1. Motor System: Reflexes, Pyramidal Tract and Basal Ganglia Richard Harlan, PhD harlanre@tulane.edu

2. 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

3. 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

4. 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

5. 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

6. 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

7. Muscle spindle

8. Innervation of muscle spindle and muscle

9. 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

10. 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

11. Stretch reflex

12. 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

13. Gamma efferents allow continued response of spindle during voluntary contraction

14. 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

15. Stretch reflex

16. 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

17. Flexor reflex

18. 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

19. Crossed extensor reflex

20. 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

22. Brainstem control over spinal reflexes 2. reticulospinal tracts: innervate (indirectly) antigravity motor neurons; activated by cortico- reticular fibers and by somatosensory inputs, especially nociceptive

23. Brainstem control over spinal reflexes 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

25. Brainstem reflexes A. blink reflexes B. feeding mechanisms: rhythmic chewing and licking movements C. micturition (urination) reflex D. gaze control

26. Overview of Motor Systems Spinal and brainstem reflexes Corticospinal and corticobulbar tracts Cortical-subcortical-thalamo-cortical systems –Involving basal ganglia –Involving pons and cerebellum

27. 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

28. 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

29. Pyramidal tract origin

30. 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

31. 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

32. Control of movement by motor cortex 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)

33. Control of movement by motor cortex 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

34. Overview of Motor Systems Spinal and brainstem reflexes Corticospinal and corticobulbar tracts Cortical-subcortical-thalamo-cortical systems –Involving basal ganglia –Involving pons and cerebellum

35. Cortex Subcortical Structures Thalamus Cortical-Subcortical-Thalamo-Cortical Loops

36. Motor Hierarchy and Loops

37. Pallidum Striatum Motor Thalamus: VA Motor Cortex Basal Ganglia Loop glutamate GABA glu GABA

38. 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

41. 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

42. 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

43. Medium spiny neuron

44. 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

46. 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

47. 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)

48. 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)

49. 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

50. Pallidum Striatum Motor Thalamus: VA Motor Cortex Basal Ganglia Loop Substantia Nigra glutamate GABA glu DA GABA

52. 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 thalamo-cortical neurons –Inhibits motor cortex –Inhibits movement

55. 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 thalamo-cortical neurons –Inhibits motor cortex –Inhibits movement

57. Pallidum: Gpe, GPi Striatum Motor Thalamus: VA Motor Cortex Basal Ganglia Loop Substantia Nigra glutamate GABA glu DA Direct: + Indirect: - D1R, PPTD2R, PPE Subthalamic n.

58. 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 Dopamine facilitates movement

59. 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

60. 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)

62. 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 Dopamine facilitates movement

64. 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

68. 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)

69. 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

72. NormalHuntington’s Chorea

73. 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)