Thalamocortical disruptions underlie covert awareness after TBI

By Will Boggs MD

NEW YORK (Reuters Health) - After severe brain injuries, disruptions in connections between the thalamus and the motor cortex can underlie the absence of overt motor behavior in covertly aware patients, researchers report.

"Clinicians should be aware that lack of responsiveness after severe brain injury should not always be interpreted as a sign of lack of awareness," Dr. Davinia Fernandez-Espejo, from the University of Birmingham, England, told Reuters Health by email. "Some patients may simply be unable to respond due to a very specific structural damage to their motor network."

A subset of covertly aware patients can show clear signs of awareness on neuroimaging techniques that do not rely on production of an external response. Why these patients are able to imagine a motor act, but not perform it, remains something of a mystery.

Dr. Fernandez-Espejo's team used functional magnetic resonance imaging (fMRI) and diffusion tensor imaging (DTI) tractography to investigate differences in the activation of the thalamus and motor cortical regions between motor imagery and execution in 15 healthy volunteers and then in two patients with traumatic brain injury (TBI) - one with covert awareness, the other with reliable behavioral evidence of command following.

Motor execution, or actually moving, in healthy volunteers was accompanied by significant neural activity in the precentral gyrus (M1) and juxtapositional lobule (SMA), as well as in the thalamus, whereas motor imagery, or imagining movement, elicited activity in the precentral gyrus and juxtapositional lobule but not in the thalamus.

When participants moved their right hand, neural activity in the left precentral gyrus (M1) was driven by significant enhancement of the excitatory influence exerted by the left thalamus, according to the October 19 JAMA Neurology online report.

Based on further modeling, the researchers suggest that "the change in activity in the thalamus and M1 is more likely to be caused by an excitatory influence during execution than an inhibitory influence during imagery."

The patient with covert awareness showed marked damage in the fibers connecting the thalamus and M1, whereas such damage was not present in the patient who was capable of overt command following.

"We suggest that nonresponsive patients who appear to be in a vegetative state be assessed for the presence of structural damage to the connections between thalamus and motor cortex (or more generally damage to the thalamocortical fragment of the corticospinal tract)," Dr. Fernandez-Espejo said.

"If such damage is identified, the possibility that the patient may retain covert cognitive function and awareness should be considered. For practical reasons, functional neuroimaging assessments to identify covert awareness may not be available to all patients who appear to be in a vegetative state. Our suggested biomarker could thus help identify patients who are firm candidates for further specialized neuroimaging assessments," the researcher added.

This technology is widely available. Dr. Fernandez-Espejo said, "Diffusion tensor imaging sequences are available in most clinical grade MRI scanners, and in fact, are routinely acquired as part of clinical MRI assessments in severely brain-injured patients."

In their paper, the researchers say, "These results not only may suggest a possible early diagnostic biomarker for this recently discovered group of covertly aware patients but also may pave the road for the development of therapies aimed at restoring their lost motor abilities (e.g., deep brain stimulation of the ventrolateral thalamic nuclei)."

Dr. Nicholas D. Schiff, from Weill Cornell Medical College's Fell Family Brain and Mind Research Institute, New York, who wrote an editorial related to this report, told Reuters Health by email, "Routine clinical EEG (electroencephalography) identification of normal or near normal features of a wakeful background activity in a patient appearing to fulfill behavioral criteria for vegetative state or a low level minimally conscious state (without evidence of command following or a communication system) should prompt further evaluation with imaging and electrophysiological approaches to identify these individuals."

He proposes "cognitive motor dissociation (CMD)" as the diagnostic term for these individuals.

"Aggressive efforts to develop brain-computer interface testing for CMD patients would be the next step as there is an urgency to figure out who could benefit and how such patients might be enabled with these technologies, as they have special challenges resulting from injuries within the central nervous system that are not limited to the motor outflow channels," Dr. Schiff said.

His editorial notes that two independent studies of about 50 patients in different research centers each found four to five patients with CMD, "indicating that a substantial minority of the severely brain-injured population may harbor significant recruitable capacity to reengage with their environment. . . ., such persons have a right to medical advances aimed at restoring communication and revealing their consciousness."

Dr. Schiff added, "My colleague Dr. (Joseph J.) Fins has written a book "Rights Come to Mind" on the ethical, policy, and legal aspects of this problem that frame these issues in detail. He is giving a keynote at the Society for Neuroscience (annual meeting) on the same day this editorial publishes that highlights one of our CMD patients and others."

Senior author Dr. Adrian M. Owen, from the University of Western Ontario's Brain and Mind Institute, London, Ontario, Canada, told Reuters Health by email, "Neuroscientists are starting to understand how some types of brain damage can lead to startlingly unlikely clinical situations - 10 years ago, it was thought to be entirely impossible that a patient could appear to be entirely vegetative, clinically and behaviorally, yet in reality turn out to be in some sort of complete 'locked in' situation. Now we know that this is possible, not entirely uncommon, and we are also beginning to know why. Physicians should look out for these conditions and know that they are not always what they seem."

"In order to develop effective therapeutic interventions we have to understand exactly where the brain damage is that causes these complex conditions," Dr. Owen said. "This paper sheds light on that question and therefore points towards a likely locus of injury. Potential interventions (such as deep brain stimulation) might be more readily guided by information provided by this study."

The Canadian Institutes for Health Research and the Canada Excellence Research Chairs Program supported this research.

SOURCE: http://bit.ly/1XhBWVX and http://bit.ly/1Rm1Wf4

JAMA Neurol 2015.

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