Lectures 19 & 20 (Nina Milosavljevic)

Question 1

Where is the cerebellum located?

Week 10 - Cerebellum

Answer 1

• back of brain, underlying the occipital & temporal lobes of the cerebral cortex
• more specifically in the posterior cranial fossa

Question 2

What proportion of the brain does the cerebellum account for

Week 10 - Cerebellum

Answer 2

10% of the brain’s volume but contains over 50% of the total number of neurons, which are tightly packed in a single circuit of 5 main types of neurons arranged in a stereotypical pattern.

Question 3

What is the ratio of inputs to outputs for the cerebellum

Week 10 - Cerebellum

Answer 3

40x more inputs than outputs

40:1

Week 10 - Cerebellum

Question 4

What is the cerebellum not necessary for

Week 10 - Cerebellum

Answer 4

• not necessary for perception and action - removing it does not alter contraction strength or sensory thresholds

Question 5

What can damage to the cerebellum lead to

(5)

Week 10 - Cerebellum

Answer 5

• Reduced muscle tone
• Impaired balance and motor learning
• Disrupts spatial accuracy
• Disrupts temporal coordination of movement
• can also impair various cognitive functions

Question 6

What are the main functions of the cerebellum

(4)

Week 10 - Cerebellum

Answer 6

• maintenance of balance & posture - important for making postural adjustments
• co-ordination of voluntary movements - coordinates timing & force of muscle groups used to prouce fluid limb movements
• motor learning - major role in adapting& fine tuning motor programs to make accurate movements through trial and error
• Cognitive functions - i.e learning & emotional processing , recently discovered

Question 7

What are the components of the cerebellums global anatomy

Week 10 - Cerebellum

Answer 7

It consists of an outer mantle of grey matter, inner white matter, and three pairs of deep nuclei

Question 8

What are the three deep nuclei in the cerebellum and what is collectively important about them

Week 10 - Cerebellum

Answer 8

Dentate,
Interposed (containing globose and emboliform nuclei),
Fastigial nuclei.

Cerebellar outputs originate from cell bodies in the deep nuclei,

(with an exception of output from the flocculonodular lobe.)

Question 9

How is the cerebellum connected to the brainstem?

Week 10 - Cerebellum

Answer 9

via three symmetrical pairs of tracts: the Inferior, Middle, and Superior cerebellar peduncles,

with the Superior peduncle containing most of the output projections.

Question 10

What are folia?

Week 10 - Cerebellum

Answer 10

Parallel convolutions that run horizontally across the cerebellums surface

Question 11

How is the cerebellum divided?

lobes, fissures, furrows

Week 10 - Cerebellum

Answer 11

into three lobes:
Anterior, Posterior, and Flocculonodular lobes, separated by two deep transverse fissures.

each lobe is further subdivided

Anterior & posterior lobes divided by primary fissure (runs across dorsal surface)

Flocculonodular lobe seperated by potsterolateral fissure

two longitudinal furrows run down the middle of cerebellar cortex forming an elevated ridge known as the vermis

Question 12

What are the functions and anatomical locations of the cerebellar nuclei?

Week 10 - Cerebellum

Answer 12

The Fastigial nucleus, situated medially, receives inputs from the vermis and various sensory afferents, projecting to the vestibular nuclei and reticular formation.

The Interposed nuclei, located laterally, receive input from the intermediate zone and project to the contralateral red nucleus.

The Dentate nucleus, the largest, receives inputs from the lateral hemisphere and projects to the contralateral red nucleus and ventrolateral thalamic nucleus.

Question 13

What is the significance of cerebellar nuclei lesions?

Week 10 - Cerebellum

Answer 13

Lesions to the cerebellar nuclei have similar effects as complete lesions of the entire cerebellum, highlighting their importance in motor and cognitive functions.

Question 14

How are the cerebellar hemispheres divided, and what are the functional regions based on this division?

Week 10 - Cerebellum

Answer 14

The cerebellar hemispheres are divided into intermediate and lateral regions on either side of the vermis.

Functionally, the cerebellum is divided into the Vestibulocerebellum, Spinocerebellum, and Cerebrocerebellum.

Question 15

What are the functions, input and outputs of the Vestibulocerebellum?

