Mélanie Boly

Detecting Awareness in the Vegetative State

We used functional magnetic resonance imaging to demonstrate preserved conscious awareness in a patient fulfilling the criteria for a diagnosis of vegetative state. When asked to imagine playing tennis or moving around her home, the patient activated predicted cortical areas in a manner indistinguishable from that of healthy volunteers.

Willful Modulation of Brain Activity in Disorders of Consciousness

BACKGROUND The differential diagnosis of disorders of consciousness is challenging. The rate of misdiagnosis is approximately 40%, and new methods are required to complement bedside testing, particularly if the patients capacity to show behavioral signs of awareness is diminished. METHODS At two major referral centers in Cambridge, United Kingdom, and Liege, Belgium, we performed a study involving 54 patients with disorders of consciousness. We used functional magnetic resonance imaging (MRI) to assess each patients ability to generate willful, neuroanatomically specific, blood-oxygenation-level-dependent responses during two established mental-imagery tasks. A technique was then developed to determine whether such tasks could be used to communicate yes-or-no answers to simple questions. RESULTS Of the 54 patients enrolled in the study, 5 were able to willfully modulate their brain activity. In three of these patients, additional bedside testing revealed some sign of awareness, but in the other two patients, no voluntary behavior could be detected by means of clinical assessment. One patient was able to use our technique to answer yes or no to questions during functional MRI; however, it remained impossible to establish any form of communication at the bedside. CONCLUSIONS These results show that a small proportion of patients in a vegetative or minimally conscious state have brain activation reflecting some awareness and cognition. Careful clinical examination will result in reclassification of the state of consciousness in some of these patients. This technique may be useful in establishing basic communication with patients who appear to be unresponsive.

Baseline brain activity fluctuations predict somatosensory perception in humans.

In perceptual experiments, within-individual fluctuations in perception are observed across multiple presentations of the same stimuli, a phenomenon that remains only partially understood. Here, by means of thulium–yttrium/aluminum–garnet laser and event-related functional MRI, we tested whether variability in perception of identical stimuli relates to differences in prestimulus, baseline brain activity. Results indicate a positive relationship between conscious perception of low-intensity somatosensory stimuli and immediately preceding levels of baseline activity in medial thalamus and the lateral frontoparietal network, respectively, which are thought to relate to vigilance and “external monitoring.” Conversely, there was a negative correlation between subsequent reporting of conscious perception and baseline activity in a set of regions encompassing posterior cingulate/precuneus and temporoparietal cortices, possibly relating to introspection and self-oriented processes. At nociceptive levels of stimulation, pain-intensity ratings positively correlated with baseline fluctuations in anterior cingulate cortex in an area known to be involved in the affective dimension of pain. These results suggest that baseline brain-activity fluctuations may profoundly modify our conscious perception of the external world.

Breakdown of within- and between-network Resting State Functional Magnetic Resonance Imaging Connectivity during Propofol-induced Loss of Consciousness

Background:Mechanisms of anesthesia-induced loss of consciousness remain poorly understood. Resting-state functional magnetic resonance imaging allows investigating whole-brain connectivity changes during pharmacological modulation of the level of consciousness. Methods:Low-frequency spontaneous blood oxygen level-dependent fluctuations were measured in 19 healthy volunteers during wakefulness, mild sedation, deep sedation with clinical unconsciousness, and subsequent recovery of consciousness. Results:Propofol-induced decrease in consciousness linearly correlates with decreased corticocortical and thalamocortical connectivity in frontoparietal networks (i.e., default- and executive-control networks). Furthermore, during propofol-induced unconsciousness, a negative correlation was identified between thalamic and cortical activity in these networks. Finally, negative correlations between default network and lateral frontoparietal cortices activity, present during wakefulness, decreased proportionally to propofol-induced loss of consciousness. In contrast, connectivity was globally preserved in low-level sensory cortices, (i.e., in auditory and visual networks across sedation stages). This was paired with preserved thalamocortical connectivity in these networks. Rather, waning of consciousness was associated with a loss of cross-modal interactions between visual and auditory networks. Conclusions:Our results shed light on the functional significance of spontaneous brain activity fluctuations observed in functional magnetic resonance imaging. They suggest that propofol-induced unconsciousness could be linked to a breakdown of cerebral temporal architecture that modifies both within- and between-network connectivity and thus prevents communication between low-level sensory and higher-order frontoparietal cortices, thought to be necessary for perception of external stimuli. They emphasize the importance of thalamocortical connectivity in higher-order cognitive brain networks in the genesis of conscious perception.

