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)

1st Summer School on ADVANCED TECHNOLOGIES FOR NEURO-

MOTOR ASSESSMENT AND REHABILITATION

18-24 June 2006 Monte San Pietro

BOLOGNA, ITALY

(modified from Kandel et al., 1991)

Overview of the Neural Mechanisms Involved in Posture and Movement Control

• The motor system consists of three levels of control organised both hierarchically and in parallel• The motor areas of the cerebral cortex can influence the spinal cord both directly and through the brain stem descending systems• All three levels of the motor system receive sensory inputsand are under the influence of two independent subcortical systems: the basal ganglia and the cerebellum• Both the basal ganglia and cerebellum act on the cerebral cortex through relay nuclei in the thalamus

Cerebral cortexCerebral cortex

ThalamusThalamus

BasalBasalgangliaganglia

CerebellumCerebellumBrainBrainstemstem

Sensory consequencesof movement

Musclecontraction, movement,

gait

SensorySensoryreceptorsreceptors

Spinal cordSpinal cordreflexesreflexes

CentralCentral Pattern Pattern GeneratorGenerator

LabyrinthLabyrinth

Neck Neck proprioceptorsproprioceptors

VisionVision

Cerebral cortexCerebral cortex

ThalamusThalamus

BasalBasalgangliaganglia

CerebellumCerebellumBrainBrainstemstem

Sensory consequencesof movement

Musclecontraction, movement,

gait

SensorySensoryreceptorsreceptors

Spinal cordSpinal cordreflexesreflexes

CentralCentral Pattern Pattern GeneratorGenerator

LabyrinthLabyrinth

Neck Neck proprioceptorsproprioceptors

VisionVision

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 neuronesproject to the cortex

Primary Somatosensory Cortex

• The primary somatosensorycortex corresponds toBrodmann’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’sarea 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 tothe 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: ventralcorticospinal 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

(from Kandel, 1991)

• The main components of the medial pathways (A) are the reticulospinal (pontineand 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 dorsolateral column

• Motor Unit: a singlealpha MN with its targetmuscle fibres• A typical muscle consists of many thousands of muscle fibres working in parallel and organized into a smaller numberof motor units• The muscle fibres innervated by a single MN are not usually adjacent to one another

Motor Units

• When a MN sends anaction potential to its muscle fibers, they all contract at the same time• The size of a MU is determined by the numberof 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

Motor Units

(from Burke et al, 1974)

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

Types of Motor Units

• aerobic• postural muscles

• glicolitic metabolism• non-postural muscles

Single MU twitch

Single MU tetanic tension

Force produced byeach single MU tetanic tension

• intermediate characteristics

Recruitment of MUs – Size Principle (E. Henneman)

• Recruitment is the spatial summation from small to large MUs• Derecruitmentproceeds in the opposite order: the large unit drops out first

Cat Medial Gastrocnemius

(from Walmsley et al, 1978)

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)

Relative Occurrence of Slow-Twitch Fibers in some Muscles of the Human Body

(from Nardone et al., 1997)

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

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

Reactive force to lengthening (stiffness)• passive: depends on viscoelasticity (in-series and in-parallel elastic elements)• active: depends on contractile elements

Muscle Tone

(drawn from a model proposed by A.V. Hill, 1949)

Active Muscles during Quiet Stance

(adapted from Kendell FP, McCreary EK, 1983)

A and B: the idealalignment in stancerequiring minimal muscular effort tosustain the verticalpositionC: the muscles that are tonically active duringthe control of quietstance

General Feedback and Feed-Forward Circuitsin Posture and Movement Control

(from Kandel et al. 1991)

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 postureB. 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 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 between the collagen fibres(adapted from Schmidt, 1983; Swett and Schoultz, 1975)

Spindle Primaries and Secondaries and theirDischarge to Lengthening

(from Kandel, 1991)

• 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

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 • tends to automatically counteract the stretch, enhancing the spring-like properties of the muscles• assists in maintenanceof posture (posturaltone) • compensates for the non-linear passivemechanical propertiesof the muscle

