Neuro 4 - psychopharmacology, epilepsy and memory Flashcards
Common features of monoamine pathways in cortical innervation
Serotonin, dopamine and noradrenaline are monoamine neurotransmitters
- few cell bodies, arise in upper brainstem
- radiate to most cortical areas
- modulatory function - released from varicosities on axon, not direct synapse-synapse transmission as with glutamate (so good drug target, less extreme)
Locus coeruleus - NA nucleus
Raphe nucleus - Serotonin
Substantia nigra - Dopamine
Monoamine neurotransmitter functions
NORADRENALINE
Attention
Arousal
SEROTONIN
Impulsivity
Flexibility
DOPAMINE
Reward
Learning
Have all -> cognition, emotion
NA + S -> anxiety, irritability
NA + D -> motivation
D + S -> appetite, aggression
Re-uptake inhibitors
Tricyclic antidepressants mainly!
Anxiety - SSRI’s, tricyclic antidepressants
Eating disorders - SSRI’s in anorexia/bulimia, amphetamine, sibutramine as anti-obesity
Behavioural disorders - cognitive enhancers. For ADHD - methylphenidate, amphetamine salts, atomoxetrine, modafinil
Addiction - buproprion to aid smoking cessation
(monoamine dysfunction may not be part of cause of disease, but drugs improve symptoms)
Attention deficit hyperactivity disorder
ADHD
Symptoms - inattention, hyperactivity, impulsivity
Type I - combined
Type II - predominantly inattentive
Type III - predominantly hyperactive-impulsive
Usually in children, some grow out of, sometimes persists into adulthood
Unsure of cause - probable neurodevelopment
> cortical / subcortical hypofunction - dysregulation of neurotransmission
Use ritalin, atomoxetine to increase cortical NA/DA - restore monoamine transmitter levels
Action of stimulant drugs
Noradrenaline enhances signals via α2A
Dopamine decreases noise via D1 stimulation
-> together, optimal attention
Unguided attention - too much noise - low D1/α2A
Misguided attention - high D1/α2A
Cognitive dysfunction in neurodegenerative disorders
Parksinson’s, Alzheimer’s
NA degeneration in both
- acetylcholinesterase inhibitors - learning and memory
- anti-muscarinics and dopaminergics - motor dysfunction
? noradrenergics and cognitive enhancers help? (maybe memory impaired as distracted)
Treating impulsive behaviours
ADHD, + addiction/obesity/aggression
ADHD in children - methylphenidate, amphetamine
Smoking cessation - DA and NA re-uptake inhibitor
ADHD - non-stimulant NAT inhibitor
Non-stimulants, so options for treating addiction
Is drug abuse voluntary?
Initially, yes
Only 10-15% who try get addicted, some people more vulnerable
Drug addicts - reduced self control, altered judgement and decision making, changes in learning and memory - impaired dopamine system
-> drugs stimulate pleasure and reward, brain designed to learn to repeat these, reduced control
Drugs to treat obesity
Consider obesity as impulse control disorder - not just less food more exercise
Amphetamine - very effective!
