1. Lecture XIII. Brain Diseases I - Parkinsonism Bio 3411 Wednesday October 7, 2009 1Lecture XIII. Brain Diseases - I.

2. October 7, 2009Lecture XIII. Brain Diseases - I.2 Brain Diseases I NEUROSCIENCE THE BRAIN ATLAS 3 rd ed PageFigureFeature 46518.10Substantia Nigra in Parkinsonism 466Box 18AParkinson’s Disease: An Opportunity… 46018.6Neurons in basal ganglia 39816.1Schema of motor pathways 40-45 Brainstem with basal ganglia 72 Coronal Section including SN 130Axial section including SN 200-201 Direct Corticospinal tract 212-213Basal Ganglia Pathways

3. October 7, 2009Lecture XIII. Brain Diseases - I.3 References † Barker RA, Dunnett SB 1999 Functional integration of neural grafts in Parkinson’s disease. Nature Neuroscience 2:1047-1048. † Gulie S 2007 A shock to the system: to slow the progress of Parkinson’s disease, doctors planted electrodes deep in my brain. Then they turned on the juice. [http://www.wired.com/wired/archive/15.03/brainsurgery.html?pg=2&top ic=brainsurgery&topic_set=] (check out the video!!) † Perlmutter JS 2006 [http:/www.Harrisonline.Com/audio/parkinsons.Mp3] † Starr PA, Vitek JL, Bakay RAE 1998 Ablative surgery and deep brain stimulation for Parkinson’s disease. Neurosurgery 43:989-1015. † Wichmann T, DeLong MR 1998 Models of basal ganglia function and pathophysiology of movement disorders. Neurosurgery Clinics of North America 9:223-236. _______ † Articles/Abstract/Audio posted on website.

4. October 7, 2009Lecture XIII. Brain Diseases - I.4 What this lecture is about: Motor Systems - Reprise Pyramidal and Extrapyramidal (Basal ganglia) Parkinsonism a Movement Disorder Mechanisms and Treatment Strategies

5. October 7, 2009Lecture XIII. Brain Diseases - I.5 Sources of Descending Pathways for Movement Control 4. 3. 2. 1. 4. Medulla (Reticular Formation and Vestibular Nuclei) 3. Pons (Reticular Formation) 2. Midbrain (Red Nucleus & Superior Colliculus) 1. Forebrain (Cortex)

6. October 7, 2009Lecture XIII. Brain Diseases - I.6 Descending systems from the brain influence cells in the spinal cord to create movements. The cerebellum and the basal ganglia indirectly influence movements as indicated schematically here. Neuroscience, Fig 16.1, p. 398

7. The basal ganglia inhibit unwanted movement patterns and permit selected ones. They may also inhibit unwanted mental activities such as inappropriate utterances, and permit selected ones, such as proper speech. Basal Ganglia (Extrapyramidal) Pathways. October 7, 20097Lecture XIII. Brain Diseases - I.

