Higher brain function Flashcards
What are the different types of memory?
Declarative memory (explicit)- available for conscious recollection- facts and events, easy to learn easy to forget
Non declarative memory (implicit)- not available for recollection
Requires repetition over time, less likely to be forgotten
What is amnesia?
Loss of memory and learning ability Caused by concussion, tumour, stroke, alcoholism, encephalitis Dissociated amnesia- no other deficits Retrograde or anterograde Transient global amnesia
Where are memories stored?
Declarative- cortex- info from sensory modsality stored in the cortical region that serves that modality
Visual memories- extrastriatal cortex
Temporal lobes store complex memories
Describe the temporal lobe and declarative memory
Temporal neocortex- long termn memory storage
Limbic system- formation of declarative memory
Object recognition
Temporal lobectomy- loss of short term memory
Loss of anterograde and retrograde memory
Maintains some long term memory
Medial temporal lobe- memory processing, consolidation of declarative, temporary memory storage (consolidation in cortex)
Describe the hippocampus and memory
Spatial memory
Working memory
Relational memory
What is Hebbs theory?
Engram of an object+ assembly of cortical cells activate by the external stimulus
Reciprocally interconnected- short term
Fire together and wire together- long term consolidation
Synaptic modifications triggered by neuronal activity
LTP- Long-term potentiation
LTD- Long-term depression
What is required for LTP?
Coincidence of pre- and postsynaptic firing allows Ca influx through the NMDA receptor coincidence detector
Increase AMDA receptor conductance through CaMK2-dependent phosphorylation- and increased insertion into the membrane
What is the function of LTD?
Keep unspecified synapses in check
Weakens connections between occasionally coinciding firing
What is synaptic plasticity?
Neurones grow new processes, mold to requirement
Limbic system is very plastic
Primary sensory and motor areas are not very plastic
What is schizophrenia?
Severe psychiatric disorder, distortion of thoughts and perception, also mood
Early adulthood
Repeated episodes or chronic
Type 1: positive symptoms- presence of abnormal thoughts and behaviours
Delusions, hallucinations, disorganised speech, grossly disorganised or catatonic behaviour
Type 2: negative sympotoms- absence of normal behaviours- decreased expression of emotion, social withdrawal
What are the possible causes of schizophrenia?
Strong but not invariable hereditary component- suggests environment has impact
Slow viral infection and associated autoimmune response
Poor maternal nutrition and possibly resulting developmental abnormalities
Dopamine hypothesis- dopaminergic hyperactivity underlies schizophrenia (amphetamine abuse can lead to schizophrenic type 1 like symptoms- potent D2 agonists)
List some typical neuroleptic drugs
Phenothiazides: Chloropromazine- attenuates positive symptoms without excessive sedation
Fluphenazine
Butyrophenones: haloperidol, droperidol
Thioxanthines: fluoenthixol, clopenthixol
Block a variety of receptors- D1&2, muscarinic ACh, H1, alpha adrenoceptors, 5-HT
List some atypical neuroleptic drugs
Selective dopamine D2/3 antagonists- sulpiride, amisulpride
Multi acting receptor antagonist (MARTAs)- clozapine, olanzapine
Serotonin-dopamine antagonist- risperidone, zoteprine, sertindole
More recently developed
Distinguished from typical by pharmacological profile, fewer extrapyrimdal side effects, more effect against type 2 symptoms and treatment resistant groups
What are the dopamine pathways in the brain associated with schizophrenia?
Hyper function of the mesocortical pathway
Hypofunction of the mesolimbic pathway
Aripiprazole D2 partial agonist- agonist where low, functional antagonist where hiugh- normalisation of hypo/hyper function
List some side effects of neuroleptic drugs
Antiemetic- dopamine block in the chemoreceptor trigger zone
Increased prolactin release- breast swelling, pain, lactation
Motor disturbances- parkinsonian like symptoms- tremour at rest, muscle rigidity and decreased mobility
Acute dystonias- involuntary movements
Tardive dyskinesia- slow developing, severely disabling motor disturbances arising from chronic treatment, generally irreversible- involuntary movements
What are the problems with the dopamine hypothesis of schizophrenia?
Take weeks to work- secondary effects, adaptive changes
Less effective on type 2 symptoms- therefore too simplistic
Dysfunction of dopaminergic systems may not be primary cause
Many neuroleptic block many different receptors eg 5-HT(2A)
What are the major anxiolytics?
Benzodiazepines
Diazepam, nitrazepam
Reduce anxiety and aggression and sleep inducing
Bind to the allosteric site on the GABA-A receptor to increase binding affinity and increase Cl influx and hyperpolarisation
However sedation can be a problem and if mixed with alcohol can result in serious respiratory depression
Long term use can easily in tolerance and dependence
Describe some novel anxiolytics
5-HT(1A) partial agonist
Buspirone
Slow to act
Fewer side effects than benzodiazepines- no sedation, dependence or withdrawal
What drug can be used for situational phobias?
