A 38-year-old severely brain-injured man who has been unable to communicate or eat by mouth for 6 years now performs both tasks daily, after surgeons -- in an investigational study -- used deep brain stimulation (DBS) to try and improve function within residual brain networks that they knew were still there.
The man's DBS-associated improvements in communication, complex movement and eating are unique, and the technique has never been applied to this patient population before.
Reporting in the Aug. 2 issue of Nature -- in a study entitled "Behavioral Improvements with Thalamic Stimulation After Severe Traumatic Brain Injury" -- the researchers say that if these results are replicated in other patients, it could change the standard of care for these chronically under-responsive individuals. Most patients in a minimally conscious state (MCS) are now cared for in long-term nursing facilities, without the benefit of rehabilitation or status-changing treatment.
The research that culminated in this achievement was led by physician-scientists at the NewYork-Presbyterian Hospital/Weill Cornell Medical Center Department of Neurology and Neuroscience, in New York City; JFK Johnson Rehabilitation Institute-Center for Head Injuries, in Edison, NJ; and the Cleveland Clinic Center for Neurological Restoration. The original concept for the groundbreaking work was developed at NewYork-Presbyterian/Weill Cornell more than a decade ago by neurologist/neuroscientist and lead author Dr. Nicholas D. Schiff.
The tri-institutional team together developed the research plan leading to the formulation of this study: The operation was performed at the Cleveland Clinic by neurosurgeon and senior author Dr. Ali R. Rezai. All aspects of the post-surgical study protocol were conducted at the JFK Johnson Rehabilitation Institute by a neurorehabilitation team led by neuropsychologist and co-lead author Dr. Joseph T. Giacino. NewYork-Presbyterian/Weill Cornell physician-ethicist and co-author Dr. Joseph J. Fins formulated the ethical framework that guided the design and execution of this study, which received multi-center Institutional Review Board approval and which was conducted under an FDA IDE (investigational device exemption).
The patient's family has requested that he not be identified at this time. But the patient's mother notes: "My son, as well as the entire family, had little hope of further recovery. If it were not for the DBS surgery and rehabilitation, we would be no further along than we were in 1999. Now, my son can eat, express himself and let us know if he is in pain. He enjoys a quality of life we never thought possible."
"The changes in the man's functional abilities were statistically linked to the use of DBS, and those changes have been remarkable and sustained," says Dr. Rezai, the paper's senior author, Director of the Cleveland Clinic's Center for Neurological Restoration, and Professor of Neurosurgery. "We hope that the first use of DBS to treat patients in a MCS marks the beginning of a significant period of innovation in our approach to traumatic brain injury."
"Prior to the use of DBS, the patient's communication ability was inconsistent, including only slight eye or finger movements. Now, he regularly uses words and gestures and responds to questions quickly," says Dr. Giacino, the study's co-lead author and Associate Director of Neuropsychology at JFK Johnson Rehabilitation Institue and the New Jersey Neuroscience Institute. "In addition, he now chews and swallows his food and no longer requires a feeding tube. Before, he could not use his limbs for functional movement, but he can now perform some complex movements, including those required for drinking from a cup or brushing hair. Years of severe immobility and tendon contracture, however, do greatly limit him from carrying out these tasks."
"The work challenges the existing practice of early treatment discontinuation for this patient population and also changes the approach to assessment and evaluation of the MCS patient," says Dr. Schiff, the study's lead author, Associate Professor of Neurology and Neuroscience at Weill Cornell, and Associate Attending Neurologist at NewYork-Presbyterian Hospital/Weill Cornell Medical Center.
"This innovative procedure holds the potential for patients to recapture a lost personhood as they regain an ability to communicate through a prosthetic device that helps them participate in the human community," says Dr. Fins, Professor of Medicine, Professor of Public Health and Professor of Medicine in Psychiatry at Weill Cornell, and Director of Medical Ethics at NewYork-Presbyterian/Weill Cornell. "This clearly speaks to an ethical mandate to further such clinical trials designed to improve function in these patients."
Indeed, six years after an assault left the man severely brain-injured, he has now regained the power to interact with family and friends. Late recovery of this magnitude is exceedingly rare in patients with chronic MCS. The minimally conscious state is distinct from either a persistent vegetative state or coma, in that patients show intermittent signs of awareness and may even attempt to communicate using simple words or signals. However, these glimpses of consciousness are usually rare, fleeting and unsustained.
Experts estimate that from 100,000 to 300,000 patients with traumatic brain injury are now diagnosed as MCS. Under the current standard of care, most do not receive active rehabilitation and are cared for in long-term nursing facilities.
However, based on prior brain-imaging studies, the researchers speculated that DBS -- the electrical stimulation of key parts of the brain -- might help.
"We knew that some patients in MCS, including our subject, retain functioning brain networks above the brainstem," explains Dr. Schiff, who is also Weill Cornell's Director of the Laboratory for Neuromodulation. "Activity within these integrated neural networks is supported by cells in an area of the brain called the central thalamus, which is thought to be key to adjusting brain activity as it responds to cognitive demands," he says.
"Our theory was that electrical impulses targeted to this area would help amplify the existing low level of activity that we thought was already there," adds Dr. Giacino. "In other words, we assume that the signals that help drive speech and movement are still present in the brain -- we're just 'bumping up' their efficiency and function, to help get them working better."
The DBS surgery targets deep-brain structures with millimeter-precision using computer-generated maps, image-guided navigation and physiological brain mapping. Tiny electrodes are implanted into these deep-brain structures and connected to programmable pacemaker batteries in the chest. The operation was complicated by the extensive damage to the patient's brain from the traumatic injury. The procedure was performed in two stages and lasted 10 hours. DBS surgery is FDA-approved and routinely performed for patients with Parkinson's disease. Various clinical trials using DBS for the treatment of epilepsy, obsessive- compulsive disorder and depression are also underway.
