N9 - Cerebellum and Basal Ganglia

Ventral pallidum

Superior portion of substantia innominata

Huntington's Disease (HD) Pathology

Symmetric atrophy of caudate nucleus, with lesser involvement of putamen - Cortical neurons are also depleted but less severely Due to defective gene for huntingtin, a large cytoplasmic protein of unknown function - The first exon of the gene contains repeats of the trinucleotide CAG, which *encodes Glutamine*

Indirect Pathway

Transiently *increases Inhibition* of the *Thalamus* - Direct and Indirect pathways have opposing effects on basal ganglia output to thalamus

Clarke's Nucleus

Unconscious Proprioception, Found in Intermediate Gray Matter - Medial surface of base of posterior horn. *C8-L3*. Axons run up dorsal spinocerebellar tract

Vestibulocerebellum

Vermis + flocculonodular lobes - Control balance and eye movements - Receives input directly from, and projects directly back to, vestibular nuclei

Basal Ganglia and Cerebellum

influence the cerebral cortex via feedback loops through the thalamus

Cardinal Signs of Cerebellar Disease Memory Device

"*A-Taxi Driver Intends (to get) Tips Disproportionately High*" A-Taxi: Ataxia Driver: Driving = movement (also remember MEter - the taxi's Driving Meter), Dysmetria = decomposition of Movement Intends = Intention Tremor Tips = Titubation Disproportionately = Dysarthira, Explosive speech, Explosive is a disproportionate response High = Hypotonia

Interposed Nucleus

(Globose Nucleus + Emboliform Nucleus) *Input* from intermediate part of hemisphere *Output* to red nucleus and (via VL thalamus) to motor cortex

Modulation of limbic loop connections:

*Dopamine neurons in ventral tegmental area of midbrain project to ventral striatum (mesolimbic pathway)* - All known addictive drugs directly or indirectly increase dopaminergic activity of this pathway e.g., hypothalamic β-endorphin neurons that project to the ventral tegmental area are affected by opiate narcotics All "rewarding" behaviors (e.g., eating, sex, gambling, checking your email) may involve this dopaminergic pathway to various degrees

Dentate Nucleus

*Input* from lateral part of hemisphere *Output* (via VL thalamus) to premotor cortex and many other cortical areas

Fastigial Nucleus

*Input* from vermis and flocculonodular lobe *Output* to vestibular nuclei, reticular formation, motor cortex

Cell Types and Connections in Cerebellar Cortex

*Inputs*: 2 types of Afferent fibers to Purkinje cells, both Excitatory: - Climbing Fibers - Mossy Fibers *Outputs*: 1 type of Efferent fibers, all Inhibitory: - Purkinje Cells "Excited to CuM IN, Inhibit Pulling Out" Excitatory CuM = Climbing (climax, cum) Moss, IN = Input; Inhibit (stop), Pulling = Purkinje, Out=Output

Basal Ganglia Circuits

*Modulate cortical output* - Circuits are characterized by *inhibitory connections* - Inhibitory neurons provide both braking and release mechanisms for movement. - Basal ganglia lesions can result in loss of inhibition or overinhibition of movement, or both, depending on the site of lesion

Vascular territories of the cerebellum

*PICA*: Posterior inferior portion of the cerebellum, Inferior cerebellar peduncle, Nucleus ambiguus, Vagus motor nucleus, Spinal trigeminal nucleus, Solitary nucleus, Vestibulocochlear nuclei *AICA*: Anterior portion of the inferior cerebellum, Middle cerebellar peduncle, Facial (CN VII) and Vestibulocochlear nerves (CN VIII) *SCA*: Most of the Cerebellar Cortex, Cerebellar Nuclei, Superior Cerebellar Peduncles

Purkinje Cells

- Most Purkinje cell axons *project to the deep nuclei of the cerebellum*, where they make *Inhibitory synapses* - Some Purkinje cell axons *From the flocculonodular lobe and vermis* project directly *to vestibular nuclei* - Purkinje cell axon terminals all release *GABA*

Efferent Fibers in the Cerebellar Cortex

1 source of efferent fibers, all *Inhibitory*: the *Purkinje cells* - Most Purkinje cell axons project to the deep nuclei of the cerebellum, where they make inhibitory synapses - Some Purkinje cell axons from the flocculonodular lobe and vermis project directly to vestibular nuclei - Purkinje cell axon terminals all release *GABA*