Atomoxetine
Symptoms of schizophrenia
POSITIVE
- delusions
- hallucinations
- disorganised thought
- abnormal behaviour
- –> can be treated well with antipsychotics, but need to consider other elements
NEGATIVE
- blunted emotions
- anhedonia - can’t feel pleasure/reward
- speech poverty
- attention impairment
- loss of motivation
COGNITION IMPAIRMENT
- new learning
- memory
- executive function
MOOD
- depression
- anxiety
- impulse control
Antipsychotic drugs (= neuroleptics)
Two classes:
TYPICAL - D2 antagonists, but also bind to many others
- phenothiazines - chlorpromazine
- butyrophenones - haloperidol
ATYPICAL - 5-HT2 (serotonin) and D2 antagonists, less extrapyramidal side effects
- clozapine
- risperidone
- aripriprazole
Aetiology of schizophrenia
Poorly understood
- Environmental and genetic factors
- pregnancy complications - flue, pre-eclampsia, delivery, gestational diabetes
- socioeconomic group
- stress
- cannabis
Hypoglutamergic/hyperdopaminergic function alters impact to cortex
Neurochemistry behind schizophrenia
Hyperdopaminergic - treat with D2 receptor blockade
Serotonergic dysfunction - treat to block 5-HT2 also
Glutamate hypofunction - treat with NMDA agonists
(serotonin, dopamine, noradrenaline and GABA all work together)
D2 receptor blockade effects
(typical antipsychotics)
In mesolimbic pathway - reduces positive symptoms
In mesocortical pathway - increases negative symptoms, cognitive deficits
In nigrostriatal pathway - induces motor side-effects (parksinsonism)
In tuberoinfundibular pathway - some increased hormone secretion
-> good effect on positive symptoms, but major side effects
Old treatments for schizophrenia
Insulin-induced coma
Prefrontal lobotomy
Electroconvulsive shock therapy (ECT)
D2 and 5-HT2 blockade effects
(atypical antipsychotics)
Improved efficacy, fewer side effects
- Faster on/off kinetics - easily displaced by endogenous agonist (eg in motor pathway)
- 5-HT2 antagonism
- Other targets
Aripriprazole
D2 receptor partial agonist (atypical antispychotics) AND 5-HT2 antagonist
Where excessive dopamine, antagonist effect (eg mesolimbic pathway)
Where low dopamine, agonist effect (eg mesocortical pathway)
-> prevents total blockage of D2 receptors, conserves some normal function - agonises where necessary
Receptor blockade in schizophrenia treatment and associated side effects
D2 - extrapyramidal (involuntary motor), prolactin elevation
M1 - cognitive deficits, dry mouth, constipation, increased HR, urinary retention, blurred vision
H1 - sedation, weight gain, dizziness
alpha1 - hypotension
5HT2c - satiety (appetite) blocked -> weight gain
Mental state examination
Appearance and behaviour Speech Mood Anxiety Hallucinations? Thought content Features of thought disorder? Cognition Insight
Drugs of abuse
- most stimulate nucleus accumbens, centre for reward and learning
- best drugs have fast on/off pharmacokinetics, to best mimic endogenous neurotransmitters
- 15% of those abusing drugs -> addicted
Opioids (drugs of abuse)
Target μ opioid receptor (MOP)
- > reduce GABA inhibition of dopamine neurones - disinhibition
- > induces feelings of euphoria
HEROIN
- diamorphine
- more rapid, as more methyl groups, more lipophilic
- > constipation, respiratory depression (most common cause of overdose death)
- – treat with naloxone in overdose
Stimulants (drugs of abuse)
COCAINE
- blocks dopamine re-uptake to presynaptic membrane
-> continued stimulation of nucleus accumbens
Mixed with bicarbonate -> crack cocaine - as is more unionised so enters cells faster
Fastest effects when smoked
AMPHETAMINE/METHAMPHETAMINE = speed, crystal meth
- cause dopamine release, and inhibits reuptake
- meth more popular - extra methyl group so more lipid soluble, faster uptake and effect
MDMA (drugs of abuse)
= ecstasy
- 5HT (serotonin) release, inhibits 5HT reuptake
(this directly stimulates nucleus accumbens)
Cannabis (drugs of abuse)
THC is active ingredient - tetrahydrocannibinol
- highly lipophilic, so rapid onset, but persists for long time
CB1 receptors in brain