Stretch reflex

Muscle Load

Spindle

Muscle length changeForce

Motoneuronfiring

Alphamotorneuron

Disturbance

Spindleafferent

discharge

Descendingfacilitation

and inhibition

Length change of triceps surae

Force m

Stretch Reflex acts like a Negative Feedback Loop

The controlled variable is muscle length. The desired value is determined by descending signals to the motoneurone. If a disturbancecauses muscle length to increase, the spindle increases its firing rate, causing the motoneuroneto fire and the muscle to shorten. Decreases in 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 StretchReflex in Postural Perturbation

SLR (= T reflex = monosynaptic stretch reflex) is• decreased or absent in peripheral neuropathy• increased in upper motoneuron lesion

Toe-Up Rotation

0

0.5

1

1.5

2

50 100 150 200 250 300 350 4000

0.5

1

1.5

2

50 100 150 200 250 300 350 400

00.5

11.5

22.5

33.5

50 100 150 200 250 300 350 4000

0.51

1.52

2.53

3.5

50 100 150 200 250 300 350 4000

0.51

1.52

2.53

3.5

50 100 150 200 250 300 350 400

0

0.5

1

1.5

2

50 100 150 200 250 300 350 400

Normal Charcot-Marie-Tooth 1A Spastic

EMG

resp

onse

s in

mV

(x10

,000

)

Sol

FDB

SLR

SLR

SLR

SLR

MLR

MLR MLRMLR

MLRMLR

Time in ms

(from Nardone et al., 2001)

Vibration Stimulates Spindle Primary but not Secondary Endings

Vibration

Primary

Secondary

Vibration

• 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

30.000 60.000 90.000

200 µV Wrist flexor

Wrist extensor

Vibration

Effect of Muscle Vibration on the Sense of JointPosition 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, spindleprimary endings and Ia afferent fibres are involved

Spindle group Ia afferent fibres from the neck appear to reconfigure the internal references for body orientation during stance

Proprioceptive afference from neck extensor muscles

Vestibular Nuclei Reticular Formation

Spinal Cord

(from Nardone et al., 2004)

Effect of Muscle Vibration on Posture

Spindle group Ia afferent fibres from the triceps suraeappear to reconfigure the internal references for body orientation during stance

Proprioceptive afference from triceps surae muscle

Perception of muscle lengthening

Perception of forward body inclination

Perception of foot dorsal flexion

Compensatory backward

body inclination

(from Nardone et al., 2004)

Effect of Muscle Vibration on Posture

(from Schieppati and Nardone, Progress in Brain Research, 1999)

EO

EC

Soggetto Normale

Malattia di CMT1A

DD

P

A A

SS

Piedi distanti 10

cm

P

D SS

4 cm

D

EO

EC

Soggetto Normale

Malattia di CMT1A

DD

P

A A

SS

Piedi distanti 10

cm

P

D SS

4 cm

D

EO

EC

Soggetto Normale

Malattia di CMT1A

DD

P

A A

SS

Piedi distanti 10

cm

P

D SS

4 cm

D

Loss of Large Diameter Sensory Fibres does not affect BalanceDespite patients with Charcot-Marie-Tooth disease have lost large afferent fibres, their

body sway during quiet stance is largely normal

Body Sway in Different Neuropathies under Static Condition

• In diabeticpolyneuropathy, at variance with CMT1A disease, small fibresare impaired in additionto 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)

Feet 10 cm Apart

Presynaptic Inhibition (PSI) of Primary Afferents

• 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 spinalIN) on the IN mediating presynaptic inhibition

group Ia

α

PSIγ

descending fibres

Muscle spindle

group Ia

α

PSIγ

descending fibres

Muscle spindle

Primary

Secondary

Vibration

group Ia

α

PSIγ

descending fibres

Muscle spindle

group Ia

α

PSIγ

descending fibres

Muscle spindle

Primary

Secondary

Vibration

group Ia

α

PSIγ

descending fibres

Muscle spindle

group Ia

α

PSIγ

descending fibres

Muscle spindle

Primary

Secondary

Vibration

(from Schieppati and Nardone)

