PBL Topic 3 Case 7 Flashcards
Identify three roles of the cerebellum
- Timings of motor activities
- Intensity of muscle contraction
- Interplay between agonist and antagonist muscles
Identify the three lobes of the cerebellum
- Anterior lobe
- Posterior lobe
- Flocculonodular lobe
Where is the vermis located and what is its function?
- Longitudinal band in the centre of the cerebellum
- Control for muscle movements of the axial body, neck, shoulders and hips
Identify the two zones of the cerebellar hemipsheres and their function
- Intermediate zone, control of muscle contractions in hands, fingers, feet and toes
- Lateral zone, planning of sequential movements
Describe the topographical representation in the cerebellum
- Axial portions of the body lie in the vermis
- Limbs and facial regions lie in the intermediate zones
Why does the lateral zone of the cerebellar hemisphere not have topographical representations?
- It receives signals directly from the cerebral cortex
- For the planning and co-ordination of sequential muscular activities
Describe the course of the corticopontocerebellar pathway
- Afferent pathway from motor cortex
- Passes by way of pontocerebellar tracts
- Terminates in lateral divisions of the cerebellar hemispheres
- To the opposite side of the brain
Describe the course of the olivocerebellar pathway
- Afferent pathway from inferior olive
- Which are excited by fibres from motor cortex, basal ganglia, reticular formation and spinal cord
- Terminates on all parts of the cerebellum
Describe the course of the vestibulocerebellar fibres
- Afferent pathway from vestibular apparatus and brainstem vestibular nuclei
- Terminate in flocculonodular lobe and fastigial nucleus of the cerebellum
Describe the course of the dorsal spinocerebellar tract
- From muscle spindles, Golgi tendon organs, tactile receptors through dorsal tracts
- Pass into cerebellum through inferior cerebellar peduncle
- Terminates in vermis and intermediate zones
Describe the course of the ventral spinocerebellar tract
- From motor signals in the anterior horns
- Through corticospinal and rubrospinal tracts
- Tells cerebellum which signals have arrived at anterior horns and which have not
What is the speed of conduction in the spinocerebellar tracts?
- 120 m/sec
- Most rapid pathway transmission in any pathway in the CNS
Identify two other pathways that relay information to the cerebellum
- Spinoreticular pathway
- Spino-olivary pathway
Identify the four deep nuclei of the cerebellum
- Fastigial nucleus, associated with vestibular apparatus
- Globose nucleus, associated with co-ordination of agonist and antagonist muscles
- Emboliform nucleus, associated with co-ordination of agonist and antagonist muscles
- Dentate nucleus, associated with co-ordination of sequential movements
- Globose and emboliform are known collectively as interposed nuclei
Outline the three layers of the cerebellar cortex, where are the deep cerebellar nuclei located relative to these layers?
- Molecular layer
- Purkinje layer
- Granule cell layer
- Deep cerebellar nuclei are located deep to these layers
Identify the efferent outputs of the cerebellum
- Purkinje cell
- Deep nuclear cell
Identify the afferent inputs to the cerebellum
- Climbing fibres from inferior olives of the medulla, which send signals to deep nuclear cells and then to Purkinje cells
- Mossy fibres from higher brain, brainstem and spinal cord, which synapse with granule cells before sending signals to Purkinje cells
Describe the impulse from a climbing fibre
- Single strong impulse causes a prolonged action potential followed by several weaker spikes
- Known as a complex spike
Describe the impulse from a mossy fibre
- Impulse duration is much smaller and action potential is less prolonged
- Known as a simple strike
How are deep nuclear cells inhibited and what is the importance of this?
- Inhibited by Purkinje cells
- So that an inhibitory signal sis to the output motor pathway
- Damping function stops muscle movement overshooting its mark
Identify two other inhibitory cells of the cerebellum and in which cell layer they are located
- Basket cells
- Stellate cells
- Molecular layer
- Lateral inhibition
What is meant by vestibulocerebellum / archicerebellum?