Week 10 - Cerebellum

Answer 15

The Vestibulocerebellum, comprising the flocculonodular lobe, regulates balance and eye movements.

It receives inputs from vestibular organs and visual information (from SC and V1 via pontine nucleus), projecting to the lateral vestibular nuclei to adjust posture during stance and gait.

Question 16

What are common problems associated with damage to the Vestibulocerebellum?

Week 10 - Cerebellum

Answer 16

difficulty coordinating eye movements during head rotations and challenges in coordinating body movements during standing and walking.

Patients may compensate by spreading their legs apart in a wide stance.

Question 17

Describe the Spinocerebellum and its functional details.

(3)

Week 10 - Cerebellum

Answer 17

includes the vermis and adjacent parts of the hemispheres

processes sensory inputs and modulates proximal and distal muscle control.

receives inputs from the spinal cord and projects to medial and lateral descending systems controlling posture and locomotion.

Question 18

What inputs does the Spinocerebellum receive, and how are they transmitted?

Week 10 - Cerebellum

Answer 18

Inputs originate from interneurons in the spinal cord and end as mossy fibers in the intermediate cortex and vermis.

The ventral and dorsal spinocerebellar tracts provide the cerebellum with a combination of descending commands and sensory information from the legs.

Question 19

What is the role of the Cerebrocerebellum, and how does it differ from other regions?

Week 10 - Cerebellum

Answer 19

The Cerebrocerebellum solely receives inputs from the cerebral cortex and participates in planning and executing complex motor actions.

It projects outputs via the dentate nucleus to prefrontal, motor, and premotor cortex.

Question 20

What somatotopic mapping is observed in the Spinocerebellum?

Week 10 - Cerebellum

Answer 20

Mapping studies reveal inverted somatotopic maps in the Spinocerebellum.

The posterior vermis maps the head, while the dorsal and ventral portions of the vermis map the neck and trunk, indicating a fractured somatotopy.

Question 21

How does the organization of the cerebellum contribute to its role in motor control and coordination?

Week 10 - Cerebellum

Answer 21

The cerebellum’s intricate organization and functional specialization contribute to its role in motor control, balance, and coordination.

Each region plays a unique role in processing sensory inputs and modulating motor outputs, highlighting the complexity of cerebellar function.

Question 22

What are the three distinct layers of the cerebellar cortex, and what types of neurons are present?

Week 10 - Cerebellum

Answer 22

The three layers are the Molecular layer, Purkinje cell layer, and Granular layer.

5 types of Neurons in the cerebellum
4 inhibitory: stellate, basket, Purkinje, and Golgi neurons
1 excitatory: granule cells

Question 23

Describe the composition and function of the Molecular layer.

Week 10 - Cerebellum

Answer 23

contains the cell bodies of stellate and basket cells, along with dendrites of Purkinje cells and excitatory axons of granule cells (parallel fibers).

Purkinje cells receive inputs from parallel fibers and climbing fibers in this layer.

Question 24

How do parallel fibers interact with Purkinje cells?

Week 10 - Cerebellum

Answer 24

Parallel fibers, formed by axons of granule cells, run parallel to the long axis of the folia.

Each parallel fiber can connect with many Purkinje cells, whose dendritic fields are oriented perpendicular to the parallel fibers.

Question 25

What is the structure and function of the Purkinje layer?

Week 10 - Cerebellum

Answer 25

The Purkinje layer lies beneath the Molecular layer and consists of a single layer of Purkinje cells.

These cells receive inputs from parallel fibers and climbing fibers and are the output neurons of the cerebellar cortex, making the layer entirely inhibitory.

Question 26

What inputs do Purkinje cells receive, and what is the role of climbing fibers?

Week 10 - Cerebellum

Answer 26

Purkinje cells receive inputs from parallel fibers and climbing fibers.

Climbing fibers wrap around the soma and dendrites of Purkinje cells, making multiple connections.

Climbing fibers provide powerful input to Purkinje cells, influencing motor learning and coordination.

Question 27

Describe the Granular layer of the cerebellar cortex.

Week 10 - Cerebellum

Answer 27

The Granular layer is the innermost layer of the cerebellar cortex, containing a vast number of granule cell bodies and a few larger Golgi interneurons.

