Basal Ganglia and Cerebellum

Basal ganglia

group of deep cerebral nuclei planning/intention to move and controlling complex patterns of muscle movement ○ Examples: drawing, writing ○ Controls intensities of separate movements ■ How fast and the directions of movements ■ Sequencing of multiple successive and parallel movements ● To achieving specific complicated motor goals - shooting a basketball

Dysfunction of the Basal Ganglia

produces distinctive movement abnormalities ○ Slowed or diminished movement ○ Involuntary movements - choreatic movements are a sign of early stage Huntington's disease ○ Generalized alterations in muscle tone - muscles being abnormally activated (or not) when you have these dysfunctions occurring

Internal capsule

space between caudate and putamen where almost all motor/sensory fibers connecting to cerebral cortex and spinal cord pass through ○ Capacity for the exchange of information so the basal ganglia can directly modulate those systems ○ Intimate association between B.G. and corticospinal system

Climbing fibers

specifically come from the contralateral inferior olive; Go to the opposite side of the cerebellum ■ One climbing fiber will send signals to one Purkinje cell ● Finite, specific interaction ● Synapse on the dendrites of the Purkinje cell and excite it

Parkinson's disease

sporadic (some genetic forms; rare) loss of substantia nigra (compact) dopaminergic neurons = (so decreased dopamine) - decreased direct pathway - increased indirect pathway - net effect = "move less" (though some have tremors depending on which areas of the brain are degenerating) (enhanced output of globus pallidus = inhibition of thalamus = less cortical output = less movement)

Cerebellum Structures

○ *Anterior lobe* ○ *Posterior lobe* ○ *Flocculonodular lobe* ○ *Vermis*: midline ○ *Intermediate zone*: just lateral to the vermis on either side ○ *Lateral hemisphere*: area beyond the intermediate zone ○ *Tonsils*: at the bottom of the posterior lobe ○ *Primary fissure*: separates the anterior and posterior lobes ○ *Posterorlateral fissure*: separates the flocculonodular and posterior lobes

Cyclical signalling system

○ Alters motor activity via the cerebral cortex - basal ganglia and cerebellum do not have direct effects on motor neurons ● Basal ganglia receive information from the cerebral cortex, put it all together, and feed it back to the cerebral cortex ● Facilitates and suppresses neuronal activity leaving cortex ○ Monitoring and making sure the goal movement is achieved ● Controls intensity of movements

Too much BG inhibition

○ Insufficient activation of cortex = loss of movement ■ Parkinson's disease ■ The substantia nigra is degenerating and there is less dopamine to encourage the direct pathway

Huntington's Disease Symptoms

○ Involuntary jerking or writhing (chorea; "dance") ○ Dystonia and muscle rigidity ○ Rabid twitching of face, tongue, and limbs ○ Slow, uncoordinated limb and eye movements ○ Impaired gait, posture, and balance ○ Dysarthria (difficulty speaking physically) and dysphagia (difficulty swallowing) ○ Dementia and personality changes - there is degeneration in other areas of the brain, and the basal ganglia plays a role in the emotional loops of the brain

Functions of the Cerebellum

○ Modulates fine movement coordination ○ Balance and equilibrium ○ Muscle tone ○ Learning motor behavior ○ Cognition - minor role ● Helps you stand upright, move around, and keep your balance at the same time ○ Keeping your balance while riding a bike ○ Smooth pursuit of one movement to the next ● Removal/injury causes body movements to be highly abnormal

Too little BG inhibition

○ Too much activation of cortex = excess movement that are unplanned/unwanted ■ Huntington's disease ■ Hemiballism

Parkinson's Disease Symptoms

○ Tremor ○ Muscle rigidity ○ Impaired postural reflexes ○ Bradykinesia (slow movement, shuffle that PD patients often have) ○ Hypokinesia (fewer movements overall) ■ Decreased blinking ■ Expressionless face ■ Absence of arm movements when walking ○ Dyskinesia (involuntary movement, ticks)

Principle Afferent Tracts to the Cerebellum

● All of these pathways are happening at the same time ● Everything occurs in fractions of seconds

Cerebellum Cellular Organization

● Arbor Vitae: "tree of life," white matter infoldings ○ Cellular signalling is composed within these ● Molecular layer (ML): outer layer; Parallel fibers from granular cells; climbing fiber axons synapse on purkinje cell ● Purkinje layer (P): cell bodies of Purkinje cells, main functional output form the cerebellum ○ Purkinje cells inhibit the deep cerebellar nuclei depending on how much they have been activated ● Granular cell layer (G): contains some of the mossy fibers that send information to the Purkinje cell from the outside sources