- Flocculonodular lobes and vermis
- Involved in equilibrium and agonist/antagonist muscle contractions
What is meant by spinocerebellum / paleocerebellum?
- Vermis and intermediate zones
- Involved in coordinating movement in distal limbs
What is meant by cerebrocerebellum / pontocerebellum / neocerebellum?
- Lateral zones
- Motor imagery, planning of movements in advance to the movement
With regards to the vestibulocerebellum, what is meant by anticipatory correction?
- Ability of cerebellum to calculate the rate and direction of movement during next few milliseconds
- Based on signals from periphery
How does the spinocerebellum co-ordinate movement in distal limbs?
- Receives from motor cortex red nucleus and peripheral proprioceptors
- Deep nuclear cells of interposed nucleus send signals back to cerebral cortex through relay nuclei in the thalamus and through rubrospinal tract
Explain the basis of an intention tremor
- Must movements are pendular and thus have a tendency to overshoot due to momentum
- Cerebellum has a damping system to prevent this overshoot
- Failure of which causes limb to oscillate in opposite directions
What is meant by ballistic movements and how is this affected by cerebellar destruction?
- Rapid movements such as typing and reading
- That are preplanned, set in to motion for a specific distance then stop
- Cerebellar destruction results in movements that are slow to develop, weak force, and slow termination of movement
Describe how the cerebrocerebellum is involved in planning and timing of sequential movements
- Plan begins in sensory and premotor areas
- Two way signals sent between cerebellum and cerebral cortex
What is meant by dysdiadochokinesia?
- Impairment of rapidly alternating hand movement
- Because motor system fails to predict where different parts of the body will be at different times
What is meant by dysmetria and ataxia?
- Overshoot of movements over intended mark and subsequent overcompensation (dysmetria) resulting in uncoordinated movements (ataxia)
- Due to lesions in the spinocerebellar tract
What is meant by nystagmus?
- Tremor of eyeballs when fixating on one side of head
- Damage of flocculonodular lobes, with subsequent loss of equilibrium
What is meant by intention tremor?
- Oscillation of movement caused by overshoot followed by back and forth vibration
What is meant by scanning dysarthria?
- Failure of intensity or duration of sound results in jerky, explosive or slurred speech
What is meant by hypotonia?
- Decreased tone
- Caused by damage to dentate and interposed nuclei on same side of lesion and subsequent loss of facilitation of the motor cortex
Identify three roles of the basal ganglia
- Relative intensities of separate movements
- Directions of movements
- Sequencing of successive movements
Identify the different structures of the basal ganglia
- Caudate nucleus and putamen (corpus striatum)
- Putamen and globus pallidus [internal and external] (lentiform nucleus
- Substantia nigra [pars reticulata and pars compacta]
- Subthalamic nucleus
What is meant by the direct and indirect pathways of the motor loop of the basal ganglia?
- Direct loop: traverses corpus striatum and thalamus and involves consecutive sets of neurons
- Indirect pathway, traverse subthalamic nucleus and involves seven sets of neurons
Which neurotransmitter is involved in projections from cerebral cortex and thalamus?
- Glutaminergic
Which neurotransmitter is involved in projections from the striatum and globus pallidus?
- GABAergic
What are the two different synapses involved in the nigrostriatal pathway?
- Direct pathway = Facilitatory D1 receptors
- Indirect pathway = Inhibitory D2 receptors
Which regions of the basal ganglia are somatotopically organised?
- Putamen
- Globus pallidus
Outline the direct pathay
- Excitatory signals from sensorimotor cortex to striatum
- This excites the striatum, which sends inhibitory signals to internal globus pallidus
- This inbhits the internal globus pallidus, which inhibits the inhibitory signals to the thalamus
- Disinhibition of the thalamus results in activation of the supplementary motor area
- Which modifies ongoing corticostriate activity and initiates impulse trains along the corticospinal and corticoreticular fibres.
