family history of alcoholism (or depression) Medical illness > 25% of severe chronic illness develop MDD ADHD > ~15% of MDD have ADHD (underdiagnosed) Parental death before age 11, divorce/separation etc

Answer 5

F ± M earlier onset (20-30yrs) in male & more mania More severe and faster cycling in females Family history of depression/mania

Answer 6

Twin studies Concordance rate MZ twins: 54% Unipolar, 79% Bipolar DZ twins: 19% Unipolar, 24% bipolar Children of depressed are (compared to kids of non- depressed) – 3X more likely to develop MDD or phobias – 5X as likely to develop panic disorder or drug abuse – more likely to function poorly in school, work, marriage Six fold increase in suicide among biological relatives of depressed adoptees

Answer 7

5-HTT polymorphism: short and long allele Assessments over two decades from age of 3 > Stressful life events 1) Romantic disasters 2) Bereavements 3) Illnesses 4) Job crises > Depressive symptoms Short allele: #no. of stressors positively correlated with MDD episodes Long allele: correlation not there, suggests long genotype more or less protected individuals from multiple life events increasing the risk to develop MDD

Answer 8

Monoamine hypothesis Neurotrophic hypothesis HPA-axis

Answer 9

depression due to deficit of monoamines and mania due to an excess Monoamine transmitters are found in the serotonergic and adrenergic system

Answer 10

MAOIs > Prevent degradation of neurotransmitters in synapse. E.g. phenelzine (Nardil) Tricyclics > A class of drugs used to treat depression; inhibits the reuptake of norepinephrine and serotonin; named for the specific molecular structure. E.g. Amitriptyline (Elavil) SSRIs > inhibits the reuptake of serotonin without affecting the reuptake of other neurotransmitters. E.g. fluoxetine (Prozac) SSRI & SNRI (5-HT and/or NE reuptake inhibitors) 60-70% response rate < full remission rate 30-40% relapse! Side effects: many, but among them suicide ideation

Answer 11

L-Tryptophan is the precursor of serotonin > decreased L-Tryptophan in depressives > Tryptophan depletion produces/exacerbates depression (humans and rats; oversensitive to pain, altered patterns of eating and satiety) > decreased levels of 5-HIAA (end product) in suicide victims

Answer 12

Problems > lag time > flattened mood > low efficiency > relieves symptoms (doesnt address cause) > SSRI treatment effect is slow (no evidence for low 5HT-imbalance) - may suggest involvement of down-stream gene expression of other factors

Answer 13

> 20% smaller hippocampi in stressed rats > 15% smaller hippocampi in depressed people > Might be common in many internalizing disorders > Autopsies indicate fewer cells in PFC of depressed > SSRIs prompt cell division in hippocampus & PFC – so does exercise Stress leads to decreased growth factors > Normal state = equilibrium between synapses and dendrites > Stressed state: add on of glucocorticoids, decrease in number of synapses that are connected

Answer 14

Orbitofrontal cortex & PFC > Decreased activity (correlated with severity) - Treatment = higher activity - Note: only anteromedial OFC increases activity in depressed vs remitted state > Decreased grey matter volume - Right side: correlates with insomnia - Less cells Amygdala > bigger in depressed > increased activity (correlated to severity) > treatment = decreased activity Anterior cingulate > decreased activity > treatment = increased activity Hippocampus > smaller > decreased metabolic activity > treatment = more cells PFC: planning, personality, decisions social behavior; many connections to the limbic system (emotion); gives top-down control over the amygdala Orbital frontal cortex: emotion, taste, smell and reward in decision making Amygdala: helps direct attention to stimuli that are emotionally salient and major impact Anterior cingulate cortex: stress response, emotional expression, social behavior, processing difficult information Hippocampus: memory, fear-related thoughts

Answer 15

Twins 1: a) exposed to stress & dev. PTSD b) not stress-exposed & no PTSD Twins 2: a) stress-exposed & no PTSD b) not stress-exposed & no PTSD Twins 1 have smaller hippocampus than twins 2

Answer 16

onset of REM occurs earlier after the onset of sleep – increase REM during first 1/3 of night (in normals last 1/3) - During REM: little - no control of adrenergic system (control is silent during that time) - Insufficient silencing of locus coeruleus (origin of adrenergic system) impairs sleep- related brain plasicity - REM latency much lower in MDD patients - Bidirection relation: Insufficient sleep -> stress; stress accumulation leads to deterioration of mental health and contributes to development of psychiatric disorders chronobiological hypothesis of depression: – Many depressed patients show insomnia – Sleep deprivation reduced depressive symptoms in ~60% - Effect reversed with sleep, short-lasting, could be applied repeatedly – Prevent relapse by co-administration with antidepressants and morning light – Amygdala is activated upon sleep deprivation (& important for memory!) – “Zeitgebers” also play role in: * Seasonal affective disorders * Bipolar * Schizophrenia – CBT for insomnia effective for insomnia and comorbid depression Depressive rating goes down if there is sleep deprivation Another night of sleep = return to original phase Some may be more vulnerable to sleep factor than others Responders: respond in early onset of sleep deprivation (shows efficacy)

