Dextromethorphan/Quinidine Alleviates Pseudobulbar Affect and Rapidly Eliminates Suicidal Ideation...

FUNCTIONAL NEUROLOGY, REHABILITATION, AND ERGONOMICS

Volume 4, Number, 4, 2014

TABLE OF CONTENTS

Editorial - Mind Your Own Business 247 Gerry Leisman

Dextromethorphan/Quinidine Alleviates Pseudobulbar Affect and Rapidly Eliminates Suicidal Ideation in Individuals with Traumatic Brain Injury 253

JL Fellus, PA DeFina, CM Carson, C Machado, and M Chinchilla

68-Year-Old Female with Apallesthesia Improved through Brain-Based Rehabilitation: A Case Study 265

David Traster

IAFNR News and Events 275

Literature Calling: A Survey of Recent Publications of Interest to Functional Neurology 297

New York

Journal of

Functional Neurology, Rehabilitation, and Ergonomics

The Official Journal of the International Association of Functional Neurology and Rehabilitation

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Editor-In-Chief

Gerry Leisman Nazareth, Israel Karmiel, Israel

Co-Editor-In-Chief

Robert Melillo Rockville Centre, NY USA

Assistant Editor - Production

Janet Groschel Gilbert, AZ USA

Editorial Board Members

Sergio Azzolino San Francisco, CA USA

Randy Beck

Perth, Australia

Paul Berger-Gross Bayside, NY USA

Eti Ben-Simon Tel-Aviv, Israel

John A. Brabyn

San Francisco, CA USA

Orit Braun-Benjamin Karmiel, Israel

Lynn M. Carlson

West Springfield, MA USA

Emmanuel Donchin Tampa, FL USA

Andrew L. Egel

College Park, MD USA

Khosrow Eghtesadi West Palm Beach, FL USA

Newton Howard Cambridge, MA USA

Megan L. Hudson

West Springfield, MA USA

Efraim Jaul Jerusalem, Israel

Datis Kharrazian

Carlspoor, CA USA

Samuel Landsberger Los Angeles, CA USA

Calixto Machado

Havana, Cuba

Joy MacDermid Hamilton, Ontario Canada

Joav Merrick

Jerusalem, Israel

Raed Mualem Nazareth, Israel

Paul Noone

Hampton E. Victoria, Australia

Jackie Oldham Manchester, UK

Chandler Phillips Dayton, OH USA

Anthony L. Rosner

Boston, MA USA

Peter Scire Peachtree City, GA USA

Fredric Schiffer Boston, MA USA

Suryakumar Shah Scottsdale, AZ USA

Joseph Weisberg

Great Neck, NY USA

Leslie Weiser Boston, MA USA

Seung Won Lee Seoul, S. Korea

Funct Neurol Rehabil Ergon 2014;4(4):247-252 ISSN: 2156-941X © Nova Science Publishers, Inc.

EDITORIAL - MIND YOUR OWN BUSINESS

Gerry Leisman Editor-in-Chief FNRE The National Institute for Brain and Rehabilitation Sciences, Nazareth, Israel O.R.T.-Braude College of Engineering, Karmiel, Israel Universidad de Ciencias Médicas de la Habana, Facultad Manuel Fajardo

[email protected]

My now deceased friend and colleague, Dr. Ze’ev Hed and I concocted this scheme to be able to measure disease by sound. This, we thought, was the “hottest thing since sliced bread.” And it actually was!! We could tell the difference between a cyst, polyp, and tumor in the large bowel, a knee injury with or without a torn meniscus with or without fluid all purely on the basis of sound. So, we discovered that a military aircraft manufacturer had done a similar thing independently of us, with obviously different applications. Smart as we were, we went to the new business development office of the company in question with the idea of forming a partnership to run with the independently developed concept jointly. They agreed and the larger company’s president cut the project on the spot. He said, “We are not in the medical business and although there are millions to be made, we don’t understand the nuances of the medical marketplace and should not be in the business even after paying for consultants.” This very wise man was right!

Also, years ago my former mentor, and Editor-in-Chief of a prestigious journal in the Neurosciences, published a paper in his journal by clinical researchers at the University of Thrace, Greece on the effects of magnetic fields in the treatment of epileptic foci. [1] The authors mistakenly used the word “cure” in the title of their paper and the editor unfortunately let the bad word slide. The data, however, was replicable. That should have ended the problem. Scientific orthodoxy, unfortunately stepped in to the picture. The journal Science, the flagship world-renowned publication of the American Association for the Advancement of Science, dispatched a reporter to interview the “opinions” of “mavens” in the neuroscience who of course had not examined the data of the group in Greece. These guys were just rendering opinions stated as facts and the journal Science was now the arbiter of scientific orthodoxy without replicating published results and additionally

Gerry Leisman 248

one might also ask what business was it of theirs anyway to deal with the editorial policy of another journal. True, there was not ample data in the paper to allow for appropriate replication and a comment or letter to the editor of the journal should have sufficed. Data from the authors could also have been obtained. The tools of science, however should have sufficed. Those tools were not used. [2]

One needs to know what one’s business is and what it is not.

So, without ranting on, I am partly reproducing here a report from the blog “Honest Reporting” summarizing issues about the Lancet’s editorial policy that I think clearly and succinctly indicates the problem of “Editorial Bias” and we, like the company above, should “Mind our OWN Business.” After reading the excerpt from the blog, please find a letter from the Editor of the esteemed medical journal the Lancet. Please make of it what you wish and as usual, get in touch with your comments and thoughts.

While I think that it is inappropriate for an editor of a medical or scientific journal to play politics through editorial policy, you will note below that conflicts of interests were ignored by the editor of the Lancet allowing biased reports to appear within his pages thereby diminishing the glorious history of the Lancet and the veracity of the papers themselves. The editor relents at the end. The following is an example of why we as science editors should “Mind Our Own Business.”

Each year, the UK medical journal, The Lancet, publishes a series of special reports exploring health conditions in the Palestinian territories. The journal is regarded as a prestigious publication and submitted articles are peer reviewed and indexed in PubMed among other indexing sources [see 3].

The Lancet’s 2013 report contains some 35 contributions, most of which, at first glance, appear to deal with quantifying genuine medical issues without unwelcome politicization. A closer look, however, reveals that the journal is still tainted with anti-Israel bias.

In 2010, the journal employed active supporters of the boycott, divestment and sanctions (BDS) campaign against Israel as supposedly expert commentators on the situation.

The history of politicization of science for political ends is long, and sadly, destructive. [see 4].

Formerly credible medical media outlets such as the British Medical Journal have drifted away from scientific exploration to scientific exploitation, particularly when concerned with the Israeli-Palestinian conflict. The Lancet describes itself as “one of the world’s leading medical journals” and claims an online registration of some 1.8 million users. On July 2, 2010, it published the “best peer-reviewed abstracts” from a meeting of the 2nd Lancet-Palestinian Health Alliance Conference. A cornerstone of most peer-reviewed journals is freedom from bias. No conference or article today can be promoted or published without a clear declaration of conflict of interest by its authors or promoters. No such declarations are published in The Lancet series.

A medical background is no guarantee of objectivity or lack of bias when it comes to the Israeli-Palestinian conflict. After all, some of the Hamas leadership such as Mahmoud al-Zahar and the late Abdel Aziz Rantisi were medical professionals.

Some research into the background of contributors to The Lancet’s articles reveals some disturbing information and calls into question the credibility of the content, particularly as most of those below are active supporters of the boycott, divestment and sanctions (BDS) campaign against Israel.

Weamm Hammoudeh: Testified at the US trial of her own brother, indicted for providing material support for a terrorist organization. The indictment included Hammoudeh’s Florida school where she studied, which was believed to be a front for supporting Islamic Jihad. While Hammoudeh’s brother was eventually acquitted, he and other members of the family were deported from the US after Immigration and Customs Enforcement said they believed that “Hammoudeh had ties to terrorists,” despite his acquittal.

Rita Giacaman: The co-author of three of the featured articles has appeared on a panel with none other than Noam Chomsky, railing (somewhat ironically considering the contents of this communiqué) at the power of pro-Israel lobby groups silencing criticism of Israel in medical journals. [see 5] She co-authored a report [6] on the effect on

Editorial 249

Palestinian living conditions during Israel’s 2002 Operation Defensive Shield, concluding “What this population experienced in this unilateral war cannot be justified simply by the prerogative of Israeli security, and can only point to a more insidious purpose for the re-invasion, a purpose that in the Palestinian experience, could only have been the destruction of the structures and framework for the survival and the social development of the Palestinian nation.” She also authored a 2005 paper in Nature magazine entitled “A boycott could do good in Israel, as in South Africa.” [7]

Majdi Ashour: During his time as a student in the US, was a supporter of the Third Annual Palestine Solidarity and Divestment Conference at Rutgers, and a signatory to a petition [8] that spoke of the Palestinian fight “against apartheid all over historic Palestine occupied in 1948″ and “ethnic supremacy and pursuit of purity” being carried out by Israel.

David Henley: On the Board of Advisors to the Gaza Community Mental Health Programme,[9] described by NGO Monitor [9] as politically biased, attributes social problems in Gaza only to the Israeli “occupation,” and ignores intra-Palestinian violence and corruption. It is involved in political campaigning: has signed petitions for economic [10] and academic boycotts of Israel [11] and on November 12, 2005, GCMHP hosted a delegation of European Parliamentarians [12] and described to them the “psychological violence” waged by Israel in Gaza and claimed that “the disengage-ment was a mirage to be consumed by the Western Media.”

Rika Fujiya: Listed as the contact for a Tokyo event as part of a global mobilization of the Palestinian Grassroots Anti-Apartheid Wall Campaign.[13]

Espen Bjertness: Co-author of five of the featured articles, is a prominent supporter [14] of an academic boycott of Israel in Norway and was a signatory to a petition [15] in support of boycotts, divestment and sanctions of Israel calling “upon all those

who oppose occupation, apartheid, ethnic cleansing, and war crimes.”

Gerd Holmboe-Ottesen, Co-author of two of the featured articles, was also a signatory to the same petition [15] in support of boycotts, divestment and sanctions of Israel as described above.

Abdullatif Husseini: Co-authored a report [6] on the effect on Palestinian living conditions during Israel’s 2002 Operation Defensive Shield, concluding “What this population experienced in this unilateral war cannot be justified simply by the prerogative of Israeli security, and can only point to a more insidious purpose for the re-invasion, a purpose that in the Palestinian experience, could only have been the destruction of the structures and framework for the survival and the social development of the Palestinian nation.”…

Judy Makhoul: Signatory to the Lebanese academic boycott [16] of Israel which calls on “our colleagues worldwide to support the call by the Palestinian Campaign for the Academic and Cultural Boycott of Israel to comprehensively and consistently boycott and disinvest from all Israeli academic and cultural institutions, and to refrain from participation in any form of academic and cultural cooperation, collaboration or joining projects with Israeli institutions as a contribution to the struggle to end Israel’s occupation, colonization and system of apartheid.”

Sawsan Abdulrahim: Signatory to a 2006 statement [17] criticizing the Lebanese government for not embracing the “Lebanese Resistance Operation” – code for Hezbollah. Also a signatory to the Lebanese academic boycott of Israel as described above.

Angelo Stefanini: Signatory to a 2009 petition [18] calling for the removal of Israeli Dr. Yoram Blachar as head of the World Medical Association and a 2009 petition [19] calling on the University of Trondheim to boycott Israel.

Gerry Leisman 250

Misinformation and Bias Indeed, the overall impression that The Lancet

seeks to bring can be summed up by an article [20] that states:

On Feb 28, the day that international contributors to the conference were arriving in Ramallah, hundreds of Israeli settlers, escorted by Israeli security forces, stormed the Al-Aqsa Mosque in East Jerusalem. There was tension in the air; the smell of violence everywhere; and denial or restricted access from one part of the West Bank to another and to East Jerusalem. Of course, there was no such incident as a storming of the Al-Aqsa Mosque by anyone let alone “hundreds of Israeli settlers”. Another article states [21]: “1400 people were estimated to have died, and many were injured during the Israeli attack on the Gaza Strip, occupied Palestinian territory, from Dec 27, 2008, to Jan 18, 2009; and the destruction of infrastructure, including homes, was unprecedented.” Even without addressing the fact that the report

ignores that terrorists were part of the estimated number of casualties, have the authors forgotten that Israel withdrew from Gaza in 2005? How can it be described as “occupied Palestinian territory”?

This same mistaken description appears again in another article under the emotive title “Women in labour and midwives during Israeli assault on Gaza Strip: between bullets and labour pains“: [22] We report the personal accounts of childbirth experiences and coping skills of women and midwives during the 23 days of the Israeli assault on the Gaza Strip, occupied Palestinian territory, in December, 2008, and January, 2009. This article also includes allegations lacking in context from so-called “eyewitnesses” that do not belong in a credible medical study: As one woman said “nights were like ‘ghouls’…I was not thinking like other people in face of death or shelling…but was only thinking of my case! What would happen if I had labor pains at night? How will I manage? They were shelling even ambulances!”

Another outrageous claim that “pregnant mothers were denied access to hospitals for birth care”

appears in a related article. [23] While freedom of Palestinian movement has been restricted due to legitimate Israeli security concerns (context that is not mentioned in any of the reports), it is simply disingenuous to imply that Israel has deliberately withheld healthcare for pregnant Palestinian women. Indeed, one is left with the overall impression from many of the articles that deficiencies in Palestinian health are purely Israel’s fault as this article [24] suggests:

One of the most important achievements in Palestinian science was the publication of five reports from the ICPH in The Lancet 2009 Series Health in the Occupied Palestinian Territory. This Series showed that Palestinian right to health was compromised because of Israeli occupation (squeezed economy, movement restrictions, spread of fear, uncertainty, insecurity), and confirmed adverse health effects due to occupation and systematic and avoidable differences in health implying health inequity.

Omissions and Lack of Context The above examples are but a tiny sample of how

this large number of articles combines to create an overall bias against Israel. Also notable is what has been omitted from the articles. There is no mention of:

The vehicles and uniforms as cover for

terrorist operations during Operation Cast Lead, in clear violation of the Law of Armed Conflict. This included the extensive use of ambulances bearing the protective emblems of the Red Cross and Red Crescent to transport operatives and weaponry; the use of ambulances to “evacuate” terrorists from the battlefield; and the use of hospitals and medical infrastructure as headquarters, situation-rooms, command centers, and hiding places.

The number of Gazans coming into Israel for medical treatment.

No acknowledgement of the fact that there were terrorists amongst those killed during Operation Cast Lead.

Editorial 251

No mention of Israeli humanitarian aid to Gaza both during and after military operations.

No mention of Hamas or Palestinian rocket and terror attacks.

Calling on Doctors to Take Action Anti-Israel bias should have no place in medical

journals. Getting an article or study published in such places as The Lancet is supposedly extremely difficult and subject to intense scrutiny through peer-review.

Why is it that the bar is lowered to allow the publication of articles by medical professionals and others who have clearly demonstrated a politicized anti-Israel agenda that goes way beyond the field of medicine?

If you are a certified medical professional, please

contact The Lancet’s Ombudsman, Charles Warlow – [email protected]

Having read all of this, the Editor-in Chief on the

Lancet recently paid a visit to Israel and this is what he reported on 11 October 2014 [25].

The abstract follows [25] and the full report is to

be found at the following link and the abstract reproduced below:

http://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2814%2961782-7/fulltext

The Lancet, Volume 384, Issue 9951, Page 1332, 11 October 2014

doi:10.1016/S0140-6736(14)61782-7 Copyright © 2014 Elsevier Ltd All rights reserved.

Offline: People to people Richard Horton “Last week was a turning point in the sometimes angry debate that followed publication of a letter from Paola Manduca and colleagues during the recent war in Gaza and southern Israel. Among the many responses we received, one quite different letter stood out. Professor Karl Skorecki, Director of the Rappaport Research Institute at Technion and

Director of Medical Research and Development at the Rambam Health Care Campus in Haifa, wrote to invite me to Israel “because of the intense interest that the editorial leadership of The Lancet has attracted, focusing on issues of medical professional responsibility and accountability for the tragic loss of life and human suffering of Gaza civilians including children”. I visited Rambam last week thanks to the hospitality—and courage—of Prof Skorecki, Prof Rafael Beyar (Director-General of the Rambam Health Care Campus), and Prof A Mark Clarfield (Director, Medical School for International Health, Ben-Gurion University). At Rambam I saw an inspiring model of partnership between Jews and Arabs in a part of Israel where 40% of the population is Arab. I saw Rambam offering an open hand, gladly grasped by families from Gaza, the West Bank, and Syria, who were living with life-threatening health-care needs. I saw Rambam as one example of a vision for a peaceful and productive future between peoples, which I learned exists throughout Israel's hospitals. I also met Israel's Minister of Health, Yael German, who not only endorsed this visit but also welcomed future collaboration. Out of this exchange has emerged an extraordinary opportunity.” I have nothing more to say and welcome your

comments.

References

[1] Anninos PA, Tsagas N. Localization and cure of epileptic foci with the use of MEG measurements. Int J Neurosci. 1989;46(3-4):235-242.

[2] Leisman G, Koch P, Zemcov A, Ze’ev Hed A, Arcidiacono T, Zenhausern R, Tefera T, Altchek E, Vitori R, Leisman D, Eugenio L. Biomagnetism, Big Science, Political Science, and Fisticuffs. Int J Neurosci. 1990;55:147-149.

[3] Honest Reporting [website http://honestreporting.com /the-lancet-injecting-politics-into-medicine/] downloaded 28 October 2014.

[4] Honest Reporting [website http://honestreporting.com /israel-skewered-by-medical-journal-2/] downloaded 28 October, 2014.

[5] Youtube. [https://www.youtube.com/watch?v=sFOEsOV13kc] downloaded 28 October, 2014.

Gerry Leisman 252

[6] Giacaman R, Husseini A. Shattern lives. Cairo: al-Ahram [http://weekly.ahram.org.eg/2002/588/re10.htm] downloaded 28 October 2014.

[7] Giacaman R, Sfeir J, al-Shakhshir I. A boycott could do good in Israel, as in South Africa. Nature. 2005; 435:736 (9 June 2005) | doi:10.1038/435736d; Published online 8 June 2005.

[8] [http://www.iacenter.org/Palestine/palest-div.htm] downloaded 28 October, 2014

[9] [http://www.ngo-monitor.org/article/gaza_community_mental_health_programme_gcmhp_0]downloaded 28 October 2014.

[10] [http://www.pacbi.org/etemplate.php?id=66] downloaded 28 October 2014.

[11] [http://www.al-awda.org/academicboycott.html] downloaded 28 October 2014.

[12] [http://www.pchrgaza.org/Library/gcmhp11-05.htm] downloaded 28 October 2014.

[13] [http://www.stopthewall.org/] downloaded 28 October 2014.

[14] [http://www.uniforum.uio.no/nyheter/2009/01/vil-ha-akademisk-boikott-av-israel.html]downloaded 28 October 2014.

[15] [http://www.pchrgaza.org/special/call.htm] downloaded 28 October 2014.

[16] [http://boycottzionism.wordpress.com/] downloaded 28 October 2014.

[17] [http://www.engageonline.org.uk/blog/article.php?id=601] downloaded 28 October 2014.

[18] [http://www.bricup.org.uk/documents/medical/BlacharWMA.pdf] downloaded 28 October 2014.

[19] http://www.ccun.org/Opinion%20Editorials/2009/November/21%20o/Petition%20To%20Board%20of%20Directors%20of%20the%20University%20of%20Trondheim%20Voting%20to%20Academically%20Boycott%20Israel%20By%20Mohamed%20Khodr.htm] downloaded 28 October 2014.

[20] [http://download.thelancet.com/flatcontentassets/pdfs /palestine/S0140673610610318.pdf] downloaded 28 October 2014.

[21] [http://download.thelancet.com/flatcontentassets/pdfs /palestine/S014067361060846X.pdf] downloaded 28 October 2014.




[25] [http://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2814%2961782-7/fulltext] downloaded 28 October 2014.


DEXTROMETHORPHAN/QUINIDINE ALLEVIATES

PSEUDOBULBAR AFFECT AND RAPIDLY ELIMINATES SUICIDAL

IDEATION IN INDIVIDUALS WITH TRAUMATIC BRAIN INJURY

JL Fellus1, PA DeFina1, CM Carson1, C Machado2, and M Chinchilla3 1International Brain Research Foundation 2Institute for Neurology and Neurosurgery, Havana, Cuba 3 Hermanos Ameijeiras Hospital, Havana, Cuba

Correspondence: Christine M Carson, International Brain

Research Foundation, 227 Route 206 North; Building 2, Suite 101, Flanders, NJ 07836 E-mail: [email protected]

Abstract Recent prevalence estimates of pseudobulbar affect (PBA) symptomatology secondary to traumatic brain injury (TBI) exceed 55%. Treatment with dextromethorphan/quinidine (DMQ) has been shown to robustly diminish the frequency and severity of PBA episodes associated with different neurological conditions. Objective. This retrospective case study aims to demonstrate the efficacy of DMQ to minimize PBA symptoms in a series of patients with traumatic brain injury (TBI) and describe unforeseen evidence of its additional therapeutic potential to mitigate diverse neuropsychiatric sequelae. Methods. The case histories of five patients were reviewed according to the clinical observations of their neurologist (JLF). Five patients sustained TBI an average of nine years prior, presenting with a stable history of PBA and frequent suicidal ideation. DMQ therapy was indicated for all five patients to ameliorate paroxysmal episodes of laughter, crying or both. Results. The results of this clinical case study confirm DMQ as a potent treatment for PBA and reveal its potential to ameliorate additional neuropsychiatric behaviors associated with TBI. Surprisingly, concomitant suicidal ideation and associated impulsivity were discovered to rapidly resolve following treatment with DMQ. Conclusions. The rapid onset and sustained tolerability of DMQ suggest it deserves consideration as an alternative to conventional pharma-cotherapies for managing PBA, suicidal ideation and associated impulsivity. DMQ therapy holds promise to significantly reduce morbidity and mortality, profoundly enhance quality of life and fundamentally improve long-term outcome for TBI survivors.

JL Fellus, PA DeFina, CM Carson et al.

254

Keywords: Pseudobulabar effect, Dextromethorphan/quinidine, TBI, Dementia Disclosures: JLF has been a consultant for, member of the Speaker's Bureau and is a current shareholder of Avanir Pharma-ceuticals. PAD and CMZ do not have affiliations with or financial interest in any organization that might pose a conflict of interest. CM and MC do not have affiliations with or financial interest in any organization that might pose a conflict of interest.

Introduction According to the classic definition, pseudobulbar

affect (PBA), emotional lability, labile affect or emotional incontinence refers to a neurologic disorder characterized by involuntary or uncontroll-able episodes of crying and/or laughing, or other emotional displays. [1-10] The pathophysiology of various neurological conditions compromises pathways that regulate emotional expression and produces emotional outbursts that are contextually inappropriate or exaggerated relative to underlying mood states. [11] Typically, an intact network inhibits contextually inappropriate behaviors and regulates affect such that it is proportional to the intensity of the emotional experience. [8, 12] PBA is distinct from disorders of mood. Sometimes termed “emotional incontinence” or “pathological laughter and crying”, PBA reflects a disabling state of mood-incongruent affect. [11]

PBA is most commonly observed in people with neurologic injuries such as traumatic brain injury (TBI) and stroke, and neurologic diseases such as dementias including Alzheimer's disease, multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), Lyme Disease, PANDAS in children and adults, and Parkinson's disease (PD). [13-17] PBA has also been observed in association with a variety of other brain disorders, including brain tumors, Wilson’s disease, syphilitic pseudobulbar palsy, and various encephalitides. Rarer conditions associated with PBA include gelastic epilepsy, dacrystic epilepsy, central pontine myelinolysis, olivopontinocerebellar atrophy, lipid storage diseases, chemical exposure (e.g., nitrous oxide and insecticides), fou rire prodromique, and Angelman syndrome. [18, 19]

Outdated prevalence estimates of PBA that range as low as 5% emphasize the classic incidence of PBA in neurological disorders such as ALS and MS. However, prevalence estimates of more recent studies exceed 55% in survivors of TBI and reveal the potential to develop PBA symptoms in the context of diverse neurological disorders. [20]

Results from a recent investigation estimates the prevalence of pseudobulbar affect associated with traumatic brain injury (TBI) to exceed more than 55% of survivors. [20, 21] Mechanical forces that cause significant traumatic brain injury typically produce a mixture of focal parenchymal and diffuse axonal injury. Pathways connecting the subcortical structures and neocortex are disrupted. Cascades of excitotoxic, inflammatory and apoptotic processes set in motion by the initial injury further disrupt delicately balanced networks mediating or modulating affective display. These patterns of damage likely account for the high prevalence of PBA secondary to TBI. [22]

Neuropsychiatric sequelae of TBI are heterogeneous, complicated and difficult, which makes it challenging to distinguish primary from secondary disorders. [11, 23] Without collecting a thorough and detailed history, clinicians could misdiagnose PBA as depression, especially with regard to crying which is the most common manifestation of PBA. [7, 12, 24] According to the DSM-IV TR, the difference between mood and affect is the duration; mood refers to a sustained emotional climate, whereas affect describes variable changes in emotional weather. [25] Depressive features must be present most of the day, nearly every day for two weeks in order to qualify for a diagnosis of Major Depressive Episode. In the diagnosis of PBA, episodes are typically brief—on the order of seconds to minutes. [23] Features associated with Major Depressive Episodes include disturbance of mood, interest, appetite, sleep, energy, activity, concentration and feelings of worthlessness or guilt. Notwithstanding, it cannot be ruled out that any of the required features associated with Major Depressive Episodes are not direct consequences of the TBI. A primary diagnosis of mood disorder is clearly excluded in the case of PBA secondary to TBI. [7, 23, 24]

PBA is frequently associated with significant psychosocial disability, including withdrawal and

Dextromethorphan/Quinidine Alleviates Pseudobulbar Affect …

255

social isolation. [16, 18, 19, 26-28] Generally, suicide risk is greater among patients with physical illnesses than among the general population. Almost one in five people living with TBI will attempt suicide, while an even greater proportion contemplate it. The significant emotional, behavioral, psychosocial, and physical disability that burdens survivors of TBI likely accounts for their preoccupation with suicide. [7, 8, 29-32]

For individuals with TBI, the reality is that symptoms will endure in some modified form across the lifespan; the survivor will never be exactly the same as he or she was before the injury. The probable realization that post-injury complications are permanent foreshadows an uncertain future for survivors with impaired problem-solving abilities. When lability surfaces and emotions vacillate to the negative end of the spectrum, panic may trigger impulsive behaviors likely to cause self-harm. It is not difficult to imagine how suicidal ideation frequently provokes attempted suicide. [3, 4, 7, 10]

Dextromethorphan hydrobromide and quinidine sulfate (DMQ, 20/10, Avanir Pharmaceuticals, Nuedexta) has been shown to robustly diminish the frequency and severity of PBA episodes. [20] FDA-approved to treat PBA arising from any neurological disorder, dextromethorphan, the active ingredient, is a non-competitive antagonist of the N-methyl-D-aspartate (NMDA) receptor, in addition to being an agonist of the sigma-1 (σ-1) receptor. Dextromethorphan also modulates monoaminergic and glutamatergic neuro-transmission through its interactions with the pre- and post-synaptic NMDA complex. Quinidine, the inactive component, has traditionally been used as an anti-arrhythmic agent, at doses ranging from 600-1800mg. However, only 10-30mg of quinidine is required to inhibit hepatic metabolism of dextromethorphan allowing it to cross the blood-brain barrier and exert central therapeutic

actions. Specifically, quinidine inhibits the CYP2D6 enzyme and increases the bioavailability of dextro methorphan nearly 20-fold. [25, 33]

This study aims to reaffirm the efficacy of DMQ in ameliorating PBA episodes in individuals with TBI and provides evidence of its ability to improve diverse neuropsychiatric sequelae.

