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Neurophysiology of Movement and Posture

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    Neurophysiology of Movement and Posture Neurophysiology of Movement and Posture Document Transcript

    • 1st Summer School on ADVANCED TECHNOLOGIES FOR NEURO- MOTOR ASSESSMENT AND REHABILITATION 18-24 June 2006 Monte San Pietro BOLOGNA, ITALY Neurophysiology of Movement and Posture Antonio Nardone, M.D., Ph.D. Laboratorio di Postura e Movimento Divisione di Recupero e Rieducazione Funzionale Istituto Scientifico di Veruno Fondazione ‘Salvatore Maugeri’ (IRCCS) Overview of the Neural Mechanisms Involved in Posture and Movement Control • The motor system consists of Cerebral cortex three levels of control organised both hierarchically and in parallel Thalamus • The motor areas of the Vision Basal cerebral cortex can influence the ganglia Neck spinal cord both directly and Brain proprioceptors Cerebellum stem through the brain stem Labyrinth descending systems Muscle • All three levels of the motor Spinal cord contraction, system receive sensory inputs movement, reflexes gait and are under the influence of Central Pattern two independent subcortical Generator systems: the basal ganglia and Sensory receptors the cerebellum Sensory consequences • Both the basal ganglia and of movement cerebellum act on the cerebral cortex through relay nuclei in the (modified from Kandel et al., 1991) thalamus
    • Dorsal-column Leminiscal Pathway • Principally conveys tactile discrimination, vibratory and position senses • 1st order sensory neurones run on the same side and synapse with 2nd order neurones in the dorsal column nuclei • 2nd order neurones integrate the input and their axons cross to the opposite side. These ascend through the medial leminiscus • Further integration in the thalamus and 3rd order neurones project to the cortex Primary Somatosensory Cortex • The primary somatosensory cortex corresponds to Brodmann’s areas 3, 1, 2 • Somatosensory neurones from one side of the body project to the opposite side of the cortex • The area of the cortex allocated to each part of the body surface is proportional to the sensitivity of that part • Somatosensory pathways pass through the thalamus (nucleus VPL) before they project to their relevant cortical area
    • Primary Motor Cortex • The primary motor cortex corresponds to Brodmann’s area 4 • It contains a motor map of the body: the head is represented near the central sulcus; above it are representation of the arms, trunk and legs • The parts of the body used in tasks requiring precision and fine control, such as the face and hands, have a disproportionately large representation in the motor map The Descending Cortical Pathways to the Spinal Segments • The crossed lateral corticospinal tract (A) originates from Brodmann’s area 4 and 6, and sensory areas 3, 2, 1 • Corticorubral neurones are mainly located in area 6 • The principal area of termination of the corticospinal neurones originating from the sensory cortex is the medial portion of the dorsal horn of the spinal cord • Uncrossed pathways (B: ventral corticospinal tract) originate principally in Brodmann’s area 6 and in zones controlling the neck and trunk in area 4. Terminations are bilateral and collaterals project to the medial brainstem pathways
    • The Cortico-Spinal Neurones discharges before the Onset of Movement • The apparatus permits the animal altenatively to flex and extends its wrist • Record of a cortico-spinal tract neuron that increases its activity with flexion of the wrist. Note that the cell starts firing before movement (adapted from Evarts, 1968) The Activity of Motor Cortical Neurones codes the Direction of Force Exerted • Electromyograms of flexor and extensor muscles and discharge records of a cortico- spinal tract neuron under different load conditions • Absence of neuronal activity with extensor load indicates that the neuron codes for force rather than displacement (adapted from Evarts, 1968)
    • Two Groups of Descending Brain Stem Pathways control Different Groups of Neurons • The main components of the medial pathways (A) are the reticulospinal (pontine and medullary), the medial and lateral vestibulospinal, and the tectospinal tracts that descend in the ventral columns • The main lateral pathway (B) is the rubrospinal tract, which originates in the caudal, magnocellular portion of the red nucleus, and descends in the contralateral (from Kandel, 1991) dorsolateral column Motor Units • Motor Unit: a single alpha MN with its target muscle fibres • A typical muscle consists of many thousands of muscle fibres working in parallel and organized into a smaller number of motor units • The muscle fibres innervated by a single MN are not usually adjacent to one another