4 Functional Circuits of the Basal Ganglia

1-2.) Motor and Oculomotor Circuits 3.) Prefrontal (Cognitive) Circuit 4.) Limbic Circuit "Move, Look (Eye motors), Think, and Feel"

Cardinal Signs of Cerebellar Disease

1.) *Ataxia* in execution of voluntary movements. 2.) *Dysmetria* and decomposition of movement. 2.) *Intention tremor* of limb movement. 3.) *Titubation* - tremor of trunk during standing or sitting. 4.) *Dysarthria* - slurring and slowing of speech; "scanning" or "explosive" speech. 5.) *Hypotonia* - diminished resistance and delayed response to passive movements "*A-Taxi Driver Intends (to get) Tips Disproportionately High*" "DANISH Dysdiachokinesis, Ataxia, Nystagmus, Intension tremor, Slurred speech and Hypotonia"

General Characteristics of Cerebellar Disease

1.) *Motor signs* produced by cerebellar lesions are *ipsilateral* 2.) Cerebellar damage does NOT cause sensory changes or motor weakness 3.) Most severe disturbances are produced by lesions of *Superior peduncles and Deep nuclei* 4.) Symptoms tend to improve gradually with time, if disease itself does not progress

Symptoms of Basal Ganglia Disease

1.) Abnormal movements (dyskinesia), includes "BAT": - Ballismus (flailing or throwing movements) - Athetosis (slow, writhing movements) - Tremor - chorea (brisk, jerky movements) 2.) Abnormal muscle tone (dystonia) Basal Ganglia disease makes patients a little "BATdy" (dy = dystonia, also dyskinesia)

Deep Nuclei of the Cerebellum

1.) Dentate Nucleus 2.) Interposed Nucleus 3.) Fastigial Nucleus

Arm and Upper Trunk Receptors

1.) From receptors in the arm and upper trunk, branches from the *Fasciculus Cuneatus synapse* on neurons in the *Lateral (External/Accessory) Cuneate Nucleus* (different from Nucelus Cuneatus which does fine touch) 2.) Axons from the Lateral Cuneate Nucleus form the *Cuneocerebellar Tract*, which runs *Ipsilaterally*, together with the posterior (Dorsal) spinocerebellar tract. - Lateral Cuneate nucleus is thus analogous to Clarke's nucleus, for upper limb

Leg Receptors

1.) From receptors in the leg, branches of *primary afferents synapse* on neurons in *Clarke's Nucleus* 2.) Axons from Clarke's nucleus *ascend Ipsilaterally* in the *Dorsal Spinocerebellar Tract* located at the lateral surface of the spinal cord 3,) *Enter the Vermis* of the cerebellum through the *Inferior Peduncle* - Axons of neurons in other regions of the spinal cord make up the Ventral (Anterior) Spinocerebellar Tract; however, this tract appears to be sparse and relatively unimportant in humans.

Cerebellum Supplied by PICA - Memory List

1.) Solitary (single lonely candle) 2.) Vestibulocochlear nuclei (2 ears) - a Swan holding a hearing trumpet 3.) Trigeminal Nucleus - Tri=3, 3 gems coming out of a butt 4.) Vagus motor nucleus - a Ship with a Vague Motor (no one can find it, but they know it's there...) 5.) PIC (Posterior Inferiot Cerebellum) - PICk your nose with a Hook 6.) ICP (Inferior cerebellar peduncle) - I See someone Peeing in a Golf Club (google "UroClub..") 7.) Nucleus Ambiguus - Ambiggus Shark? Is he really a shark...?