8. October 7, 2009Lecture XIII. Brain Diseases - I.8 THE BRAIN ATLAS, 3 rd ed p 24

9. October 7, 2009Lecture XIII. Brain Diseases - I.9 THE BRAIN ATLAS, 3 rd ed pp 43-44

10. October 7, 2009Lecture XIII. Brain Diseases - I.10 Sections THE BRAIN ATLAS, 3 rd ed p 213

11. October 7, 2009Lecture XIII. Brain Diseases - I.11 Caudate Nucleus & Putamen THE BRAIN ATLAS, 3 rd ed p 213

12. October 7, 2009Lecture XIII. Brain Diseases - I.12 Globus Pallidus THE BRAIN ATLAS, 3 rd ed p 213

13. October 7, 2009Lecture XIII. Brain Diseases - I.13 Subthalamic Nucleus THE BRAIN ATLAS, 3 rd ed p 213

14. October 7, 2009Lecture XIII. Brain Diseases - I.14 Substantia Nigra THE BRAIN ATLAS, 3 rd ed p 213

15. October 7, 2009Lecture XIII. Brain Diseases - I.15 Thalamus THE BRAIN ATLAS, 3 rd ed p 213

16. October 7, 2009Lecture XIII. Brain Diseases - I.16 THE BRAIN ATLAS, 3 rd ed p 213

17. October 7, 2009Lecture XIII. Brain Diseases - I.17 Movie Clip # 1 Patient(s) with tremor and paralysis

18. October 7, 2009Lecture XIII. Brain Diseases - I.18 Symptoms and Signs: akinesia (no movement or bradykinesia, poverty of movement); poor sequences of movement; rigidity; tremor at rest Prevalence: ≤ 1% Predisposition/cause: probably not genetic, occurs after encephalitis (brain inflammation), certain toxins, but largely unknown Prevention: none known Pathophysiology: loss of dopamine neurons in substantia nigra that project to caudate and putamen Diagnosis: physical examination Parkinsonism

19. October 7, 2009Lecture XIII. Brain Diseases - I.19 Substantia Nigra THE BRAIN ATLAS, 3 rd ed p 74

20. October 7, 2009Lecture XIII. Brain Diseases - I.20 THE BRAIN ATLAS, 3rd ed p 139 Substantia Nigra

21. October 7, 2009Lecture XIII. Brain Diseases - I.21 The dopaminergic cells of the substantia nigra (pars compacta - compact or cellular part) make a pigment (neuromelanin) as a by-product of dopamine synthesis which identifies them and the region to the naked eye. These cells are lost in persons with Parkinson’s Disease (PD). Compare left (normal) to right (PD) in these sections through the midbrain. NEUROSCIENCE, fig 18.10 A, p. 465

22. October 7, 2009Lecture XIII. Brain Diseases - I.22 Dopaminergic Pathways THE BRAIN ATLAS, 3 rd ed p 235

23. October 7, 2009Lecture XIII. Brain Diseases - I.23 excitatory inhibitory (See NEUROSCIENCE, fig 18.11, p 467)

24. October 7, 2009Lecture XIII. Brain Diseases - I.24 NEUROSCIENCE, Fig 18.6 p 460

25. October 7, 2009Lecture XIII. Brain Diseases - I.25 THE BRAIN ATLAS, 3 rd ed p 213

26. October 7, 2009Lecture XIII. Brain Diseases - I.26 (See NEUROSCIENCE, fig 18.11, p 467) excitatory inhibitory 1) Supply Dopamine 2) Reduce inhibition

27. October 7, 2009Lecture XIII. Brain Diseases - I.27 Movie Clip # 2 L-DOPA relieves the tremors and paralysis but can produce involuntary (choreiform) movements

28. October 7, 2009Lecture XIII. Brain Diseases - I.28 This is a perioperative MRI of a patient whose PD was relieved by lesions of the internal part of the globus pallidus in the coronal (left) and parasagittal (right) planes.

29. October 7, 2009Lecture XIII. Brain Diseases - I.29 To release inhibition of the thalamus, the source of fibers to the thalamus in the globus pallidus is lesioned. This mimics (under control) a stroke that “cured” a patient of PD. These drawings of images in the coronal plane show the planned trajectory to target electrodes and the resulting electrolytic lesions (circles). The procedure is done in awake patients and accuracy of the targeting of the electrodes is determined by imaging and stimulating the brain. Currents necessary to activate nearby structures the optic tract (OT) and the cortical spinal tract (CST) are indicated.

30. October 7, 2009Lecture XIII. Brain Diseases - I.30 This is a post operative MRI in the coronal plane of a patient whose PD was relieved by lesions of the internal part of the globus pallidus. The upper arrow shows the reaction along the electrode tract; the lower arrow changes in the globus pallidus (compare to the opposite side.)

31. October 7, 2009Lecture XIII. Brain Diseases - I.31 This is a post operative MRI of a patient whose PD was relieved by lesions of the internal part of the globus pallidus. The images in the axial plane show that the globus pallidus is missing (arrows). (Compare to intact GP on the opposite side.) In this plane the proximity of the GP to the posterior limb of the internal capsule in which axons of the corticospinal tract travel is apparent (arrow).

