Pierre Maquet

Functional neuroimaging of normal human sleep by positron emission tomography

Functional neuroimaging using positron emission tomography has recently yielded original data on the functional neuroanatomy of human sleep. This paper attempts to describe the possibilities and limitations of the technique and clarify its usefulness in sleep research. A short overview of the methods of acquisition and statistical analysis (statistical parametric mapping, SPM) is presented before the results of PET sleep studies are reviewed. The discussion attempts to integrate the functional neuroimaging data into the body of knowledge already acquired on sleep in animals and humans using various other techniques (intracellular recordings, in situ neurophysiology, lesional and pharmacological trials, scalp EEG recordings, behavioural or psychological description). The published PET data describe a very reproducible functional neuroanatomy in sleep. The core characteristics of this ‘canonical’ sleep may be summarized as follows. In slow‐wave sleep, most deactivated areas are located in the dorsal pons and mesencephalon, cerebellum, thalami, basal ganglia, basal forebrain/hypothalamus, prefrontal cortex, anterior cingulate cortex, precuneus and in the mesial aspect of the temporal lobe. During rapid‐eye movement sleep, significant activations were found in the pontine tegmentum, thalamic nuclei, limbic areas (amygdaloid complexes, hippocampal formation, anterior cingulate cortex) and in the posterior cortices (temporo‐occipital areas). In contrast, the dorso‐lateral prefrontal cortex, parietal cortex, as well as the posterior cingulate cortex and precuneus, were the least active brain regions. These preliminary studies open up a whole field in sleep research. More detailed explorations of sleep in humans are now accessible to experimental challenges using PET and other neuroimaging techniques. These new methods will contribute to a better understanding of sleep functions.

Neural correlates of perceptual learning: A functional MRI study of visual texture discrimination

Visual texture discrimination has been shown to induce long-lasting behavioral improvement restricted to the trained eye and trained location in visual field [Karni, A. & Sagi, D. (1991) Proc. Natl. Acad. Sci. USA 88, 4966–4970]. We tested the hypothesis that such learning involves durable neural modifications at the earliest cortical stages of the visual system, where eye specificity, orientation, and location information are mapped with highest resolution. Using functional magnetic resonance imaging in humans, we measured neural activity 24 h after a single session of intensive monocular training on visual texture discrimination, performed in one visual quadrant. Within-subject comparisons between trained and untrained eye for targets presented within the same quadrant revealed higher activity in a corresponding retinotopic area of visual cortex. Functional connectivity analysis showed that these learning-dependent changes were not associated with an increased engagement of other brain areas remote from early visual cortex. We suggest that these new data are consistent with recent proposals that the cellular mechanisms underlying this type of perceptual learning may involve changes in local connections within primary visual cortex. Our findings provide a direct demonstration of learning-dependent reorganization at early processing stages in the visual cortex of adult humans.

Impaired effective cortical connectivity in vegetative state: preliminary investigation using PET.

Vegetative state (VS) is a condition of abolished awareness with persistence of arousal. Awareness is part of consciousness, which itself is thought to represent an emergent property of cerebral neural networks. Our hypothesis was that part of the neural correlate underlying VS is an altered connectivity, especially between the associative cortices. We assessed regional cerebral glucose metabolism (rCMRGlu) and effective cortical connectivity in four patients in VS by means of statistical parametric mapping and [18F]fluorodeoxyglucose-positron emission tomography. Our data showed a common pattern of impaired rCMRGlu in the prefrontal, premotor, and parietotemporal association areas and posterior cingulate cortex/precuneus in VS. In a next step, we demonstrated that in VS patients various prefrontal and premotor areas have in common that they are less tightly connected with the posterior cingulate cortex than in normal controls. These results provide a strong argument for an alteration of cortical connectivity in VS patients.

Distinct Regions of the Medial Prefrontal Cortex Are Associated with Self-referential Processing and Perspective Taking

The medial prefrontal cortex (MPFC) appears to play a prominent role in two fundamental aspects of social cognition, that is, self-referential processing and perspective taking. However, it is currently unclear whether the same or different regions of the MPFC mediate these two interdependent processes. This functional magnetic resonance imaging study sought to clarify the issue by manipulating both dimensions in a factorial design. Participants judged the extent to which trait adjectives described their own personality (e.g., Are you sociable?) or the personality of a close friend (e.g., Is Caroline sociable?) and were also asked to put themselves in the place of their friend (i.e., to take a third-person perspective) and estimate how this person would judge the adjectives, with the target of the judgments again being either the self (e.g., According to Caroline, are you sociable?) or the other person (e.g., According to Caroline, is she sociable?). We found that self-referential processing (i.e., judgments targeting the self vs. the other person) yielded activation in the ventral and dorsal anterior MPFC, whereas perspective taking (i.e., adopting the other persons perspective, rather than ones own, when making judgments) resulted in activation in the posterior dorsal MPFC; the interaction between the two dimensions yielded activation in the left dorsal MPFC. These findings show that self-referential processing and perspective taking recruit distinct regions of the MPFC and suggest that the left dorsal MPFC may be involved in decoupling ones own from other peoples perspectives on the self.

Restoration of thalamocortical connectivity after recovery from persistent vegetative state

By use of H2(15)O positron emission tomography we have shown that functional connectivity between intralaminar thalamic nuclei and prefrontal and anterior cingulate cortices was altered during vegetative state but not after recovery of consciousness.

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.

