Motor Systems

1. Motor Systems Muscles and Lower Motor Neurons Motor systems of the CNS Pyramidal Cerebellum Extrapyramidal Motor Disorders Basal Ganglia Disorders: Parkinson’s Disease Huntington’s Disease Tourette’s syndrome

2. “To move is all that mankind can do..for such the sole execution is muscle, whether in whispering a syllable or in felling a forest.” Charles Sherrington, 1924

3. Muscles Smooth muscles Glands, arteries, digestive system Striated muscles Cardiac muscles Skeletal muscles

4. Spinal Cord Motor Programs Reflexes Proprioceptors Painful stimuli Central Pattern Generators

5. Central pattern generators

6. Cortex Goal-directed behavior Activation of many cortical areas Parietal cortex, somatosensory, frontal cortex, visual cortex Motor planning Prefrontal cortex Movement selection Premotor and supplementary motor areas Movement initiation Primary motor cortex Somatotopic organization

9. Primary Motor Cortex

10. Corticospinal tractaka pyramidal system

11. Brainstem motor nuclei Reticular Formation Reflexes (sneezing, coughing, vomiting) Posture control

12. Major descending spinal tracts

14. Cerebellum Motor sequencing Motor learning Ballistic movements

15. Damage to the cerebellum Jerky, erratic, uncoordinated movement (Ataxia) Dysdiadochokinesis Altered gait Intension tremors Nystagmus

16. Basal GangliaExtrapyramidal Motor system Caudate Putamen Globus pallidus Subthalamus Substantia Nigra Modulation of motor control Modulation of cognitive control

20. Brain circuits

21. Basal Ganglia- Thalamic- Cortical- Loops

22. Basal Ganglia- cortical loops Direct pathway: Excite cortex Indirect pathway: Inhibit cortex

23. Two hypothesis regarding the direct and indirect pathways 1) Direct activates the desired motor program whereas the indirect inhibits unwanted motor programs 2) The direct and indirect act on the same motor program, allowing for greater control of movement

24. Dopamine modulates the basal ganglia Dopamine excites the direct pathway (via D1 receptors) Dopamine inhibits the indirect pathway (via D2 receptors)

25. Consider what happens if there is an imbalance in direct/indirect pathway activation Overactivation of the direct pathway, or underactivation of the indirect pathway leads to excessive movements, or undesired movements Overactivation of the indirect pathway or underactivation of the direct pathway leads to a poverty of movement

26. Basal Ganglia Disorders Parkinson’s syndrome Hemiballismus Huntington’s syndrome Tourette’s syndrome

27. Motor disorder terms Akinesia Difficulty in initiating willed movements Hypokinesia Paucity of movement Bradykinesia Slowness of movement Dyskinesia Dysfunctional movement Hyperkinesia Excessive movement

28. Parkinson’s Disease

29. Parkinson’s Disease 1817 James Parkinson “shaking palsy” Akinesia and bradykinesia Resting tremor Muscle rigidity Shuffling gait Postural instability Loss of facial muscle tone

31. Loss of DA cells in the substantia nigra

33. Basal Ganglia Dysfunction D1 DA receptors facilitate transmission of the direct pathway D2 DA receptors reduce transmission of the indirect pathway Underactive Direct: akinesia Overactive Indirect: Bradykinesia

36. Lewy bodies

37. What causes the neuropathology? Genetic and environmental factors Early onset (may be related more to genetic factors) Late onset

38. The frozen addicts

39. Mitochondrial dysfunction and mishandling of abnormal proteins may be a common pathogenic event

41. TreatmentsHistorical Look 19th century-1960 Surgery Motor cortex, spinal pathways, frontal lobotomy 1940s & 1950s Pallidotomy, basal ganglia surgeries Drug therapies L-dopa

42. TreatmentsCurrent Surgeries Pallidotomies (internal) Subthalamotomy Thalamotomy (most effective for tremor) Drug treatments L-dopa Deprenyl (MAO B inhibitor) Tissue Transplantation Adrenal tissue Fetal tissue Pig tissue (xenografts) Co-administration of trophic factors

