“The Brain for Not-So-Dummies”Osher Lifelong Learning InstituteDuke Continuing StudiesDuke University

Eric W. Harris, PhD.

Follow-up from last week

Dyslexia – equally common in boys and girls

More common in left-handers Slightly more left-handed boys than girls (11% vs 9%)

Follow-up from last week

Interesting area for research in potential treatment of AD…. In the heart, brain, muscles and almost every other tissue examined, the blood of young mice

seems to bring new life to ageing organs, making old mice stronger, smarter and healthier. It even makes their fur shinier.

Aged blood also impaired young mice Some potential specific targets already identified:

The growth factor GDF11 is reduced in aged mice, has rejuvenative effects on its own Converselythe cytokine CCL11 is elevated in aged mice, impairs adult neurogenesis

Clinical trial of young blood in mild to moderate AD underway…!

blood from young, healthy people!?

Week 8 - Treatment of Neurological & Psychiatric Disorders

Treatment Modalities

Surgery

Drugs

Electrical stimulation

Cognitive/behavioral

Neurofeedback

Diet

Surgical treatment – e.g., epilepsy

But first: A few words about brain surgery A few words about epilepsy

Surgical Treatment - Brain surgery

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)

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

Representative EEG

How neurosurgeons identify what regions trigger seizures

Epileptiform activityIndicative of an“epileptic focus”

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., corpus callosotomy => “split brain”

Drugs for brain disorders

But First:

A few words about the process of drug development…

Drugs – 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 Of the “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

No drug is perfectly “safe” in the whole human population

The drug approval process is based on trial population “benefit/risk”

Drug action is often not as a as simple “decreases this”, or “increases this”

Drugs - Parkinson’s Disease (but first a quick review about PD)

Caused by loss of dopaminergic (dopamine-releasing) neurons

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)

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, Example 1

No drug

(

With drug

Action potentials

Electrical stimulation of neuron

(time )

And often just one effect is not enough - Antipsychotics

Recall the neuronal circuitry change in PD

Lightning bolts=sites at which stimulationmight restore balance

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)

Other types of “Neuromodulation”

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 SNC cells before them

May need at least 100,000 embryonic cells to get benefit (equivalent to 3 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

“Gene Therapy” for PD (“gene implant therapy”)

Use a virus to implant the gene for making neurotransmitter, or growth factors “viral vector therapy”

Early days, but good safety profile, efficacy in a minority, but is enduring (~2-4 years so far)

Cognitive Behavior Therapy / Dialectical Behavior Therapy Different from psychotherapy

Does not focus on the “why” of mood or cognitive problem Focuses on how to deal with mood or cognitive problem

Focus is on identifying problem thoughts and behaviors, and tools: “coping ahead”, identifying and avoiding “triggers”, formats for effective

communication, self-soothing etc.

Useful for a variety of disorders, including mood and anxiety disorders, personality disorders, substance abuse disorders, sleep disorders and psychotic disorders.

Can be helpful for “neurologically typicals” too

CBT found to alter EEG changes during anxiety-producing situations

DBT is a modification of CBT designed to improve acceptance, particularly with Borderline Personality Disorder patients, incorporates “mindfulness”

Attention Deficit Hyperactivity Disorder (aka ADD)

Begins in early childhood, usually persists into adulthood

Boys (13.2%) were more likely than girls (5.6%) to have ever been diagnosed with ADHD.

Children with an ADHD diagnosis increased, from 7.8% in 2003 to 9.5% in 2007 and to 11.0% in 2011.

But – criteria have changed over time, treatment options have changed, stigma has changed

ADHD Treatment

Drugs can work okay Several options: stimulants (amphetamines, Ritalin), Strattera, others Some evidence of small reduction in growth Some concern about dependence, not “fixing the problem” However, brains of medicated ADHD look more “normal” than unmedicated

Neurofeedback is quite promising Presumed to produce a lasting “fix” rather than “provide a crutch” Seems to lack the side effects of drugs

Lack of standardized, intensive safety reporting as is required for drugs Expensive – varying degrees of reimbursement by insurance

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…

Meta-Analysis of Efficacy of Neurofeedback in ADHD

Diet for brain disorders

Ketogenic diet for epilepsy High-fat, low carb diet – used mostly in children poorly-controlled by drugs

Increasing evidence that, for example, gluten sensitivity can, in a minority of people, cause any of a variety of symptoms that resolve with diet change

I am not suggesting that everyone needs to or even should go “grain free” My point is that diet should always be considered as a possible contributor to hard to

diagnose brain disorders

Treating brain disorders – there are many optionsBe an informed and involved consumer

Thank you for your attention

Questions? Comments?