Tuesday, February 12, 2013

Can Images Unlock the Mystery of a Healing Brain?


Maybe. Maybe not. But they can offer pathways for investigation. This article comes from MedPage Today.

Can Images Unlock the Mystery of a Healing Brain?

By Nancy Walsh, Staff Writer, MedPage Today
Published: February 01, 2013



Reports that sophisticated imaging had revealed residual brain activity in former Israeli prime minister Ariel Sharon, who's been comatose for more than 6 years, focused on the spectacular technology involved, but overlooked a more important clinical story -- that some patients with severe brain injury actually do regain some degree of cognitive function.

The concept of the minimally conscious state as a separate entity from the vegetative state has been a crucial diagnostic refinement in recent years, according to Nicholas D. Schiff, MD, who directs the Laboratory of Cognitive Neuromodulation at Weill Cornell Medical College in New York City.

"In the past, these patients were all lumped together, until we started asking the question of why it should matter if some patients appear to have some awareness and ability to track although they can't speak, respond, or organize movements," he said.

"Actually, it turns out that it matters a lot," Schiff told MedPage Today.

Consciousness and Recovery

What the brain imaging studies and neural research have demonstrated is that, in the weeks and months following brain injury, there is a vast difference in evolution of their condition between patients with minimal consciousness and those who are truly vegetative.

"Recent studies have demonstrated that it is important to disentangle both clinical entities as functional neuroimaging studies have shown differences in residual cerebral processing and hence, conscious perception, as well as important differences in outcome," Schiff wrote online in the journal NeuroImage.

What the research has begun to show is that recovery of important neural networks may be an occult process in some patients, with no visible changes in their ability to speak or move, he explained.

In one program that has prospectively followed 400 patients with traumatic brain injury over the course of 5 years, a significant proportion of patients advanced at least to a minimally conscious state despite having initially been at the lowest level of the Glasgow coma scale.

Approximately one-third of the patients regained some degree of independent function, and some even acquired vocational re-entry level of functioning, according to Schiff.

One possible factor in the gradual return of consciousness after injury, sometimes over a long period of time, "is that the normal recovery process ... includes a component of structural remodeling that could plausibly relate to reestablishment of goal-directed behaviors and driving of learning and memory mechanisms," Schiff wrote in the December 2009 issue of Trends in Neurosciences.

Imaging the Broken Brain

Following reports of spontaneous cognitive recovery after brain injury, a group of researchers from Cambridge, England, and Liege, Belgium, conducted a series of experiments in which they attempted to identify the level of awareness and the ability to communicate in 54 patients with severe brain injury.

Functional MRI tests in healthy controls have shown that the same areas of the brain activated by motor and spatial tasks can also have increased blood flow when the person imagines doing an activity such as playing tennis or walking through a house.

First, the researchers requested that the patients, while in the MRI scanner, imagine performing those activities.

For patients whose functional brain scans revealed increased intensity in the motor cortex or parahippocampal gyrus, the researchers then increased the complexity of the task, asking a series of autobiographical questions that would have yes or no answers, such as if the patient had a brother named Tom.

To answer yes, patients were instructed to imagine playing tennis, and to answer no, to imagine walking through the house.

The hypothesis was that the motor area of the brain would light up with an affirmative response, while the parahippocampal area that reflects spatial function would show increased signal intensity with a negative reply.

Among the 54 patients, five were able to "willfully modulate their brain activity," in response to the task instructions -- in effect, correctly answering the questions, wrote Martin M. Monti, PhD, now of the University of California Los Angeles.

This proved that "in a minority of cases, patients who meet the behavioral criteria for a vegetative state have residual cognitive function and even conscious awareness," Monti and colleagues reported in the Feb. 18, 2010 issue of New England Journal of Medicine.

But functional MRI is expensive and not always accessible, so another group tested 16 apparently vegetative patients using easily available electroencephalography (EEG) techniques and found that three were able to provide appropriate responses to commands that they imagine moving their hands and feet.

The EEG results were equivalent to what is seen for healthy controls, Adrian M. Owen, PhD, of the University of Western Ontario, and colleagues reported in Nov. 10, 2011 issue of The Lancet.