    • Motor Units • When a MN sends an action potential to its muscle fibers, they all contract at the same time • The size of a MU is determined by the number of muscle fibres it includes • Small MUs include fewer than ten muscle fibres: fine, precise movements • Large MUs include hundreds of muscle fibres: powerful movements not requiring precision Types of Motor Units Single MU twitch Single MU tetanic tension Force produced by each single MU tetanic tension • aerobic • intermediate • glicolitic metabolism • postural muscles characteristics • non-postural muscles Twitch tetanic force and fatigability vary in different types of motor units. Slow, fast fatigue-resistant, and fast fatigable motor units were activated by stimulating motor neurons intracellularly (from Burke et al, 1974)
    • Recruitment of MUs – Size Principle (E. Henneman) Cat Medial Gastrocnemius • Recruitment is the spatial summation from small to large MUs • Derecruitment proceeds in the opposite order: the large unit drops out first (from Walmsley et al, 1978) Relative Occurrence of Slow-Twitch Fibers in some Muscles of the Human Body The muscle samples are obtained post mortem, within 24 hours after the death of the person. The death has occurred suddenly in all cases. and no known diseases of muscles were present. Reprinted from Sultin B, Henriksson J, Nygaard E, et al. Fiber types and metabolic potentials of skeletal muscles in sedentary man and endurance runners. (Ann Ny Acad Sci. 301:3, 1977 with permission of New York Academy of Science)
    • Effects of Fatiguing Exercise on Postural Control * • After a fatiguing treadmill exercise, body sway during * quiet stance increases significantly but the duration of the effect * lasts only about 5 * min (from Nardone et al., 1997) Different Parts of the MU are susceptible to Different Diseases • The cell body can be damaged in polio or amyotrophic lateral sclerosis • The axon can be damaged by trauma or metabolic diseases (e.g., diabetes) • The synapse can fall in myasthenia gravis • The muscle fibres can be damaged in muscular dystrophy
    • Muscle Tone (drawn from a model proposed by A.V. Hill, 1949) Reactive force to lengthening (stiffness) • passive: depends on viscoelasticity (in-series and in- parallel elastic elements) • active: depends on contractile elements Active Muscles during Quiet Stance A and B: the ideal alignment in stance requiring minimal muscular effort to sustain the vertical position C: the muscles that are tonically active during the control of quiet stance (adapted from Kendell FP, McCreary EK, 1983)
    • General Feedback and Feed-Forward Circuits in Posture and Movement Control A. In a feedback system, a feedback signal is compared to a reference signal by a comparator. The difference between the feedback signal and the reference is the error signal. Feedback control is usually used for slow movements and to maintain posture B. In a feed-forward control, state variables (e.g., joint angle) and advance information about disturbance are received by sensors and fed forward by the controller. Feed-forward control is essential for rapid movements and relies on advance information to (from Kandel et al. 1991) adjust controlled variables Proprioreceptors • Intrinsic knowledge of limb position is known as kinaesthesia • Information is provided by sensory input from muscle spindles (Ia and II) and Golgi tendon organs • These are mechanoreceptors and provide the CNS with information on muscle length, position and tension
    • Muscle Spindles and Golgi Tendon Organs • They are encapsulated structures in skeletal muscles • Muscle spindle has a fusiform shape, is arranged in parallel with extrafusal fibres and is innervated by both afferent (group Ia and group II fibres) and efferent fibres • Golgi tendon organ is at the junction between a group of extrafusal fibres and the tendon; it is therefore in series with extrafusal fibres • A single Ib axon enters the capsule of tendon organ and branches into many unmyelinated endings that wrap around and (adapted from Schmidt, 1983; Swett and Schoultz, 1975) between the collagen fibres Spindle Primaries and Secondaries and their Discharge to Lengthening • Muscle spindle primaries are innervated by group Ia afferent fibres, are rapidly adapting (dynamic) and are sensitive to rapid changes in muscle length • Muscle spindle secondaries are innervated by group II afferent fibres, are slowly adapting (static) and are sensitive to absolute length of the muscle (from Kandel, 1991)
