Imaging Shows Cognitive Processes in Vegetative Patients

Pauline Anderson

March 03, 2015

A new study using functional MRI (fMRI) has shown signs of high-level cognitive processes thought to be crucial to consciousness in people deemed to be in a vegetative state due to severe brain injury.

The imaging study showed that 3 of 8 patients judged to be in a vegetative state demonstrated a mental state of at least minimal consciousness.

"That's huge," commented lead study author Martin Monti, PhD, assistant professor, Department of Psychology, University of California at Los Angeles. "This is one of the biggest numbers that we have ever gotten in a neuroimaging study, percentagewise."

Dr Martin Monti

The new results mean that researchers are getting better at determining which patients thought to have a disorder of consciousness (DOC), such as vegetative state (VS) or minimally conscious state (MCS), might actually be conscious but can't show it. They also suggest that some patients with VS are being misdiagnosed.

The study was published in the January 13 issue of Neurology.

Willful Brain Behavior

On the spectrum of consciousness, coma (eyes closed and unresponsive) is at the bottom, above which is VS (awake but unconscious), followed by MCS– (demonstrating low-level behavioral responses, such as visual pursuit; localization of noxious stimulation; or contingent behavior, such as appropriate smiling or crying to emotional stimuli), MCS+ (demonstrating high-level behavioral responses, such as a command following, intelligible verbalization, or nonfunctional communications), and then exit MCS (eMCS).

"The day that patients are able to either respond to 6 questions out of 6, or to demonstrate a high level of consciousness which might be the functional use of an object, like taking a mug to the mouth, they are said to exit MCS," explained Dr Monti.

There are no clinical tools to directly determine consciousness in DOC patients. "It would be great if there was a thermometer you could put in someone's ear and if it's 100 degrees it means this person is conscious," said Dr Monti. Instead, clinicians use protocols of assessments that involve asking patients to do things such as blink twice or move their right hand or look to a particular side.

But some patients may be conscious but can't show it, said Dr Monti. "Maybe someone can't move their hands or finger or blink to tell us they're conscious, but they might be able to do something with their brain that I can recognize as willful."

Brain activation from a sample volunteer and a sample patient. Courtesy Martin Monti

That's where neuroimaging studies such as this new one come in. The analysis included 16 healthy volunteers and 28 patients with DOC: 8 with VS, 16 with MCS (4 with MCS– and 12 with MCS+), and 4 with eMCS.

While in the MRI scanner, patients and volunteers were told to listen to blocks of words repeated in random order and then to focus on or count the number of times a "target" word was presented. The words were "neutral" (not words that are intrinsically salient, such as "fire") and individualized and randomized for each patient.

Because connections between the thalamus and cortex are believed to be important in maintaining large-scale neural circuits integral to conscious behavior, the researchers concentrated on this section of the brain.

Hypothalamus, in blue, and its connection to frontal cortex, in red. Courtesy Martin Monti

"One of the theories of why people lose consciousness and then recover it is that the connection between thalamus and prefrontal cortex becomes hypoactive," said Dr Monti. "This lack of activity seems to be correlated with absence of consciousness; when consciousness comes back, this connection between the thalamus and prefrontal cortex tends to come back."

The analysis uncovered significant activations for the count minus listen contrast in 10 of the 28 patients. This included 3 of 8 VS patients who demonstrated a mental state of at least minimal consciousness, 6 of 12 MCS+ patients, and 1 of 4 eMCS patients.

"It turns out that the only difference we found between the patients who did respond to the task and those who did not respond to task was the degree of connection between the thalamus and prefrontal cortex," commented Dr Monti.

According to the authors, it is "remarkable" that the incidence of residual high-level cognitive processing identified in this study (37%) is larger than what has been reported in previous neuroimaging investigations, which Dr Monti said was about 20%.

"This tells us that some patients diagnosed as VS in fact have some level of consciousness."

It means that imaging technology is getting better at telling which patients who "fall in this grey area where they might be conscious but can't show it," are actually conscious, said Dr Monti.

On the other hand, 12 of 19 patients who could demonstrate consciousness in standard bedside assessments failed to show any detectable activation in the imaging study, he said.

This shouldn't rule anything out, though, he noted. "The fMRI is not a recognized diagnostic tool," said Dr Monti. "If you see positive signs in the fMRI, you can say this patient has to be conscious to see these signs, but if you don't see these positive signs, you can't say anything."

Still, it's not "a justifiable leap" to conclude from this study that every patient in VS should undergo fMRI to determine consciousness, said Dr Monti.

Six of the 10 responders in the study had a nontraumatic brain injury. Of these, 2 VS patients and 1 MCS+ patients had anoxic brain injuries while the remaining 2 MCS+ patients and 1 eMCS patient had an intracerebral hemorrhage.

Dr Monti pointed out that patients with traumatic brain injury, for example from a car accident, generally fare better than patients with nontraumatic brain injury, such as a stroke, because the nontraumatic injury tends to affect deeper parts of the brain, particularly the thalamus.

Stimulating the thalamus-prefrontal cortex region may improve consciousness, according to results of some recent research. Studies in which electrodes were inserted into the thalamus and an electrical stimulation resulted in patients going from MCS– to MCS+, possibly to eMCS, he noted.

Crucially Important

The findings reinforce two "crucially important" clinical implications for practicing neurologists, according to an accompanying editorial by Serge Goldman, MD, PhD, professor, Laboratory of Cerebral Functional Cartography and PET/Biomedical Cyclotron Unit, Erasmus Hospital, ULB Institute of Neuroscience, Brussels, Belgium, and Nicholas Schiff, MD, professor, neurosciences, Weill Cornell Medical College, New York, New York.

The first implication is that the results helps demonstrate that clinical assessments of patients with severe brain injuries often can't discriminate large differences in underlying integrative brain functions.

Conversely, a second implication is that sophisticated functional neuroimaging techniques "can fail to identify the capacity to deploy high-level integrative brain functions in patients in whom this capacity appears indisputable on bedside examination," the editorialists write.

"As such, this work adds an important, cleanly constructed tool for the study of DOC and supports growing evidence of the generalizability of its results."

Dr Goldman and Dr Schiff note that a limitation impeding the widespread use of functional neuroimaging for DOC evaluation is the lack of an external gold standard that would support the diagnostic value of neuroimaging for signs of consciousness.

A concern with this and other studies carried out in specialty research centers is that they may not reflect the wider DOC patient population, "a fundamental issue in the era of evidence-based medicine," write the commentators.

Patients enrolled in this and similar studies are selected by health institutions referring patients to a specialized center where the neuroimaging study is conducted, they say. "Obviously this mode of selection likely introduces biases that could affect outcomes. For instance, motivation for referring some patients and not others to the expert center might reflect underlying doubts about the actual status of the patient."

The study was supported by a James S. McDonnell Foundation Scholar Award, the Medical Research Council, and the European Commission ICT Programme. Dr Monti, Dr Goldman, and Dr Schiff have disclosed no relevant financial relationships.

Neurology. 2015;84:167-173. Abstract Editorial

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