Anatomy and Function of the Basal Ganglia Flashcards
L9 and L10
1
Q
Give an overview of Basal Ganglia anatomy
A
- Lentiform nucleus
- Putamen
- Globus pallidus
- Corpus striatum
- Caudate nucleus
- Putamen
- Pallidum
- globus pallidus internal + external
- Neostriatum = dorsal striatum
- Caudate
- Putamen
2
Q
Explain how the basal ganglia interfaces with the cortex
A
- the striatum and pallidum form the basal ganglia which transmits information to the thalamus
- the thalamus interfaces with the cerebral cortex which feedback to the Basal Ganglia
- There are 4 basal ganglia loops, two motor, and two-non-motor
- Motor
- Oculomotor
- Prefrontal
- Limbic
3
Q
Explain the Loops in the basal ganglia
A
- each have a Cortical Input –>
- motor, premotor somatosensory cortex
- posterior parietal, prefrontal cortex
- Dorsolateral prefrontal cortex
- Amygdala, hippocampus, orbitofrontal, anterior cingulate, temporal cortex
- striatum –>
- putamen
- body of the caudate
- anterior caudate
- ventral striatum
- pallidum –>
- lateral, globus pallidus, internal segment
- Globus pallidus, internal segment, substantia nigra pars reticulata (x2)
- ventral pallidum
- thalamus –>
- ventral lateral and lateral anterior nuclei
- mediodorsal and ventral anterior nuclei (x2)
- Mediodorsal nucleus
- then back to the cortex
4
Q
Explain the Direct pathway
A
- promotes movement
- provides a disnihibtory effect
5
Q
Explain the indirect/ hyper-direct pathway
A
6
Q
Give an overview of how the basal ganglia pathways work
A
- Inhibitory signals are the release of GABA
- Excitatory signals are the release of Glutamate
- Cortex –> striatum is excitatory
- Striatum outputs –> inhibitory
- Thalamus –> cortex is excitatory
- The inhibition of thalamus prevents movement
- Reducing inhibition of thalamus facilitates movement
7
Q
How is the input from the cortex modulated by the Striatum?
A
- Controlled by DA and ACh
- 2 populations of specialised dopamine receptors D1 and D2 medium spiny neurons
- D1: use G-proteins that increase cAMP - enhance the excitatory input from the cortex
- D2: use G-proteins that decrease cAMP - suppress the excitatory input from the cortex
- There are Striatum interneurons that use ACh
- this opposes the action of DA, tipping the pathway towards prevention of movement
- the release of Dopamine tips pathway towards the promotion of movement
8
Q
Explain the basal ganglia syndrome Hemiballismus
A
- it is a hyperkinertic movement disorder that causes ballistic involuntary movements of the limbs
- caused by damage to the subthalamic nucleus
- stroke in the STN is the most common cause
9
Q
Give a description of Tic disorders
A
- Brief repetitive stereotypes movements with a premonitory urge.
- Simple: like blinking, coughing
- Complex: jumping or twirling
- Plus: motor disorder
- Coprolalia: swearing - rare
- Reduced by distraction and concentration
- Worse with anxiety or fatigue.
- 50% have ADHD
- 33.3% have OCD
- Up to 50% have anxiety
- Tourette syndrome is the more severe expression of a spectrum of tic disorders,
10
Q
What is this an MRI of?
A
Subthalamic Nucleus Stroke
- can cause Hemiballismus
11
Q
Explain the action Prefrontal (cognitive loop) in the basal ganglia and its presentation in Parkinson’s Disease (PD)
A
- Pre-frontal cortex (dorso-lateral) → Caudate → Anterior Putamen → Globus Pallidus →Ventral anterior (VA) thalamic nucleus →Prefrontal cortex.
- Role in forward planning of complex motor intentions (volition).
- Therefore when a motor task becomes automatic, the motor loop of the basal ganglia takes over.
- PD patients have impairment of working memory
- Activation of the supplementary motor area on intended movements – Barietschaft potential which can be recorded Neurophysiologically and useful for assessing patients with a functional neurological disorder.
12
Q
Explain the action of the Limbic loop in the basal ganglia and it’s presentation in Parkinsons Disease (PD)
A
- Inferior prefrontal cortex → Nucleus Accumbens → Ventral Pallidum → Medio-dorsal nucleus of the thalamus → Inferior frontal cortex.
- Role in the visible expression of emotion. E.g smiling, showing aggression.
- This may explain why PD patiends have facial masking.
13
Q
Explain the action of the Oculomotor loop in the basal ganglia and its presentation in Parkinson’s Disease (PD)
A
- Frontal eye field and parietal cortex → Caudate nucleus → Substantia Nigra (Pr) → VA nucleus of thalamus → Frontal eye field and parietal cortex
- Ocular fixation is held by tonic activity (repetitive impulses) in the SN (Pr)
- When a saccade (voluntary movement) is made, the superior colliculus is disinhibited by the activated oculomotor loop.