    • Monosynaptic Stretch Reflex (MSR) • Ia afferent fibres make monosynaptic excitatory connections to alpha MNs innervating the same (homonymous) muscle from which they arise and MNs innervating synergist muscles • Ia afferents also inhibit MNs to antagonist muscles through an inhibitory IN (reciprocal inhibition) • When a muscle is stretched the Ia afferents increase their firing rate. This leads to contraction of the same muscle and its synergists and relaxation of the antagonist Functions of the Monosynaptic Stretch Reflex (MSR) MSR Stretch reflex • tends to automatically counteract the stretch, enhancing the spring- like properties of the muscles • assists in maintenance of posture (postural tone) • compensates for the non-linear passive mechanical properties of the muscle
    • Stretch Reflex acts like a Negative Feedback Loop Disturbance Alpha motor neuron Muscle Motoneuron length Descending firing Muscle Force Load change facilitation and inhibition Spindle afferent discharge Spindle The controlled variable is muscle length. The Force m desired value is determined by descending signals to the motoneurone. If a disturbance causes muscle length to increase, the spindle increases its firing rate, causing the motoneurone to fire and the muscle to shorten. Decreases in Length change of triceps surae muscle length produce the opposite effect. This system therefore corrects for deviations from the desired muscle length. Role of Tendon Reflex Testing in Clinical Evaluation T Reflexes (= monosynaptic stretch reflexes) • are important since they provide an objective sign indicating an abnormality, and some indication of the level of abnormality • may be graded as absent, reduced, normal, increased In general, • disease of lower motoneuron, peripheral sensory system and muscle all decrease T reflexes • lesion of upper motoneuron increases T reflexes due to loss of descending inhibition; muscle tone is increased partly due to velocity-dependent hyperreflexia
    • Changes in Amplitude of Stretch Reflex in Postural Perturbation Toe-Up Rotation Normal Charcot-Marie-Tooth 1A Spastic 2 2 2 MLR EMG responses in mV (x10,000) 1.5 1.5 1.5 MLR MLR 1 SLR 1 1 SLR 0.5 0.5 0.5 0 0 0 FDB 50 100 150 200 250 300 350 400 50 100 150 200 250 300 350 400 50 100 150 200 250 300 350 400 3.5 3.5 3.5 3 2.5 SLR 3 2.5 3 2.5 SLR 2 2 MLR 2 MLR 1.5 1 MLR 1.5 1 1.5 1 0.5 0 0.5 0 0.5 0 Sol 50 100 150 200 250 300 350 400 50 100 150 200 250 300 350 400 50 100 150 200 250 300 350 400 Time in ms SLR (= T reflex = monosynaptic stretch reflex) is • decreased or absent in peripheral neuropathy • increased in upper motoneuron lesion (from Nardone et al., 2001) Vibration Stimulates Spindle Primary but not Secondary Endings 200 µV Wrist flexor Wrist extensor Vibration Vibration 30.000 60.000 90.000 Vibration Primary Secondary • Alpha- and gamma-MNs respectively innervate extra- and intrafusal muscle fibres • Ia afferent fibres impinge onto both the alpha-MNs and also sends collateral axons to the supraspinal centres along dorsal columns • Vibration (100 Hz) excites spindle primary endings generating trains of action potentials along the Ia afferents in phase with spindle lengthening • A Tonic Vibration Reflex is evoked in the vibrated muscle, and lasts for the whole period of vibration
    • Effect of Muscle Vibration on the Sense of Joint Position at the Elbow • Spindle primaries transduce velocity of muscle lengthening • Subject perceives the vibrated elbow to be more extended than it is • Our sense of position is via muscle spindles • In particular, spindle primary endings and Ia afferent fibres are involved Effect of Muscle Vibration on Posture Proprioceptive afference from neck extensor muscles Vestibular Nuclei Reticular Formation Spinal Cord Spindle group Ia afferent fibres from the neck appear to reconfigure the internal references for body orientation during stance (from Nardone et al., 2004)
