Neurophysiology Flashcards
What electrical values describe:
- Resting potential
- Threshold value for Na+ channels to open (Na+ influx) to initiate action potential
- Threshold value for K+ channels to open (K+ outflow) to signal end of action potential
- resting potential -70mV
- when the synaptic signals received by the dendrites and soma of the axon hillock reach -55mV Na+ channels open and Na+ ions enter the axon - “depolarisation”
- When the membrane potential is reversed to +40mV the Na+ channels close and the voltage gated ion channels open causing K+ to move out - “repolarisation”
Describe three types of synapses
a) Chemical - neurotransmitters/chemical molecules released from presynaptic neuron induces changes on the post synaptic neuron
b) Electrical - there is purely electrical communication between the presynaptic and post-synaptic neuron
c) Conjoint - mixture of both electrical and chemical stimulation
What is meant by the following terms in the context of communication between synapses:
a) Facilitation
b) Spatial summation
c) Temporal stimulation
a) Facilitation refers to a presynaptic neuron inducing changes in the post-synaptic neuron which means an action potential is more likely. While some pre-synaptic neurons may directly induce an action potential in the post-synaptic neuron others will cause either slight depolarisation (excitatory neurotransmitters) or hyperpolarisation (inhibitory neurotransmitters) which serve to make an action potential respectively more or less likely
b) Spatial summation indicates that a post-synaptic neuron may be connected to several nearby pre-synaptic neurons. These pre-synaptic neurons may work together to increase/decrease the likelihood of an action potential
c) Temporal summation refers to when one post-synaptic neuron is stimulated several times by the same pre-synaptic neuron the summation of these effects increases/decreases the likelihoog of an action potential.
What are the satiety and feeding centres
- Ventromedial hypothalamus is the feeding centre
- Lateral hypothalamus is the satiety centre
Describe mediators of appetite (oxigenic) and satiety (anorexigenic)
Oxigenic:
-Ghrelin (only oxigenic mediator produced in the CNS)
- Neuropeptide Y
Anorexigenic:
- Leptin (produced by adipose tissue)
- Cholecystokinin
- Serotonin
Food and food cues increase dopaminergic activity in nucleus accumbens - destruction of dopamine pathways reduces eating behaviour
In obesity D2 receptors are reduced in the striatum
What are the hypothermia and hyperthermia centres
- Preoptic anterior hypothalamus - hypothermia centre. Stimulation here causes sweating and vasodilation from parasympathetic drive
- Posterior hypothalamus - hyperthermia centre. Stimulation here causes shivering and vasoconstriction leading to hyperthermia.
A lesion in BLANK would affect diurnal body temperature
Median eminence
How does malignant hyperthermia arise?
Through abnormal excitation-contraction coupling in skeletal muscles
Can levodopa withdrawal cause NMS
Yes - NMS causes hyperthermia
What fibres carry pain sensation to the dorsal horn of the spinal cord?
- C fibres (unmyelinated)
- A-delta fibres (sparsely myelinated)
Which routes are responsible for fast and slow transmission of pain
Fast transmission of pain occurs through lateral spinothalamic tract - this aids localisation of pain
Slow transmission of pain occurs through recticulothalamic tract (this aids subjective sensation)
Name some neurochemical inputs that can modulate pain perception
- Opiod receptors in the dorsal horn and periaquetal grey matter (brain stem) modulate pain intensity
- Serotonergic raphne nuclei provide descending fibres that may affect how pain is perceived - explains the role of TCAs in pain
What is thalamic pain syndrome?