Answer 17

HPA axis activated by stress impaired negative feedback by cortisol > hypersecretion of CRF > adrenal hypertrophy > excess cortisol released > desensitization of cortisol receptors = disturbances in noradrenaline and serotonin transmission Disturbed HPA axis in depressed patients – Dexamethasone suppression test – High cortisol levels in serum – Upregulation of 5-HT2A with chronic stress – Decreased hippocampal volume may be a risk-factor

Answer 18

Dexamethasoneis a synthetic corticosteroid (cortisol agonist) > when administered: normal system will reduce its cortisol production due to increased negative feedback > in MDD: failure to suppress system via dexamethasone

Answer 19

Addicts have a higher change to develop depression (males: 3x, females: 4x) > Holds for generally accepted drugs like nicotine, alcohol (high numbers) as well as for gambling addiction Addiction can start at an early age: adolescence [Anxiety (late adolescence) often precedes depression (adult)] Alcohol * Alcoholism and depression: either disease doubled risk for other disease * Alcoholism occurs more often in families with depression history * Gender issues: males: first addicted than depressed, females reversed? Smoking * MDD 2x more often in smokers than non-smokers * Smokers started early during development and persist – Ruin their brain and now self-medication?

Answer 20

Any neurological disease that is marked by the progressive loss of (specific populations of) neurons Diseases are progressive: start in a focal way and then progress Many NDs are associated with abnormal intra- or extracellular protein aggregations in the brain

Answer 21

> Neurons in spinal cord (specifically ventral horn where there are motor neurons) die = progressively you lose capability of muscle control = eventually progresses to the heart > Atrophy is rapidly progressive and fatal > Juvenile onset = slower progression > Related to FTD > People retain their full capacity of cog abilities (unlike FTD) > Expectancy: <5 years after diagnosis Incidence: ±2 in 100,000 Prevalence: ±6 in 100,000

Answer 22

> Twitching and cramping of muscles, especially those in the hands and feet. > Loss of motor control in the hands and arms. > Trouble using arms and legs. > Tripping and falling. > Dropping things. > Lasting severe tiredness (fatigue) > Uncontrollable periods of laughing or crying

Answer 23

Incidence: ±3 in 100,000 Prevalence: ±18 in 100,000 > atrophy / degeneration in frontal and temporal lobe > Lose cog abilities > Different subtypes: bvFTD, nfvPPA, svPPA

Answer 24

behavioral variant > disinhibition, apathy, loss of empathy, impaired decision-making, changes in social cognition non-fluent variant primary progressive aphasia > aphasia, slurred and hesitant speech semantic variant primary progressive aphasia > loss of semantic abilities, impaired word comprehension and object naming, maintains fluent speech different genetic causes

Answer 25

emotional blunting or apathy, changes in personality/behavior, language difficulties, impaired executive function, loss of empathy or social skills etc etc

Answer 26

Some genetic forms of ALS are caused by mutations in the SOD1 gene Free radical oxygens form > SOD1 enzyme involved in making sure free radicals are dampened out Mutation in this gene = this step is affected = Oxidative stress in ALS

Answer 27

Genetics: hereditary 10% ALS; 30% FTD. Children have a 50% chance of inheriting the gene * C9orf72: FTD & ALS (repeat expansion in gene) * SOD1: ALS: superoxide dismutase 1 (mitochrondria) * TARDBP”: FTD & ALS: TDP-43, DNA binding protein involved in RNA processing * Age: ALS: Risk increases with age up to age 75. ALS: 60 - mid-80s FTD: 40-65 yrs * Sex: Before the age of 65, slightly more men than women develop ALS. This sex difference disappears after age 70. FTD: equal * Smoking: Environmental risk factor for ALS. Women who smoke seem to be at even higher risk, particularly after menopause. * Environmental toxin exposure: Exposure to lead or other substances might be linked to ALS. Much study has been done, but no one agent or chemical has been consistently associated with ALS.