Basic circuits

● Begin and end in cortex (we are focusing on the motor circuit) ● Connections of B.G. are complex ○ From sources outside B.G. ○ Interconnections between B.G. nuclei ○ Output from B.G. to motor centers elsewhere in the brain ● Series of parallel circuits: cortex, B.G., thalamus, cortex ○ *Motor loop (learned movements)* ○ *Oculomotor loop (voluntary saccades)* ○ *Prefrontal (cognitive) loop (motor intention)* ○ *Limbic loop (emotional aspects of movement)*

Cerebellar Peduncles

● Highways in and out of the cerebellum ○ Fibers going in or out of the cerebellum go through one of these 3 peduncles; Attach the cerebellum to the rest of the brain ● Superior cerebellar peduncle (decussates at midbrain) ● Middle cerebellar peduncle ● Inferior cerebellar peduncle

Cerebellar Efferent Outputs

● Information leaving the cerebellum after all of it has been collected and is leaving the deep cerebellar nuclei to produce an effect ● The deep cerebellar nuclei send information down the brainstem both contralaterally and ipsilaterally ○ On the contralateral side, it will go up through the thalamus to the motor/premotor cortex

Cerebellum Features

● Largest structure in the posterior fossa ● 10% of the brain's total weight ● Located behind brainstem at level of pons ● Attached by the peduncles: superior, middle, and inferior cerebellar peduncles

Anterior Lobe Syndrome

● Loss of gait stability ● Clumsy movement of lower limbs ○ Legs are farther down on the somatotopic map ● Results from malnutrition accompanying chronic alcoholism

Principle inputs to Basal Ganglia

● No matter what loop you are discussing, these are coming from the cerebral cortex ○ The cortex signals to the putamen, caudate nucleus, nucleus accumbens, and subthalamic nuclei ○ These are all excitatory signals via glutamate

Cerebellar Efferents from Dentate Nucleus

● Origin: dentate nucleus (biggest one, most lateral) ● Terminates: contralateral red nucleus and thalamus ● Peduncle: superior cerebellar (decussates here) ● Function: planning, initiation and control of voluntary movements

Cerebellar Efferents from Fastigial Nucleus

● Origin: fastigial nucleus ● Terminates: bilateral to vestibular nuclei and reticular formation ● Peduncle: inferior cerebellar peduncle ● Function: balance (you need information to go to both sides in order to maintain balance)

Cerebellar Efferents from Interposed Nucleus

● Origin: interposed nucleus ● Terminates: contralateral red nucleus/thalamus/brainstem nuclei ● Peduncle: superior cerebellar and descending limb of superior cerebellar ● Function: adjusting limb movements

Huntington's Disease Treatments

● There are no treatments to alter the course it ● Medications can lessen some symptoms of movement and psychiatric issues ● Other interventions can help a person adapt to change in abilities ○ Diet (difficulty maintaining weight, which can further progress the disease by depriving the brain of nutrients) ○ Sleep (aides - improving the pt's sleep could decrease symptoms the next day) ○ Exercise Drugs to reduce movement and treat psychiatric component Other treatments: psychotherapy, speech therapy, physical therapy, occupational therapy

Treatment for Ataxia

● There is no specific treatment ● In some cases, treating the underlying cause resolves it (inflammation) ○ In other cases, such as that results from chickenpox or other viral infections, it is likely to resolve on its own over time ■ Adaptive devices or therapies help ● Canes or walkers for walking ● Modified utensils for eating ● Communication aids for speaking ● Treating other symptoms/issues: depression, vertigo, sleep, tremor, rigidity, nystagmus, physical, speach, and occupational therapy, etc.

Flocculonodular Lobe Syndrome

● Truncal ataxia ● Disturbances of balance and lack of coordination of paraxial muscles ● Walk in wide base with trunk swaying ● Lesion of flocculonodular lobe and posterior vermis (bottom of cerebellum) ● Usually seen in children with medulloblastomas in roof of 4th ventricle (impinge upon flocculonodular lobe)

Basal ganglia motor function examples

● Writing letters of the alphabet ● Cutting papers with scissors ● Hammering nails ● Shooting a basketball ● Passing a football ● Throwing a baseball ● Shoveling dirt ● Motor aspects of vocalization - pts with Huntington's disease will have difficulty speaking ● Controlled movement of the eyes (saccades) ● All other "skilled" movements performed subconsciously