Stroke affecting thalamoperforating branches of posterior cerebral artery - here light cutaneous stimulation may cause contralateral loss of sensation with burning or aching pain
What areas of the brain play a role in the regulation of thirst
Subfornical organ
Organum vasculosum
Lamina terminalis
Name some inputs that may increase thirst
- Angiotensin II –> neurotransmitter that increases thirst
- Baroreceptors in aorta and carotid
How does ADH maintain a normal body fluid balance
Increases water reabsorption at renal tubules and maintains normal body fluid balance
Syndrome of inappropriate ADH secretion:
- Damage to paraventricular and supraoptic hypothalamic nuclei
- Carbamazepine or chlorpromazine
- Neoplastic syndromes
–> findings are low sodium, reduced osmolarity, normal renal excretion of sodium and high urine osmolality
How do the following disorders have abnormalities of physiological drives?
a) Kluver Bucy Syndrome
b) Laurence Moon-Biedl Syndrome
c) Prader-Wili Syndrome
d) Kleine-Levin Syndrome
e) Psychogenic polydipsia
a) Bilateral lesions of amygdala and hypothalamus. Reduced aggressive behaviour, examine objects with mouth, hypermetamorphosis, prominent oral exploratory behaviour and hypersexuality
b) Autosomal recessive genetic locus 11q13. Hypogonadism, obesity, low IQ, retinitis pigmentosa (no hypothalamic lesion)
c) Paternal deletion 15q11-q13. Reduced oxytocin neurons and satiety neurons. Poor control of body temperature and daytime hypersomnolence - related to hypothalamic disturbance. Obesity, short stature, hyperphagia, hypogenitalism, impaired glucose tolerance, hypotonia.
d) Kleine-Levin Syndrome - viral illness, resolves by 3rd decade of life. Compulsive eating, hyperphagia, hypersomnolence, hyperactivity, hypersexuality, exhibitionism - hypothalamic abnormality
e) Increase water intake not related to hypovolaemia or hypernatraemia
In fetal life where does neurogenesis occur?
Subventricular zone (surrounds the ventricles of the neural tube)
After neurons are produced in the subventricular zone they migrate outwards towards the cortical plate.
Thalamic axons that project to the cortical plate first synapse onto a transient layer of neurons called subplate neurons.
In normal development these axons detach from the subplate neurons and proceed to synapse to true cortical cells. This may not occur as readily in Schizophrenia
What is heterotopia?
Abnormalities of neural migration and neurons staying in ectopic positions
When does neuronal migration take place?
First 6 months of gestation
What is radial migration?
The process that excitatory neurons reach the cortex. Here radial glial cells form scaffolding that helps guide migrating neuronal cells - the cells accumulate in an inside out pattern (newest on outside) to form Rakic’s cortical columns
How does neuronal migration differ for inhibitory interneurons?
In external and internal granular layers - these cells tangentially migrate
Describe the time points that myelination occurs?
Starts around 4th gestational month
Largely completed by year 2
In association cortix may reach full extent by third decade of life
Which disease are associated with excessive vs. reduced synaptic pruning?
Schizophrenia - excessive
ASD - reduced
Synaptogenesis occurs between 2nd trimester - 10 years (peaks period < 2 years). By mid-childhood more neurons and cellular processes are established than needed for adult brain therefore pruning occurs into teenage years
What does cerebral plasticity refer to?
Ability of the capability of the brain to be moulded throughout life.
Cortical sensory maps can be reorganised - i.e. with practice for jugglers, musicians etc.
Phantom limb pain - amputated limb may show reorganisation so that area is on cortical face area
What hormones are released from the following areas?
a) Anterior pituitary
b) Posterior pituitary
c) Hypothalamus
Anterior pituitary:
- Growth Hormone
- Luetenizing hormone (gonadotrophin)
- Follicular stimulating hormone (gonadotrophin)
- Adrenocorticotrophic hormone (corticotrophin)
- Thyroid stimulating hormone (thyrotropin)
- Prolactin
Posterior pituitary:
- Vasopressin (ADH - antidiuretic hormone)
- Oxytocin
Hypothalamus:
- Corticotrophin releasing hormone
- Growth hormone releasing hormone
- Gonadotrophin releasing hormone
- Thyrotrophin releasing hormone (increases prolactin release)
- Somatostatin (inhibits GH)
- Prolactin inhibitory factor (dopamine)
Name some factors that affect the release of vasopressin?