Answer 28

Mitochondria produce ATP via O2 and e- from glucose Oxygen radicals are produced as side products during OXPHOS (oxidative stress) Oxygen radicals cause damage to DNA, proteins and lipids Oxygen radical cause mitochondrial dysfunction Oxidative stress is an important neurotoxic event in many NDs

Answer 29

Prevalence – Every year 1/4,000 people of 50 years and over get PD – 1/40 people will get PD at some time during life

Answer 30

self-study?? (Check if it should be learned) Atrophy of the basal ganglia Enlargement of the lateral ventricles caused by a polyglutamine (polyQ) insertion in the huntingtin protein HD is a monogenic autosomal dominant disorder affecting 1/10,000 people (most NDs are complex, polygenic diseases)

Answer 31

Hypokinetic disorder (reduced motor activity) Tremor (4-7 Hz) of the limbs Increased muscle tone Muscle rigidity Difficulty in initiating movements (akinesia) Slow movements (bradykinesia) Mask-like facial expression Low eye blink rate Bend back during walking Shuffling gait

Answer 32

generally idiopathic (cause unknown) > There is genetic predisposition for idiopathic PD Familial PD is rare – Mutations in the gene encoding alpha-synuclein – Presence of Lewy bodies Sporadic PD – Head trauma – Brain tumors – Environmental toxins: MPTP

Answer 33

Loss of dopamine neurons in the substantia nigra pars compacta (SNpc; nigrostriatal pathway) > SNpc neurons die from ox stress DA metabolism enhances oxygen radical formation Neuromelanin binds Fe++ and promotes hydroxyl radical formation A 50% loss of SNpc neurons is necessary for onset of symptoms Other dopamine neurons, noradrenergic neurons and cholinergic neurons also die, but to a lesser extent Lewy bodies (a-synuclein aggregates) – Cytoplasmic inclusions with a core of alpha-synuclein and a halo of ubiquitin > alpha-Synuclein is mutated (causes ox stress & neurodegeneration) > Ubiquitin: small protein that is coupled to other proteins and marks these proteins for degradation > but a-synuclein is not degraded and instead aggregates > Other mutations that are linked to PD are found in proteins that are involved in the protein degradation pathway

Answer 34

MPTP is a side product of opioid synthesis When broken down, MPTP metabolites (MPP+) block the electron transport chain MPP+ looks a lot like a herbicide lots of herbicides look like this which are then taken up by dopaminergic neurons causing them to die Mitochondria are affected, they stop their energy capacity Dopaminergic cells die off

Answer 35

The earliest affected brain structures in PD are the dorsal nuclei in the brain stem and the olfactory bulb

Answer 36

Olfactory neurons directly enter the brain The olfactory bulb contains dopaminergic neurons Smell tests seem to accurately detect PD in the pre-symptomatic phase

Answer 37

L-DOPA (+ DOPA decarboxylase inhibitor) > Has to be administered in bursts > Stimulation of dopamine synthesis only works when dopaminergic neurons are there > Increases dopamine synthesis MAO inhibitors – Prevents breakdown of dopamine Antioxidants (vitamin E) – Bind free oxygen radical Dopamine receptor agonists – Stimulate dopamine receptors on striatal neurons

Answer 38

Bilateral electrical stimulation of neurons in the subthalamic nuclei Stimulation of places where dopamine arises, even if dopamine neurons are there you can stimulate the sites that would be Awake surgery of implantation of electrode Downside: potential bleeding, depending on frequency & pulse you may have side effects eg erratic behavior

Answer 39

Commonest cause of dementia in the elderly Affects 5% of people over 70 and 20% of people over 80 Causes serious cognitive impairment > Loss of memory > Decreased attention and motivation Progression is uneven in different individuals > Stress can accelerate progression Most AD patients also have PD and suffer from depression Life expectancy after diagnosis is ~5 yrs

Answer 40

Atrophy of (sub)cortical brain regions Enlargement of cerebral ventricles and brain sulci 30-40% reduction in brain weight Neuritic plaques – Extracellular lesions containing an insoluble form of the peptide beta-amyloid Neurofibrillary tangles – Cytoplasmic bundles of hyper-phosphorylated tau proteins (tau tangles) Neurons dying: Cholinergic neurons in septum and nucleus basalis of Meyndert (NBM) > Impairment of memory consolidation Glutamatergic pyramidal cells in the cortex > Probably accounts for most of the cognitive deficits Noradrenergic and serotonergic neurons Neurodegeneration may start in the olfactory bulb

Answer 41

tau tangles present in other neurodegenerative diseases

Answer 42

no-AD or non-AD dementia: no A-beta plaques pre-AD or non-AD dementia: sparse/small plaques in neocortex, entorhinial etc etc symptomatic AD: plaques in substantia nigra, medulla oblongata, cerebellum etc etc

Answer 43

Most AD cases are idiopathic, possibly with genetic predisposition – Apolipoprotein E (apoE) E4 is a risk factor for developing AD, and seems to enhance aggregation of amyloid-beta in neuritic plaques Familial AD cases may start early (early-onset AD) and are caused by mutations in three genes – Amyloid precursor protein (APP) – Presenilin 1 – Presenilin 2

