Human Motor Control

Celebrating Mark Hallett’s 30 Years of Research

BY DEVERA G. SCHOENBERG, NINDS

Internationally renowned classical pianist Leon Fleisher has Mark Hallett to thank for restoring his ability to play the piano. At the height of his career in the 1960s, Fleisher lost the use of his right hand when it became permanently cramped with its fingers curled under like claws. Back then, doctors were stumped and didn’t know how to treat the problem. Fleisher was discouraged but eventually learned to perform one-handed repertoires.

After many misdiagnoses and failed treatments, he was finally diagnosed in 1991 with focal hand dystonia, or “musician’s cramp,” and referred to Mark Hallett in the National Institute of Neurological Disorders and Stroke (NINDS). Hallett was pioneering the use of botulinum toxin (Botox) to block the release of the neurotransmitter acetylcholine, which normally causes muscles spasms. He injected small amounts of Botox into the musician’s hand, and soon Fleisher was playing the piano two-handedly again. Fleisher is still performing with symphony orchestras around the world today.

Not only was Hallett one of the pioneers in the therapeutic use of botulinum toxin, but he is also well known for differentiating a multitude of movement disorders using neurophysiological methods. His first major achievement was the classification of myoclonus (the sudden involuntary jerking of muscles) and using neurophysiological methods—such as electromyograms and electroencephalograms—to determine where the different kinds of myoclonus originated in the brain.

Hallett led the field in understanding the physiology of the bradykinesia (overall slowness of movement) experienced by Parkinson patients. He explained the pathophysiology of dystonia (involuntary muscle contractions that cause twitching and slow repetitive movements or abnormal postures) and was one of the first to use transcranial magnetic stimulation (TMS) to study the central nervous system.

To celebrate the accomplishments of both Hallett and the Human Motor Control Section (HMCS), a one-day symposium, entitled “Human Motor Control: 30 Years of Research at NIH and Beyond,” was held at NIH on April 24, 2014. More than 100 neurologists and neuroscientists from around the world, many of them former fellows and colleagues, attended the gathering.

Presentations covered overviews of movement disorders; dystonia; TMS in disease and cognition; and neuroplasticity and learning. Mahlon DeLong (Emory University, Atlanta) presented “Overview of Movement Disorders”; Günther Deuschl (Christian-Albrechts University, Kiel, Germany) presented “Tremor, Physiology and the HMCS”; Sabine Meunier (Université Pierre et Marie Curie, Paris) presented “Dystonia: A Basal Ganglia or Cerebellar Dysfunction”; Alvaro Pascual-Leone (Harvard Medical School, Boston) presented “TMS to Treat Movement Disorders”; Eric Wassermann (NINDS) spoke on “TMS as a Probe in Cognition and Non-motor Behavior”; and Leonardo Cohen (NINDS) discussed “Neuroplasticity, Learning, and Rehabilitation.”

A key player

Hallett has been one of the key players in the field of movement disorders even before it became a subspecialty of neurology in the 1980s.

“At that time, therapy for movement disorders was largely limited to levodopa as a treatment for Parkinson’s disease,” according to an editorial in a 2011 issue of Movement Disorders. “The science of movement disorders was in its infancy.” (Mov Disord 26:935–936, 2011)

And Hallett was just the guy to help nurture and develop the profession. He had developed an early interest in movement disorders and had been nurtured by some of the best in the burgeoning field. After receiving his M.D. from Harvard Medical School and completing an internship in internal medicine at Peter Bent Brigham Hospital (Boston), he came to NIH for the first time in 1970 as a “yellow beret.” During the Vietnam War, doctors were drafted and could fulfill their military obligation by entering either the armed services or the Public Health Service (PHS). The ones who opted for the PHS called themselves the “yellow berets”—in contrast to the “green berets”—who were proud to fulfill their military obligation in the “Battle of Bethesda.”