-> feeling of wellbeing, appetite stimulant, effects on cerebellum (movement), reduced memory (hippocampus)
Long term -> reduced motivation, cognitive deficiciency, potentially induces schizophrenic episodes
Calls to legalise for medicinal use - pain, muscle spasms (parksinson’s)
Ketamine (drugs of abuse)
NMDA antagonists
- reduced glutamate activity to interneurones, so can’t have inhibitory effect on nucleus accumbens
Long term -> ketamine induced ulcerative cystitis needing bladder removal - Bristol bladder! and psychosis possible
Nicotine (legal high - drugs of abuse)
Stimulates dopamine release to nucleus accumbens
+ in combination with tobacco -> highly addictive - psychological, physical dependence, tolerance
90% lung cancer deaths
80% emphysema deaths (COPD)
Lowers birth weight in pregnancy
Ethanol (legal high - drugs of abuse)
Increased inhibition of GABA inhibition to dopamine neurones
- so increased dopamine release to nucleus accumbens
also -> aggression, poor coordination, amnesia, liver damage
(when taken with cocaine, converts cocaine to toxic metabolite)
Treatment of addiction
Reduce withdrawal syndrome
- ‘easy’ part, manage symptoms with replacement therapy or directly targeting symptoms
Reduce cravings
- most will relapse 3 months later (well past withdrawal), so need to use eg CBT
Reduce relapse
- treat underlying reason for drug use - CBT/partial agonist/psychological management/support groups
Definition of anxiety
Fear response - series of defensive responses, autonomic reflexes, and states of arousal/alertness to (potentially) negative stimuli - NORMAL
Anxiety - anticipation of fear in the absence of external stimuli, general feeling or according to certain situations - ABNORMAL
- brain regions for fear response (eg amygdala) should be shut down usually, here they are not inhibited
- disruption of serotonergic (5-HT) system
Types of anxiety
General anxiety disorder - general increase in anxiousness, no clear stimulus causing
Social anxiety disorder (clear stimulus)
Phobias - is stimulus, but wouldn’t usually trigger fear response in others
Panic disorder - sudden attacks of overwhelming fear, particularly physical symptoms
Post traumatic stress disorder - recall of traumatic event
Obsessive compulsive disorder - compulsive, ritualistic behaviour driven by irrational anxiety
Body dismorphic disorder - distorted view of appearance causing anxiety
Psychological interventions to anxiety
FIRST LINE - not drugs!
Counselling
Psychotherapy
Cognitive behavioural therapy
Pharmacological interventions to anxiety
SECOND LINE to psychotherapy
Antidepressants - but slow onset action (3-4w), sometimes increases anxiety initially
Benzodiazepines - faster onset, but induce dependence and have side effects
5-HT₁ₐ receptor agonists - slow onset action (3-4w), sometimes increases anxiety initially
Antiepileptic drugs - gabapentin, pregabalin, tiagabine, valproate - can be effective in general anxiety disorder
β adrenoreceptor antagonists - treat symptoms not cause
Anti-psychotics - helpful in some types (rare)
Anxiolytic, sedative and hypnotic definitions
ANXIOLYTICS
Help to bring down over-aroused nervous system
SEDATIVES
Depress level of nervous system to below normal - helpful in acute anxiety, or before stressful experience eg surgery
HYPNOTIC
Further depress nervous system, cause sleep - eg in insomnia
Anxiolytic drugs
Antidepressants
Buspirone (5HT1a agonist)
β adrenoreceptor antagonists
Relieve anxiety only
Hypnotic drugs
Antihistamines
(chloral hydrate, sodium oxybate)
NOT anxiolytic, just sleepy
Anxiolytic, sedative and hypnotic drugs
Benzodiazepines
Z drugs - Zopiclone (similar), used mainly as hypnotics
Barbituates - phenobarbitone
Antidepressants use for anxiety
Usually first drug class to try
SSRIs common
- selective serotonin re-uptake inhibitors, inhibit 5-HT transporter so serotonin remains for longer
- sertraline, citralopram, fluoxetine
(something else going on, or would have rapid response)
SNRIs maybe
- venlafaxine
MAOIs/TCAs not as common - side effects severe, less effective generally. Used after others not effective maybe.
