The Brain for NotSoDummies Osher Lifelong Learning Institute

“The Brain for Not-So-Dummies” Osher Lifelong Learning Institute NCSU Eric W. Harris, Ph. D.

Follow up/News 1. Huntington’s Disease prevalence § Worldwide `5 -10 per 100, 000 § Varies regionally: e. g. , higher in W. Eur. than Asia, very high near Lake Maricaibo § Prevalence has risen, but could be due to detection, reporting, survival. (Data from UK) Incidence seems stable (Spanish data)

Follow up/News 2. Finding a disease gene is useful: Cystic fibrosis gene found in 1989, And Kalydeco approved in 2012 for patients with certain mutations § Unfortunately not useful for patients with the most common mutation. 3. Great news about potential efficacy of drug Alzheimer’s Disease (AD), but: § Significant benefit seen in only 1 of 2 measures § Serious side-effect in subjects with Apo. E-4 gene (~40% of AD cases) § It targets amyloid – but accumulation of “tau” may be primary cause of dementia.

Interesting news…?

Week 4 - Treatment of Neurological (& Psychiatric) Disorders Treatment Modalities § Surgery § Drugs § Electrical stimulation § Cognitive/behavioral § Biofeedback § Diet

Caveat – I am not a clinician

Pain § Pain is the #1 reason for seeking medical treatment § Many types of pain (acute, chronic, visceral, migraine…) § Many causes (injury, inflammation, swelling, infection, neuropathy, MS, fibromyalgia…) § Gold-standard measurement: 10 -point “Likert Scale” § Pain is a subjective experience, with many causes and heavily influenced by many things

Assessing pain is complicated, and dependent on context Interesting studies looking in the brain (f. MRI):

Different types of pain § Nociceptive pain: signals damage or potential damage (e. g. , wound, cold…) § Neuropathic pain: results from disorders of the peripheral nervous system or the central nervous system. § Diabetic neuropathy is PNS neuropathic pain § Post-stroke neuropathic pain is CNS neuropathic pain § Many causes: radiation, injury, infection (e. g. , post-herpetic neuralgia)… § Neuropathic pain may be associated with abnormal sensations (dysesthesia), pain from normally non-painful stimuli (allodynia). Common qualities include burning or coldness, "pins and needles", numbness and itching, aching. § Not synonymous with “neuropathy” (with means a nervous system dysfunction) § Neuropathic pain is a huge unmet medical need and market…

…But first a few words about drugs § Prescription drugs, unlike most things you can buy “over the counter”, go through a very rigorous approval process § In the US, this is regulated by the FDA

BRIEF Overview of Drug Development Process

Drug approvals are based on evaluation of a lot of data This is not the case for many medical treatments or claims (e. g. , supplements, surgery, “alternative medicine”…)

Many things affect how well a drug will work for any given patient § Weight & body type § Genetics § Gender § Genetics of “target tissue” AND of “off-target” tissue § Liver and other metabolism (active metabolites? ) § Diet § Foods (e. g. grapefruit), supplements, other drugs § § Disease status Dosing time of day Compliance …

A rare (unique? ) ideal case

Drug Development - Comments § FDA-regulated drug development is a huge, demanding, but scientific process § Drug action is often not as a as simple “decreases this”, or “increases this” § No drug is perfectly “safe” in the whole human population § The drug approval process is based on trial population “benefit/risk”

Drugs for Pain § Anesthetics § E. g. , lidocaine, Novocain – block action potential propagation (via Na-channels) § Analgesics § Opioids (activate “opiod receptors” that are activated by “endorphins”) § NSAIDs (aspirin, ibuprofen, acetaminophen…) § COX-2 inhibitors (most withdrawn due to cardiovascular concerns) § Drugs for neuropathic pain § Steroids (reduce inflammation) § Neurontin (gabapentin), Lyrica (pregabalin) – interesting discovery § Antidepressnats and anticonvulsants often used for pain (e. g. , carbamazepine for trigeminal neuralgia) § May be direct effect, may be effect on mood or sleep

Drugs for Pain – help from an unlikely source… § Cone snails – very, very interesting predators (? !) § (videos) § Their venom contains numerous substances designed to do one of three things § “Taser” their prey § “Narcotioze” their prey § Paralyze their prey § One peptide in particular has found utility in the treatment of pain § Ω-conopeptide MVIIa = ziconotide = Prialt ; targets “N-type calcium channels” § Must be administered intrathecally (into the CSF around the spinal cord) § “For the management of severe chronic pain in patients for whom intrathecal therapy is warranted, and who are intolerant of or refractory to other treatment…”

Other interesting treatments for pain § “Mirror Box” for phantom limb pain • Not universally effective • Perhaps most effective for “motor” pain (e. g. , cramping) § Transcutaneous Electrical Nerve Stimulation (TENS) § Capsaicin patch Not the same 0. 1%

Parkinson’s Disease (PD) § 2 nd most common neurodegenerative disease (after Alzheimer’s) § 4 Cardinal Symptoms: § Tremor - usually starts in limb or hand, rubbing of thumb & forefinger (pillrolling); tremor of hand at rest. § Rigidity – stiffness, movement may become painful § Bradykinesia – slowed movement, dragging of feet § Postural instability – stooped, balance problem § Other common symptoms: § Loss of automatic movements –less blinking, smiling, swinging arms when walking, less gesturing when talking § Speech changes - sofy, quick, slurred; hesitating before talking; monotone § Writing changes - writing may be small (micrographia) and become difficult § Loss of sense of smell

Parkinson’s Disease - pathology Loss neurons in the Substantia Nigra (SN) that secrete dopamine (DA) SN is named for its dark pigmentation (due to neuromelanin in DA-releasing SN neurons) “Lewy Bodies”, made of the protein a-synuclein Normal PD Brown is an a-synuclein specific stain