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	Faculty
	Statement of Need
	Activity Goal
	Learning Objectives
	Target Audience
	Financial Support
	Credit Information

neuroscienceCME Journal Club

Premiere Date: Monday, October 19, 2009

This activity offers CE credit for:

1. Physicians (ACCME/AMA PRA Category 1)
2. Nurses (CNE)
3. Pharmacists (ACPE)
4. Psychologists (APA)
5. Social Workers (NASW)
6. Certified Case Managers (CCMC)

All other clinicians will either receive a CME Attendance Certificate or may choose any of the types of CE credit being offered.
Credit Expiration Date:
Tuesday, October 19, 2010

Faculty

Thomas Roth, PhD (Guest Host) Director, Sleep Disorders and Research Center Henry Ford Hospital Clinical Professor of Psychiatry University of Michigan School of Medicine Detroit, MI

Edgar Garcia-Rill, PhD (Featured Author) Director, Center for Translational Neuroscience Professor, Department of Neurobiology & Developmental Sciences University of Arkansas for Medical Sciences Little Rock, AR

Statement of Need

Evolving research in the field of sleep-wake medicine has offered insights regarding the linkage between sleep disturbances and adverse consequences related to performance, mood, behavior, and medical illness. Unremitting symptoms of excessive sleepiness related to sleep disordered breathing or circadian misalignment can have a significant impact on overall health and quality of life. As developments in the science of sleep-wake medicine emerge, there is a need to understand the implications of the data for clinical practice and for improved patient outcomes. In these interactive, evidence-based neuroscienceCME Journal Club sessions, the faculty will explore data on the genetic link to sleep loss and circadian misalignment, the impact of sleep disordered breathing on quality of life, and the neurobiology of sleep-wake control and translate the evidence into clinical insights that can improve patient outcomes.

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• Shepard JW Jr, Buysse DJ, Chesson AL Jr, et al. History of the development of sleep medicine in the United States. J Clin Sleep Med 2005;1:61-82.

Featured Article: Beck P, Odle A, Wallace-Huitt T, Skinner R, Garcia-Rill E. Modafinil increases arousal determined by P13 potential amplitude: an effect blocked by gap junction antagonists. Sleep 2008;31:1647-1654.
View Abstract

Summary: Study investigators recorded the effects of administration of modafinil on the amplitude of the sleep state-dependent auditory P13 evoked potential in freely moving rats. P13 is a measure of arousal thought to be generated by the cholinergic arm of the reticular activating system (RAS), specifically the pedunculopontine nucleus (PPN). They discovered that some cells in the PPN, involved in waking and REM sleep, and in the subcoeruleus nucleus (SubC), a descending target of the PPN involved in REM sleep, were electrically coupled. A landmark study(1) recently showed that modafinil, an agent approved for use in treating excessive sleepiness in narcolepsy, residual excessive sleepiness in patients with obstructive sleep apnea who are being treated with CPAP, and for shift work sleep disorder,(2) increased electrical coupling between cortical, reticular thalamic and inferior olive neurons. Study investigators then showed that modafinil decreased input resistance in electrically coupled PPN and SubC neurons, an effect that could be reversed by the gap junction blockers mefloquine or carbenoxolone. The study also examined the effects of modafinil on the P13 potential in the freely moving animal, the rodent equivalent of the sleep state-dependent P50 potential. The P13 is present during waking and REM sleep, but absent during slow wave sleep, in parallel with the activity pattern of PPN neurons. Modafinil was found to increase P13 potential amplitude in a dose-dependent manner, an effect that was blocked by both carbenoxolone and mefloquine.

Study investigators hypothesized that the role of such coupling may be to enhance ensemble rhythmic activity across populations of cells within each nucleus. While some individual neurons manifest intrinsic rhythmic firing properties, it is the coherence of activity across the population that would lead to the propagation of rhythms such as are involved in changes in arousal state, e.g. in the transition to waking or REM sleep. They proposed that electrical coupling is not involved in generating oscillations in individual neurons, which appear to be due to intrinsic properties and neurochemically modulated interactions, rather, gap junctions promote ensemble activation of cell populations. An audience clapping in synchrony is louder than one in which each member is clapping out of rhythm.

