ARTICLE IN BRIEF:
Severely brain-injured patients had normal brain responses to spoken language as measured by electroencephalography, researchers reported.
A new screening test using electroencephalography (EEG) accurately detected covert consciousness in severely brain-damaged patients who appear clinically unresponsive at the bedside, according to a December 3, 2018, paper published in Current Biology.
Coming 12 years after the first such patients were identified with the use of a functional MRI (fMRI) technique, the new EEG test may eventually make it practical for general neurologists to identify those in nursing homes who are covertly conscious but are currently considered to be unaware of their surroundings, according to an accompanying commentary. At present, only a handful of centers in North America and Europe have neurologists trained in conducting the costly fMRI exams.
Those fMRI exams involve asking patients with disorders of consciousness to follow spoken instructions by imagining that they are playing tennis or walking through their homes, and then seeing if the resulting pattern of brain activity is consistent with the requested imaginary tasks.
The new test protocol does not require patients to follow such commands, making it among the first reports of a purely passive measure of awareness that is correlated with an fMRI-based motor imagery task. Instead, patients simply listen on earphones to spoken language — such as stories and memories about their lives prior to their injury shared by family members — and the pattern of their EEG response is compared to that of normal controls.
In the study of 21 severely brain-injured patients, all ten whose pattern of EEG response was indistinguishable from that of 13 healthy controls were shown to be covertly conscious in the fMRI test; none of the 11 who had abnormal EEG responses showed signs of following instructions while in the fMRI.
The authors and other neurologists who specialize in disorders of consciousness emphasized that the findings need to be replicated in a larger group, and that the new technique would likely be used only as a screening test to identify those who should be referred for further testing in an fMRI. Moreover, the test as currently designed requires a more sophisticated EEG device than most neurologists have access to and requires analysis of the readout by a specially trained technician.
But with hundreds of thousands of patients around the world living in nursing facilities or homes with a diagnosis of persistent vegetative state, and upwards of 20 percent of them estimated to retain covert awareness, neurologists familiar with the paper said it presents a challenge to the field.
“The thought of a single person with covert consciousness being unrecognized and voiceless is alarming,” stated the commentary by Brian L. Edlow, MD, director of the Laboratory for NeuroImaging of Coma and Consciousness at Massachusetts General Hospital, and assistant professor of neurology at Harvard Medical School. “The possibility that thousands of people around the world may be covertly conscious is a call to action.”
In his commentary, Dr. Edlow called the study “a major contribution to the field” because it presents a practical means of identifying a large number of those individuals at last.
The EEG measurements used in the study sought to identify the brain's response to what is known as the “natural speech envelope,” or NSE, the brain wave activity that occurs in response to speech. The average combined response seen in healthy controls show two peaks of activity, one coming about 90 milliseconds after the NSE, the other coming about 200 milliseconds after.
Among the 21 brain-injured patients, only 10 demonstrated statistically significant blood oxygen-level-dependent activation during the active imagery task [on fMRI] as compared with the resting state condition, the study found. These same 10 patients showed a pattern of activation on the EEG test that was statistically similar to that of the healthy controls; that is, their two peaks of activity came at the same speed.
“There's a part of the brain wave activity that essentially follows the up-and-down intensity of speech,” said the senior author of the paper, Nicholas D. Schiff, MD, professor of neurology and neuroscience at the Feil Family Brain and Mind Research Institute at Weill Cornell Medicine. “You can measure the correlation between the envelope of up-and-down speech and the EEG signals. It was a surprise to see that people who can do the fMRI command-following were statistically indistinguishable from healthy controls. It's probably a marker for the integrity of systems in working memory and other brain areas that we know must be functioning.”
His research team at Weill Cornell has been studying other means to identify patients with covert consciousness, Dr. Schiff said. “Their resting metabolism, their degree of preservation of the sleep-and-wake cycle, their overall anatomy in general looks better preserved than those who cannot do the high-level motor imagery tasks in an fMRI. What makes this EEG measure attractive is that you get a single value related to processing speed.”
The results, he told Neurology Today, “could massively improve the diagnosis of covert consciousness. Right now it's impractical to use fMRI to screen everybody who appears to be minimally conscious or in a vegetative state. An EEG, because it's cheap and easy, could be acquired any time. It could be very useful in identifying people you should consider testing in the fMRI. The value here is to find a way to go out and screen the community of brain-injured patients to figure out who looks like they're not processing anything but [who are] in fact processing at a very high level.”