    • Effect of Muscle Vibration on Posture Proprioceptive afference from triceps surae muscle Perception of muscle lengthening Perception of foot dorsal flexion Compensatory Perception of forward backward body inclination body inclination Spindle group Ia afferent fibres from the triceps surae appear to reconfigure the internal references for body orientation during stance (from Nardone et al., 2004) Loss of Large Diameter Sensory Fibres does not affect Balance Despite patients with Charcot-Marie-Tooth disease have lost large afferent fibres, their body sway during quiet stance is largely normal Soggetto Malattia Normale Piedi di CMT1A distanti 10 A A cm S D S D EO 4 cm S D S D EC (from Schieppati and Nardone, P P Progress in Brain Research, 1999)
    • Body Sway in Different Neuropathies under Static Condition Feet 10 cm Apart • In diabetic polyneuropathy, at variance with CMT1A disease, small fibres are impaired in addition to large ones • Body sway area is increased in diabetc polyneuropathies with respect to normal subjects and CMT1A patients • Further, diabetic patients show a forward leaning of the body, a sign of attempt to increase their stability (from Schieppati and Nardone, 2004) Presynaptic Inhibition (PSI) of Primary Afferents descending fibres group Ia Muscle spindle PSI γ α Vibration Primary Secondary • Alpha- and gamma-MNs respectively innervate extra- and intrafusal muscle fibres • Ia afferent fibres impinge onto both the alpha-MNs and the IN responsible for the presynaptic inhibition (PSI) of the Ia-alpha MN synapse • Fibres from supraspinal centres are not only directed to alpha- and gamma-MNs but also exert excitatory or inhibitory effects (through a spinal IN) on the IN mediating presynaptic inhibition (from Schieppati and Nardone)
    • Effects of Achilles Tendon Vibration on SLR and MLR Toe-Up Rotation 500 Control iEMG (µV) SLR MLR 0 right 500 left Achilles Tendon iEMG (µV) Vibration (90 Hz) SLR MLR 0 50 ms • In normal subjects, vibration decreases SLR through presynaptic inhibition of Ia afferents • In hemiparetic patients, vibration fails to decrease SLR on the affected side due to altered descending control on presynaptic inhibitory IN (from Bove et al., 2003; Nardone and Schieppati, 2005) SLR and MLR are Stretch Reflexes mediated by Different Afferent Fibres and Spinal Circuits Toe-Up Rotation (from Nardone et al., 1998)
    • Schema of the Afferent Fibres and Spinal Circuits mediating the SLR and MLR • Short-Latency Response (SLR) corresponds to the monosynaptic stretch reflex, mediated by group Ia afferent fibres • Medium-Latency Response (MLR) is a stretch-related response evoked by the stimulation of spindle secondaries, and mediated by group II afferent fibres. Its central pathway consists in an olygosynaptic spinal circuit (here represented by only one IN for simplicity) (from Nardone and Schieppati) CV of Group Ia, Alpha Axon, Group II Fibres and Central Delay of FDB-MLR cat (adapted from Boyd and Davey, 1968) (Schieppati M and Nardone A, Progress in Brain Research, 1999)
    • The Flexion Withdrawal Reflex involves Coordinated Contractions of Numerous Muscles in the Limbs • Stimulation of Flexor Reflex Afferents (group II or Aβ, III or Aδ, IV or C) • The flexion withdrawal reflex produces flexion of the stimulated limb and extension of the opposite limb (crossed extensor reflex) Supraspinal Modulation of Flexor Reflex Pathways • Flexor reflex pathways are normally held in a somewhat inhibited state by descending pathways from the brainstem • Only noxious stimuli will normally result in strong flexion reflex • If descending influences are removed (e.g., complete spinal cord lesion, hemiparesis) reflex flexion can result from harmless somatosensory stimuli (e.g., Babinski sign)
    • Decerebrate Rigidity (from Pollock and Davis, 1927) Decerebrate rigidity is mediated primarily by the vestibulospinal and reticulospinal pathways, which are tonically active when disconnected from cerebral control. Decerebrate rigidity is modulated by the cerebellum and is enhanced following removal of the anterior lobe of the cerebellum because a major inhibitory input to the lateral vestibular nucleus, the Purkinje neurons, is then removed. Excitatory and inhibitory reticulospinal influences on extensor motor neurons tend to cancel each other; however, reticulospinal inhibition of interneurons mediating flexion reflexes adds to the overall extensor bias. Integrity of Brainstem Centres is Necessary for Postural Tone and Control 1. Spinal animal is not able to maintain the body weight 2. Animal decerebrated between the superior and inferior colliculus (level 2) maintains the body weight but is not able to generate postural adjustments 3. Animal decerebrated rostrally to superior colliculi (level 1: the mesencephalon has been spared) exhibits righting reflexes first triggered by vestibular and then by neck reflexes
