1. Making Things Happen - 2 Motor Disorders How Your Brain Works - Week 7 Dr. Jan Schnupp jan.schnupp@dpag.ox.ac.uk HowYourBrainWorks.net

2. Subcortical Motor Structures

3. The Basal Ganglia GPi = globus pallidus internal segment GPe = globus pallidus external STN= subthalamic nucleus Sub Nig = Substantia Nigra (pars compacta)

4. The Motor Loop Excitatory (Glutamatergic) connections shown in dark green Inhibitory (GABAergic) connections shown in red Dopaminergic connections shown in sky blue

5. Parkinson’s Disease The cause of Parkinson’s disease is a degeneration of dopaminergic neurons in the substantia nigra pars compacta

6. Dopamine Biosynthesis and L-DOPA

7. Why Substantia Nigra neurons are black

8. Parkinsonian Tremor & Bradykinesia http://www.youtube.com/watch?v=jclJVrLODQA

9. Parkinsonian Gait and L-DOPA treatment http://www.youtube.com/watch?v=sf1N0Zf5IqA

10. Dyskinesia A common side-effect of L-DOPA therapy The case shown here is quite severe

11. Michael Fox backs stem cell research

12. Cell Differentiation

14. MPPP and MPTP MPPP is a synthetic heroin substitute MPTP is a contaminant that can arise from MPPP synthesis. It kills dopaminergic neurons and makes people (or animals) instantly Parkinsonian. Some successes have been reported in treating MPTP poisoned addicts with embryonic tissue grafts.

15. Break

16. Deep Brain Stimulation DBS most commonly targets the subthalamic nucleus

17. Treating Parkinsonian Tremor with DBS http://www.youtube.com/watch?v=g5Y9f4Xr42o

18. Dystonia before and after DBS

19. Huntington’s Disease A genetic mutation of the HTT gene on chromosome 4 causes premature neural cell death in homozygous carriers. Spiny stellate neurons projecting from putamen to the GPe are the first affected. As the disease progresses, damage is more widespread.

20. Motor Related Areas of Cortex Somatosensory Cortex Somatosensory Cortex Somatosensory Cortex Premotor Area Frontal Eye FieldsPrimary Motor Cortex Supplementary Motor Area Broca’s Area

21. The Forebrain: Loops Upon Loops

22. Mesolimbic Mesocortical Dopamine Pathways

23. Huntington’s Chorea

24. Reported prevalences of behavioural and psychiatric symptoms in Huntington's disease[[ Reported prevalences of behavioral and psychiatric symptoms in Huntington's disease [10] [10] Irritability38–73% Apathy34–76% Anxiety34–61% Depressed mood33–69% Obsessive and compulsive10–52% Psychotic3–11%

25. Dopaminergic Antagonists Dopamine Chlorpromazine Numerous dopamine antagonists are used to treat diseases including obsessive-compulsive disorder, Tourette’s syndrome, anxiety disorders and psychotic states. Parkinson-like symptoms are common side effects.

26. A Look Ahead Today’s lecture revolved around the role of “tonic” Dopamine levels as a sort of “thermostat” of activity levels in motor, cognitive and limbic loops around the brain. However, the activity of dopaminergic neurons in the SN and VTA also changes in a “phasic” manner that appears to predict how “rewarding” a particular activity is likely to be.