ARTICLE IN BRIEF
Investigators observed an abnormally active area within the limbic region that seems tied to the default mode network, the state when the brain is at rest, and suggest that it may be a potential target for therapeutic intervention.
About 10 years ago, a team of scientists using brain scans to observe the working brain stumbled onto a baseline activity when it was not doing anything — awake but with eyes closed. They called it the default mode network (DMN) and it's now become the “go-to” area in neuroscience when scientists want to figure out how the brain is organized. The DMN is the brain at rest — an activated group of cells in anterior and posterior midline cortices that drop into the background when the brain starts to attend to something from the outside.
It was no surprise then that the DMN is even quieter than normal in patients in a minimally conscious state (MCS) or vegetative state (VS). But a group of European investigators has looked more closely at the brains of patients with consciousness disorders and, for the first time, observed an abnormally active area within the limbic region that seems tied to the DMN.
This limbic hyperconnectivity may actually be a key to identifying ways to help the brain become more alert, said Steven Laureys, MD, PhD, head of the Coma Science Group in the neurology department at the University Hospital of Liege in Belgium. The idea would be to quiet this limbic noise and that, in turn, might normalize the DMN, which is thought to be the brain's baseline cognitive state.
In a paper published in the Sept. 18 online edition of Neurology, Dr. Laureys; Carol Di Perri, MD, of the University of Pavia, Italy; and colleagues throughout Europe, investigated the functional connectivity between the DMN and other networks in 11 patients in a VS and seven in a MCS. They also scanned an age-and gender-matched group of healthy controls. They relied on two separate analyses of data collected from discrete brain regions generated during resting-state MRI temporal scans to identify connections between cortical areas.
As expected, the DMN in MCS and VS showed a hypoconnectivity. But they were not expecting to see that DMN functional connectivity shifted “and paradoxically increases in limbic structures, including the orbitofrontal cortex, insula, hypothalamus, and the ventral tegmental area.”
There was increased connectivity between the DMN and the limbic regions in VS patients compared with MCS patients. The connectivity of these networks may be critical to “emotional and motivational interactions with the external environment,” the authors said. “In our field we considered patient unresponsiveness as a reflection of lost connectivity in the brain. This study shows us that parts of the brain are still active.”
But what does it mean? Dr. Laureys suspects that this persistent engagement of limbic activity could be disrupting normal patterns of connectivity. If so, shutting down or quieting this abnormal activity could lead to access of the DMN and the possibility of re-activating the machinery involved in memory and executive functions. According to the scientists who carried out the study, disorders of consciousness “may not be simply a function of DMN hypoconnectivity, but rather a more complex, dysfunctional brain connectivity architecture.”
Dr. Laureys said that having the ability to extract the DMN in resting states has been an important tool for understanding disorders of consciousness. “For us, this is interesting because we care whether patients are having some thoughts. We record resting state activity and try to give meaning to what we are measuring.”
Dr. Laureys said that his team previously measured DMN and found no connectivity in patients on the heels of brain death when their hearts are still working. They and others also have looked at the DMN in patients in locked-in states to coma and found decreasing levels of connectivity in those in more severe states of unconsciousness.
“We think this is informative and reflects conscious cognition,” said Dr. Laureys. He cautioned, however, that more work needs to be done to better understand these signals. “I don't think that one study will give us all the answers. But from a practical point, it is easy to acquire an MRI scan and it could help in our understanding of what a person might be capable of experiencing. But we need to be careful when we are using this information to address levels of consciousness.”
He and colleagues are now hoping to study individual patients over time to see if this increased connectivity changes and reflects patient outcomes. Depending on what they find, he said that it would be interesting to see whether treating these hyperconnected circuits with a tool like deep brain stimulation could help improve awareness.
EXPERTS WEIGH IN
When Marcus E. Raichle, MD, professor of radiology, neurology, neurobiology and biomedical engineering at Washington University in St. Louis, first saw a signal in the brain that was active in a resting state he was actually surprised that he had never considered that there would be a hierarchy of functional organization and that there was a network that was central to how things got organized. He and his colleagues who were involved in developing PET and fMRI never saw it because, for the most part, they were always asking volunteers to do something in the scanner.
“What we discovered was that when someone engaged in a goal-directed task, one that had no self-reference, there was an increase in the brain's attention systems, and a reduction in an area we dubbed the default mode network. “Of course, this made sense. If you had to be selective in how you use resources there has to be some order.”
Dr. Raichle said that it is interesting that “when the DMN is taken out of operation other areas misbehave.” He thinks that the finding raises the possibility that something could be done to change the imbalance in the system. “It might be attackable with deep brain stimulation or transcranial magnetic stimulation,” he added.
Joseph T. Giacino, PhD, director of rehabilitation neuropsychology in the department of physical medicine and rehabilitation at the Spaulding Rehabilitation Hospital and a neuropsychologist in the department of psychiatry at Massachusetts General Hospital, concurred that “if you could reverse this hyperconnectivity you may be able to restore some function.”
While he agrees that there are probably many roads that lead to unconsciousness — diminished network activity and abnormal connectivity — he wonders if limbic hyperconnectivity might relate to the recurrent episodes of spontaneous crying that are sometimes observed in patients who otherwise appear to be unconscious (that is, in a vegetative state). “Such a hypothesis could be tested,” he said, “by applying transcranial magnetic stimulation or transcranial direct current stimulation and observing for concomitant decreases in crying and limbic hyperconnectivity. Abatement of the crying would not imply re-emergence of awareness but would lend further support to the authors' theory.”
“The scientists offer an intriguing alternative paradigm for disorders of consciousness,” said James L. Bernat, MD, the Louis and Ruth Frank Professorship in Neuroscience at the Geisel School of Medicine at Dartmouth University. “The standard view is that there is interference with brain circuits necessary for conscious awareness. This finding shows that it is part of it but not the whole story. This hyperconnectivity of other circuits means it is possible that it is diverting neural circuits away from conscious awareness. Like so many advances, it shows us that our previous understanding was oversimplified.”
Dr. Bernat said that the finding may help explain the handful of reports that suggest that some MCS patients who were given zolpidem appear to be more alert and interactive. “No one has been able to say why this is happening but it could be having an effect on this pathological hyperconnectivity,” added Dr. Bernat, who is a member of the editorial advisory board of Neurology Today.
In a report in the Sept. 19 issue of Neurology Today, “A New Tool for Assessing Consciousness,” investigators reported that they had developed an index — using a mathematical formula from signals derived from high-density electroencephalography recordings while patients are undergoing transcranial magnetic stimulation — that helps distinguish between different levels of consciousness. See the article in the Sept. 19 archive on neurotodayonline.com.
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•. Fernandez-Espejo D, Soddu A, Cruse D, et al. A role for the default mode network in the bases of disorders of consciousness. Ann Neurol. 2012; 72:335–343.
•. Whyte J, Myers R.. Incidence of clinically significant responses to zolpidem among patients with disorders of consciousness: a preliminary placebo controlled trial. Am J Phys Med Rehabil. 2009; 88:(5):410–418.