Motor System: Reflexes, Pyramidal Tract and Basal Ganglia Richard Harlan, PhD [email protected]

Motor System: Reflexes, Pyramidal Tract and Basal

GangliaRichard Harlan, PhD

[email protected]

Overview of Motor Systems

• Spinal and brainstem reflexes• Corticospinal and corticobulbar tracts• Cortical-subcortical-thalamo-cortical

systems– Involving basal ganglia– Involving pons and cerebellum– Involving nucleus accumbens

Spinal and Brainstem Reflexes: Agonist and Antagonist Muscle

Groups• Sensory side–Muscle spindles– Golgi tendon organs

• Motor side– Alpha motor neurons: innervate skeletal

muscles, causing contraction– Gamma motor neurons: innervate

muscle spindles

Golgi tendon organ

• found in tendons near junctions with muscle fibers: stretch receptors innervated by Ib fibers: heavily myelinated with fast conduction; Ib fibers go to ventral horn and activate interneurons which inhibit (glycinergic) alpha motor neurons (opposite of muscle spindle effect; negative feedback); higher threshold than for muscle spindle

Muscle spindles• encapsulated structures within skeletal

muscle, containing intrafusal muscle fibers, in parallel with extrafusal muscle fibers (normal skeletal muscle); multiple nuclei in central region and intrafusal fibers at each end; two morphological/functional types of spindles

Muscle spindles: Types• Nuclear bag fibers: clustered nuclei in center of spindle;

dynamic: sensitive to rate of change in muscle length; static: sensitive to total change in muscle length; innervated by type Ia fibers: heavily myelinated, fast conduction: annulospiral nerve endings: firing frequency proportional to degree of muscle stretch; also innervated by dynamic or static gamma motor neurons: can contract the intrafusal fibers, stretching the central region, activating Ia afferents

• Nuclear chain fibers: nuclei in row; sensitive to change in muscle length; innervated by type II fibers: flower spray ending: codes event of stretch, not rate; gamma motor efferents

Muscle spindle

Innervation of muscle spindle and muscle

Spinal cord circuits

• 1a afferents: activated by stretch of muscle; innervate alpha motor neurons, causing reflex contraction of muscle

• 1b afferents: activated by contraction of muscle; innervate interneurons, that inhibit alpha motor neurons, causing reflex relaxation of muscle

Stretch reflexes

• 1. passive stretch of muscle (e.g. by tapping tendon) activates Ia afferents, which activate alpha motor neurons, causing contraction of stretched muscle: monosynaptic reflex

• 2. passive contraction of muscle (stimulation of alpha motor neurons) causes decreased activity of muscle spindles, leading to decreased activity of alpha motor neurons

Stretch reflex

Stretch reflexes• 3. gamma loop: supraspinal input (e.g.

corticospinal) activates gamma motor neurons, activating intrafusal fibers that stretch the muscle spindle, activating Ia fibers, which activate alpha motor neurons

• 4. voluntary muscle contraction against a load: corticospinal fibers activate both alpha and gamma motor neurons, allowing Ia fibers to continue to sense muscle length while muscle is contracting: alpha-gamma coactivation

Gamma efferents allow continued response of spindle during voluntary contraction

Stretch reflexes

• 5. reciprocal or autogenic inhibition: activation of agonist and inhibition of antagonist muscles; stretch of muscle spindles activates Ia fibers, which monosynaptically activate agonist alpha motor neurons, and Ia fibers also activate glycinergic interneurons which inhibit antagonist alpha motor neurons

Stretch reflex

Stretch reflexes

• 6. flexor reflex: activation of A-delta and c fibers by nociceptive stimuli activates excitatory and inhibitory interneurons in ventral horn, which activate flexor alpha motor neurons and inhibit extensor motor neurons; involves several spinal cord segments

Flexor reflex

Stretch reflexes

• 7. crossed extensor reflex: activation of A-delta and c fibers by nociceptive stimuli activates excitatory and inhibitory interneurons in ventral horn, which project across midline to activate or inhibit interneurons, resulting in activation of extensor and inhibition of flexor motor neurons

Crossed extensor reflex

Brainstem control over spinal reflexes

• 1. vestibulospinal tracts– a. medial tract: originates in medial and inferior vestibular

nuclei; projects bilaterally to cervical and thoracic spinal cord; mostly controls neck muscles: reflex control of head position: vestibular apparatus (semicircular canals, sacculus, utriculus) activate vestibular ganglion neurons that activate central vestibular neurons

– b. lateral tract: originates in lateral vestibular nucleus; projects ipsilaterally to entire spinal cord; innervates alpha motor neurons (directly or indirectly) that control deep back extensors and proximal limb extensors: maintain balance, antigravity muscles


• 2. reticulospinal tracts: innervate (indirectly) antigravity motor neurons; activated by cortico-reticular fibers and by somatosensory inputs, especially nociceptive


