Light modulates task-dependent thalamo-cortical connectivity during an auditory attentional task.

Exposure to blue wavelength light stimulates alertness and performance by modulating a widespread set of task-dependent cortical and subcortical areas. How light affects the crosstalk between brain areas to trigger this stimulating effect is not established. Here we record the brain activity of 19 healthy young participants (24.05±2.63; 12 women) while they complete an auditory attentional task in darkness or under an active (blue-enriched) or a control (orange) light, in an ultra-high-field 7 Tesla MRI scanner. We test if light modulates the effective connectivity between an area of the posterior associative thalamus, encompassing the pulvinar, and the intraparietal sulcus (IPS), key areas in the regulation of attention. We find that only the blue-enriched light strengthens the connection from the posterior thalamus to the IPS. To the best of our knowledge, our results provide the first empirical data supporting that blue wavelength light affects ongoing non-visual cognitive activity by modulating task-dependent information flow from subcortical to cortical areas.

Comparing Neural Correlates of Consciousness: From Psychedelics to Hypnosis and Meditation.

BACKGROUND: Pharmacological and nonpharmacological methods of inducing altered states of consciousness (ASCs) are becoming increasingly relevant in the treatment of psychiatric disorders. While comparisons between them are often drawn, to date no study has directly compared their neural correlates. METHODS: To address this knowledge gap, we directly compared 2 pharmacological methods (psilocybin 0.2 mg/kg orally [n = 23] and lysergic acid diethylamide [LSD] 100 µg orally [n = 25]) and 2 nonpharmacological methods (hypnosis [n = 30] and meditation [n = 29]) using resting-state functional connectivity magnetic resonance imaging and assessed the predictive value of the data using a machine learning approach. RESULTS: We found that 1) no network reached significance in all 4 ASC methods; 2) pharmacological and nonpharmacological interventions of inducing ASCs showed distinct connectivity patterns that were predictive at the individual level; 3) hypnosis and meditation showed differences in functional connectivity when compared directly and also drove distinct differences when jointly compared with the pharmacological ASC interventions; and 4) psilocybin and LSD showed no differences in functional connectivity when directly compared with each other, but they did show distinct behavioral-neural relationships. CONCLUSIONS: Overall, these results extend our understanding of the mechanisms of action of ASCs and highlight the importance of exploring how these effects can be leveraged in the treatment of psychiatric disorders.

Neural Patterns in Linguistic Cortices Discriminate the Content of Verbal Working Memory.

An influential theoretical account of working memory (WM) considers that WM is based on direct activation of long-term memory knowledge. While there is empirical support for this position in the visual WM domain, direct evidence is scarce in the verbal WM domain. This question is critical for models of verbal WM, as the question of whether short-term maintenance of verbal information relies on direct activation within the long-term linguistic knowledge base or not is still debated. In this study, we examined the extent to which short-term maintenance of lexico-semantic knowledge relies on neural activation patterns in linguistic cortices, and this by using a fast encoding running span task for word and nonword stimuli minimizing strategic encoding mechanisms. Multivariate analyses showed specific neural patterns for the encoding and maintenance of word versus nonword stimuli. These patterns were not detectable anymore when participants were instructed to stop maintaining the memoranda. The patterns involved specific regions within the dorsal and ventral pathways, which are considered to support phonological and semantic processing to various degrees. This study provides novel evidence for a role of linguistic cortices in the representation of long-term memory linguistic knowledge during WM processing.

Cognitive brain responses during circadian wake-promotion: evidence for sleep-pressure-dependent hypothalamic activations.

The two-process model of sleep-wake regulation posits that sleep-wake-dependent homeostatic processes interact with the circadian timing system to affect human behavior. The circadian timing system is fundamental to maintaining stable cognitive performance, as it counteracts growing homeostatic sleep pressure during daytime. Using magnetic resonance imaging, we explored brain responses underlying working memory performance during the time of maximal circadian wake-promotion under varying sleep pressure conditions. Circadian wake-promoting strength was derived from the ability to sleep during an evening nap. Hypothalamic BOLD activity was positively linked to circadian wake-promoting strength under normal, but not under disproportionally high or low sleep pressure levels. Furthermore, higher hypothalamic activity under normal sleep pressure levels predicted better performance under sleep loss. Our results reappraise the two-process model by revealing a homeostatic-dose-dependent association between circadian wake-promotion and cognition-related hypothalamic activity.