Effects of Achilles Tendon Vibration on SLR and MLR

• In normal subjects, vibration decreases SLR through presynaptic inhibition of Ia afferents

• In hemiparetic patients, vibration fails to decrease SLR on the affectedside due to altered descending control on presynaptic inhibitory IN

Control

iEM

G (µ

V)iE

MG

(µV)

0

500

right

left

SLRMLR

0

500

Achilles TendonVibration (90 Hz)

MLRSLR

50 ms

Toe-Up Rotation

(from Bove et al., 2003; Nardone and Schieppati, 2005)

(from Nardone et al., 1998)

SLR and MLR are Stretch Reflexes mediated by Different

Afferent Fibres and Spinal CircuitsToe-Up Rotation

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 afferentfibres. 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

(Schieppati M and Nardone A, Progress in Brain Research, 1999)

cat

(adapted from Boyd and Davey, 1968)

The Flexion Withdrawal Reflex involves

Coordinated Contractions of Numerous Muscles in

the Limbs

• Stimulation of Flexor ReflexAfferents (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)

(from Pollock and Davis, 1927)

Decerebrate Rigidity

Decerebrate rigidity is mediated primarilyby 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 weight2. 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 activatedby Descending Signals from the

Brain Stem

(from Pearson, 1976)

• 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 extension

Vestibulospinal Pathways and Projections

Medialvestibulospinaltracts

Lateralvestibulospinaltract

Spinal cord C3

Lateralvestibulospinaltract

Spinal cord C5

Tolimb extensor

Toaxial muscle

Lateralvestibularnucleus

Medial vestibularnucleus

Semicircularcanals and otolith organs

Forearmextensors

Soleus

100μV

2mV

Landing100 msonset of fall

Vestibular Reflexes prepare the Subject for Landing

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

To distinguish the effects of vestibularand neck reflexes, the dorsal roots innervating the first two cervical 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)

Vestibular and Neck Reflexes have Opposing Actions on Limb Muscles

Neck reflexes are readily elicited in newborns and are expressed in adults whenposture requires optimalcontrol and in ordinary voluntary activities

Neck Reflexes on the Limb Muscles of Humans

(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

Sensory consequences of movement

Muscle contraction and

movement

Sensory Receptors

Spinal Cord

• SLR

• MLR

• LLR?

(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 CCMIn 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

• 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

Toe-Up Rotation

(from Nardone)

0

5 0

10 0

15 0

20 0

25 0

30 0

0

5 0

10 0

15 0

20 0

25 0

30 0

35 0

40 0

CCM

SLR

MLR

LLR

100 ms

0

50

100

150

200

250

300

0

50

100

150

200

250

300

Normal

Sol

EM

G (μ

V)TA

EM

G (μ

V)

SLR

MLR

LLR

Body Sway during Quiet Stance in CCM is increased

• 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)

Feet spaced 10 cm apart

Normal CCM

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)

• Time course of the average changes in amplitude of SLR and MLRs evoked before and after administration of placebo and tizanidine • MLRs are modulated by brainstem monoaminergicdescending pathways (possibly from locus coeruleus) (from Corna et al., 1995)

Tizanidine Affects MLRs but not SLR

Sol-SLR

FDB-MLR

TA- MLR

* *

* *

*

-60 -30 0 30 60 90 120 150 180

1201101009080706050

1201101009080706050

1201101009080706050

Time relative to oral intake of substance (min)

Are

a of

EM

Gre

spon

se(%

of c

ontr

ol)

Sol-SLR

FDB-MLR

TA- MLR

* *

* *

*

-60 -30 0 30 60 90 120 150 180

1201101009080706050

1201101009080706050

1201101009080706050

Time relative to oral intake of substance (min)

Are

a of

EM

Gre

spon

se(%

of c

ontr

ol)

• Tizanidine (Sirdalud®) is a noradrenergic drug

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 toanticipate 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)

Centralcommand

Limbmovement

Posturaldisturbance

Feedbackfor unexpected postural

disturbancePosturaladjustment

Feed-forwardfor expected postural

disturbance

Postural and prime mover activity are coordinated by a central command

(adapted from Cordo and Nashner, 1982)