• 3. rubrospinal tract: crossed descending systems controlling mostly upper limbs; inputs from cerebral cortex and cerebellum– a. from magnocellular RN: rubrospinal

tract; excites motor neurons controlling proximal flexors

– b. from parvocellular RN: rubro-olivary tract

Brainstem reflexes

• A. blink reflexes

• B. feeding mechanisms: rhythmic chewing and licking movements

• C. micturition (urination) reflex

• D. gaze control


• Spinal and brainstem reflexes

• Corticospinal and corticobulbar tracts

• Cortical-subcortical-thalamo-cortical systems– Involving basal ganglia– Involving pons and cerebellum

Corticospinal tract• Origins: primary motor cortex (MI),

premotor cortex, supplemental motor cortex, anterior paracentral gyrus, parietal lobe (including SI) and cingulate gyrus

• collaterals: small percentage of corticospinal neurons– 1. midbrain (primarily red nucleus)– 2. trigeminal nuclei– 3. pontine nuclei

Corticospinal tract

• Termination in spinal cord: mostly laminae 3-7, few in ventral horn and laminae 1-2; mostly innervating interneurons, although some innervation of alpha motor neurons

• Neurotransmitter: glutamate and/or aspartate

Pyramidal tract origin

Corticobulbar tracts• A. control over facial muscles; bilateral input to motor

neurons controlling muscles in upper face, but contralateral input to motor neurons controlling lower face (in humans, not sure about rodents)

• B. control over muscles of mastication: motor trigeminal, and RF

• C. control over external eye muscles: input comes from frontal and parietal eye fields, rather than from MI; projection to midbrain and paramedian pontine RF

• D. control over tongue: hypoglossal and RF• E. control over swallowing reflexes: nucleus

ambiguus and RF

Control of movement by motor cortex

• A. microstimulation studies: in MI movements of particular contralateral joints (e.g. distal finger) can be elicited by microstimulation; in MII contractions of groups of muscles sequentially to produce overall movements of limbs, often bilaterally


• B. electrical activity during movement: corticospinal neurons active just before initiation of a movement; activity related to amount of force necessary to produce the movement; directionally-sensitive corticospinal neurons; higher-order motor cortex involved in calculating trajectories in space (probably in close communication with cerebellum) and in planning larger-scale movements (probably in close communication with the basal ganglia)


• C imaging studies in humans: random movements of digits activates MI (precentral gyrus); planned movements activate MI and supplemental motor cortex; thinking about planned movements activates supplemental motor cortex, but not MI


• Spinal and brainstem reflexes

• Corticospinal and corticobulbar tracts

• Cortical-subcortical-thalamo-cortical systems– Involving basal ganglia– Involving pons and cerebellum

Cortex SubcorticalStructures

Thalamus

Cortical-Subcortical-Thalamo-Cortical Loops

Motor Hierarchy and Loops

Pallidum

Striatum

Motor Thalamus: VA

Motor Cortex

Basal Ganglia Loop

glutamate

GABAglu

GABA

Basal Ganglia Structures

• Striatum: dorsal striatum (caudate and putamen), ventral striatum (nucleus accumbens and olfactory tubercle)

• Pallidum: external and internal segments of globus pallidus

• Subthalamic nucleus• Substantia nigra

QuickTime™ and aGIF decompressor

are needed to see this picture.



Striatum: extent

• dorsal vs. ventral: dorsal = caudate and putamen; ventral = nucleus accumbens (Acb) and olfactory tubercle Tu; Tu separated from striatum by ventral pallidum

• core vs. shell of nucleus accumbens: core similar to caudate, shell transition between striatum and extended amygdala

Striatum: cell types• medium spiny: GABAergic projection neurons

that co-express neuropeptides:– enkephalinergic: PPE gene; D2 receptors

– tachykininergic: extensive co-localization with dynorphin: PPD/SP; D1 receptors

– other neuropeptides in much lower abundance

• large cells: interneurons– cholinergic: muscarinic receptors found on PPE and

PPD/SP neurons

– NOS/NADPH d/somatostatin: GABAergic

Medium spiny neuron

Striatum: patch-matrix organization

• Mu receptors: demonstrate patches• Calbindin: most of matrix• Dendrites and axon collaterals of

projection neurons mostly (but not always) restricted to the compartment of the parent neuron; dendrites and axons of large neurons readily cross patch-matrix boundaries

Striatum: Afferent connections

• cerebral cortex: come from layers 5 and 6: 5a and superficial 6 go to matrix, 5b and deep 6 go to patch: may be related to development; glutamatergic

• thalamus: input mostly from medial thalamus, including midline and intralaminar nuclei, many are collaterals of projections to cortex, primarily Fr2 and Cg and insular

• substantia nigra: dopaminergic

Striatum: Dopaminergic Afferents

• From substantia nigra in midbrain

• Nigra divided into pars compacta (SNc; contains most of dopaminergic cell bodies) and pars reticulata (SNr; contains dendrites of dopaminergic neurons and GABAergic local neurons)