Also treats depression that may be associated with anxiety - good
Benzodiazepines
- eg NITRAZEPAM, LOPRAZOLAM, ZOLPIDEM, DIAZEPAM
Anxiolytic, sedative and hypnotic drug
Clinical use - anti-anxiety - sedative - hypnotic - anticonvulsant - muscle relaxant (used pre surgery, to aid sleep, anti-epileptic)
Side effects
- drowsiness (bad in treating general anxiety), confusion, amnesia, impaired motor coordination, lack of depth perception, reduced REM sleep
SHOULD NOT BE USED ROUTINELY TO TREAT ANXIETY - may be useful in acute, severe situation for up to 4 weeks
- Different lengths of action contribute to function (eg short half life useful for insomnia, not anxiety)
- Become tolerant long term
- Physical dependence, withdrawal symptoms, need to withdraw slowly
Benzodiazepines mechanism of action
Bind to GABAₐ receptor (2 alpha, 2 beta, 1 gamma subunit - pentameric structure. Also variations in subunits, many many combinations possible, some variations more/less sensitive to drugs than others)
Enhance affinity of GABA binding
Increase frequency of Cl- ion channel opening
(-> hyperpolarise, more negative, inhibits neurone firing)
- though channel open more frequently, still open for same amount of time
Flumazenil
Benzodiazepine antagonist
- reverses actions, but not recommended for overdose treatment as side effects eg seizures
-> anxiety in those who don’t take benzodiazepines
Barbituates
eg PHENOBARBITONE
Anxiolytic, sedative and hypnotic
Agonise GABAₐ receptors - but non selective
- channel opens same number of times, but open for longer
Common use before benzodiazepines, now not
- tolerance
- dependence
- anaesthesia and death in overdose
Still used as anaesthetics, rarely anxiety
5-HT₁ₐ receptor agonists
eg BUSPIRONE
Anxiolytics
PARTIAL agonists - less sedation and motor side effects - safer
Some side effects - nausea, dizziness, headache, restlessness, but fewer than others
- no tolerance
- no dependence
Ineffective against panic attacks or severe anxiety
- takes weeks to have therapeutic action
- may initially increase anxiety
(yet only licensed for short term use, few months)
5-HT₁ₐ receptors are somatodendritic autoreceptors (expressed on cell body/dendrites of serotonergic neurones) in raphe nucleus
- receptors desensitise on repeated exposure
- so enhanced 5-HT release all over brain
(so repeated treatment -> anxiolytic effect, good to desensitise receptors)
HENCE why takes weeks to have effect
β adrenoreceptor antagonists
eg PROPANOLOL
Anxiolytic
Remove peripheral symptoms only, doesn’t treat anxiety
(palpitations, sweating, tremor)
- so useful for eg panic attack
No CNS effect
Hypnotic drugs
Antihistamines
- diphenhydramine, promethazine
- uses drowsiness (side effect) as main effect, though do get hangover
Melatonin receptor agonists
- pineal gland hormone - increased secretion at night to synchronise circadian rhythm -> sleep
- effective esp in elderly, autistic children
Viral Encephalitis/Meningitis/Neuritis
ENCEPHALITIS Inflammation of brain - altered consciousness - change in emotions, personality, behaviour - focal neurological signs \+ fever, headache, seizures
MENINGITIS Inflammation of meninges - constant severe headache - photophobia - neck stiffness (more common in summer)
NEURITIS
Inflammation of nerve
- nerve function altered or damaged
Viral meningitis agents
Enterovirus - 30-50% causes, faeco-oral route, usually self limiting, milder
Parechovirus
Mumps virus
Herpes simplex 2
Varicella zoster virus
Viral encephalitis agents
Herpes group virus - severe, often fatal
Flavivirus encephalitis Togavirus encephalitis (equine) Enterovirus Rabies Retrovirus (HIV)
Viral infections of spinal cord agents
Poliovirus (and other enteroviruses)
Varicella zoster
HTLV
Aseptic viral meningitis
Can’t identify causative organism
Often from partially treated bacterial meningitis in community setting, not got rid of organism
OR
No organism at all - inflammatory process only
- sore throat for one week
- increasing headache last 24 hours
- nausea comiting
- no alteration in conscious level or neurological function
- neck stiffness
- photophobia
(worse in neonates - irritable, feverish)
Management of meningitis
Investigate:
- lumbar puncture (if no raised ICP)
- look for raised white cells, lymphocytes, raised protein, low serum glucose in CSF
- symptom management, bed rest, analgesics, anti-emetics
(excellent prognosis)
Types of viral encephalitis, and key clinical features
Sporadic
Post-infectious
Epidemic
Chronic progressive
- fever
- altered behaviour
- confusion/drowsiness
- seizures
- autonomic instability
- raised ICP
Do PCR to detect viral nucleic acid in CSF
Sporadic encephalitis
Most common
Herpes simplex virus type 1 most common
Herpes simplex encephalitis
10% of viral encephalitis
-> haemorrhages, blood vessel inflammation, nuclear DNA
Often localises to orbital-frontotemporal lobes (more diffuse in children)
-> short term memory loss
Aciclovir to treat - only treatable virus here!