    • In Mammals Rhythmic Locomotor patterns are generated by Intrinsic Spinal Cord Circuits that are activated by Descending Signals from the Brain Stem • In a spinalised cat (transected at b’- b), the hindlimbs are still able to walk on a treadmill • Decerebration at the level a’-a isolates the spinal cord and brainstem • In decerebration, locomotion can be produced by electrical stimulation of the mesencephalic locomotor region. As the stimulus intensity increases, the gait becomes faster • As the cat progresses from trotting to galloping, the hindlimbs shift from alternating to simultaneous flexion and (from Pearson, 1976) extension Vestibulospinal Pathways Semicircular canals and otolith organs and Projections Medial vestibular nucleus Lateral vestibular nucleus Medial vestibulospinal tracts Lateral vestibulospinal tract Spinal cord C3 To axial muscle Lateral vestibulospinal tract Spinal cord C5 To limb extensor
    • Vestibular Reflexes prepare the Subject for Landing Forearm extensors 100μV Soleus 2mV 100 ms Landing onset of fall 1. After about 80 ms from the onset of fall from a small height, forearm extensors and soleus muscles are activated by vestibulo-spinal pathways and prepare the landing phase Vestibular and Neck To distinguish the effects of vestibular and neck reflexes, the dorsal roots Reflexes have Opposing innervating the first two cervical Actions on Limb Muscles vertebrae were sectioned in a decerebrate cat. Vestibular reflexes were then elicited by tilting the head. Neck reflexes were produced by turning the second cervical vertebra, thus activating afferents at levels below C2. This procedure has the same effect as would occur when the intact animal rotates the head, but without stimulating the otoliths. The upper panels of the figure show how vestibular reflexes are elicited by tilting the head with the vertebrae fixed in the normal orientation. The circle with vertical line represents the orientation of the vertebrae and spinous process. The lower panels show how neck reflexes are evoked by rotation of the axis (see the reorientation of the spinous process). (Adapted from Roberts, 1978) 
    • Neck Reflexes on the Limb Muscles of Humans Neck reflexes are readily elicited in newborns and are expressed in adults when posture requires optimal control and in ordinary voluntary activities (Adapted from Fukuda, 1961) Long-Loop Reflex • Neurons in the motor cortex have receptive fields in the periphery • The cortical neurones are activated by either stretch of muscle or stimulation of skin • This pathways mediate the long- loop reflexes • The motor cortex may function in parallel with the spinal stretch reflex • The long-loop reflex would provide assistance, supplementing the stretch reflex, when the moving limb encounters unexpected obstacles 
    • Nervous Pathways Mediating Spinal and Transcerebral Postural Responses Sensorimotor Cortex Thalamus • LLR? Muscle contraction and Spinal Cord movement Sensory • SLR Receptors • MLR Sensory consequences of movement (from Nardone) MRI showing Cervical Spondylotic Myelopathy • MRI remains the imaging modality of choice for CSM, even in an initial evaluation, because of its superior ability to show pathology of neural structures • MRI allows for clear visualization of cord impingement or compression, and can be used to accurately measure space within the spinal canal 
    • Postural Responses to Toe-Up Perturbation in CCM In compressive cervical myelopathy (CCM), TA long- latency response is delayed (red vertical line represents its normal latency) while Sol short- and medium-latency responses show normal latency Normal CCM Toe-Up Rotation 300 30 0 Sol EMG (μV) 250 25 0 SLR 20 0 SLR 200 150 15 0 100 MLR 10 0 MLR 50 50 0 0 300 40 0 35 0 250 TA EMG (μV) 30 0 200 LLR 25 0 20 0 LLR 150 15 0 100 10 0 50 50 0 0 100 ms • Delay of TA LLR is in keeping with its transmission through a supraspinal pathway • Sol SLR and MLR show normal latency since they are mediated through the spinal cord (from Nardone) Body Sway during Quiet Stance in CCM is increased Feet spaced 10 cm apart Normal CCM • In CCM, body sway area is increased and CoP is shifted forward, a sign of attempt to increase stability • The delayed TA-LLR might play a role in ataxia in these patients (from Nardone) 
