Neuro 5/6: Neurobiology and neurochemistry in mental health Flashcards
what is the stress diathesis model? (schizophrenia)
stress = in utero insults (hypoxia)
psychological stress cannabis use
diathesis = genes such as COMT, dysbindin1 and NRG1, these are polygenic and partial penetrance.
define psychosis
‘break from reality’ defined as 7 days of psychotic sx but they can be on a continuum.
what are the sx of schizophrenia
Positive:Voices, delusions, thought insertion/withdrawal/broadcast
Negative: Neglect, isolation, lack of emotional expression, avolition
Cognitive: Reduced concentration and attention, reduced executive functioning (ability to plan complex tasks)
what is dopamine and what is its precursor?
Monoamine neurotransmitter
Metabotropic, G-protein coupled receptors
Precursor = Tyrosine
what does dopamine do?
Executive functions Motor control Motivation Reward Lactation Nausea
describe the different pathways
Mesocortical (VTA-> cortex)
mesolimbic (VTA-> nucleus accumbens)
nigrostriatal (susbtanantia nigra -> caudate nucleus putamen)
tuberoinfundibular (hypothalamus -> pituitary)
how does SCZ affect the pathways?
upregulation of DA in mesolimbic -> +ve sx
downregulation in mesocortical -> -ve sx
how would a typical antipsychotic work?
blocks DA in both mesocortical and mesolimbic making +ve sx better but -ve sx worse
why do antipsychotics cause hyperprolactinaemia
Dopamine has inhibitory effect on prolactin release.
Reduced dopamine by D2 antipsychotics therefore causes
Hyperprolactinaemia
why would the dopamine theory not be the correct one?
New atypical antipsychotics work in different ways on non-dopaminergic pathways
Illicit drugs that don’t work on dopamine can mimic psychosis (e.g. magic mushrooms, PCP)
Medical conditions affecting different receptors can cause psychosis
how do antipsychotics cause EPSE?
Too little dopamine effect in Nigrostriatum causes Extrapyramidal Side Effects
what are some reasons as to why glutamate would be involved in psychosis?
Ketamine and PCP (angel dust) act on NMDA glutamate receptor and are powerful causes of psychosis
Research shows too little glutamate in pre-frontal cortex mirrors psychosis
NMDA receptor autoimmune encephalitis causes psychosis
how does Glu lead to psychosis?
Reduction in glutamate release leads to direct loss of dopamine release in PFC via mesocortical pathway
Reduction in glutamate release leads to increased positive symptoms by mesolimbic pathway
how does GABA cause psychosis?
GABA is the brain’s main inhibitory neurotransmitter
Reduction in glutamate release leads to reduced GABA inhibition which increases positive symptoms (dopamine hyperactivity in mesolimbic pathway)
what is serotonin?
5-HT
what are the anatomical changes seen in schizophrenia?
Enlarged ventricles
Reduced grey matter volumes
Decreased gyrification
Loss of asymmetry of planum temporale (associated with auditory processing)
what are some organic causes of psychosis?
NMDA receptor autoimmune encephalitis Huntingdon’s Chorea Temporal Lobe Epilepsy Wilson’s Disease Parkinson’s Disease
what is NMDA receptor encephalitis?
Antibodies form against NR1 and NR2 subunits of NMDA (glutamate) receptor
Associated with teratomas
Presents with flu like illness or encephalitis or psychotic symptoms
May need ITU due to autonomic instability
Immunosuppression with steroids
what is temporal lobe epilepsy and how can it cause psychosis?
Can have no impairment of consciousness during seizure
Depending on part of temporal lobe can have hallucinations in all modalities, extreme fear, amnesia, difficulty maintaining thoughts, dissociation
Can have post-ictal psychosis
Can have inter-ictal (between seizures) psychosis
Require EEG and neurologist input
What is wilson’s disease?