Hallett joined Ichiji Taskaki’s lab in the National Institute of Mental Health (NIMH) to work on the biophysics of nerve excitation. At NIMH he was influenced by Ed Evarts—a pioneer in the study of the motor system who perfected the technique of recording single nerve-cell activity—and one of Evarts’s senior fellows, Mahlon DeLong—who later made several important discoveries about Parkinson disease and other movement disorders and eventually became the chair of neurology at Emory.

Hallett returned to Boston in 1972 to do a residency in neurology at Massachusetts General Hospital (1972–1975) and research on the motor system. Then he did a yearlong fellowship with British neurologist C. David Marsden—one of the world’s leading authorities on movement disorders—at the Institute of Psychiatry (London).

Back in Boston in 1976, Hallett headed the Clinical Neurophysiology Laboratories at the Peter Bent Brigham Hospital; developed a program in movement disorders and clinical neurophysiology; and worked his way up to associate professor at Harvard Medical School.

Founding HCMS

In April 1984, he returned to NIH and became the clinical director of NINDS, and founded the HCMS, to pursue the study of the physiology of normal human voluntary movement and the pathophysiology of different movement disorders. Already recognized as one of the leaders in movement-disorders research, Hallett was asked to join the founding board of the journal Movement Disorders, which was launched in 1986, a year after the Movement Disorders Society was established. The journal was the first to combine printed and video formats. The editors believed that the videos were a good way to “illustrate a movement that is unusual [and to] demonstrate the results of therapeutic trials.” (Mov Disord 1:1–2, 1986)

At NIH, Hallett first began training clinical neurophysiologists who were interested in movement problems and then movement-disorder neurologists who were interested in neurophysiology. More than 100 neurologists have completed fellowships under Hallett and have gone on to have successful careers.

Over the past 30 years, Hallett and the HMCS have distinguished themselves in the study of the:

• Physiology and classification of myoclonus (little is being done at NIH now)
• Processes behind human motor learning (currently the focus of NINDS senior investigator Leonardo Cohen and NINDS staff clinician Eric Wassermann, who both trained under Hallett)
• Pathophysiology of psychogenic movement disorders (now directed by clinical fellow Carine Maurer)
• Pathophysiology of disorders of volition (conscious control of movement)
• Pathophysiology of Parkinson disease (now being led by Staff Clinician Codrin Lungu)
• Pathophysiology of tremor, including essential tremor (Dietrich Haubenberger, a former fellow, is returning from Austria to become head of the new NINDS Clinical Trials unit and assume the leadership for this project.)

In addition to his NIH responsibilities, Hallett has held leadership positions in several professional organizations including the presidency of the Movement Disorder Society, the American Association of Electrodiagnostic Medicine, the International Federation of Clinical Neurophysiology, and the Brainstem Society. He has been on the editorial boards of 18 journals and was editor-in-chief of Clinical Neurophysiology and World Neurology and associate editor of Brain and Brain Stimulation. He also chaired the medical advisory boards of the Benign Essential Blepharospasm Research Foundation and the International Essential Tremor Foundation for many years.

He has also published more than 650 manuscripts and won many awards. Hallett gave up being the NINDS clinical director in 2000 so he could devote all his time to research. He remains chief of HCMS.

In the years since Hallett founded HMCS, “there has been an astonishing growth in the field of movement disorders,” according to the 2011 Movement Disorders editorial. “Gene mutations responsible for Parkinson’s disease [and] many other movement disorders have now been identified…. The introduction of deep-brain stimulation has given us the opportunity to probe the basal ganglia and other deep-brain structures of patients with movement disorders and has greatly increased our understanding of how the basal ganglia are organized in physiologic and pathologic conditions. There have been major advances in the fields of molecular biology, genetics, pathology, neuroimaging, clinical trial design, and so forth.” (Mov Disord 26:935–936, 2011)

“Mark has had an exceedingly stellar career and has completely pioneered the field of movement disorders,” said current NINDS clinical director Avindra Nath. Most fortunate for everyone is that Hallett is still pioneering newer aspects of movement disorders and the fellows keep coming to study with the “master.”