Pain, stress , exercise, morphine, nicotine and barbituates increase release
Alcohol decreases release
Vasopressin is structurally very similar to Oxyctocin.
Vasopressin is involved in attention, memory and learning
What behaviours is Oxytocin involved in?
Bonding - initiation and maintenance of maternal behaviour, social bonding and sexual receptivity
Describe the pathway of thryoid hormone release?
TRH from hypothalamus –> TSH from anterior pituitary –> Thyroxine (T4) and Triidothyronine (T3, more potent. T4 is converted to T3 at target organs)
Patients with depression, mania, alcohol withdrawal and anorexia may show a blunted TSH response to exogenous administration of TRH
T3 activates nerve growth factor genes in early development but not in the adults brain
Hypothyroidism implicated in change to rapid cycling bipolar from previously stable. GAD associated with hyperthyroidism
Lithium may predisopose to hypothroidism in middle aged women who carry antithyroid autoantibodies
What is the pathway for cortisol release?
CRH (hypothalamus) –> ACTH (anterior pituitary) –> cortisol (adrenal glands)
How does chronic stress cause atrophy in the hippocampus
- Decreased neurogenesis in the hippocampus and atrophy of dendrites
- Atrophy of the hippocampus can cause impaired memory performance - additional as they may be aborisation of the dendrites in the basolateral amygdala there can be a memory bias towards negative events
When do cortisol levels peak?
6-7am and there is diurnal variation
Outline how cortisol levels have been found to vary in
a) Depression, Mania, (psychotic), OCD and Schizoaffective Disorder
b) PTSD
a) Hypercortisolemia - there may be loss of diurnal variation –> seen especially in melancholic depression
b) PTSD - due to increased glucocorticoid receptors in the pituitary there may be hypocortisolemia (? genetic vulnerability causing)
Outline how failure to suppress ACTH/CRH and cortisol production is shown with the dexamethasone suppression test:
At 11pm 1mg dexamethasone is administered with baseline cortisol measurement
The next day at 8am, 4pm and 11pm - serum cortisol is measured again
If any samples have > 5mcg/L this indicates non-suppression
DST non suppression is shown in….
DST suppression is shown in…
Non-suppression:
- Depression (especially if psychotic features/melancholic -sensitivity increases from 50% to 60-70%), mania, schizoaffective disorder
- Cushing’s, alcohol use disorder, extreme weight loss pregnany
- Use of other drugs that reduces dexamethasone availability - barbituates, anticonvulsants
Suppression:
- Hypopituitarism
- Steroids
- High-dose benzodiazepine
- Addisons
How does DST affect prognosis in depression:
- If non-suppression despite recovery from symptoms evidence suggests may be more likely to relapse, poor prognosis and possible later suicidality
Where are pinealocytes found and what do they secrete?
Pinealocytes are found in the pineal gland (epiphysis) and secrete serotonin and melatonin
What is corpora arenacea or brain sand?
Corpora Arenacea/Brain sand are calcium deposits that are found in the pineal gland that become more prominent with age
How is melatonin synthesised in the pineal gland?
Through the action of 2 enzymes:
- Serotonin-N-acetlyase
- 5-hydroxyindole-O-methylytansferase
Apart from the light-dark cycle what else regulates the pineal gland activity?
Beta-adrenergic system
- Beta-adrenergic antagonists (Propanolol) can decrease melatonin production
State some hormonal changes that occur at the following time points during sleep:
- Start
- Slow waves sleep
- REM sleep
- Early morning sleep
- Start of sleep increased testosterone
- Slow wave sleep: increased GH and SST with reduced cortisol
- REM sleep: reduced melatonin
- Early morning sleep: increased prolactin
What circadian rhythm properties does melatonin have?