Cerebellar Afferent Inputs

●Information entering into the cerebellum from elsewhere ●Everything from the motor cortex is going through the pons and crossing over to the other side ○ Anything from the the L motor cortex is going to the R cerebellar cortex by way of the pons ○ Inferior olive is also contralateral ●Everything from the spinal cord is going to go ipsilaterally ○ Information from muscle spindles about hitting the ground hard enough with my R leg while walking will go up to my R cerebellar cortex ○ Vestibular nucleus (medulla) is also ipsilateral

Cerebellar dysfunction

Caused by: cancer, genetic disorders (degeneration), stroke - *ataxia*-a disturbance that alters the direction and extent of voluntary movements; abnormal gait and uncoordinated movements - *dysmetria*- altered range of motion (misjudge distance) - vestibular signs - *nystagmus* (eyes moving back and forth in unnatural manner)

Modulation of Excitation in the Thalamus

Done by the basal ganglia for movement The thalamus is the "highway" to the cerebral cortex. Many things that enter the cortex go by way of the thalamus, so the basal ganglia are indirectly modulating the cortex.

Hemiballism

"Half Ballistic" ● Lesion in subthalamic nuclei ○ Stroke or aneurysm ○ Disruption of indirect pathway = less "move less" = a lot more movement ● Symptoms: ○ Wild flailing of arm and/or leg on one side of the body (contralateral to the lesion) ○ The area of the brain initiating the movement is on the opposite side ○ Lesion on R side of brain → uncontrolled movement on L side of body

Substantia nigra

(compact part) "The 3rd piece": modulates striatum (influences direct and indirect pathways) Secretes dopamine to either excite direct pathway or inhibit indirect pathway - Net effect = more movement

Vestibulocerebellum

(flocculonodular lobe)- projects to fastigial nucleus - balance and gait; Postural maintenance

Cerebrocerebellum

(lateral hemisphere and some intermediate hemisphere)- projects to dentate nucleus (largest) - Evaluating sensory information for action - motor planning - Cognitive functions

Spinocerebellum

(vermis and some intermediate hemisphere)- projects to interposed nucleus - coordinating adjustment of limb musculature (hands, feet, fingers, toes from IH and neck+hip from vermis) - comparator between intended and actual movements

Basal Ganglia Structures

*Deep middle cerebral structures* ● Nucleus accumbens ● Caudate nucleus ● Putamen ● Globus pallidus (internal (GPi) and external (GPe) segments) *In rostral midbrain* ● Substantia nigra *In diencephalon* ● Subthalamic nucleus (Compact (SNc) and Reticular (SNr)) Caudate nucleus and putamen together = *striatum* Putamen and globus pallidus together = *lenticular nucleus*

Functional subdivisions

*Vestibulocerebellum (flocculonodular lobe)* *Spinocerebellum (vermis and some intermediate hemisphere)* *Cerebrocerebellum (lateral hemisphere and some intermediate hemisphere)*

Posterior Spinocerebellar Pathway

afferents to cerebellar cortex ● Origin: clarks nucleus in spinal cord ● Terminates: ipsilateral vermis and intermediate zone ● Peduncle: inferior cerebellar ● Function: limb and joint proprioceptive information

Olivocerebellar Pathway

afferents to cerebellar cortex ● Origin: inferior olivary nuclei and accessory olivary nuclei ● Terminates: contralateral cerebellar hemisphere ● Peduncle: inferior cerebellar ● Function: motor coordination and motor learning

Pontocerebellar Pathway

afferents to cerebellar cortex ● Origin: pontine nuclei ● Terminates: contralateral anterior and posterior cerebellar lobes ● Peduncle: middle cerebellar ● Function: cortical information relevant to motor commands and planned motor activities - walking

Mossy fibers

carry all other afferents coming through the cerebellum ○ Join and become granule cells, which send out many dendrites up into the parallel fibers ■ The granular cells become the parallel fibers ○ The parallel fibers will interact with and excite particular Purkinje cells a number of times ■ Parallel fibers excite a ton of Purkinje cells (vs. climbing fibers that excite one Purkinje cell)

Principle Outputs from Basal Ganglia

coming from the internal segment of the globus pallidus and the reticular component of the substantia nigra (pars reticulata) ○ Send inhibitory signals (GABA) to inhibit the thalamus

Nuclei Projecting to Cerebellar Cortex

Brainstem ● Pontine nuclei (pons; mossy fibers and granular cells) ● Vestibular nuclei (mossy fibers and granular cells) ● Inferior olivary nucleus (where climbing fibers come from) Spinal cord ● Clark's nucleus (C8 → L2-3) (mossy fibers within spinal cord, information from muscle spindles about proprioception)

