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New Functional Imaging Study of PVS Sheds Light on Nature of Consciousness

ARTICLE IN BRIEF

A new study in patients in a persistent vegetative state strengthens the case for functional neuroimaging as a complement to bedside diagnosis in this patient population, and sheds light on the neural network at the root of consciousness.

Awake but unaware, patients in a persistent vegetative state (PVS) present a stark illustration of the complexity of “consciousness.” They also present one of the most difficult diagnostic and prognostic challenges for the neurologist in the neurological intensive care unit.

Now, a new study in patients in a PVS strengthens the case for functional neuroimaging as a complement to bedside diagnosis in this patient population, and sheds light on the neural network at the root of consciousness. The study will be published online Jan. 26 ahead of the print edition of Neurology.

“Recognizing unambiguous signs of conscious perception of the environment and of the self in some brain-damaged patients can be very challenging,” since patients are unable to communicate, and their performance on behavioral tests can fluctuate from day to day and even moment to moment, said the lead study author Stein Silva, MD, a researcher in functional neuroimaging at the National Institutes of Health and Medical Research (INSERM) U825 and a physician at the Purpan University Hospital Center of Toulouse, France.

Functional neuroimaging has shown that although cortical metabolism in PVS patients is lower than in normal patients, they have “islands of preserved brain activity,” he said. “But what is really interesting is that in some patients who recover, they stay in the same state of lower cerebral metabolism. This suggests that the problem is not one of global cerebral metabolism, but is a more regional problem.”

AROUSAL AND AWARENESS

Consciousness requires two distinct components: arousal or wakefulness, and awareness of the self and the environment. A brainstem structure, the ascending reticular activating system (ARAS), has long been recognized as the central modulator of wakefulness, and its metabolism is preserved in PVS patients.

Recent work has led to a better understanding of awareness. Studies in normal volunteers and in consciousness-impaired patients have shown that “the brain is intrinsically organized into dynamic functional networks,” Dr. Silva said, and one of these, called the “default mode network,” or DMN, appears to be central to conscious awareness. It is most active when the brain is awake and at rest, not processing sensory information.

“The functional role of the default mode network is mainly to monitor the difference between self and the environment,” he said. When activity in other networks increases — for instance, when engaging in language, motor activity, or visual processing — activity in the DMN decreases.

Figure

ON THE BASIS OF PET measurement of cerebral blood flow during rest or during a sensory stimulus, investigators highlighted the role of two major areas: the Ascending Reticular Activating System (ARAS), and the precuneus. PVS patients showed less regional cerebral blow flow in the (A) precunes (showing three different slices of this structure). Investigators identified a higher regional cerebral blood flow in the (B) ARAS (showing three slices of the structure).Courtesy: Dr. Silva Stein

One particular brain structure, the precuneus, appears to be central to the DMN. Located in the posterior medial cortex — between the somotosensory and visual cortex —“the precuneus may be the key node of rest brain activity,” Dr. Silva said. It is a highly associative area, with links to many different regions of the brain. Previous work had shown that its activity decreases in PVS, and in one patient who was imaged before and after recovery, restoration of precuneus activity correlated with restoration of consciousness.

These observations led Dr. Silva and colleagues to explore the activity of both ARAS and precuneus in patients with PVS. They performed PET imaging of regional cerebral blood flow, both at rest and during a nonpainful proprioceptive stimulation — the passive movement of one finger. They tested 10 controls and 10 PVS patients, six with traumatic brain injury and four with anoxic injury.

Surprisingly, patients had higher rest activity in the ARAS. “Our work is the first to show hypermetabolism in ARAS in PVS,” Dr. Stein noted. Normally, higher activity in ARAS facilitates perception of external stimuli, he pointed out. But in PVS patients, the functional connection between ARAS and higher centers is interrupted.

The investigators found that at rest, DMN activity and precuneus activity in particular was significantly lower in patients compared to controls, in keeping with previous findings, and consistent with a general decline in cortical activity in PVS.

Figure

ARAS, whose activity was functionally correlated to that of precuneus in controls, was not in patients in a persistent vegetative state.Courtesy: Dr. Silva Stein

During stimulation, activity in the DMN decreased also as expected. But the decrease in patients was much less than in controls, independent of etiology, suggesting that the shift in awareness from the resting pattern to the active pattern was greatly impaired. At the same time, the increase in activity in sensorimotor areas was also less in patients.

Finally, by comparing the metabolism in ARAS and precuneus, they showed that activity in the two centers was highly correlated in controls, but not in patients.

The results of this study specifically implicate an important functional connection between ARAS and precuneus. “The novelty of our work is this link between a subcortical area responsible for arousal, and a higher cortical area responsible for a lot of cognitive processes,” Dr. Stein said. These results suggest that that link is central to consciousness.

It is not yet known whether that connection is anatomically direct, or whether it is through an intermediate structure such as the thalamus. But whichever it is, he said, “impaired functional connectivity between the two structures in PVS highlights the dysfunction which may underlie altered conscious perception.”

This connection is “in accord with the emergence of consciousness within a ‘global workspace,’” a model of conscious activity gaining acceptance among neuroscientists. In this model, sensory information enters consciousness when cortical centers distribute its contents among multiple brain regions for processing. During that process, attention is shifted from the internal to the external environment, represented by reduced metabolism in the DMN and increases metabolism in other networks. That shift is impaired in PVS patients, according to this study.

Clinically, Dr. Stein said, “we hope to stay humble.” While the potential for functional neuroimaging to play a role in diagnosis is increasing, “for the foreseeable future, it can only complement clinical assessment, not replace it.” While the study points to the importance of the integrity of the ARAS-precuneus connection, there are not yet clear ways forward in restoring that connection. “It may be possible to facilitate any remaining connections with drugs, but that is a long way off.”

EXPERT COMMENTARY

In an interview with Neurology Today, Joseph Giacino, MD, associate director of neuropsychology at the JFK Johnson Rehabilitation Institute in Edison, NJ, said this study “demonstrates again the importance of the default network in modulating conscious awareness. Historically, there is no question there is an interplay between brainstem and cortex in the process of consciousness. What's new is that people are now tying that specifically to the DMN, with the precuneus as an essential node, and interface between them.”

The study also lends support to the use of functional neuroimaging in diagnostic assessment. Because diagnosis is so difficult, he said, “if a patient is behaviorally ambiguous, and I am concerned that the patient is functionally locked in,” rather than being in a vegetative state, “I might move to neuroimaging, and ask, ‘Does that look like controls, or like a vegetative state?’”

It is too soon to contemplate using imaging alone, Dr. Giacino said, “but you can make the case that this tool is a complementary measure for gauging the level of consciousness, when paired with behavioral findings.”

REFERENCES

• S Silva, X Alacoque, O Fourcade, et al. Wakefulness and loss of awareness: Brain and brainstem interaction in the vegetative state. Neurology 2010; E-pub 2010 Jan. 26.