- Synchronising
- Phase-shifting properties
Circadian rhythm day to day regulation of biological processes
By.1 month of age - 24-hr core body temperature rhythm
By 2 months - nocturnal sleeping pattern
By 3 months - melatonin and cortisol rhythms are established
Outline some ways that the physiology of sleep is measured?
Actigraphy:
- Assess sleep-wake patterns and movement disorders during sleep
Polysomnography:
- Includes electromyogram, electrooculogram, ECG, pulse oximeter and respiratory monitor
- Assesses and diagnoses sleep disorders such as narcolepsy, sleep apnoea, REM behavioural disorder and restless legs
Define the following terms:
- Sleep latency
- REM latency
- Non-REM latency
- Sleep efficiency
- Multiple sleep latency test
- Time from bed to sleep onset
- Time from sleep onset to first REM
- Time from sleep onset to first Non-REM episode
- (Time in asleep/Time in bed) x 100
- Helps assess daytime somonlence and daytime REM onset in narcolepsy
How much sleep is NREM vs REM?
NREM sleep makes up 75% of sleep
REM sleep makes up 25% of sleep
Outline stages 1-4 of NREM
Stage 1
- 5% of sleep
- Low voltage theta activity and sharp V waves
- Drowsy - deny being asleep if awoken
Stage 2
- 45% of sleep
- Sleep spindles and K complexes
Stage 3
- 12% of sleep
- < 50% of delta waves
Stage 4
- 13% of sleep
- > 50% of delta waves
Through stages 1-4 of NREM amplitude of EEG increases but frequency decreases
Stages 3&4 together make up slow wave sleep - dominates initial part of sleep
How does the physiology of NREM sleep and REM sleep compare to physiology of wakefulness
NREM sleep (reduced activity to wakefulness):
- Increased parasympathetic activity (decreased HR, BP, cerebral blood flow)
- Absent tendon reflexes
- Upward ocular gaze with no/or less movements
- Unable to recall dreams - night terrors is a NREM disorder - children can’t recall the terror
REM sleep (similar activity to wakefulness):
- Increased sympathetic activity (increased HR, BP, cerebral blood flow)
- Blood flow to genitals increased (active autonomic functions) - penile erections, vaginal blood flow
- Increased protein synthesis
- Can recall vivid dreams - nightmares occur in REM sleep
- Muscle tone lost most however with some myoclonic jerks
Describe EEG of REM sleep?
- Mixed frequency (slow alpha and theta) with mixed voltage
- Brain activity and physiology similar to wakefulness
When do the following EEG waves occur:
a) Sleep spindles
b) K complexes
c) V waves
a) Stage 2 sleep. Symmetric runs of upper alpha/low beta frequency. Parasagittal region
b) K complexes - occur when aroused from sleep. Large amplitude delta frequency waves (although sometimes generalised theta waves can follow K complex pattern - arousal burst). Throughout brain but bilateral in frontal areas mostly. Mediated by thalamocortical circuits
c) V waves. Bilateral in vertex of brain. Occur in stage 1 and 2 predominantly. Occur after sleep disturbances (sometimes when semiaroused like K complexes)
Where is the SCN located?
Anterior hypothalamus
Which inputs reset the SCN?
- The SCN is controlled by light input - receives via melanopsin-containing retinal ganglion cells project via retinohypothalamic tract
- Melatonin from pineal gland - during darkness and if delayed sleep onset or jet lag
In addition to the SCN what other brain area is important for promoting sleep onset?
Ventrolateral preoptic nucleus - this inhibits ascending arousal system thus preventing arousal nuclei
VLPO nucleus is inhibited by -ve feedback from monoaminergic system to allow people to wake up (i.e. ascending arousal pathways are active)
Orexin neurons in the hypothalamus reinforce the arousal system
What is the ascending reticular activating system?
