L10 MedNeuro2 Sp25 Lec10 Cerebellum PDF

Cerebellum DO-SYS-725 Med Neuro II Lecture 10 Tony Harper, Ph.D Tues Jan 28 @11am READING: Young, Young and Tolbert (3rd ed): Ch 9 pgs 104-122 1 Lecture Objectives Describe t...

Cerebellum DO-SYS-725 Med Neuro II Lecture 10 Tony Harper, Ph.D Tues Jan 28 @11am READING: Young, Young and Tolbert (3rd ed): Ch 9 pgs 104-122 1 Lecture Objectives Describe the functional specialization of the different lobes (anterior, posterior, flocculonodular), regions (vermis, paravermis, lateral hemisphere), and peduncles (superior, middle, inferior) of the cerebellum Describe the cell types and synaptic connections found in the cerebellar cortex and deep nuclei Diagnose the cerebellar disorders mentioned in the lecture (Dandy-Walker Syndrome, Arnold-Chiari malformation, Anterior lobe syndrome, posterior lobe syndrome, flocculonodular syndrome, pancerebellar syndrome ) 3  Graceful Words Ataxia/Dyssynergia/Asynergia unorderly muscle recruitment, often causing lack of coordination and impaired balance Hemiataxia Unilateral ataxia Dystaxia A mild form of ataxia Apraxia: Difficulty planning and executing skilled movements, usually from parietal lobe damage Dysdiadochokinesia Inability to perform rapidly alternating muscle movements (e.g. pronation – supination) Dysmetria Inability to precisely locate limbs or judge distance in the space around body Hypermetria: Consistently overshooting targets when reaching with limb. Cerebellum underestimates limb inertia, so initiates contractions too slowly, then increases agonist muscle contraction as limb veers off course Hypometria: Consistently undershooting targets when reaching with limb. Cerebellum overestimates inertia of limb and Initiates movements too forcefully, then antagonist muscles slow down limb too rapidly. Can be corrected by adding weights to patient’s limb. 4  Motor Thalamus and Motor Cortex “Extrapyramidal” control of corticospinal neurons comes from both the Cerebellum and Basal ganglia The superior Cerebellar Peduncle, Medial Globus Pallidus and Substantia Nigra pars Reticulata project to the Ventral Anterior(VA) and Ventral Lateral(VL) nuclei of the thalamus CerebelLum projects more to the ventral Lateral nucleus bAsal ganglia projects more to the ventral Anterior nucleus For this class, we can just think of VA/VL as “the motor thalamus” Basal ganglia have more of a role in skeletomotor action selection (all or nothing) Cerebellum smooths out ongoing (pre-approved) movements 5  The Cerebellum is Very Important The Cerebellum contains ~ ½ of the brain’s neurons in ~10% of the braincase volume Has important functions including: Maintaining muscle tone Cerebellum is like conductor for ongoing motor actions. Unconscious proprioception Like a musical conductor, the cerebellum does not directly (spinocerebellar tracts) play an instrument (synapse on motor neurons) A lot more… Individual musicians/muscles do not need the cerebellum to play a solo (act individually; e.g. extending a finger) 6  The Cerebellum is maybe not that Important Cerebellum stores motor patterns through associative learning, and is not active before birth People can be born without a functional cerebellum (Dandy Walker Syndrome), and can apparently store learned motor patterns in the cerebrum Probably no Cerebellum is better than a dysfunctional cerebellum CT images of asymptomatic man with Dandy-Walker syndrome 7  Arnold-Chiari Malformation Dandy Walker Malformation Herniation of cerebellar tonsils down into the cervical spinal canal Only tiny vermis forms Common associated with spina bifida May be symptomless Affects lower four cranial nerves Most symptoms from associated hydrocephalus Affects medullary reticular formation Commonly associated with syringomyelia Affects pyramidal decussation – UMN signs and symptoms Headaches, neck pain 8  White Matter: Arbor