Beta-adrenoceptors antagonist
Describe anxiety
General anxiety disorder (GAD)
Restlessness, tachycardia, sweating, sleep disturbances
Overactive hypothalamic-pituitary-adrenocortical axis?
Hypothalamus- CRF➡️ anterior pituitary- ACTH➡️ adrenal gland- cortisol- stress response
Describe clinical depression
Unipolar or bipolar
Misery, despair, loss of motivation and appetite, suicidal thoughts
The monoamine theory of depression- ‘depression is due to hypoactivity at monoaminergic (NA, 5-HT) synapses in the brain
Some evidence against- AD take 1-3 weeks to work
What drugs are used as antidepressants
Monoamine oxidase inhibitors (MAOI)- immediate euphoria, AD action- 4 weeks eg. Phenelzine- displaces NA from vesicles, anti-muscarinic effects and alpha1 antagonism
Tricyclic antidepressants (TCA)- slow onset, eg. Amitriptyline, imipramine, inhibit 5-HT/NA reuptake- also anti-muscarinic and sedative
Selective re-uptake inhibitors (SSRI)- 2-4 weeks delay eg. Fluoxetine, paroxetine, fewer side effects
‘Atypical’ antidepressants
What is the new theory for depression?
Increase CRF and cortisol in CSF- hyperactivity of the neuroendocrine stress response
Mechanism of drug action could be that increase monoamines promote neurogenesis and restore neuronal network???
Requires more understanding of neurobiology
Potential in CRF antagonists
Define seizure
The clinical manifestation of an abnormal and excessive excitation of a population of cortical neurones
Abnormal synchronous paroxysmal neural discharge in the brain causing abnormal function
Define epilepsy
A tent endemic toward recite t seizures unprovoked by stein or neurological insults
Define epileptogenesis
Sequence of events that convert a normal neuronal network into a hyper excitable network
What might cause symptomatic seizures?
Drugs Severe sleep deprivation Cardiovascular disease Stroke Inter cranial surgery Hypoglycaemia Low ion content
Describe SUDEP
Sudden unexpected death in epilepsy
Unknown cause- autonomic system being stimulated in hyperactive neurone can effect heart and lung function
What is an EEG?
Electroencephalogram
Measure small voltage fluctuations
Represents currents due to synaptic excitation of dendrites of pyramidal neurones In the cerebral cortex
Reflects synchronous nerve activity
What are the mechanisms of epilepsy?
Divergent connections- one neurone excited multiple neurone
Effective synapses- high chance that a neurone will fire a potential in the other neurones is innervates
Firing depends on intrinsic membrane properties- channels, synapse transmitter
Minimum aggregate- large enough neurone network- electrical activity can return to a neurone along a path long enough to allow time for that neurones refractory period and so it can fire again
How is excessive network firing normally controlled in the body?
Excitatory neurones also innervates inhibitory neurones that synapse in many local neurones to suppress activity
There are many different types of interneurones in the hippocampus
How do you classify epilepsy?
Generalised- site of onset cannot be resolved to one hemisphere- cortex and thalamus back to the cortex- absence- stop response, myoclonic- motor seizures, atonic- lose tone, tonic- increase in tone, tonic-clonic- increase in tone and rhythmic contraction
Partial- originate in a specific part of the brain, quite short, may be impairment of consciousness in a partial complex seizure or not in a simple seizure
Describe absence seizures
Interactions between the cortex and thalamus
If the thalamus is stimulated enough it can excite the cortex again after the neurones have been through the refractory period
Glutamate and GABA synapses generate rhythmicity
What are the causes of epilepsy?
Infancy- birth injury, congenital malformation- neuronal migration disorders, metabolic disorders
Adolescence- head injury, Unknown, idiopathic
Older- strokes and brain tumours
What is status epilepticus?
An epileptic seizure that lasts for 30 min or longer or a series did seizures without regaining consciousness in between
Describe animal models of epilepsy
Drug-induced seizures in mice using pilocarpine (muscarinic cholinergic agonist), kainic acid (glutamate receptor agonist), bucuculline (GABA receptor antagonist), can induce status epilepticus, correlated with tonic-clonic seizures and pentylenetetrazole correlated with absence seizures
Maximal electroshock- correlated with tonic-clinic and partial seizures, model of cortically focus des seizure
Kindling models- lowering threshold for seizures induced by repeated intracerebral electrical stimulation in limbus areas, a model of plastic changes in synaptic strength
Inbred, spontaneously-seizing rodents- GAERS rat a model of absence seizures, analogous to certain human epilepsies of identifiable genetic causes
In-vitro preparation eg. Brain slices- permit induction of repetitive discharge, study of underlying cellular and synaptic mechanisms and for drug mechanisms
What are the main mechanisms of anti-epileptic drug action?