Autosomal recessive disease
Faulty ATP7B gene affecting Wilson’s disease protein
Leads to copper deposition in brain and liver
Affects Basal Ganglia
Neuropsychiatric complications include cognitive impairement, depression and psychosis
Don’t forget to look for kayser-Fleischer rings in the eyes
what is Hungtington’s Chorea?
Autosomal dominant – CAG triplet repeats in the Huntingtin gene
CAG >28 unstable during replication
28-35 is subthreshold, 35-40 “reduced penetrance”
Every generation increases the instability of the CAG triplets and therefore risks increasing the number of repeats.
This leads to earlier onset and more severe symptoms (particularly if subthreshold parent)
This is called genetic anticipation
Pathophysiology of psychosis unclear, ?dopamine overload following cell death
what are the 2 types of Bipolar affective disorder?
Discrete episodes of depression AND mania/hypomania.Bipolar Type 1 = Depression and ManiaBipolar Type 2 = Depression and Hypomania
what is the role of the limbic system?
Role of limbic system:
Emotional regulation
Memory formation
Learning
how are emotions processed?
There is both communication TO PFC as well as “Top down” regulation FROM the PFC.Oschner 2005
This allows for executive control of emotional states
what is the theory of limbic dysregulation in Bipolar disorder?
Underactivation of pre-frontal cortex seen using fMRI Chen et al 2011
AND
PFC volume loss observed as disease progresses
LEADS TO
Reduced “Topdown” regulation
Reduced connectivity between PFC and amygdala
what is the role of the amygdala in bipolar disorder?
Overactivity of Amygala on fMRI in response to faces
Decreased volume of amygdala seen in pediatric cases and those with bipolar and first episode psychosis.
what are the physical changes in the brain in bipolar?
Loss of prefrontal cortex mass and progressive hypoactivation
Sustained hyperactivity of amygdala and increasing volume size
what are the 3 key sx of depression?
Low mood
Anhedonia
Tiredness
what are some additional sx seen in depression?
Cognitive (hopelessness, helplessness, worthlessness, guilt, poor concentration, poor attention, lack of motivation) Somatic (early morning waking, loss of appetite, weight loss, libido) Motor symptoms (slow motor movements – “Motor Retardation”)
What is the stress diathesis model for depression?
stress = Divorce BereavementRelationship Breakup Job Loss
diathesis = Female Gender
genetic vulnerability
what is the monoamine theory?
All derived from aromatic acids Receptors act downstream on Adenyl Cyclase or Phospholipase C
All have designated monoamine transporters for transport in/out of cell e.g. Seretonin Transporter, Dopamine transporter etc…All are broken down by Monoamine Oxidase
what is evidence for low serotonin in MDD?
Dietary depletion of tryptophan (precursor for serotonin) can cause relapse of depression in patients who have previous diagnosis or family members
Reserpine – An antihypertensive that causes rapid depletion of serotonin in the synaptic cleft classically causes depression
Selective Serotonin Reuptake Inhibitors (SSRIs) work by blocking the reuptake of serotonin in to the pre-synaptic neuron
how is NA involved in MDD?
Noradrenaline projects from the Locus Coreleus to innervate the limbic system and frontal lobe
Decreased noradrenergic receptor density seen in some patients with depression
what is the difference between an anxiety disorder and fear?
Fear (Imminent danger) vs. Anxiety (anticipation of potential threat)
what occurs in the amygdala in anxiety?
The Amygdala differentiates the sensory information sent by the thalamus to identify threat from no threat.
If a threat is perceived through the conscious or unconscious pathways, the Amygdala can initiate a physiological response that we see in stress reactions and anxiety disorders
what are the characteristic signs of PTSD?
Post Traumatic Stress Disorder characterised by hypervigilence, flashbacks, nightmares and avoidance.
In PTSD the hippocampus shrinks
describe the step by step of how PTSD occurs?
trigger -> hippocampus recalls a small fragment of memory -> amygdala reacts to memory -> PFC unable to rationalise situtation -> unable to recognise person is safe -> person attempts to avoid or escape.