Fighting Sleep at Night: Brain Correlates and Vulnerability to Sleep Loss.

OBJECTIVE: Even though wakefulness at night leads to profound performance deterioration and is regularly experienced by shift workers, its cerebral correlates remain virtually unexplored. METHODS: We assessed brain activity in young healthy adults during a vigilant attention task under high and low sleep pressure during night-time, coinciding with strongest circadian sleep drive. We examined sleep-loss-related attentional vulnerability by considering a PERIOD3 polymorphism presumably impacting on sleep homeostasis. RESULTS: Our results link higher sleep-loss-related attentional vulnerability to cortical and subcortical deactivation patterns during slow reaction times (i.e., suboptimal vigilant attention). Concomitantly, thalamic regions were progressively less recruited with time-on-task and functionally less connected to task-related and arousal-promoting brain regions in those volunteers showing higher attentional instability in their behavior. The data further suggest that the latter is linked to shifts into a task-inactive default-mode network in between task-relevant stimulus occurrence. INTERPRETATION: We provide a multifaceted view on cerebral correlates of sleep loss at night and propose that genetic predisposition entails differential cerebral coping mechanisms, potentially compromising adequate performance during night work.

Memory reactivation during rapid eye movement sleep promotes its generalization and integration in cortical stores.

STUDY OBJECTIVES: Memory reactivation appears to be a fundamental process in memory consolidation. In this study we tested the influence of memory reactivation during rapid eye movement (REM) sleep on memory performance and brain responses at retrieval in healthy human participants. PARTICIPANTS: Fifty-six healthy subjects (28 women and 28 men, age [mean ± standard deviation]: 21.6 ± 2.2 y) participated in this functional magnetic resonance imaging (fMRI) study. METHODS AND RESULTS: Auditory cues were associated with pictures of faces during their encoding. These memory cues delivered during REM sleep enhanced subsequent accurate recollections but also false recognitions. These results suggest that reactivated memories interacted with semantically related representations, and induced new creative associations, which subsequently reduced the distinction between new and previously encoded exemplars. Cues had no effect if presented during stage 2 sleep, or if they were not associated with faces during encoding. Functional magnetic resonance imaging revealed that following exposure to conditioned cues during REM sleep, responses to faces during retrieval were enhanced both in a visual area and in a cortical region of multisensory (auditory-visual) convergence. CONCLUSIONS: These results show that reactivating memories during REM sleep enhances cortical responses during retrieval, suggesting the integration of recent memories within cortical circuits, favoring the generalization and schematization of the information.

Biased binomial assessment of cross-validated estimation of classification accuracies illustrated in diagnosis predictions.

Multivariate classification is used in neuroimaging studies to infer brain activation or in medical applications to infer diagnosis. Their results are often assessed through either a binomial or a permutation test. Here, we simulated classification results of generated random data to assess the influence of the cross-validation scheme on the significance of results. Distributions built from classification of random data with cross-validation did not follow the binomial distribution. The binomial test is therefore not adapted. On the contrary, the permutation test was unaffected by the cross-validation scheme. The influence of the cross-validation was further illustrated on real-data from a brain-computer interface experiment in patients with disorders of consciousness and from an fMRI study on patients with Parkinson disease. Three out of 16 patients with disorders of consciousness had significant accuracy on binomial testing, but only one showed significant accuracy using permutation testing. In the fMRI experiment, the mental imagery of gait could discriminate significantly between idiopathic Parkinson's disease patients and healthy subjects according to the permutation test but not according to the binomial test. Hence, binomial testing could lead to biased estimation of significance and false positive or negative results. In our view, permutation testing is thus recommended for clinical application of classification with cross-validation.

Changes in effective connectivity by propofol sedation.