Anticipatory Postural Adjustments during Arm Movements

• Once the intention to pull the handle is realized, the cortex relays a message, probably via subcorticalstructures, to contract the gastrocnemius muscle even faster than the signal to contract the biceps brachii

(Nardone and Schieppati, Exp Brain Res, 1988)

Rising on toe tips

Sol

TA

Quad

BiFe

acoustic GO signal reaction time

APA

Sol

TA

Quad

BiFe

acoustic GO signal reaction time

APA

Sol

TA

Quad

BiFe

acoustic GO signal reaction time

APA

• APA consists in activation of TA before soleus muscle in order to counteract the forthcoming backward inclination of the body

The CerebellumThought 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 CerebellumOutput

Fastigial nucleus,vestibulospinal andreticulospinal tractInterpositus nucleus, nucleus ruber, reticular formationDentate nucleus, nucleus ruber, VL thalamus

Input

Vestibular canals, otoliths, vestibularnucleiSpinocerebellar tracts

Pontine nuclei, inferior olives

(from Kandel et al., 2000)

Structure

Flocculus, nodulus(archicerebellum)

Anterior lobe(paleocerebellum)

Cerebellar hemisphere(neocerebellum)

Function and Dysfunction of the CerebellumStructure

Flocculus, nodulus(archicerebellum)

Anterior lobe(paleocerebellum)

Cerebellar hemisphere(neocerebellum)

Function

Stabilization of the trunk, scaling of the VOR

Stabilization of upright stanceand locomotion

Control of limb movements, parametrization of velocity, acceleration, timing of EMG activity, motor learning

Dysfunction

Ataxia while sitting, standing and walking, omnidirectionalbody sway

Ataxia of stance, 3 Hz AP body tremor, kinetic tremor in the heel-shin test

Dysmetria, dysdiadochokinesia, kinetic tremor, dyskinesia, dysarthria

(from Kandel, 2000)

Output

Fastigial nucleus,vestibulospinal andreticulospinal tract

Interpositus nucleus, nucleus ruber, reticular formation

Dentate nucleus, nucleus ruber, VL thalamus

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

(from Thach, 1978)

• Deep nuclei activity occurs before muscle activity and before movement • Prior to a voluntary (reaction time) movement of the monkey’swrist, 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 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 depression of the efficacy of synaptic input of parallel fibres on Purkinje cells induced by climbing fibres is one theory of how the cerebellum might correct movement and allow motor learning

CORTEX

InferiorOlive

Spinal Cord

Cortico-Spinal Tract

ErrorCorrection

Feedback from actual movement

Spino-Cerebellar Tract

Reference Signal

Efferent Copy

CORTEXCORTEX

InferiorOlive

InferiorOlive

Spinal CordSpinal Cord

Cortico-Spinal Tract

ErrorCorrection

Feedback from actual movementFeedback from actual movement

Spino-Cerebellar Tract

Reference Signal

Efferent Copy

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 On

Prisms Off

The Cerebellum and Motor Learning

Position of Basal Ganglia in the Brain

Basal GangliaThey 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

CONNECTIONS IN THE NORMAL CORTICO-

BASAL GANGLIA LOOP

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 movementDopamine 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 muscletone 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 ata 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

0

20

40

60

80

100NormalParkinsonian

Sol TAFDB

Are

a of

EM

G R

espo

nse

(x0.

1m

V*m

s) (+

SEM

)

*

0

20

40

60

80

100NormalParkinsonian

Sol TAFDB

Are

a of

EM

G R

espo

nse

(x0.