Answer 44

APP is the precursor protein for beta-amyloid Presenilins are part of the gamma-secretase complex Normal role APP: regulating embryonic stem cells into neural precursor cells (ao progesterone) Mutations = APP is cleaved differently, creating beta-amyloid peptides that aggregate

Answer 45

Poorly understood but thought that Abeta binds Cu++ and may act as an antioxidant When Abeta binds Cu++ it produces H2O2 and causes oxidative stress Small Abeta aggregates cause damage to axons and synapses Abeta-derived diffusible ligands (ADDLs) may specifically impair synaptic function (inhibit LTP) and cause neuronal apoptosis

Answer 46

Intermediate protein aggregates are toxic (oxidative stress) > Inhibition of their formation may improve ND symptoms (upstream) Formation of final protein aggregates (plaques, tangles, Lewy bodies, etc) may protect from toxicity > Inhibition of their formation may cause accumulation of intermediate aggregates and enhance ND symptoms (downstream)

Answer 47

Acetylcholinesterase inhibitors (neostygmine, donezepil) > Improves cholinergic functions (memory consolidation). Not very successful. Anti-inflammatory drugs (indomethacin) > Targets inflammatory components of AD. Vaccination against Abeta > Not successful. Causes brain inflammation. Chelating agents (clioquinol) > Binds Cu++ and Zn++. Antioxidants > Bind free oxygen radicals. Neurotrophins > Proteins that promote neuronal survival and growth. Inhibitors of beta- and gamma-secretase Aducanumab/Lecanemab > antibody directed to protein = takes out protein > Ab’s given by infusion, should clear amyloid proteins from the brain EMA refused license December 2021 Too little effect on symptoms Side effects (a.o): brain swelling or bleeding

Answer 48

Therapies that are aimed at prevention of neuronal loss in ND only work when started before the onset of symptoms Much research focuses on early detection methods * Smell tests * Peripheral blood/CSF markers * PET scanning

Answer 49

All disorders now grouped together as ‘autistic spectrum disorders’ in DSM-5 > Persistent deficits in social communication and social interaction > Restricted, repetitive patterns of behavior, interests, or activities > Symptoms must be present in the early developmental period (but may not become fully manifest until social demands exceed limited capacities, or may be masked by learned strategies in later life (camouflaging) > Symptoms cause clinically significant impairment in social, occupational, or other important areas of current functioning > These disturbances are not better explained by intellectual disability or global developmental delay (Intellectual Disability and Autism Spectrum Disorders have high comorbidity and it is possible to have a joint diagnosis) Note: ASD is related to but separate from ‘social communication disorders (SCDs) and Sensory Processing Disorder (SPD)

Answer 50

1) stereotypes or repetitive motor movements, use of objects, or speech 2) insistence on sameness, inflexible adherence to routines, or ritualized patterns or verbal nonverbal behavior 3) Highly restricted, fixated interests that are abnormal in intensity or focus 4) hyper- or hyporeactivity to sensory input or unusual interests in sensory aspects of the environment

Answer 51

1) deficits in social-emotional reciprocity > abnormal social approach > failure of normal back-and-forth conversation > reduced sharing of interests, emotions, or affect > failure to initiate or respond to social interactions 2) deficits in nonverbal communicative behaviors used for social interaction > poorly verbal and nonverbal communication > abnormalities in eye contact and body language > deficits in understanding and use of gestures > total lack of facial expressions 3) deficits in developing, maintaining, and understanding relationships > difficulties in adjusting behavior to suit various social contexts > difficulties in sharing imaginative play or in making friends > absence of interest in peers

Answer 52

30% increase in 2 years Under-diagnoses in the past: 2-3 times more males are affected. Females with ASD might have been under-recognised (or maybe due to better 'camouflage' in females) More awareness and societal acceptance of ASD makes that parents and caretakers will recognise the symptoms sooner and will visit the doctor for a diagnosis A diagnosis can be beneficial (increased services and behavioral interventions)

Answer 53

Profound autism: Severely affected children, non-verbal, inflicting self-harm, need round-the-clock care. Neurodiversity: “High-functioning” people with autism that don’t need medical attention.