A set of interconnected nuclei responsible for regulating wakefulness and sleep wake transitions
Outline some neurotransmitters involved in ARAS, where they are produced and their function
Acetyl choline - midbrain pons nuclei - REM on neurons - i.e. induces REM sleep
Noradrenaline - locus coerlus - REM off neurons - i.e. switches off/reduces REM sleep
Dopamine - periaqeuductal gray matter - enhances REM sleep
Serotonin - raphne nuclei - maintains arousal
Histamine - tuberomammilary nucleus - maintains arousal
Name some activation procedures used in EEG to bring up abnormal discharges?
- Hyperventilation
- Photic stimulation (stobe)
- Sleep deprivation (paroxysmal EEG discharges)
What is EEG used for?
Exclude neuropsych conditions e.g. epilepsy, metabolic encephalopathy, CJD
Monitoring of sleep in polysomnography
Outline the following EEG with regards to their frequency, region predominately expressed and when may be observed:
a) Delta (slow)
b) Theta (slow)
c) Alpha (fast)
d) Sigma
e) Beta (fast)
f) Gamma
g) Mu
h) Lambda
a) 1-4Hx - frontal in adults/posterior in children - SWS (stages III and IV), if found when awake strongly suggests pathology
b) 4-8Hz - generalised - stage I sleep (drowsy/sleeping), small amounts when awake in frontotemporal region but if a lot it strongly indicates pathology
c) 8-13Hz - posterior (occipitoparietal areas) - when eyes closed and relaxing i.e meditation. Not present if anxiety or eyes open. With age its dominance over other waves down
d) 12-14Hz - frontal and central - is sleep spindles occurs in stage 2 sleep (with K complexes)
e) 12-30Hz - frontal and central - when busy or concentrating (awake)
f) 30-100Hz - no specific areas - only for very advanced meditators
g) 7-11Hz - over motor cortex (arch like wave attenuated by movement of the contralateral limb)
h) Single waves - triangular shape, produced with visual scanning when awake (reading) or in light sleep
When does the EEG show characteristic appearance of an adult
12-14 years EEG essentially has appearance of adult
Newborns - delta and theta predominate
Infants - irregular medium to high voltage delta waves
Early childhood - alpha waves begin to develop in posterior regions
When may the following changes been seen on an EEG?
- Diffuse slowing of background EEG
- Focal slowing
- Epileptiform discharges (interictally)
- Epileptiform discharges lateralised and periodic
- Diffuse slowing of background EEG is seen in encephalopathy
- Focal slowing - a local mass lesion - oedema, haematoma or focal seizure
- Epileptiform discharges inter-ictally indicate a seizure disorder (however these are rare) - in outpatient setting EEG detects 30-50%
- Epileptiform discharges (lateralised and periodic) indicate acute destructive brain lesion
What are the EEG findings in the following seizure disorders:
a) Typical absence
b) Atypical absence
c) Focal
d) Myoclonic
e) Generalised tonic-clonic
f) Atonic
a) Generalised 3Hz spike and wave
b) Slow (< 2.5Hz) spike and wave
c) Focal spikes
d) Generalied 3-6Hz polyspike and discharge
e) Fast rhythmic spikes in tonic stage vs. bursts of spikes and after slow-coming in clonic stage. Post ictal there is irregular slow activity
f) Generalised spike and wave with atonia at time of slow wave
How does EEG affect the following drugs?
a) Antipsychotics
b) Antidepressants
c) Lithium
d) Anticonvulsants
a) Slowing of beta, increase alpha, theta and delta
b) Slowing of beta, increase alpha, theta and delta
c) Slowing of alpha or paroxysmal activity
d) No effect on awake EEG
What has better spatial resolution - EEG or MEG?