Methods The case histories of five patients were reviewed,

derived from clinical records of one of the authors (JLF). The Institutional Review Board of the International Brain Research Foundation approved this retrospective case study. Five patients sustained TBI, as the result of motor vehicle collisions (n=2) or falls (n=3) on average of 9.4 years prior. All 5 patients had a stable history of PBA and reported frequent impulsivity, including suicidal ideation. Although no patient had actually attempted suicide, all patients were burdened by an omnipresent threat that they may act upon these impulsive thoughts. All 5 patients experienced previous or current treatment failures with between two and eight antidepressants, (atypical) anti-psychotics or mood stabilizers. No patient had a current diagnosis or history of Major Depressive or Manic Episodes, Bipolar I or Bipolar II disorders; although one patient had a premorbid diagnosis of panic disorder and another patient was diagnosed with schizophrenia one year post-remote initial TBI (SCID-I). [27] The severity of PBA was formally assessed with the Center for Neurologic Study Lability Scale (CNS-LS), the first self-report instrument to quantify PBA symptomatology. [28] The CNS-LS comprises seven questions; three that assess involuntary crying and four that address uncontrollable laughter (See Figure).


256

Figure 1. The CNS-LS comprises seven questions.

Results

Case 1 A 31-year-old, right-handed female with 18 years

of education sustained a TBI 13 years prior due to motor vehicle collision. Glasgow Coma Scale was 5, indicating severe TBI. CT revealed left-sided temporal contusion and trace amounts of blood in the occipital horn. Length of coma was four weeks and post-traumatic amnesia persisted for an additional eight weeks. Despite poor prognosis, the patient was able to return to school, obtain her Master's degree and is employed full-time. Nevertheless, she struggles with ongoing cognitive, emotional and behavioral dysfunction. Paroxysmal episodes of rage and aggression compromised interpersonal relationships and threatened the sustainability of her employment. These outbursts created significant conflict, loss, and legal complications, triggering uninhibited episodes of crying and suicidal ideation. Treatment with citalopram, amitriptyline, sertraline, venlafaxine,

buspirone, aripiprazole, alprazolam and divalproex sodium provided no sustained benefit. CNS-LS was 27, indicating moderate to severe PBA. Upon initiation of DMQ therapy, she was taking 100mg lamotrigine daily for mood stabilization and 400mg modafinil daily to improve concentration and fatigue. She reported experiencing an elevated sense of wellbeing within hours of her first dose of DMQ. CNS-LS improved to 17, consistent with mild PBA. Paroxysmal episodes of crying became significantly more manageable, although she now reports experiencing “mildly exaggerated laughter” in appropriate contexts, when confronted with genuinely funny situations. She feels much more open to social interaction and now accepts her individuality. She is unable to fathom how she considered suicide an option and instead chooses to focus on her indomitable spirit. Interpersonal interaction no longer inevitably creates conflict, causing her to become irritated and embarrass herself. She reports increased patience and frustration tolerance when dealing with others, including law enforcement. At one point, lapsed insurance coverage forced her to temporarily


257

discontinue DMQ. Within several weeks, a triggering event caused her mildly euphoric mood to quickly abate and suicidal ideation resurfaced. Strikingly, this preoccupation was rapidly eliminated upon reinitiation of DMQ. Stated the patient, “Within hours of taking Nuedexta, a sense of calm settles in and I know everything is going to be okay.”

Case 2 A 64 year-old, right-handed female with 14 years

of education suffered TBI 13years prior when she fell down a flight of stairs. At the time of injury, blood alcohol content was 0.25 g/dL. Glasgow Coma Scale of 3 indicated severe TBI. She underwent subtotal right frontal lobectomy for hemorrhagic contusion. Length of coma was two weeks, while post-traumatic amnesia persisted for another 10 days. Premorbid medical history includes hypothyroidism. Her reported involvement in several physically abusive relationships resulted in an undocumented history of repeated closed head injury. Since her most recent fall, she reported executive dysfunction, poor impulse control, anosmia, chronic headaches, insomnia, mental lethargy, physical fatigue, and difficulty concentrating and impaired short-term memory. She exhibited mild word-finding difficulties and tangential or clinically disorganized communication. She was defensive, irritable, agitated, extremely anxious and displayed easily provoked, exaggerated episodes of crying. She expressed significant suicidal ideation, but denied any active plan. Treatment with fluoxetine and lamotrigine had only partial or inconsistent effect on affective lability. CNS-LS was 13, indicating mild PBA. Upon initiation of DMQ therapy, she was taking atorvastatin for hyperlipidemia; montelukast for asthma; 20mg dextroamphetamine daily for fatigue; 12.5mg zolpidem as needed for insomnia; 2mg clonazepam and 60mg duloxetine daily for anxious mood. Within three doses of DMQ, she reported feeling a remarkable elevation in her mood. CNS-LS dropped to 11—below the threshold for clinically significant PBA. Uninhibited episodes of crying remitted completely, although she reported the rare occurrence of exaggerated laughter since beginning treatment. Overall, she demonstrates a significantly improved ability to contextually modulate emotional

expression. Suicidal ideation completely resolved. She expresses hopefulness and genuinely looks forward to the future. Irritability and agitation became significantly more manageable. She feels much more tolerant of individual differences and rarely argues with other people. At one point, delayed insurance coverage forced her to temporarily halt DMQ therapy. She reported, “I could feel myself receding back into my dark space. Since beginning treatment with Nuedexta, I feel like a reinvented person.”


of education initially experienced TBI 30 years ago as a result of a motor vehicle collision. One year later, she was diagnosed with schizophrenia. The diagnosis was later modified to schizoaffective disorder. As a preadolescent, she endured physical and sexual abuse. In her thirties, she was treated with 36 sessions of electroconvulsive therapy. She earned her Master's Degree in her early forties. Her second and third concussive events occurred approximately two years prior to presentation; first falling down a metal staircase, then two days later striking the right side of her head on a table. Glasgow Coma Scale was 15 after these most recent incidents indicating mild TBI. Although duration of unconsciousness was unspecified, post-traumatic amnesia persisted for several hours. Post-traumatic medical history included central fever of unknown origin, which was successfully resolved after 18 months on antivirals. She presented to outpatient evaluation displaying paroxysmal episodes of crying and emotional lability. She reported irritability, agitation, mild word-finding difficulty, impaired short-term memory and heightened distractibility. Family history is remarkable for paternal suicide (notably increasing her own risk). She was treated with trazodone and lithium without sustained therapeutic benefit. In her own words, “I had no more fight left in me. I finally surrendered and prepared myself to die.” CNS-LS was 16, indicating mild PBA. Upon initiation of DMQ therapy, she was taking 30mg aripiprazole daily to control auditory and visual hallucinations; 30mg temazepam as needed for insomnia; 5mg donepezil hydrochloride daily to improve cognition; 30mg


258

escitalopram and 150mg venlafaxine daily for anxious mood. Mood became elevated within hours of her first dose of DMQ and at follow up CNS-LS was 9 (below the accepted cutoff of 13 or above needed to diagnose PBA). She appeared much happier and more animated; uninhibited episodes of crying remitted completely. She reported diminished agitation and irritability overall, but continued to become emotional when confronting appropriately frustrating triggers. Suicidal ideation completely resolved. She additionally reported feeling hopeful, thinking more clearly and having more energy. Mild expressive aphasia and ability to concentrate reportedly improved. Furthermore, she reported no longer feeling disoriented and dissociated. A major locus of chronic back pain totally remitted; unexpectedly, she reported alsomst complete abatement of auditory and visual hallucinations. She remarked, “Nuedexta performs miracles! Where things felt dark and bleak before—now there is light.”


of education acquired TBI seven years ago when she fell down a flight of stairs. Initial Glasgow Coma Scale was 13, however CT revealed contusions of bilateral inferior frontal gyri and left temporal lobe. Length of coma was nine days, while post-traumatic amnesia persisted for another three days. Post-traumatic history includes absent olfactory and gustatory perception. Upon recent evaluation, her paroxysmal episodes of laughter and crying occurring completely outside the context of the inciting event. She reported bursting out in laughter in the midst of an argument. In addition to crying more than 20 times a day, she frequently displayed agitation, irritability and significant suicidal ideation. She insisted maternal responsibilities prevented her from developing a plan. She reported heightened distractibility, impaired short-term memory, and displayed emotional lability. Treatment with lithium, venlafaxine and escitalopram provided suboptimal therapeutic benefit. CNS-LS was 27, indicating moderate to severe PBA. Upon initiation of DMQ therapy, she was taking up to 40mg dextroamphetamine daily for fatigue and distractibility; 10mg donepezil hydrochloride daily to

improve cognition; and 40 mg fluoxetine daily for premenstrual dysphoric disorder. Within two doses of DMQ, she reported feeling considerably less agitated and anxious. PBA dramatically improved and paroxsymal episodes of crying totally resolved, although she continues to experience “facetious laughter.” CNS-LS was19, indicating mild PBA. Suicidal ideation abated completely and other impulsive behaviors are significantly more manageable. The patient reports, “I am no longer living in perpetual misery. Now I see my future through rose-colored glasses—thanks to this medication.”


of education sustained severe TBI 13 years ago when involved in a motor vehicle collision. CT revealed contusions and hematoma in the anterior frontal lobes. Length of coma was three days, while post-traumatic amnesia persisted for two additional weeks. Premorbid medical history is remarkable for agoraphobia. Post-traumatic complications reportedly included paroxysmal episodes of crying, insomnia and sleep apnea. Daily migraines were poorly managed with topiramate, while treatment of lethargy and severe fatigue with dextroamphetamine, modafinil and methyl-phenidate had suboptimal benefit. Various sources of pain accounted for a ten year history of chronic opiate use. She frequently expressed suicidal ideation, but reported maternal dedication prevented her from formulating a plan. Nevertheless, she constantly imagined scenarios like a “truck mowing me down” or “lightning striking me dead”. CNS-LS was 19, indicating mild PBA. Upon initiation of DMQ therapy, she was taking irbesartan, hydro-chlorothiazide and amlodipine for hypertension; levothyroxine for hypothyroidism; 2.5mg clonazepam daily to manage acute panic and 225 mg venlafaxine daily for agoraphobia. Within hours of her first dose of DMQ, she reported feeling giddy and amused (this symptom resolved within a few days). Although CNS-LS remained steady at 19, the scoring pattern of the questions shifted. The scaling for the questions related to crying shifted from 4's and 5's (occurring frequently or most of the time) before, to 1's(never a problem)


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post-treatment; whereas those questions related to laughter, previously 1's increased to 2's and 3's (happening rarely or occasionally) since initiating treatment with DMQ. She no longer reports episodes of acute panic and feels “much less anxious” since beginning treatment. Suicidal ideation abated completely. When treatment was temporarily interrupted, debilitating anxiety and suicidal ideation quickly resurfaced. She reports, “This medication is amazing! If I forget a dose or two, I am literally a cry-baby. Within hours of taking Nuedexta, I am able to reassert control.”

Discussion Several recent studies emphasize the relatively

high rates of suicide ideation or completed suicides in the US population of TBI. Moreover, suicidal ideation, non-suicidal self-injury and suicide attempts are common in military personnel and veterans, and in the general TBI adult population. Hence, this explains the importance of this paper, demonstrating the dramatic therapeutic impact of DMQ on suicidal ideation and associated impulsivity in our patients. [34, 37]

PBA must be distinguished from other disorders of affect and from mood and personality disorders. Depression is probably the most commonly applied misdiagnosis in patients with PBA. However, many clinical features distinguish PBA episodes from depression symptoms. The most prominent difference is duration. Depression symptoms, including depressed mood, typically last weeks to months, while an episode of PBA lasts seconds to minutes. In addition, crying, as a symptom of PBA, may be unrelated or exaggerated relative to subjective mood, while crying is congruent with subjective mood in depression. Other symptoms of depression, such as fatigue, anorexia, insomnia, anhedonia and feelings of hopelessness and guilt, are not associated with PBA. PBA can also be differentiated from bipolar disorders with rapid cycling or mixed mood episodes because of the relatively brief duration of laughing or crying episodes (with no mood disturbance between episodes), compared with the sustained changes in mood, cognition and behavior recognized in bipolar disorders. [16, 33, 38-40]

Mechanistically, PBA is a disinhibition syndrome in which pathways involving serotonin and glutamate are disrupted. This conceptualization has resulted in (off-label) treatment for many years with anti-depressants, particularly tricyclic anti-depressants and selective serotonin reuptake inhibitors. Although it is most commonly misidentified as a mood disorder, particularly depression or a bipolar disorder, there are characteristic features that can be recognized clinically or assessed by validated scales (particularly the CNS-LS), resulting in accurate identification of PBA, and thus permitting proper management and treatment. [2, 3, 41]

Hence, we carefully classified and diagnosed PBA in our TBI patients who happened to have also reported suicidal ideation. PBA episodes are characterized by transient paroxysms of emotional lability, while mood disorders are defined by the sustained duration of depression or irritation. One cannot purely diagnose primary depression, not otherwise accounted for by TBI because the etiological relationship between neuropsychiatric symptomatology, organicity and neurological injury are impossible to disentangle. [20]

A recent therapeutic breakthrough occurred with the approval by the Food and Drug Administration of a dextromethorphan/quinidine combination as being safe and effective for treatment of PBA. Side effect profiles and contraindications differ for the various treatment options, and the clinician must be familiar with these when choosing the best therapy for individuals, particularly elderly patients and those with multiple comorbidities and concomitant medications. Dextromethorphan/quinidine (Nuedexta) is a potent s-1 receptor agonist, inhibiting glutamatergic signaling. s-1 receptors are primarily expressed in the brainstem and cerebellum; thus, dextromethorphan acts in brain regions believed to be associated with emotional expression disorders, without causing significant, unwanted systemic effects. Quinidine, the other drug in the combination, is a metabolic inhibitor enabling therapeutic dextromethorphan concentrations to be reached. [4, 12]

Nonetheless, the theoretical basis of this dramatic therapeutic effect on PBA with associated suicidal ideation remains controversial. Wilson initially proposed the existence of two separate, mutually


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inhibitory pathways to laughter and crying: a voluntary pathway originating in the motor cortex and an involuntary pathway whose origins remained to be determined. Both pathways were thought to lead to the brainstem region, the laughter and crying “center” in the upper pons, responsible for coordinating facial-respiratory actions, emphasizing the role of the corticobulbar pathways in modulating emotional expression in a top-down model, and theorized that PBA occurs when bilateral lesions in the descending corticobulbar tract cause failure of voluntary control of emotion, which leads to the disinhibition, or release, of laughing/crying centers in the brainstem. [1] Other theories implicate the prefrontal cortex. These authors posited that PBA arose when lesions disrupt the voluntary pathway, thereby releasing the involuntary connections to the laughing and crying center. [42] According to Ghaffar et al. a widely dispersed neural network involving frontal, parietal, and brainstem regions underlies the pathophysiology of PBA. [43] The specific pathophysiology involved in this frequently debilitating condition is still under investigation; the primary pathogenic mechanisms of PBA remain controversial. [43, 44]

The results of this clinical case-review confirm DMQ as a potent treatment for PBA and emphasize its potential to mitigate additional neuropsychiatric behaviors associated with TBI. DMQ was indicated

for all cases to manage paroxysmal episodes of laughter, crying or both, in addition to demonstrating several unforeseen benefits. Additional therapeutic responses were revealed in all 5 patients as suicidal ideation was rapidly eliminated within the first few doses of DMQ. Frequency and intensity of PBA episodes were significantly reduced. This potent effect was illustrated robustly with regard to the first case. In her own words, “Treatment with Nuedexta has literally saved my life time and time again! The challenges and obstacles that I constantly face as a survivor drove me to a precipice—now it seems a fulfilling life after TBI is possible.”

DMQ was well tolerated in all; no patients discontinued use or experienced adverse side effects. Several patients experienced significantly elevated mood, although these transient episodes were not associated with social or occupational dysfunction. Interestingly, several patients remarked their post-treatment disposition appeared to encourage more prosocial behavior overall. Indeed, several patients reported a preference for “mildly exaggerated laughter” to suicidality. Most importantly, the therapeutic benefits of DMQ therapy superseded that of the numerous mood stabilizers, psycho-stimulants, antidepressants, anxiolytics and antipsychotics with which the patients were being currently treated. [20, 33]

Table 1. Demographics and Treatment Response

Age / Gender

Injury type

Time from injury to PBA diagnosis

Time from DMQ initiation to efficacy

Side Effects

Neurobehavioral/ Cognitive/ Psychiatric benefits of DMQ therapy

32 Female

TBI

13 years

6 hours

None

Reduced crying paroxysms/suicidal ideation/ Increased laughter Enhanced well-being

63 Female

TBI

12 years

36 hours

None

Reduced crying paroxysms/suicidal ideation Increased laughter Enhanced well-being

47 Female

TBI

2 years

6 hours

None

Reduced crying paroxysms/suicidal ideation Enhanced well-being


261

Age / Gender

Injury type

Time from injury to PBA diagnosis

Time from DMQ initiation to efficacy

Side effects

Neurobehavioral/ Cognitive/ Psychiatric benefits of DMQ therapy

43 Female

TBI

7 years

24 hours

None


64 Female

TBI

13 years

6 hours

None


The unforeseen therapeutic potential of DMQ therapy suggests that an expanded definition of PBA may be forthcoming. Sudden outbursts of crying and laughing represent impulsive responses of affect without corresponding changes in mood. Similarly, suicidal ideation in these patients in no way reflects genuine hopelessness. Rather in these cases, suicidal ideation represented a transient reaction to the frustration and seemingly endless trial of obstacles facing TBI survivors. From the perspective of a larger syndrome of disinhibition or impulsivity, suicidal ideation in this population more likely reflects a cognitive impulse superimposed on poor problem-solving (dysexecutive) abilities. Alternatively, and particularly in light of dysfunctional brain pathways linked to cerebellar control in PBA following TBI, the manifestation of suicidality may reflect a kind of ‘cognitive dysmetria’, leading the individual to overshoot in response to unrelenting daily frustrations and tribulations. The symptomatology associated with depressive episodes (anhedonia, apathy, anergia and abulia) was not a feature of the psychopathology experienced by patients in this sample. Perhaps future discussions of PBA secondary to TBI should describe a spectrum of behavior, whose positive and negative valence is laughter and crying and acknowledge impulsivity along that spectrum as a core feature for the differential diagnosis.

In the absence of a prospective, randomized and controlled clinical trial, the primary limitation of these remarkable findings is the small sample size. However, the wholly unexpected observation of resolved suicidal ideation across all cases increases the likelihood that these results will generalize across the population of individuals with heterogeneous neuropsychiatric sequelae secondary to TBI. Case 1

followed a naturalistic ABAB design; thus representing the strongest evidence that DMQ therapy repeatedly and rapidly reverses suicidal ideation.

Conclusion The results of this investigation confirm DMQ as

a potent treatment for PBA associated with TBI and emphasize its rapid onset, sustained tolerability, continuous duration of efficacy and additional therapeutic potential. These dramatic clinical outcomes reflect successful inhibition of impulsive thoughts underlying suicidal ideation, thus reducing the likelihood that these individuals would tragically act upon the urge to commit self-harm. Even many years following injury, DMQ may have the potential to reduce risk of morbidity and mortality, thereby significantly improving long-term outcome and quality of life for individuals living with various neuropsychiatric sequelae associated with TBI.

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68-YEAR-OLD FEMALE WITH APALLESTHESIA IMPROVED

THROUGH BRAIN-BASED REHABILITATION: A CASE STUDY

David Traster Life University, Atlanta, Georgia, USA

Correspondence: Author: David Traster, 1320 Windy Ridge

Ln. Atlanta, Ga 30339 USA. E-mail: [email protected]

Abstract Objective: The purpose of this study is to illustrate an example of utilizing chiropractic care in concert with other brain-based rehabilitation therapies to effectively manage a patient with persistent symptoms following a motor vehicle accident. Clinical Features: A 68 year old female patient presented to the clinic with a two year history of complete vibration loss in both legs following a motor vehicle accident. The clinical impression was that of a traumatic brain injury presenting as a centrally maintained vestibulopathy. Intervention and Outcomes: Interventions utilized spinal and extra-spinal manipulations, gaze stabilization exercises, earth-vertical axis rotations, multi-planar movements of the right arm, and breathing exercises. The patient regained vibration in both legs and experienced such significant improvements in regards to her gait and balance that she was able to begin exercising at a fitness center for the first time in over fifteen years. Conclusion: This case suggests that chiropractic care in conjunction with other brain-based exercises can be an effective, conservative treatment for patients with persistent neurological deficits following a traumatic brain injury. Keywords: Brain-based rehabilitation, Traumatic brain injury, Apallesthesia, Vestibulopathy

Introduction The purpose of this paper is to illustrate an

example of using chiropractic care in conjunction with other brain-based therapies to treat a single patient

David Traster

266

with persistent symptoms following a traumatic brain injury.

Epidemiology Traumatic brain injury (TBI) is a critical public

health and socio-economic problem throughout the world. A TBI is a complex pathophysiological process affecting the brain, induced by traumatic biomechanical forces. [1] Approximately 1.7 million people sustain a TBI annually in the United States. An estimated 292,202 people every year suffer a TBI from a motor vehicle accident in the United States. This is second only to falls which has an estimated 595,095 victims annually. [2] Although 80-90% of TBI victims have their symptoms resolve spontaneously within ten days, others suffer from functional deficits that can last for weeks to years. [3] The estimated amount of people living with a TBI-related disability is 5.3 million in the United States and 7.7 million in the European Union. [4] TBIs were estimated to cost the United States $76.5 billion dollars in 2000 due to cost of medical care and lost productivity. [5] The number of cases of brain injury that go undiagnosed and cannot be accounted for in these statistics is thought to be far greater. [6-8]

Signs and Symptoms of a Traumatic Brain Injury

TBI can produce a wide range of clinical signs

and symptoms due to underlying neuronal dysfunction. [9] This may include physical signs, behavioral changes, cognitive impairment, sleep disturbances, somatic symptoms, cognitive symptoms and/or emotional symptoms. [8] Common physical signs and symptoms include headache, nausea, vomiting, blurred or double vision, seeing stars or lights, balance problems, dizziness, fatigue, sensitivity to light or noise and tinnitus. [10, 11] Sensory processing deficits are a key feature in TBI, the most common deficit being the inability to properly coordinate the vestibular, visual and proprioceptive systems in order to maintain proper balance and posture. [12-16] Vestibular complaints such as unsteadiness, dizziness and spatial disorientation are

the most frequent sequelae of TBI. [16] Oculomotor dysfunctions are seen in 90% of TBI and are becoming more recognized as an integral part in diagnosis, monitoring and managing TBIs. [17-19]

These include dysfunction in accommodation, version, vergence, strabismus, cranial nerve palsy, increased saccadic latencies, altered gain in the vestibulo-ocular reflex, as well as higher variability in smooth pursuit eye movements. [17-26]

Systemic complaints include autonomic dysfunction, systemic inflammation and organ dysfunction. The vestibular system contributes to autonomic regulation and anatomical connections between the vestibular system and autonomic nervous system are known. Of particular importance is the autonomic control during postural perturbations. [27-30] Lesions of the vestibular system have shown to impair posturally-related cardiovascular responses resulting in postural hypotension and impaired cerebral blood flow regulation. [27, 28] Many patients also complain of gastrointestinal dysfunction. Studies in mice show a decreased expression of intestinal tight junction proteins following brain injury leading to increased intestinal permeability, motility abnormalities, and mucosal alterations. [31] The precise mechanism of this is unknown but one study has shown that stimulation of the dorsal motor nucleus of vagus prior to TBI in mice prevents intestinal dysfunction. [32]

Pathophysiology Rotational acceleration and deceleration forces

are thought to play an important role in TBI. [9] An acceleration and deceleration injury can occur either by impact or impulse. Impact consists of a concussive blow which makes direct contact with the head. Impulse refers to an accelerative force which sets the head in motion without directly striking it. Regardless of how the concussive insult occurs, the inertial loading due to translational and rotational acceleration and deceleration sets the brain in motion. The brain is suspended in cerebrospinal fluid within the subarachnoid space which acts as protection from the bony skull. However, if the momentum of head becomes forceful enough, the brain will come into violent contact with the skull causing deformation,

68-Year-Old Female with Apallesthesia Improved through Brain-Based Rehabilitation

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distortion or compression of neural tissue. More severe head trauma may result in contusions or lacerations. [33] Anatomically, brainstem fibers have an increased susceptibility to rotational loads due to their linear alignment. In regards to severity of TBI, impact location, linear and rotational acceleration and whether the person is aware of the impending blow are the major factors. [34]

TBI is followed by a complex cascade of ionic, metabolic and physiologic events. Immediately after a TBI, there is a disruption of neuronal membranes, axonal stretching, and a release of excitatory transmitters such as glutamate with an efflux of potassium resulting in a brief period of hyperglycolysis. This is followed by mitochondrial dysfunction with decreased oxidative metabolism, diminished cerebral glucose metabolism, reduced cerebral blood flow, and axonal injury. Late events in the cascade include recovery of glucose metabolism and cerebral blood flow, delayed cell death, chronic alterations in neurotransmission, and axonal discon-nection. Traumatic injury to the developing brain may lead to long-lasting changes, even when there is little evidence of an initial deficit. Repeated brain injury within a particular time frame can lead to increased anatomical or behavioral impairment. The second insult may be in the form of another traumatic brain injury, or it may occur in the form of premature activation or over-stimulation of the injured brain. [35]

Chronic traumatic encephalopathy (CTE) is a progressive tauopathy as a result of repetitive head injuries. CTE is characterized by a reduction in brain weight, enlargement of the lateral and third ventricles, thinning of the corpus callosum, cavum septum pellucidum with fenestrations, and scarring and neuronal loss of the cerebellar tonsils. Neuronal loss is common in the hippocampus, entorhinal cortex, amygdala, subcallosal and insular cortex, frontal cortex and temporal cortex. Neuronal death may be from direct physical damage, necrosis from the immediate release of excitatory transmitters such as glutamate, diffuse delayed cell death involving both necrotic and apoptotic death cascades, and deafferentation. [9] Depending on the lesion location, a combination of various cerebellar, pyramidal and extrapyramidal syndromes including traumatic Parkinsonism may occur with the progressive

cognitive decline predominating later in the disorder. [36]

Case Report

Patient History The patient was a 68 year-old Caucasian female,

who presented to the Life University Center for Health and Optimum Performance (C-HOP) chiropractic clinic on May 23rd 2013, with a chief complaint of vibration loss in both legs. The symptoms began in October 2011 following a motor vehicle accident. She reported that the plantar surfaces of both feet constantly felt slimy, cold and numb. She also reported difficulty in both her balance and gait. She initially had concomitant low back and neck pain which had resolved with previous chiropractic care.

Physical Exam Upon initial inspection, the patient presented with

a pathological left ocular tilt reaction, consisting of a right hypertropia and left head tilt. Heart auscultation revealed a consistent and significant arrhythmia. Large varicose veins were present distal to the knee bilaterally. Gait examination revealed a slow, wide based gait with small stride lengths, right lateropulsion and a right foot drop. Dual mental tasking, where the patient was asked to say every other month of the year out-loud while walking, created hesitations, decreased speed of gait and stride length, and increased right lateropulsion and foot-drop.

Palpation revealed paraspinal musculature hypotonia bilaterally with myospasm of the complexus cervical musculature and increased tonus of the rectus capitus posterior major and minor bilaterally. Respiratory excursion was severely compromised on the right, however auscultation and percussion of the lungs were normal.