Vitae Cerebellar Peduncles Gray Matter: Cortex Deep Nuclei Friends: Inferior olivary nucleus: source of cerebellar Climbing Fibers (remember “olives in tree”), have 1:1 correspondence with contralateral Purkinje cells Dorsal cochlear nucleus 9  Anterior Lobe (Paleocerebellum) Maintains ongoing movements Most connections to spinal cord Gets superior cerebellar artery Posterior Lobe (Neocerebellum) Most connections to cerebrum Flocculonodular Lobe (Archicerebellum) Most connections to vestibular nerve and nuclei (through juxtarestiform body) Vermis (midline) Connections to vestibular nerve and nuclei, The vermis corresponds to axial muscles related to posture (e.g. anterior corticospinal tract) Paravermis (Intermediate Zone) Coordinates distal limb muscles (e.g. lateral corticospinal tract) Lateral Hemispheres Related to complex multilimb movements and hand-eye coordination 10  There are at least 3 separate motor maps (homunculi) in each cerebellar hemisphere Lesions to vermis –truncal ataxia wide gait, drunk speech Lesions to paravermis – distal limb ataxia Lesions to posterior lobe (Posterior Lobe Syndrome) – intention tremor, hypotonia, dysmetria, dysdiadochokinesia Lesions to anterior lobe (Anterior Lobe Syndrome). Usually starts anteriorly fist, from malnutrition and/or alcoholism. Starts with lower limb ataxia (but not wide stance necessarily) Lesions to flocculonodular lobe (Flocculonodular Syndrome). Uncoordinated trunk muscles, balance deficits. Wide stance, and difficulty with eye movements 11 Superior cerebellar peduncle (aka brachium conjunctivum) : Connects to midbrain Mostly efferent (relative to cerebellum) E.g. projects to contralateral motor thalamus Efferent: Dentatorubrothalamic, Interopositorubrothalamic, fastigiothalamic, fastigeovestibular tracts Afferent: ventral spinocerebellar, trigeminocerebellar(from mesencephalic nucleus), ceruleocerebellar tracts Middle Cerebellar Peduncle: Connects to pons Pontocerebellar fibers from contralateral pons to posterior lobe Inferior cerebellar peduncle: Connects to medulla Trigeminocerebellar fibers from chief and spinal nuclei The Cerebellum has much more afferent(sensory) input than Composed of: motor output coming through the “cerebellar peduncles”. Restiform body: afferent fibers –Dorsal Spinocerebellar Cuneocerebellar Olivocerebellar tracts Juxtarestiform body: Afferent: fibers to vestibular lobe and CN8 to But cerebellar lesions usually cause motor problems vestibulocerebellum. Efferent: from fastigial nucleus(fastigeobulbar) and flocculonodular lobe to vestibular nuclei. Lesions to the cerebellar peduncles/tracts usually cause more dramatic symptoms than lesions to the cerebellum itself 12  The Cerebellum is a Comparator The cerebellum stores “smooth” motor patterns through M ot “associative learning” or In te n It needs to be given an “approved” “sm oo t io n motor intention and unconscious th ed proprioceptive information on how ”m ov the movement is going em en t Intended movement An Error Signal generated from the difference of 2 types of ce unconscious proprioception signals e ren af f (both coming from mossy fibers) Re Actual self-generated movement py Co Movement Error = actual n ce movement(Reafference) – intended re fe movement (Efference Copy) Ef * The cerebellum provides “feed-forward” correction of ongoing movements, and can’t correct for movements already occurring in skeletal muscles 13  Afferent: Intended Motion Corticopontine fibers from contralateral cerebral cortex Out of the ~20 million fibers in cerebral peduncles, only ~2 million are corticospinal fibers, the rest are corticopontine fibers (traveling through anterior limb of internal capsule) Pontocerebellar fibers decussate to enter contralateral middle cerebellar peduncle In white matter stain, pontine nuclei are white spaces between black vertical and transverse fibers 