32. October 7, 2009Lecture XIII. Brain Diseases - I.32 This is a post operative MRI of a patient whose PD was relieved by lesions of the thalamus. The images in the axial plane show (left) and in the coronal plane (right) show the lesion site (arrows). (Compare to intact thalamus the opposite side.)

33. October 7, 2009Lecture XIII. Brain Diseases - I.33 This is a post-operative X-ray of a patient whose PD was relieved by electrical stimulation of the globus pallidus. Film in the lateral (side) projection shows the electrode site (arrow). The wires connect to a controllable stimulator usually implanted under the skin of the chest.

34. October 7, 2009Lecture XIII. Brain Diseases - I.34 These are post- operative MRIs of a patient whose PD was relieved by electrical stimulation of the subtalamic nucleus. The axial, coronal and sagittal planes (left to right) show the position of the stimulating electrode in the target.

35. October 7, 2009Lecture XIII. Brain Diseases - I.35 Movie Clip # 3 When the electrode is targeted the tremors cease

36. October 7, 2009Lecture XIII. Brain Diseases - I.36 Parkinsonism Treatment: – a) replace missing DA - levodopa; transplant – b) counter tonic imbalances - make lesions; stimulate Long Term Changes: improvement with drugs and others above Brain Science: DA, pathways, model of treatment for other brain diseases Prevention – if there are contributions from the environment.

37. October 7, 2009Lecture XIII. Brain Diseases - I.37 Shows prominent deficits with loss of neurons making dopamine. The disease has been mimicked by a toxin and can be treated by increasing the levels of dopa (levodopa), possibly by transplanting or engineering dopa producing cells (particularly stem cells) in the vicinity of the basal ganglia, or by restoring balance to the “extrapyramidal” circuit by lesions (mimics “cures” by stroke) or by stimulation (may work as a reversible or intermittent lesion). Parkinsonism

38. October 7, 2009Lecture XIII. Brain Diseases - I.38 Movie Clip # 4 Two weeks later with the stimulator off the tremor returns; with the stimulator on it ceases

39. October 7, 2009Lecture XIII. Brain Diseases - I.39 THE BRAIN ATLAS, 3 rd ed pp 59, 60

40. October 7, 2009Lecture XIII. Brain Diseases - I.40 excitatory inhibitory (See NEUROSCIENCE, fig 18.11, p 467)

41. October 7, 2009Lecture XIII. Brain Diseases - I.41 excitatory inhibitory excitatory inhibitory (See NEUROSCIENCE, fig 18.11, p 467)

42. October 7, 2009Lecture XIII. Brain Diseases - I.42 Atrophy (shrinkage) of the Caudate Nucleus Atrophy (shrinkage) of the Putamen Huntington’s disease is an autosomal dominate condition (the gene is called Huntingtin) in which affected individuals have movement disorders characterized by writhing sinuous involuntary movements called chorea (as in choreography for dancing). Cells of the caudate nucleus and putamen degenerate and these nuclei atrophy (shrink).

43. October 7, 2009Lecture XIII. Brain Diseases - I.43 See NEUROSCIENCE, fig 18.11, p 467 excitatory inhibitory excitatory inhibitory

44. October 7, 2009Lecture XIII. Brain Diseases - I.44 Movie Clip # 2 L-DOPA relieves the tremors and paralysis but can produce involuntary (choreiform) movements

45. October 7, 2009Lecture XIII. Brain Diseases - I.45 Movie Clip # 5 Stimulators allow modulation of Rx in real time. Here the patient walks out of the hospital on her way home.

46. October 7, 2009Lecture XIII. Brain Diseases - I.46 Science, medicine ≠ ignorance, politics

47. October 7, 2009Lecture XIII. Brain Diseases - I.47 What this lecture was about: Motor Systems a Reprise Pyramidal and Extrapyramidal (Basal ganglia) Parkinsonism a Movement Disorder Mechanisms and Treatment Strategies

48. END October 7, 200948Lecture XIII. Brain Diseases - I.