    • Holding onto a Stable Frame reduces the Amplitude of MLR and LLR but not SLR Different descending modulation from supraspinal centres on the different postural responses (from Nardone) Tizanidine Affects 120 MLRs but not SLR 110 100 90 • Tizanidine (Sirdalud®) is a 80 Sol-SLR noradrenergic drug 70 60 Area of EMG response (%of control) • Time course of the average 50 120 changes in amplitude of SLR 110 100 and MLRs evoked before and 90 80 FDB-MLR after administration of 70 60 * * placebo and tizanidine 50 120 • MLRs are modulated by 110 100 brainstem monoaminergic 90 TA- MLR descending pathways 80 * 70 (possibly from locus 60 * * 50 coeruleus) (from Corna et al., 1995) -60 -30 0 30 60 90 120 150 180 Time relative to oral intake of substance (min) 
    • Postural and prime mover activity are coordinated by a central command Central Limb Postural command movement disturbance Feed-forward Feedback for expected postural for unexpected postural disturbance Postural disturbance adjustment Illustration of the idea that postural and prime mover activity are coordinated by a central command. Thus, the command to move a limb is linked to (‘feed-forward’) commands to postural muscles designed to anticipate the effect that the movement will have on the position of the body. If the postural activity is incorrect, or if the limb encounters some unforeseen disturbance, then reflex (‘feedback’) corrections of posture also occur (adapted from Gahéry and Massion, 1981) Anticipatory Postural Adjustments during Arm Movements • Once the intention to pull the handle is realized, the cortex relays a message, probably via subcortical structures, to contract the gastrocnemius muscle even faster than the signal to contract the biceps brachii (adapted from Cordo and Nashner, 1982) 
    • Rising on toe tips Sol TA Quad BiFe APA acoustic GO signal reaction time • APA consists in activation of TA before soleus muscle in order to counteract the forthcoming backward inclination of the body (Nardone and Schieppati, Exp Brain Res, 1988) The Cerebellum Thought to be involved in: • Balance • Proper execution of planned motor acts • Establishing direction, timing and force of planned motor acts • Coordinating movement • Comparing intended movement with the ongoing movement • Motor learning 
    • Anatomical Organization of the Cerebellum Structure Input Output Flocculus, nodulus Vestibular canals, Fastigial nucleus, (archicerebellum) otoliths, vestibular vestibulospinal and nuclei reticulospinal tract Anterior lobe Spinocerebellar Interpositus nucleus, (paleocerebellum) tracts nucleus ruber, reticular formation Cerebellar Pontine nuclei, Dentate nucleus, hemisphere inferior olives nucleus ruber, (neocerebellum) VL thalamus (from Kandel et al., 2000) Function and Dysfunction of the Cerebellum Structure Output Function Dysfunction Flocculus, Fastigial nucleus, Stabilization of the trunk, Ataxia while sitting, standing nodulus vestibulospinal and scaling of the VOR and walking, omnidirectional (archicerebellum) reticulospinal tract body sway Anterior lobe Interpositus nucleus, Stabilization of upright stance Ataxia of stance, 3 Hz AP body (paleocerebellum) nucleus ruber, and locomotion tremor, kinetic tremor in the reticular formation heel-shin test Cerebellar Dentate nucleus, Control of limb movements, Dysmetria, dysdiadochokinesia, hemisphere nucleus ruber, parametrization of velocity, kinetic tremor, dyskinesia, (neocerebellum) VL thalamus acceleration, timing of EMG dysarthria activity, motor learning (from Kandel, 2000) 
    • Hypermetric Muscle Responses in Anterior Lobe Cerebellar Degeneration Motor Deficits due to Inactivation of Deep Cerebellar Nuclei are Ipsilateral to the Microinjection of Muscimol • Fastigial nucleus causes problems with stance • Interpositus nucleus causes prominent arm tremor during reaching • Dentate nucleus causes deficits in reaching and pinching (from Thach et al., 1992, Fig. 2) 
    • Role of Cerebellum in Movement • Deep nuclei activity occurs before muscle activity and before movement • Prior to a voluntary (reaction time) movement of the monkey’s wrist, cells start to fire first in dentate and motor cortex • Activity occurs slightly later in interpositus and muscle • A patient with a lesion in one cerebellar hemisphere will show a delay in the initiation of movement with the ipsilateral (from Thach, 1978) arm Motor Deficits in Lesions of the Cerebellum • Ataxia: incoordination of movement • Dysmetria (hypo-, hypermetria): inaccuracy in range and direction and unsmooth movement with increased tremor on approaching the target • Action or intention tremor • Dysdiadochokynesia: an irregular pattern of voluntary alternating movements • Stance ataxia • Gait ataxia • Oculomotor deficits 