Mark Hallett is scheduled to give a talk on “Focal Hand Dystonia: A Failure of Just One Highly Skilled Movement,” at the NIH Research Festival’s Opening Plenary Session (Monday, September 22, 10:00 a.m.–12:00 p.m.).

High Praise for Mark Hallett

Mark Hallett has stayed in touch with his former fellows and colleagues over the years. Many have returned to NIH to collaborate on research projects with him. Here is what a few of them have to say about him.

Eric Wassermann, M.D. (former fellow)
Staff clinician, Behavioral Neurology Unit, NINDS
Research Interests: Pursuing studies in human cognition and traumatic brain injuries; clinical interests: behavioral neurology, clinical neurophysiology, and chemical casualty care
“Mark has several extraordinary strengths as a scientist, clinician, and teacher. Chief among these are the strategic ability to attack complex problems with achievable projects, extreme orderliness of thought, and great intellectual scope and curiosity. Under his leadership the HMCS has extracted an amazing range of basic and clinical information, through the narrow peephole of noninvasive neurophysiology in humans, at every level from the motor unit to the cortical network. Anyone can perform the experiments, but the inferential and synthetic process, which turns incomplete data into reliable knowledge, requires a great mind.”

Sabine Meunier, M.D., Ph.D. (former fellow)
Université Pierre et Marie Curie, Paris
Research interests: Brain neurochemical changes in dystonic patients; returning to NIH in July to collaborate on a project
“Dr. Hallett remains for me a model of broad scientific knowledge combined with an open-minded way of managing a lab. I will always cherish his high regard for human qualities at least as much as I do for the scientific and medical ones.”

Stephen Reich, M.D. (colleague)
Professor of Neurology, University of Maryland School of Medicine (Baltimore)
Special interests: Movement disorders; Botox injections for dystonia; comprehensive care of patients with Parkinson diseases
He considers Hallett “a mentor, colleague, role model, and friend…. When there are diagnostic disputes, Mark usually emerges as the voice of reason and authority. There is not a single area in movement disorders where Hallett has not made his mark as an investigator and clinician.”

Robert Chen, M.D. (former fellow)
Professor, Department of Medicine, Division of Neurology University of Toronto
Research: Intracortical networks in neurological diseases; dystonia, Parkinson disease, and other movement disorders; deep-brain stimulation; electroencephalography; transcranial magnetic stimulation; functional magnetic resonance
“I had a great time learning not only clinical skills in movement disorders and technical skills in research, but also how to design a good research study, writing of manuscripts, and approaches to laboratory management. What I learned played a pivotal role in my own research program, and that influence is still present today. I also established long-lasting friendship with many colleagues, which is very helpful in my research and makes scientific meetings much more fun to attend!”

Leonardo Cohen, M.D. (former fellow)
Senior Investigator, Human Cortical Physiology and Stroke Neurorehabilitation, NINDS
Research: Understanding the mechanisms underlying plastic changes in the human central nervous system; developing novel therapeutic approaches for recovery of function; has made notable discoveries about the success of post-stroke rehabilitation
“Mark guided me in learning how to identify [and] focus [on] research issues most important in biological science and most relevant to patient-oriented clinical neurology.”

Zoltan Mari, M.D. (former fellow)
Assistant Professor, Neurology, Johns Hopkins School of Medicine (Baltimore)
Research interests: Parkinson disease modification and neuroprotection; neurophysiology of and motor control in movement disorders, especially dystonia; clinical interest in deep-brain stimulation and Botox therapy
“As the years go by since leaving NIH, I increasingly recognize that my own clinical and research conduct, habits, and even teaching style clearly bear the marks of my fellowship training at NIH with Dr. Hallett.”