GABA facilitators- vigabatrin, valproate decrease GABA metabolism, tiagabine decreases GABA uptake via GAT1, benzodiazepines enhance GABA binding via allosteric binding, barbiturates increase channel open time
Use dependent block of Na channel- bind to the channel when it is inactive- selective block for over-active neurones eg. Carbamazepine, phenytoin, topiramate, lamotrigine, valproate, zonisamide
Calcium (t-type) channel blockers- TC neurones involved in absence epilepsy- valproate, ethosuxamide
Describe the drugs used to treat tonic-clinic and partial seizures
Phenobarbital/Primidone- barbiturates
Metabolised from Primidone to phenobarbital
Serious problems with sedation, tolerance and drug interactions, respiratory depression with lethal dose, rebound seizures with withdrawal
Phenytoin- a hydantoin
Non-sedative, narrow therapeutic index, side effects- vertigo, ataxia, confusion, anaemia, hypersensitive, teratogenicity
Carbamazepine- tricyclic structure
Short half life, used in psychomotor epilepsy, trigeminal neuralgia, side effects- drowsiness, water retention, ataxia, hypersensitivity, blurred vision, leukopenia, drug interactions
Valproate- a branched fatty acid
Most broad acting, fewer side effects, best drug for myoclonic seizure and used in absence seizures- side effects- nausea, hair loss, weight gain, hepatic and pancreatic toxicity, teratogenicity
Diazepam- benzodiazepines
Non-lethal in overdose, useful in absence seizures, side effects- sedation, dependence and withdrawal, weight gain
Vigabatrin- GABA analogue
Broad spectrum, useful when other drugs fail, side effects- sedation, behavioural and mood changes
Describe temporal lobe epilepsy
Partial seizures originating in the temporal lobe
Symptoms- deja vu, jamais vu, amnesia, recall of a single memory or set of memory, auditory, gustatory, olfactory hallucinations
Describe the drugs used in absence seizures
Ethosuxamide- t type Ca channel blocker
Side effects- anorexia, nausea
Valproate- branched fatty acid
Also used in tonic-clinic and partial seizures, side effects- nausea, hair loss, weight gain, hepatic and pancreatic toxicity, teratogenicity
Diazepam- benzodiazepine
Non-lethal in overdose, also used for tonic-clinic and partial seizures, side effects- sedation, dependence and withdrawal, weight gain
List the drugs used for status epilepticus
Lorazepam
Clonazepam
Diazepam
Describe some new antiepileptic drugs that work by prolonging Ca channel inactivation
Lamotrigine- broad profile- decrease glutamate release, skin rashes and ataxia
Topiramate- glutamate receptor antagonist, fewer side effects- but teratogenic
Zonisamide- also a T type Ca channel blocker- se- drowsiness, anorexia, ataxia
Levitracetam- adjunctive therapy for partial seizures, dose adjustment for renal impairment, not advised in pregnancy, se- drowsiness, headache, GI disturbances, mood changes and skin rash, binds synaptic vesicular protein 2A to reduce glutamate release??
Gabapentin- partial seizures, relatively safe in OD, mild se, acts presynaptically? Ca channel block?
Describe some new antiepileptic drug targets
Reducing glutamatergic transmission- NMDA-R blockers, mGluR blockers
Felbamate- use-dependent NMDA-R subunit antagonist, se in humans- aplastic anaemia
Target voltage gated K channels- retigabine activates M-currents and is seizure protective in animal models, A current activators are also potentially antiepileptic
Subunit-selective GABA-A receptor modulators
What is dementia?
An acquired global impairment of intellect, memory and personality, without impairment of consciousness
Briefly describe the differences in synaptic plasticity
More plastic- limbic system
More rigid- primary sensory and motor areas
More cell loss in more plastic areas
What is Alzheimer’s disease?
A progressive dementia of long duration that increases in prevalence with age that is irreversible and eventually leaves to early death
Deficits in memory, decision making, judgement, language, and visuo-spatial processing
Procedural memory, some aspects of language, motor skills, sensation and elementary visual perception are spared
Describe the pathology of Alzheimer’s
Silver stained plaques and tangles in the brain
Parietal and frontal lobe atrophy
Amaloid plaques made from insoluble beta amaloid
Microglia and astrocytes gather around release growth factors and cytokines and so neurites grow into the plaques
Tangles made from loose tau protein that gets phosphorylated forms double helix with similar molecules and becomes insoluble and accumulates within cells and if the cells die the tangles stay- mostly in hippocampus- so tangles produce the symptoms
What are the possible contributes to Alzheimer’s?
Age Myocardial infarction Low physical activity High pressure Atherosclerosis Smoking Cholesterol Diabetes Menopause Low education Head injury
What is the difference between Parkinson’s with dementia and lewy body dementia?
Parkinson’s manifest motor symptoms first
Lewy body develops Alzheimer’s symptoms first
What is picks disease?
Tau tangles in the frontal region of the brain
What are the possible approaches to treatment?
Increase brain metabolism Increase cerebral circulation Protection of brain from physical and chemical damage Increase alertness Decrease depression Modulate the affected neurotransmitter systems Disease modifying therapy??? Currently only symptomatic treatment
What is donepezil?
Alzheimer’s drug
Enhances cholinergic transmission
Modest short term benefit for cognition, mood and behaviour with adverse effects and relapse after discontinuation