Cranial nerve exam revealed a prominent right palatal paresis was noted upon phonation. Pupils were miotic bilaterally. Pupillary light reflex was normal, however the accommodation response during convergence was not as brisk as the pupillary light

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response. Opthalmoscopic exam of the retina revealed a four to one venous to arterial diameter ratio bilaterally. Ocular motor exam revealed significant blepherospasms of the eyelids and a weak right lateral rectus muscle upon right abduction. When testing the vestibulo-ocular reflex, there was an observed decreased gain in rightward Halmagyi head impulse testing. Saccadic pursuits were observed in all directions, with the vertical pursuits being more compromised than the horizontal. Rightward saccades had long latencies of initiation, slow velocities and were hypometric, while vertical saccades were hypometric and slow in both the upward and downward direction. Optokinetic testing revealed appropriate optokinetic nystagmus in all directions, however there was an observed decrease of gain in vertical optokinetic responses compared to the horizontal responses.

Sensory examination revealed complete vibration loss bilaterally on the lower extremities distal to the greater trochanters. Graphesthesia in the lower extremities was also absent. However, joint position sense, two-point discrimination, point localization, sharp-dull testing, and temperature discrimination were all unremarkable. Pinwheel testing showed increased sensitivity in the legs bilaterally.

Motor and coordination exam revealed sluggish and pendular patella reflexes, which were graded 1+ on the Wexler Reflex Scale bilaterally. All other myotatic stretch reflexes and muscle strength tests were normal. Plantar reflex induced up-going toes with an increased flexor reflex afferent response bilaterally. Clinical tests for extremity ataxia, including finger to nose, heel to shin, and dysdiodochokinesia, were performed and all revealed decrease coordination bilaterally, with the right side being more compromised. Finger tapping, as described in the Unified Parkinson’s Disease Rating Scale, was tested looking for decreased speed and/or amplitude, hesitations, or halts. It was graded with a four on the right due to freezing, and a three on the left due to small amplitude and hesitations. When performing Rhomberg’s test, the patient fell consistently posterior and to the right within two seconds of closing her eyes. However, when asked to perform Rhomberg’s test while opening and closing her right hand, she was able to perform the test

without falling. The test was ended after thirty second after observing her improved stability.

Clinical Impression The above findings led to the diagnosis of

concussive brain injury presenting as a centrally maintained vestibulopathy.

Intervention The patient was treated at Life University Clinic

for Health and Optimum Performance (C-HOP) approximately two to three times a week for three months. Spinal and extra-spinal chiropractic adjustments aimed at reducing subluxations were given primarily on the right side of her body using an Activator IV Adjusting Instrument. Manual high velocity, low amplitude manipulations were administered to her ribcage when an asymmetry in respiratory excursion was observed.

The Activator IV is a manually assisted short lever adjusting instrument and is a FDA approved device used by many chiropractors to reduce subluxations. [37] The Activator IV can be held by one hand of the clinician and is used to deliver a specific, spring-loaded force to the anatomy of the patient. The device has a rubber tip on the contacting surface to reduce point tenderness to site being adjusted. There are four variable settings that may be used depending on the thickness of the anatomical structure. [38] Although there is an assessment technique that is often used in conjunction with the instrument, they are not dependent on each other in order to be effective. [39] The instrument produces less peak force, in less time, compared to other manual adjusting techniques [40] but produces enough energy for relative movement of a bone when utilized correctly. [41]

Passive complex movements of the right extremities were performed, where two examiners would simultaneously move her right arm and leg in a figure eight pattern in opposing directions for three sets of ten repetitions.

Leftward optokinetic stimulations were administered for a duration of fifteen seconds,


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followed by rightward earth-vertical axis rotations in a wheeled office chair. The rotation durations were ten seconds, with four seconds to accelerate, two seconds of peak velocity, and four seconds to decelerate. This montage was repeated three times.

Eye movement training included obliquely oriented optokinetic stimulations in the direction of up and right, followed by down and left. Microsaccades up and to the right were performed with gaze holding of intersaccadic targets. Gaze holding consisted of passive horizontal and vertical head rotations while she was visually fixating on a dot. A three to one ratio of gaze holding was used in regards to vertical versus horizontal rotations.

Breathing exercises were also performed, where the patient was instructed to breathe in through her nose for a count of three seconds and out through her mouth for six seconds.

Outcome Follow up examination on August 29, 2013

revealed significant improvements. The patient was able to begin exercising in a fitness center for the first time in over fifteen years. She no longer reported any “slimy”, “cold” or “numb” sensations on the plantar surfaces of her feet. She reported her equilibrium had improved to the point where she no longer felt unstable walking up stairs, in darkness, or in a crowded environment.

Upon examination, vibration, pinwheel and graphesthesia testing in the lower extremities were all normal. Her stability was drastically improved as reflected by her ability to perform rhomberg’s test for over one minute with minimal sway. Gait parameters all improved, such that there was an increase in gait speed and stride length while no longer exhibiting any right lateropulsion or right foot drop. Palpation revealed a decrease in cervical myospasm with an increase in paraspinal tone, and symmetrical respiratory excursion was observed. The pathological left ocular tilt reaction was absent due to a decrease in amplitude of the right hypertropia and an absence of any observed head tilt. All eye movements showed improvements, however, there were still deficits in the vertical eye movements when compared to the horizontal. Vein to artery ratio was three to one

bilaterally on opthalmoscopic exam of the retina and there was an observed improvement in the varicosities of her legs bilaterally. Plantar response no longer elicited increased flexor afferent responses, however there were still up-going toes bilaterally. Finger tapping improved and was graded as a two bilaterally due to amplitude. Motor and coordination exam showed that all reflexes were 2+ on the Wexler Reflex Scale, however patella reflexes were still slightly pendular bilaterally.

Discussion Traumatic brain injuries constitutes one of the

leading causes of mortality and disability around the world, leaving motor and cognitive impairments that vary depending on aetiology, extent and severity of damage. [42] TBIs may impact multiple body systems, inflicting a wide range of pathologies, impairments, functional limitations and disabilities. [43] Despite reports that 80-90% of TBI victims have spontaneous recoveries within the first two weeks, long-term vestibular problems such as balance and stability are observed. [21, 44, 45] Traditional management of TBI has been focused on orthopedic, integumentary, neurocognitive, and neurobehavioral consequences. However, assessing and managing vestibular complaints is essential for an optimal return to activities of daily living, quality of life and return to work. Despite TBI causing a high incidence of both peripheral and central vestibular pathology, it is estimated that only a small percentage of TBI victims have had their vestibular system formally assessed or treated. [43]

The vestibular system processes information about head movement and orientation. Uniquely, the vestibular system does not have a unimodal cortical integrating center. Instead, vestibular afferents are combined with many other sensory signals in the cortex, such that vestibular input influences the processing of other sensory modalities. This evolutionary primitive system is neuroanatomically different from other sensory pathways, since its cortical projections are widely distributed in the brain and are always shared with other sensory modalities. This allows the vestibular system to participate in a form of sensory signal management, changing the

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balance between the various sensory systems as the relation between the body and the external environment changes. Vestibular inputs have been shown to directly increase tactile perceptual processing, and directly decrease perceptual processing of nociceptive stimuli. [46] Tactile perception is essential to interact with the environment. Tactile and proprioceptive systems continuously transmit information about body location in space and the presence of obstacles, which may affect movement. The secondary somatosensory cortex (SII) contains multimodal neurons which respond to both vestibular and proprioceptive inputs and has been shown to be integral in the processing of cross-modal information for correct interactions with the environment. [47]

Brain plasticity or neuroplasticity has been described as the brain’s ability to adapt and evolve. Having the capability to constantly change shape and function is an intrinsic property of the nervous system that persists throughout life and plays an important role in maturity, development, and learning. Brain plasticity is also fundamental for functional recovery from a TBI, being the mechanism underlying the potential capability of the brain to compensate for lesions [42]. The brain is capable of a large degree of self-repair by synaptic turnover. Synaptic turnover refers to the ongoing change in the dendritic branches of neurons in response to changes in synaptic connectivity patterns, which are largely experience dependent [48] When a pathway in the nervous system is fired repetitively, the presynaptic pathway will develop increasingly more axonal sprouts. This will create more synapses than originally destined to be, resulting in an increase of firing probability through specific channels. [42, 48-51] Therefore, specific brain-based rehabilitation therapies has the potential to induce reconnections of damaged neural circuits, guiding in the recovery process. [42]

Management and Rationale A combination of therapeutic interventions aimed

at inducing positive neuroplasticity was administered through activation of receptor potentials of specific neuronal pathways. Therapeutic modalities were chosen in attempts to improve overall vestibular

function, including, visual gaze fixation, balance and gait, tactile perception, oxygenation of tissues, and increase global cortical activation with a bias towards the left hemisphere of the cerebral cortex. Therapies used were spinal and extra-spinal chiropractic adjustments, gaze stabilization exercises, earth-vertical axis rotations, multi-planar movements of the right-sided extremities, specific eye movement therapies, and breathing exercises.

For over one-hundred years, the Chiropractic profession has made claims that manipulation of joints, referred to as an adjustment, has a direct impact on the central nervous system. [52] A growing body of evidence suggests that manipulation of joints activates somatic neural receptors, inducing central nervous system plasticity, directly influencing cortical processing, sensorimotor integration and central pain modulation [53-71]. Accurate execution of movement depends on the ability of the central nervous system to integrate somatosensory, vestibular, and visual information regarding the position of the body. Spinal adjustments have shown to not only improve proprioceptive processing of the spine, but also of the extremities [53-57, 59-62, 65, 66].

Chiropractic spinal adjustments have been performed during PET scans and have proven to impact the inferior prefrontal cortex, anterior cingulate cortex, middle temporal gyrus, cerebellar vermis and visual association cortex. [67] Somatosensory evoked potential studies as well as electromyography studies have shown altered spinal and cortical integration twenty to thirty minutes post-adjustment. [54-57] Of particular importance in terms of rehabilitation is the possibility of selectively activating neuronal circuits of the brain with joint manipulations. Spinal and extra-spinal manipulations have shown a greater activation of the contralateral hemisphere of the cerebral cortex compared to the ipsilateral hemisphere. [63,64] Central nervous system plasticity induced by joint manipulations offer exciting therapeutic possibilities in the realm of brain rehabilitation, such as seen in TBI. In the present case, a majority of somatosensory activation was administered on the right side of the patient’s body in an attempt to activate neuronal circuitry associated with the left cerebral hemisphere. These interventions included spinal and extra-spinal chiropractic


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adjustments using an Activator IV instrument and passive, multi-planar movement of the extremities.

Vestibular rehabilitation therapy (VRT) is an exercise-based treatment program designed to promote vestibular adaptation and substitution. The main goals of VRT are to enhance gaze stability, enhance postural stability, improve any vertigo, and improve daily living activities. [15, 20,71] VRT is indicated for any stable but poorly compensated vestibular lesion, regardless of the patient’s age, the cause, and symptom duration and intensity. [16, 71] The overall mechanisms of recovery from vestibular lesions are vestibular adaptation and vestibular substitution. Vestibular adaptation involves readjusting the gain of the vestibulo-ocular reflex or vestibulospinal reflex, whereas vestibular substitution recruits alternative strategies to replace the lost vestibular function.

Gaze instability is due to a decreased gain of the vestibular system in response to head movements. The best stimulus for increasing the gain of the vestibular response is the error signal induced by retinal slip. Retinal slip may be induced by horizontal or vertical head movements while maintaining visual fixation on a target or by optokinetic visual stimulation. [71]. Both vertical and horizontal head movements, where the patient’s head was passively rotated left and right then extended and flexed while she was fixated on a dot, were used therapeutically. A 3:1 ratio, of vertical to horizontal head movements were used due to the increased compromise of eye movements in the vertical plane compared to horizontal.

Targets were placed in an oblique line where the patient would micro-saccade to a dot placed up and to the right, and then perform one set of passive gaze stabilization exercises. Saccades are fast eye movements aimed at moving visual fixation from one target to another. Saccades are generated by the contralateral frontal lobe and superior colliculus. [72] Therefore, right and upward micro-saccades were given in order to increase activity in neuronal networks associated with the left cerebral cortex and superior colliculus.

Rightward earth-vertical axis rotations, in a rotational chair, were utilized as part of the VRT in response to the vestibulo-ocular compensation being incomplete for rotations towards the lesioned side. [73] Whole body rotational stimulation has been

shown to increase postural stability, decrease sway, and improve gait parameters. [74, 75] Through vestibular afferents, rotational exercises activate the temporoparietal cortex, the insula, the putamen, the anterior cingulate cortex, the hippocampal formation, retrospenail cortex and the subiculum. [75]

Optokinetic visual stimulation was also administered as a treatment modality to enhance gaze stability. [71] Optokinetic nystagmus (OKN) is a component of visual motion processing and contributes to the stabilization of images on the fovea during either object-motion or self-motion. OKN is induced by unidirectional motion, which induces a rhythmic train of saw-tooth like reflexive eye movements, one being slowly in the direction of motion interspersed with one being rapidly in the opposite direction. [76] Independent of stimulus direction, optokinetic stimulation induces bilateral cortical and subcortical activation of the occipitotemporal cortex, posterior parietal cortex, precentral and posterior median frontal gyrus, prefortonal cortex, medial part of the superior frontal gyrus, caudate nucleus, putamen, globus pallidus and paramedian thalamus, as well as ocular motor structures. [77]

Optokinetic stimulation converges with somatosensory and vestibular stimuli in the secondary somatosensory cortex to influence sensorimotor integration. [47] OKN has also shown to charge the vestibular velocity storage mechanism which is an important function in generating appropriate vestibular responses. [78]

Leftward, right and upward, as well as left and downward optokinetic stimulation was used therapeutically with this patient with an effort to increase velocity storage, increase the performance of the right vestibulo-ocular reflex, activate motor neuronal pools associated with the left midbrain, and create neuroplasticity in both cortical and subcortical neuronal networks.

Breathing exercises were performed aiming to increase the amount of oxygen available for tissue saturation. This consisted of a three second inhalation through the nose, followed by a six second exhalation through the mouth. When an observed asymmetry of rib cage mechanics was present, a high-velocity-low-force manipulation was made to the costal

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articulations resulting in immediate symmetry of movement.

Conclusion This single case illustrates an example of specific

therapeutic interventions aimed at inducing neuroplasticity as an effective treatment for a patient with persistent neurological deficits following a traumatic brain injury. It suggests that this approach may be an option for other patients with brain injuries seeking a conservative non-surgical approach for resolution of persistent symptoms.

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Received: August 17 2014 Revised: November 1 2014

Accepted: November 4 2014


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Conferences December 2014

IEEE 2014 28th Convention of Electrical and Electronics Engineers

Engineering in Medicine and Biology

December 3-5, Eilat, Israel

Website: http://www.eng.tau.ac.il/~ieee/convention2014/index%202014.html

January 2015

Keystone Symposia: Neuroinflammation in Diseases of the Central Nervous System

January 25-30, 2015 Taos, NM, USA

Abstract: Neuroinflammation, the response of the central nervous system (CNS) to disturbed homeostasis, typifies all neurological diseases, from primary-inflammatory; to developmental; traumatic; ischemic;

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neoplastic; and neurodegenerative. This meeting will be the first Keystone Symposia meeting on neuroinflammation and will be the first to bring together the many communities of disease-focused neuroscientists and immunologists with an interest in the CNS. This nascent field needs a committed, interactive community and this Keystone Symposia conference promises to play a key role.

Topics: neurobiology, inflammation, immunology, neurodegenerative disease

Weblink: http://www.keystonesymposia.org/15A5

Contact: Attendee Services; Phone: [970-262-1230 or 800-253-0865]; Email: [email protected]

February 2015

March 2015

International Convention of Psychological Science

Amsterdam, The Netherlands

March 12-14, 2015

The Association for Psychological Science and the members of the Initiative for Integrative Psychological Science invite the international community of psychological scientists and related disciplines to a major new event: The International Convention of Psychological Science. ICPS is the culmination of efforts by APS and an international network of organizations and individual scientists to stimulate scientific advances that are integrative; that is, in which investigators attack scientific problems by drawing broadly on research conducted at multiple levels of analysis and in multiple branches of psychological science, the cognitive sciences, the neurosciences, and other related disciplines. The initiative has been designed, in essence, to surmount artificial disciplinary boundaries that can impede scientific progress and to highlight areas of investigation in which those boundaries have already been overcome. These efforts respond to developments in our rapidly changing field. Increasingly, challenges in psychological science can only be met by boundary-spanning investigations that address a phenomenon with diverse methods and at multiple levels of analysis. Such efforts require collaboration across academic disciplines and geographic boundaries. Seizing these opportunities requires a global effort and the involvement of the full range of disciplines, from those that study societies and cultures to those that investigate genetics and neural mechanisms.

Website: http://icps.psychologicalscience.org


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1st International Brain Stimulation Conference

March 2-4, 2015 Singapore, Singapore

Abstract: Brain stimulation methods are new approaches to research how the brain works and to treat diseases. In many ways the field of brain stimulation is a new paradigm shift, replacing the prominent neuropsychopharmacological paradigm of the past three decades. Currently there are single theme meetings around the world that are either technique or profession based. This international meeting, organized by Elsevier and sponsored by and integrated with the journal Brain Stimulation: Basic, Translational, and Clinical Research in Neuromodulation, will be the first ever brain stimulation meeting with integration of all of the various techniques and subspecialties involved in this exciting field.

Weblink: http://www.brainstimconference.com/

WSPC 2015 — 16th World Congress of Pain Clinicians

March 5-7, 2015 Miami Beach, USA

Abstract: WSPC 2015 will attract some of the world’s top pain experts. By focusing on participant-friendly educational activities together with hands-on courses, WSPC 2015 will facilitate an important discussion regarding interventional techniques for pain management. Topics: Pain, palliative, opioid, anesthesia, anaesthesia, intensive care, Acupuncture, acupressure, Epiduroscopy, pidural adhesiolysis, Fibromyalgia, Headache, Osteoporoses, kyphoplasty, pain medicine, migraine, neuropathic pain Weblink: http://www.kenes.com/wspc

Keystone Symposia: Pathways of Neurodevelopmental Disorders

March 16-20, 2015 Tahoe City, CA, USA

Abstract: The goal of this conference is to stimulate new treatments and biomarkers to assess treatments in neurodevelopmental disorders and to stimulate early intervention with prophylactic and targeted treatments. This conference is innovative because it pulls together basic science and translational clinical trials. By going from bench to bedside and mixing clinicians with molecular and neurobiologists we stimulate new ideas for treatment that will be beneficial across the spectrum of neurodevelopmental disorders. Topics: neurobiology, neurodegenerative diseases, development, neurodevelopmental disorders Weblink: http://www.keystonesymposia.org/15C8 Contact: Attendee Services; Phone: [970-262-1230 or 800-253-0865]; Email: [email protected]

AD/PD 2015 — The 12th International Conference on Alzheimer’s and

Parkinson’s Diseases

March 18-22, 2015 Nice, France Abstract: AD/PD will build on its well-earned reputation for unravelling the mechanisms and improving the treatment of Alzheimer's, Parkinson's and other related neurodegenerative diseases.


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Topics: Degenerative Disorders, Movement disorder, alzheimer’s, parkinson’s , dementia, lewy bodies, lobar degeneration, huntington’s Weblink: http://www.kenes.com/adpd Contact: Rachel Zablow Katzir Kenes International 1-3, Rue du Chantepoulet; P.O. Box 1726 CH-1211 Geneva 1, Switzerland; Phone: [+41 22 908 0488]; Email: [email protected]

International Ataxia Research Conference

March 25-28, 2015 Old Windsor, Berkshire, United Kingdom

Weblink: http://www.ataxia.org.uk/events.php

COMS online registration: https://www.conference-service.com/ARC-2015/welcome.cgi

The Lancet Neurology Autoimmune Disorders Conference

March 26-27, 2015 Barcelona, Spain

Abstract: The Lancet Neurology Autoimmune Disorders Conference will bring together international experts to review cutting-edge clinical and laboratory findings and take part in an authoritative discussion of autoimmune targets in the CNS and the crucial role of the NMDA receptor in synaptic function, paving the way for future research into immunological mechanisms of brain disease. The event will have a translational focus, covering mechanisms of immunity in the CNS, clinical consequences of autoimmunity, and experimental models to study anti-NMDA receptor encephalitis and other neurological diseases. Weblink: http://www.nmdareceptorconference.com

April 2015

17th International Neuroscience Winters Conference

April 7-11, 2015 Soelden, Austria

Abstract: This conference has been established as a high-quality meeting on contemporary neuroscience in the past years. For the 17th conference we aim at topping previous programs by inviting most distinguished neuroscientists as keynote speakers and select high-quality symposia.

Weblink: http://www.winterneuroscience.org/2015

ECNR - The Pierre Lasjaunias Course in Neuroradiology, Diagnostic

and Interventional, 12th Cycle, 2nd Course, Brain Tumors

April 8-13, 2015 Athens, Greece

Weblink: http://www.esnr.org/en/ecnr-12th-cycle-2nd-course


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ADI 2015 — 30th International Conference of Alzheimer's Disease International

April 15-18, 2015 Perth, Australia Weblink: http://www.alzint.org Contact Email: [email protected]

AACNS 2015 — The 14th Asian Australasian Congress of Neurological

Surgeons

April 15-18, 2015 Jeju, South Korea Abstract: The four-day congress will feature an exciting line-up of expert speakers including top practitioners, opinion leaders and researchers. Delegates can look forward to an intensive knowledge-sharing event comprising plenary sessions, oral presentations and video screenings. There will be a host of networking opportunities for delegates to rub shoulders with top experts and opinion leaders. Topics: Glial tumors, metastatic tumors, Spinal cord tumors, spinal column tumors, Tumors of peripheral nerves, Medulloblastoma, Craniopharyngioma, sellar lesions, Acoustic tumors, Skull-base lesions, Pediatric low-grade gliomas, Germ-cell tumors, Moder imaging techniques, Chemotherapy for brain and spinal cord tumors, Radiotherapy, Proton Beam debate, Neurofibromatosis, CNS neoplasms Weblink: http://aacns2015.com Contact: Gabriel Heng; Phone: [+65 295 6984]; Email: [email protected]

The European Stroke Organization Conference 2015

April 17-19, 2015 Glasgow, United Kingdom Abstract: The aim of the European Stroke Organisation is to provide medical education to healthcare professionals and the public of Europe, reducing the incidence and impact of stroke by changing the ways that stroke is viewed and treated. Topics: Stroke, ischemia, cerebrovascular disorder, cerebrovascular attack, brain attack, ischemic stroke, hemorrhagic stroke, ischaemic stroke, haemorrhagic stroke Contact: Keren Shurkin , Kenes International; Phone: [+41 22 908 0488]; Email: [email protected]

Jahrestagung der Gesellschaft für Neuropaediatrie und 12.

Fortbildungsakademie

April 23-26, 2015 Basel, Switzerland

Weblink: http://www.neuropaediatrie-congress.de


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May 2015

The 4th ISCoS and ASIA Joint Scientific Meeting, 2015

May 14-16, 2015 Montreal, Canada Abstract: The 4th ISCoS and ASIA Joint Scientific Meeting 2015 will take place at the Fairmont Queen Elizabeth Hotel in Montreal, Canada. Topics: ISCoS, ISCoS 2015, ASIA, ASIA 2015, ISCoS / ASIA 2015, Spine, Spinal Cord Injury, Spine Surgery, Neurology, Orthopaedics, Participation/QoL, Clinical Trials, Endocrinopathy in SCI, Non-traumatic SCI, Exoskeletons/Robotics, Urology/Sex/Fertility, Activity Dependant Rehab, Immunological Factors, Respiratory Care/Issues, Clinical Practice Guidelines, Surgical Treatment Weblink: http://www.iscosasia2015.org Contact: Organising Secretariat Contendam Ltd 26-28 Hammersmith Grove London W6 7HA; Phone: [+44 (0) 208 748 8868]; Email: [email protected]

IHC 2015 — 17th Congress of the International Headache Society

May 14-17, 2015 Valencia, Spain Abstract: Join your colleagues at beautiful Valencia for the 17th Congress of the International Headache Society (IHC 2015) and benefit from an unparalleled educational forum, where you will learn about the newest developments, and innovative techniques in reducing the pain and suffering caused by headaches. Topics: Migraine, persistent headache, Clinical Trial Methodology, Cluster Headache and Other Trigeminal Autonomic Cephalalgias, Drug Therapy of Other Headaches, Epidemiology, Pharmacoeconomics, Refractory Headache, Genetics and Biomarkers of Headache Disorders Weblink: http://www.ihc2015.com Contact: Joanne Katz , Kenes International, Switzerland; Phone: [+41 22 908 0488]; Email: [email protected]

NeuPSIG2015 — 5th International Congress on Neuropathic Pain

May 14-17, 2015 Nice, France Abstract: NeuPSIG 2015 is an international forum that provides the latest research and developments in understanding the mechanisms, assessment, prevention and treatment of neuropathic pain. Topics: neuropathic pain, neuropathy, pain management, microgial, opioids Weblink: http://www.kenes.com/neuropathic Contact: Raya Van Hugten, Kenes International, Switzerland; Phone: [+41 22 908 0488]; Email: [email protected]


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EPNS 2015 - 11th European Pediatric Neurology Society Congress

May 26-30, 2015 Vienna, Austria

Weblink: http://www.epns2015.org

Gordon Research Conference — CAG Triplet Repeat Disorders 2015

May 31 – June 5, 2015 Lucca, Italy Abstract: Trinucleotide CAG expansion mutations cause a number of progressive neurodegenerative disorders including Huntington’s disease (HD), the spinocerebellar ataxias (SCAs) 1, 2, 3, 6, 7 and 17, and spinal and bulbar muscular atrophy (SBMA). These diseases are thought to primarily result from aberrant protein gain-of-function effects, although the recent discovery of antisense transcripts at several of these loci and a new appreciation for the complexity of gene expression and epigenetic changes across the genome has raised additional possibilities. The Gordon Conference on CAG Triplet Repeat Disorders and the associated Gordon Research Seminar (GRS) will bring together scientists from around the world to discuss cutting-edge research on the molecular and cellular mechanisms of these disorders and the various therapeutic strategies which are being developed to combat them.

Weblink: http://www.grc.org/programs.aspx?id=12982

Gordon Research Conference — Neurotrophic Factors 2015

May 31 – June 5, 2015 Newport, USA

Abstract: Neurotrophic factors play essential roles in the developing and mature nervous system. While Nerve growth factor (NGF) was the first neurotrophic factor when it was identified more than 50 years ago, a large set of related and unrelated extracellular proteins are now known to exert neurotrophic effects in the developing and mature nervous system. The roles of neurotrophic factors include regulation of cell proliferation, survival, differentiation, migration, axon and dendrite growth, synaptic plasticity and the interactions of neuronal and glial cells. As a result, neurotrophic factors affect complex behaviors including feeding, anxiety, depression and learning, and aberrations in the activities of neurotrophic factors have been implicated in multiple neurologic and psychiatric disorders. The Neurotrophic Factors Gordon Conference provides a great opportunity to learn of recent advances in this broad field, and enhances collaborations among scientists and students. The meeting will feature work on diverse neurotrophic factors and their roles in neurogenesis, neuronal migration, survival, plasticity, behavior and diseases, including disorders of neural development such as autism and epilepsy and degenerative disorders such as Alzheimer's disease and peripheral neuropathies. Emphasis will be placed on the most recent developments.


17th Congress of the International Pain Society

May 14-17, 2015 Valencia, Spain

Join your colleagues at beautiful Valencia for the 17th Congress of the International Headache Society (IHC 2015) and benefit from an unparalleled educational forum, where you will learn about the newest developments, and innovative techniques in reducing the pain and suffering caused by headaches. IHC 2015 will include satellite symposia, teaching sessions, scientific sessions, debates sessions, platform presentations, networking sessions, and more, all presented by international experts. This is your


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opportunity to gain new knowledge in the field of Headaches and exchange new ideas with experts and colleagues from around the world.