Answer 54

Most cases: underlying cause is unknown Either genetic and/or environmental factors play key roles env: - Use of Valproic Acid during pregnancy Anti-Epileptic, Mood-Stabilising Drug GABAergic modulation 3-fold increase in risk of autism in children exposed to VPA - Folic acid supplements before conception and during early pregnancy seem to be protective - cerebellar injury at birth 36x increased risk Cerebellum and forebrain are bidirectionally linked in an orderly mapping Cerebellum may guide the maturation of remote non-motor neural circuitry and influence cognitive development genetic: Strong correlation between proportion of genome shared and risk for ASD Studies in DZ twins and MZ: heritability rates of 38–90% The remaining variation in the phenotype (ASD) is accounted for by environmental or epigenetic factors Monogenic disorder: Rare monogenic mutations, regardless of genetic background Complex disorder: a combination of different (lower risk) genetic mutations w/ genetic background determine the overall risk. 4-5% of ASD cases are monogenetic (e.g. fragile X syndrome (FMR1 gene), Rett syndrome (MECP2 gene)

Answer 55

The refrigerator mother: A cold, distant, and career-oriented mother as the prevailing explanation as to why some children develop severe emotional and behavioral problems. > First explanation of autism > Prevailing hypothesis until the 1970s and 1980s > lack of epidemiological evidence, biological plausibility Vaccines (mumps, measles, and rubella (MMR)): The MMR vaccine is administered to 12- to 18-month-old children. At this age also the first signs of autism become noticeable. > claimed the measles vaccine triggered inflammation of the colon which would cause autism. > connection between autism and the MMR vaccine has been discredited by dozens of studies investigating the epidemiology of autism and the biological effects of MMR and the mumps virus both have no statistically sig link to autism

Answer 56

synaptic genes are overrepresented in the genes associated with ASD > Autism risk genes are associated with specific processes in the synapse 3 interconnected pathways involved in ASD: Synaptic function > Controls synaptic strength and synaptic plasticity WNT signalling: > Controls key transcriptional programmes that affect neuronal maturation and circuit formation. > Depends on synaptic activity Translation: > localized translation at the synapse underlies synaptic plasticity and cognition > synaptic translation is stimulated by synaptic activity

Answer 57

Morphological and connectivity differences Disturbance of excitation/inhibition balance

Answer 58

Layered and columnar organisation of the cortex > Neuronal and synaptic density increases in the cortex during early postnatal development. > In sensory cortex, neurons are arranged in columns, with a layered structure. > These columns are 500um wide and can also be divided into microcolumns around 50um wide. > Layered and columnar organisation is important for information processing Increased neuronal density in ASD > increased density of neurons in cortical layers > suggest that the cortical microcolumn is smaller in ASD. > Functional consequences are unknown: it could suggest greater connectivity between neurons locally Decreased long-range connectivity in ASD > High-functioning ASD subjects and age-matched controls were scanned using fMRI during rest and specific tasks. > Measured connectivity scores for activation between different brain regions, including many frontal cortical areas. > ASD subjects had lower connectivity scores between regions than controls, suggesting decreased long-range activity between these regions. Opposed changes in long- and short-range connectivity in ASD Connectivity model: > ASD brains have decreased long-range connectivity (hypoconnectivity). > ASD brains have increased short-range local connectivity (hyperconnectivity). > Could be in line with poor or weak “central coherence” in ASD. Many people with ASD are believed to perceive details better than people without ASD, but have difficulty in seeing the larger context

Answer 59

Normally, a balance of excitatory (usually glutamatergic) and inhibitory (usually GABAergic) neurons in network When balance is disrupted: excessive inhibition = no activity excessive excitation = epileptiform activity (over-excitation) The very specific connectivity between Glutamatergic and GABAergic neurons shapes the computational properties of the cortical column (define how info is processed)

Answer 60

High comorbidity (~20%) with epilepsy Single-cell RNA sequencing shows enriched expression of ASD risk genes in inhibitory neurons Altered E/I balance in animal models for autism

Answer 61

number of synapses synaptic strength excitability

Answer 62

Impaired visual orientation discrimination in Fragile X patients Similar impaired orientation discrimination in FRX (Fmr1-KO) mice These deficits likely arise from an E/I imbalance, due to impaired GABAergic inhibition, especially involving PV+ interneurons Parvalbumin interneurons (GABAergic): > inhibit pyramidal cells in all layers within a cortical column > are thought to play a role in orientation tuning > Calcium imaging shows reduced activity in Parvalbumin neurons during visual stimulation DREADD technology: > Introduce an engineered receptor (hM3Dq) in Parvalbumin neurons > Activating the receptor with CNO will excite the PV neurons Restoring activity in Parvalbumin neurons in FRX mice rescues orientation discrimination in these animals

Answer 63

GABA has excitatory effect in immature neurons but inhibitory effect in mature neurons > Delayed GABAergic maturation in Fragile X (FRX) and Valproic Acid (VPA) treated rodent models for ASD Bumetanide restores E/I balance in ASD animal models by rescuing the inhibitory function of GABAergic synapses > Bumetanide decreases intracellular chloride concentrations in the cell > Bumetanide clinical trials are underway in children with autism