80% mortality without treatment, often still need neurological rehab
Herpex simplex virus 2
Primary infection, then stays latent with no symptoms
Immunodeficiency can lead to fatal dissemination
Varicella zoster virus
-> chickenpox and shingles
Highly contagious, marked seasonality in winter and spring
Respiratory route spread
Transports along sensory nerves to ganglia, where becomes latent
-> dermatomal rash, acute ganglionitis, intense inflammation, cell necrosis
SHINGLES
50% over 85s get - as immunity declines with age
5 days before rash, dyesthesia (tingling pain), can persist for months after
Immune suppression -> reactivation, life threatening
Post-infectious viral encephalitis
Rare complication of acute viral illness (measles, chickenpox, influenza, mumps, rubella)
Immune response to virus in brain
Chronic progressive viral encephalitis
Continued infection after acute
-> progressive loss of brain function, often -> death
SSPE - subacute sclerosing panencephalitis
Children and young usually
3:1 more in males
Severe, often death 1-3 years later, dementia, motor function, seizures
(years after exposure to eg measles)
(may have normal lumbar puncture)
PML - progressive multifocal leukoencephalopathy
Papovavirus family eg papilloma
Initially infects GI and resp tract, then moves to CNS and other organs
-> visual deficits, cognitive impairment, motor weakness, gait disturbance
Global disturbance - takes up large part of cortex
-> death in 3-6 months if not treated
(look for JC virus antibodies in PCR)
No specific treatment, just help to restore immunocompetence
CNS manifestations of HIV
Shouldn’t have, if have treatment
Space occupying lesions - toxoplasmosis, lymphoma, PML, tuberculoma
Diffuse disease - cryptococcal, meningitis, acute infection, HIV dementia
Diagnosing encephalitis
CT/MRI
CSF examination shows many cells, lymphocytes, normal glucose, elevated protein
HSV or VZV DNA detection by PCR
Detect enterovirus or RNA in CSF for other viruses
Monitor antibody responses
(viral culture usually unsuccessful)
Epilepsy vs seizure
Seizure = abnormal electrical activity, focal or generalised to include whole brain
Epilepsy = paroxysmal brain disorder, with tendency of recurrence of seizures (multiple seizures in lifetime)
- important, patients don’t want label of epilepsy
Epilepsy epidemiology
Common, 5/1000 have
M = F
Peak in childhood (congenital) and in elderly, secondary to cerebrovascular and degenerative disease
Complex partial most common
(can also have febrile seizures in children, makes them more likely to get epilepsy later)
Classifying epileptic seizures
PARTIAL
= focal, localised
- complex/simple/secondary
- focally aware (= simple, conscious throughout)/impaired awareness (= complex, change in awareness)
GENERALISED
- always cause change in consciousness, usually unconscious - NEVER remain aware
- absence/atypical absence/myoclonic/clonic/tonic/tonic-clonic
UNCLASSIFIED
Generalised seizures
SYNCOPE
- many causes - vasovagal (faint), cardiogenic, postural hypotension
SUBARACHNOID HAEMORRHAGE
HYPOGLYCAEMIA
NON-EPILEPTIC ATTACKS (non electrical, still look like seziures)
Causes of ‘funny turn’
eg Absences, myoclonic jerks, simple/complex partial seizures
- migraine
- transient ischaemic attack
- transient global amnesia
- psychogenic events
Seizure vs syncope
SEIZURE
- most have some aura of warning (deja vu or smell)
- sudden onset, any position
- eyes open, rigidity, fall backwards, convulsions
- recovery - confused, headache, sleepy, focal deficit
- also tongue biting, often loss of bladder control
- -> wouldn’t be diagnosed without thorough history with witnesses, or often patients bring video
SYNCOPE
- warning is feeling faint, lightheaded, blurred vision
- only occurs sitting or standing, avoidable by change in posture
- eyes closed, limp, fall forwards, minor twitching only
- recovery - pale, sweaty, cold, clammy
- rare to have loss of bladder control
Provoked seizure
(not epilepsy)
Secondary to event eg head injury, tumour, CNS infection, fever, surgery
Important to separate from epilepsy, for eg driving
