Higher brain function

Question 1

What are the different types of memory?

Answer 1

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

Question 2

What is amnesia?

Answer 2

Loss of memory and learning ability
Caused by concussion, tumour, stroke, alcoholism, encephalitis
Dissociated amnesia- no other deficits
Retrograde or anterograde
Transient global amnesia

Question 3

Where are memories stored?

Answer 3

Declarative- cortex- info from sensory modsality stored in the cortical region that serves that modality
Visual memories- extrastriatal cortex
Temporal lobes store complex memories

Question 4

Describe the hippocampus and memory

Answer 4

Spatial memory
Working memory
Relational memory

Question 5

What is Hebbs theory?

Answer 5

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

Question 6

What is required for LTP?

Answer 6

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

Question 7

What is the function of LTD?

Answer 7

Keep unspecified synapses in check

Weakens connections between occasionally coinciding firing

Question 8

What is synaptic plasticity?

Answer 8

Neurones grow new processes, mold to requirement
Limbic system is very plastic
Primary sensory and motor areas are not very plastic

Question 9

What is schizophrenia?

Answer 9

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

Question 10

What are the possible causes of schizophrenia?

Answer 10

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)

Question 11

List some typical neuroleptic drugs

Answer 11

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

Question 12

List some atypical neuroleptic drugs

Answer 12

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

Question 13

What are the dopamine pathways in the brain associated with schizophrenia?

Answer 13

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

Question 14

List some side effects of neuroleptic drugs

Answer 14

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

Question 15

What are the problems with the dopamine hypothesis of schizophrenia?

Answer 15

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)

Question 16

What are the major anxiolytics?

Answer 16

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

Question 17

Describe some novel anxiolytics

Answer 17

5-HT(1A) partial agonist
Buspirone
Slow to act
Fewer side effects than benzodiazepines- no sedation, dependence or withdrawal

Question 18

What drug can be used for situational phobias?

Answer 18

Beta-adrenoceptors antagonist

Question 19

Describe anxiety

Answer 19

General anxiety disorder (GAD)
Restlessness, tachycardia, sweating, sleep disturbances
Overactive hypothalamic-pituitary-adrenocortical axis?
Hypothalamus- CRF➡️ anterior pituitary- ACTH➡️ adrenal gland- cortisol- stress response

Question 20

Describe clinical depression

Answer 20

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

Question 21

What drugs are used as antidepressants

Answer 21

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

Question 22

What is the new theory for depression?

Answer 22

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

Question 23

Define seizure

Answer 23

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

Question 24

Define epilepsy

Answer 24

A tent endemic toward recite t seizures unprovoked by stein or neurological insults

Question 25

Define epileptogenesis

Answer 25

Sequence of events that convert a normal neuronal network into a hyper excitable network

Question 26

What might cause symptomatic seizures?

Answer 26

``` Drugs Severe sleep deprivation Cardiovascular disease Stroke Inter cranial surgery Hypoglycaemia Low ion content ```

Question 27

Describe SUDEP

Answer 27

Sudden unexpected death in epilepsy | Unknown cause- autonomic system being stimulated in hyperactive neurone can effect heart and lung function

Question 28

What is an EEG?

Answer 28

Electroencephalogram Measure small voltage fluctuations Represents currents due to synaptic excitation of dendrites of pyramidal neurones In the cerebral cortex Reflects synchronous nerve activity

Question 29

What are the mechanisms of epilepsy?

Answer 29

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

Question 30

How do you classify epilepsy?

Answer 30

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

Question 31

Describe absence seizures

Answer 31

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

Question 32

What are the causes of epilepsy?

Answer 32

Infancy- birth injury, congenital malformation- neuronal migration disorders, metabolic disorders Adolescence- head injury, Unknown, idiopathic Older- strokes and brain tumours

Question 33

What is status epilepticus?

Answer 33

An epileptic seizure that lasts for 30 min or longer or a series did seizures without regaining consciousness in between

Question 34

What are the main mechanisms of anti-epileptic drug action?

Answer 34

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

Question 35

Describe temporal lobe epilepsy

Answer 35

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

Question 36

Describe the drugs used in absence seizures

Answer 36

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

Question 37

List the drugs used for status epilepticus

Answer 37

Lorazepam Clonazepam Diazepam

Question 38

Describe some new antiepileptic drugs that work by prolonging Ca channel inactivation

Answer 38

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?

Question 39

Describe some new antiepileptic drug targets

Answer 39

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

Question 40

What is dementia?

Answer 40

An acquired global impairment of intellect, memory and personality, without impairment of consciousness

Question 41

Briefly describe the differences in synaptic plasticity

Answer 41

More plastic- limbic system More rigid- primary sensory and motor areas More cell loss in more plastic areas

Question 42

What is Alzheimer's disease?

Answer 42

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

Question 43

Describe the pathology of Alzheimer's

Answer 43

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

Question 44

What are the possible contributes to Alzheimer's?

Answer 44

``` Age Myocardial infarction Low physical activity High pressure Atherosclerosis Smoking Cholesterol Diabetes Menopause Low education Head injury ```

Question 45

What is the difference between Parkinson's with dementia and lewy body dementia?

Answer 45

Parkinson's manifest motor symptoms first | Lewy body develops Alzheimer's symptoms first

Question 46

What are the possible approaches to treatment?

Answer 46

``` 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 ```

Question 47

What is donepezil?

Answer 47

Alzheimer's drug Enhances cholinergic transmission Modest short term benefit for cognition, mood and behaviour with adverse effects and relapse after discontinuation