Mechanisms of propofol-induced loss of consciousness remain poorly understood. Recent fMRI studies have shown decreases in functional connectivity during unconsciousness induced by this anesthetic agent. Functional connectivity does not provide information of directional changes in the dynamics observed during unconsciousness. The aim of the present study was to investigate, in healthy humans during an auditory task, the changes in effective connectivity resulting from propofol induced loss of consciousness. We used Dynamic Causal Modeling for fMRI (fMRI-DCM) to assess how causal connectivity is influenced by the anesthetic agent in the auditory system. Our results suggest that the dynamic observed in the auditory system during unconsciousness induced by propofol, can result in a mixture of two effects: a local inhibitory connectivity increase and a decrease in the effective connectivity in sensory cortices.

Impact of blindness onset on the functional organization and the connectivity of the occipital cortex.

Contrasting the impact of congenital versus late-onset acquired blindness provides a unique model to probe how experience at different developmental periods shapes the functional organization of the occipital cortex. We used functional magnetic resonance imaging to characterize brain activations of congenitally blind, late-onset blind and two groups of sighted control individuals while they processed either the pitch or the spatial attributes of sounds. Whereas both blind groups recruited occipital regions for sound processing, activity in bilateral cuneus was only apparent in the congenitally blind, highlighting the existence of region-specific critical periods for crossmodal plasticity. Most importantly, the preferential activation of the right dorsal stream (middle occipital gyrus and cuneus) for the spatial processing of sounds was only observed in the congenitally blind. This demonstrates that vision has to be lost during an early sensitive period in order to transfer its functional specialization for space processing toward a non-visual modality. We then used a combination of dynamic causal modelling with Bayesian model selection to demonstrate that auditory-driven activity in primary visual cortex is better explained by direct connections with primary auditory cortex in the congenitally blind whereas it relies more on feedback inputs from parietal regions in the late-onset blind group. Taken together, these results demonstrate the crucial role of the developmental period of visual deprivation in (re)shaping the functional architecture and the connectivity of the occipital cortex. Such findings are clinically important now that a growing number of medical interventions may restore vision after a period of visual deprivation.

Blue light stimulates cognitive brain activity in visually blind individuals.

Light regulates multiple non-image-forming (or nonvisual) circadian, neuroendocrine, and neurobehavioral functions, via outputs from intrinsically photosensitive retinal ganglion cells (ipRGCs). Exposure to light directly enhances alertness and performance, so light is an important regulator of wakefulness and cognition. The roles of rods, cones, and ipRGCs in the impact of light on cognitive brain functions remain unclear, however. A small percentage of blind individuals retain non-image-forming photoreception and offer a unique opportunity to investigate light impacts in the absence of conscious vision, presumably through ipRGCs. Here, we show that three such patients were able to choose nonrandomly about the presence of light despite their complete lack of sight. Furthermore, 2 sec of blue light modified EEG activity when administered simultaneously to auditory stimulations. fMRI further showed that, during an auditory working memory task, less than a minute of blue light triggered the recruitment of supplemental prefrontal and thalamic brain regions involved in alertness and cognition regulation as well as key areas of the default mode network. These results, which have to be considered as a proof of concept, show that non-image-forming photoreception triggers some awareness for light and can have a more rapid impact on human cognition than previously understood, if brain processing is actively engaged. Furthermore, light stimulates higher cognitive brain activity, independently of vision, and engages supplemental brain areas to perform an ongoing cognitive process. To our knowledge, our results constitute the first indication that ipRGC signaling may rapidly affect fundamental cerebral organization, so that it could potentially participate to the regulation of numerous aspects of human brain function.

Decoding semi-constrained brain activity from FMRI using support vector machines and gaussian processes.

Predicting a particular cognitive state from a specific pattern of fMRI voxel values is still a methodological challenge. Decoding brain activity is usually performed in highly controlled experimental paradigms characterized by a series of distinct states induced by a temporally constrained experimental design. In more realistic conditions, the number, sequence and duration of mental states are unpredictably generated by the individual, resulting in complex and imbalanced fMRI data sets. This study tests the classification of brain activity, acquired on 16 volunteers using fMRI, during mental imagery, a condition in which the number and duration of mental events were not externally imposed but self-generated. To deal with these issues, two classification techniques were considered (Support Vector Machines, SVM, and Gaussian Processes, GP), as well as different feature extraction methods (General Linear Model, GLM and SVM). These techniques were combined in order to identify the procedures leading to the highest accuracy measures. Our results showed that 12 data sets out of 16 could be significantly modeled by either SVM or GP. Model accuracies tended to be related to the degree of imbalance between classes and to task performance of the volunteers. We also conclude that the GP technique tends to be more robust than SVM to model unbalanced data sets.