Outline the effect of the nigrostriatal system on the direct pathway
- Excitatory dopamine signals from pars compacta to striatum
- This further excites the striatum
- So causes more disinhibition of the thalamus
- Turning up motor activity
Outline the indirect pathway
- Excitatory signals from sensorimotor cortex to striatum
- This excites the striatum, which sends inhibitory signals to external globus pallidus
- This inhibits the external globus pallidus, which inhibits the inhibitory signals to the subthalamic nucleus
- The subthalamic nucleus nucleus now sends excitatory signals to the internal globus pallidus
- Which sends inhibitory signals to the thalamus, inhibiting the signals to the supplementary motor area.
Outline the effect of the nigrostriatal system on the indirect pathway
- Inhibitory dopamine signals from pars compacta to striatum
- This inhibits the striatum
- So fewer inhibitory signals are sent to the external globus pallidus
- More inhibition of subthalamic nucleus, so it is unable to send excitatory projections to the globus pallidus internus
- So more excitatory projections to thalamus, so more motor activity.
Outline 3 abnormalities of the basal ganglia
- Athetosis, lesion in global pallidus, producing spontaneous and continuous writhing movements of the hand
- Hemiballismus, lesions int he subthalamic nucleus, producing sudden flailing movements of the entire limb
- Chorea, a lesion in the putamen, producing a flicking movement of the hand or face
Outline the biosynthesis of acetylcholine
- Choline is acetylated by choline acetyltransferase
- Which transfers the acetyl group from acetyl coenzyme A
How is acetylcholine inactivated?
- Hydrolysis by acetylcholinesterase
Identify two types of acetylcholine receptors
- Nicotinic ACh receptors (nAChRs)
- Muscarinic ACh receptors (mAChRs)
What type of receptors are nAChRs?
- Ligand gated ionotropic channels
What type of receptors are mAChRs?
- G-protein coupled receptors
Outline three main classes of nAChRs
- Muscle receptors confined to neuromuscular junctions
- Ganglionic receptors
- CNS-type receptors
Outline the subtypes of muscarinic receptors
- M1-M5
- Odd numbered are excitatory as they excite inositol phosphate pathway allowing calcium influx and depolarisation
- Even numbered are inhibitory as they inhibit adenylyl cyclase pathway allowing potassium efflux with hyperpolarisation
Which muscarinic receptor is the neural type, how does it work?
- M1
- Causes a decrease in k+ conductance which causes membrane depolarisation
Where are cholinergic neurons located?
- Nucleus basalis of Meynert
- A forebrain nuclei
Which nucleus provides the main cholinergic output to the hippocampus and is involved in memory?
- Septohippocampal nucleus
Outline three main functions ascribed to cholinergic pathways with relation to each pathway.
- Arousal (nucleus basal to cortex)
- Memory (septum pellucidum to hippocampus)
- Motor control (cholinergic interneurons in striatum)
Where is dopamine most abundant in the brain?
- Corpus striatum
Outline the biosynthesis of dopamine
- L-tyrosine is converted to dihydroxyphenylalanine (dopa) by tyrosine hydroxylase
- Dopa is then converted to dopamine by dopa decarboxylase.
Why do dopaminergic neurons not convert dopamine to noradrenaline?
- They lack dopamine beta-hydroxylase (DBH)
How is dopamine metabolised and what is the clinical significance of the product?
- Uptake into presynaptic neuron or glial cell by DAT
- Monoamine oxidase
- Catechol-o-methyl transferase
- Which produces homovanillic acid (HVA)
- Which is used as an index to dopamine turnover
- Drugs that cause the release of dopamine increase HVA
Outline the four main dopaminergic pathways in the brain
- Nigrostriatal pathway
- Mesolimbic pathway
- Mesocortical pathway - Tuberohypophyseal pathway
Describe the course of the nigrostriatal pathway and its function
- Cell bodies in substantia nigra
- Whose axons run in medial forebrain bundle
- And terminate in corpus striatum
- Involved in motor control
Describe the course of the mesolimbic pathway and its function
- Cell bodies in ventral tegmental area
- Whose axons run in medial forebrain bundle
- To nucleus accumbens and amygdaloid nucleus
- Involved in behaviour
Describe the course of the mesocortical pathway and its function
- Cell bodies lie in ventral tegmental area
- Whose axons run in medial forebrain bundle
- To prefrontal cortex
- Involved in behaviour
Describe the course of the tuberohypophyseal pathway and its function
- Cell bodies lie in hypothalamus
- To pituitary gland
- Involved in endocrine control
Identify the two types of dopamine receptor, what kind of receptor are they?