43. Basal Ganglia- Thalamic- Cortical- Loops

44. Deep Brain Stimulation

45. TreatmentsCurrent Surgeries Pallidotomies (internal) Thalamotomy Subthalamotomy Drug treatments L-dopa Deprenyl (MAO B inhibitor) Tissue Transplantation Adrenal tissue Fetal tissue Pig tissue (xenografts) Co-administration of trophic factors

47. TreatmentsCurrent Surgeries Pallidotomies (internal) Thalamotomy Subthalamotomy Drug treatments L-dopa Deprenyl (MAO B inhibitor) Tissue Transplantation Adrenal tissue Fetal tissue Pig tissue (xenografts) Co-administration of trophic factors

48. Freed paper discussion First prospective study comparing transplantation with a control Issues of sham surgery Measure symptom severity at 12 months UPDRS Schwab and England scale Subjective global rating by patients

49. Freed paper (cont) Results Improvement in UPDRS and Schwab & England scales, but only in younger Parkinson’s patients

50. Transplants reduced motor symptoms

51. Transplants increased striatal dopaminergic activity

52. Transplants established connections and became functional

53. Adverse side effects Dyskinesia developed in 15% of patients

54. Freed paper What would you do differently in this study? Do you think that the adverse outcomes were too risky?

56. Success of transplants depend on many factors Age of fetal tissue Amount of tissue Placement of tissue Suspension of fetal tissue Age of patient Difficulty creating a standardized procedure

57. TreatmentsCurrent Surgeries Pallidotomies (internal) Thalamotomy Subthalamotomy Drug treatments L-dopa Deprenyl (MAO B inhibitor) Tissue Transplantation Adrenal tissue Fetal tissue Pig tissue (xenografts) Co-administration of trophic factors

58. TreatmentsFuture Stem cells Gene Therapies

59. DA neurons from embryonic stem cells in a non-human primate

60. Transplanted cells differentiate into dopaminergic neurons

61. Huntington’s Disease Symptoms become evident in 30s or 40s Chorea Eventual bradykinesia, immobility, and death Cognitive impairments, dementia, psychiatric disorders (depression, anxiety, obsessive-compulsive disorder, psychosis)

62. Huntington’s disease Loss of GABA neurons in striatum Reduces activity of indirect loop Progression—more extensive damage and loss of movement

63. Huntington’s Neuropathology Here you can see the neuropathology, with loss of cells in the striatum ,as well as cortex, a bit. And widening of the lateral ventricles.Here you can see the neuropathology, with loss of cells in the striatum ,as well as cortex, a bit. And widening of the lateral ventricles.

64. Huntington’s disease Genetic Dominant Chromosome 4, multiple trinucleotide repeats (CAG) (protein: Huntingtin protein) Longer the repeats, the earlier the symptoms

65. Huntingtin protein May alter glucose metabolism (Burke et al., 1996) Huntingtin may facilitate the production and transport of BDNF, which is necessary for survival of neurons in the striatum Animal studies show that altered huntingtin protein leads to apoptotic cell death

67. Nancy Wexler Genetic Test to determine if the individual is a carrier of this mutation Would you want to know?

68. Treatments No treatment to stop progression DA antagonists may reduce symptoms early in the disorder Environmental factors may delay onset and progression

69. Environmental-Gene interactions Animal studies show that environmental enrichment delays onset and progression

70. Tourette’s syndrome Motor tics Simple complex Vocal tics Simple complex

72. Tourette Syndrome

73. “When I was nine-years old, an imp took up residence in me. One afternoon he prodded the left side of my face from the inside, causing my lips to purse and curl askew toward my squinting left eye. Without yet knowing why, I rapidly blinked and shrugged. I grunted. I threw back my head and squeaked while my fists smacked my bruised abdomen.”

74. Tourette’s syndrome First published account: 1825 Jean-Mark Itard 1885: George Albert Edward Brutus Gilles de la Tourette Estimated 100,000 Americans with TS Occurs 3-4 times more in males than females. Onset usually in late childhood Increased incidence of ADHD and OCD

76. Pathophysiology Imaging studies: Reduction in volume and other abnormalities in basal ganglia