Influence of acute sleep loss on the neural correlates of alerting, orientating and executive attention components.

The Attention Network Test (ANT) is deemed to assess the alerting, orientating and executive components of human attention. Capitalizing on the opportunity to investigate three facets of attention in a single task, we used functional magnetic resonance imaging (fMRI) to assess the effect of sleep deprivation (SD) on brain responses associated with the three attentional components elicited by the ANT. Twelve healthy volunteers were scanned in two conditions 1 week apart, after a normal night of sleep (rested wakefulness, RW) or after one night of total sleep deprivation. Sleep deprivation was associated with a global increase in reaction times, which did not affect specifically any of the three attention effects. Brain responses associated with the alerting effect did not differ between RW and SD. Higher-order attention components (orientating and conflict effects) were associated with significantly larger thalamic responses during SD than during RW. These results suggest that SD influences different components of human attention non-selectively, through mechanisms that might either affect centrencephalic structures maintaining vigilance or ubiquitously perturb neuronal function. Compensatory responses can counter these effects transiently by recruiting thalamic responses, thereby supporting thalamocortical function.

Homeostatic sleep pressure and responses to sustained attention in the suprachiasmatic area.

Throughout the day, cognitive performance is under the combined influence of circadian processes and homeostatic sleep pressure. Some people perform best in the morning, whereas others are more alert in the evening. These chronotypes provide a unique way to study the effects of sleep-wake regulation on the cerebral mechanisms supporting cognition. Using functional magnetic resonance imaging in extreme chronotypes, we found that maintaining attention in the evening was associated with higher activity in evening than morning chronotypes in a region of the locus coeruleus and in a suprachiasmatic area (SCA) including the circadian master clock. Activity in the SCA decreased with increasing homeostatic sleep pressure. This result shows the direct influence of the homeostatic and circadian interaction on the neural activity underpinning human behavior.

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.

An in computo investigation of the Landau-Kleffner syndrome.

We describe a computational model of the thalamus and the cortex able to reproduce some essential epileptiform features commonly observed in the Landau-Kleffner syndrome. Investigation with this realistic model leads us to the formulation of a cellular mechanism that could be responsible for the epileptic discharges occuring with this severe syndrome. Understanding this mechanism is of prime importance for developing new therapeutical strategies.

Daytime light exposure dynamically enhances brain responses.

In humans, light enhances both alertness and performance during nighttime and daytime [1-4] and influences regional brain function [5]. These effects do not correspond to classical visual responses but involve a non-image forming (NIF) system, which elicits greater endocrine, physiological, neurophysiological, and behavioral responses to shorter light wavelengths than to wavelengths geared toward the visual system [6-11]. During daytime, the neural changes induced by light exposure, and their time courses, are largely unknown. With functional magnetic resonance imaging (fMRI), we characterized the neural correlates of the alerting effect of daytime light by assessing the responses to an auditory oddball task [12-15], before and after a short exposure to a bright white light. Light-induced improvement in subjective alertness was linearly related to responses in the posterior thalamus. In addition, light enhanced responses in a set of cortical areas supporting attentional oddball effects, and it prevented decreases of activity otherwise observed during continuous darkness. Responses to light were remarkably dynamic. They declined within minutes after the end of the light stimulus, following various region-specific time courses. These findings suggest that light can modulate activity of subcortical structures involved in alertness, thereby dynamically promoting cortical activity in networks involved in ongoing nonvisual cognitive processes.

Cerebral correlates of delta waves during non-REM sleep revisited.