Website: http://www.ihc2015.com

June 2015

5th IDKD Intensive Course in China: Diseases of the Brain, Head, Neck and Spine

June 6-8, 2015 Beijing, China

Weblink: http://www.idkd.org/cms/Public/Documents/China2015Flyer.pdf

International Neuromodulation Society 12th World Congress

June 6-11, 2015 Montreal, Canada

Abstract: The International Neuromodulation Society 12th World Congress will take place in Montreal, Canada on June 6 – 11, 2015. We have chosen the title “Neuromodulation: Medicine Evolving Through Technology,” to emphasize our field’s transformative force on the treatment of disease states – how it is approached now and will be approached in the not too distant future. We see almost daily reports in the mainstream media of innovation in the area of neuromodulation treating not only pain, but many conditions of the cardiovascular, neurological, gastrointestinal, urological and other systems. This meeting will mark an important time for our field. Weblink: http://www.neuromodulation.com/inscongress

Gordon Research Conference — Excitatory Synapses & Brain Function

June 7-12, 2015 Newport, United States

Abstract: Perhaps no other structure is more fundamental to our understanding of the brain than the synapse. In the central nervous system, excitatory synapses represent the primary source of information communication between neurons, whether for local interactions within circuits or for linking discrete regions of the brain. One of the most extraordinary properties of excitatory synapses is the ability to under activity-dependent long-lasting changes in synaptic strength, providing the most compelling cellular model for learning and memory. Synapses also serve as the site of action for many commonly prescribed medications and synaptic disruption contributes to many neurological and psychiatric disorders. These include schizophrenia, autism, depression, substance abuse and addiction, Parkinson’s disease, Alzheimer’s


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disease, traumatic brain injury, stroke and epilepsy. In some cases, synaptic dysfunction is causal in disease, whereas in other cases it represents the downstream sequelae of one or more underlying molecular defects. In either case, a fundamental understanding of the formation, structure, molecular organization, signaling function, and plasticity of synapses is essential to achieving progress in lessening the burden of human neurological disease and for predicting and improving mental health.


EMRI Course: Central Nervous System I

June 8-12, 2015 London, United Kingdom

Weblink: http://www.emricourse.org/cns1_2015.html

Continuing Education Cruise Conference — Neurology and Pain

Management Cruise to France and Spain

June 13-20, 2015 Southampton, United Kingdom

Organizer: Continuing Education Inc.

Weblink: http://www.continuingeducation.net/schedule.php

EMBO | EMBL Symposium — Mechanisms of neurodegeneration

June 14-16, 2015 Heidelberg, Germany

Topics: Neuroscience, Molecular Medicine

Weblink: http://www.embo.org/events

EMBO | EMBL Symposium: Mechanisms of Neurodegeneration

June 14-17, 2015 Heidelberg, Germany

Abstract: Neurodegenerative diseases represent a major challenge for today’s society in terms of the large and rapidly increasing number of the population that are afflicted and the general lack of effective treatments. The emphasis of this symposium will be on the genetic, cellular and molecular basis of neurodegenerative diseases including Alzheimer’s, Parkinson’s, Huntington’s, Amyotrophic Lateral Sclerosis and Prion disease. The meeting will cover the major mechanisms linked to neurodegeneration and highlight the similarities and differences between the diseases. A strong emphasis will be placed on the development of targeted drug therapies and potential treatment options.

Topics: Neurons, Genetics, Biology, Molecular Biology, Disease, Neurodegeneration, Cell Biology, Treatment

Weblink: http://www.embo-embl-symposia.org/symposia/2015/EES15-03/index.html


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Gordon Research Conference — Infections of the Nervous System: Pathogenesis and Worldwide Impact

June 14-19, 2015 Hong Kong, China

Abstract: In comparison to studies on infections of the nervous system in western societies, studies on diseases of such nature in the developing world have been neglected. This is paradoxical as neurotropic pathogens are frequent in the developing world and contribute significantly to human suffering and disease burden. Moreover living with neurological handicap and/or cognitive dysfunction will have a significant impact on socio-economic development. As the central nervous system is usually not the primary target site of infection, a window of opportunity exists to interfere with pathogen spreading. The Gordon Research Conference on "Infections of the nervous system" will advance knowledge in the field and promote exchanges between medical research centers in resource-rich and -poor regions. The format of GRC (community-based, small audience, focus on unpublished material) is ideal to create a multidisciplinary dialogue that will involve both clinicians and scientists studying disease mechanisms and host genetics, the molecular make-up of neurotropic infectious agents, and the innate and adaptive immune response to neurotropic pathogens. In addition, groups working on developing new technologies for diagnosis and prognosis will be included. This new series will bring together renowned clinicians and scientists, who investigate clinical disease manifestations and the molecular mechanisms underlying worldwide infections of the nervous system in humans. This will foster collaborations to accelerate/expand investigations and use new technologies allowing fast development of diagnostic/prognostic tools and pioneering drug discoveries.


Jahrestagung der Sektion Kindertraumatologie in der DGU

June 19-20, 2015 Koblenz, Germany

Weblink: http://www.intercongress.de

Gordon Research Conference — Modulation of Neural Circuits &

Behavior

June 21-26, 2015 Hong Kong, China

Abstract: An essential function of the nervous system is to generate optimal behavioral responses to diverse environmental cues. Experience can profoundly modulate this process by modifying the properties of the underlying neural circuits. With prolonged activity, sensory inputs can also shape the development of neural circuits to produce adaptation. An ever-increasing number of neuromodulators, including monoamines, peptides and growth factors, act on neural networks to regulate a wide range of behavioral and physiological traits, including emotion, sleep, motivation, as well as learning and memory. A mechanistic understanding of neuromodulation faces two fundamental challenges: first, how are sensory signals transduced into specific and time-dependent release of neuromodulators; second, how are neurons organized into circuits that release or respond to neuromodulators? Neuromodulation, while essential to nervous system function, has been significantly more difficult to study than classical neurotransmission. However, in the past decade, several advances have led to dramatic progress. These advances include the mapping of neuromodulatory circuits, physiological analysis of circuit dynamics, theoretical modeling of circuit properties, and interrogation of circuit function using genetic methods. More recently, stunning technological advances in imaging and light-controlled neural excitation have enabled high resolution studies of specific neural circuits. These interdisciplinary efforts have led to rapid progress in our


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understanding of how neural circuits are modulated to generate adaptive behaviors. This new conference will bring together researchers from a variety of disciplines and model systems, all with an eye on the common goal of understanding neuromodulation. By design, this conference will foster cross-disciplinary collaborations that will help drive the next breakthroughs in our understanding of neuromodulatory control of behavior. The meeting will cover research and technical developments in both invertebrate and vertebrate model systems, as well as draw in expertise in modeling and imaging. Our goal is to organize a dynamic conference that will highlight the exciting advances in neuromodulation and attract new talent and energy to this rapidly developing field. The neuroscience research in Asia has grown tremendously in the past few years and many scholars in China and Japan have made remarkable contributions to our understanding of neural circuits. Thus, this Gordon Research Conference will be held in Hong Kong, a central meeting point that reflects the global efforts to understand neuromodulation.


The 2015 Alzheimer's Disease Congress

June 23-25, 2015 London, United Kingdom

Abstract: This three day event will discuss aspects of Alzheimer's Disease development and treatment in an informal academic setting. Topics for discussion include prediction and prevention strategies, vaccine development, drug discovery and care. With plenty of opportunity for networking and debate, this informal international meeting will bring you up to date with current research and thinking regarding Alzheimer's Disease.

Weblink: https://www.regonline.co.uk/Alz2015

BRAIN, BRAIN PET2015 — 27th International Symposium on

Cerebral Blood Flow, Metabolism and Function and 12th International Conference on Quantification of brain function with PET

June 27-30, 2015 Vancouver, Canada Abstract: Brain2015 will debate, discuss and analyze research in brain protection and neurodegeneration, and will advance understanding of brain function under physiological and pathological conditions. Topics: Cerebral blood flow, biomarkers, brain edema, neuroimaging, stroke, hyperemia, ischemia, brain mapping, stroke

Weblink: http://brain.kenes.com

Contact: Charlotte Boskila c/o Kenes International; Phone: [+41 22 908 0488]; Email: [email protected]

Brain ‘15

June 27-30 2015 Vancouver, Canada

BRAIN’15 and BRAINPET’15 together form a niche biennial meeting targeting researchers in the neuroscience, neurology and neurosurgery fields. International brain specialists will join for an educational forum whose ultimate aim is to shape the future of brain research. To address all major facets of this highly complex discipline, a progressive and wide ranging scientific program has been organized that will feature renowned speakers, ground-breaking research topics, enlightening sessions and stimulating debates.

Website: http://brain.kenes.com


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Gordon Research Conference — Parkinson's Disease: Emerging Research in the Etiology and Pathogenesis of a Complex Disease 2015

June 28 – July 3, 2015 New London, United States

Abstract: Parkinson’s disease (PD) is the most common motor disorder. Over the past fifteen years, the discovery of disease-causing mutations in a growing number of genes has accelerated the pace of our understanding of disease mechanisms. Simultaneous discoveries in cell biology and immunological processes are rapidly providing insights into the processes that lead to this disease. This creates an exciting series of challenges and opportunities to be addressed by discussion and exchange of ideas. There has to our knowledge never been a basic research conference devoted to Parkinson’s, and this conference will bring together investigators with diverse scientific backgrounds who share an interest in the cellular mechanisms that produce PD and its related disorders. The specific content of the Conference will evolve as our understanding of PD evolves. For the first Conference, topics will include: The normal function of PD-related genes; The cellular response to toxic protein aggregates; Endoplasmic reticulum stress; Proteasomal and autophagic processes; Neuroimmune pathways; and Prion-like aggregate pathogenesis.


July 2015 Continuing Education Cruise Conference — Primary Care: Neurology

Update 2015

July 15-27, 2015 Amsterdam, The Netherlands

Organizer: Continuing Education Inc.

Weblink: http://www.continuingeducation.net/schedule.php

Gordon Research Conference — Neural Crest & Cranial Placodes

July 19-24, 2015 Waltham, USA

Abstract: Neural crest cells and cranial sensory placodes are of central importance to the development and evolution of vertebrates, and are also of high clinical significance. This conference is designed to facilitate shared insights among attendees and fuel further advances in our understanding of the mechanisms governing the formation, behavior and differentiation of these two cell populations, as well as to catalyze the application of this knowledge to the field of regenerative medicine. The central goals of the conference are to accelerate the exchange of information across different model systems, to promote technological innovations in the field, and to further a genome and proteome scale understanding of the mechanisms that govern the development of neural crest cells and cranial sensory placodes. Both neural crest cells and cranial placode cells make extensive contributions to embryonic structures, and defects in their development underlie a broad range of congenital disorders. Neural crest cells display stem cell attributes, and neural crest-derived cells persist as stem cells into adulthood; studies of these cells provide broad insights into stem cell biology. Moreover, neural crest cells undergo migratory and invasive behavior driven by core EMT regulatory factors, and understanding how their behavior is regulated provides insights into the related invasive behavior of metastatic tumor cells. Cranial placode cells play important roles in the development of cranial sensory structures; mutations in genes that regulate their development lead to human syndromes with severe sensory deficits and dysregulated cell cycle control in numerous cancers. The conference will bring together a diverse group of scientists in a collegial atmosphere that fosters


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substantive discussions and promotes collaborative interactions between basic and clinical scientists in this important area of biomedical research.


August 2015

Gordon Research Conference — Amygdala in Health and Disease

August 2-7, 2015 Easton, USA

Abstract: The amygdala, a temporal lobe structure that forms part of the limbic system, plays a key role in emotional processing. Its relevance to fear and anxiety in animals has been well known since the classic experiments of Kluver and Bucy, who made mid-temporal lesions in monkeys and found profound effects on the emotional and social behaviour of these animals. Focus on studies of the amygdala expanded greatly when its role in fear conditioning was established. Fear conditioning is a simple Pavlovian conditioning task in which a neutral stimulus is contingently paired with an aversive stimulus. The simple nature of this learning task, and the readily measured physiological changes that accompany it, have made the study of fear conditioning a very attractive target for the study of learning and memory consolidation. As the neural circuitry that underlies fear conditioning is simple and appears to be preserved between species, it presents an accessible model for the study of learning and memory formation in the mammalian nervous system. Because of the physiological similarities between animal and human fear, fear conditioning is seen as relevant to the genesis of anxiety disorders in humans. Moreover, recent research indicates that changes in amygdala function may contribute more generally to pathological forms of emotional learning such as drug addiction. Functional magnetic resonance imaging in humans has clearly established the role of the amygdala in emotional processing. Interest in amygdala function has therefore attracted growing interest in both animal and human experiments using both simple behavioural tests and functional imaging. This Conference focuses on research investigating the role of the amygdala in the formation of emotional memories, both normal and pathological.


Gordon Research Conference — Cerebellum

August 9-14, 2015 Lewiston, USA

Abstract: The Gordon Research Conference on the Cerebellum will bring together scientists studying the cerebellum at all levels of analysis, with a goal of fostering dialogue among people engaged in different subfields of cerebellar research. The scientific program has been designed to provide a venue for anatomists, electrophysiologists, developmental biologists, and behavioral neuroscientists, and other researchers with interest in the cerebellum to communicate their latest work to one another. Scientific sessions will cover a wide range of topics, including cerebellar development, human cerebellar function, sensorimotor integration, cerebellar connections to the inferior olive and basal ganglia, emerging technologies to study the cerebellum, cerebellar anatomy, synaptic and circuit mechanisms, and the cerebellum in autism, dystonia, and ataxia. Speakers include senior and junior researchers from all over the world, and the meeting will provide opportunities for scientists of diverse backgrounds and career stages to interact and discuss their hypotheses and discoveries with all other attendees, from leading cerebellar scientists to promising trainees. In addition to the thematic sessions, poster sessions will provide opportunities for attendees to present their work, and a subset of submitted abstracts will be selected to permit graduate students and/or postdoctoral fellows to give short talks. The Conference promises to generate a lively and collegial exchange of ideas, cultivate meaningful collaborations, and ultimately lead to a better understanding of the cerebellum in health and disease.



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Gordon Research Conference — Inhibition in the CNS

August 16-21, 2015 Lewiston, USA

Abstract: Inhibitory control of neural circuits is critical to the function of the central nervous system and represents a major target for therapeutics. The 2015 Gordon Research Conference on Inhibition in the CNS will present cutting edge research on molecular, synaptic and circuit-level mechanisms of inhibition, with the goal of facilitating in-depth discussions and collaborations between investigators to advance knowledge in the field. The program will feature prominent investigators that explore fundamental aspects of inhibitory neural function at all levels. Scientific sessions will cover topics including regulation of inhibitory synaptic transmission and plasticity, the role of GABA in developing circuits as well as the development of inhibitory synapses and interneuron diversity, inhibition in intact circuits, and GABAA receptors as drug targets. The meeting will offer a collegial atmosphere with substantial time for interactions among scientists and trainees during the multiple poster sessions and informal gatherings. Some poster presenters will be selected for short talks. The conference promotes opportunities for junior scientists to present research and interact with leaders in the field. The preceding Gordon Research Seminar (GRS) will make this meeting particularly attractive for graduate students and postdoctoral fellows, providing a forum for oral and poster presentations that will prepare junior scientists for the subsequent GRC. The conference promises high-quality and cutting-edge scientific sessions, a lively and collegial exchange of ideas, and a deeper understanding of fundamental mechanisms of inhibition in brain function.


ISN-APSN in conjunction with ANS 2015 — International Society for

Neurochemistry Asian-Pacific Society for Neurochemistry 25th Biennial Joint Meeting in conjunction with the Australasian Neuroscience

Society August 23-27, 2015 Cairns, Australia

Abstract: The ISN-APSN in conjunction with ANS 2015 biennial meeting promises to be an exciting scientific meeting, providing an opportunity to engage with the best researchers in cellular and molecular neuroscience in a stunning environment.

Topics: neurochemistry, neuroscience, cellular neuroscience, molecular neuroscience, neurotransmitter, psychopharmaceutical, neurotransmission

Weblink: http://www.neurochemistry.org/biennial-meeting/isn-2015-biennial-meeting.html

Contact: Ronit Eisenbach , Kenes International; Phone: [+41 22 906 9151]; Email: [email protected]

September, 2015

EMRI Course Central Nervous System II

September 4-8, 2015 Dubrovnik, Croatia

Weblink: http://www.emricourse.org/cns2_2015.html


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October 2015

International Association of Functional Neurology and Rehabilitation

6th Annual Conference and Awards Dinner

October 8-11, 2015

ORLANDO, FLORIDA!

International Congress of the International Neuropsychiatric Assn

October 14-16, 2015 Jerusalem, Israel

Weblink: http://www.ina2015.com/

Society for Neuroscience 2015 Annual Meeting

October 17-21, 2015 Chicago, USA

Abstract: Neuroscience 2015 is the premier venue for neuroscientists to present emerging science, learn from experts, forge collaborations with peers, explore new tools and technologies, and advance careers. Join more than 30,000 colleagues from more than 80 countries at the world’s largest marketplace of ideas and tools for global neuroscience.

Weblink: http://www.sfn.org/annual-meeting/past-and-future-annual-meetings

WCN 2015 — XXII World Congress of Neurology

October 31 – November 5, 2015 Santiago, Chile

Abstract: The XXII World Congress of Neurology will unite top international neurologists. Featuring several tracks on various neurological disorders, WCN 2015 will be one of the world’s prime events on neurology.

Topics: Neurology, parkinson’s, epilepsy, stroke, movement disorder, headache, neurorehabilitation, autonomic nervous system, ANS, central nervous system, CNS, neuropathy, neurotoxin, neuroimaging, neuromuscular, dementia, neuroradiology, multiple sclerosis, MS, demyelinating disease

Weblink: http://www.wcn-neurology.com/

Contact: Rene Chait, Kenes International; Phone: [+41 22 908 0488]; Email: [email protected]


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Recent Conference Presentations 1. Leisman, G. Children’s Language Production: How Cognitive Neuroscience & Industrial Engineering Can

Inform Public Education Policy and Practice [Invited Paper Presented at the Oxford University Roundtable on Public Policy, 11-15 March, 2012] (http://www.oxfordroundtable.com/index.php/view/Sessions-Item/id/141)

2. Leisman, G. The Brain on Art: Auditory, Visual, Spatial Aesthetic, and Artistic Training Facilitates Brain Plasticity [Invited presentation, International Association of Functional Neurology and Rehabilitation, Phoenix, AZ USA 24-28 October, 2012] (http://www.frcarrickresearchinstitute.org/conference)

3. Jubran, F. Leisman G. Intersensory Integration in Functional Neurology: An Engineer's Perspective of Music as an Interventionary Medium. [Paper presented, International Association of Functional Neurology and Rehabilitation, Phoenix, AZ USA 24-28 Oct., 2012] (http://www.frcarrickresearchinstitute.org/conference)

4. Rosner, A. F., Leisman, G., Gilchriest, J. Reliability and validity of therapy localization in applied kinesiology. [Paper presented at the Society for Neuroscience, New Orleans, October 16-18, 2012] (http://www.sfn.org/am2012/)

5. Leisman, G. The Brain on Art: Auditory, Visual, Spatial Aesthetic, and Artistic Training Facilitates Brain Plasticity. [Invited paper presented at Conference of the International Association of Functional Neurology and Rehabilitation, Phoenix, Arizona, USA, 25-28 Oct., 2012] (http://frcarrickawardsdinner.charityhappenings .org)

6. Leisman, G. Brains, Bilinguals, and Functional Connectivities: Neural Networks Play Out in the Classroom. [Paper presented at the London Education Research Symposium. London England 19-21 November, 2012]. (http://www.london-education-research-symposium.com/).

7. Leisman, G. Organizer of Conference on “Globalizing Science in Nazareth” [Friday 7 December 2012] 8. Leisman, G. Melillo, R., Machado, C., Rodriguez-Rojas,R. Batista, K. Carballo,M. Mualem,R. Functional

Disconnectivities in Autistic Spectrum Individuals [Paper presented at the International Conference of Child Health and Human Development, Jerusalem, Israel December, 2012] (http://www.isas.co.il/chhd/)

9. Leisman, G. Functional Connectivities in the Post-Natal Development of Consciousness. [Paper presented at the International Conference of Child Health and Human Development, Jerusalem, Israel December, 2012] (http://www.isas.co.il/chhd/)

10. Estévez, M., Machado, C., Leisman, G., Melillo, R., Machado, A., Hernández-Cruz, A., Arias A., Rodríguez-Rojas R., Carballo M. Eegconn: A Software Tool for Offline qEEG Analysis, Including Spectral Univariate and Bivariate Processes and Linear and Non-Linear Indices of Brain Connectivity in Autistic Spectrum Disorder. [Paper presented at the International Conference of Child Health and Human Development, Jerusalem, Israel December, 2012] (http://www.isas.co.il/chhd/)

11. Rodriguez-Rojas, R, Batista, K, Carballo, M, Machado, C, Leisman, G, Estévez, M., Melillo, R. Anatomical And Topological Connectivity Reveal Different Attributes of Disrupted Small-World Networks in Autistic Children. [Paper presented at the International Conference of Child Health and Human Development, Jerusalem, Israel December, 2012] (http://www.isas.co.il/chhd/)

12. Jammalieh, J. Mualem, R., Leisman, G. Clinical effects of the development of physiological rhythms in premature infants.[Paper presented at the International Conference of Child Health and Human Development, Jerusalem, Israel December, 2012] (http://www.isas.co.il/chhd/)

13. How Cognitive Neuroscience & Industrial Engineering Can Inform Decision Making Using Optimization Models in Diagnosis, Treatment and in the Evaluation of Effectiveness in Rehabilitation Environments. [Paper presented to Israel Medical Association December, 2012]. (http://moked.it/ame/files/2012/12/IMA-WF_conference_program_December_2012.pdf)

14. Leisman, G. Optimization Methodology and Functional Connectivities Inform the Cognitive Modifiability in the Rehabilitation of Developmental Language Difficulties [Invited Plenary Paper presented at the Conference on Cognitive Modifiability, Jerusalem, Israel 3-5 June 2013]. (http://www.brainconvention.org/en/index.php?page_id=48)

15. Leisman, G. If It Is Localization then There Is No Development, Education, & Rehabilitation: It’s the Networks Silly. [Invited Plenary Paper presented at the 4th Conference of the International Association for Functional Neurology, and Rehabilitation, 10-13 October, 2013 Phoenix, Arizona].

16. Leisman, G., Machado, C., Melillo, R. The Development of Fetal And Neonatal Consciousness [Invited Plenary Address, VI International Conference on Brain Death and Disorders of Consciousness, 3-6 December, 2013] (http://www.komascience-cuba.com/)


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17. Leisman, G. & Mualem, R. Brains, Bilinguals, and Functional Connectivities: Neural Networks Play Out in the Classroom. [Invited Speaker Oxford Education Research Symposium at St. Edmund Hall, Oxford University. 25-26 March 2014] (http://www.oxford-education-research-symposium.com/)

18. Leisman, G. Functional Connectivities and Re-connectivities Reflect Cognitive Modifiability in Neurorehabilitation. [Invited paper presented at the Second Annual Conference in Rehabilitation Medicine, Balitmore MD, USA 1-16 July 2014]. (http://dx.doi.org/10.4172/2329-9096.S1.006)

19. Leisman, G. Optimization Models for Quantifying Visual Search Scanpath Efficiency: Measuring Treatment Recovery in Traumatic Brain Injury. [Invited paper presented at the Second Annual Conference in Rehabilitation Medicine, Baltimore MD, USA 1-16 July 2014]. (http://dx.doi.org/10.4172/2329-9096.S1.006)

20. Leisman, G., Gilchriest. J., Rodriguez-Rojas, R., Estevez, M., Machado, C., Kaspi, M., Melillo, R. A Method for Quantifying Visual Search Scanpath Efficiency in Elucidating Cognitive Status Post Traumatic Brain Injury. [Paper to be presented IEEE-Israel, Eilat, Israel 2-5 December, 2014].

21. Leisman, G., Rodríguez Rojas, R., Batista, K., Carballo, M., Morales, J.M., Iturria, Y., Machado, C. Measurement of Axonal Fiber Connectivity in Consciousness Evaluation. [Paper to be presented IEEE-Israel, Eilat, Israel 2-5 December, 2014].

22. Leisman, G. The Coincident Decline of Movement and Cognitive Ability: Movement Sciences in the Aid of Public Health Policy Intervention. [Paper presented at the 4 t h International Conference on Pediatric Disease, Disability and Human Development, 20-23 January, 2015, Jerusalem Israel]

23. Mualem, R., Leisman, G., Mograbie, S.K., Boshnak S. Brain-Based Learning During Preschool: An Underused Window of Opportunity. [Paper presented at the 4th International Conference on Pediatric Disease, Disability and Human Development, 20-23 January, 2015, Jerusalem Israel]

24. Leisman, G. Machado, C. Thinking, Walking, Talking: The Development of Integratory Brain Function [Paper presented as part of a Symposium on Movement and Thought at the International Convention of Psychological Sciences, Amsterdam, The Netherlands, 12-14 March, 2014]

25. Leisman, G. and Braun-Benjamin, O. Symposium on Movement and Thought at the International Convention of Psychological Sciences, Amsterdam, The Netherlands, 12- 14 March, 2014]

Recent Books and Chapters 1. Melillo, R. M. and Leisman, G. Neurobehavioral Disorders of Childhood Beijing, China: People's

Medical Publishing House (PMPH) 2012 [China Translation]. 2. Leisman, G and Melillo, R. The Development of the Frontal Lobes in Infancy and Childhood:

Asymmetry and the Nature of Temperament and Adjustment. In: Cavanna, A.E. (Ed.) Frontal Lobe: Anatomy, Functions and Injuries. Hauppauge, NY: Nova Science Publishers, 2012. (https://www.novapublishers.com/catalog/product_info.php?products_id=33647&osCsid=ca12dd85a94460fd325d2daa3dbcf2d4)

3. Leisman,. G. Melillo, R. The Basal Ganglia: Motor and Cognitive Relationships in a Clinical Neurobehavioral Context In: E. Franz (Ed) Basal Ganglia, Rijeka, Croatia: In: Tech, 2012. [ISBN 980-953-307-193-5] (http://www.intechopen.com/booksprocess/aboutthebook/chapter/78485/book/26 04)

4. Leisman, G., Melillo, R., Mualem, R., Machado, C. The effect of music training and production on functional brain organization and cerebral asymmetry. In: Art, Science and Technology. Tatyana Kravchuk, Alec Groysman, Celestino Soddu, Enrica Colabella, Gerry Leisman (Eds).] Mialno, Italy; Domus Argenia Publisher, 2012, pp. 133-139. [ISBN: 978-88-96610-24-4] (www.artscience-ebookshop.com/1stAST_proceedings.pdf)

5. Leisman, G. Optimization Methodology and Functional Connectivities Inform the Cognitive Modifiability in the Rehabilitation of Developmental Language Difficulties. Cognitive Modifiability. Bologna, Italia: Medimond s.r.l. 2013 (http://www.medimond.com/ebook/Q602.pdf)

6. Estevez, M., Machado, C., Leisman, G., Melillo, R., Machado, A., Hernandez-Cruz, A., Arias, A., Rodriguez-Rojas, R., Carballo, M. EEGConn: A Software Tool for Offline qEEG Analysis, Including Spectral Univariate and Bivariate Processes and Linear and Non-Linear Indices of Brian Connectivity in Autistic Spectrum Disorder. Chronic Disease and Disability in Childhood. Hauppauge, NY: Nova Science Publishers, 2013, p. 65.


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7. Jammalieh, J., Mualem, R., Leisman, G. Clinical Effects of Physiological Rhythms in Premature Infants. Chronic Disease and Disability in Childhood. Hauppauge, NY: Nova Science Publishers, 2013, p. 109.

8. Leisman, G. Advances in Cognitive Neuroscience and Optimization Can Inform The Rehabilitation Process in Developmental Language Difficulties. Chronic Disease and Disability in Childhood. Hauppauge, NY: Nova Science Publishers, 2013, p. 123.

9. Leisman, G. Functional Connectivities in the Postnatal Development of Consciousness. Chronic Disease and Disability in Childhood. Hauppauge, NY: Nova Science Publishers, 2013, p. 124.