Answer 64

excess of normal functions e.g Psychotic episodes >delusions - a strong belief or impression maintained despite being contradicted by reality or rational argument - e.g paranoid delusion, delusion that you are poisoned, referential delusion, grandiose delusions (megalomania), religious delusion, sexual delusion, leaky mind > hallucinations - perceiving things that do not exist e.g auditory, visual, tactile, gustatory, olfactory Psychotic episodes can also be a symptoms of other psychiatric diseases e.g BPD, MDD

Answer 65

Reduction in normal functions > blunted affect: restrictions in range and intensity of emotional expression > dysfunction of motivation: reduced motivation in persistence, passivity, reduced ability to understand and complete everyday tasks > anhedinoa: dysfunction of capacity for pleasure > asociality: reduced social drive & interaction

Answer 66

> Executive dysfunction: problems w/ planning, maintaining goals > disorganized speech & behavior > Attentional problems > Agitation

Answer 67

Symptoms of schizophrenia arise from malfunctioning brain circuits > diff symptoms involve diff circuits Dopamine hypothesis Glutamate hypothesis Neurodevelopmental hypothesis

Answer 68

Dysregulation of mesolimbic and mesocortical circuits Dopamine pathways a) nigrostriatial > stays normal (normal firing rate) b) mesolimbic > positive symptoms arise because of hyperactive DA neurons in mesolimbic circuit (too much DA in ventral striatum) c) mesocortical > negative and cog symptoms arise because of hypoactive DA neurons in mesocortical circuit (too little DA in PFC) d) tuberoinfunidibular > stays normal

Answer 69

cocaine (DAT reuptake inhibitor) & amphetamine (DA releaser & DAT reuptake inhibitor) more DA in synapse > psychosis

Answer 70

Classic antipsychotics > e.g halloperidol > D2 receptor antagonist (dopamine receptor blocker) > blocks hyperactive mesolimbic circuit > reduction in positive symptoms BUT D2 antagonist will also affect other pathways e.g nigrostriatal pathways > involved in motor coordination > not enough motor signalling for this dopamine system > develop parkinson-like symptoms > results in extrapyramidal symptoms

Answer 71

NMDA receptor hypofunction in corticobrainstem projection > NMDA-antagonists (e.g ketamine) = temporary state similar to symptoms of schizophrenia - Normally: corticobrainstem projection communicates directly with DA neurons of mesocortical pathway - Glu stimulates mesocortical DA neurons via AMPA-R and NMDA-R > activation of mesocortical pathway - In schizophrenia: NMDA-R hypoactive > less activation mesocortical DA neurons > less DA release in PFC > negative and cog symptoms > NMDA-R hypofunction causes hypoactivation mesocortical DA pathway = coupling glutamate- and dopamine hypothesis for negative symptoms Positive symptoms - Normally: corticobrainstem projection acts as brake (inhibition) on mesolimbic DA pathway via GABA interneuron (connecting GLU neuron to DA neuron) - Glu stimulates GABA-neuron > more GABA release > GABA inhibitions DA neurons > less DA release in ventral striatum (nucleus accumbens) - In schizophrenia: NMDA-R hypoactive > less GABA release > less inhibition of DA neurons > more DA release in ventral striatum > positive symptoms schizophrenia - NMDA-R hypofunction causes hyperactivation of mesolimbic DA pathway Next, hypofunction NMDA-R causes ‘sensory filter’ of thalamus dysfunction - Thalamus ‘decides’ which part of sensory information is sent to the cortex and can be perceived consciously - In schizophrenia efficacy of sensory filter reduced > more sensory input relayed to cortex = sensory overload > psychosis - from midbrain: there is an overactive DA neuron going to nucleus accumbens causing an inhibitory effect, too much DA leads to inhibition of the GABA neuron (connecting nucleus accumbens to thalamus) = this inhibitory neuron is less active = thalamus inhibitory function is less active = more signals make it through to the cortex Glutamate pathways a) corticobrainstem glutamate projection b) corticostriatal glutamate pathway c) thalamocortical d) corticothalamic e) cirticocortical glutametergic

Answer 72

Ketamine used in brain imagine research as schizophrenia-like model Ketamine-induced psychosis is not common Recreational drug and antidepressant

Answer 73

Corticostriatal and thalamocortical (glutamate pathway) loop creates a sensory filter Corticostriatal: Glutamate neuron from PFC to nucleus accumbens fires as normal frequency GABA neurons in nucleus accumbens inhibit activity in the thalamus Thalamocortical projection, glutamate neurons project back into the cortex to decide what is actively percieved > not all neurons make it up to the cortex (due to sensory filter inhibiting some signals)