We aimed at characterizing the neural correlates of delta activity during Non Rapid Eye Movement (NREM) sleep in non-sleep-deprived normal young adults, based on the statistical analysis of a positron emission tomography (PET) sleep data set. One hundred fifteen PET scans were obtained using H(2)(15)O under continuous polygraphic monitoring during stages 2-4 of NREM sleep. Correlations between regional cerebral blood flow (rCBF) and delta power (1.5-4 Hz) spectral density were analyzed using statistical parametric mapping (SPM2). Delta power values obtained at central scalp locations negatively correlated during NREM sleep with rCBF in the ventromedial prefrontal cortex, the basal forebrain, the striatum, the anterior insula, and the precuneus. These regions embrace the set of brain areas in which rCBF decreases during slow wave sleep (SWS) as compared to Rapid Eye Movement (REM) sleep and wakefulness (Maquet, P., Degueldre, C., Delfiore, G., Aerts, J., Peters, J.M., Luxen, A., Franck, G., 1997. Functional neuroanatomy of human slow wave sleep. J. Neurosci. 17, 2807-S2812), supporting the notion that delta activity is a valuable prominent feature of NREM sleep. A strong association was observed between rCBF in the ventromedial prefrontal regions and delta power, in agreement with electrophysiological studies. In contrast to the results of a previous PET study investigating the brain correlates of delta activity (Hofle, N., Paus, T., Reutens, D., Fiset, P., Gotman, J., Evans, A.C., Jones, B.E., 1997. Regional cerebral blood flow changes as a function of delta and spindle activity during slow wave sleep in humans. J. Neurosci. 17, 4800-4808), in which waking scans were mixed with NREM sleep scans, no correlation was found with thalamus activity. This latter result stresses the importance of an extra-thalamic delta rhythm among the synchronous NREM sleep oscillations. Consequently, this rCBF distribution might preferentially reflect a particular modulation of the cellular processes involved in the generation of cortical delta waves during NREM sleep.

Increased cerebral functional connectivity underlying the antinociceptive effects of hypnosis.

The neural mechanisms underlying the antinociceptive effects of hypnosis are not well understood. Using positron emission tomography (PET), we recently showed that the activity in the anterior cingulate cortex (midcingulate area 24a') covaries with the hypnosis-induced reduction of affective and sensory responses to noxious thermal stimulation [Faymonville et al., Anesthesiology 92 (2000) 1257-1267]. In the present study, we assessed changes in cerebral functional connectivity related to the hypnotic state, compared to simple distraction and the resting state. Nineteen highly hypnotizable right-handed volunteers were studied using H2(15)O-PET. The experimental conditions were hot noxious or warm non-noxious stimulation of the right hand during resting state, mental imagery and hypnotic state. Using a psychophysiological interaction analysis, we identified brain areas that would respond to noxious stimulations under the modulatory action of the midcingulate cortex in, and only in, the hypnotic state. Hypnosis, compared to the resting state, reduced pain perception by 50%. Pain perception during rest and mental imagery was not significantly different. Analysis of PET data showed that the hypnotic state, compared to normal alertness (i.e., rest and mental imagery), significantly enhanced the functional modulation between midcingulate cortex and a large neural network encompassing bilateral insula, pregenual anterior cingulate cortex, pre-supplementary motor area, right prefrontal cortex and striatum, thalamus and brainstem. These findings point to a critical role for the midcingulate cortex in the modulation of a large cortical and subcortical network underlying its influence on sensory, affective, cognitive and behavioral aspects of nociception, in the specific context of hypnosis.

Brain function in the vegetative state.

Positron emission tomography (PET) techniques represent a useful tool to better understand the residual brain function in vegetative state patients. It has been shown that overall cerebral metabolic rates for glucose are massively reduced in this condition. However, the recovery of consciousness from vegetative state is not always associated with substantial changes in global metabolism. This finding led us to hypothesize that some vegetative patients are unconscious not just because of a global loss of neuronal function, but rather due to an altered activity in some critical brain regions and to the abolished functional connections between them. We used voxel-based Statistical Parametric Mapping (SPM) approaches to characterize the functional neuroanatomy of the vegetative state. The most dysfunctional brain regions were bilateral frontal and parieto-temporal associative cortices. Despite the metabolic impairment, external stimulation still induced a significant neuronal activation (i.e., change in blood flow) in vegetative patients as shown by both auditory click stimuli and noxious somatosensory stimuli. However, this activation was limited to primary cortices and dissociated from higher-order associative cortices, thought to be necessary for conscious perception. Finally, we demonstrated that vegetative patients have impaired functional connections between distant cortical areas and between the thalami and the cortex and, more importantly, that recovery of consciousness is paralleled by a restoration of this cortico-thalamo-cortical interaction.