Study Reveals High Frequency of Undetected Responsiveness in Severe Brain Injury Cases

With surprising frequency, patients with severe brain injury can show clear signs of cognitive function on brain scans in response to requests to carry out complex mental work, even when they can’t move or speak, according to an international study co-led by Weill Cornell Medicine and NewYork-Presbyterian investigators.

The study, published Aug. 15 in the New England Journal of Medicine, was the largest-ever investigation of the prevalence of this condition, which is called cognitive-motor dissociation. The researchers observed that among 241 patients in a coma or vegetative state who could not make visible responses to bedside commands, one-fourth had sustained and relevant cognitive responses as shown on electroencephalography (EEG) readouts or functional magnetic resonance imaging (fMRI) scans. The patients were tested with consent from a surrogate at six academic medical centers, all part of a larger consortium that undertook the study.

“We find that this kind of sharp dissociation of retained cognitive capabilities and no behavioral evidence of them is not uncommon,” said study corresponding author Dr. Nicholas Schiff, the Jerold B. Katz Professor of Neurology and Neuroscience in the Feil Family Brain and Mind Research Institute at Weill Cornell Medicine, a neurologist at NewYork-Presbyterian/Weill Cornell Medical Center and administrative lead of the consortium. “I think we now have an ethical obligation to engage with these patients, to try to help them connect to the world.”

The patients in the study were evaluated at NewYork-Presbyterian/Weill Cornell Medical Center, NewYork-Presbyterian/Columbia University Irving Medical Center, The Rockefeller University Hospital and Massachusetts General Hospital in the United States, and in medical centers at the University of Cambridge, the University of Liege and the University of Paris. The Icahn School of Medicine at Mount Sinai served as the coordinating center of the study and conducted the statistical analysis of the patient data.

Cognitive-motor dissociation is thought to be closer to the better-known “locked-in” state that isolates an intact brain, typically through either strokes or degeneration of only the motor neurons in amyotrophic lateral sclerosis. But it is seen in patients with more extensive brain injuries who otherwise seem mostly or entirely unaware of their surroundings.

For the study, the researchers enrolled a total of 353 adults with “disorders of consciousness,” usually stemming from severe traumatic brain injuries or interrupted oxygen supply to the brain following strokes or heart attacks. Most were under care at home or in long-term care facilities, and the median time from injury was about eight months.

The researchers repeatedly asked each patient to perform a series of continuous motor tasks (e.g., “keep wiggling your toes”), as well as motor-related cognitive tasks (“keep imagining wiggling your toes”) for multiple bouts of 15 to 30 seconds of performance separated by equal length rest periods, using rigorous protocols the investigators had designed and validated to avoid false positives.

Of the 241 patients who were unable to demonstrate bedside command following, 25% were able to perform the cognitive tasks – matching patterns of EEG- and/or fMRI-measured brain activity seen in healthy subjects in response to the same commands.

While a higher percentage (38%) of the 112 patients who demonstrated motor response to spoken commands at the bedside performed these cognitive tasks, the majority of these patient controls did not demonstrate the cognitive performance. This further dissociation emphasizes that the fMRI and EEG mental imagery tasks demand the sustained use of several cognitive resources, such as short-term memory, that are not required for following bedside commands or even simple communication. The fact that one-quarter of the motor-unresponsive patients with cognitive-motor dissociation successfully performed the tasks suggests that many seemingly unconscious patients may be aware and capable of cognition, the researchers said.

“Some patients with severe brain injury do not appear to be processing their external world. However, when they are assessed with advanced techniques such as task-based fMRI and EEG, we can detect brain activity that suggests otherwise,” said lead study author Dr. Yelena Bodien, an investigator for the Spaulding-Harvard Traumatic Brain Injury Model Systems and Massachusetts General Hospital’s Center for Neurotechnology and Neurorecovery. “These results bring up critical ethical, clinical and scientific questions – such as, how can we harness that unseen cognitive capacity to establish a system of communication and promote further recovery?”

In the United States alone, the number of people estimated to be in a chronic vegetative state ranges from 5,000 to 42,000, while estimates for those in a minimally conscious state range from 112,000 to 280,000 individuals.

The findings are likely to lead to several new lines of research. One is to investigate easier methods of detecting this dissociation – methods that, unlike task-based fMRI and EEG, could be used in a greater variety of clinics.

Another is to explore the potential clinical value of detecting cognitive-motor dissociation, since prior studies suggest that patients with this condition may have a greater chance of recovery compared with those who cannot perform cognitive tasks.

“Just knowing that a patient has this ability to respond cognitively can be a game-changer in terms of life-support decisions and the degree of engagement of caregivers and family members,” Schiff said.

He added that the findings should also lead to studies of specific interventions –likely including brain-computer interfaces – to improve the quality of life for these patients and further boost their chances of recovery.

“What we need here is what we in our consortium have been trying to get started for 20 years: a sustained effort to benefit patients who have disorders of consciousness with systematic medical research, technology development and better clinical infrastructure,” Schiff said.

Dr. Barry Coller, physician-in-chief of The Rockefeller University Hospital, led the effort to develop a model clinical infrastructure to support the research and credits Schiff and Dr. Joseph J. Fins, the E. William Davis, Jr., M.D. Professor of Medical Ethics at Weill Cornell Medicine and chief of the Division of Medical Ethics at Weill Cornell Medicine and NewYork-Presbyterian/Weill Cornell Medical Center, with conceiving the study.

“I realized the importance of bringing hope to these patients and their loved ones,” Coller said. “We are proud to be a part of this pioneering research, which has creatively harnessed all of the power of modern science, and we are very gratified by the results.”