14  Afferent: From spinal levels, reafference comes from 2nd Order sensory Reafference neurons in special nuclei. Accessory/External Cuneate Nucleus is lateral to DC-ML Nucleus Cuneatus – Gives rise to Cuneocerebellar Tract carrying reafference from ipsilateral upper limb Clarke’s Nucleus (Nucleus Thoracis) is in medial lamina 7 in spinal levels T1 – L2 (same as intermediolateral nucleus) - Gives Rise to Dorsal/Posterior Spinocerebellar Tract carrying reafference from ipsilateral lower limb Both reafferent tracts receive somatosensory information (mechanosensory, unconscious proprioception) from 1st Order neurons in the Dorsal Columns Both enter cerebellum through ipsilateral Inferior Cerebellar Peduncle (restifom body) 15  Afferent: Efference Copy (Corollary Discharge) from spinal levels originates from “border cells” in spinal gray matter, which receive copies of motor neuron and Efference Copy interneuron firing patterns in the intermediate gray matter and ventral gray horn. Rostral spinocerebellar tract: cervical (brachial) expansion spinal levels in intermediate zone of spinal gray matter. Runs ipsilateral through inferior and superior cerebellar peduncles. Ventral/Anterior Spinocerebellar Tract (Gower’s Tract): originates from spinal gray matter neurons in lumbar levels of intermediate zone and ventral gray horn. Decussates in ventral white commissure of spinal cord and ascends on contralateral side of cord. Decussates again in superior cerebellar peduncle to reach ipsilateral cerebellum. 16  Spinocerebellar Tracts: What's important? Pontocerebellar is main tract in middle Ipsilateral lower cerebellar peduncle limb dystaxia Important spinocerebellar tracts are on superficial lateral margin of spinal cord (between the rootlets) Even unilateral lesions to lateral cord can cause some bilateral lower limb ataxia, Contralateral lower and hypotonia limb dystaxia All spinocerebellar tract afferent fibers enter the cerebellar cortex as “mossy fibers” 17 Efferent: Cerebellar Connections Most cerebellar projections are excitatory motor thalamus red nucleus vestibular nuclei reticular formation 18  For the Afferent Mossy Fiber tracts (shown in the last few slides): 1a) Colateral branches 2a) Mossy fibers synapse synapse on Deep Nuclei - > in the cerebellar cortex -> 2b) yadayadayada … -> 1b) deep Nuclei then send excitatory projections back 2c) Information leaves the cerebellar cortex as axons to contralateral motor of Purkinje cells synapsing thalamus and other on deep nuclei -> All Afferents into Cerebellum (Mossy Fibers and Climbing subcortical nuclei 2d) Deep Nuclei then send Fibers) can take 1 of 2 routes through the cerebellum: excitatory projections back 1) skipping the cortex to contralateral motor 2) through the cortex. thalamus and other subcortical nuclei The cerebellar deep nuclei are the only efferent neurons of the whole cerebellum. * It takes ~ 20 milliseconds for information to loop through the cerebellar cortex all pathways have to leave through the deep nuclei 19 Cerebellar Unlike Cerebral Cortex: Cortex Has folds called folia (not gyri) Does not reach consciousness Mostly controls ipsilateral side of body Has 3 Layers: Outer: Molecular Layer Middle: Purkinje Cell Layer Inner: Granule cell Layer 20 Cerebellar Folium molecular layer Purkinje cell layer granule cell layer white matter 21 Cerebellar Folium Purkinje cell Climbing fiber dendrite Granule cell parallel fiber Mossy fiber dendrite synapse Not shown (low yield OMS1 Med Neuro): Stellate cells terminal Basket cells terminal (synapse) Golgi cells axon to the deep nuclei 22  Main Cortical Loop Mossy fibers: Bring all afferent information to cerebellum. Several converge to each granule cell, and collateral branches synapse on deep nuclei. Granule Cells: The most abundant cell type in the CNS, and the only excitatory cells with cell bodies