Granule cells, the smallest neurons in the brain, receive input from mossy fibers, the main source of input into the cerebellum.

Question 28

What is the significance of mossy fibers in the Granular layer?

Week 10 - Cerebellum.

Answer 28

Mossy fibers terminate in the Granular layer and form synaptic complexes called cerebellar glomeruli, where they contact granule cells and Golgi neurons.

These fibers provide essential sensory and motor information to the cerebellum.

Question 29

: What are the two main inputs to the cerebellum, and what types of information do they carry?

Week 10 - Cerebellum

Answer 29

Mossy fibers and Climbing fibers.

Mossy fibers originate from the spinal cord and brainstem nuclei, carrying sensory input from the periphery and cerebral cortex.

Climbing fibers originate from the olivary nucleus, conveying somatosensory, visual, or cerebral cortical information.

Question 30

Describe the activation and function of Mossy fibers in the cerebellum.

Week 10 - Cerebellum

Answer 30

Mossy fibers make excitatory connections to dendrites of granule cells.

Granule cell axons (parallel fibers) activate multiple Purkinje cells, with each Purkinje cell receiving input from as many as 1 million granule cells.

Mossy fibers respond differently to sensory stimulation and motor activity, firing rapidly during voluntary movements and sensory stimulation.

Question 31

Explain the role and activation of Climbing fibers in cerebellar function.

Week 10 - Cerebellum

Answer 31

Climbing fibers wrap around cell bodies and proximal dendrites of Purkinje neurons, making multiple synaptic contacts.

Activation of climbing fibers causes prolonged voltage-gated calcium conductance in Purkinje cells, generating complex spikes.

Climbing fibers fire at low rates and rarely more than 3 spikes per second, showing little change during voluntary

Question 32

What are complex spikes, and how do they differ from simple spikes?

Week 10 - Cerebellum

Answer 32

Complex spikes are generated by activation of climbing fibers, characterized by an initial large-amplitude spike followed by a high-frequency burst of smaller-amplitude action potentials.

Simple spikes are produced by parallel fibers and generate a single action potential in Purkinje cells.

Question 33

How do center-surround interactions contribute to cerebellar function?

Week 10 - Cerebellum

Answer 33

Purkinje cells activated by parallel fibers generate simple spikes, while stellate, basket, and Golgi interneurons inhibit Purkinje cell activity.

Stellate cells inhibit nearby Purkinje cell dendrites, while basket cells inhibit Purkinje neurons anterior and posterior to the parallel fiber beam, creating center-surround antagonism.

Question 34

What is the potential role of complex spikes in coding information?

Week 10 - Cerebellum

Answer 34

generated by climbing fibers, provide a timing signal rather than encoding the magnitude or duration of stimuli.

Synchronous firing of multiple Purkinje cells in response to complex spikes could be driven by synchronized firing of neurons in the inferior olivary nucleus.

Question 35

How does synchronous activity in different sets of Purkinje neurons correlate with phases of natural behavior?

Week 10 - Cerebellum

Answer 35

Studies have found that different patterns of synchronous activity in different sets of Purkinje neurons are correlated with different phases of natural behavior, suggesting a role in behavior modulation.

Question 36

What are the effects of climbing fiber activity on parallel fiber inputs to Purkinje cells?

Answer 36

Climbing fiber complex spikes slightly reduce the strength of parallel fiber input to Purkinje cells.

Additionally, climbing fiber activity can induce long-term depression in the synapses of parallel fibers that are active concurrently.

Question 37

How does long-term depression (LTD) contribute to cerebellar function?

Week 10 - Cerebellum

Answer 37

LTD is specific to parallel fibers that were coactive with climbing fibers.

occurs when parallel fibers are active within 100-200ms of the climbing fiber complex spike.

LTD can last for hours and is thought to play an important role in motor learning by modifying the strength of synaptic connections.

Question 38

What is the mechanism underlying long-term depression (LTD) in the cerebellum?

Week 10 - Cerebellum

Answer 38

The large influx of calcium in Purkinje cell dendrites during climbing fiber activity is essential for inducing LTD.

Almost simultaneous stimulation of climbing fibers and parallel fibers depresses the parallel fibers, leading to a smaller response upon later stimulation of the same parallel fibers.