Childhood absence epilepsy
Absence seizures - generalised, whole brain, presents only in childhood
- ‘day-dreaming’
- more in females
- age 3-12, remits in teens
- autosomal dominant condition
- normal intellect
- treat with ethosuximide
Juvenile myoclonic epilepsy
- early morning myoclonic jerks (sudden movement of limb) and generalised tonic-clonic seizures (GTCS)
- presents 10-20 years old, lifelong
- childhood absence seizures in 30%
- treat with sodium valproate
- worse on phenytonin/carbamezapine
Identifying where seizure starts
Focal limb jerking - motor cortex
Focal tingling - somatosensory cortex
Olfactory/gustatory hallucination - temporal lobe
Visual hallucination - occipital lobe
Limb posturing - supplementary motor area
Swallowing/chewing movements - temporal lobe
Generalised
- generalised stiffening (tonic)
- repeated generalised jerking (clonic)
- absence
- atonic drop attacks
Immediate management of seizure
Airway breathing circulation
Immediate blood glucose - metabolic cause possible
Full blood tests - if something imbalanced here, easily remedied
Pregnancy test - preeclampsia risk
ECG - for anyone with transient loss of consciousness
Lumbar puncture only if suspicious of CNS infection
Neuroimaging if intracranial lesion suspected
Guidelines following first seizure
Urgent specialist opinion within 2 weeks - refer to ‘first seizure clinic’ at hospital
EEG for all within 4 weeks
(MRI if needed within 4 weeks)
- advise to inform DVLA (no license for 1 year, 6 months if ECG and scan normal), avoid driving/triggers/hazardous activities, avoid sleep deprivation and alcohol esp
- if recurrent seizures, license revoked until seizure free for 1 year
Starting anti-epileptic drugs
2 or more unprovoked seizures within 6-12 months
Monotherapy preferable - drug that is effective against all seizure types shown with minimal side effects
Start low dose then escalate until therapeutic
70% can be controlled on AED therapy, 80% of which are monotherapy
Choice of anti-epileptic drugs
(not all suitable as monotherapy)
Focal epilepsy - carbamezapine, phenytoin (only emergency as many side effects), lacosamide
Both - lamotrigine, levetriacetam, valproate (many side effects)
Generalised epilepsy - ethosuximide (childhood absence), clonazepam and piracetam (myoclonus)
Ideally AEDs are:
- orally active
- not sedative, allow normal function
- non-toxic
- low incidence interaction with other drugs
Side effects of AEDs
All -> sedation Also often: - diplopia and ataxia - rash - GI side effects - weight gain - weight loss - reversible hair loss - teratogenic effects, birth defects
SUDEP
Sudden death in epilepsy
- risk discussed with all patients
- not only in poorly controlled seizure
- often resp arrest
- usually at night
- highest risk in GTCS
0.5% epileptics per year
Convulsive status epilepticus
MEDICAL EMERGENCY
= patient not recovering from seizure, back to back seizures - continuously or recurrently for at least 30 mins without recovery of consciousness in between
Will -> cerebral damage and death
Treat - immediate lorazepam - phenytoin if continuing Early administration essential Very high dose needed to stop status Consider interaction with hormonal contraception!!
Epilepsy surgery
Only where refractory to drug treatment, disabling seizures, recurrent/frequent
Usually in temporal lobe epilepsy or lesional epilepsy
Will -> deficit, as part of brain is removed
Plasticity
The nervous system is constantly modifiable
-> allows adaptation to environment, learning, development of skills, storing information
Plasticity can occur physiologically due to activity, or due to injury or disease
Types of neuroplasticity
ENHANCEMENT OF EXISTING CONNECTIONS
Synapse development - physiological mechanism - ms-hours duration
Synapse strengthening - biochemical mechanism - hours-days duration
FORMATION OF NEW CONNECTIONS
Unmasking - physiological mechanism - minutes-days duration
Sprouting - structural mechanism - days-months duration
Types of cortical plasticity
Functional cortical plasticity