- D1 and D2
- Which are G-protein transmembrane receptors
What is the D1 family?
- Contains D1 and D5
- Excitatory, linked to stimulation of adenylyl cyclase
What is the D2 family?
- Contains D2, D3 and D4
- Inhibitory, linked to inhibition of adenylyl cyclase, activation of K+ channels and inhibition of Ca2+ channels
Identify a dopamine antagonist
- Chlorpromazine an antipsychotic
Why must glutamate be synthesised in neurons from local precursors?
- It does not cross the blood brain barrier
Identify two local precursors for the synthesis of glutamate
- From glucose, via Krebs cycle, by action of GABA transaminase
- From glutamine, produced by glial cells, which is converted to glutamate by glutaminase
How is glutamate recycled?
- Taken up by astrocytes
- And converted into glutamine
Identify the three main subtypes of ionotropic glutamate receptors
- NMDA, involved in slower excitatory responses
- AMPA, involved in fast excitatory responses
- Kainate, involved in fast excitatory responses
Identify three special features of NMDA receptors
- Highly permeable to Ca2+ so effective in promoting Ca2+ entry
- Blocked by Mg2+ when polarised
- Activation requires glycine and glutamate
Identify the metatropic glutamate receptors
- mGlu1-8
- mGlu1 receptors are excitatory postsynaptic receptors
- mGlu2 and mGlu3 receptors are presynaptic inhibitory receptors
Outline the biosynthesis of GABA
- Glutamic acid decarboxylase
- Which converts glutamate to GABA
Where is GABA most abundant in the CNS?
- Nigrostriatal system
How is GABA taken up and how is it destroyed?
- Taken up by GABAergic neurons and astrocytes via specific transporters
- Destroyed by GABA transaminase, converting it to succinic acid.
What percentage of neurons in the CNS are GABAergic?
- 20%
Identify the two main types of GABA receptors
- GABAA, ligand gated ion channels, postsynaptic fast inhibition
- GABAB, G-protein coupled receptors, presynaptic and postsynaptic inhibition by blocking Ca2+ and increasing K+ conductance
Where is glycine most abundant?
- Spinal cord grey matter
Describe the glycine receptor
- Resembles GABAA
- Ligand gated postsynaptic channel that causes fast inhibition
What are Lewy bodies and how do they form?
- Intracellular protein aggregates
- Caused by mutation of alpha-synuclein, a vesicular protein
- Which becomes resistant to degradation so builds up within cells
How do Lewy bodies result in neurotoxicity
- Vesicular storage of dopamine is impaired
- Leading to an increase in cytosolic dopamine
- Degradation of which produces reactive oxygen species
Outline the effect of degradation of nigrostriatal neurons on the striatum
- Loss of facilitation of spiny striatal neurons bearing D1 receptors, disengaging the direct pathway
- Loss of inhibition of D2 receptors, engaging the indirect pathway
How does engagement of the indirect pathway result in movement problems?
- Sensorimotor cortex strongly activates GABAergic neurons in striatum which act on external globus pallidus
- Causing disinhibition of subthalamic nucleus
- Which discharges glutamine strongly onto internal globus pallidus
- Which discharges GABA strongly onto ventral nucleus of thalamus
- Reduced output to fibres travelling to supplementary motor area
What is bradykinesia, what causes bradykinesia and how does it present?
- Suppression of voluntary movement
- Due to muscle rigidity and inertia of motor system (so motor activity is difficult to stop and start)
- Routine activities such as opening a door require deliberate planning
What is the frequency of a resting tremor?