    • Simplified Cerebellar Feedback Circuit in Motor Learning • Long term CORTEX depression of the Error Correction efficacy of synaptic Cortico- input of parallel Spinal Tract fibres on Purkinje cells induced by Efferent Copy Reference climbing fibres is one Signal Inferior Olive theory of how the cerebellum might Spino- correct movement Cerebellar Tract and allow motor Spinal Cord Feedback from learning actual movement The Cerebellum and Motor Learning The Cerebellum is thought to be involved in motor learning and the maintenance of movement accuracy because patients with cerebellar lesions are impaired at learning novel motor tasks. Evidence from prism adaptation (Thach et al., 1992) No Prisms Prisms Off Prisms On 
    • Position of Basal Ganglia in the Brain Basal Ganglia They consists of five large subcortical nuclei that participate in control of movement • Caudate Nucleus • Putamen • Globus Pallidus • Subthalamic Nucleus • Substantia Nigra • Caudate and Putamen form the Neostriatum. This receives almost all afferent input to basal ganglia • The principal target of efferent connections from the basal ganglia is the thalamus (VL and VA nuclei) • Substabtia Nigra (pars compacta) sends dopaminergic projections to the striatum 
    • CONNECTIONS IN THE NORMAL CORTICO- BASAL GANGLIA LOOP pars compacta There are two different pathways through the basal ganglia • the direct route from the striatum to the output nuclei: it favours movement • the indirect route through the Subthalamic Nucleus: it opposes movement Dopamine facilitates movement since it has • excitatory effects on the direct route • inhibitory effects on the indirect route Possible Roles of Basal Ganglia in Movement - 1 • Output of the basal ganglia (Globus Pallidus internal segment) is inhibitory: e.g., inhibition of unwanted movement and facilitation of desired movement • Basal ganglia seem to selectively facilitate processing related to task performance and inactivate other processes (e.g., decrease postural muscle tone during the execution of a finalized task). The result may be an “energization” of the production of the desired focal activity 
    • Reduced “Energization” of the Agonist Muscle during Arm Movement in a PD Patient • EMG recording of flexion movement of the forearm in a PD patient performing at a velocity of 10° (A), 20° (B) and 40° (C) • EMG traces show repeated bursts of activations • A normal subject would only show an agonist burst followed by a braking burst in the antagonist • The desired movement is slow in the PD patient EMG Responses to Platform Perturbation in PD Normal Parkinsonian 100 Normal Area of EMG Response (x0.1 mV*ms) (+SEM) 500 500 Parkinsonian iEMG (μV) MLR 80 SLR MLR FDB SLR 0 Toe-up 0 60 * 500 500 iEMG (μV) MLR MLR μVSol μV SLR SLR 40 0 Toe-up 0 iEMG (μV) 500 500 ML 20 MLR 50 TA R Toe-down 0 0 0 50 ms FDB Sol TA • Latency of postural responses is largely normal in PD but amplitude may be affected • The Medium-Latency Responses (MLRs) show increased amplitude in leg muscles of PD patients, and this might play a role in the increased muscle tone observed in both agonist and antagonist muscles (from Nardone) 
    • Impaired Modulation of Medium-Latency Responses in Parkinsonians Normal Parkinsonian 200 200 The ability of PD TA (μV) MLR MLR free stance patients of reducing 0 0 the amplitude of 200 200 postural responses to TA (μV) MLR MLR holding a balance perturbation 0 0 50 ms when changing 80 Area of TA-MLR (% of postural “set” free stance) (+SEM) * 60 (standing and holding 40 onto a stable frame) is 20 impaired 0 Normals Parkinsonians Possible Roles of Basal Ganglia in Movement - 2 • Cells in Putamen, Globus Pallidus, Substantia Nigra (pars reticulata) and Subthalamic Nucleus change their discharge frequency in association with contralateral movements • Neuron activity occurs with movement, but is often after onset of agonist muscle activity: indeed, in Parkinson’s Disease, reaction times are largely normal but onset and duration of movement are prolonged (bradykinesia) • Discharge of basal ganglia is related with direction rather than force of movement • Basal ganglia play a role in the smooth execution of a sequence of different movements: switching from one movement to another 
