Transcript File - The Brain for Not-so

“The Brain for Not-So-Dummies”
Osher Lifelong Learning Institute
Duke Continuing Studies
Duke 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…. blood from young, healthy people!?
 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…!
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 activity
Indicative 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
Electrical stimulation of neuron
Action potentials
(time )
With drug
No drug
(
And often just one effect is not enough - Antipsychotics
Recall the neuronal circuitry change in PD
Lightning bolts=
sites at which stimulation
might 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 options
Be an informed and involved consumer
Thank you for your attention
Questions? Comments?