- 3-6 hertz
What is the commonest sequence of limb involvement of resting tremor in Parkinson’s?
- One upper limb to ipsilateral lower limb in 1 year
- Contralateral limb involvement within 3 years
What is a pill-rolling movement?
- Index and middle finger move against thumb pad
Why do Parkinson’s patients have a stooped posture?
- Rigidity mainly affecting flexors
What is meant by lead pipe rigidity?
- Limb is rigid throughout entire range of motion
- Cogwheel sensation
What is the first line treatment for Parkinson’s?
- Levodopa
- Combined with a decarboxylase inhibitor (co-beneldopa)
Why is levodopa combined with a decarboxylase inhibitor?
- Reduces dopamine synthesis in periphery
- Which would cause troublesome side effects
Why do patients become tolerant to levodopa?
- Reflects natural progression of the disease
Identify the main unwanted effects of levodopa
- Involuntary writhing movements (athetosis)
- Rapid fluctuations in clinical state, reflecting the fluctuating plasma concentration of dopamine
- Hypotension, nausea and schizophrenia-like syndrome
Identify two dopamine agonists and their troublesome side effects
- Bromocriptine, inhibits prolactin from anterior pituitary gland, causing nausea, vomiting and somnolence
- Pergolide, believed to cause heart disease
Identify two replacements of dopamine agonists
- Non-ergot compounds
- Such as pramipexole and ropinirole - Which are better tolerated
What is Selegiline and its advantages?
- Selective MAO-B inhibitor which targets mainly dopamine
- So does not provoke cheese reaction or interact with other drugs
- Protects dopamine from extra neuronal degradation
Explain one disadvantage of selegiline and name a similar drug that does not cause these side effects
- Metabolised to amphetamine so can cause excitement, anxiety and insomnia
- Rasagiline
What does deep brain stimulation involve in the treatment of Parkinson’s?
- Paralysis of subthalamic nucleus (inhibiting internal globus pallidus causing disinhibition of the thalamus)
What is Complementary and Alternative Medicine?
- Therapies and interventions that are
- Non standard
- Non prescription
- Non surgical
How does complementary medicine differ to alternative medicine?
- Complementary medicines are taken as well as conventional treatment
- Alternative medicines are taken instead of conventional treatment.
What is a placebo?
- Any therapy that has no specific activity for the condition being treated
- It has no active ingredient and no direct physiological effect
- Example is sugar pill
What is the placebo effect?
- Any psychological or psychophysiological effect produced by placebos
- In a clinical trial, this effect can be worked out by excluding the known specific effects of the treatment under investigation.
What is the nocebo effect?
- Adverse psychological or psychophysiological effects produced by a placebo
What are outcome expectancies with relation to placebo?
- Beliefs that treatment will have positive effects on health status
What are self-efficacy expectancies with relation to placebo?
- Beliefs that one can carry out the actions necessary for successful management of a disease
Outline four other explanations of the placebo effect
- Conditioning
- Anxiety reduction
- Social support
- Psychophysiological mechanisms
Outline four examples of CAM in Parkinson’s
- Nicotine
- Cannabis
- Caffeine
- Acupuncture
Why are CAM potentially harmful in the treatment of Parkinson’s
- Used as alternative to traditional medicine such as levodopa
- Harmful side effects and interactions with prescribed medicines
Describe the course of the limbic loop of the basal ganglia
- From prefrontal cortex
- Through the nucleus accumbens (ventral striatum)
- Returns to prefrontal cortex via the mediodorsal nucleus of the thalamus
What is the role of the limbic lobe of the basal ganglia?
- Gives motor expression to emotions
- Such as smiling, gesturing, aggressive or submissive posture
Outline the epidemiology of Parkinson’s disease
- Increases with age (1:200 over 80)
- More common in males (1.5:1 M:F)
- Environmental factors include pesticide exposure, rural living and non-smokers
- Several genetic loci designated PARK-1 to PARK-11
Which genetic locus and subsequent protien is responsible for formation of Lewy bodies?