The implications for sleep-wake control are considerable. Most electrically coupled neurons appear to be GABAergic, which exhibit high input resistance and can be induced to fire by minimal input. If electrical coupling is increased, input resistance is shunted and these cells decrease firing, thus disinhibiting their targets, presumably the mechanism by which modafinil promotes alertness. Agents that block gap junctions include halothane, propofol, oleamide and anadamide, all of which promote sleep or anesthesia. The gap junction blockers carbenoxolone and mefloquine are both somnogenic. One possibility arising from this research is that a mechanism behind anesthesia is gap junction blockade, especially in the RAS.

Clinically, disturbances in electrical coupling can be expected to have a wide range of effects beginning with a decrement in synchronization, especially of fast rhythms such as gamma oscillations, leading to decreased alertness, such as is present in narcolepsy and other conditions inducing excessive sleepiness. In REM sleep behavior disorder, the atonia of REM sleep is absent, so that it would be interesting to determine if modafinil affects this disturbance. Similarly, restless legs syndrome may be modulated by this agent since it appears to smooth out motor dysregulation in Parkinson's disease* patients, presumably by affecting coupling in the inferior olive. Study investigators also recently found that modafinil may affect electrical coupling in spinal cord neurons since oral treatment normalized excessive reflexes induced by spinal cord transection, suggesting that this agent may be useful for the treatment of hyperreflexia* and spasticity*. (*Please note: modafinil is not currently FDA approved for the treatment of these disorders or conditions).

Electrical coupling introduces another layer of control to the manifestation of sleep-wake cycles. More generally, the finding that gap junctions modulate arousal states introduces an added mechanism by which sleep and waking may be controlled.

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1. Urbano FJ, Leznik E, Llinás RR. Modafinil enhances thalamocortical activity by increasing neuronal electrotonic coupling. PNAS 2007;104(30):12554-12559.
2. Schwartz JR. Modafinil: new indications for wake promotion. Expert Opin Pharmacother 2005;6:115-129. Available at http://www.modafinil.com/new-indications.html

Activity Goal

To translate new evidence in the literature into improved treatment of sleep-wake disorders.

Learning Objectives

At the end of this CE activity, participants should be able to:

• Link the neuronal process of electrical coupling to sleep-wake control.

The following learning objectives pertain only to those requesting CNE credit:

• Describe the physiology of electrical couple and the relationship to sleep-wake control.
• Describe the impact of medication on electrical coupling and ability to modulate arousal.

Target Audience

Physicians, physician assistants, nurse practitioners, nurses, psychologists, social workers, certified case managers, pharmacists, and other healthcare professionals interested in sleep-wake medicine.

Financial Support

CME Outfitters, LLC, gratefully acknowledges an independent educational grant from Cephalon, Inc., in support of this CE activity.

Credit Information

CME Credit (Physicians):
CME Outfitters, LLC, is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. CME Outfitters, LLC, designates this educational activity for a maximum of 1.0 AMA PRA Category 1 Credit(s)�. Physicians should only claim credit commensurate with the extent of their participation in the activity.
Note to Physician Assistants: AAPA accepts Category I credit from AOACCME, Prescribed credit from AAFP, and AMA Category I CME credit for the PRA from organizations accredited by ACCME.

CNE Credit (Nurses):
This continuing nursing education activity was approved by the New York State Nurses Association, an accredited approver by the American Nurses Credentialing Center’s Commission on Accreditation.

It has been assigned approval code 7ZEJDF-10. 1.0 contact hours will be awarded upon successful completion.

CEP Credit (Psychologists):
CME Outfitters is approved by the American Psychological Association to sponsor continuing education for psychologists. CME Outfitters maintains responsibility for this program and its content. (1.0 CE credits)

NASW Credit (Social Workers):
This program was approved by the National Association of Social Workers (provider #886407722) for 1 continuing education contact hour.

CCMC Credit (Certified Case Managers):
This program has been approved for 1 hour by the Commission for Case Manager Certification (CCMC).