- The superior colliculus neurons cause the eyes to make a rapid movement to a new target. The Sn(Pr) then resume tonic activity holding the visual gaze in that position.
- In PD: loss of dopamine neurons in the SN (Pr) means there is less disinhibition of the superior colliculus neurons resulting in slow eye movement (ocular hypokinesia).
14
Q
What is Chorea and when would choreiform movements present?
A
- Jerky, brief, irregular contractions that are not repetitive or rhythmic, but appear to flow from one muscle to the next. patient appears fidgety, restless
- Can present when
- there is a pathology in the STN
- Huntington’s disease
- Neuroleptic drugs
15
Q
Explain what Huntington’s Disease is
A
- autosomal dominant degenerative disease
- CAG trinucleotide repeat on chromosome 4
- the longer the repeat sequence the earlier the onset- seems to ‘anticipate’ with each generation
- Cognitive presentation
- inability to make a decision and multitask, slowness of thought
- Behavioural presentaion
- irritability, depression, apathy, anxiety, delusions
- Physical presentation
- Chorea, motor persistence, dystonia, eye movements
16
Q
What is Dystonia?
A
- Unintentional sustained muscle contractions leading to abnormal postures, can be painful
Pathophysiology
- Functional PET studies suggest abnormal activity in the motor cortex, supplementary motor areas, cerebellum and basal ganglia
- Abnormal DA activity in basal ganglia: some caused by blocking DA receptors, some dystonia being Levodopa responsive
Causes
- Stroke, Brain Injury
- Encephalitis
- PD
- Huntingtons disease
17
Q
What is Myoclonus?
A
- Myoclonus is a sudden muscle spasm. The movement is involuntary and can’t be stopped or controlled
- possibly an imbalance between excitatory and inhibitory neurotransmitters
- hence can be treated with antiepileptic drugs
- maybe a perturbation of the motor control system –> disequilibrium
- Caused by
- Juvenile Myoclonic Epilepsy
- Brain Hypoxia
- Prion disease
18
Q
What is Tremor?
Essential tremor treatment?
A
- Involuntary, rhythmic, sinusoidal alternating movements of part of the body, and affects different parts of the body
- Occurs at different times: Rest, Postural, Kinetic (Essential Tremor (ET) is most common)
Pathophysiology
- Postulated theory: Increased activity in the cerebellothalamocortical circuit.
- PD: Dopamine dysfunction in the pallidum results in this.
- ET: GABAergic dysfunction in the cerebellum causes this.
- Ultrasound therapy?
19
Q
What drug treatment is there for hyperkinetic movement disorders?
A
Tics/Chorea/Ballismus
-
Dopamine receptor blocking agents
- eg haloperidol, chlorpromazine, pimozide, risperidone
-
Dopamine depleting agents
- eg Tetrabenazine, Reserpine
-
Atypical anti-psychotics
- eg Clozapine, Olanzapine, Aripiprazole
20
Q
What is the response of the basal ganglia to DA blocking agents
A
- acute problems
- Oculogyric crisis
- Neuroleptic malignant syndrome
- subacute problems
- drug-induced Parkinsonism
- long term dyskinesia
21
Q
What is an Oculgyric crisis?
A
- acute response to DA blocking drugs causing
- Fixed stare, upward deviation of eyes
- Neck extension, Trunk extension
- Jaw spasms +/- tongue protrusion
- ‘Acute dystonic’ reaction
22
Q
What is Neuroleptic Malignant Syndrome?
A
- Acute medical emergency developing over hours/ days in response to Dopamine blocking drugs
- Rigidity/ muscle breakdown – raised CPK.
- Fever
- Autonomic instability (volatile BP/PR)
- Confusion
- Serotonin syndrome can be distinguished from NMS., SS occurs within 24 hours. NMS (days to weeks), SS: Hyperreactivity, NMS: hyporeflexia, severe muscular rigidity
23
Q
What is Tardive Dyskinesia?
A
- Choreic oral-facial movements (video), dystonic trunk posturing
- clinical manifestations including chorea, athetosis, dystonia, akathisia, stereotyped behaviours, rarely tremor.