Two other nuclei are modulators of the direct and indirect pathways:

1.) Substantia Nigra (Moduates Striatum) 2.) Subthalamic Nucleus (modulates Globus Pallidus Internal Segment - GPi) Although their synaptic actions are different, the dopaminergic inputs to the two pathways lead to the same effect—*Reducing inhibition of the thalamocortical neurons and thus facilitating movement*

Spinal Pathways to the Cerebellum

1.) Ventral Spinocerebellar Tract 2.) Dorsal Spinocerebellar Tract 3.) Cuneocerebellar Tract

Functional divisions of cerebellar cortex

1.) Vermis + flocculonodular lobes (Vestibulocerebellum) 2.) Intermediate Part (Spinocerebellum) 3.) Lateral Part (Cerebrocerebellum)

Cerebellar Output Pathways

1.) Vestibulocerebellum 2.) Spinocerebellum 3.) Cerebrocerebeullum

Afferent Fibers in the Cerebellar Cortex

2 types of afferent fibers, both *Excitatory* to Purkinje cells: 1.) *Climbing Fibers* from contralateral inferior olivary nuclei - Synapse directly on Purkinje cell dendrites 2.) *Mossy Fibers* from everywhere else - Input from sensory pathways (vestibular nuclei, spinal cord) is mostly ipsilateral. Input from cerebral cortex (via pontine nuclei) is contralateral - Mossy fibers synapse on granule cells, which send parallel fibers to synapse on Purkinje dendrites

Location of Caudate Nucleus in relation to the internal capsule

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Location of Globus Pallidus in relation to the internal capsule

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Location of Putamen in relation to the internal capsule

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Muscle Atrophy in ALS

A section of skeletal muscle showing classic neurogenic atrophy,characterized by atrophy of muscle fibers and an *angulated, shrunken appearance to the degenerated fibers*

Fasciculus Cuneatus

Above T6, additional fibers originating chiefly from the upper limb are added lateral to the fasciculus gracilis, forming the ___________ _________ (Contributes to the Nucleus Cuneatus AND the Accessory Cuneate Nucleus)

Subthalamic Nucleus Modulates Globus Pallidus Internal Segment (GPi)

Acts on GPi, for *suppression of unwanted movements* - *Input*: From cortex and from external segment of globus pallidus (GPe) - *Output*: Sends axons to GPi

Cerebellum Non-Motor Functions

Also has higher-level, cognitive functions that are only now beginning to be understood. Non-motor regions of cerebral cortex send *axons to pontine nuclei for relay to cerebellum* - Humans and other apes have much larger lateral cerebellar hemispheres and dentate nuclei than do other mammals

Cerebellar Lobes

Anterior Posterior Flocculonodular

Cerebellum Supplied by AICA

Anterior portion of the inferior cerebellum, Middle cerebellar peduncle Facial (CN VII) Nerve Vestibulocochlear Nerve (CN VIII)

Huntington's Disease (HD)

Autosomal dominant disorder, principally affecting whites of northwestern European ancestry Symptoms usually begin around age 40, but can be older or younger *Clinical signs:* - Choreiform movements - Cognitive and emotional disturbances

Ranking of Common Movement Disorders by Movement Speed (Slow to Fast)

Bradykinesia, Hypokineasia Rigidity Dystonia Athetosis Chorea Ballismus Tics Myoclonus Tremor- --> Slow OR Fast depending on type

Dorsal Striatum

Caudate and Putamen

Parkinson's Disease Pathology

Cell loss is chiefly in *Substantia Nigra Pars Compacta* - Asymptomatic until about 80% of cells are lost - Some cell loss also occurs in locus ceruleus (norepinephrine neurons) and raphe nuclei (serotonin neurons).

Unconscious Proprioception

Collaterals of *posterior column afferents* (Facilis/Nucleus Gracilis and Cuneatus), especially from muscle spindles and Golgi tendon organs, convey unconscious proprioception information to the cerebellum

Cerebellar Peduncles

Connect cerebellum to brainstem: *Inferior*: mostly input, from spinal cord and medulla *Middle*: all input, from pons *Superior*: mostly output, to midbrain and VL thalamus

ALS Pathophysiology

Defining feature of ALS is the death of both upper and lower motor neurons in the motor cortex of the brain, the brain stem, and the spinal cord. Prior to their destruction, motor neurons develop protein-rich inclusions in their cell bodies and axons. This may be partly due to defects in protein degradation. - Inclusions often contain ubiquitin, and generally incorporate one of the ALS-associated proteins: SOD1, TAR DNA binding protein (TDP-43, or TARDBP), or FUS.