After an initial "titration" period -- during which the team calibrated the best dose and timing -- the patient began a 6-month, double-blinded on/off "crossover" trial, with periods of DBS alternating with periods where he did not receive the therapy.
"Without further study, we have no means of knowing for sure that the functional improvements we have observed will be seen in other subjects, yet we expect that we will find other patients who will respond," Dr. Schiff says. "We can say that this patient's recovery of oral feeding and communication abilities was strongly linked to the DBS. But even more encouraging is the fact that the patient's functional gains continued even during the off-phase, suggesting a carryover effect from treatment."
Will the DBS-treated patient continue to improve? The researchers say it's still unclear, although the brain's innate plasticity means the man could build on the gains he has already made. In one recent, highly publicized case involving some members of the same research team, 39-year-old Terry Wallis suddenly regained speech and movement nearly 20 years after a truck accident left him in a minimally conscious state. Writing last year in the Journal of Clinical Investigation, Dr. Schiff and collaborators proposed that the slow regrowth over time of essential neural neworks may have contributed to Wallis' "awakening."
"This patient's improvement is remarkable but requires longer-term follow-up and additional patient enrollment to further determine the utility of DBS for patients with severe brain injury," Dr. Rezai points out.
"That's why it's so essential that we identify other possible candidates for this FDA-approved pilot study, which is designed to include 12 such patients in MCS," says Dr. Giacino. "Each patient may respond differently, depending on their own potential for neural recovery. But we certainly need to replicate these findings before we can be sure this effect is real."
"If this achievement is replicated, its success could usher in a whole new era for the treatment of patients in MCS generally," says Dr. Fins, who is also Chief of the Division of Medical Ethics at Weill Cornell and has written extensively on the issue.
"Any intervention that can unlock the neurological potential of patients in MCS should have us reconsider how we care for these individuals," he adds. "It will force us to take a second look at each case and -- for appropriate patients -- move away from the therapeutic nihilism that has so plagued this population, most of whom are ignored, receiving what is euphemistically described as 'custodial care.'"
"This remarkable study by Dr. Schiff and colleagues shows that deep brain stimulation, a technique widely accepted for treating some movement disorders and psychiatric conditions, may improve the function of individuals who have suffered a traumatic brain injury," says Dr. Joseph J. Pancrazio, a program director at the National Institute of Neurological Disorders and Stroke (NINDS) of the NIH, which helped to fund this work. "These individuals have few if any other treatment options. This work reflects the exciting emerging idea that some neurological disorders can be treated by focusing on neural circuit changes rather than drug treatments and gene therapy. However, we still need to understand how DBS works for these disorders and to define which patients can benefit from this treatment."
The collaborative study drew on the unique skills and long-standing leadership of Drs. Schiff, Giacino, Rezai and Fins in interacting but different domains. Dr. Giacino, a neuropsychologist, was the lead author of the consensus statement defining MCS and the co-developer of the Coma Recovery Scale (Revised), the standardized behavioral assessment tool used as the primary outcome measure in the study. Dr. Rezai, a pioneer in the field of DBS and leading functional neurosurgeon, has been at the forefront of new developments in this field for more than a decade, including the use of DBS for treatment of obsessive-compulsive disorder and depression.
Dr. Fins, a leading American bioethicist and physician, has engaged these issues since the inception of the research program and was the first ethicist to address the issues surrounding the emerging neuroscience of impaired consciousness. Dr. Schiff, a neurologist and neuroscientist, first developed the underlying concept and -- through NIH-supported training awards and a planning grant -- developed preliminary studies and led the formation of the research team. All four of the investigators have interacted in this collaboration for nearly a decade to complete this first patient study.
Additionally, as the patient's personal physician, Dr. Caroline McCagg -- JFK Johnson Rehabilitation Institute's Associate Medical Director and a study co-author -- supervised the patient's care. And a team of experienced therapists and physicians at the Institute helped to care for the patient and to carry out the extensive data collection done in this study.
Deep brain stimulation (DBS) is a surgical procedure in which electrodes are implanted within the brain to deliver electrical impulses that relieve the symptoms of conditions like Parkinson's disease, dystonia, obsessive-compulsive disorder, depression, and now, a minimally conscious state (MCS) caused by severe traumatic brain injury. This first DBS procedure is part of an FDA-approved pilot study that will include 12 patients in post-traumatic MCS.
The work was funded by the National Institute of Neurological Disorders and Stroke (NINDS) of the NIH, Charles A. Dana Foundation, Cleveland Clinic Foundation Brain Neuromodulation Center, Ohio Department of Development BRTT and Third Frontier Program, Jane and Lee Seidman Neuromodulation Research Fund, Cleveland Clinic Innovations, IntElect Medical, Inc. and the National Institute on Disability and Rehabilitation Research (NIDDR).
Co-researchers include Dr. Kathleen Kalmar, Mindy Gerber, Dr. Brian Fritz, Beth Eisenberg and Jeanne O'Connor, all of the JFK Johnson Rehabilitation Institue-Center for Head Injuries, Edison, NJ; Dr. Jonathan D. Victor, Dr. Erik J. Kobylarz and Dr. Fred Plum, of NewYork-Presbyterian/Weill Cornell, New York City; and Sierra Farris, Dr. Andre Machado and Dr. Kenneth Baker, of the Cleveland Clinic, Cleveland, OH.
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