Answer 74

Prevalence of Gen pop: 1% onset in adolescence (age 15-25) Concordance rate DZ twins: 17% Condordance rate MZ twins : 48% Heritability of schizophrenia: 80% > symptom variation: 80% is caused by genetic variation

Answer 75

There are genes that are impacted in neuronal development, synaptogenesis, glutamate neurotransmission and long-term potentiation Genes regulating neuronal connectivity and synaptogenesis: DISC-1, neuregulin, dysbinding, BDNF Disconnectivity - DISC-1 > certain allele of DISC-1: there is inadequate neurogenesis, producing dysfunctional neurons or neuronal death > inadequate outgrowth of neurites = not forming all connections you should make - Neuregulin > abnormal glia development = abnormal myelination of axons Both can cause poor neuronal migration Abnormal synaptogenesis > proper function of the 4 genes = normal synapse function > flawed 4 genes: abnormal synapse formation In schizophrenia you have abnormal synaptic strengthening - Risk genes for schizophrenia > Genes implicated in neuronal development, synaptogenesis, glutamate neurotransmission and LTP > dysfunctional brain circuits and hypofunction NMDA-R During synaptogenesis > No Long-Term Potentiation > synapses stay ‘weak’ During adolescence aberrant elimination of weakened synapses

Answer 76

1. NMDA-R hypofunction > Glu of corticostriatal pathway less effect on excitatory NMDA (and AMPA) receptors receptors on GABA cellbody and dendrites [NMDA and AMPA receptors are both excitatory glutamate receptors) 2. Excess DA (from mesolimbic pathway) inhibits GABA-neuron via inhibitory dopamine receptors on GABA cell body and dendrites

Answer 77

Normal situation: lots of connections, not all are important, during adolescence connections are pruned (removed from brain) Neurodevelopmental hypothesis Schizophrenia: during early development proper connections are not straightened = aberrant elimination of connections during adolescence

Answer 78

- Stress, infection, malnutrition during pregnancy (hunger winter WWII) – Hypoxia during birth – Born in winter / spring (northern hemisphere) – Living in urbanised environment – Ethnic minorities – Trauma/abuse (influence via epigenetic modifications) – Use of cannabis Life event > combined with adaptive personality / good coping skills and risk gene = circuits keep firing at normal levels = normal phenotype > combined with a maladaptive personality / coping skill and risk gene = overactive brain circuits = psychiatric symptoms > combination of personality, stress, life events, risk genes = whether you develop schizophrenia or not

Answer 79

Protons spin randomly > magnetic field is applied = the proton spins align with magnetic field Radio pulses push protons out of equilibrium Recovery (back into aligned spin) emits a radio signal (energy) which is different for different tissue types Pulse sequences designed for different types of imaging T1-weighted and T2-weighted Measuring: protons ~ hydrogen (H) ~ water (and fat) Segmentation: assign label to each voxel (volume pixel), ~ 1 x 1 x 1 mm3

Answer 80

Brain structure X is smaller in disease Y: - Structural imaging on a group of patients with disease Y and controls - Automated segmentation of brain structure X - Quality control (affected by movement or metal object in person) - Counting the volume (#assigned voxels x voxel volume) - Statistical test of group differences between patients and controls

Answer 81

1.5 Tesla – 3 Tesla – 7 Tesla > Higher field strength = better signal-to-noise ratio > can be used for better resolution, faster scanning, less artifacts (anything that distorts the image) > High field strengths (>= 7T are less suitable for large scale live imaging)

Answer 82

Provides a temporal image of the brain at rest or during a task > based on Blood Oxygen Level Dependent (BOLD) contrast - oxygenated blood shows more signal than deoxygenated blood Interpretation: neuronal activity requires oxygen, therefore the BOLD signal contrast is an indication of brain activity time series in every voxel 3x3x3 mm3

Answer 83

More brain activity in region X in disease Y: - Functional task-based imaging in a group of patients with disease Y and controls - task related to activity in region X - Post-processing of time series signal and quality control - Statistical test of group differences in task-rest contrast between patients and controls compare resting state with task-based state: > eyes closed then eyes opened

Answer 84

The resting brain is active! (during rest not sleep, measured with eyes closed) Resting state signal in different brain regions fluctuate together: correlation of the signal suggests functional connectivity Functional connectivity implies a structural connection between brain regions – but can be indirect. > Structural connections are formed by the WM of the brain > Note: WM consists of the axons that are part of the gray matter neurons

Answer 85

Resting state networks are not fully explained by respiratory or cardiac rhythms (there is also other stuff) Resting state networks seem functionally relevant (overlap with networks of known function – possible exception: the default mode network) Default Mode Network: dorsal medial prefrontal cortex, posterior cingulate cortex, precuneus and angular gyrus. Default Mode Network becomes more active at rest (not sleep!) Interpretation is under debate: absence of task-related activity, thinking about the self, or others (theory of mind), mind wandering