Vermis + flocculonodular lobes (Vestibulocerebellum) Damage

Disease here leads to *ataxic gait, wide-based stance, and nystagmus* - Medulloblastomas in roof of 4th ventricle are the most common cause of flocculonodular lobe damage [like a little green army man: wide stance (feet glued to plastic platform) ataxia (bc it is hard to walk when your feet are glued to a platform), nystagmus (bc hopping around on a platform can make you dizzy - OR picture him with a bayonet that he will Ny-STAB-mus you with). Also arm man's plastic base is shaped like flocculonodular lobe]

Intermediate Zone (Spinocerebellum) Damage

Disease of the *Anterior lobe*, often seen in *chronic Alcoholics*, can cause *gait Ataxia* (anterior lobe consists primarily of vermis and intermediate zone).

Substantia Nigra Modulates Striatum

Dopamine neurons of the substantia nigra (pars compacta) send axons to striatum (nigrostiatal pathway), where they make two kinds of synapses: 1.) Synapses on *Direct Pathway Projection neurons* = *Facilitatory*, using *D1 Receptors* 2.) Synapses on *Indirect Pathway Projection Neurons* = *Inhibitory*, using *D2 Receptors*

Direct (Principal) Pathway

Facilitates movement by exciting the premotor cortex and supplementary motor area: *Sensorimotor Cortex --> Putamen --> Globus Pallidus Internal Segment (GPi) ---> VL/VA Thalamus --> Premotor & Supplementary Motor Cortex* **Cortical excitation of direct pathway inhibits inhibition of the thalamus, resulting in movement**

Direct vs Indirect Pathays

Helpful diagram

Cerebellum 3D Pic

Helpful picture to visualize Cerebellum

Abnormal Posture (PD)

Hunched over ("simian") posture

Parkinson's Disease (PD)

Idiopathic, with some degree of genetic influence Typically appears at age 40 to 70; life expectancy is unaffected (14 years after onset) *Clinical signs:* 1.) *Resting tremor*: Present when limbs are at rest (except during sleep); increased by stress, and diminishes during voluntary movement - Characteristic "pill-rolling" movement of hands 2.) *Rigidity*: Increased tone in all muscles, detected by increased resistance to passive movement ("lead-pipe" rigidity) - May be interruped by brief relaxations ("cog-wheel" rigidity) 3.) *Abnormal posture* Hunched over ("simian") posture 4.) *Bradykinesia*: Slowing of voluntary movements (even blinking), loss of facial expression; may also be difficult for patients to stop walking once they start *Parkinson's patients also have increased incidence of depression and dementia*

Cerebral inputs to Pontine Nuclei --> Cerebellum

Includes Association and Motor areas

Rigidity

Increased tone in all muscles, detected by increased resistance to passive movement ("lead-pipe" rigidity) - May be interruped by brief relaxations ("cog-wheel" rigidity)

Multiple sclerosis (MS)

Inflammatory disease in which myelin in CNS is damaged (thought to be autoimmune attack) disrupting the ability of parts of the nervous system to communicate, resulting in a wide range of signs and symptoms, including physical, mental and sometimes psychiatric problems. MS takes several forms, with new symptoms either occurring in isolated attacks (relapsing forms) or building up over time (progressive forms). Between attacks, symptoms may go away completely; however, permanent neurological problems often occur, especially as the disease advances.

Spinocerebellum

Intermediate part of the Cerebellum Adjusts ongoing movements and muscle tone *Vermis* is concerned with head, trunk, and proximal limbs - Receives vestibular, auditory, visual, and somatosensory input *Intermediate zone* (lateral to the Vermis) is concerned with distal limbs

"More Useful way of Dividing the Cerebellum"

Into the *Midline Vermis* and the *Intermediate and Lateral parts of the Hemispheres* - Vermis + flocculonodular lobes is sometimes called the *Vestibulocerebellum* - Intermediate part is sometimes called the *Spinocerebellum* - Lateral hemispheres are sometimes called the *Cerebrocerebellum* (or Pontocerebellum or Neocerebellum)

Motor and Oculomotor Circuits

Involved in *Scaling the strength* of muscle contractions, and in helping the supplementary motor area *organize sequences of excitation* in primary motor cortex - Direct (Principal) Pathway - Indirect Pathway