Dr. Schiff noted that the patient response rate on the EEG test was 100 percent among those who also could imagine either playing tennis or walking while in the fMRI. However, he pointed out, that the latency difference separating the distributions around the average EEG response times between those who can do the fMRI motor imagery tasks and those who cannot is so wide, on the order of tens of milliseconds, that it should be a highly useful screening tool. But, he said, the study included a small sample of just ten patients. “We need to replicate these findings in a larger population of findings to see if it holds true,” he said.
As a clinician, he said, encountering just one of these patients underscores the seriousness of the issue. “You are observing a person who appears unconscious but is able to do high-level cognition,” he said. “We ought to be aggressively working to identify and aid them.”
In August 2018, the AAN in collaboration with the American Congress of Rehabilitation Medicine, and the National Institute on Disability, Independent Living and Rehabilitation published an updated practice guideline on disorders of consciousness. The guideline, which was published in Neurology, included task-based fMRI and EEG measures as potentially relevant diagnostic tests in disorders of consciousness. If the new study results are replicated in a larger group of patients, it could well be that those guidelines will need to be updated, Dr. Schiff said. [Neurology Today featured the guideline in a Q&A with the lead author of the guideline: http://bit.ly/NT-DOC.]
The neuroscientist who first described the fMRI test 12 years ago in the journal Science expressed concerns about some of the details of the new paper.
“I'm surprised that they didn't present data from each individual,” said Adrian M. Owen, PhD, the Canada Excellence Research Chair in Cognitive Neuroscience and Imaging at the Brain and Mind Institute of the University of Western University in Ontario. “As a group, the ten patients who could imagine playing tennis had a different signature on the EEG test than those who couldn't. That's fine, but it needs to be shown in individual patients. At the moment they're only halfway there.”
Dr. Edlow, who wrote the accompanying commentary, told Neurology Today that he agrees that positive results on the EEG test cannot be considered proof of covert awareness.
“What Dr. Schiff's lab has developed is a screening test,” Dr. Edlow said. “It only suggests that someone is likely to be covertly conscious. It's measuring the electrophysiological signature of the brain's response to spoken language. The patient is not being asked to modulate his or her brain activity in a volitional manner. The current consensus of the field is that for a patient to demonstrate consciousness, he or she has to show volitional command following.”
But there may be patients who are capable of hearing and understanding language but who lack the cognitive capacity to follow commands, said Stefanie Blain-Moraes, PhD, an assistant professor in the School of Physical and Occupational Therapy at McGill University in Montreal. The EEG test, she said, could prove even more sensitive to detecting covert awareness than does the fMRI exam.
“The big step forward here is that this is a passive test,” said Dr. Blain-Moraes, who has spent the past seven years studying and developing technologies to facilitate communication for such patients. “You don't have to be able to visualize playing tennis. You don't have to be able to pay close attention. Those require a lot of higher-level functions that need to be online.”
Dr. Owen noted that EEG is far cheaper than fMRI and can be conducted at the bedside. But, he said, “The downside of the EEG technique [described in this study] is that they have to prepare audio narratives from the patients' families. That requires a fair amount of preparation per patient. We don't do any preparation with our fMRI approach. We put them in the device and say, ‘Imagine playing tennis.’”
Dr. Blain-Moraes emphasized that however promising the new technique may be, the test is not yet ready for translation to the clinic. “It requires some high-density EEG, which is not equipment you typically have in a neurology clinic,” Dr. Blain-Moraes said. “But I strongly suspect that this or other groups will try to translate this research into a clinic-ready device.”
Should the results hold up, the implications for patient care could be significant, she said.
“In the United States, in order to qualify for rehabilitation, you have to show you have the potential to benefit from it,” Dr. Blain-Moraes said. “Because the vast majority of people with disorders of consciousness don't show behavioral signs of awareness, there's nothing to measure. They don't qualify. This study takes us one step closer to showing which individuals — those we call vegetative but who may be aware — can potentially follow commands, and if we give them rehabilitation, they could potentially regain some function. Right now that's not an option.”
Dr. Schiff disclosed that he, the first author, and one other author have submitted a patent application on the use of these EEG methods for diagnostic purposes. There is no existing intellectual property or other potential financial relationship. He also stated he is a member of the scientific advisory board for EnspireDBS, Inc., and holds stock options in this start-up company developing a stroke therapy unrelated to the topic of the present article. These options have zero value. Dr. Owen disclosed that he is the author of Into The Gray Zone: A Neuroscientist Explores the Border Between Life and Death, for which he received an advance payment from Simon and Schuster as well as profits from foreign sales. The subject matter overlaps with some of the issues covered in this article. Drs. Edlow and Blain-Moraes had no disclosures.