    • PET Study with F-DOPA in Parkinson’s Disease • Parkinson’s Disease is characterised by severe loss of dopaminergic neurons in Substantia Nigra (pars compacta) • Neuroimaging techniques show loss of dopamine in the Striatum 
    • pars compacta In Parkinson’s Disease, degeneration of Substantia Nigra (pars compacta) leads to reduced dopamine release in the striatum • the direct route (that favours movement) is disfacilitated • the indirect route (that opposes movement) is disinhibited The net result is a paucity of movement (hypokynesia) Major Symptoms of Parkinson’s Disease • Bradykinesia: slowness in initiation and execution of voluntary movements • Rigidity: increased muscle tone and resistance to movement (arms and legs stiff) • Tremor: usually tremor at rest when person sits; tremor stops when person attempts to grab something • Postural Instability: abnormal fixation of posture (stoop when standing), equilibrium, and righting reflexes • Gait Disturbance: shuffling feet 
    • Effects of L-Dopa on the Symptoms of Parkinson Disease • L-Dopa is fairly effective in eliminating most of the symptoms of Parkinson Disease • Bradykinesia and rigidity quickly respond to L-Dopa • Reduction in tremor effect with continued therapy • L-Dopa is less effective in eliminating postural instability and shuffling gait meaning other neurotransmitters are involved in these disorders Possible Circuits implied in the Generation of a Rhythmic Movement Without External Signals With External Signals (internally generated movement) (externally generated movement) SMA Thalamus PMA Thalamus DLPC (VL, VA) PC(40) (X) BG Cerebellum • The circuit through SMA (Supplementary Motor Area) is implied in the internal generation of movement; DLPC (Dorso-Lateral Prefrontal Cortex), BG (Basal ganglia), VL and VA (Ventralis-Lateralis and Ventralis-Anterior thalamic nuclei) • The circuit through PMA (Pre-Motor Area) is implied in the external generation of movement (obtained with visual or auditory cues); X, nucleus X of thalamus; PC(40), Parietal Cortex (Brodmann’s area 40) 
    • Parkinsonian Patients are dependent on External Cues for Accomplishing Motor Tasks • Difficulty in internally generating the movement (gait) • Gait velocity and stride length increase with visual cues (stripes on the ground) [from Azulay JP et al. Brain 122: 111-20 (1999)] Anticipatory Postural Adjustments are Impaired in Parkinson’s Disease • Amplitude and timing of EMG when rising onto the toes high and fast • A: 3 sample trials from a representative control and a parkinsonian subject OFF and ON • B: histogram of the mean and standard error of the GAS and TIB EMG EMG for each group shows that the magnitude of TIB and GAS activity was less for parkinsonian subjects OFF than controls and this increased for parkinsonian subjects ON [from Frank et al. JNNP 84: 2440. (2000), Fig. 2] 
    • Schematic Representation of the Basal Ganglia Nuclei and a High- Frequency Stimulation (HFS) Electrode Implanted in the Subthalamic Nucleus (STN) Inhibitory Effect of High-Frequency Stimulation (HFS) on Subthalamic Nucleus (STN) Activity (a) Decrease of subthalamic nucleus (STN) activity recorded immediately after STN-HFS (i) in patients (extracellular recordings) and (ii) in rat STN slices (whole-cell recordings). The red bar indicates duration of HFS at the stated frequency. (b) Decrease of STN activity during brief STN-HFS (i) in patients and (ii) in rats in vivo. Upper traces are recordings before suppression or scale-down of artifacts and bottom traces are recordings after this procedure. Large spikes are artifacts and red dots indicate them in (b,ii) 
    • Effects of High-Frequency Stimulation (HFS) on Subthalamic Nucleus (STN) Activity CONNECTIONS IN THE NORMAL CORTICO- BASAL GANGLIA LOOP Two fundamental mechanisms have been proposed to underlie the beneficial effects of HFS: silencing or excitation of STN neurons. Relying on recent experimental data, we suggest that both are instrumental: HFS switches off a pathological disrupted activity in the STN (a 'less' mechanism) and imposes a new type of discharge in the upper gamma-band frequency that is endowed with beneficial effects (a 'more' mechanism). Garcia L, D'Alessandro G, Bioulac B, Hammond C. High-frequency stimulation in Parkinson's disease: more or less? Trends Neurosci 2005;28:209-16 DBS can improve stance in Parkinson’s Disease 