10. Machado, C., Estevez, M., Leisman, G., Melillo, R., Machado, A., Hernanandez-Cruz, A., Arias, A., Rodriguez-Rojas, R., Carballo, M. Exploration of Resting Brain Connectivity Using Linear Coherence Measures in the Autistic Spectrum Disorder. Chronic Disease and Disability in Childhood. Hauppauge, NY: Nova Science Publishers, 2013, p. 149.

11. Machado, C. Estevez., M., Melillo, R., Leisman, G., Carrick, R., Machado, A., Hernandez-Cruz, A., Arias, A., Rodriguez-Rojas, R., Carballo, M., Quantitative Resting EEG in the Autistic Spectrum Disorder. Chronic Disease and Disability in Childhood. Hauppauge, NY: Nova Science Publishers, 2013, p. 150.

12. Melillo, R. and Leisman, G. Functional Brain Imbalance and Autistic Spectrum Disorder. Olfman, S (Ed.) The Science and Pseudoscience of Children's Mental Illness: Cutting Edge Research and Practice. Childhood In America Book Series. Santa Barbara, CA: Praeger, 2015 [In Press]. Leisman, G. and Moustafa, A. (Eds.) Thinking about Action: Integration of Functional Connections in Movement and Cognition. Frontiers in Public Health; Child Health and Human Development. Zurich. Switzerland, Frontiers, 2015. [In Press]

13. Leisman, G., Rodriguez-Rojas, R. Batista, K, Carballo, M Morales, J. M., Iturria, Y., Machado, C. Measurement of Axonal Fiber Connectivity in Consciousness Evaluation. Proceedings of the 2014 IEEE 28th Convention of Electrical and Electronics Engineers in Israel, IEEE: Minneapolis, MN, 2014.

Published Papers in Indexed Peer-reviewed Journals 1. Machado C, Estévez M, Carrick F, Melillo R, Leisman G. qEEG may increase the reliability of

diagnostic and prognostic procedures in cerebral arterial gas embolism. Clinical Neurophysiology 2012;123(2):225-226 (http://www.ncbi.nlm.nih.gov/pubmed/21784702) (http://www.sciencedirect. com/science/article/pii/S1388245711004615)

2. Machado, C. , Estevez, M., Rodriguez, R. Carrick, FR, Melillo, R., and Leisman, G. Bilateral N20 Absence in Post-Anoxic Coma: Do You Pay Attention? Clinical Neurophysiology. 2012, 123(1), 1264-1266(http://dx.doi.org/10.1016/j.clinph.2011.11.008)

3. Leisman, G., Machado, C., Melillo, R. Mualem, R. Intentionality and “Free-Will” From a Neurodevelopmental Perspective. Frontiers of Integrative Neuroscience 2012, 6:36. doi: 10.3389/ fnint.2012.00036 (http://www.frontiersin.org/Integrative_Neuroscience/10.3389/fnint.2012.00036/full)

4. Leisman, G Children’s Language Production: How Cognitive Neuroscience & Industrial Engineering Can Inform Public Education Policy and Practice Forum on Public Policy; A Journal of the Oxford Roundtable. 2012, 2012(1), 1-14. (http://forumonpublicpolicy.com/vol2012.no1/archive/leisman.pdf) (http://forumonpublicpolicy.com/vol2012.no1/earlychild2012.html)

5. Pérez-Nellar, J., Machado, C, Rodriguez-Rojas, R. Estévez, M. Leisman, G., Melillo, R. Carrick F.R. Neuroimaging Findings in Non-Fatal Central Transtentorial Herniation. Functional Neurology, Rehabilitation, and Ergonomics, 2012, 2(2), 251-266. (https://www.novapublishers.com/catalog/ product_info.php?products_id=35452)

6. Leisman, G. Auditory, Visual and Spatial Aesthetic and Artistic Training Facilitates Brain Plasticity: The Arts as a Vehicle for Rehabilitation. Functional Neurology, Rehabilitation, and Ergonomics, 2012, 2(3), 251-266.[ https://www.novapublishers.com/catalog/product_info.php?products_id=36803]

7. Jubran, F. and Leisman, G. Intersensory Integration in Functional Neurology: An Engineer's Perspective of Music as an Interventionary Medium Functional Neurology, Rehabilitation, and Ergonomics, 2012, 2(3), 215-222. (https://www.novapublishers.com/catalog/product_info.php? products _ id =36803])


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8. Machado-Ferrer, Y, Estevez, M., Machado, C. Hernández-Cruz, Leisman, G., Carrick, F. R., Melillo, R., and Beltrán, C. Heart Rate Variability for Assessing Comatose Patients with Different Glasgow Coma Scale Scores. Clinical Neurophysiology 2012, 123(3), S1388-2457(12)00630-X. (http://www.ncbi.nlm.nih.gov/pubmed/23063293)

9. Machado, C., Estévez, M., Carrick, F.R., Rodríguez, R., Pérez-Nellar, J., Chinchilla, M., Machado, Y., Pérez-Hoz, G., Carballo, M., Fleitas, M., Pando, A. Vegetative state is a pejorative term. NeuroRehabilitation. 2012;31(4), 345-347.

(http://www.ncbi.nlm.nih.gov/pubmed/23232156) 10. Oggero, E., Carrick, F.R., Pagnacco, G. Frequency content of standard posturographic measures -

biomed 2013. Biomedical Science Instrumentation. 2013;49, 48-53. (http://www.ncbi.nlm.nih.gov/ pubmed/23686180)

11. Koch, P. and Leisman G. Computational Model of Attention Brain Function Functional Neurology, Rehabilitation and Ergonomics. 2012;2(4):353-363. (https://www.novapublishers.com/catalog/ product_info.php?products_id=41117&osCsid=1578167af1850a70f1ac579581504a7e1

12. Leisman, G. and Melillo, R. The Basal Ganglia: Motor and Cognitive Relationships in a Clinical Neurobehavioral Context Reviews in the Neurosciences. 2013;24(1):9-25. doi: 10.1515/revneuro-2012-0067. (http://www.ncbi.nlm.nih.gov/pubmed/23241666)

13. Leisman, G., Machado, C., Mualem, R. The merging the neurosciences principles with educational practice in the treatment of ADHD: Function specific treatment for rehabilitation. Frontiers of Public Health: Frontiers of Child Health and Human Development. 2013, 1:22. doi: 10.3389/fpubh.2013.00022 (http://www.frontiersin.org/Journal/Abstract.aspx?ART_DOI=10.3389/fpubh.2013.00022&name=Child_Health_and_Human_Development) (http://www.ncbi.nlm.nih.gov/pubmed/24350191)

14. Machado C, Estévez M, Rodríguez R, Pérez-Nellar J, Chinchilla M, Defina P, Leisman G, Carrick FR, Melillo R, Schiavi A, Gutiérrez J, Carballo M, Machado A, Olivares A, Pérez-Cruz N. Zolpidem Arousing Effect in Persistent Vegetative State Patients: Autonomic, EEG and Behavioral Assessment. Current Pharmaceutical Design. 2013 Sep 10. [Epub ahead of print] (http://www.ncbi.nlm.nih.gov /pubmed/24025063)

15. Machado, C., Estevez, M., Leisman, G., Melillo, R., Rodriguez, R., Hermandez, A. Perez-Nellar, J., Naranjo, R., and Chinchilla, M. EEG Coherence Assessment of Autistic Children in Three Different Experimental Conditions. Journal of Autism and Developmental Disorders. DOI 10.1007/s10803 013-1909-5. (http://link.springer.com/article/10.1007/s10803-013-1909-5#page-1) (http://www.ncbi.nlm.nih.gov/pubmed/24048514)

16. Howard N. and Leisman G. DIME (Diplomatic, information, military and economic power) effects modeling system: Dual use in brain small-world connectography and rehabilitation. Functional Neurology, Rehabilitation, and Ergonomics, 2013; 3(2-3): 257-274. (https://www.novapublishers.com/catalog/product_info.php?products_id=45010)

17. Rodriguez-Rojas, R., Batista K., Iturria, Y. Machado, C. Chinchilla, M. Carballo, M. Morales JM., De Fina P., and Leisman G. Disrupted axonal fiber connectivity as a marker of impaired consciousness states. Functional Neurology, Rehabilitation and Ergonomics, 2013; 3(2-3):319-328. (https://www.novapublishers.com/catalog/product_info.php?products_id=45010)

18. Leisman, G. If It Is Localization Then There is No Development, Education, and Rehabilitation: Neuroeducation Needs to be about Building Networks. Functional Neurology, Rehabilitation, and Ergonomics. 2013:3(2-3):329-340. (https://www.novapublishers.com/catalog/product_info.php?products_id=45010)

19. Estevez, M., Machado, C., Leisman, G., Melillo, R., Machado, A., Hernandez-Cruz, A., Arias, A., Rodriguez-Rojas, R., Carballo, M. EEGConn: A Software Tool for Offline qEEG Analysis, Including Spectral Univariate and Bivariate Processes and Linear and Non-Linear Indices of Brian Connectivity in Autistic Spectrum Disorder. International Journal of Child Health and Human Development. 2013; 6(4): 427.

(https://www.novapublishers.com/catalog/product_info.php?products_id=43824) 20. Jammalieh, J., Mualem, R., Leisman, G. Clinical Effects of Physiological Rhythms in Premature

Infants. International Journal of Child Health and Human Development. 2013; 6(4): 470. (https://www.novapublishers.com/catalog/product_info.php?products_id=43824)

21. Leisman, G. Advances in Cognitive Neuroscience and Optimization Can Inform The Rehabilitation Process in Developmental Language Difficulties. International Journal of Child Health and


294

Human Development. 2013; 6(4): 484. (https://www.novapublishers.com/catalog/product_info.php?products_id=43824)

22. Leisman, G. Functional Connectivities in the Postnatal Development of Consciousness. International Journal of Child Health and Human Development. 2013; 6(4): 485. (https://www.novapublishers.com/catalog/product_info.php?products_id=43824)

23. Leisman, G., Melillo, R., Machado, C. Rodriguez-Rojas, R., Batista, K., Carballa, M., Mualem, R. Functional Disconnectivities in Individuals with Autistic Spectrum Disorders. International Journal of Child Health and Human Development. 2013; 6(4): 486. (https://www.novapublishers.com /catalog/product_info.php?products_id=43824)

24. Machado, C., Estevez, M., Leisman, G., Melillo, R., Machado, A., Hernanandez-Cruz, A., Arias, A., Rodriguez-Rojas, R., Carballo, M. Exploration of Resting Brain Connectivity Using Linear Coherence Measures in the Autistic Spectrum Disorder. International Journal of Child Health and Human Development. 2013; 6(4):510. (https://www.novapublishers.com/catalog/product_info.php?products_id=43824)

25. Rodriguez-Rojas, R., Machado, C., Alvarez, L., Carballo, M., Estevez, M., Perez-Nellar, J., Pavon, N., Chinchilla, M., Carrick, F.R., DeFina, P. Zolpidem induces paradoxical metabolic and vascular changes in a patient with PVS. Brain Injury. 2013;27(11),1320-1329. (http://www.ncbi.nlm.nih.gov/ pubmed/23924270)

26. Machado, C. Estevez, M., Melillo, R., Leisman, G., Carrick, R., Machado, A., Hernandez-Cruz, A., Arias, A., Rodriguez-Rojas, R., Carballo, M., Quantitative Resting EEG in the Autistic Spectrum Disorder. International Journal of Child Health and Human Development. 2013; 6(4):511. (https://www.novapublishers.com/catalog/product_info.php?products_id=43824)

27. Rodriguez-Rojas, R., Batista, K., Carballo, M., Iturria, Y., Sanabria, G., Machado, C., Leisman, G., Estevez, M., Melillo, R. Anatomical and Topological Connectivity Reveal Different Attributes of Disrupted Small-World Networks in Autistic Children. International Journal of Child Health and Human Development. 2013; 6(4):551. (https://www.novapublishers.com/catalog/product_info.php? products_id=43824)

28. Leisman, G., Braun-Benjamin, O., Melillo, R. Cognitive-Motor Interactions of the Basal Ganglia in Development. Frontiers in Systems Neuroscience. 2014,8:16. doi: 10.3389/fnsys.2014.00016. [Cross-referenced in Frontiers in Computational Neuroscience]. (http://www.frontiersin.org/Journal/10.3389/fnsys.2014.00016/abstract) (http://www.frontiersin.org/computational_neuroscience/researchtopics/Basal _Ganglia_XI_-_Proceedings/1118)

29. Pagnacco, G., Wright, C.H., Oggero, E., Bundle, M.W., Carrick, F.R. On "Comparison of a laboratory grade force platform with a Nintendo Wii Balance Board on measurement of postural control in single-leg stance balance tasks" by Huurnink, A., et al. [J. Biomech 46(7) (2013) 1392]: Are the conclusions stated by the authors justified? J Biomech. 2014 7;47(3):759-670. Epub 2013 Dec 4. (http://www.ncbi.nlm.nih.gov /pubmed/24359674)

30. Leisman, G. Functional Connectivities and Re-connectivities Reflect Cognitive Modifiability in Neurorehabilitation. International Journal of Rehabilitation. 2014, 2:4, 54-55. (http://dx.doi.org/ 10.4172/2329-9096.S1.006)

31. Leisman, G. Optimization Models for Quantifying Visual Search Scanpath Efficiency: Measuring Treatment Recovery in Traumatic Brain Injury. International Journal of Rehabilitation. 2014, 2:4, 43-45. (http://dx.doi.org/10.4172/2329-9096.S1.006)

Papers in Indexed Peer-Reviewed Journals Currently In Press 1. Machado, C., Pérez-Nellar, J., Rodríguez_Rojas, R., Estévez, M., DeFina, P.A., Schiavi, A., Leisman,

G. Carrick, F.R., Melillo, R., and Chinchilla, M., Unusual brainstem twisting revealed by MRI tractography in a patient who survived a severe traumatic upper spinal dislocation. Functional Neurology Rehabilitation, and Ergonomics, 2013 [In Press].

2. Disorder as a Functional Disconnection Syndrome) Harefuah, (Hebrew) [submitted] 3. Jammalieh, J. Mualem, R, Leisman, G. Clinical Effects of the Development of Physiological Rhythms

in Premature Infants. Journal of Pediatrics and Neonatology, 2014 [submitted]


295

4. Estévez, M., Machado C., Leisman, G. Melillo, R. Hernández-Cruz, A., Estévez-Hernández, T., Arias-Morales, A. Machado, A., Montes-Brown, J. Spectral Analysis of Heart Rate Variability. International Journal of Disability and Human Development. [In Press, 2015].

5. Machado, C., Pérez-Nellar, J., Rodríguez_Rojas, R., Estévez, M., DeFina, P.A., Schiavi, A., Leisman, G. Carrick, F.R., Melillo, R., and Chinchilla, M., Unusual Brainstem Twisting Revealed by MRI Tractography in a Patient who Survived a Severe Traumatic Upper Spinal Dislocation. Functional Neurology Rehabilitation, and Ergonomics, 2014, 4;2-3, [In Press].

6. Mualem, R., Leisman, G., Mograbie, K.K., and Boshnak, S. Brain-Based Learning During Preschool: An Underused Window Of Opportunity. International Journal of Child Health and Disability. 2015 [In press]

7. Leisman, G. The Coincident Decline of Movement and Cognitive Ability: Movement Sciences In the Aid of Public Health Policy Intervention. International Journal of Child Health and Disability. 2015 [In press]

8. Leisman, G. Thinking, walking, talking: The development of integratory brain function. Frontiers in Public Health: Child Health and Human Development, 2015 [In Press].

9. Jammalieh, J. Mualem, R, Leisman, G. Clinical Effects of the Development of Physiological Rhythms. Journal of Pediatrics and Neonatology, 2014 [submitted]

10. Machado, C., Estévez, M., Rodríguez, R., Schiavi, A., Pastor, I.S. Carrick, F. R., Chinchilla, M., Leisman, G., Melillo, R. Brain Death is Synonym of Death: Cuban Experts’ Opinion on Two Contentious Brain-Dead Cases in USA. Journal of Medical Ethics, [Submitted, 2014].

11. Machado, C., Estévez, M. Rodríguez, R. Schiavi, A., Pastor, I. S. Leisman, G., Chinchilla, M., Carrick, F.R., Perez, J. Melillo, R., Portela, L., Pando, A. The Notion of Integration of the Organism in Brain Death. Journal of the American Medical Association, Internal Medicine. [Submitted, 2014].

12. Estévez, M., Machado C., Leisman, G., Hernández-Cruz, A., Estévez-Hernández, T., Arias- Morales, A. Machado, A., Montes-Brown, J. Spectral Analysis of Heart Rate Variability. International Journal of Disability and Human Development. [Submitted, 2014].


LITERATURE CALLING

A SURVEY OF RECENT PUBLICATIONS OF INTEREST TO FUNCTIONAL NEUROLOGY

Electronic implants and electromagnetic pulses are picking up where psychoactive drugs have failed

By Samuel K. Moore Posted 28 Feb 2006 | 21:21 GMT

Imagine a crushing sadness so severe it keeps you from eating, sleeping, or socializing. Though you can't sleep, you lack the energy and the will to get out of bed. Everyday decisions, like which clothes to wear, leave you paralyzed. You've no desire to do the things you once thought were fun; in fact, you can't bring yourself to do much of anything. Now, add to all that the realization that you've tried everything known to medicine, it hasn't worked, and there's a good chance you won't feel any different. Ever.

"I had nothing to lose," says Karmen McGuffee, who suffered from severe depression for a decade and was hospitalized five times for it. So she had surgeons cut open her neck, gently wrap an electrode around one of the nerves there, and plug the electrode into a pulse generator, which they slipped under the skin of her chest. About every 5 minutes, the pocket-watch-size device sends a buzz of current through the nerve and into her brain.

Six months after doctors switched on the pulse generator, called a vagus nerve stimulator, McGuffee's world looked totally different. "I had no idea that life didn't have to have a dark veil over it all the time," she says. Once unable to concentrate enough to read a newspaper, McGuffee is now an executive secretary.

Depression is distressingly common, affecting more than 120 million people around the world and sucking tens of billions of dollars out of the global economy through the cost of care and lost productivity. It's also deadly. Every year 850 000 people worldwide take their own lives, and 9 out of 10 of them are suffering from depression, another mental illness, or substance abuse. Statistics show that of those who had had treatment for depression just through visits to a doctor's office, 2 percent ultimately committed suicide, as did 4 percent of those who had to be hospitalized for depression.

Twenty-five percent of people with depression have no access to any form of mental health care; of those who do have access to care, only a quarter seek treatment. Of those who consult doctors, some 80 percent find relief in the form of drugs or some kind of talk therapy, such as cognitive therapy. But for the rest--people like McGuffee, prone to the most severe and chronic forms of depression, about 11 million of them in the developed world alone--drugs don't work.

For decades, the only other option for these people was electroconvulsive therapy, which because of the frightening side effect of amnesia is often rejected by patients. But this grim outlook is at last beginning to change. McGuffee was one of the first to benefit from a new crop of electromagnetic brain stimulation technologies that psychiatrists are testing, with the hope of curing--or at least helping--patients for whom little else works. By electrically manipulating specific portions of the brain with implanted electrodes, electric current, or magnetic fields, doctors aim to succeed where drugs fail, by producing long-lasting changes in the brain--and to do it without electroshock's significant side effects.

For a variety of reasons, including the large number of potential patients and the accumulated knowledge of how the disease works, depression is the primary target of most of these technologies. But

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some of these methods are already showing great promise for treating such other mental maladies as bipolar disorder, obsessive-compulsive disorder, and bulimia.

The technology McGuffee uses, vagus nerve stimulation, was the first to enter routine clinical use. A pacemakerlike device about the size of a pocket watch, implanted under the skin of the chest, pulses a nerve in the neck [see illustration, " Vagus Nerve Stimulation"]. In about 16 percent of patients like McGuffee, according to clinical studies, that electric pulsing completely quashes the symptoms of depression. It was approved as a depression therapy, for use in conjunction with drugs, by government regulators in the European Union and Canada in 2001. Last June, it became the first psychiatric device to be reviewed and approved in the United States, which has more stringent requirements for medical devices. Nevertheless, a number of psychiatrists remain unconvinced that the therapy works in enough people to outweigh the risk and cost of surgery.

Vagus nerve stimulation isn't the only technology being touted for treatment of the severely depressed. Another technique, repetitive transcranial magnetic stimulation, uses powerful magnets to generate current in well-defined portions of the brain [see illustration, " Repetitive Transcranial Magnetic Stimulation"]. Many research groups around the world have experimented with the technology. At last count the results of more than 60 depression trials performed in Australia, Israel, Taiwan, the United States, Europe, and elsewhere had been published. But clinical use is just beginning. The technology is winding its way toward a review by U.S. regulators, and the company behind it, Neuronetics Inc., in Malvern, Pa., says it could be approved within the year.

And these two are just the ones closest to the clinic. Researchers are exploring three other, more experimental technologies. One uses direct current to produce a change in the brain similar to that of magnetic stimulation. Another uses transcranial magnetic stimulators to spark seizures just as electroconvulsive therapy does but, it is hoped, without the amnesia that can accompany it. The third experimental technology borrows a device used to control the tremors of Parkinson's disease. Surgeons have begun implanting electrodes in patients' brains to switch off malfunctioning brain circuits involved in depression and obsessive-compulsive disorder.

The coming clutch of medical devices, if proven to work, could represent not just hope for the hopeless but a profound change in psychiatry. "I think it's not too big a jump to say we haven't had a new [nondrug] treatment for 40 years," says Paul Fitzgerald, an associate professor of psychiatry at Monash University, and deputy director of the Alfred Psychiatry Research Center, both in Melbourne, Australia. Fitzgerald, who does transcranial magnetic stimulation research, notes that even the drug therapies are largely derivative of each other. "Now we're really faced with the potential for a significant expansion of treatments, as long as they are introduced carefully," he adds. Noting psychiatry's often disastrous history of nondrug treatments, such as the embrace of prefrontal lobotomy in the mid-20th century, he thinks the field is approaching a watershed, for the better. "We're getting it right this time."

That psychiatrists can use both drugs and electricity to battle illness testifies to the fact that the brain is both a chemical and an electrical organ. Every brain cell has a halo of short projections attached to its body and a long trunk, called an axon. To communicate with another cell, it sends a pulse of voltage down the axon. The axon usually terminates at one of the short projections of another brain cell. Rather than make a direct electrical connection, two brain cells communicate via a puff of chemical transmitters released from the end of the axon when the voltage pulse reaches it. These transmitters cross the nanometers between the end of the axon and the next cell's projections and bind with receptor molecules there. Depending on the type of chemical signal, this binding can lead to a variety of things, but the simplest is an influx or outflow of current that briefly raises or drops the target cell's voltage. The cell integrates the voltage changes from its many projections, and, if the combination of them is big enough, it will trigger a voltage pulse down the target cell's axon. The process of integration and signaling continues as signals propagate through the brain's millions of specialized circuits and is the basis of everything that occurs inside our heads: thoughts, emotions, moods, memories, and dreams.

Psychoactive drugs, such as Prozac, work on the chemical side to ultimately affect electrical signals. Depression, at least in part, involves a problem with the electrical signaling between certain parts of the brain whose cells signal with a chemical transmitter called serotonin. By inhibiting the reabsorption of serotonin, Prozac lets more of the chemical accumulate in the space between the end of the axon and the next brain cell, thus restoring the signaling.

One problem with this approach is that drugs work everywhere in the brain that their chemical target exists, regardless of whether those parts have anything to do with depression or any other disease, and that leads to side effects. Prozac, for example, has been known to reduce sex drive and can cause insomnia.

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Another problem is that brain chemistry varies from person to person, so no single drug will work in everyone.

The shared goal behind the new electromagnetic therapies, on the other hand, is to use electricity itself to restore the signaling, ideally, only in those parts of the brain affected by disease. Decades ago, neuroscientists demonstrated that electrically stimulating a neuron alters, in the long term, the strength of its connections to other neurons--making an electrical signal from one neuron more likely or less likely to jump to the next neuron. Though little is known in detail about how the new therapies work, it's likely that, to varying degrees, they depend on that phenomenon.

Because they are new and in some cases relatively unproven, the device-based technologies are being tested exclusively in people for whom all the available drugs have failed to work. For a minority of these patients, electroconvulsive therapy, a 70-year-old technique, is the treatment of last resort. So it is with electroconvulsive therapy that the new technologies are generally compared.

Unfortunately, your view of electroconvulsive therapy, like that of many potential patients, was probably formed by the 1975 movie One Flew Over the Cuckoo's Nest, in which it was used as a means of punishment and control. Even if Jack Nicholson's performance has no influence on your view of psychiatry, the idea of the therapy's main side effect, amnesia, is far more fearsome than Prozac's decreased libido or even the maladies associated with more powerful drugs, because memory is so tied up with our sense of self. But the reality is that the severity of electroconvulsive therapy's side effects has been minimized over the years, its use is carefully controlled, and, quite simply, nothing is as effective at breaking through the worst forms of depression. Still, in the United States, only about 100 000 people a year agree to it, despite the millions whom no drug helps.

"Electroconvulsive therapy can be dramatically effective at restoring a person's health and getting their life back on track," says Sarah H. Lisanby, director of the Brain Stimulation and Neuromodulation Division of the Columbia University Medical Center, in New York City. "The potential for the new brain stimulation techniques is to get those kinds of dramatic effects in medication-resistant populations without the downside."

Vagus nerve stimulation began in the 1980s with Jacob Zabara, a neurophysiologist at Temple University, in Philadelphia, demonstrating that he could quell epileptic seizures in a dog by electrically jolting its vagus nerve, one of twelve pairs of nerves that emerge from the brain instead of the spinal cord. He showed the technique to pacemaker designer Reese Terry, and a few years later they formed a company called Cyberonics Inc., in Houston, to develop a treatment for epilepsy.

Using off-the-shelf integrated circuits, design help from friends in the field, and a new kind of helical electrode, Terry put together an implantable device that periodically shocks the vagus nerve. Cyberonics has made more than 30 000 of them, using the same basic design. The implantable device looks and acts like a heart pacemaker. Though a doctor can program in a wide range of stimuli, the device typically delivers 1- to 2-milliampere, 250-microsecond pulses at 20 to 30 hertz for 30 seconds every 5 minutes.

Terry and his co-workers always envisioned uses beyond epilepsy. Depression was a good place to start, because the malady has been linked to epilepsy for so long that even Hippocrates wrote about it. About a quarter of people with severe epilepsy also have chronic depression--a far greater ratio than in either the general population or other groups with chronic illnesses. Also, intriguingly, early in Cyberonics' tests, some epilepsy patients reported that the device had improved their mood.

Researchers don't really know why the device works against depression. But they do have some theories. Phillip C. Jobe at the University of Illinois College of Medicine, in Peoria, proposes that the brain's natural defenses against both epileptic seizures and depression are weakened by chemical and structural flaws in the same two systems of neurons buried deep within the most primitive part of the brain. Vagus nerve stimulation alters activity in both those areas, although the nerve does not connect directly to either of them.

Terry, naturally, takes an engineer's view of things. "The way I look at it," he says, "the brain is a very finely controlled feedback system." For some diseases, he suggests that the "control system is a little bit out of balance." The periodic pulses from his device in effect "pace" the vagus nerve, he believes, restabilizing the control system.

But a bigger question than how it works, and one the company is still trying to answer for doctors, is whether or not it actually does work. In the late 1990s, a pilot study of patients with chronic or recurrent depression that resisted treatment with drugs gave promising results. McGuffee was among the first patients to receive an implant, in February 1999. One month after she got the implant, her family began to see an improvement; a few months later, McGuffee noticed it, too.