Question 39

What are the common symptoms of cerebellar disorders?

(3)

Week 10 - Cerebellum

Answer 39

cerebellar hypotonia, dysmetria, and ataxia.

Question 40

Describe ataxia and its manifestations.

Week 10 - Cerebellum

Answer 40

Ataxia is a group of disorders that cause impairments in movement coordination accuracy. Manifestations include difficulties in coordination, balance, speech, and swallowing.

Question 41

How do lesions in the vestibulocerebellum manifest?

Week 10 - Cerebellum

Answer 41

result in disturbances of posture or gait, leading to difficulty maintaining posture and the development of abnormal gait and stances to compensate.

Question 42

What are the manifestations of dysdiadochokinesia?

Week 10 - Cerebellum

Answer 42

Dysdiadochokinesia is characterized by the inability to perform rapid alternating movements. Muscle responses are slow or awkward, particularly in the upper and lower limbs.

Question 43

What are the causes of dysdiadochokinesia?

Week 10 - Cerebellum

Answer 43

It is primarily caused by cerebellar lesions but can also be secondary to conditions like multiple sclerosis, tumors, or metabolic diseases.

Question 44

How is dysdiadochokinesia diagnosed?

Answer 44

Diagnosis involves evaluating the patient’s ability to perform fast, alternating movements such as rapid hand movements, foot tapping, and repeating syllables. The patient’s performance indicates which muscles are affected by cerebellar lesions.

Question 45

What does the ‘basal’ part of basal ganglia refer to?

Answer 45

That the structures part of this are found near to the base of the brain.

Question 46

Describe the basal ganglia.

Answer 46

It’s a group of subcortical nuclei situated at the base of the forebrain and the top of the midbrain.

They are not separated into smaller parts and are instead a cohesive unit.

Therefore basal ganglia is a collective name for grey matter structures within the hemispheres that work as a functional cohesive unit.

Question 47

Where does the basal ganglia have strong connections to?

Answer 47

Cerebral Cortex

Thalamus

Brainstem

etc…

Question 48

What are the 5 main structures within the basal ganglia grouping?

Answer 48

Caudate Nucleus

Putamen

Globus Pallidus

Substantia Nigra

Subthalamic Nucleus

Question 49

Which two structures form part of the striatum? Describe their primary transmission type and their strong connections.

Answer 49

Caudate Nucleus and the Putamen.

They are mainly (96%) GABAergic neurons in this structure.

They strongly connect with the cortex and the thalamus.

Question 50

What are the names of the two substructures within the globus pallidus?

Answer 50

Internal Globus Pallidus (GPi)

External Globus Pallidus (GPe)

Question 51

What are the names of the two substructures of the substantia nigra?

Answer 51

Pars Reticulata (SNr)

Pars Compacta (SNc)

Question 52

Give an overview of the structure, location and connections of each part of the caudate nucleus.

Answer 52

It is a ‘C’- shaped structure that lies deep inside the brain near the thalamus.

There is one caudate nucleus within each hemisphere of the brain.

The C-shape structure has three parts: a wider ‘head’ at the front, tapering to a ‘body’ and a ‘tail’ (cauda in latin).

The ‘head’ of the caudate nucleus is connected to the frontal lobe.

The ‘body’ of the caudate nucleus is connected to the parietal and occipital lobe.

The ‘tail’ interacts with the temporal lobe.

Question 53

Give an overview of the structure and location of the putamen.

Answer 53

It is a continuation of the caudate nucleus and in the transverse section it is clear the putamen is located between the thalamus and insula.

Question 54

What is the Globus Pallidus divided by and into what?

Answer 54

The medial medullary lamina.

GPi = internal

GPe = external

Question 55

Outline the input and output transmission types of the GPi and GPe.

Answer 55

Both receive GABAergic axonal inputs from the striatum (more complex variety of inputs but this is what lecture specifies).

They output GABA, therefore they inhibit their thalamic targets

Question 56

What is the internal capsule?

Answer 56

The internal capsule is a major white matter structure in the brain that plays a crucial role in connecting different brain regions.

It contains both ascending and descending axons - going to and from the cortex.

Question 57

What separates the caudate nucleus and the thalamus from the putamen and the globus pallidus?