In effect, all these researchers were having simple conversations with their patients, Michael S. Beauchamp, PhD, of the department of neurobiology and anatomy at the University of Texas in Houston, told MedPage Today.

The Need for Assessment

Although the spectacular achievements being seen with neuroimaging have been garnering headlines, Schiff argued that another important need is far from being met.

"What's missing is an articulated framework for tracking patients and translating what we're learning from the research side into a system of care where they are reassessed over time," he toldMedPage Today.

Right now a person who is severely brain injured typically leaves the hospital with a diagnosis of vegetative state. There is no ICD code for minimally conscious state, no registry to follow these patients, and there is no requirement that the person undergo follow-up examinations.

The heightened understanding that the brain can undergo recovery has not been incorporated into the system, according to Schiff. Follow-up assessments are not reimbursed by insurance companies, and there aren't even many centers that provide these services.

The real hindrance has been this structural flaw in the system, he stated.

Thus far the only progress has been made by the defense department, which has proposed -- although not yet implemented -- the establishment of polytrauma centers, where brain injured veterans will be provided with reassessment of levels of consciousness to allow for adjustments in treatment, Schiff explained.

"As of now, it's very much the case that people just keep the diagnosis they were given when they leave the hospital," he said.

That may not be of tremendous concern for a patient who has been comatose for 5 or 10 years. "But certainly a person who is minimally conscious after a couple of months can have a very wide range of outcomes, including some that might not be acceptable to many patients and others that would be acceptable to all," he said.

Beauchamp concurred with the importance of differentiating patients who have no residual brain activity from those who may improve over time, particularly with regard to their treatment.

"If someone is truly brain dead, and there's no brain activity at all, it's probably not worth investing tremendous time and effort in attempting to rehabilitate them. But if there is some brain function and they just have not been able to let you know, you would definitely want to try to help them," he said.

And while it may be only up to 10% of comatose patients who have this minimal consciousness, it would be a tremendous service to provide more aggressive treatment to the one patient in 10 who does have potential for recovery, Beauchamp told MedPage Today.

Limitations and Next Steps

As to the implications of the brain scan results on prime minister Sharon, both Schiff and Beauchamp agreed that, while the specifics of the tests have not been publicly revealed, it seems unlikely that the treatment team found the types of responses seen in the published imaging studies, where patients were able to follow commands and perform other complex tasks.

Imaging studies have also demonstrated that patients who are vegetative can have a considerable amount of ambiguous brain activity, such as apparently responding to one's name or to a familiar face.

"The researchers who tested Sharon said they saw a response to his son's voice, but that's a lot simpler than being able to answer a yes or no question," Beauchamp said.

"They were very careful not to speculate about any possibility of recovery," he added.

"Animal studies also show that there is quite a lot of highly differentiated activity in the brain occurring without any conscious processing," Schiff noted.

Accordingly, imaging tests such as those given Sharon are really not ready for prime time in the clinic, according to Schiff.

In fact, they will probably not ever be useful as screening tests, because they aren't sufficiently sensitive. The false-negative rate is much too high, he said.

The most important role for brain imaging in these patients is for confirming the presence of consciousness. "When the technology works it's an unambiguous rule-in test," Schiff said.

That imaging tests remain imperfect tools for assessing consciousness was echoed by Stuart Hameroff, MD, director of the Center for Consciousness Studies at the University of Arizona in Tucson.

"Imaging studies don't tell us about awareness, they tell us about neuronal activity, behavior, and perception, which may be conscious or nonconscious," Hameroff told MedPage Today.

"Most people would say that consciousness is an emergent effect happening at a higher level of complexity, but my personal belief is that consciousness happens at a deeper level, inside the neuron, and is perhaps even a quantum effect," he said in an interview.

What's most needed now is the adoption of a variety of tools not only including ever-advancing imaging technology but also skilled clinical examinations being done on a regular basis, to identify misdiagnoses and signs of recovery and adjust treatment as needed, according to Schiff.

"We are trying to fundamentally understand what's happening when recovery occurs in a severely structurally damaged brain and to develop models of the underlying physiology, and then to develop rational therapies for those patients we can help," he concluded.
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