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The pilot study was enough to convince European and Canadian regulators to allow the stimulator's use in their jurisdictions. To get more conclusive data that might satisfy the tougher U.S. regulations, Cyberonics embarked on a 235-patient, eight-week study. To tease out any placebo effect, all the patients received implants, but only half of the implants were turned on. Here again, too few patients improved to tell if the device was the cause of the improvement. So at the end of the study the company asked doctors to turn on the implant for anyone who wanted it and instructed them to continue treating the patients with anything that might benefit them. "It would have been inappropriate to withhold treatment," says chief medical officer Richard Rudolph. "But now we had nothing to compare the outcomes with."

Strapped for cash but not ready to give up on a group of patients with no options, to say nothing of a potential US $1 billion market, the company continued to try to prove the stimulator would work for depression. Plan B, according to Rudolph, was to follow the patients from the original study, find a group of very similar patients without stimulators, and compare how they fared over two years, a much longer period than is generally used in a trial of a new antidepressant drug.

After one year, one in six patients treated with the nerve stimulator was free of depression, and 56 percent got some meaningful benefit--as measured by a standardized questionnaire used to rate the severity of a patient's depression. Of those who did respond, about 70 percent continued to benefit after two years. But waiting a year to see if the treatment worked in a disease that comes at irregular intervals was highly unusual. The lack of a control group that had the device implanted but not turned on to counteract the placebo effect was stranger still. In August 2004, the U.S. Food and Drug Administration, which regulates the marketing of medical devices, decided not to allow Cyberonics to sell the vagus nerve stimulator as a depression treatment, overruling its own advisors in the process. Cyberonics' CEO, Robert P. ("Skip") Cummins, who lost both his mother and grandfather to depression-related suicide, refused to give up. His company gathered more data, and went straight to the FDA's top brass. By February 2005 the company had won conditional approval. But it still had hoops to jump through on the way to full approval: there was controversy when Public Citizen, a prominent Washington, D.C., advocacy group, questioned whether the device worked at all. At the same time, an investor lawsuit began regarding the timing of some executive stock sales. And then there was a halfhearted investigation by a U.S. Senate committee into why the FDA had decided against the device. Full approval finally came last July.

Cyberonics says it has trained 2000 psychiatrists in vagus nerve therapy so far, but many physicians are still skeptical. Perminder Sachdev, a professor of psychiatry at the University of New South Wales, Sydney, Australia, thinks the technology has shown some promise but has a way to go before the results are convincing. "It's a hard area to investigate," he says. The placebo effect is difficult to eliminate, the nature of depression is that it waxes and wanes, and the treatment takes a long time to show an effect. The combination of all that means you need a great many patients to prove a device is working, he believes. Sachdev and others expect the picture to clear somewhat after the results of a study going on now in Europe are reported. In the meantime Cyberonics is running pilot trials to see if the device will work to control other mental illnesses, such as bulimia and obsessive-compulsive disorder.

Cyberonics' duel with U.S. regulators was watched closely by psychiatrists, patients, and competing companies. Executives at Neuronetics were particularly interested, because their device, a repetitive transcranial magnetic stimulator specially designed for treating depression, will be the next such technology weighed by the FDA. The company plans to send its data to the agency next month and could get a decision before the year is out.

How the vagus nerve stimulator fared offers some important lessons for Neuronetics, says Mark Riehl, the company's vice president of product development and operations and the leader of the team that designed the device. "The FDA and the market expect a trial modeled after pharmaceutical trial design," he says. Drug tests are designed so that patients are selected at random to get the treatment or get a placebo--and neither the patients nor their doctors know which patients are getting the treatment. So that's what Neuronetics is doing (and, of course, that's what Cyberonics originally set out to do).

The basic idea behind repetitive transcranial magnetic stimulation (rTMS) is to use a strong, varying, and concentrated magnetic field to induce the flow of current in a few cubic centimeters of the part of your brain above your eyeballs. This block of neurons, the prefrontal cortex, has to do with making decisions, but neuroscientists have also implicated it in depression, and it connects directly to mood-regulating structures deeper in the brain. The neural activity in the prefrontal cortex is abnormal in people with depression, but electroconvulsive therapy and drugs like Prozac alter it to restore normal mood. The theory is that you can get the same restoration by repeatedly generating a magnetically induced current there. To

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treat depression, the current must be strong enough to trigger spikes of voltage in brain cells but not so strong or high in frequency that it sparks a seizure.

A transcranial magnetic stimulation device is simple. Basically, it's just a very big capacitor that discharges into the coil of an electromagnet, which generates the magnetic field. But the magnetic field it generates is impressive. At 2 tesla, the field is 50 percent stronger than that of a typical full-size magnetic resonance imager. To make a field like that, 8000 amperes, driven by more than a kilovolt, typically course through the coil's windings.

Early research on the use of rTMS to fight treatment-resistant depression showedinconsistent results and relatively small rates of response, providing a benefit on average to only about 30 percent of patients. The problem with the early work, according to Monash University's Fitzgerald, was that there was little consistency as to exactly where in the brain the stimulator was producing its current.

But incorporating magnetic resonance maps of patients' brains and other techniques have improved the therapy's accuracy. And now a few carefully done direct comparisons between rTMS and electroconvulsive therapy, hitherto the most effective treatment, suggest that with certain exceptions, the same proportion of patients would benefit from either. There are many, however, who think the seizures provoked by the long-used electroconvulsive therapy will prove more effective than rTMS.

Columbia's Lisanby is one. Electroconvulsive therapy "had great value in helping patients who were extremely depressed, but it also had some drawbacks," she says, referring to the possible amnesia. So she has been developing magnetic seizure therapy, a version of rTMS that triggers seizures.

Electroconvulsive therapy triggers seizures with pulses of current that are spread over a large area of the brain. Because rTMS limits current to well-defined, centimeter-scale portions of the brain, Lisanby reasons, magnetic seizure therapy could allow doctors to better control where in the brain a seizure originates and where it spreads to, with the aim of minimizing side effects.

So far, rTMS practitioners have been studiously avoiding inducing seizures in their patients by limiting both the device's power and its frequency, so the available technology was not easily suited to actually inducing seizures by magnetic means. The first system, used in neurology experiments in London in 1985, could generate a single on-off pulse only every four seconds, says Reza Jalinous, its coinventor and vice president of operations at The Magstim Co., in Carmarthenshire, Wales. The device could generate pulses only at a low frequency, because all the energy from the charge was lost as heat in the coil winding, so the capacitor had to be completely recharged after each pulse. But scientists, and later psychiatrists, wanted higher frequencies, to more closely match the electrical characteristics of brain cells. So Jalinous reshaped the technology.

"To go faster you have to dissipate as little energy as possible in the winding in the coil," he says. It turned out to be a simple matter to go from one pulse every four seconds to five pulses per second. Jalinous replaced the on-off pulse with an alternating-current sinusoid, so current flowed first in one direction and then in the other. The system loses little energy in the coil and returns about 70 percent of it to the capacitor. So the power supply can top off the capacitor quickly, and the stimulator can produce its next pulse in a fraction of a second. By upgrading the power supply and making a few other improvements, Jalinous has produced a system for Lisanby with a top frequency of 100 Hz, as opposed to the more typical 20 Hz or less, that can be sustained for up to 10 seconds. Lisanby expects to begin using the new device on patients this year.

Of course, too many pulses too close together will generate too much heat for the coil windings to handle. "The bottleneck right now is actually heating in the stimulating coil," says Angel Peterchev, a power electronics engineer doing postdoctoral research in Lisanby's laboratory.

In the devices now in use, there are two types of electromagnetic coils: air-core and iron-core. The air-core types, favored by Magstim and Medtronic Inc., of Minneapolis, are meant to be handheld and easier to move, so neurologists can experiment with their effects on different parts of the brain. But the air-core coils are less efficient and generate more heat. The iron-core kind, used by Neuronetics, is meant for clinical use. Although it consumes less power and generates less heat, it would have to be redesigned using a different core material and fewer coil windings to deliver magnetic field strengths of more than 2 T, which might be useful in magnetic seizure therapy.

Psychiatrists are beginning to look at an even simpler technology than transcranial magnetic stimulation to fight depression. "It's like hooking the patient up to a car battery," jokes Sachdev. "But with safety features," his colleague Colleen Loo, a senior research fellow, hastily adds. Crude or not, it's a pretty accurate description of an experimental technique called, or tDCS. Basically, it subjects the front half of the brain to a minutes-long 1-mA direct current once a day for several weeks.

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The simplicity of tDCS makes it sound almost suspicious, and indeed its origins stretch back into the murk of 19th-century quackery. But the principle of how tDCS seems to work in the brain is roughly the same as that of rTMS. They both seek to make neurons in the prefrontal cortex, the decision-making part of the brain, more excitable, that is, more likely to propagate a signal from neuron to neuron. In tDCS's case a small current, delivered via electrodes on the temples, biases brain cells, making them more likely to emit a spike of voltage, says Alvaro Pascual-Leone, associate professor of neurology studying tDCS at Harvard University, in Cambridge, Mass. The effect, studies have shown, lasts long after the current is turned off.

The concept and technology are so simple, in fact, that Pascual-Leone and his colleagues suggested in The British Journal of Psychiatry that tDCS be used in the developing world as a first-line treatment for depression instead of rather expensive antidepressant drugs. But Sachdev thinks this is a terrible idea. "We need to know a lot more about tDCS before it is accepted as an effective treatment and must await the results of many ongoing trials," he wrote in a rebuttal. "In the meantime, depressed patients in the developing world should be dissuaded from unplugging their car batteries and clamping them on their foreheads."

Pascual-Leone says he has results showing tDCS fought treatment-resistant depression as well as rTMS did in experiments done at the University of São Paulo School of Medicine, in Brazil, but at press time the study had not yet been published in a peer-reviewed journal.

If "hooking the patient up to a car battery" is the least invasive new psychiatric technology, then deep-brain stimulation is its opposite. It is meant only for the most desperate patients, those not helped even by electroconvulsive therapy. It requires having a surgeon bore two holes in the skull, insert a pair of electrodes deep into the brain, run wires beneath the skin of the neck, and connect them with a pacemakerlike device implanted in the chest under the skin. The device sends pulses of electricity to the electrode tips, shutting down activity in the few cubic millimeters of brain tissue there.

The results can be instantaneous. Thomas Schlaepfer, vice chair and professor of psychiatry and psychotherapy at the University of Bonn, in Germany, described the case of one of his patients to IEEE Spectrum. A host of drugs and even electroconvulsive therapy had failed to lift her depression and halt her desperate urge to kill herself. But last August she had one of Medtronic's deep-brain stimulators implanted. When Schlaepfer turned the device on and asked her how she was feeling, she replied that she was still as depressed as ever but that she would like to start bowling again.

Bowling had once been her favorite pastime, but she had not enjoyed it for years. The inability to enjoy things that once gave you pleasure--psychiatrists call it anhedonia--is a key characteristic of major depression. The parts of the brain responsible for it, the reward centers, are among the prime targets of the new therapy.

Deep-brain stimulation has been in use for years to treat the tremors of Parkinson's disease. In that case, 3- to 5-volt pulses at about 100 Hz are applied to a part of a brain circuit that malfunctions and causes the tremors. The stimulation suppresses the activity of neurons near the electrode, mimicking their surgical destruction, but with a key twist. "Basically, it's reversible and tunable brain surgery," says Schlaepfer. Turn the device on, and that section of the brain goes off-line. Turn it off, and the neurons spring back into action. It's a simplistic view, of course, and scientists still don't know if the electrode's current blocks brain traffic by holding the cells at too high a voltage to propagate a signal, exhausts their supply of chemical transmitters, overlays a meaningless jamming signal on them, or does something different entirely.

The device has also been used to treat severe obsessive-compulsive disorder; indeed, this was its first use in psychiatry. In that treatment, neurosurgeons had been destroying a few cubic millimeters of a particular structure in the brain. Now surgeons have begun inserting electrodes instead of destroying those tiny parts of the brain.

A group based at the University of Toronto and led by neurosurgeon Andres Lozano and neurologist Helen S. Mayberg reported the first trial of deep-brain stimulation for depression only a year ago. (Mayberg has since become a professor at Emory University, in Atlanta.) Imaging studies led them to Broadmann area 25, a pair of structures deep in the brain just above and behind the eyes that become active when people are sad. It has abnormally high blood flow in people with treatment-resistant depression; antidepressant drugs tend to reduce the amount of blood flow there. So the Toronto researchers implanted electrodes powered by a Medtronic stimulator in that spot in six patients. Five of the six responded well initially, and four continued to do so six months out. According to Lozano, those four are still doing well two years later. Lozano, who has been implanting deep-brain stimulators for more than a decade, says that not enough is known about why patients respond or don't respond to the procedure to say if there is a need to tweak the technology. "We don't know if it's the electrodes or the patients," he says.

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Although the seminal work was done using stimulators made by Medtronic, another maker of implantable stimulators, Advanced Neuromodulation Systems Inc. (ANS), in Plano, Texas, holds the relevant intellectual property rights, according to Rohan Hoare, the company's vice president of corporate strategy and development. ANS is now replicating Mayberg and Lozano's results in a pilot study using its Libra deep brain stimulation system. The main difference between the Medtronic systems used in Toronto and Bonn and ANS's devices is that Medtronic's delivers a constant-voltage pulse, which allows the current to vary depending on the impedance of the brain, while its competitor delivers constant current, allowing the voltage to vary. ANS's vice president for scientific affairs, Tracy Cameron, notes that most animal research has been done using constant-current stimulators and hypothesizes that this approach may be more in tune with the brain's physiology.

The debates don't end with the technology. Researchers also disagree about which brain structures to stimulate, although all the contenders are in the same neighborhood, behind and above the eyes. Research at Brown University Medical School and Butler Hospital, both in Providence, R.I., stimulate a much larger structure than Broadmann 25, called the anterior limb of the internal capsule. And Schlaepfer and his colleagues in Europe are working on the area related to anhedonia, called the nucleus accumbens.

Assuming that all the new brain stimulation techniques prove effective in the many upcoming trials, the psychiatrist's toolbox will look very different a decade from now. Patients will probably first be offered the less invasive techniques, such as transcranial direct current and magnetic stimulation; then the more invasive ones, such as the seizure therapies; and finally such surgical technologies as deep-brain stimulation and vagus nerve stimulation. "A significant portion of patients will want to try the less invasive treatment first," says Monash University's Fitzgerald. "For some it will be sufficient."

But don't cash out of your drug company stock just yet. Even if the more easily applied therapies are proven effective, drug firms have little to worry about. "Drugs are always the first preference, because you don't have to show up every day," says the University of New South Wales's Sachdev.

Of course, a better way than simply trying one therapy after another is to figure out how each works and why they work well for some people rather than others. That won't happen soon, because it will require experience with many patients and a much better understanding of the brain. And though such brain-imaging technologies as positron-emission tomography have been useful for finding target areas for deep brain stimulation and for understanding the effects of stimulation technologies, they can't yet predict who will respond to a treatment and who won't. "We've got the diagnostic tools; we just need to refine them," says Harvard's Pascual-Leone. And when that's done, psychiatrists will have both a road map of the mind and the tools to fix the potholes. Refererences

[1] For a more complete roundup of the clinical research into the new device-based therapies, see Brain Stimulation in Psychiatric Treatment , edited by Sarah H. Lisanby, Washington, D.C., American Psychiatric Publishing (2004).

[2] A Neuronetics executive teaches you how to design a transcranial magnetic stimulator in "Designing Transcranial Magnetic Stimulation Systems," by K. Davey and M. Riehl, IEEE Transactions on Magnetics, March 2005, pp. 1142–48.

[3] More details of vagus nerve stimulators are laid out in "Vagus Nerve Stimulation for the Treatment of Depression," by Dorin Panescu, IEEE Engineering in Medicine and Biology Magazine, November–December 2005, pp. 68–72.

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Smartphone App Could Flag Mood Swings in People With Bipolar Disorder

IEEE SPECTRUM By Eliza Strickland Posted 9 May 2014 | 13:00 GMT Psychiatrists know that they shouldn't just listen to what their patients say, but also how they say it. And now researchers at the University of Michigan have created a smartphone app [1] that mimics that listening behavior. By analyzing the phone conversations of people with bipolar disorder, researchers say they've detected the speech patterns associated with manic and depressive episodes.

The small study included only six patients, and was intended as a proof of concept. Next the researchers want to develop an app that detects early signals of mood swings in people with bipolar disorder, allowing for prompt medical intervention. The researchers presented their paper [2] this week at the IEEE International Conference on Acoustics, Speech, and Signal Processing.

There's growing interest in using smartphone apps in psychiatry, both to help people manage their own illnesses and to let clinicians keep a closer eye on patients with ailments like depression, schizophrenia, and PTSD. In one experiment that's rather similar to this bipolar study, researchers with the Boston company Cogito tested an app [3] that analyzed vocal and social activity to look for symptoms of PTSD.

The University of Michigan researchers designed their tool, called Priori, as a smartphone app that unobtrusively records and analyzes the user's outgoing speech during phone calls (incoming speech is not recorded or analyzed). Because the app is recording the user's personal conversations, patient privacy is a key issue. The recordings are therefore encrypted and off-limits to the researchers, who only have access to the results of the computer analyses.

The Priori system tracked the user's patterns of speech and silence, the pitch of the user's voice, and other acoustic features. To teach the system which features were associated with mania, depression, or the calm of a normal mood, the researchers made a weekly phone call to each user, in which they assessed the user's mood and labeled it. Then the researchers tested their model by having the Priori system analyze the user's other conversations on the day of the assessment and the days immediately before and after, when the user's mood was assumed to be about the same. While the signals of mania or depression were more subtle in those "unstructured" conversations, they were detectable. References

[1] [http://www.eurekalert.org/pub_releases/2014-05/uomh-ltb050614.php] downloaded 29 October 2014. [2] Karam ZN, Provost EM, Singh S, Montgomery J, Archer C, Harrington G, McInnis, MG. Ecologically

Valid Long-Term Mood Monitoring of Individuals with Bipolar Disorder Using Speech. Paper presented at the IEEE International Conference on Acoustics, Speech, and Signal Processing, Firense, Italy, 2014. [http://web.eecs.umich.edu/~emilykmp/EmilyPapers/Karam2014_ICASSP.pdf]

[3] [http://spectrum.ieee.org/biomedical/diagnostics/app-captures-the-boston-bombings-psychological-effects] downloaded 30 October 2014

FOR NEURONS TO WORK AS A TEAM, IT HELPS TO HAVE A BEAT

ScienceDaily (Sep. 20, 2010) When it comes to conducting complex tasks, it turns out that the brain needs rhythm, according to researchers at the University of California, Berkeley. Specifically, cortical rhythms, or oscillations, can effectively rally groups of neurons in widely dispersed regions of the brain to engage in coordinated activity, much like a conductor will summon up various sections of an orchestra in a symphony.

Even the simple act of catching a ball necessitates an impressive coordination of multiple groups of neurons to perceive the object, judge its speed and trajectory, decide when it's time to catch it and then

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direct the muscles in the body to grasp it before it whizzes by or drops to the ground. Until now, neuroscientists had not fully understood how these neuron groups in widely dispersed regions of the brain first get linked together so they can work in concert for such complex tasks. The UC Berkeley findings are being published in the online early edition of the journal Proceedings of the National Academy of Sciences. [1, 2]

"One of the key problems in neuroscience right now is how you go from billions of diverse and independent neurons, on the one hand, to a unified brain able to act and survive in a complex world, on the other," said principal investigator Jose Carmena, UC Berkeley assistant professor at the Department of Electrical Engineering and Computer Sciences, the Program in Cognitive Science, and the Helen Wills Neuroscience Institute. "Evidence from this study supports the idea that neuronal oscillations are a critical mechanism for organizing the activity of individual neurons into larger functional groups."

The idea behind anatomically dispersed but functionally related groups of neurons is credited to neuroscientist Donald Hebb, who put forward the concept in his 1949 book "The Organization of Behavior." "Hebb basically said that single neurons weren't the most important unit of brain operation, and that it's really the cell assembly that matters," said study lead author Ryan Canolty, a UC Berkeley postdoctoral fellow in the Carmena lab.

It took decades after Hebb's book for scientists to start unraveling how groups of neurons dynamically assemble. Not only do neuron groups need to work together for the task of perception -- such as following the course of a baseball as it makes its way through the air -- but they then need to join forces with groups of neurons in other parts of the brain, such as in regions responsible for cognition and body control.

At UC Berkeley, neuroscientists examined existing data recorded over the past four years from four macaque monkeys. Half of the subjects were engaged in brain-machine interface tasks, and the other half were participating in working memory tasks. The researchers looked at how the timing of electrical spikes -- or action potentials -- emitted by nerve cells was related to rhythms occurring in multiple areas across the brain.

Among the squiggly lines, patterns emerged that give literal meaning to the phrase "tuned in." The timing of when individual neurons spiked was synchronized with brain rhythms occurring in distinct frequency bands in other regions of the brain. For example, the high-beta band -- 25 to 40 hertz (cycles per second) -- was especially important for brain areas involved in motor control and planning.

"Many neurons are thought to respond to a receptive field, so that if I look at one motor neuron as I move my hand to the left, I'll see it fire more often, but if I move my hand to the right, the neuron fires less often," said Carmena. "What we've shown here is that, in addition to these traditional 'external' receptive fields, many neurons also respond to 'internal' receptive fields. Those internal fields focus on large-scale patterns of synchronization involving distinct cortical areas within a larger functional network."

The researchers expressed surprise that this spike dependence was not restricted to the neuron's local environment. It turns out that this local-to-global connection is vital for organizing spatially distributed neuronal groups.

"If neurons only cared about what was happening in their local environment, then it would be difficult to get neurons to work together if they happened to be in different cortical areas," said Canolty. "But when multiple neurons spread all over the brain are tuned in to a specific pattern of electrical activity at a specific frequency, then whenever that global activity pattern occurs, those neurons can act as a coordinated assembly."

The researchers pointed out that this mechanism of cell assembly formation via oscillatory phase coupling is selective. Two neurons that are sensitive to different frequencies or to different spatial coupling patterns will exhibit independent activity, no matter how close they are spatially, and will not be part of the same assembly. Conversely, two neurons that prefer a similar pattern of coupling will exhibit similar spiking activity over time, even if they are widely separated or in different brain areas.

"It is like the radio communication between emergency first responders at an earthquake," Canolty said. "You have many people spread out over a large area, and the police need to be able to talk to each other on the radio to coordinate their action without interfering with the firefighters, and the firefighters need to be able to communicate without disrupting the EMTs. So each group tunes into and uses a different radio frequency, providing each group with an independent channel of communication despite the fact that they are spatially spread out and overlapping."

The authors noted that this local-to-global relationship in brain activity may prove useful for improving the performance of brain-machine interfaces, or lead to novel strategies for regulating dysfunctional brain networks through electrical stimulation. Treatment of movement disorders through

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deep brain stimulation, for example, usually targets a single area. This study suggests that gentler rhythmic stimulation in several areas at once may also prove effective, the authors said.

Other co-authors of the study are Jonathan Wallis, UC Berkeley associate professor of psychology; Dr. Karunesh Ganguly, UC Berkeley post-doctoral fellow in the Carmena lab and staff scientist at the San Francisco Veterans Affairs Medical Center; Steven Kennerley, now a senior lecturer at University College London's Institute of Neurology; Charles Cadieu, UC Berkeley post-doctoral researcher in neuroscience; and Kilian Koepsell, UC Berkeley assistant researcher in neuroscience.

This is an illustration of how brain rhythms organize distributed groups of neurons into functional cell assemblies. The colors represent different cell assemblies. Neurons in widely separated brain areas often need to work together without interfering with other, spatially overlapping groups. Each assembly is sensitive to different frequencies, producing independent patterns of coordinated neural activity, depicted as color traces to the right of each network. (Credit: Ryan Canolty, UC Berkeley) References

[1] Canolty RT(1), Ganguly K, Kennerley SW, Cadieu CF, Koepsell K, Wallis JD, Carmena JM. Oscillatory phase coupling coordinates anatomically dispersed functional cell assemblies. Proc Natl Acad Sci U S A. 2010 Oct 5;107(40):17356-17361. doi: 10.1073/pnas.1008306107. Epub 2010 Sep 20.

[2] Koch P, Leisman G. Wave theory of large-scale organization of cortical activity. Int J Neurosci. 1996 Sep;86(3-4):179-96.

PAYING ATTENTION SETS OFF SYMPHONY OF CELL SYNCHRONIZATION

ScienceDaily (Dec. 26, 2006) You know the sensation. When something has your full attention you see it vividly. And when you don't pay attention, you're liable to miss something important. Now a new Northwestern University study sheds light on how attention operates.

The mystery of how attention improves the perception of incoming sensory stimulation has been a long-time concern of scientists. One hypothesis is that when you pay attention neurons produce stronger brain activity, as if the stimulus itself was stronger. That would mean that paying attention might make something appear more intense, and possibly distort its actual appearance.

In the Northwestern study, EEG measures of brain activity were used to show precisely how attention alters brain activity. The team of psychologists and neuroscientists used a new strategy for understanding the mechanisms whereby sustained attention makes us process things more effectively, literally making the world come into sharper focus.

"When you pay attention cells aren't only responding more strongly to stimuli," said co-author Marcia Grabowecky, research assistant professor of psychology in Northwestern's Weinberg College of Arts and Sciences. "Rather a population of cells is responding more coherently. It is almost like a conductor stepping

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in to control a large set of unruly musicians in an orchestra so that they all play together. Cells synchronize precisely to the conductor's cues."

The article, "Attention Induces Synchronization-Based Response Gain in Steady-State Visual Evoked Potentials," was published in Nature Neuroscience.

Each participant in the study wore a cap with 64 electrodes to record their brain waves. The brain waves fluctuated in sync with flickering stimuli that appeared on a computer screen. At any given time, two target patterns were shown, but subjects were told to pay attention to one and ignore the other. Sometimes the target patterns were fairly dim. At other times they were quite bright.

EEG responses from the participants showed more brain activity for brighter stimuli, as expected, but responses also varied depending on attention. The patterns of these brain waves allowed the investigators to obtain a thorough description of how attention altered neural function.

"For dynamic stimuli at the focus of attention, the timing of brain activity became more precisely synchronized with the flickering," said Satoru Suzuki, associate professor of psychology at Northwestern and co-author of the study.

The results suggest that attention can make a stimulus stand out by making brain responses to the stimulus more coherent. "This doesn't change the stimulus but can make it more effective for guiding our behavior," Grabowecky said.

"When you need to dig deep to summon that extra ounce of attention, it's as if you engage a symphony of brain activity that can come to your rescue as millions of neurons together make the music that represents a vivid conscious experience," added Ken Paller, professor of psychology at Northwestern and co-investigator of the study.

Besides Grabowecky, Suzuki and Paller, the other authors of "Attention Induces Synchronization-Based Response Gain in Steady-State Visual Evoked Potentials" are Northwestern's Yee Joon Kim and and Krishnakumar Muthu. REFERENCES

[1] Kim YJ, Grabowecky M, Paller KA, Muthu K, Suzuki S.Nat Neurosci. Attention induces synchronization-based response gain in steady-state visual evoked potentials. 2007;10(1):117-25. Epub 2006 Dec 17.

BRAIN WORKS BEST WHEN CELLS KEEP RIGHT RHYTHMS

ScienceDaily (Apr. 26, 2009) It is said that each of us marches to the beat of a different drum, but new Stanford University research suggests that brain cells need to follow specific rhythms that must be kept for proper brain functioning. These rhythms don't appear to be working correctly in such diseases as schizophrenia and autism, and now two papers due to be published online this week by the journals Nature and Science demonstrate that precisely tuning the oscillation frequencies of certain neurons can affect how the brain processes information and implements feelings of reward.

"A unifying theme here is that of brain rhythms and 'arrhythmias'," said Karl Deisseroth, MD, PhD, associate professor of bioengineering and of psychiatry and behavioral sciences and senior author of both papers.