A Theoretically Based Index of Consciousness Independent of Sensory Processing and Behavior

A theory-derived index of consciousness, which quantifies the complexity of the brain’s response to a stimulus, measures the level of consciousness in awake, sleeping, anesthetized, and brain-damaged subjects. Quantifying the Unquantifiable Manipulation of consciousness is an everyday medical trick—think anesthesia—but physicians have only the crudest of tools to detect when a person is not aware. The usual question or physical stimulus does not always provide reliable reactions, and a more precise index is needed to avoid, for example, the conclusion that people who have locked-in syndrome (in which they are aware but cannot respond) are unconscious. Here, Casali et al. have extended their previous work on electrical correlates of consciousness to define an electroencephalographic-derived index of human consciousness [the perturbational complexity index (PCI)] that reflects the information content of the brain’s response to a magnetic stimulus. The PCI could allow tracking of consciousness in individual patients. The authors used data already collected from previous experiments, in which they had stimulated people’s brains with transcranial magnetic stimulation. By calculating the likely brain regional sources of the signals and then comparing the unique information in each, the authors derived PCI values. The values ranged from 0.44 to 0.67 in 32 awake healthy people, but fell to 0.18 to 0.28 during nonrapid eye movement (NREM) sleep. Then, to see whether a completely different way of inducing unconsciousness had the same effect on PCI, the authors assessed data from patients given various amounts of the anesthetics midazolam, xenon, and propofol. These agents too caused low “unconscious” values for the PCI: midazolam deep sedation, 0.23 to 0.31; propofol, 0.13 to 0.30; and xenon, 0.12 to 0.31. However, what about patients who suffer brain damage and who exhibit various levels of consciousness by conventional assessment methods? In these people, consciousness varies widely, as does the underlying damage from stroke or trauma. Here, too, the authors found promising results in those who had emerged from coma but were in a vegetative state or minimally conscious state, or exhibited locked-in syndrome. The PCI values from these patients clearly reflected the state of their consciousness, with the six patients in a vegetative state clearly unconscious (0.19 to 0.31), the two with locked-in syndrome clearly aware (0.51 to 0.62), and those in a minimally conscious state showing intermediate values (0.32 to 0.49). The validity of PCI for clinical application will need to be assessed in prospective trials, but it has the advantage of being derived from a simple noninvasive measurement. The new index reported by Casali et al. appears to be a robust measure that distinguishes conscious from unconscious states well enough to be used on an individual basis, a prerequisite for deployment in the clinic. One challenging aspect of the clinical assessment of brain-injured, unresponsive patients is the lack of an objective measure of consciousness that is independent of the subject’s ability to interact with the external environment. Theoretical considerations suggest that consciousness depends on the brain’s ability to support complex activity patterns that are, at once, distributed among interacting cortical areas (integrated) and differentiated in space and time (information-rich). We introduce and test a theory-driven index of the level of consciousness called the perturbational complexity index (PCI). PCI is calculated by (i) perturbing the cortex with transcranial magnetic stimulation (TMS) to engage distributed interactions in the brain (integration) and (ii) compressing the spatiotemporal pattern of these electrocortical responses to measure their algorithmic complexity (information). We test PCI on a large data set of TMS-evoked potentials recorded in healthy subjects during wakefulness, dreaming, nonrapid eye movement sleep, and different levels of sedation induced by anesthetic agents (midazolam, xenon, and propofol), as well as in patients who had emerged from coma (vegetative state, minimally conscious state, and locked-in syndrome). PCI reliably discriminated the level of consciousness in single individuals during wakefulness, sleep, and anesthesia, as well as in patients who had emerged from coma and recovered a minimal level of consciousness. PCI can potentially be used for objective determination of the level of consciousness at the bedside.

Preserved Feedforward But Impaired Top-Down Processes in the Vegetative State

Discerning the neural correlates of (un)consciousness sheds light on the mechanisms underlying vegetative states. Frontoparietal cortex is involved in the explicit processing (awareness) of stimuli. Frontoparietal activation has also been found in studies of subliminal stimulus processing. We hypothesized that an impairment of top-down processes, involved in recurrent neuronal message-passing and the generation of long-latency electrophysiological responses, might provide a more reliable correlate of consciousness in severely brain-damaged patients, than frontoparietal responses. We measured effective connectivity during a mismatch negativity paradigm and found that the only significant difference between patients in a vegetative state and controls was an impairment of backward connectivity from frontal to temporal cortices. This result emphasizes the importance of top-down projections in recurrent processing that involve high-order associative cortices for conscious perception.