Answer 57

The Internal Capsule.

Question 58

What does substantia nigra mean and why is it called this?

Answer 58

Substantia Nigra (SN) is Latin for “black substance”, referring to the face that parts of the substantia nigra appear darker than neighbouring areas.

This is due to high levels of neuromelanin in dopaminergic neurons.

Question 59

What does the substantia nigra have important roles in? (3)

Answer 59

Reward, addiction and movement

Question 60

What is the role of the Pars Reticulata (SNr)?

Answer 60

It is one of the two output nuclei of the basal ganglia that inhibits the thalamus.

Question 61

What is the role of the Pars Compacta (SNc)?

Answer 61

It produces modulatory dopamine and has a major role in reward-motivated behaviour.

Question 62

What is the Subthalamic Nucleus’ (STN) output transmission type and what are its inputs?

Answer 62

It is the only excitatory (glutamatergic) nucleus in the basal ganglia.

It receives inhibitory input from the GPe.

Question 63

What is the preferred target of Deep Brain Stimulation and why?

Answer 63

STN is the preferred target for Deep Brain Stimulation (DBS) in patients with advanced Parkinson’s disease. The electrodes are surgically inserted in the STN and can be activated with a pacemaker.

The (over)stimulation of STN reduces its output activity which is excitatory, thus reducing its effect on the thalamus.

Therefore, the aim of DBS is to alter the abnormal electrical circuits to help stabilise the feedback loops, and thus reducing symptoms such as tremor, slowness, rigidity, dystonia and dyskinesia.

Question 64

Describe the Direct Pathway of the Basal Ganglia and what it leads to.

Answer 64

It starts with the cortex which send excitation to the Striatum, which is inhibitory to the SNr and GPi.

This inhibits the nuclei which reduces their inputs to the thalamus, which is excitatory to the thalamus (due to less inhibition to it).

This is called the disinhibition principle = refers to the selective and transient reduction of synaptic inhibition.

This means that the thalamus is less inhibited so can send more excitatory signals to the cortex, which leads to more stimulation of muscles.

Leading to the HYPERkinetic state of the muscles = the inception of the movement of muscles.

Question 65

Describe the Indirect Pathway of the Basal Ganglia and what it leads to.

Answer 65

This pathway is inhibitory (opposite to the direct pathway) and its role is to terminate movement, so it’s outcome is the decrease in muscular activity.

The cortex excites the striatum, which inhibits the GPe, which sends inhibitory fibres to the STN instead of directly to the thalamus (hence the indirect name).

Then the STN sends excitatory outputs to the GPi and SNr, which then continues as the direct pathway by inhibiting the thalamus via GABAergic neurons.

This causes a reduced signal from the thalamus, therefore less to cortex and less to muscle.

= Decreased activity of cortical motor neurons and suppression of muscles - HYPOkinetic state.

Question 66

What is the overarching role of dopamine within the basal ganglia? (think general)

Answer 66

Modulation with the pathways.

Question 67

What are the two types of dopamine neurons in the basal ganglia, which pathways are they associated with and what is their role?

Answer 67

The direct pathway neurons that project to the output nuclei express D1 dopamine receptors - role in facilitating movement.

The indirect pathway neurons projecting to external segment express D2 dopamine receptors - role in inhibiting movement.

Question 68

How does dopamine effect its role in the direct pathway?

Answer 68

Dopamine binds to excitatory D1 receptors in the striatum.

This increases the striatum’s inhibition of the Globus Pallidus internal (GPi).

Less active GPi means reduced inhibition of the thalamus.

The disinhibited thalamus sends increased excitatory output to the cortex.

Overall Effect: Dopamine in the direct pathway directly facilitates movement by increasing cortical excitation.

Question 69

How does dopamine effect its role in the indirect pathway?

Answer 69

Dopamine binds to inhibitory D2 receptors in the striatum.
This reduces the striatum’s inhibition of the Globus Pallidus external (GPe).

Increased GPe activity then strongly inhibits the Subthalamic Nucleus (STN).

Reduced STN excitation leads to decreased activation of the Globus Pallidus internal (GPi).

Less active GPi means reduced inhibition of the thalamus.

The disinhibited thalamus sends increased excitatory output to the cortex.