An arrhythmia is what cardiologists call a seriously irregular heartbeat. The new findings suggest that, like the cells that keep the beat of the heart (or the coxswain on a rowing team that calls out the rhythm of the strokes), certain brain cells can orchestrate oscillations that ultimately help govern behavior of other cells that are guided by those rhythms. The brain's bit rate In the Nature study [1], which will be published online April 26 along with a companion paper from MIT on which Deisseroth and graduate student Feng Zhang are also authors, Deisseroth's team focused on neurons in mice that produce a protein called parvalbumin. Some researchers have suspected that these neurons drive "gamma" brain waves that oscillate at a frequency of 40 times a second (or Hertz). These waves, according to the hypothesis, might affect the flow of information in the brain. To date this could never be proved because no one could selectively control the neurons and see the resulting effect on the information flow, or oscillations.

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"This has been a fundamental mystery. We have these cells that could be crucially involved in high-level, complex information processing and we see these oscillations that are happening, but people don't really know how to put all this together," Deisseroth said. "But this is exactly the kind of thing now that we can address using optical methods."

That's because Desisseroth's group has developed a technique, called optogenetics, in which specific cells can be genetically engineered to be controlled by pulses of visible light. The team did this with parvalbumin neurons in mice and found that by exciting or inhibiting them, they could produce or suppress "gamma" waves and see a marked change in the "bit rate" or quantity of information flowing through brain circuits.

"What we found is that if you crank the parvalbumin neurons down, you see fewer of these 40-Hertz oscillations. If you crank them up you see more of these gamma oscillations," Deisseroth said. "That's the first real proof that these neurons are indeed involved in generating these gamma brain waves.

"Then we found that we could quantify in bits the effect of oscillations on information flow through neural circuits and we found that the oscillations specifically enhance information flow among different cell types in the frontal cortex of these mammals." Deisseroth added. "The final outcome of this is that parvalbumin neurons and gamma oscillations work together to enhance the flow of real information in the brain."

The potential link to disease comes from the fact that in autism the gamma oscillations appear to be present at the wrong intensity, while in schizophrenia there appear to be too few parvalbumin neurons.

"This is a new perspective relevant to both schizophrenia and autism, conditions in which information comes in but it isn't necessarily processed correctly," Deisseroth said.

The paper's first authors were Zhang and psychiatrist Vikaas Sohal, MD. Postdoctoral researcher Ofer Yizhar, PhD, also contributed to the work. The research was funded by the university and several foundations including the National Institutes of Health, the McKnight Foundation, the Coulter Foundation and the William M. Keck Foundation. Feeling reward In the Science paper, Deisseroth led a team of researchers at Stanford and the University of California-San Francisco in investigating the effect of controlling the oscillations of neurons that emit the brain chemical dopamine. The group, made up of neuroscience, bioengineering and psychiatry researchers, wanted to see if varying the oscillations led freely-behaving mice to sense varying levels of reward.

To conduct the experiment, they optogenetically engineered dopamine neurons in a specific area of the brains of the mice. Then they placed the mice into a box with three chambers in a row. At first, none of the mice had a predictable preference for which chamber to occupy. Then the researchers exposed them to two days of conditioning in which their engineered dopamine neurons were exposed to high-frequency pulses of light while in a chamber on one end, and low-frequency pulses while in the chamber on the other end. Specifically, the mice were split into two groups in which the different stimuli were associated with opposite ends of the box.

At the end of the experiment, the mice were placed in the middle chamber and exposed to no further light pulses. Each of the mice preferred to return to whichever chamber it was in when its dopamine neurons were subjected to the high-frequency light pulses, indicating that firing dopamine neurons at high-frequency rhythm correlates with stronger reward learning.

"We tested different rhythms in the dopamine neurons and we found that lower-frequency rhythms were much less effective, but the high-frequency bursts were powerfully effective in giving rise to this behavioral effect of reward," Deisseroth said.

"Understanding more about these dopamine neurons has implications not only for drugs of abuse that directly access these feelings of reward, but also for depression because in depressed people, one of the most prominent and debilitating symptoms is the inability to enjoy things."

In some sense, the papers suggest that people who aren't thinking clearly or feeling happy might just be out of step, or rather have brain cells that quite literally don't have rhythm.

The other Stanford authors of the Science paper are lead authors Zhang and graduate student Hsing-Chen Tsai; medical research associate Antoine Adamantidis, PhD; and psychiatry and behavioral sciences professor Luis de Lecea, PhD. The UCSF researchers are Garret Stuber, PhD, and Antonello Bonci, MD. The research was supported by several fellowships and foundations including the National Institutes of Mental Health and Drug Abuse, as well as the Keck and McKnight foundations.

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REFERENCES

[1] Nature. 2009 Jun 4;459(7247):698-702. doi: 10.1038/nature07991. Epub 2009 Apr 26. Parvalbumin neurons and gamma rhythms enhance cortical circuit performance. Sohal VS(1), Zhang F, Yizhar O, Deisseroth K.

ATTENTION MAKES SENSORY SIGNALS STANDOUT AMIDST

BACKGROUND NOISE IN BRAIN ScienceDaily (Sep. 28, 2009) The brain never sits idle. Whether we are awake or asleep, watch TV or close our eyes, waves of spontaneous nerve signals wash through our brains. Researchers at the Salk Institute for Biological Studies studying visual attention have discovered a novel mechanism that explains how incoming sensory signals make themselves heard amidst the constant background rumblings so they can be reliably processed and passed on.

"We live with the illusion that our visual system processes all the information that is available in the visual scene in a single glimpse," says John H. Reynolds, Ph.D., an associate professor in the Systems Neurobiology Laboratory at the Salk Institute and senior author of the current study. "In reality, there is far too much detail in a typical scene for the visual system to take it in all at once. So our perception of the world around us is in a sense pieced together from what we pay attention to."

Researchers had known for some time that paying attention to visual details increases the firing rate of neurons tuned for attended stimulus. Until now, it was assumed that these attention-dependent increases in neural activity were the primary cause of the improvement in perceptual discrimination that we experience when we focus a sensory stimulus.

The findings of the Salk researchers, published in the September 24, 2009 issue of the journal Neuron, reveal that the uptick in the firing rate is only a small part of the story. "What we found is that attention also reduces background activity," says postdoctoral researcher and first author Jude Mitchell, Ph.D. "We estimate that this noise reduction increases the fidelity of the neural signal by a factor that is as much as four times as large as the improvement caused by attention-dependent increases in firing rate. This reduction in noise may account for as much as 80% of the attention story."

When light hits the retina, visual information is translated into a cascade of nerve impulses sending signals deep into the brain. It is here, in the brain's visual cortex, which resides in the occipital lobe at the back of the skull, that these signals are interpreted and give rise to perception. But the visual system has limited capacity and cannot process everything that falls onto the retina. Instead, the brain relies on attention to bring details of interest into focus so it can select them out from background clutter.

In their study, Reynolds, Mitchell, and former graduate student Kristy Sundberg asked whether attention, which so efficiently tunes out external distractions, does the same for the internal racket. Attention generally increases the firing rate of responsive neurons: The stronger the stimulus, the more impulses are sent per second, which improves the quality of the signal somewhat. "It's a little bit like turning up the volume from very low to high on a stereo," says Reynolds. "You are not hearing it very clearly at low volume not only because the signal is weak but because ambient noise is masking the stimulus. As you increase the volume, the signal becomes clearer."

But even under the most controlled laboratory conditions, the responses evoked by identically repeated stimuli vary from trial to trial. "Neurons are very noisy computing devices," says Mitchell. "Each neuron receives input from thousands of neurons and needs to distinguish the incoming information from the background noise."

If each neuron produced random noise that is independent from what its neighbor neuron is doing, the brain cell on the receiving end could simply pool all incoming signals and average out the noise. Reynolds compares it to diversifying risk in a stock portfolio: "If you have a portfolio of stocks whose prices vary independently, you can reduce fluctuations by dividing your investment among a large pool of stocks."

Unfortunately, for neurons this option is off the table since most of the brain's background noise originates in waves of spontaneous nerve signals that undulate across a large population of brain cells. Says Mitchell, "These fluctuations can't be simply averaged out since they are shared across the neural

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population." To extend the investment analogy, say you put your money into a pool of real estate investments. Your portfolio is subject to fluctuations in the real estate market – the correlated fluctuations in the values of individual investments – no matter how big the pool.

But an interesting thing happened when the researchers measured the activity of a large population of visual neurons in animals trained to play a simple video game that required rapt attention to a visual stimulus on the screen. The internal fluctuations or shared noise quieted down, increasing the visibility of the incoming sensory information.

"Attention is an essential part of perception," says Reynolds. "Brain disorders in which attention fails therefore have devastating effects. Gaining insight into the neural mechanisms of attention is essential if we are to understand the causes of these perceptual deficits and find ways to treat them. By revealing a major new attentional mechanism, Jude has taken a major step toward understanding the neural mechanisms of conscious awareness."

References

[1] Boersma M(1), Kemner C, de Reus MA, Collin G, Snijders TM, Hofman D, Buitelaar JK, Stam CJ, van den Heuvel MP. Disrupted functional brain networks in autistic toddlers. Brain Connect. 2013;3(1):41-9. doi: 10.1089/brain.2012.0127.

AMPUTEES DISCERN FAMILIAR SENSATIONS ACROSS PROSTHETIC HAND

NEUROSCIENCE NEWS OCTOBER 8, 2014 Even before he lost his right hand to an industrial accident 4 years ago, Igor Spetic had family open his medicine bottles. Cotton balls give him goose bumps. Now, blindfolded during an experiment, he feels his arm hairs rise when a researcher brushes the back of his prosthetic hand with a cotton ball.

Spetic, of course, can’t feel the ball. But patterns of electric signals are sent by a computer into nerves in his arm and to his brain, which tells him different. “I knew immediately it was cotton,” he said. That’s one of several types of sensation Spetic, of Madison, Ohio, can feel with the prosthetic system being developed by Case Western Reserve University and the Louis Stokes Cleveland Veterans Affairs Medical Center.

Spetic was excited just to “feel” again, and quickly received an unexpected benefit. The phantom pain he’d suffered, which he’s described as a vice crushing his closed fist, subsided almost completely. A second patient, who had less phantom pain after losing his right hand and much of his forearm in an accident, said his, too, is nearly gone.

Despite having phantom pain, both men said that the first time they were connected to the system and received the electrical stimulation, was the first time they’d felt their hands since their accidents. In the ensuing months, they began feeling sensations that were familiar and were able to control their prosthetic hands with more – well – dexterity.

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Despite having phantom pain, both men said that the first time they were connected to the system and received the electrical stimulation, was the first time they’d felt their hands since their accidents. In the ensuing months, they began feeling sensations that were familiar and were able to control their prosthetic hands with more – well – dexterity. Credit Case Western Reserve University

“The sense of touch is one of the ways we interact with objects around us,” said Dustin Tyler, an associate professor of biomedical engineering at Case Western Reserve and director of the research. “Our goal is not just to restore function, but to build a reconnection to the world. This is long-lasting, chronic restoration of sensation over multiple points across the hand.”

“The work reactivates areas of the brain that produce the sense of touch, said Tyler, who is also associate director of the Advanced Platform Technology Center at the Cleveland VA. “When the hand is lost, the inputs that switched on these areas were lost.”

How the system works and the results will be published online in the journal Science Translational Medicine Oct. 8, 2014. “The sense of touch actually gets better,” said Keith Vonderhuevel, of Sidney, Ohio, who lost his hand in 2005 and had the system implanted in January 2013. “They change things on the computer to change the sensation. “One time,” he said, “it felt like water running across the back of my hand.”

The system, which is limited to the lab at this point, uses electrical stimulation to give the sense of feeling. But there are key differences from other reported efforts. First, the nerves that used to relay the sense of touch to the brain are stimulated by contact points on cuffs that encircle major nerve bundles in the arm, not by electrodes inserted through the protective nerve membranes.

Surgeons Michael W Keith, MD and J. Robert Anderson, MD, from Case Western Reserve School of Medicine and Cleveland VA, implanted three electrode cuffs in Spetic’s forearm, enabling him to feel 19 distinct points; and two cuffs in Vonderhuevel’s upper arm, enabling him to feel 16 distinct locations.

Second, when they began the study, the sensation Spetic felt when a sensor was touched was a tingle. To provide more natural sensations, the research team has developed algorithms that convert the input from sensors taped to a patient’s hand into varying patterns and intensities of electrical signals. The sensors themselves aren’t sophisticated enough to discern textures, they detect only pressure.

The different signal patterns, passed through the cuffs, are read as different stimuli by the brain. The scientists continue to fine-tune the patterns, and Spetic and Vonderhuevel appear to be becoming more attuned to them.

Third, the system has worked for 2 ½ years in Spetic and 1½ in Vonderhueval. Other research has reported sensation lasting one month and, in some cases, the ability to feel began to fade over weeks. A blindfolded Vonderhuevel has held grapes or cherries in his prosthetic hand—the signals enabling him to gauge how tightly he’s squeezing—and pulled out the stems.“When the sensation’s on, it’s not too hard,” he said. “When it’s off, you make a lot of grape juice.”

Different signal patterns interpreted as sandpaper, a smooth surface and a ridged surface enabled a blindfolded Spetic to discern each as they were applied to his hand. And when researchers touched two different locations with two different textures at the same time, he could discern the type and location of each.

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Tyler believes that everyone creates a map of sensations from their life history that enables them to correlate an input to a given sensation. “I don’t presume the stimuli we’re giving is hitting the spots on the map exactly, but they’re familiar enough that the brain identifies what it is,” he said.

Because of Vonderheuval’s and Spetic’s continuing progress, Tyler is hopeful the method can lead to a lifetime of use. He’s optimistic his team can develop a system a patient could use at home, within five years.

In addition to hand prosthetics, Tyler believes the technology can be used to help those using prosthetic legs receive input from the ground and adjust to gravel or uneven surfaces. Beyond that, the neural interfacing and new stimulation techniques may be useful in controlling tremors, deep brain stimulation and more. References

[1] Tan DW, Schiefer MA, Keith MK, Anderson JR, Tyler J, Tyler DJ. A neural interface provides long-term stable natural touch perception Science Translational Medicine. Published online October 8 2014 doi:10.1126/scitranslmed.3008669 Video Source: https://www.youtube.com/watch?v=IAqx7joKwAA

CHEMICAL DERIVED FROM BROCCOLI SPROUTS SHOWS

PROMISE IN TREATING AUTISM Neuroscience News October 13, 2014 Results of a small clinical trial suggest that a chemical derived from broccoli sprouts — and best known for claims that it can help prevent certain cancers — may ease classic behavioral symptoms in those with autism spectrum disorders (ASDs).

The study, a joint effort by scientists at MassGeneral Hospital for Children and the Johns Hopkins University School of Medicine, involved 40 teenage boys and young men, ages 13 to 27, with moderate to severe autism. In a report published online in the journal Proceedings of the National Academy of Sciences during the week of Oct. 13, the researchers say that many of those who received a daily dose of the chemical sulforaphane experienced substantial improvements in their social interaction and verbal communication, along with decreases in repetitive, ritualistic behaviors, compared to those who received a placebo.

“We believe that this may be preliminary evidence for the first treatment for autism that improves symptoms by apparently correcting some of the underlying cellular problems,” says Paul Talalay, M.D., professor of pharmacology and molecular sciences, who has researched these vegetable compounds for the past 25 years.

“We are far from being able to declare a victory over autism, but this gives us important insights into what might help,” says co-investigator Andrew Zimmerman, M.D., now a professor of pediatric neurology at UMass Memorial Medical Center.

ASD experts estimate that the group of disorders affects 1 to 2 percent of the world’s population, with a much higher incidence in boys than girls. Its behavioral symptoms, such as poor social interaction and verbal communication, are well known and were first described 70 years ago by Leo Kanner, M.D., the founder of pediatric psychiatry at The Johns Hopkins University.

Most of those who responded to sulforaphane showed significant improvements by the first measurement at four weeks and continued to improve during the rest of the treatment.

Unfortunately, its root causes remain elusive, though progress has been made, Talalay says, in describing some of the biochemical and molecular abnormalities that tend to accompany ASD. Many of these are related to the efficiency of energy generation in cells. He says that studies show that the cells of those with ASD often have high levels of oxidative stress, the buildup of harmful, unintended byproducts from the cell’s use of oxygen that can cause inflammation, damage DNA, and lead to cancer and other chronic diseases.

In 1992, Talalay’s research group discovered that sulforaphane has some ability to bolster the body’s natural defenses against oxidative stress, inflammation and DNA damage. In addition, the chemical later

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turned out to improve the body’s heat-shock response — a cascade of events used to protect cells from the stress caused by high temperatures, including those experienced when people have fever.

Intriguingly, he says, about one-half of parents report that their children’s autistic behavior improves noticeably when they have a fever, then reverts back when the fever is gone. In 2007, Zimmerman, a principal collaborator in the current study, tested this anecdotal trend clinically and found it to be true, though a mechanism for the fever effect was not identified.

Because fevers, like sulforaphane, initiate the body’s heat-shock response, Zimmerman and Talalay wondered if sulforaphane could cause the same temporary improvement in autism that fevers do. The current study was designed to find out.

Before the start of the trial, the patients’ caregivers and physicians filled out three standard behavioral assessments: the Aberrant Behavior Checklist (ABC), the Social Responsiveness Scale (SRS) and the Clinical Global Impressions-Improvement scale (CGI-I). The assessments measure sensory sensitivities, ability to relate to others, verbal communication skills, social interactions and other behaviors related to autism.

Twenty-six of the subjects were randomly selected to receive, based on their weight, 9 to 27 milligrams of sulforaphane daily, and 14 received placebos. Behavioral assessments were again completed at four, 10 and 18 weeks while treatment continued. A final assessment was completed for most of the participants four weeks after the treatment had stopped.

Most of those who responded to sulforaphane showed significant improvements by the first measurement at four weeks and continued to improve during the rest of the treatment. After 18 weeks of treatment, the average ABC and SRS scores of those who received sulforaphane had decreased 34 and 17 percent, respectively, with improvements in bouts of irritability, lethargy, repetitive movements, hyperactivity, awareness, communication, motivation and mannerisms.

After 18 weeks of treatment, according to the CGI-I scale, 46, 54 and 42 percent of sulforaphane recipients experienced noticeable improvements in social interaction, aberrant behaviors and verbal communication, respectively.

Talalay notes that the scores of those who took sulforaphane trended back toward their original values after they stopped taking the chemical, just like what happens to those who experience improvements during a fever. “It seems like sulforaphane is temporarily helping cells to cope with their handicaps,” he says.

Zimmerman adds that before they learned which subjects got the sulforaphane or placebo, the impressions of the clinical team — including parents — were that 13 of the participants noticeably improved. For example, some treated subjects looked them in the eye and shook their hands, which they had not done before. They found out later that all 13 had been taking sulforaphane, which is half of the treatment group.

Talalay cautions that the levels of sulforaphane precursors present in different varieties of broccoli are highly variable. Furthermore, the capacity of individuals to convert these precursors to active sulforaphane also varies greatly. It would be very difficult to achieve the levels of sulforaphane used in this study by eating large amounts of broccoli or other cruciferous vegetables. References

[1] Singh K, Connors SL, Macklin EA, Smith KD, Fahey JW, Talalay P, Zimmerman AW. Sulforaphane treatment of autism spectrum disorder (ASD). Proc Natl Acad Sci U S A. 2014 Oct 28;111(43):15550-15555. doi: 10.1073/pnas.1416940111. Epub 2014 Oct 13.

DOCTORS HAVE ETHICAL OBLIGATION TO EDUCATE, PROTECT

ATHLETES FROM CONCUSSION Neuroscience News July 9, 2014 Position statement released as AAN hosts first sports concussion conference in Chicago.

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The American Academy of Neurology (AAN), the largest professional association of neurologists and a leading authority on sports concussion, is releasing a new position paper that states doctors have an ethical obligation to educate and protect athletes from sports concussion and clear them to play only when the athlete is medically ready, standing firm against objections from players, parents or coaches. The statement is published in the July 9, 2014, online issue of Neurology, the medical journal of the AAN, and is being released ahead of The Sports Concussion Conference, July 11-13, 2014, in Chicago, where the AAN will share the latest scientific advances in diagnosing and treating sports concussion.

The statement concludes that physicians caring for athletes during and after a sports-related concussion should have adequate training and experience in the recognition and evaluation of both the existence and severity of potential brain injury. This image is for illustrative purposes only.

The AAN position statement calls for doctors to safeguard the future mental and physical health of athletes as a top priority, especially regarding return-to-play decision-making. Physicians also must educate patients and their families about the dangers of concussion in all relevant sports, according to the statement.

The Academy has spent several years analyzing all of the available research and ethical issues to develop this official position paper, which corresponds with the AAN’s guideline on sports concussion.

“With nearly four million sports-related concussions in the US each year, it is imperative doctors are educated and protect these athletes who may have sustained a concussion,” said lead author Matthew P. Kirschen, MD, PhD, a neurologist with The Children’s Hospital of Philadelphia and a member of the American Academy of Neurology. “Concussions can have devastating effects such as short-term impairments in athletes’ cognitive and athletic performance. Repeat concussions have been linked to long-term impairments in brain function, such as problems with learning, memory and behavior.”

The statement also: Supports wider use of baseline cognitive testing Recommends that concussion evaluation and management training be added to neurology

residency programs Suggests the development of a national concussion registry with mandatory reporting, which may

help to document more rigorously the incidence and recurrence of concussion at all levels of play. Ethically, the statement concludes that physicians caring for athletes during and after a sports-related

concussion should have adequate training and experience in the recognition and evaluation of both the existence and severity of potential brain injury.

“These strategies could help identify the threshold at which the number and severity of head injuries leads to irreversible brain injury. They may also help to clarify how concussion risk varies with factors like age, gender, puberty stage and ethnicity so athletes and parents can make informed decisions about playing contact sports,” said Kirschen. References

[1] Kirschen MP, Tsou A, Nelson SB, Russell JA, Larriviere D. Legal and ethical implications in the evaluation and management of sports-related concussion. On behalf of the Ethics, Law, and Humanities Committee, a Joint Committee of the American Academy of Neurology, American Neurological Association, and Child Neurology Society in Neurology. Published online July 9 2014 doi:10.1212/WNL.0000000000000613

THE RACE TO THE TOP: THE USE OF ‘SMART DRUGS’ TO EXCEL IN

ACADEMIA AND IN THE PROFESSIONAL WORLD Neuroscience News May 30, 2014 Jane Jones has been preparing to take the Medical College Admission Test for months since the culmination of her junior undergraduate studies. She has taken a rigorous course load to fulfill the prerequisites of her desired medical school programs and has built an impressive résumé as a result of her dedication to several clubs and campus-wide activities. Like many prospective medical students, Jane is faced with the imminent pressures to succeed in every area of her academic life, fearing that a single slip could extinguish her dreams of becoming a practicing doctor. To increase her focus as she prepares, Jane

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begins taking a combination of herbal supplements specifically aimed at improving cognition and closer to exam day she plans on taking modafinil, which is typically prescribed to treat narcolepsy, with hopes of increasing her productivity and overall performance.

Most of the criticism over Jane’s intentions of obtaining a high score on the test would rely on the premise that she is cheating by depending upon nootropics, or nontoxic substances with memory enhancing properties, to achieve success, which may or may not grant her a seat at an institution to begin with. Arguments of this form are valid, but uncritical and inadequate; to correctly evaluate the severity of a healthy person using nervous system stimulants as a means of programming oneself to compete on the same level as the “mentally elite” or simply to get ahead in one’s field, we must take into consideration the reasons why strides are ever made towards improving technologies, and further, neuro-technologies. I am inclined to believe that although such pharmaceuticals can provide a seemingly unfair advantage to users over nonusers, it is not sufficient to categorize medically safe – “safe” in this context meaning addiction-free with minimal side effects – cognitive enhancers as cheat sheets, for they aid in maximizing human performance. After all, to be an active citizen of the Digital Age is to accept the technologies that allow us to augment our capabilities and outputs. Otherwise, we lack a competitive edge.

Before we dive into the arguments surrounding nootropics use as a ‘smart drug,’ it would be vital to our formulation of any perceptions to familiarize ourselves with their known pharmacological effects on cognition. I should take a moment to address that while many people would differentiate between nootropics and cognitive enhancers, I consider the two to be synonymous with each other due to the ways in which they facilitate an increase in neurotransmitter activity in the human brain and I will be using these terms interchangeably. Background In 1972, a Romanian chemist by the name of Dr. Corneliu E. Giurgea along with a team of Belgian scientists synthesized piracetam, the first known ‘memory drug’ and still one of the most popular of its kind, and classified this psychoactive substance as a new class of drug known as nootropes (Gualtieri, 2004). The compounds of the drug were observed to support memory processes, especially in people who are experiencing neurodegenerative diseases such as Alzheimer’s disease (AD). Research suggests that it can improve cognitive function through consistent use and has shown promise in delaying the progression of cognitive deterioration in patients (Croisile et. al., 1993). Healthy individuals also reported benefits from piracetam claiming they required less sleep, it increased their verbal fluency, and increased creative thought and abstract thinking.

The discovery of piracetam has propelled the synthesis of various modern smart pills like modafinil. In recent reports, the manufacturers of Provigil, the commercial name for modafinil, have “publicly downplayed the idea that the drug can be used as a smart pill” (Talbot, 2009). To test its infamous properties as a cognitive enhancer, researchers at Cambridge University conducted various standard cognitive tests in which a control group consisting of healthy young male volunteers received modafinil and another group received a placebo. Those who received modafinil performed better in recalling and repeating long strings of numbers, both forward and backward, as well as recognizing visual patterns. The experimenters in this study stated in a 2002 edition of the journal Psychopharmacology that “modafinil selectively improves neuropsychological task performance” (Turner et. al., 2002), meaning the drug provided neural benefits in conjunction with behavioral benefits like alertness and attentiveness. Artificial Memory Enhancement and the Definition of ‘Health’ The ethical implications of “cosmetic neurology,” or the practice of strengthening ordinary cognition as coined by Anjan Chatterjee, a neurologist at the University of Pennsylvania, are of plenty, but they all fall short in their distinctions of who should be allowed to consume neural enhancement medication. For instance, take into consideration the number of students and adults diagnosed with Attention-Deficit/Hyperactivity Disorder (ADHD) who have been prescribed drugs like Ritalin or Adderall to suppress impairments of neural function. These individuals would not be able to participate in academia or in the professional world as successfully as those without the disorder if they are not medicated. Traditional philosophers on this subject might insist that the act of medicating people with ADHD gives medicine too much power and responsibility. Such philosophers may also support Daniel Callahan’s proposal that the World Health Organization’s (WHO) definition of health is too broad and should not describe mental or social states. However, confining the states of health to account for only a physical state is illogical when disciplines supporting mental health and social wellbeing have been established. The definition of health

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need be broad for this reason and the marriage of medicine and illness need be broken to accommodate for medicating the healthy. People who seek to aggrandize their cognitive strengths via consumption of nontoxic, neuro-protecting substances should not be precluded from maximizing their cognitive potential especially during a time when pressures to succeed are amplified by the ever-so competitive nature of placement exams and nerve-wracking interviews. Further, a lack of mental deficiency is not enough reason to restrict the acquisition of performance enhancing substances from individuals who seek to improve their cognitive abilities. Enhancing Drugs and Individual Autonomy Boosting the brain’s information-retention capacity via consumption of nootropics, as you can imagine, appeals to students who are aiming to achieve academic distinction at the top-tier of their class and adults with demanding careers just as readily as a next-generation iPhone appeals to people who are technologically savvy. However, these substances are currently classified as medicines and non-medical uses are considered illegal (Bell, 2006). If we are not deprived of technological luxuries like the iPhone when we have the means of purchasing one, why should individuals who are healthy and looking to become more efficient members of society be deprived of access to neuro-enhancing supplements? To deprive someone of the ability to expand his or her neural capabilities is of the same nature of selfishness as denying a Wall Street stockbroker of access to his or her smartphone, which he or she may depend upon to communicate effectively through share-related apps and services. People who are opposed to any enhancement technologies enforce restrictions of these substances on the grounds that they are not safe, but these are the same people who fail to recognize common nootropics such as caffeine and their popularity among students and career-oriented individuals. There is potential for abuse of any drug, on or off the market, but nootropics that have been clinically tested like modafinil and caffeine are known to have tolerable adverse effects or even none at all on humans. Thus, the power to decide to adopt nootropics into one’s daily diet should be on the potential user alone, given that he or she has extensively weighed the benefits over the risks under a realistic mindset of the implications of both on his or her life. Should a physician advise against nootropic usage and the patient be so quick to agree with his or her physician’s orders without questioning would be to take a step backward to the dark ages of paternalism in medicine.