- learning of new skill -> changes in density of grey and white matter of brain
(hand part of motor cortex enlarged in piano players)
Developmental cortical plasticity
- cortical remapping in response to stimulus
Injury dependent cortical plasticity
- in eg amputated fingers, adjacent territories for other digits will expand to include areas that were previously digits 2-3
Synaptic rearrangement
Activity dependent
- relies on competition between different inputs and different neurones - one presynaptic neurone ‘wins’ by producing more activity and will have more inputs onto postsynaptic cells
(more activity -> more synaptic connections)
- change from one pattern to another
- consequence of neural activity/synaptic transmission before and after birth
- happens in critical period
If input from some neurones stops (eg whiskers removed), neighbouring neurones expand to become more sensitive
Axon sprouting
Neurones can make new innervations
- common where there is damage to pathway
Injured neurone, and postsynaptic neurone now missing innervation releases signals
- nerve growth factor (NGF) released
- promotes neuronal/axonal survival to neighbours
- stimulates neurites to sprout and look for NGF
- post-synaptic cell now innervated from alternate input
Cellular connectivity theory of memory
Increasing/decreasing strength between neurones in eg hippocampus -> memory
Strength of synapse can be changed
NMDA glutamate receptor key to produce long term changes in synaptic efficiency
Neurones that fire together, wire together
(fire at the same time, increased synaptic strength between them) - Hebb’s postulate
What is synaptic plasticity
Change in strength of synapse
- seconds/mins - short-term memory
- hours/days - intermediate memory
- months/years - long-term memory
Changes take place via
- presynaptic terminal (more neurotransmitter)
- postsynaptic membrane (more receptors)
- postsynaptic nucleus (more gene expression)
Long-term potentiation
LTP
Type of synaptic plasticity
Stimulation of axons -> EPSP
Repeated stimulation -> higher response
NMDA receptor responsible for LTP induction - glutamate binds to NMDA, channel opens, Mg ions block channel until cell depolarised
Depolarisation needed to remove Mg is achieved by repeated activation of synapse, summation
When channel open, Ca and Na ions can enter
Ca activates intracellular signalling molecules
In hippocampus:
- long-lasting
- input specific (only at stimulated synapses)
- cooperative
- associative
Causes of epilepsy
Birth and perinatal injuries Congenital malformations Genetic - ion channels, GABA system Vascular insults Chronic drug/alcohol abuse Neoplasia Infection Idiopathic
- > upregulation of excitatory (glutamergic) transmission, or downregulation of inhibitory (GABAergic) transmission
- > change in excitatory-inhibitory microcircuits
- > hypofunction of brain region
Acute seizures caused by eg head trauma, stroke, drug abuse are NOT epilepsy
Epileptic seizure triggers
Altered blood glucose/pH
Stress
Fatigue
Flashing lights and noise
(or no apparent cause)
Strategies for anti-epileptic drugs
Increase inhibitory (GABAergic) synaptic transmission Decrease neuronal firing rates (Na+ channels) Inhibit neurotransmitter release (Ca2+ channels) Decrease excitatory (glutamate) synaptic transmission
GABA
Gamma-amino-butyric acid
Synthesised from glutamine -> glutamate -> GABA
using glutaminase and glutamic acid decarboxylase enzymes
Then uptake into neurones and glia via GABA transporter
Degraded by GABA transaminase to succinate and glutamine
GABAa receptor - ionotropic, for Cl- ions
GABAb receptor - metabotropic, inhibit Ca channels, open K channels, reduce cAMP levels when open
Drugs to enhance GABAergic transmission (anxiolytic and AEDs)
Potentiate GABA actions at GABAa receptors
- benzodiazepines
- barbituates
- sodium valproate
Inhibit GABA transaminase/enzymes to degrade
- vigabatrin
- sodium valproate
Inhibit GABA reuptake
- tiagabine
Drugs to reduce glutamergic transmission (AEDs)
Reduce glutamate actions
- AMPA antagonists - perampanel
- NMDA antagonists -felbamate
Reduce glutamate release
- future?