Overall Effect: Dopamine in the indirect pathway ultimately facilitates movement by increasing cortical excitation.

Question 70

What are the three parallel loops of the basal ganglia?

Answer 70

Motor

Associative

Limbic

Question 71

What is the motor loop of the basal ganglia?

Answer 71

Motor Loop is formed between the motor and premotor cortices including the striatum.

The functions of the motor loop are regulation of motor actions.

Question 72

What is the associative loop of the basal ganglia?

Answer 72

Associative loop is formed between the dorsolateral prefrontal cortex (DLPFC) and central regions of the striatum.

The functions of the associative loop are in regulations of cognitive functions.

Question 73

What is the limbic loop of the basal ganglia?

Answer 73

Limbic loop is formed between the orbital and medial prefrontal cortex (OMPFC) and striatum.

The limbic loop is important in emotions and motivation as well as in the acquisition of reward-based behaviours.

Question 74

What are the global functions of the basal ganglia?

Answer 74

The basal ganglia are involved in guiding all aspects of motor control from walking, running, smiling, writing etc.

Importantly, in case of injury or disease such as Parkinson Disease, or Huntington disease, their function is impacted which in turn directly affects motor functions.

They also serve as a bridge between the cortex and the limbic system.

The basal ganglia are also involved in emotional and motivational functioning. Injury to these nuclei can lead to Obsessive Compulsive Disorder, Schizophrenia (catatonia), Drug addiction etc.

Question 75

What is Parkinson’s disease caused by? Why does this cause it?

Answer 75

Parkinson’s disease is caused by degeneration of dopaminergic neurons in SNc (pars compacta of Substantia Nigra).

The SNc has a crucial function in balancing between excitation and inhibition of motion, enabling overall muscle control.

Therefore, the loss of dopamine has effects on both direct and indirect pathways by directly affecting the output to the striatum.

In the case of the direct pathway, loss of dopamine impacts the ability to initiate the movement, while in the indirect pathway, it causes too much inhibition of movement.

Question 76

What are the symptoms of Parkinson’s? (8)

Answer 76

loss of face expressiveness

muscular rigidity (resistant to passive movement)

slow movements (bradykinesia - brady = slow, kinesia = movement)

tremor of hands at rest

shuffling gait

flexed posture and impaired balance

possible hallucinations and visuospatial problems

depression and cognitive impairment (memory, attention).

Question 77

Provide an overview of the most common treatment of Parkinson’s.

Answer 77

The most common treatment for Parkinson’s disease is levodopa (precursor of dopamine).

L-dopa is converted to dopamine in the brain (through enzymes).

Treatment with L-DOPA provides a dramatic reversal of symptoms.

Can be associated with serious side effects (dyskinesia), which get worse with time.

Unfortunately, drug therapies usually begin to lose their effectiveness within around five years.

Question 78

Summarise hyperkinetic disorders.

Answer 78

In humans small strokes restricted to the STN result in involuntary, often violent, movements of contralateral limbs (“ballism”).

Lesions in the STN reduce activity in the internal pallidal segment, which leads to abnormal disinhibition of the thalamocortical pathway, and therefore to excessive activity of motor cortex.

Ballism movements: may be confined to one limb (monoballism), one side (hemiballism), both legs (paraballism), or generalised (biballism).

Pharmacological treatment is based on dopamine receptor antagonists.

Ballism is 500 times less common than Parkinson’s disease. Symptoms often decrease/disappear spontaneously after a few months.

Question 79

Summarise Huntington’s disease.

Answer 79

Huntington’s Disease is inherited, caused by a genetic defect discovered by George Huntington (1872). In 1993, the IT15 gene was identified.

It encodes protein huntingtin, which carries an unstable and expanded CAG repeat in patients.

Huntington’s disease is an autosomal dominant genetic disorder.

There is a degeneration of brain nerve cells in basal ganglia but the earliest degeneration is in the striatum.

Neurons of the indirect pathway are preferentially lost which can explain the motor symptoms by reduced activity of the basal ganglia output nuclei leading to disinhibition of thalamocortical pathway.

The behavioural effect of Huntington’s disease is that patients have uncontrollable muscular movements.

It is a progressive degenerative condition which causes a change in physical and emotional state.