MEG - magnetic field less obscured by scalp/skull and can detect activity to specific gyri and sulci
What is an ERP
Event related potential - how change in activity links to a time-locked event (can happen after a stimulus or due to the absence of one)
Compare and contrast early, mid and late latency ERPs
Early ERPs:
- Evoked or brain stem evoked responses
- Refer to early response to sensory info e.g. sounds, flashes, or electrical stimulation (somatosensory EP)
Mid latency ERPs:
- N100, P50, P200
- Occur after BAER
- Habituation reduces amplitudes (habituation response or sensory gating)
Late ERPs:
- Cognitive pathways studied here with EEGs reflecting neuropsychological functions e.g, attention, memory
- P300 and MMNs are late ERPs
What are P300, MMN and CNV
Specific ERPs:
- P300 is a positive late ERP that occurs when a rare target stimulus occurs with more frequent stimuli auditory “oddball” protocol - trait marker of schizophrenia. P300 is related to ongoing function of working memory
- Mismatch negative (MMN) –> negative ERP between 100-200ms that occurs when an unexpected sound occurs following previous standard ones, with the ppts not actively attending to deviant stimuli - decrease in MMN amplitude is seen in Schizophrenia
- Contigent negative variation - is a slow negative shift in the interval between two paired stimuli presented one after the other i.e. cue then an another stimulus that one should respond. In Schizohrenia there is a reduction in CNV in central electrodes
Describe the role of neurotransmitters during sleep:
As light fades noradrenaline and sertonin are released (from locus coerlus and rapnhe nucleus) into the lateral hypothalamus - this prevents orexin release and wakefulness is not stabilised
Ventrolateral preoptic nuclei and GABA then take charge and suppress all arousal neurotransmitters
Melatonin is secreted at night in dark
Acetylcholine - REM activating, lowest in phase 4
Dopamine, histamine, serotonin, noradrenaline - most active in phase 2 and lowest in REM
How do stimulants affect sleep?
Reduce both REM and SWS (phases 3 and 4):
- On cessation of stimulants (exlucding modafinil) REM rebound occurs - true for methylphenidate
How do benzodiazepines affect sleep?
Reduced sleep latency
Increased sleep time
Reduced phase 1
Increased phase 2 sleep
Reduced phase 3-4 sleep
Reduced REM sleep
REM rebound on cessation
Is rTMS an emerging treatment for dystonia?
Yes
What clinical neurotransmitter receptor finding has been replicated after a course ECT for depression?
Reduced post-synaptic beta-adrenergic receptors
- Effects of ECT on serotonin are controversial
What is Angelman’s syndrome and how does the EEG alter?
- Severe development disorder - movement abnormalities (ataxia, temor), odd behaviour (frequent laughter), speech delays
- Seizures begin 1-3 years
- EEG shows by age 2 - prolonged runs of high amplitude 2-3Hz frontal activity with superimposed interictal epileptiform discharges AND occipital high amplitude 3-6Hz rhythmic activity faciliated by eye closure
For depression where is the coil in rTMS?
- Left PFC (left DLPFC) - affects activity in other regions
In a patient with a healthy sleep pattern what is the REM latency (sleep onset to first REM episode)?
90 minutes
4-5 sequential cycles of sleep each lasting between 90-110 minutes.
As night goes on REM sleep increases and time in delta sleep decreases.
What do benzodiazepine and barbituates do to beta activity?
Both benzodiazapines and barbituates show a significant increase in beta activity
When do growth hormones levels peak during sleep?
Slow wave sleep - stage III and IV
What is Kleine Levin Syndrome?
- Periodic attacks of hyperphagia, hypersomnia that has a predominance in males
In neonates which phase of sleep predominates?
REM sleep - most neonates spend 50% of sleep time her (sleep for 16-20hrs)
Where are CB1 and CB2 receptors located?
CB1 - primarily CNS
CB2 - lower levels in CNS - in vascular areas and microglia
Anandamide is a partial agonist - low affinity for CB1 and v low for CB2
2-AG has a high affinity for both
Do cortical lewy bodies have a halo?
No - subcortical lewy bodies have a halo
The posterior cranial fossa contains?