• Pars compacta divided into dorsal tier (co-localized with calbindin; projects to patch and part of cortex) and ventral tier (no calbindin; projects to matrix)

Striatum: Efferent connections

• Globus pallidus: external and internal segments; in rat, GP = GPe and entopeduncular n. = GPi

• SNr: GABAergic neurons that inhibit dopaminergic neurons; also projections to thalamus (VL, VM)

Cortico-striatal-pallidal-thalamo-cortical loops

• Direct path: cortex activates medium spiny neurons, which inhibit GPi neurons, decreasing the inhibition of thalamo-cortical neurons; net effect is disinhibition of the thalamus and facilitation of movement

• Indirect path: cortex activates medium spiny neurons, which inhibit GPe neurons, which inhibit subthalamic neurons, which tonically activate GPi neurons, which inhibit thalamo-cortical neurons; net effect is inhibition of thalamo-cortical neurons and inhibition of movement

Pallidum

Striatum

Motor Thalamus: VA

Motor Cortex

Basal Ganglia Loop

SubstantiaNigra

glutamate

GABAgluDA

GABA

Direct and Indirect Pathways

• Direct pathway– Disinhibits motor

thalamus– Thus activates

thalamo-cortical neurons

– Activates motor cortex

– Facilitates movement

• Indirect pathway– Inhibits motor

thalamus– Thus inhibits


– Inhibits motor cortex

– Inhibits movement

Direct and Indirect Pathways

• Direct pathway– Disinhibits motor

thalamus– Thus activates


– Activates motor cortex

– Facilitates movement

• Indirect pathway– Inhibits motor

thalamus– Thus inhibits


– Inhibits motor cortex

– Inhibits movement

Pallidum: Gpe, GPi

Striatum

Motor Thalamus: VA

Motor Cortex

Basal Ganglia Loop

SubstantiaNigra

glutamate

GABAglu

DA

Direct: +

Indirect: -

D1R, PPTD2R, PPE

Subthalamic n.

Dopaminergic control of striatum

• Direct path: facilitates movement

• Dopamine acts on D1 receptors, which facilitate information flow

• Dopamine facilitates movement

• Indirect path: inhibits movement

• Dopamine acts on D2 receptors, which inhibit information flow, thus disinhibition


Direct and Indirect Pathways• Direct: DA binds to D1

receptors• activating adenylyl cyclase,

increasing cAMP, activating PKA

• PKA phosphorylates DARPP32

• P-DARPP32 inhibits PP1 phosphatase

• unopposed phosphorylation of various ion channels

• Indirect: DA binds to D2 receptors

• inhibits AC, decreases cAMP, decreases activity of PKA

• reduces phosphorylation of DARPP32

• reduces inhibition of PP1• de-phosphorylates NR1

Clinical problems in basal ganglia

• Movement disorders are one aspect; cognitive and memory impairments may also occur

• Hypokinesias: akinesia (difficulty in planning and initiating movements); bradykinesia (reduction in velocity and amplitude of movement): inappropriate activity in antagonist muscles

– Striatal strokes – Parkinson’s disease

• Dyskinesias (unwanted movements)



Dopaminergic control of striatum

• Direct path: facilitates movement

• Dopamine acts on D1 receptors, which facilitate information flow


• Indirect path: inhibits movement

• Dopamine acts on D2 receptors, which inhibit information flow, thus disinhibition


Treatments for Parkinson’s disease• Pharmacological

– L-DOPA plus carbidopa to increase dopamine levels; usually initial improvements, but then progressive loss; D1 receptor agonists can induce tardive dyskinesia

• Neurosurgical– implantation of dopamine-producing cells: very

controversial

– lesions of thalamic or pallidal structures: blocks overactivity of pallido-thalamic projection

– overstimulation of subthalamus to inhibit subthalamic activity: deep brain stimulation



Dyskinesias and hyperkinesias

• choreiform movements: “dance-like movements” e.g. Huntington's disease

• ballisms and hemiballisms; usually vascular lesions of contralateral subthalamic nucleus

• athetoid movements: continual writhing movements of distal extremity

• myoclonus: sudden jerky movements• dystonia: chronic muscular contractions leading to

bending or twisting• tardive dyskinesia: iatrogenic (caused by

medications)

Clinical problems in basal ganglia

• Huntington’s chorea– Progressive, untreatable, decreased function

and dementia– Genetic defect in gene called huntingtin– Choreiform movements leading to severe

impairment; death within 15 years– Loss of about 90% of striatal neurons,

especially of indirect pathway: overactivity of direct pathway: uncontrolled movements







Normal Huntington’s Chorea

Functions of striatum

• Much evidence for involvement in stimulus-response learning, or procedural memory: Packard and Knowlton, Ann. Rev. Neurosci 25: 563-593, 2002

• Large-scale movements and motivated behaviors (especially in ventral striatum)

Documents

Motor System: Reflexes, Pyramidal Tract and Basal Ganglia Richard Harlan, PhD [email protected]