- older patients:
- Protruding and twisting movements of the tongue
- Pouting, puckering, or smacking movements of the lips
- Retraction of the corners of the mouth
- Bulging of the cheeks
- Chewing movements
- Blepharospasm
- likely due to dopamine supersensitivity of basal ganglia
- i.e. secondary receptor/ plastic changes
- Treatment:
- gradual withdrawal of offending agent, substitution with an atypical anti-psychotic;
- use of a dopamine depleting agent (tetrabenazine);
- use of a benzodiazepine (clonazepam) if distressing
24
Q
Explain the symptoms and physical signs of Parkinson’s Disease is?
motor and non-motor
A
- symptoms are:
- Slowness of movement (also thought/ psychomotor retardation)
- Stiffness
- Shaking.
- physical signs include:
- Slowness and poverty of movement (bradykinesia) e.g. loss of facial expression and arm swing, difficulty with fine movements
- Voluntary movements harder to initiate (akinesia)
- non-motor symptoms
- Mood: Depression, anxiety
- Dementia: slowed thought, mental inflexibility,
- Autonomic involvement: Postural hypotension, Hypersalivation
- Sleep disturbance: Restless legs, REM parasomnia
- Reduced sense of smell
25
What is the pathophysiology of Parkinson's Disease?
* Decreased dopamine input leads to reduced activation of direct pathway and reduced inhibition of the indirect pathway
* leads to reduced movements
26
What is Parkinson's disease and some of it's causes?
* A neurodegenerative condition, primarily affecting dopaminergic cells of the substantia nigra
* Lewy bodies are seen in histopathological exams
_Neurodegenerative_
* (Idiopathic) Parkinson’s disease \>80%
* Diffuse Lewy body disease
* Atypical Parkinsonism (MSA, PSP, CBD)
* **M**ultiple **s**ystem **a**trophy, **P**rogressive **s**upranuclear **p**alsy, **C**ortico**b**asal **d**egeneration
_Secondary_
* Drugs (eg haloperidol, MPTP)
* Cerebrovascular disease
* Hydrocephalus
* Toxicity/ metal deposition disorders
_Genetic_
* Metabolic - Wilson’s disease (copper deposition)
* Rare familial (dominant/ recessive) causes
27
What are some PD early drug therapies?
* **Amantadine**
* **** Initially anti-flu agent
* Glutamate agonist
* **Anticholinergics** – **Procyclidine, Benzhexol**
* May help with tremor
* Limited by side effects (confusion, urinary retention, dry mouth…)
* **Monoamine oxidase inhibitors**
28
Monoamine Oxidase Inhibitors (MAO-I)
* Prevent breakdown of monoamine chemical neurotransmitters; 2 isoforms:
* MAO- type A: serotonin, adrenaline, noradrenaline, dopamine
* MAO- type B: dopamine
* Non-selective MAO-I: for depression (Moclobemide);
* rarely used now due to problems with metabolising dietary amines/ tryptophans – the risk of hypertensive crisis – cheese, red wine, marmite
* More selective MAO- IB: for Parkinson’s disease **(Selegiline, Rasagiline)** – no dietary restrictions
29
Go over the use of L-Dopa in treating Dyskinesias
* always combined with Dopa decarboxylase inhibitor to prevent peripheral conversion to dopamine
* gets progressively less effective as the disease progresses
30
what is Entacapone/Tolcapone
* reduces peripheral metabolism of L-dopa,
* increases duration of action of L-dopa, increases efficacy
* makes dyskinesia worse, diarrhoea and tolcapone causes liver disease
31
What is Duodopa?
* it's a duodenal L-dopa infusion for advanced PD
* absorption affected by poor gastric motility/constipation and diet/ poor protein load
* Unpredictable bioavailability makes it very difficult to hit narrow therapeutic window in advanced PD (for ON without dyskinesia)
* Direct delivery of L-dopa to the duodenum via infusion pump potentially very useful strategy to manage motor fluctuations.
* But very cumbersome/expensive (20K/year)
* Does not affect disease progression
32
What Dopamine agonists are used in treating PD?
- what are the pros and cons
_Example_
* Pramipexole, Ropinirole (non-ergot)
* Rotigotine
* Apomorphine
* Bypass degenerating nigrostriatal neurons
* Directly activate dopamine receptors.
* No need for enzymatic conversion.
* More stable and longer-acting.
* *can cause Dopamine dysregulation syndrome*
33
What is Apomorphine?
* It's a dopamine agonist given by s/c infusion
* PROS: every effective with and instant effect, reduces dyskinesia by allowing continuous DA stimulation
* CONS: only for the right patients, causes skin nodules
34
What are some non-drug therapies for PD?
* Deep brain stimulation
* high-frequency stimulation causing inhibition of neurons by depolarising blocks
* disrupts synchronous basal ganglia rhythms
* Targets:
* STN for PD
* Pallidum for dystonia
* Thalamus for tremor
* diseases will still progress and no effect on non-motor
* dementia, dysautonomia, postural instability
* Future treatments include: neurorestorative treatment, and neuroprotective treatments