CPE Credit (Pharmacists):
CME Outfitters, LLC, is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. 1.0 contact hours (0.1 CEUs)
Universal Program Number: 376-000-09-024-L01-P (Live), 376-000-09-024-H01-P
Activity type: Knowledge-based

Post-tests, credit request forms, and activity evaluations can be completed online at www.neuroscienceCME.com (click on the Testing/Certification link under the Activities tab—requires free account activation), and participants can print their certificate or statement of credit immediately (80% pass rate required). This website supports all browsers except Internet Explorer for Mac. For complete technical requirements and privacy policy, visit www.neuroscienceCME.com/technical.asp.

Disclosure Declaration

It is the policy of CME Outfitters, LLC, to ensure independence, balance, objectivity, and scientific rigor and integrity in all of their CE activities. Faculty must disclose to the participants any relationships with commercial companies whose products or devices may be mentioned in faculty presentations, or with the commercial supporter of this CE activity. CME Outfitters, LLC, has evaluated, identified, and attempted to resolve any potential conflicts of interest through a rigorous content validation procedure, use of evidence-based data/research, and a multidisciplinary peer review process. The following information is for participant information only. It is not assumed that these relationships will have a negative impact on the presentations.

Dr. Roth has disclosed that he receives grant support from Aventis, Cephalon, Inc., GlaxoSmithKline, Neurocrine Biosciences, Inc., Pfizer, Inc., Sanofi-aventis, Schering-Plough Corporation, Sepracor, Inc., Samaxon Pharmaceuticals, Inc., Syrex, Takeda Pharmaceuticals North America, Inc., TransOral Pharmaceuticals, Inc., Wyeth Pharmaceuticals, and XenoPort, Inc. He serves as a consultant to Abbott Laboratories, Acadia Pharmaceuticals Inc., Acoglix, Acorda Therapeutics, Actelion, Addrenex Pharmaceuticals, Inc., Alchemers, ALZA Corporation, Ancil, Arena Pharmaceuticals, AstraZeneca Pharmaceuticals LP, Aventis, AVER, Bayer, Bristol-Myers Squibb Company, BTG, Cephalon, Inc., Cypress Pharmaceutical, Inc., Dove Pharmaceuticals, Eisai Pharmaceuticals, Elan Pharmaceuticals, Inc., Eli Lilly and Company, Evotec Inc., Forest Laboratories, Inc., GlaxoSmithKline, Hypnion Inc., IMPAX Laboratories, Inc., Intec Pharma, Intra-Cellular, Jazz Pharmaceuticals, Johnson & Johnson Pharmaceutical Research & Development, L.L.C., King Pharmaceuticals, Inc., H. Lundbeck A/S, McNeil, MediciNova, Inc., Merck & Co., Inc., Neurim Pharmaceuticals, Neurocrine Biosciences, Inc., Neurogen Corporation, Novartis Pharmaceuticals Corporation, Orexo AB, Organon International, Otsuka America Pharmaceutical, Inc., Prestwick Pharmaceuticals, Inc., Proctor & Gamble, Pfizer, Inc., Purdue Pharma L.P., Resteva, Roche, Sanofi-aventis, Schering-Plough Corporation, Sepracor, Inc., Servier, Shire Pharmaceuticals, Somaxon Pharmaceuticals, Inc., Syrex, Takeda Pharmaceuticals North America, Inc., TransOral Pharmaceuticals, Inc., VANDA Pharmaceuticals, VivoMetrics, Wyeth Pharmaceuticals, Yamanouchi Pharma America, Inc., and XenoPort, Inc. He is on the speakers bureau for Cephalon, Inc., Sanofi-aventis, and Takeda Pharmaceuticals North America, Inc.

Dr. Garcia-Rill has disclosed that he receives grant support from the National Institutes of Health.

Unlabeled Use Disclosure

Faculty of this CE activity may include discussions of products or devices that are not currently labeled for use by the FDA. The faculty have been informed of their responsibility to disclose to the audience if they will be discussing off-label or investigational uses (any uses not approved by the FDA) of products or devices.

CME Outfitters, LLC, the faculty, and Cephalon, Inc., do not endorse the use of any product outside of the FDA labeled indications. Medical professionals should not utilize the procedures, products, or diagnosis techniques discussed during this activity without evaluation of their patient for contraindications or dangers of use.

Questions about this activity? Call us at 877.CME.PROS (877.263.7767).

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