- PARK-1
- Alpha Synuclein
Which genetic locus and subsequent protien is responsible for juvenile and early onset of PD?
- PARK-2
- Parkin
Outline how PET scanning can be used to detect Parkinson’s disease
- [18F]fluorodopa is injected intravenously and binds to dopamine receptors
- In Parkinson’s disease there is reduced fluorodopa binding due to reduction in dopamine receptors
- Intensity of uptake is seen as blue / green
Identify two dopa decarboxylase inhibitors
- Carbidopa (co-careldopa)
- Benserazide (co-beneldopa)
Outline the mechanism of aciton of amantadine and when it is mainly used.
- Advanced disease
- Mainly acts be incresing dopamine release
A glycine antagonists will inhibit what type of receptor?
- NMDA
Outline the genetic basis of Huntington’s disease
- Inherited as autosomal dominant disorder
- Trinucleotide repeat disease, with expansion of CAG repeats
How does the number of glutamine residues relate to development of Huntington’s disease?
- Huntingtin gene normally possesses fewer than 30 glutamine residues
- In HD there is increased number of glutamine residues on the N-terminal of the expressed protein
- The mutated huntingtin possesses more than 40 glutamine residues
What is the main clinical feature of Huntington’s? Which region of the basal ganglia is it associated with?
- Chorea
- Flicking moments of the hands, face and other body parts called chorea.
- Putamen
Outline the pathology of HD with relation to neurotransmitters
- Reduction of glutamic acid dercarboxylase, the enzyme responbible for GABA synthesis
- Resulting in a hyperactivity of dopaminergic synapses
- Mirror image of Parkinson’s
Identify 3 drugs used in the management of Huntington’s
- Tetrabenazine (inhibits of a vesicular dopamine transporter that reduces dopmaine storage)
- Chlorpromazine (dopamine antagonist)
- Baclofen (GABA agonist)
What is athetosis? Which region of the basal ganglia is it associated with? This condition is a side effect of which drug?
- Writhing movements of the hands face and neck
- Globus pallidus
- Levoopa
What is hemiballismus and what region of the basal ganglia is it associated with?
- Flailing movements of an entire limb
- Subthalamic nucleus
Which genetic locus and subsequent protien is associated with a phenotyope identical to sporadic Parkinson’s disease?
- PARK8
- LRRK2
Outline the role of ACh in Parkinson’s
- ACh release from striatum is normally inhibited by dopamine acting on D2 receptors
- In PD, there is a lack of dopamine in striatum
- So there is increased release of ACh in resutling in abnormal motor activity.
- Originally treated with mAChR antagonists though these had too many side effects e.g. dry mouth, eyes, blurred vision, urinary retention and diarrhoea
What is hyoscine and what does it cause?-
- Muscarinic antagonist
- Amnesia
Outline the role of the Pars Reticulata in the regulation of movement
- SnPR has GABAergic projections to thalamus that inhibit the thalamus
- As part of the direct pathway, GABAergic projections from the striatum inhibit the SnPR
- There is disinhibition of the thalamus as a result
Same effect as on Globus Pallidus Internus
Outline three types of care homes
- Residential home: Aimed at individuals who cannot manage at home on their own
- Nursing home: Aimed at individuals who cannot cope at home on their own and have a condition that requires 24 hour nursing care
- Specilaist care home: Aimed at individuals who cannot cope at home on their own and have a condition that requires specialist trained staff or adapted facilities
How does benserazide work?
- Inhibitor of AADC (aromatic L-amino decarboxylase)
- The enzyme responsible for converted levodopa to dopamine in the periphery
What does a standards need approach to QoL assume?
- Needs rather than wants are central to quality of life
What is the difference between a subjective and objective measure of QoL?
- Objective: Level of functioning
- Subjective: Self-appraisal of one’s own wellveing
Give an example of a unidimensional and mutlidimensional question that could be asked on a health questionnaire
- Unidimensional: How woudl you rate your mood?
- Multidimensional: How would you rate your health?