Deciding if we should opt to using cognitive enhancers in the course of daily life arises from our fears that seeking pharmaceutical assistance is equivalent to steroids use in the athletic arena. The moral permissibility of the latter is immediately defined as impermissible by national sports organizations, which would deem unnatural performance as means of creating an uneven playing field. This idea wrongfully promotes mainstream rejection of performance-enhancing substances all together – wrongfully because the playing field was never and will never truly be leveled. There will always be a more superior athlete, whether he or she is defined by his or her physical strength or locomotive speed, just as there will always be a student with higher cognitive ability as a result of genetic inheritance. Hence, claims asserting that an unfair advantage is created by the intake of neuroactive substances to assist students in surpassing their basal performance level are lacking and they prevent us from advancing in the fields of pharmaceutical technologies. Final Thoughts Mental augmentation is more than a new-age trend or improvement of a person’s lifestyle. Welcoming cognition-enhancing substances into our lives will come with the same baggage consisting of skepticism and pharmacological Calvinism, which suggests that medicine should only be consumed in the presence of illness or disease, as any emerging pharmaceutical technology has experienced in its introductory stages, but we must not tamper with the progress of such technologies by deeming them ethically impermissible when we have come so far as a people in our tolerance of applied science. While I am arguing for the permissibility of nootropic drugs as ‘smart drugs’ to bless competition in challenging environments, I am supportive of opponents’ claims that state celebrated use among people can influence a change in the way we perceive competition. Yet, I am more concerned with the ways in which it can change our definitions of ‘health’ and ‘medicine’ as we learn more about human brain physiology because in this burgeoning age of advancing medical technology, change is inevitable. We should embrace such change.

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References [1] Bell, Vaughan. “Know the Facts About Cognitive Enhancers.” Mind Performance Hacks. N.P.: O’Reilly

Media, 2006. N. pag. PDF file. 25 Apr. 2014. Callahan, Daniel. “The WHO Definition of ‘health'” The Hastings Center Studies (1978): 77-87. PDF file. 25 Apr. 2014

[2] Croisile, B., M. Trillet, J. Fondarai, B. Laurent, F. Mauguière, and M. Billardon. “Long-term and High-dose Piracetam Treatment of Alzheimer’s Disease.” National Center for Biotechnology Information. U.S. National Library of Medicine, Feb. 1993. Web. 26 Apr. 2014.

[3] Gualtieri, C. Thomas. “Cognitive Enhancers and Neuroprotectants.” Brain Injury and Mental Retardation: Psychopharmacology and Neuropsychology. N.p.: Lippincott Williams & Wilkins, 2004. 2+. Web. 27 Apr. 2014.

[4] Russell, Tony, Allen Brizee, and Elizabeth Angeli. “MLA Formatting and Style Guide.” The Purdue OWL. Purdue U Writing Lab, 4 Apr. 2010. Web. 28 Apr. 2014.

[5] Talbot, Margaret. “Brain Gain: The Underground World of “neuroenhancing” Drugs.” The New Yorker, 27 Apr. 2009. Web. 24 Apr. 2014.

[6] Turner, DC, TW Robbins, L. Clark, AR Aron, J. Dowson, and BJ Sahakian. “Cognitive Enhancing Effects of Modafinil in Healthy Volunteers.” National Center for Biotechnology Information. U.S. National Library of Medicine, 1 Nov. 2002. Web. 27 Apr. 2014.

BRAINS BECOME MORE 'PLASTIC' AFTER EXERCISE

Medica New Today Last updated: 28 October 2014 at 2am PST New research has found that memory and motor skills are increased after just thirty minutes of exercise. Neuroscientists from the University of Adelaide in South Australia studied the brain patterns of healthy adults immediately after a half an hour of exercise and again 15 minutes later to find it had positives effects on brain function and 'plasticity'.

"The more 'plastic' the brain becomes, the more it's able to reorganise itself, modifying the number and strength of connections between nerve cells and different brain areas," said Associate Professor Michael Ridding from the University of Adelaide.

Past research has shown that regular physical activity can have positive effects on brain function and plasticity, but it was not known whether a stand-alone session of exercise would also have similar positive effects.

"We now have evidence suggesting that it does," Ridding said. "This exercise-related change in the brain may, in part, explain why physical activity has a positive effect on memory and higher-level functions."

There is now mounting evidence that engaging in aerobic exercise positively influences brain function in many ways - at cellular and molecular levels, as well as in the brain's architecture.

"Although this was a small sample group, it helps us to better understand the overall picture of how exercise influences the brain,

"We know that plasticity is also important for recovery from brain damage, so this opens up potential therapeutic avenues for patients,

"Further research will be required to see what the possible long-term benefits could be for patients as well as healthy people," he said. References

[1] Smith AE, Goldsworthy MR, Garside T, Wood FM, Ridding MC. The influence of a single bout of aerobic exercise on short-interval intracortical excitability. Exp Brain Res. 2014;232(6):1875-1882. doi: 10.1007/s00221-014-3879-z. Epub 2014 Feb 26.

[2] McDonnell MN, Buckley JD, Opie GM, Ridding MC, Semmler JG. A single bout of aerobic exercise promotes motor cortical neuroplasticity. J Appl Physiol 2013;114(9):1174-1182. doi: 10.1152/japplphysiol.01378.2012. Epub 2013 Mar 14.

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Microwave-Based Stroke Diagnosis Making Global Pre-Hospital Thrombolytic Treatment Possible

Persson M, Fhager A, Trefna H, Yu Y, McKelvey T, Pegenius G, Karlsson J-E, Elam M. 2014; 61(11):2806-2817. In this paper we present a microwave-based system suitable for pre-hospital diagnosis of stroke. The motivation is to help the 15 million people who suffer a stroke each year to a better treatment. Today, most of the patients are not receiving optimal treatment. A major reason is that diagnosis must be made at hospital, by CT scanning of the head, before treatment can be started. Often the diagnosis is not made until the treatment window closes after 4.5 hours. Here we present results from two initial clinical studies using two different microwave based brain diagnostic devices. The system consists of a number of antennas worn on the head, which are used to perform scattering measurements. The results show that these devices and the associated diagnostic algorithms can differentiate haemorrhagic from ischemic stroke patients. These findings set the stage for pre-hospital stroke diagnosis and treatment.

A Head Impact Detection System Using SVM Classification and

Proximity Sensing in an Instrumented Mouthguard Wu LC, Zarnescu L, Nangia V, Cam B, Camarillo DB. Trans. Biomed Engin. 2014; 61(11): 2659-2668. Injury from blunt head impacts causes acute neurological deficits and repeated trauma may lead to chronic neurodegeneration. To prevent repeat injury, legislations such as the Lystedt Law require athletes be removed from play if suspected of sustaining head trauma. However, such legislations cannot be fully enforced due to injury under-reporting in sports. We developed a head impact detection system that has the potential to enable real-time, objective trauma screening on the field. Our system uses infrared proximity sensing and a machine learning classifier to detect head impacts, and shows 99% accuracy in a controlled laboratory evaluation.


and the F.R. Carrick Research Institute’s

6th Annual Conference and Awards Dinner October 8-11, 2015

ORLANDO, FLORIDA!

2015 Early Registration is now available! Our 6th annual conference will be held in Orlando, Florida!

It will truly be an event that you will not want to miss. Fantastic location, great speakers and truly an amazing professional and personal experience for all! Register now for easy payment plan options.

DON’T MISS OUT ON REGISTRATION SPECIALS FOR THE 2015 EVENT, WHICH ALLOW YOU TO MAKE PAYMENTS ALL YEAR!

[ ] Conference Package A = $750.00 (Entire conference, Friday event cocktail party, Saturday awards dinner.)

[ ] Conference Package B = $1300.00 (Conference package above plus hotel for Thursday, Friday, and Saturday.)

[ ] Conference w/ Room Share Package C = $1025.00 (Conference package above plus hotel for Thursday, Friday, and Saturday.) Room Share with _________________________________________________________

[ ] Student Conference Package = $500.00 (Conference Package, but for active students only.)

[ ] Extra Dinner Ticket for Companion = $125.00 (Ticket for Friday evening cocktail party and Saturday awards dinner.)

Hotel rooms cannot be cancelled or changed after 03/01/2015 due to the pre-payment policy of the hotel. Hotel rooms will be available for purchase at a discounted rate for attendees as always.

LIMITED TIME OFFER - Register Now and Take Advantage of Payment Options.

[ ] Please bill my credit card listed below in equal monthly installments (11/01/2014 – 10/01/2015).

[ ] Please bill my credit card now for payment in full. Name: __________________________________________________ Phone: ____________________________

Email Address: _____________________________________________________________________________

City/State/Country: _____________________________________________ Billing Zip Code: ______________

Credit Card Number: _________________________________________________ Exp. Date: ______________

Signature: __________________________________________________________________________________

Please email, fax or mail your registration IAFNR, 2487 S. Gilbert Rd #106-116, Gilbert, AZ 85296, Phone (480) 926-1115 * Fax (480) 813-1868 Email: [email protected]

For any information on our cancellation policy, please refer to our website. Penalties will be incurred if cancellation occurs with less than 3 months before the event.

IAFNR 5th Annual Conference

October 16-19, 2014 Henderson, Nevada

FLASH DRIVE ORDER FORM

If you were unable to attend the IAFNR 2014 Conference, you are still able to see and hear the speakers and see their presentations including the clinical workshops. A 1GB flash drive contains high quality HD Video and is available for a limited time (while supplies last). Name: _____________________________ Email: ______________________________ Mailing Address (Please print clearly): ________________________________________ City: ___________________ State: __________ Zip: _________ Country: ___________ Phone Number: _______________________________________ [ ] $225.00 for current IAFNR Members

[ ] $ 250.00 for non-members

[ ] Clinical Workshop Note Package (Additional $10.00) _______________________________________ _________________ _____________

Credit Card Number Expiration Date Security Code _______________________________________ _________________

Signature Date Order on line at www.iafnr.org

Fax to: 480-813-1868 or email to [email protected] Speakers include:

Clinical workshops by:

• Dr. Dan Siegel • Dr. Datis Kharrazian • Dr. Aristo Vojdani • Dr. Dan Murphy • Dr. Jocelyn Faubert

• Dr. Marta Herbert • Anat Baniel • Dr. Ted Carrick • Dr. Louis Cozolino • Dr. Brandon Brock

• Dr. Robert Melillo • Dr. Shane Steadman • Dr. Glen Zielinski • Dr. Guido Pagnacco • Dr. Brandon Brock • Dr. Mike Saatkamp • Dr. Mark Lamantia

Poster Presentation REQUIREMENTS for 2015 Annual Conference

October 8-11, 2015

Orlando, Florida • Abstracts must be original and must not be or have been published or presented at any

other meeting prior to the congress.

• Abstracts must be submitted in English.

• Abstracts must be received by the announced deadline. Abstracts received after the deadline will not be considered.

• The Presenting Author is required to ensure that all co-authors are aware of the content of the abstract before submission.

• Presenting Author's contact details must be included (email address, postal address, daytime and evening phone number, author and co-authors' details, full first and family name(s), authors' names must be in upper and lower case).

• Affiliation details (department, institution, hospital, city, state, country) must be included.

• Abstract title must be limited to 20 words in upper case.

• Abstract text must be limited to 250 words, including acknowledgements.

• Abstracts should clearly state: Background, Aims, Methods, Results, Conclusion

• Use only standard abbreviations. Place any special or unusual abbreviations in parentheses after the full word appears the first time. Use generic names of supplements or drugs. Do not use product identifiers. Express numbers as numerals.

• Case studies are of real cases and all identity to a patient must be kept confidential. Do not use names or identifying initials.

Tables, Graphs and Images:

•A maximum of 3 tables of up to 10 rows x 10 columns can be included per abstract.

• Each image included in the abstract is worth 30 words. A maximum of 3 images can be included per abstract. The maximum file size of each graph image is 500 kb.

• The maximum pixel size of the graph / image is 600(w) x 800 (h) pixels in .jpeg format only. • Disclosure of financial relationships that the author(s) may have with the manufacturer / supplier of any commercial product or services related to the work, should be indicated

on the abstract form. For example, if you use a certain product or diagnostic instrument in your case study, you must state that you have no conflict of interest or state whatever relationship you might have.

• All accepted poster abstracts will be printed in the conference issue of the journal of functional neurology, rehabilitation and ergonomics

• All abstracts need to be submitted.

• All abstracts must be digitally submitted to:

Dr. Gerry Leisman The National institute for Brain & Rehabilitation Sciences Nazareth, Israel [email protected] International Association of Functional Neurology & Rehabilitation 2487 S. Gilbert Rd. #106-116 Gilbert, AZ 85295 USA Phone: (480) 926-1115

The International Association for Functional Neurology and Rehabilitation was founded in 2010 to promote, protect, and advance interdisciplinary scientific and clinical Functional Neurology and Rehabilitation Sciences at the national and international levels. We plan to be one of the fastest-growing, most respected and diverse organizations in the field world-wide.


MEMBER BENEFITS

2015 As a member of IAFNR, you will not only be voicing your commitment to the science and practice of Functional Neurology and Neurological Rehabilitation Sciences, but you will also receive the following benefits: IAFNR-Journal – Functional Neurology, Rehabilitation, and Ergonomics is published by Nova Science Publishers, Inc. with Drs. Gerry Leisman and Robert Melillo as Editors-in-Chief. Stay up-to-date on the latest scientific research in Functional Neurology, as well as reports of trends in the field, special issues on pertinent topics, abstracts of the annual conference, and timely news of organizational activities. The journal will be published four times yearly. The aim and scope of this interdisciplinary journal is to provide a forum for the fields of Functional Neurology, Rehabilitation Sciences, Neuropsychology, Clinical Neurology, Human Factors and Ergonomics, and vocational assessment and training to present critical ideas, theories, proof-of-concept for technology solutions, and data-based evaluative research to facilitate more effective functional development in children and adults. FNRE accepts review papers, articles of original research, data-based and controlled case studies pertaining to Functional Neurology, Man-Machine Interaction, Rehabilitation Sciences, brain-behavior relationships, and in applied cognitive neuroscience that relate to translational research. Engineering proof-of-concept applied to functional neurology as ergonomics are also welcome.

FNRE also welcomes commentary on either the review papers or on original research as the journal intends to be an archival source of discussion of new advances in rehabilitation. IAFNR-Annual Convention – Our 6th Annual Convention in Orlando, Florida will take place October 8-11, 2015. Please contact us for more information and to register for the event! IAFNR-Library – APS will publish several book series, which will be available to Members at discounted prices. IAFNR-Online – The IAFNR and FNRE websites will offer a wealth of information for members, including in-press journal articles, searchable employment ads, the FNRE archive, an online membership directory available only to members, and much more. Advocacy – Your voice will be heard through our tireless government relations work, which works with the United States Congress and federal research agencies to increase support for our research and practice interests and training. Public Affairs – IAFNR will engage the public in Functional Neurology research through social network technologies including Facebook and Twitter, our “Brain Matters” column and our “We’re Superhuman if we only tried…” weblog. These efforts will reach an unprecedented number of people around the world. We’ll let you know how many hits we get each day. Teaching – Expand your knowledge and skills through IAFNR teaching initiatives in concert with the Carrick Institute and international university programs. For more information on these and other IAFNR member benefits, please contact us via any of the following: Membership Department International Association for Functional Neurology, Rehabilitation, and Ergonomics 2487 S. Gilbert Road, Suite 106-116 Gilbert, AZ 85295 USA Phone: 1-480-926-1115 Fax: 1-480-813-1868 E-mail: [email protected]


APPLICATION FOR NEW MEMBERSHIP

(Renewing & Reinstated Members: Please note any changes in contact information or education below.)

CONTACT INFORMATION Member Last Name: ___________________________ First Name: ____________________ MI: _______ Organization/Institution/Affiliation: ________________________________________________________ Mailing Address: _______________________________________________________________________ City: ____________________________ State: ___________________ Postal Code: __________________ Country: ________________________ Email Address: _________________________________________ Office Phone (Include extension): __________________________________________________________ Home Telephone: __________________________________________ Fax: ________________________ Personal Web Address: __________________________________________________________________ EDUCATION ______________________________________________________________________________________ Highest Degree (in Primary Discipline) College or University Discipline Yr. of Degree ______________________________________________________________________________________ Graduate Degrees College or University Discipline Yr. of Degree ______________________________________________________________________________________ Other Graduate Degrees College or University Discipline Yr. of Degree ______________________________________________________________________________________ Undergraduate Degrees College or University Discipline Yr. of Degree ______________________________________________________________________________________ Professional Licenses ______________________________________________________________________________________ Field Jurisdiction Number Year

MAJOR FIELD (Circle one) • Medicine • Chiropractic •Occupational Therapy • Law • Psychology • Physiotherapy • Engineering • Forensic Science • Basic Sciences • Optometry • Sports Science/Kinesiology • Other: ______________________________________ MINOR FIELD & INTERESTS (Circle all that apply) • Neurology • Neuropsychology • Physical Med. & Rehab • Mobility • Biomedical Engineering • Nutritional Sciences & Biochem. • Orthotics/Prosthetic • Other: _______________________________________________________________________________ PRACTICE/RESEARCH AREA DESCRIPTION ______________________________________________________________________________________ ______________________________________________________________________________________ ______________________________________________________________________________________ EMPLOYMENT SECTOR (circle one) • University • Private-Practice • Hospital • 4 YR. College • Not-for-Profit • 2 Yr. College • Professional School • Research Institute • Government • Retired • Student: _____________________________________________________________________________ (Where and when do you expect to graduate?) CLASS OF MEMBERSHIP FOR WHICH APPLYING [ ] Member [ ] Student Member [ ] Affiliate Member (non-professional) [ ] Fellow* [ ] Life Member+ [ ] Life Member AND Fellow+ [ ] Sustaining Member° [ ] Sustaining Member and Fellow° *Fellowship status is granted by the IAFNR in recognition of significant and sustained contribution to the field of Functional Neurology and Rehabilitation Sciences of greater than ten years. +Life membership provides IAFNR membership at the appropriate grade of Member and/or Fellow status for life with the payment of a single membership fee indicated below and never having to pay dues, the journal subscription will be included for life. °Sustaining membership and/or fellowship is obtained by a multiyear dues payment as indicated below.

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PAYMENT INFORMATION [ ] Check enclosed made payable to: International Association for Functional Neurology and Rehabilitation (IAFNR) Please Charge my: [ ] Visa [ ] MasterCard [ ] American Express Card Number: __________________________________________________________________________ Expiration Date: ______________________ CVV: _______________ Billing Zip Code: ______________ Name on Card: _________________________________________________________________________ Signature: _____________________________________________________________________________ MEMBERSHIP CATEGORIES [ ] 3 Year Member (through 12/31/17) $750 [ ] 2 Year Member (through 12/31/16) $500 [ ] 1 Year Member (including FNRE journal subscription) OPTIONAL DONATION TO RESEARCH • Please charge my credit card $____________________ in monthly installments. (For donations to the F. R. Carrick Institute only, please see below.) OPTIONAL CONTRIBUTION TO THE F. R. CARRICK INSTITUTE • Please charge my credit card $____________________ in monthly installments.

PLEASE SEND YOUR REMITTANCE TO ANY OF THE FOLLOWING: Membership Department International Association of Functional Neurology and Rehabilitation 2487 S. Gilbert Road, Suite #106-116 Gilbert, AZ 85295, USA Fax: 1-480-813-1868 Email: [email protected]

AIM AND SCOPE OF THE JOURNAL The aim and scope of this interdisciplinary journal is to provide a forum for the fields of biomedical and rehabilitation engineering, neuropsychology, clinical neurology, human factors and ergonomics, and vocational assessment and training to present critical ideas, theories, proof-of-concept for technology solutions, and data-based evaluative research to facilitate return to work or more effective functional development in children and adults. FNRE accepts review papers, articles of original research, data-based and controlled case studies pertaining to functional neurology, man-machine interactions, rehabilitation sciences, brain-behavior relationships, and in applied cognitive neuroscience that relate to translational research. Engineering proof-of-concept applied to functional neurology as ergonomics are also welcome. FNRE also welcomes commentary on either the review papers or on original research as the journal intends to be an archival source of discussion of new advances in rehabilitation. Description of the Fields Covered

Assessment & Rehabilitation in Neurological Disorders

• Diseases and trauma of the brain • Cognitive, language, motor, sensory (e.g. visual, auditory, pain, vestibular, etc.) and behavioral disorders • Developmental disabilities • Autism in childhood and adults • Diseases and trauma of the spinal cord • Neuropathy, myopathy, and peripheral nerve lesions • Diseases and trauma impacting on vestibular function Assessment & Rehabilitation in Orthopedic and Musculoskeletal Disorders

• Limb disease, trauma, and amputation • Rheumatic diseases; osteoporosis • Back and neck pain Assessment & Rehabilitation in Other Specific Populations

• Geriatric rehabilitation • Pediatric rehabilitation • Special medical conditions (e.g., heart disease; respiratory disorders; cancer; burns; vegetative state)

Topics of General Interest in P&RM

Organization and management of rehabilitation services: rehabilitation in the framework of hospitalization and in the community; quality control in rehabilitation; vocational rehabilitation. Scope of the specialty: educational needs; ethical and medico-legal aspects; role for alternative/complementary medicine practices in P&RM. Functional assessment & outcome measurement at various levels: impairment; disability (activity); handicap (participation); quality-of-life (QOL); WHO-ICF system. Management of commonly encountered disabling conditions: pain; sexual disability; spasticity; postural instability & recurrent falls; wounds; sleep disorders; disability related emotional disorders. Other topics of general interest in P&RM: secondary and tertiary prevention in medical rehabilitation; nursing of disabled persons; sports medicine and sports for the disabled; rehabilitation of terror victims; electrodiagnosis; kinesiology; walking analysis; movement analysis; posturography; orthotic devices; advanced technologies in P&RM; augmentative devices; neuromuscular electrical stimulation; biofeedback; ergonomic considerations in the home and workplace of disabled persons. Rationale for Why the Journal Is Needed

The field of Rehabilitation does not presently exist as a cohesive discipline. Rehabilitation specialists define themselves as neurologists, practitioners of physical medicine and rehabilitation, vocational experts, engineers, psychologists, educators, social workers, physical therapists, occupational therapists and the like. The intrinsic cross-disciplinary nature of the rehabilitation process and the requirement for clinical-driven applied and basic science is not represented in any presently published journal, or for that matter, professional organization. The International Association of Functional Neurology and Rehabilitation and the F. R. Carrick Institute for Clinical Ergonomics, Rehabilitation, and Applied Neuroscience, the host organization and research institution for the journal FNRE, is addressing the foregoing by training interdisciplinary rehabilitation professionals whose dissertations also require patent and product development, the establishment of cross-disciplinary research laboratories and projects, the transfer of technology into community based services such as free medical equipment and services for those in need of getting to or back to work, regional clinical program integration systems, and international academic and research cooperative agreements. It is expected that the proposed journal will strongly reflect the structure and philosophy of science and practice. Description of the Peer Review Process

Papers will be solicited through the organs of fields impacting on rehabilitation science. Peer review will be performed on each paper but will be blind. Periodically, papers linking a particular cogent theme applied to rehabilitation will be compiled within a single issue and published in book form. Papers will be ranked as accepted without revision, accepted but with minor revision, requiring major rework and an additional review, or rejected. We do desire to create dialogue within the rehabilitation community, and reviewer’s comments, when appropriate, will be included with the published paper.

INSTRUCTIONS FOR AUTHORS

Manuscripts for the Journal of Functional Neurology, Rehabilitation, and Ergonomics (FNRE) may be submitted to the Editor-in-Chief at the F. R. Carrick Institute for Clinical Ergonomics, Rehabilitation, and Applied Neurosciences (CERAN), 647 Franklin Avenue, Garden City New York 11530 USA. Articles must also be submitted by email: to [email protected]. Type of Manuscripts Accepted FNRE accepts review papers, articles of original research, data-based and controlled case studies pertaining to Functional Neurology, Man-Machine Interaction, Rehabilitation Sciences, brain-behavior relationships, and in applied cognitive neuroscience that relate to translational research. Engineering proof-of-concept applied to functional neurology as ergonomics are also welcome. FNRE also welcomes commentary on either the review papers or on original research as the journal intends to be an archival source of discussion of new advances in rehabilitation. Manuscript Requirements

[1] Manuscripts must be written in English and be typewritten with double spacing throughout the entire text and with margins of at least 2.5 cm. An original on 8½" 11" heavy duty white bond paper and two duplicate copies should be provided. An email copy as a file attachment in MS WORD for WINDOWS or a text file must also be submitted by email to the above indicated email address.

[2] Each manuscript must have a title (first) page that includes the title, the authors’ full names, the laboratory or origin of the data, a running head, a list of 6-8 key words and the name, address and FAX number of the person to whom correspondence and proofs should be mailed.

[3] Full length review articles should be divided into sections in the following order: Synopsis, Body (with relevant sub-headings), Acknowledgements, and References. Short notes should contain no sections. Number pages consecutively.

[4] Abbreviations should be defined when first used by placing in parentheses after the full term; e.g., acetylcholin-esterase (AChE).

[5] References will follow the "Uniform requirements for manuscripts submitted to biomedical journals" format (also called the Vancouver style, see http://www.icmje.org/index.html) determined by the International Committee of Medical Journal Editors and used for PubMed/Medline journals. Abbreviations of journal names should conform to the Index Medicus.

References (maximum of 25 for articles, 40 for review articles and 5 for case reports) should be cited consecutively (enclosing the number in parenthesis) in the text and listed in the same numerical order at the end of the paper. The Vancouver Style is required (http://www.icmje.org/).The first reference in the text should be (1) and the next (2) and so forth and then listed accordingly at the end of the paper after discussion or after acknowledgements. Examples:

Journal article Damianopoulos EN, Carey RJ. Pavlovian conditioning of CNS drug effects: a critical review and new experimental design. Rev Neurosci 1992; 3: 65-77. Note: no comma in between name an initials, no italics or bold, no capitol letters in title except at the begining of sentence, no period between jorunal name and year, year;vol:page-page without space betwwen and last page number shortened. All authors must be cited. Journal name abbreviated according to the international standard found at PubMed Journal Database. (http://www.ncbi.nlm.nih.gov/sites/entrez?db=journals)

Book Melillo R, Leisman G Neurobehavioral disorders of childhood: An evolutionary approach. New York: Kluwer, 2004.

Book chapter Leisman G, Melillo R. Cortical asymmetry and learning efficiency: A direction for the rehabilitation process. In: Randall SV Learning disabilities: New research. Hauppauge, NY: Nova. 2006: 1-24.

Research report Shek DTL. A positive youth development program in Hong Kong. Hong Kong: Soc Welfare Pract Res Centre, Univ Hong Kong, 2004. (Chinese)

Unpublished thesis Kaplan SJ. Post-hospital home health care: The elderly’s access and utilization. Dissertation. St Louis: MO: Washington Univ, 1995.

Internet materials / publication Internet journal: Morse SS. Factors in the emergence of infectious diseases. Emer Infect Dis 2006;5:1.

Internet material Morse SS. Factors in the emergence of infectious diseases. Emer Infect Dis 2006. Accessed 2007 Jun 05. URL: http://www.cdc.gov/ncidod/EID/eid.htm

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- International Committee of Medical Journal Editors ("Uniform Requirements for Manuscripts Submitted to Biomedical Journals") - February 2006

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