The foramen magnum, the occipital lobes, the cerebellum, the medulla and occipital bones
Anterior cranial fossa - frontal lobes, lesser wing of sphenoid bone, ethmoid bone
Middle cranial fossa - temporal lobes, greater wing of the sphenoid bone
Differentiate UMN and LMN signs
UMN
- Weakness
- Upgoing plantars
- Increased tone (spasticity)
- Increased reflexes
- Mild atrophy
- Clonus
LMN:
- Weakness
- Decreased tone
- Decreased reflexes
- Fasiculations
- Atrophy
Can serotonin cross the BBB
No! - L-tryptophan can but serotonin cannot
Where is somatostatin produced and what does it do?
Hypothalamus - inhibits TSH and GH release
Pancreas alongside Insulin, Glucagon, Pancreatic polypeptide
Other actions:
- Inhibit release of gastrin (stomach) secretin & CCK (duodenum), glucagon (pancreas)
Cholecytokinin, Leptin and Serotonin
inhibit appetite
Ghrelin (produced in stomach) and Neuropeptide Y stimulate appetite
What is the central sulcus also known as?
Fissure of rolando
Outline the four types of gene studies
Basic genetic epidemiology - estimates how much familial aggregation and heritability estimates
Advanced genetic epidemiology - explores the mechanism of action of genetic risk factors
Gene finding - locates the genomic location and finds the genes
Molecular genetics - identifies the biological pathway from DNA
Gene mapping refers to any methodology used to identify the location of a gene
How does pairwise concordance and proband concordance vary?
Pairwise concordace:
- Number of affected twins both with disorder / total pairs
Proband concordance:
- Number of affected co-twins in previously identified index cases
How does the family study method differ to the family history method?
Family history method only interviews the index person - often many false negatives
Family study method interviews all - more expensive but more reliable
How does complete case ascertainment differ to multiple incomplete ascertainment?
Both methods of identifying cases from family studies
- Complete case ascertainment identifies all cases that have occurred
- Multiple incomplete ascertainment looks at consecutive referrals - some individuals may not have reached target age to develop - important to apply age correction (Weinberg short equation)
What is recombination?
The process of generating new genetic codes through crossing over or synapsis of loci
Crossing over is more likely to occur if loci are further apart (but on same chromosome)
Loci close together are less likely to cross over
The recombination frequency assess the distance between two loci by estimating the rate that crossing over occurs (0% - no crossing over i.e. vary close vs. 50% crossing over). Measured in centiMorgans
What is a LOD score?
A way of assessing linkage between genes
LOD = log10 (probability the recombination frequency is the observed value)
> 3 high evidence of linkage
< -2 no linkage
What is linkage disequilibrium?
When different combinations of alleles at the loci are seen on chromosomes more often than chance
Alleles close together are unlikely to cross over - therefore certain combinations without cross-over is likely - exhibit linkage disequilibrium
What is positional cloning?
Studying genes due to their position on the genome rather than function
Outline some problems with association studies?
Candidate genes are chosen - biased
There may be association despite irrelevant genes if cases and controls are not ethnically well matched
Outline the criteria that endophenotypes need to fulfill?
- Must be associated with candidate gene or region
- Must be present with high risk relative cosegragating with actual illness
- Must be a parameter associated with biological plausibility
- Must be independently assessed in a clinical state (must not be a state but trait marker)
- Must be heritable
- Must be present in relatives more often than the general population
Who termed the coin epigenetics?
Waddington
Do psychiatric conditions follow non-contingent gene-disorder relationships?
No - the majority follow contingent gene-disorder relationships i.e the relationship between gene and disorder depends on multiple other factors
What two models exist regarding causal modelling of genetic in psychiatry
common disease - rare variant model:
- There are various but rare mutations that cause the disease and at risk families may inherit one of them. When these variant occurs the disease occurs. Each variant is sufficient but not necessary to cause the disease
common disease - common variants:
- Diseases may arise from the action of many co-occurring polymorphisms. These are common but alone not sufficient to cause the disease but when together susceptibility of disorder increases - this is the philosophical underpinning of current linkage and association studies.