in the cerebellar cortex. Send out long axons called Parallel Fibers to excite Purkinje cells Parallel fibers: Reach Molecular layer and travel parallel to folia(mediolateral) for several mm and even cross sides. One parallel fiber synapse on many Purkinje cells 23 Mossy Fibers Originates in the… molecular layer Spinocerebellar pathway Ascending (from spinal cord) Most fibers do not cross Most fibers enter cerebellum through the inferior cerebellar peduncle Pons granule cell layer Descending (from cerebral cortex) mossy These fibers must cross in the fibers cerebral peduncles (corticopontine fibers) Enter cerebellum through the middle cerebellar peduncle Projects to the granule cell layer, where it synapse on the “claws” of the granule cells Excitatory 24 Granule Cells Receives input from mossy fibers in molecular layer the granule cell layer parallel fiber Extends “claws” to grab the mossy fiber terminus Projects to molecular layer, where the “parallel fibers” then run parallel to the folia surface (mediolateral) granule cell layer These “parallel fibers” synapse on granule cell and excite Purkinje cell dendrites One synapse per Purkinje cell One parallel fiber connects many Purkinje cells The coincidence of parallel and climbing fiber excitation of the Purkinje cell results in learning related to coordination 25 Inhibitory Interneurons Stellate cell Molecular layer Basket cell Cell body in molecular layer Projections wrap around Purkinje cell Purkinje cell basket cell body Golgi cell Granule cell layer 26  Purkinje Cells The only cells that project out of the cerebellar cortex ( to deep nuclei and vestibular nuclei) Are GABAeric Live in the 1-cell wide middle layer of cerebellar cortex. Apical dendrite branches a lot and is covered with spines, narrowest in direction parallel to folia Spontaneous firing rate ~ 50-200 Hz Receives input from ~200,000 parallel fibers, which represent over a million mossy fibers. These excitatory signals produce simple spikes. Excited by parallel( excites whole mediolateral row) and climbing fibers(each Purkinjie cells only gets 1 climbing fiber) Inhibited(GABA) by stellate and basket cells in molecular layer (lateral inhibition within mediolateral rows) 27 Purkinje Cell One Purkinje cell receives input molecular layer from… One climbing fiber Purkinje cell Many parallel fibers (up to a dendrite million) Inter-Purkinje cell connections via parallel fibers allow motor coordination to occur granule cell layer Purkinje cell body Projects to and inhibits the deep nuclear cells 28  Motor Learning Like a musical conductor, the cerebellum works differently during rehearsal and a concert Climbing Fibers (olivocerebellar) are excitatory to the deep nuclei and Purkinje cells, using aspartate as neurotransmitter. Ascend from contralateral (to cerebellar hemisphere) inferior olivary nucleus, through ipsilateral restiform body. Each climbing fiber innervates a few Purkinje cells (but each Purkinje cell only receives 1 climbing fiber). Fire slowly (~1Hz) but provide enough EPSP to cause ~5 Purkinje cell action potentials, making a complex spike. Produce long term depression in response to parallel fiber firing (making them harder to excite) 29 Climbing Fibers Cell bodies reside in the inferior olive molecular layer Projects to the Purkinje cell layer, where one climbing fiber synapses with one Purkinje cell Excitatory Climbing fiber input weakens the excitatory effect of parallel fibers on granule cell layer the Purkinje cell climbing fiber Fire at high rates when learning movement, low rates during learned movement 30  Cerebellar Deep Nuclei Receive inhibitory input from Purkinje cortical cells Fastigial (medial) nucleus Project to brainstem and thalamus Globose/emboliform (intermediate) nuclei Each nucleus has a separate body Dentate (lateral) nucleus map Help initiate movement 31 