1. Recall the neuronal circuitry change in PD Normal Parkinson’s

2. Risk Factors for Parkinson’s Diseases (PD)  Age  Incidence 1% >60 years of age, only 0.01% <45 years of age  Genetics  More men than women (2:1) – could be genetic, could be hormonal  15 -25 % of patients have a relative with PD (suggestive of genetic factor)  Several mutations associated with PD (but is only a minority of cases)  α-Synuclein mutation – “causative” gene  LRRK2 mutations – “associated” gene (i.e., risk factor)  “parkin” gene mutation  juvenile onset (no Lewy bodies, so not typical PD)  Environmental?  Earliest identified risk factor was use of well-water  At least two pesticides (rotenone and paraquat) associated with increased risk  Intravenous drug use in some cases…

3. Parkinsonism – Symptoms and Signs like PD, but another cause Great NOVA show Encephalitis lethargica (“Von Economo’s Disease)

4. PD - Prognosis  PD is chronic and progressive, but quite variable  Many treatments available or under investigation (more about that in Week 8)  Drugs, but side-effects can be limiting  Surgery - not without risks  Electrical simulation of the brain - not without risks  Cell implants (e.g., stem cells) – still under investigation  No cures available yet  Caffeine may be protective  Smoking associated with lower PD risk (NOT suggesting it is healthful overall!)

5. Drugs for PD  DA-releasing cells are lost – so just give DA?  DA does not cross the “blood-brain barrier” (BBB)!  An anatomical and physiological “barrier” between the blood and the CNS  DA has unwanted peripheral effects  Arvid Carlsson: give the “precursor” of DA? (L-DOPA)  Crosses BBB – good!  But is converted into DA peripherally – side effects.  “Sinemet”  L-DOPA + carbidopa, a drug that blocks conversion of L-DOPA into DA and that doesn’t cross the BBB (blood) (brain)

6. Electrical Stimulation – for PD  Electrode = insulated wire  Electrodes are implanted through a hole in the skull into specific brain regions  Stimulation is achieved by pairs of electrodes used to pass electrical current to modulate the activity nearby  Often called “Deep Brain Stimulation’ (DBS)

7. Deep Brain Stimulation for Parkinson’s Disease Normal Parkinson’s

8. Cell Implant Therapy - PD  DA-releasing cell implant therapy for PD  From adrenals  From fetal embryonic cells  Much less successful in man than in animal models.  Difficult procedure, cells tend to die, like the Substantia Nigra cells before them  May need at least 100,000 embryonic cells to get benefit (equivalent to 3-5 embryos)  Stems cell implants – promising, but not yet ready for clinical trials  “Gene implant therapy”  Use a virus to infect cells and turn them into DA-releasing cells  Good safety profile  Moderate success in a minority of patients  Though in a minority, benefit is enduring

9. Epilepsy  Disorder of “neuronal firing”, characterized by “seizures”  “Hypersynchrony”- starts in one area disrupting its function, and can spread to other areas  Causes strange sensations, uncontrollable movements, loss of consciousness.  Sometimes generalized seizures are preceded by the experience of an “aura”  Chronic condition; seizure durations and frequency of occurrence vary widely  Many causes:  Trauma, tumor, genetics, neonatal hypoxia, error in normal development, systemic disease…  Important to control because seizures can grow in severity (“kindling effect”)  Epileptic events can get more intense each time they are triggered

10. Epilepsy – having “seizures” Representative EEG Of Generalized Seizure

11. Focal Seizure

12. Types of Epilepsy  Simple partial  Partial Complex  Primary generalized  Absence

13. Surgical treatment – e.g., epilepsy  The brain itself has no “pain sensors” (free nerve endings, nociceptors)  There are nociceptors on the tissues surrounding and protecting the brain, and on blood vessels in those structures.  Often done while patient is awake to identify areas to not disturb (e.g., involved in vision, speech, movement)

14. Brain surgery for epilepsy  Usually used for:  Drug-resistant, dire cases  Partial onset seizures  Usually either:  Resection of seizure focus (“trigger zone”)  Correction of a “structural problem” (e.g., circulatory abnormality)  Cutting fibers along which the seizure spreads  E.g., copus callosotomy = “split brain”

15. Drugs: Epilepsy – just getting there is not always enough  Seizures are caused by neuronal hypersynchronicity/hyperactivity  The challenge is how to prevent hyperactivity without interfering with normal activity  This is why many anticonvulsants exhibit “use-dependence”

16. Drugs for Epilepsy - Use-Dependence No drug With drug Action potentials Electrical stimulation of neuron (time  )

17. Ketogenic Diet for Epilepsy  used primarily to treat difficult-to-control (refractory)epilepsy in children.epilepsy  Children with a focal lesion (a single point of brain abnormality causing the epilepsy) who would make suitable candidates for surgery are more likely to become seizure-free with surgery than with the ketogenic diet. [10][31] lesionsurgery [10][31]  Long-term use of the ketogenic diet in children increases the risk of slowed or stunted growth, bone fractures and kidney stones. [6kidney stones [6

18. Neurofeedback  Like Biofeedback (e.g., for reducing blood pressure”, but feedback is dependent on modulating specific features of real-time EEG  Like “brain training” only based on EEG rather than behavior  “Technologically-assisted meditation”?  The ultimate in individualized medicine?  Is diagnosis by brain function rather than by symptoms  It is well-established that one can modulate EEG this way…  BUT, clinical efficacy is not well established for most of the claims.  Best evidence is in ADHD…

19. Some things that are good for every neuro/psych disorder  Sufficient good quality sleep  Good quality nutrition  Physical exercise  Meditation / relaxation  Mental exercise (not just “use it”, but “push it”)  Drug dosing optimization  Dose, time of day, with or without food, avoid “food/drug interactions”  Being your own best advocate  Read, surf, go to meetings, participate in trials…ask questions!