Hemodynamic cerebral correlates of sleep spindles during human non-rapid eye movement sleep

In humans, some evidence suggests that there are two different types of spindles during sleep, which differ by their scalp topography and possibly some aspects of their regulation. To test for the existence of two different spindle types, we characterized the activity associated with slow (11–13 Hz) and fast (13–15 Hz) spindles, identified as discrete events during non-rapid eye movement sleep, in non-sleep-deprived human volunteers, using simultaneous electroencephalography and functional MRI. An activation pattern common to both spindle types involved the thalami, paralimbic areas (anterior cingulate and insular cortices), and superior temporal gyri. No thalamic difference was detected in the direct comparison between slow and fast spindles although some thalamic areas were preferentially activated in relation to either spindle type. Beyond the common activation pattern, the increases in cortical activity differed significantly between the two spindle types. Slow spindles were associated with increased activity in the superior frontal gyrus. In contrast, fast spindles recruited a set of cortical regions involved in sensorimotor processing, as well as the mesial frontal cortex and hippocampus. The recruitment of partially segregated cortical networks for slow and fast spindles further supports the existence of two spindle types during human non-rapid eye movement sleep, with potentially different functional significance.

Sleep transforms the cerebral trace of declarative memories

After encoding, memory traces are initially fragile and have to be reinforced to become permanent. The initial steps of this process occur at a cellular level within minutes or hours. Besides this rapid synaptic consolidation, systems consolidation occurs within a time frame of days to years. For declarative memory, the latter is presumed to rely on an interaction between different brain regions, in particular the hippocampus and the medial prefrontal cortex (mPFC). Specifically, sleep has been proposed to provide a setting that supports such systems consolidation processes, leading to a transfer and perhaps transformation of memories. Using functional MRI, we show that postlearning sleep enhances hippocampal responses during recall of word pairs 48 h after learning, indicating intrahippocampal memory processing during sleep. At the same time, sleep induces a memory-related functional connectivity between the hippocampus and the mPFC. Six months after learning, memories activated the mPFC more strongly when they were encoded before sleep, showing that sleep leads to long-lasting changes in the representation of memories on a systems level.

Perception of pain in the minimally conscious state with PET activation: an observational study.

BACKGROUND Patients in a minimally conscious state (MCS) show restricted self or environment awareness but are unable to communicate consistently and reliably. Therefore, better understanding of cerebral noxious processing in these patients is of clinical, therapeutic, and ethical relevance. METHODS We studied brain activation induced by bilateral electrical stimulation of the median nerve in five patients in MCS (aged 18-74 years) compared with 15 controls (19-64 years) and 15 patients (19-75 years) in a persistent vegetative state (PVS) with (15)O-radiolabelled water PET. By way of psychophysiological interaction analysis, we also investigated the functional connectivity of the primary somatosensory cortex (S1) in patients and controls. Patients in MCS were scanned 57 (SD 33) days after admission, and patients in PVS 36 (9) days after admission. Stimulation intensities were 8.6 (SD 6.7) mA in patients in MCS, 7.4 (5.9) mA in controls, and 14.2 (8.7) mA in patients in PVS. Significant results were thresholded at p values of less than 0.05 and corrected for multiple comparisons. FINDINGS In patients in MCS and in controls, noxious stimulation activated the thalamus, S1, and the secondary somatosensory or insular, frontoparietal, and anterior cingulate cortices (known as the pain matrix). No area was less activated in the patients in MCS than in the controls. All areas of the cortical pain matrix showed greater activation in patients in MCS than in those in PVS. Finally, in contrast with patients in PVS, those in MCS had preserved functional connectivity between S1 and a widespread cortical network that includes the frontoparietal associative cortices. INTERPRETATION Cerebral correlates of pain processing are found in a similar network in controls and patients in MCS but are much more widespread than in patients in PVS. These findings might be objective evidence of a potential pain perception capacity in patients in MCS, which supports the idea that these patients need analgesic treatment.

Intrinsic Brain Activity in Altered States of Consciousness : How Conscious Is the Default Mode of Brain Function?

Spontaneous brain activity has recently received increasing interest in the neuroimaging community. However, the value of resting‐state studies to a better understanding of brain–behavior relationships has been challenged. That altered states of consciousness are a privileged way to study the relationships between spontaneous brain activity and behavior is proposed, and common resting‐state brain activity features observed in various states of altered consciousness are reviewed. Early positron emission tomography studies showed that states of extremely low or high brain activity are often associated with unconsciousness. However, this relationship is not absolute, and the precise link between global brain metabolism and awareness remains yet difficult to assert. In contrast, voxel‐based analyses identified a systematic impairment of associative frontoparieto–cingulate areas in altered states of consciousness, such as sleep, anesthesia, coma, vegetative state, epileptic loss of consciousness, and somnambulism. In parallel, recent functional magnetic resonance imaging studies have identified structured patterns of slow neuronal oscillations in the resting human brain. Similar coherent blood oxygen level–dependent (BOLD) systemwide patterns can also be found, in particular in the default‐mode network, in several states of unconsciousness, such as coma, anesthesia, and slow‐wave sleep. The latter results suggest that slow coherent spontaneous BOLD fluctuations cannot be exclusively a reflection of conscious mental activity, but may reflect default brain connectivity shaping brain areas of most likely interactions in a way that transcends levels of consciousness, and whose functional significance remains largely in the dark.