Limbic circuit

Involved in giving *motor expression to emotions*, and in (initiation of drive-related behaviors* - Also involved in *depression* and in *reinforcement/addictive behaviors* Principal pathway in basal ganglia limbic function: *Limbic structures --> ventral striatum --> ventral pallidum --> mediodorsal (MD) thalamus --> limbic cortex* - Ventral striatum = nucleus accumbens - Ventral pallidum = superior portion of substantia innominata

Cerebrocerebellum (Pontocerebellum or Neocerebellum)

Lateral hemispheres - Coordinates *planning of limb movement* - Part of motor cortex feedback loop - Essential to precise, rapid limb movements and fine dexterity

Emboliform Nucleus

Lies immediately to the medial side of the nucleus dentatus, and partly covering its hilus. The globose nucleus and emboliform nucleus are occasionally referred to collectively as the interposed nucleus. SUPPLEMENTAL INFO ONLY

Lateral (External/Accessory) Cuneate Nucleus

Located lateral to the cuneate nucleus in the medulla oblongata at the level of the sensory decussation (the crossing fibers of the posterior column/medial lemniscus tract). *Input* from cervical spinal nerves *Output* to the cerebellum Fibers = Cuneocerebellar (cuneate nucleus -> cerebellum) fibers *Upper extremity equivalent of Clarke's Nucleus*

D1 and D2 Receptors

Many of these are ACh-releasing neurons in caudate and putamen - Lowering ACh activity as a balance against decreased dopamine activity is the rationale for using anticholinergics in treatment of Parkinson's patients

Connections Between Basal Ganglia

Most are *Inhibitory*, using *GABA* - also other transmitters, especially *Substance P* and *Enkephalins*

Cerebellum Supplied by SCA

Most of the Cerebellar Cortex Cerebellar Nuclei Superior Cerebellar Peduncles

Cerebellum Supplied by PICA

Posterior inferior portion of the cerebellum Inferior cerebellar peduncle Nucleus Ambiguus Vagus motor nucleus Spinal trigeminal nucleus Solitary nucleus Vestibulocochlear nuclei

Resting Tremor

Present when limbs are at rest (except during sleep); increased by stress, and diminishes during voluntary movement - Characteristic "pill-rolling" movement of hands

Parkinson's Disease Pathogenesis

Nonmotor symptoms may precede and accompany motor PD, including: - Autonomic (i.e., gastrointestinal dysfunction, urinary and sexual dysfunction, orthostatic hypotension, and hyperhidrosis) - Sleep (impaired sleep initiation and maintenance, REM sleep behavior disorder [RBD]) - Sensory (pain, hyposmia, visual dysfunction) - and/or Neuropsychiatric (depression, anxiety/panic attacks, dementia, and psychosis) disturbances that cannot be explained by the nigral dopaminergic pathology of PD

Ventral striatum

Nucleus Accumbens "a portion of the striatum; consists of the nucleus accumbens and the olfactory tubercle. It is considered a reward center" (Wikipedia)

AICA Obstruction/Damage

Obstruction of the AICA can cause paresis, paralysis, and loss of sensation in the face; it can also cause hearing impairment. Moreover, it could cause an infarct of the cerebellopontine angle. This could lead to hyperacusia (dysfunction of the stapedius muscle, innervated by CN VII) and vertigo (wrong interpretation from the vestibular semi-circular canal's endolymph acceleration caused by alteration of CN VIII).

Globose Nucleus

One of the deep cerebellar nuclei Located medial to the emboliform nucleus and lateral to the fastigial nucleus. Contains primarily large and small multipolar neurons. The globose nucleus and emboliform nucleus are occasionally referred to collectively as the interposed nucleus. SUPPLEMENTAL INFO ONLY

Main Excitatory Loop

Output from the cerebellum is via a main excitatory loop through the deep nuclei - This loop is *modulated by an inhibitory side loop* passing through the cerebellar cortex

Most Common Basal Ganglia Disease

Parkinson's Disease (PD)

Pontine Nucleus

Part of the pons involved in motor activity 1.) Corticopontine Fibers (CPF) carry info from Primary Motor Cortex to the Ipsilateral Pontine Nucleus in the Ventral Pons 2.) Pontocerebellar Fibers (PCF) then carries that information to the contralateral cerebellum via the Middle Cerebellar Peduncle - Extension of these nuclei in the medulla oblongata are named arcuate nucleus (medulla) which has the same function They therefore allow modification of actions in the light of their outcome, or error correction, and are hence important in learning motor skills

Prefrontal (Cognitive) Circuit

Participates in *Planning ahead*, esp for complex motor intentions Caudate nucleus receives input from all association areas of cortex. *Association cortex --> Caudate --> Globus Pallidus Internal Segment (GPi) --> VL Thalamus --> Prefrontal Cortex* *Substantia nigra and subthalamic nucleus also modulate this pathway*

MS Lesions

Pic - not sure what we are supposed to know about this...