Basal Ganglia and Cerebellum

Coordinating movement control ● Both play a role in modulating motor function ● ______________ largely work through the thalamus to reduce movement to some degree ● ______________ plays more of an excitatory role ○ Signalling leaving the cerebellum is glutamatergic/excitatory ○ The amount of excitation will be modulated by the Purkinje cells, and their interaction with deep cerebellar nuclei, so it is not always highly excited ● There is communication between both through the thalamus or indirectly through midbrain/brainstem nuclei ○ Everything is interconnected

Posterior Lobe Syndrome

Intention Tremor ● Loss of coordination of voluntary movements ○ Posterior lobe contains a lot of the cerebral cerebellum, so voluntary movement planning is impaired ● Decreased muscle tone ● To and fro movements perpendicular to intended direction of movement ● Common causes: cerebrovascular accidents, trauma, or degenerative diseases

Cerebellar information flow

Purkinje cell = secretes GABA; inhibits deep cerebellar nuclei ■ It depends on how much excitatory signalling that gets bestowed upon the Purkinje cell to determine how much the deep cerebellar nuclei will be inhibited ● Can inhibit a lot or a little ● Know that Purkinje cells secrete GABA onto the deep cerebellar nuclei ○ The deep cerebellar nuclei are always wanting to send out excitatory signals (like the thalamus) ■ Put the brake on as needed depending on how things are occuring

Indirect pathway (to affect cortical output)

Striatum inhibits GPe which secretes GABA normally--> subthalamic nucleus inhibited less, secretes more glutamate on GPi--> dumps GABA onto thalamus, inhibiting it--> less movement *Bad Cop*

Direct Pathway (to Affect Cortical Output)

Striatum secrete GABA onto GPi and inhibit it, as long as cortex is activating striatum GPi also secretes GABA, but if inhibited by striatum will secrete less GABA--> inhibit thalamus less--> send positive glutamate signals to cortex encouraging movement *Good Cop*

Motor loop (Modulation of Excitation)

Two main pathways: 1. Direct pathway: facilitated movement ■ Exciting this pathway increases movement 2. Indirect pathway: inhibits unwanted movements ■ Monitoring for movements that are not supposed to be happening ● These pathways work together at the same time to regulate movement. The direct pathway is like the "good cop:" when things are working correctly, it keeps it moving along.

Cerebellum

like a small brain attached to the back of your brain; its own system roles in the timing of motor activities and in rapid, smooth progression from one muscle movement to the next ○ Ex: riding a bicycle and maintaining the capacity to stay balanced and upright on the bicycle while smoothly riding it without jerky movement and falling off (vestibular system) ○ Controls the intensity of muscle contraction when muscle load changes (proprioception) ○ Controls necessary instantaneous interplay between agonist and antagonist groups

Huntington's Disease

loss of striatum (caudate nucleus and putamen) - loss of motor modulation, "move more" autosomal dominant CAG trinucleotide repeat expansion in huntingtin gene - (encodes glutamine in protein) late onset (30-50) - fatal usually within 20 years of diagnosis

Parkinson's Disease treatments

medications to increase dopamine (that is lost) meds to reduce involuntary movement deep brain stimulation to reduce symptoms - (stimulate thalamus, subthalamus, globus pallidus)

Overall Goal of BG and Cerebellum

work in parallel to modulate what the upper motor neurons coming from the cerebral cortex are trying to do ○ Making sure the intention of what the movement is supposed to be is actually happening and helping correct/navigate/fine-tune it so that the outcome is correct

Purkinje cell

■ Depending on how much it has been activated will determine how much GABA it sends out ■ If it is activated a lot, there will be a lot of GABA released and the deep cerebellar nuclei will be inhibited a lot ■ If it is not activated very much, it will not send out as much GABA and the deep cerebellar nuclei will not be very inhibited ■ Much like the thalamus, the deep cerebellar nuclei want to secrete excitatory glutamate, so it is just a matter of how much GABA is released ■ Makes sure everything is right: walking the way you plan, hitting the ground the right way. If you misstep, the cerebellum helps to correct it.

Cerebellum Mechanism of Action

■ We will get signals up from the spinal cord that tell us how high I raise my leg, how forcefully I push my foot on the ground, and if that is all happening in the way I planned it to ■ Comes up the spinal cord into Clark's nucleus and feeds into the cerebellum ■ Different from basal ganglia because we are receiving information from many areas about how movement is supposed to be occurring instead of just getting it from the cerebral cortex like basal ganglia do ○ Receives continuous info about desired sequences of of muscle contractions from brain motor control areas