Recall the neuronal circuitry change in PD

Normal Parkinson’s

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…

Parkinsonism – Symptoms and Signs like PD, but another cause

Great NOVA show

Encephalitis lethargica (“Von Economo’s Disease)

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!)

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)

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)

Deep Brain Stimulation for Parkinson’s Disease

Normal Parkinson’s

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

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

Epilepsy – having “seizures”

Representative EEGOf Generalized Seizure

Focal Seizure

Types of Epilepsy

Simple partial

Partial Complex

Primary generalized

Absence

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)

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”

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”

Drugs for Epilepsy - Use-Dependence

No drugWith drug

Action potentials

Electrical stimulation of neuron

(time )

Ketogenic Diet for Epilepsy

used primarily to treat difficult-to-control (refractory)epilepsy in children.

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]

Long-term use of the ketogenic diet in children increases the risk of slowed or stunted growth, bone fractures and kidney stones.[6

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…

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!