'For the First Time,' Brainstem Region Linked to Coma

Deborah Brauser

November 22, 2016

New research has identified a small region of the brain that, when injured, may be associated with coma.

After examining brainstem lesions from 36 patients, investigators found a significant link between coma-causing lesions and the rostral dorsolateral pontine tegmentum.

While this brainstem area was functionally connected to the ventral anterior insula (AI) and the pregenual anterior cingulate cortex (pACC) in a group of healthy volunteers, further analysis showed a disruption in AI-pACC connectivity in a subset of patients with disorders of consciousness, including coma.

"For the first time, we have found a connection between the brainstem region involved in arousal and regions involved in awareness, two prerequisites for consciousness," co-investigator Michael D. Fox, MD, PhD, director of the Laboratory for Brain Network Imaging and Modulation at Beth Israel Deaconess Medical Center (BIDMC), Boston, Massachusetts, said in a release.

"The added value of thinking about coma as a network disorder is it presents possible targets for therapy, such as using brain stimulation to augment recovery," added co-investigator Aaron D. Boes, MD, PhD, formerly of BIDMC and now at the University of Iowa in Iowa City.

The findings were published online November 4 in Neurology.

In an accompanying commentary, Stefan M. Golaszewski, MD, Department of Neurology and the Neuroscience Institute at Paracelsus Medical University Salzburg, Austria, writes that, if validated, the study's insights may become important for neurologists.

Dr Stefan M. Golaszewski

"We didn't know that there is a special region in the brainstem that is responsible for consciousness. That is a new step in our knowledge," Dr Golaszewski told Medscape Medical News.

"For neurologists who are caring for patients in coma, this may eventually help to better diagnose these patients," he said.

Past Findings "Unclear"

The researchers note that despite some promising studies in rodents, it's been "unclear whether there is a human brainstem site significantly more associated with coma-causing lesions than with non-coma-causing lesions, and exactly where this site is located."

In the first part of their analysis, they used voxel-based lesion-symptom mapping to assess 12 brainstem lesions that led to coma and 24 lesions that did not lead to coma (control group).

Results showed that 84% of the coma lesions vs 4.2% of the control lesions were clustered in a small 2-mm3 region in the left pontine tegmentum, near the medial parabrachial nucleus (P < .05).

"The 2 coma lesions that spared this region involved the mid-brain immediately rostral to it," report the investigators.

They then assessed resting-state functional connectivity MRI (rs-fcMRI) data from 98 healthy adult participants (51% women). For this cohort, the rostral dorsolateral pontine tegmentum was functionally connected to the AI and pACC.

"These cortical areas aligned poorly with previously defined resting-state networks, better matching the distribution of von Economo neurons," the researchers note.

A Role in Human Consciousness?

Finally, they used rs-fcMRI to examine network functioning among 26 patients in a minimally conscious state, 19 patients in a vegetative state, and 6 patients in coma, as well as 21 age-matched healthy participants.

AI-pACC connectivity was absent in the comatose patients and significantly reduced in the other two patient groups (P < .001).

"This reduction…exceeded that of other networks (p < .05) including the default mode network, a network previously implicated in disorders of consciousness," write the study authors.

"In light of the evidence provided, it is worth speculating whether this brainstem-AI-pACC network could have a role in human consciousness."

Dr Fox noted that next steps may include assessing the same or overlapping neural networks in other types of patients who have lost consciousness.

"This is most relevant if we can use these networks as a target for brain stimulation," he said. "If we zero in on the regions and network involved, can we someday wake someone up who is in a persistent vegetative state? That's the ultimate question."

"Exciting" but Early Days

In his editorial, Dr Golaszewski notes that the misdiagnosis rate for patients with long-term disorders of consciousness is as high as 43% and that "reliable prognostic markers are rare."

While he writes that all of the current study's results are interesting, the "novel finding" is the identification of the coma-specific region in the left pontine tegmentum.

"There are stronger partial correlations between the pontine node and the AI, and between the AI and the pACC, than between the pontine node and the pACC," writes Dr Golaszewski.

"After flipping the brain activation to the right side, the left AI and pACC remained connected to the pontine mode, indicating the existence of a left-lateralized network involving the pons, AI, and pACC."

In a time when neurologists "must still recommend the best acute treatment and neurorehabilitation" for these patients, the findings may eventually help establish new diagnostic neuroimaging markers, he writes.

"If we have extensive brainstem lesions, then I think we could also connect this information with prognosis," Dr Golaszewski commented to Medscape Medical News.

That said, he noted that this was a small study that needed a better control group, and "further studies must prove this brainstem-coma connection."

"I think it's an important milestone in research, but the study is not enough [to change practice]. It's too early. But it's exciting enough that the science should move on and look into this further," he concluded.

The study was funded by the Howard Hughes Medical Institute, the Parkinson’s Disease Foundation, Shared Instrument grants from the National Institutes of Health, the American Academy of Neurology/American Brain Foundation, the Sidney R. Baer, Jr. Foundation, Harvard Catalyst, the Belgian National Funds for Scientific Research, the European Commission, the James McDonnell Foundation, the European Space Agency, Mind Science Foundation, the French Speaking Community Concerted Research Action, the Public Utility Foundation "Université Européenne du Travail," Fondazione Europea di Ricerca Biomedica, the University and University Hospital of Liège, the Center for Integrative Neuroscience, and the Max Planck Society. The study authors and Dr Golaszewsk have disclosed no relevant financial relationships.

Neurology. Published online November 4, 2016. Abstract, Commentary

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