Answer 86

Brownian motion of water molecules (present in isotropic environment) is hindered in the presence of e.g. axonal membranes (anisotropic environement) – this can be picked up in an MRI scanner Fractional ansiotropy: a function of lambda, and a measure of WM 'integrity'

Answer 87

> MRI gives us the aggregated effect of millions of cells in one voxel > Interpretation is not always clear: what are intensity changes in terms of biology - e.g interpreting cortical thinning The cortex becomes thinner during childhood and adolescence, either pruning of unneccesary synapses, or (current interpretation) myelination of the deep layers of the cortex (so appears as gray matter but is not actually thinning) - Schizophrenia patients have thinner cortices compared to controls. Current hypotheses: smaller number of synapses, smaller neurons, changes in glial cells, deviant developmental trajectory

Answer 88

We cannot predict diagnosis from brain structure (yet) > Machine learning being researched as a tool to predict “severe mental illness” from MRI

Answer 89

local differences in folding consider that in studies you are measuring a group difference > individual differences in all stages of disease > even in healthy controls there are large differences amongst participants psychiatric disorders are phenotypically and genetically heterogeneous > patients are different from controls at group level To detect small effects in heterogenous samples reliably means large samples collaboration (~ thousands of participants)

Answer 90

- Under perfect conditions, meta-analysis yields the same results as mega-analysis - Sharing of meta-data is less difficult than sharing individual data - Provided all sites are ”behaving nicely”, part of the heterogeneity is filtered out - Easier to increase sample sizes - Prospective analysis allows for optimal comparisons between studies

Answer 91

e.g schizophrenia vs 22q11 deletion syndrome 22q11 is associated w/ schizophrenia Schizophrenia: 1% of cases has 22q11 syndr BUT thinner cortex compared to controls 22q11: 23% of cases has schizophrenia BUT thicker cortex compared to controls e.g of structural connectivity in psychiatric disorders FA in fornix and cingulum (parts of limbic system) of patients – and fornix associated with duration of illness in SZ, BPD, MDD

Answer 92

Stress: changes in an organism's physiology driven by internal or external factors > environmental, biological or psychological triggers that alter homeostasis Stress response: all physiological processes that restore homeostatic balance > energy expenditure, metabolic changes > immune system activation > brain (synaptic/cellular) plasticity Adaptive behavioral strategy

Answer 93

SAM axis > sympathetic, adrenal, medulla > stress makes you alert: via secretion of noradrenaline from locus coeruleus > fight or flight response HPA axis > slower > hypothalamus > CRH > pituitary gland > ACTH > adrenal gland > glucocorticoids (negative feedback loop) Interaction between the two

Answer 94

People have a certain predisposition to how much stress we can deal with > there is a threshold and once it is passed we cannot deal with the stress and may develop pathologies > resources can help raise the threshold (e.g attachment)

Answer 95

a dynamic active process to be resilient you need 3 Rs > Regulate you reaction to stressful stimuli > Respond to adversity in an adaptive manner > Rebound from following traumatic events

Answer 96

Neuroendocrine level - HPA regulation: > reduced HPA reactivity > increased negative feedback (Epi)genetics - Expression & polymorphisms > CRH > Monoamines > BDNF Molecular level - Neuromodulation by > endocannabinoids > endogenous opioids > neuropeptide Y Circuit level - Modulation of stress-responsive brain regions > reduced reactivity of stress centers (LC, amygdala) > increased activity in PFC / mesolimbic circuit

Answer 97

not exposed to maltreatment: not much difference between cortisol levels and GG phenotype Exposed to maltreatment: GG allele will predict higher responsivity (higher cortisol levels)

Answer 98

Low MAOA allele shows higher antisocial behavior score in children with severe maltreatment compared to high MAOA allele in children with severe maltreatment short allele vs long allele > s allele associated with less serotonin transporter present > s allele shows greater probability of depressive episodes as number of life stressors increases > l allele shows not much change in probability of depressive episodes across number of life stressors

Answer 99

PTSD veterans vs healthy veterans > antagonist of autoreceptor = anxiety is pharmalogically increased > PTSD group showed increase in NP Y levels > healthy group shows an extremely large increase in NP Y levels > NP Y is a lot more present when healthy participants are experiencing stress > More NP Y you have, chances of staying healthy post stressor is increased BAI score (anxiety) > Diff amounts of NP Y is given to war veterans > higher amount of NP Y showed lower anxiety levels .

Exam 2 Flashcards

(123 cards)