1m

V*m

s) (+

SEM

)

*

0

500

0

500

0

500

0

50050

SLRMLR

MLR

SLRMLR

MLR

μVμV

0

500

0

500

SLR SLRMLRMLR

50 ms

Normal Parkinsonian

iEM

G(μ

V)iE

MG

(μV)

iEM

G(μ

V)

SolToe-up

TAToe-down

FDBToe-up

0

500

0

500

0

500

0

50050

SLRMLR

MLR

SLRMLR

MLR

μVμV

0

500

0

500

SLR SLRMLRMLR

50 ms

Normal Parkinsonian

iEM

G(μ

V)iE

MG

(μV)

iEM

G(μ

V)

SolToe-up

TAToe-down

FDBToe-up

0

500

0

500

0

500

0

50050

SLRMLR

MLR

SLRMLR

MLR

μVμV

0

500

0

500

SLR SLRMLRMLR

50 ms

Normal Parkinsonian

iEM

G(μ

V)iE

MG

(μV)

iEM

G(μ

V)

SolToe-up

TAToe-down

FDBToe-up

• 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)

0

200

0

200

0

200

0

200

0

20

40

60

80

Normals Parkinsonians

Are

a of

TA

-MLR

(% o

ffr

ee s

tanc

e) (+

SEM

) *50 ms

TA (μ

V)TA

(μV) MLR

MLRMLR

MLR

free stance

holding

Normal Parkinsonian

0

200

0

200

0

200

0

200

0

20

40

60

80

Normals Parkinsonians

Are

a of

TA

-MLR

(% o

ffr

ee s

tanc

e) (+

SEM

) *50 ms

TA (μ

V)TA

(μV) MLR

MLRMLR

MLR

free stance

holding

0

200

0

200

0

200

0

200

0

20

40

60

80

Normals Parkinsonians

Are

a of

TA

-MLR

(% o

ffr

ee s

tanc

e) (+

SEM

) *50 ms

TA (μ

V)TA

(μV) MLR

MLRMLR

MLR

free stance

holding

0

200

0

200

0

200

0

200

0

20

40

60

80

Normals Parkinsonians

Are

a of

TA

-MLR

(% o

ffr

ee s

tanc

e) (+

SEM

) *50 ms

TA (μ

V)TA

(μV) MLR

MLRMLR

MLR

free stance

holding

Normal Parkinsonian

Impaired Modulation of Medium-Latency Responses in Parkinsonians

The ability of PD patients of reducing the amplitude of postural responses to a balance perturbation when changing postural “set”(standing and holding onto a stable frame) is impaired

• 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

Possible Roles of Basal Ganglia in Movement - 2

• 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

PET Study with F-DOPA in Parkinson’s Disease

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 disinhibitedThe net result is a paucity of movement (hypokynesia)

pars compactapars compacta

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 eliminatingmost 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

SMA

DLPCThalamus(VL, VA)

BG

PMA

PC(40)Thalamus

(X)

Cerebellum

Without External Signals(internally generated movement)

With External Signals(externally generated movement)

• The circuit through SMA (Supplementary Motor Area) is implied in theinternal 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 externalgeneration of movement (obtained with visual or auditory cues); X, nucleus X of thalamus; PC(40), Parietal Cortex (Brodmann’s area 40)

• 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)]

ParkinsonianPatients are

dependent on External Cues for

Accomplishing Motor Tasks

Anticipatory Postural Adjustments are Impaired in Parkinson’s Disease

[from Frank et al. JNNP 84: 2440. (2000), Fig. 2]

• Amplitude and timing of EMG when rising onto the toes high and fast • A: 3 sample trials from arepresentative control and aparkinsonian subject OFFand ON• B: histogram of the mean and standard error of theGAS and TIB EMG EMG for each group shows that the magnitude of TIB and GASactivity was less for parkinsonian subjects OFFthan controls and this increased for parkinsonian subjects ON

Schematic Representationof the Basal GangliaNuclei and a High-

Frequency Stimulation(HFS) Electrode Implanted

in the Subthalamic Nucleus (STN)

(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 statedfrequency. (b) Decrease of STN activity during brief STN-HFS (i) in patientsand (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)

Inhibitory Effect of High-Frequency Stimulation (HFS) on Subthalamic Nucleus (STN) Activity

CONNECTIONS IN THE NORMAL CORTICO-

BASAL GANGLIA LOOP

Effects of High-Frequency Stimulation (HFS) on Subthalamic Nucleus (STN) Activity

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 inParkinson's disease: more or less? Trends Neurosci 2005;28:209-16

DBS can improve stance in Parkinson’s Disease