Deep Cerebellar Nuclei The only output of cerebellum – send mostly excitatory output to to Lesions to the cerebellar brainstem and thalamus output fibers as they Afferent excitatory synapses from collateral branches of climbing and travel through the Red mossy fibers Nucleus can cause Spontaneous fire APs at ~20-50Hz (but kept lower by Purkinje Cell Benedikt’s Syndrome( inhibition) near midline) or Claude’s Afferent inhibitory synapses from Purkinje cells Syndrome (more lateral). Both would produce contralateral (to lesion) Input hemiataxia Vermis and floculonodular lobe -> fastigial nuclei Paravermis -> Interposed Nuclei (emboliform anterior, globose posterior) Lesions to the Lateral hemispheres -> Dentate Nuclei Decussation of the Superior Cerebellar Peduncles can cause Output bilateral ataxia (one of Interposed nuclei –> mostly to red nucleus the few ways to produce bilateral cerebellar Dentatofugal fibers (plus some of the other nuclei) -> Superior cerebellar peduncle (passing through contralateral Red Nucleus and symptoms from a single dorsomedial subthalamus). Joins pallidothalamic fibers to reach lesion) contralateral motor thalamus 32 Nuclear Functions/Lesions Nucleus Input Function Lesion results in… Fastigial (medial) Vestibular Control upright stance Falls to the side of the against gravity lesion Globose/ Cerebral cortex Balance agonist and Ipsilateral action tremor emboliform Spinal cord antagonist muscles at a during voluntary (interposed) single joint movements (e.g. reaching) Dentate (lateral) Cerebral Cortex (1) Combined digit (1) Incoordination of digits movements (2) Overshoot targets in (2) Arm/leg reaching to reaching with arm/leg a visual target Movements involving multiple joints are more impaired than those involving a single joint. Patients may try to compensate by moving more slowly or moving one joint at a time. Lesions prevent several types of motor learning. 33  Flocculonodular Syndrome Medulloblastoma: Found in the roof of the fourth ventricle Truncal Ataxia Output is to trunk muscles via vestibulospinal tracts Patients lose trunk control and have wide-based standing posture Gaze dysfunction – difficulty fixing eyes on a point 34  Anterior Lobe Syndrome Results from malnutrition associated with alcoholism Purkinje cells in anterior lobe of the vermis are damaged (usually more anterior cells first) Wide-based stance with ataxia Gait ataxia Normal or only slightly impaired upper limb coordination May see hypotonia, nystagmus 35  Posterior Lobe Deficit Trauma, stroke, tumor, degenerative diseases Ataxia - Loss of coordination of voluntary movements of upper limb Intention tremor in that limb Dysmetria – under - and overshooting a target; past- pointing Dysdiadochokinesia – inability to perform rapid alternating movements Speech alterations – scanning speech, explosive speech Hypotonia 36  Pancerebellar Syndrome Just means damage to entire cerebellum Vitamin Deficiency – Vitamin E Alcohol Drugs Hyperthermia – “Heat Stroke” Neurodegenerative Diseases Example: Olivopontocerebellar Atrophy (OPCA) Can be sporadic or genetic Progressive Ataxia Liquefactive Necrosis of brain Pontine and cerebellar atrophy tissue caused by Heat Stroke. Cerebellum is particularly sensitive 37  Blood Supply to Cerebellum and Peduncles superior peduncle middle peduncle inferior peduncle 38  Practice Question 1 The lesion shown in the image would produce which of the following deficits? A) Right Limb Ataxia B) Left Limb Ataxia C) Truncal Ataxia What other symptom would be produced by this lesion? Right A) Hyperreflexia Left B) Hypotonia C) Fasciculations D) Spasticity 39  Practice Question 2 What is the source of the parallel fibers? A) Purkinje Cells B) Granule Cells C) Deep Nuclei D) Inferior Olivary Nucleus In what layer are the parallel fibers most abundant? A)Molecular B) Purkinje Cell C) Granule Cell 40