Cerebellar Damage

Problems in subtle cognitive functions such as planning and the ability to shift attention quickly from one task to another. - Functional studies indicate cerebellar involvement in word selection - Cerebellum may be important in brain development related to autism. In one study of long-term outcomes in 51 children, damage to the cerebellum at birth leads to an autism risk ratio of about 40

Basal Ganglia Input Type

Receive *Excitatory* connections from the cerebral cortex (*Corticostriate Pathway*), with *Glutamate* as the transmitter

Cerebellum Movement and Posture Regulation

Regulates movement and posture indirectly, by comparing intended movements with sensory feedback and adjusting output of descending motor commands. - Essential for learning skilled movements

Cuneocerebellar Tract

Relay information about limb position and movement to the cerebellum from the upper limbs and trunk - upper limb equivalent of the posterior (Dorsal) Spinocerebellar Tract Relays ascending spinal fibers in the dorsal funiculus and conveys information from forelimbs to the cerebellum

Lateral Zone (Cerebrocerebellum) Damage

Signs of cerebrocerebellar disorders also can originate from lesions in midbrain or pons, which have inputs to this region, rather than in cerebellum itself.

Bradykinesia

Slowing of voluntary movements (even blinking), loss of facial expression; may also be difficult for patients to stop walking once they start

Organization of Inputs to the Spinocerebellum is...

Somatatopic

Basal Ganglia Inputs

Specific areas of cortex project to different areas of striatum - *Motor and Somatosensory cortex* mostly project to *Putamen* - *Association* areas of cortex mostly project to *Caudate*

Amyotrophic Lateral Sclerosis (ALS)

Thoracic spinal cord immunostained for myelin basic protein,showing loss of myelinated fibers in the lateral columns. *Lou Gehrig's Disease* A rapidly progressive, invariably fatal neurological disease that attacks motor neurons. Characterized by rapidly progressive weakness due to muscle atrophy and muscle spasticity, difficulty in speaking (dysarthria), swallowing (dysphagia), and breathing (dyspnea). *ALS is the most common of the five motor neuron diseases* (wikipedia)

Striatum

a Subcortical part of the forebrain. Receives input from the cerebral cortex and is the primary input to the basal ganglia system. Divided by internal capsule into the caudate nucleus and putamen. - Functionally, helps coordinate motivation with body movement. It facilitates and balances motivation with both higher-level and lower-level functions, such as inhibiting one's behavior in a complex social interaction and fine-motor functions of inhibiting small voluntary movement.

Basal Ganglia

a group of interconnected subcortical nuclei of a set of parallel circuits linking the thalamus and cerebral cortex; located in the cerebrum, diencephalon, and mesencephalon 1.) Striatum - caudate nucleus - putamen 2.) Globus pallidus - external segment - internal segment 3.) Subthalamic nucleus 4.) Substantia nigra - pars compacta (pigmented, dopaminergic) - pars reticulata (actually a midbrain extension of globus pallidus internal segment)

Climbing Fibers

from *Contralateral inferior olivary nuclei* - Synapse directly on Purkinje cell dendrites "Climb the other olive tree" - climbing fibers originate from the contralateral inferior olive

Mossy Fibers

from everywhere else - Input from sensory pathways (vestibular nuclei, spinal cord) is mostly ipsilateral. Input from cerebral cortex (via pontine nuclei) is contralateral - Synapse on granule cells, which send parallel fibers to synapse on Purkinje dendrites

Choreiform Movements

involuntary spasmodic muscular twitching of the limbs and/or facial muscles

Cerebellum

involved in balance, in posture and muscle tone, and in coordination and planning of voluntary movements