Risky, brain needs glutamate - psychosis, memory impairment, motor function
Drugs to block voltage-gated sodium channels (AEDs)
To reduce action potential generation, stop spread of seizure activity
Use-dependent block, only targets overactive drugs
- carbamezepine, phenytoin, valproate
Drugs to block voltage-gated calcium channels (AEDs)
To control neurotransmitter release
- ethosuximide
- sodium valproate
- gabapentin
Structures in the limbic system
Papez circuit:
- cingulate gyrus
- parahippocampal gyrus
- hippocampus
- anterior thalamus
+
- amygdala
- mamillary bodies
- hypothalamus
- nucleus accumbens
- septal nuclei
(cortical and subcortical structures in medial and ventral regions of brain)
Limbic lobe
Consists of
- cingulate gyrus
- parahippocampal gyrus
- uncus
- hippocampus
Circuit of Papez
Cingulate gyrus - cingulum bundle to parahippocampal gyrus to - Hippocampus - fornix to - Mamillary bodies of hypothalamus - mamillothalamic tract to - Anterior thalamus - internal capsule to CG -
Critical for memory
Functions of limbic system
HOMEOSTASIS
OLFACTION
- primary olfactory cortex (medial temporal lobe) strongly connected to piriform cortex + amygdala
- limbic structures sensitive to seizure activity, very epileptogenic, often early olfactory auras
MEMORY
EMOTION
- amygdala (in medial temporal lobe) essential, fear response esp
(HOME)
Kluver-Bucy syndrome
After damage to medial temporal lobes, esp where damage around amygdala
-> aggression, reduced fear, poor (visual) recognition, oral tendencies, hypersexuality
(rare in humans, hard to get selective damage to amygdala. Present in Urbach-Wiethe disease)
The amygdala and fear and aggression
Fearful tone -> auditory cortex -> amygdala:
- > hypothalamus -> autonomic response
- > periacqueductal gray in brainstem -> behavioural response
- > cerebral cortex -> emotional experience
Also crucial circuit in aggression:
Cerebral cortex -> amygdala -> hypothalamus -> EITHER:
- ventral tegmental area in predatory aggression
- periacqueductal gray in affective aggression
Septal nuclei
Rostral to anterior commissure in medial wall
Unsure on function
Implicated in aggression - midline infarcts here -> rage behaviour
Major projection pathways to hippocampus, amygdala, ventral tegmental area
Nucleus accumbens
In rostral and ventral forebrain Has important neuromodulatory input - noradrenaline -> drive - serotonin -> mood - dopamine -> wellbeing, pleasure, reward
Memory and amnesia
Memory is maintenance of learning across time
Needs acquisition, storage and retrieval
Forgetting is due to temporal decay or interference (eg head trauma)
Amnesia is pathological form of forgetting, usually due to head injury, cerebrovascular accident or neurodegeneration
Retrograde - forget previous memories (rare)
Anterograde amnesia - unable to acquire new memories
Types of memory
SHORT TERM - held few minutes at most, needs consolidation for LTM, several STM stores related to sensory stores or higher order
LONG TERM:
Declaritive
- semantic
- episodic
From medial temporal lobe
Non-declaritive
- priming - from various in cortex
- skills and procedures - parietal cortex/striatum
- classical conditioning - cerebellum and amygdala
Classic amnesiac syndrome
Anterograde and possible retrograde amnesia
New skills learning is possible, normal perception and general intellectual functions intact
Causes of classic amnesiac syndrome
ANOXIA
- oxygen deprivation affects esp pyramidal cells in CA field of hippocampus
- due to premature birth, heart attacks, stroke, carbon monoxide inhalation
ALCOHOL
- 15% all dementia, due to cell loss and degeneration in diencephalon
- Wernicke’s encephalopathy (acute thiamine deficiency) -> Korsakoff’s syndrome
SELECTIVE BRAIN DAMAGE THROUGH TRAUMA
- eg fencing foil up nose
HERPES ENCEPHALITIS
- rare, caused by HSV-1 usually
- severe, survivors -> brain damage to temporal and frontal lobes
Forms of long term memory
Priming - biasing of performance by recent experience Skills/procedures Classical conditioning Semantic memory - meanings and knowledge Episodic memory - events and experiences
Post traumatic amnesia
Anterograde amnesia, difficulty forming new memories
Following severe concussive head injury usually
Tends to improve with time
Psychogenic/dissociative amnesia
RARE
Memory disorder - sudden retrograde autobiographical memory loss
Varied symptoms, but semantic knowledge usually intact and general intelligence unaffected
Period hours-years
Preceded by period of stress usually
Depression common
(difficult to discount possibility of ulterior motive)
Psychogenic/dissociative amnesia
RARE
Memory disorder - sudden retrograde autobiographical memory loss
Varied symptoms, but semantic knowledge usually intact and general intelligence unaffected
Period hours-years
Preceded by period of stress usually
Depression common
(difficult to discount possibility of ulterior motive, way of getting out of stressful situation)
Situation specific amnesia
Some (30%) perpetrators of violent crime claim amnesia at time
More severe in more extreme emotion
(consider blackout effects of malingering, consider malingering)