Functional connectivity in the default network during resting state is preserved in a vegetative but not in a brain dead patient

Recent studies on spontaneous fluctuations in the functional MRI blood oxygen level‐dependent (BOLD) signal in awake healthy subjects showed the presence of coherent fluctuations among functionally defined neuroanatomical networks. However, the functional significance of these spontaneous BOLD fluctuations remains poorly understood. By means of 3 T functional MRI, we demonstrate absent cortico‐thalamic BOLD functional connectivity (i.e. between posterior cingulate/precuneal cortex and medial thalamus), but preserved cortico‐cortical connectivity within the default network in a case of vegetative state (VS) studied 2.5 years following cardio‐respiratory arrest, as documented by extensive behavioral and paraclinical assessments. In the VS patient, as in age‐matched controls, anticorrelations could also be observed between posterior cingulate/precuneus and a previously identified task‐positive cortical network. Both correlations and anticorrelations were significantly reduced in VS as compared to controls. A similar approach in a brain dead patient did not show any such long‐distance functional connectivity. We conclude that some slow coherent BOLD fluctuations previously identified in healthy awake human brain can be found in alive but unaware patients, and are thus unlikely to be uniquely due to ongoing modifications of conscious thoughts. Future studies are needed to give a full characterization of default network connectivity in the VS patients population. Hum Brain Mapp, 2009.

Cerebral glucose utilization during sleep-wake cycle in man determined by positron emission tomography and [18F]2-fluoro-2-deoxy-d-glucose method

Using the [18F]fluorodeoxyglucose method and positron emission tomography, we studied cerebral glucose utilization during sleep and wakefulness in 11 young normal subjects. Each of them was studied at least thrice: during wakefulness, slow wave sleep (SWS) and rapid eye movement sleep (REMS), at 1 week intervals. Four stage 3-4 SWS and 4 REMS fulfilled the steady state conditions of the model. The control population consisted of 9 normal age-matched subjects studied twice during wakefulness at, at least, 1 week intervals. Under these conditions, the average difference between the first and the second cerebral glucose metabolic rates (CMRGlu was: -7.91 +/- 15.46%, which does not differ significantly from zero (P = 0.13). During SWS, a significant decrease in CMRGlu was observed as compared to wakefulness (mean difference: -43.80 +/- 14.10%, P less than 0.01). All brain regions were equally affected but thalamic nuclei had significantly lower glucose utilization than the average cortex. During REMS, the CMRGlu were as high as during wakefulness (mean difference: 4.30 +/- 7.40%, P = 0.35). The metabolic pattern during REMS appeared more heterogeneous than at wake. An activation of left temporal and occipital areas is suggested. It is hypothetized that energy requirements for maintaining membrane polarity are reduced during SWS because of a decreased rate of synaptic events. During REMS, cerebral glucose utilization is similar to that of wakefulness, presumably because of reactivated neurotransmission and increased need for ion gradients maintenance.

When thoughts become action: an fMRI paradigm to study volitional brain activity in non-communicative brain injured patients.

The assessment of voluntary behavior in non-communicative brain injured patients is often challenging due to the existence of profound motor impairment. In the absence of a full understanding of the neural correlates of consciousness, even a normal activation in response to passive sensory stimulation cannot be considered as proof of the presence of awareness in these patients. In contrast, predicted activation in response to the instruction to perform a mental imagery task would provide evidence of voluntary task-dependent brain activity, and hence of consciousness, in non-communicative patients. However, no data yet exist to indicate which imagery instructions would yield reliable single subject activation. The aim of the present study was to establish such a paradigm in healthy volunteers. Two exploratory experiments evaluated the reproducibility of individual brain activation elicited by four distinct mental imagery tasks. The two most robust mental imagery tasks were found to be spatial navigation and motor imagery. In a third experiment, where these two tasks were directly compared, differentiation of each task from one another and from rest periods was assessed blindly using a priori criteria and was correct for every volunteer. The spatial navigation and motor imagery tasks described here permit the identification of volitional brain activation at the single subject level, without a motor response. Volunteer as well as patient data [Owen, A.M., Coleman, M.R., Boly, M., Davis, M.H., Laureys, S., Pickard J.D., 2006. Detecting awareness in the vegetative state. Science 313, 1402] strongly suggest that this paradigm may provide a method for assessing the presence of volitional brain activity, and thus of consciousness, in non-communicative brain-injured patients.

Landau‐Kleffner Syndrome: A Clinical and EEG Study of Five Cases

Summary: : In five children with normal initial psychomotor development, a Landau‐Kleffner syndrome appeared at age 3–7 years. No neuroanatomy; lesions were noted. Aphasia and hyperkinesia were isolated in three patients and associated with global regression of higher cortical functions in one patient. Massive intellectual deterioration and psychotic behavior were associated with transient aphasia in one patient. The epilepsy (focal motor and generalized tonic‐clonic seizures, subclinical EEG focal seizures during sleep, and atypical absences) always regressed spontaneously or with antiepileptic drug (AED) treatment. The EEG in waking patients snowed focal and generalized spike‐wave discharges on a normal background rhythm. Discharge topography and pattern changed frequently. During sleep, discharges always increased. At some time during syndrome development, all patients had bilateral spike‐waves for 7gt;85% of the sleep period, while at other times the discharges were discontinuous or continuous but focal or unilaterally hemispheric. Discharge topography and abundance changed from night to night. The abnormal EEG and the impaired higher functions developed and regressed together, but not with strict temporal correlation. Our own experience suggests that the Landau‐Kleffner syndrome and epilepsy with continuous spike‐wave activity in slow‐wave sleep cannot be clearly differentiated. They may be different points on the spectrum of a single syndrome.