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.

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.

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.

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.

Abnormal hypothalamic response to light in seasonal affective disorder.

BACKGROUND: Vulnerability to the reduction in natural light associated with fall/winter is generally accepted as the main trigger of seasonal affective disorder (SAD), whereas light therapy is a treatment of choice of the disorder. However, the relationship between exposure to light and mood regulation remains unclear. As compared with green light, blue light was shown to acutely modulate emotion brain processing in healthy individuals. Here, we investigated the impact of light on emotion brain processing in patients with SAD and healthy control subjects and its relationship with retinal light sensitivity. METHODS: Fourteen symptomatic untreated patients with SAD (34.5 ± 8.2 years; 9 women) and 16 healthy control subjects (32.3 ± 7.7 years; 11 women) performed an auditory emotional task in functional magnetic resonance imaging during the fall/winter season, while being exposed to alternating blue and green monochromatic light. Scotopic and photopic retinal light sensitivities were then evaluated with electroretinography. RESULTS: Blue light enhanced responses to auditory emotional stimuli in the posterior hypothalamus in patients with SAD, whereas green light decreased these responses. These effects of blue and green light were not observed in healthy control subjects, despite similar retinal sensitivity in SAD and control subjects. CONCLUSIONS: These results point to the posterior hypothalamus as the neurobiological substrate involved in specific aspects of SAD, including a distinctive response to light and altered emotional responses.

The commonality of neural networks for verbal and visual short-term memory.

Although many neuroimaging studies have considered verbal and visual short-term memory (STM) as relying on neurally segregated short-term buffer systems, the present study explored the existence of shared neural correlates supporting verbal and visual STM. We hypothesized that networks involved in attentional and executive processes, as well as networks involved in serial order processing, underlie STM for both verbal and visual list information, with neural specificity restricted to sensory areas involved in processing the specific items to be retained. Participants were presented sequences of nonwords or unfamiliar faces, and were instructed to maintain and recognize order or item information. For encoding and retrieval phases, null conjunction analysis revealed an identical fronto-parieto-cerebellar network comprising the left intraparietal sulcus, bilateral dorsolateral prefrontal cortex, and the bilateral cerebellum, irrespective of information type and modality. A network centered around the right intraparietal sulcus supported STM for order information, in both verbal and visual modalities. Modality-specific effects were observed in left superior temporal and mid-fusiform areas associated with phonological and orthographic processing during the verbal STM tasks, and in right hippocampal and fusiform face processing areas during the visual STM tasks, wherein these modality effects were most pronounced when storing item information. The present results suggest that STM emerges from the deployment of modality-independent attentional and serial ordering processes toward sensory networks underlying the processing and storage of modality-specific item information.

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.

Perspective taking to assess self-personality: what's modified in Alzheimer's disease?

Personality changes are frequently described by caregivers of patients with Alzheimer's disease, while they are less often reported by the patients. This relative anosognosia of Alzheimer disease (AD) patients for personality changes might be related to impaired self-judgment and to decreased ability to understand their caregiver's perspective. To investigate this issue, we explored the cerebral correlates of self-assessment and perspective taking in patients with mild AD, elderly and young volunteers. All subjects assessed relevance of personality traits adjectives for self and a relative, taking either their own or their relative's perspective, during a functional imaging experiment. The comparison of subject's and relative's answers provided congruency scores used to assess self-judgment and perspective taking performance. The self-judgment "accuracy" score was diminished in AD, and when patients assessed adjectives for self-relevance, they predominantly activated bilateral intraparietal sulci (IPS). Previous studies associated IPS activation with familiarity judgment, which AD patients would use more than recollection when retrieving information to assess self-personality. When taking a third-person perspective, patients activated prefrontal regions (similarly to young volunteers), while elderly controls recruited visual associative areas (also activated by young volunteers). This suggests that mild AD patients relied more on reasoning processes than on visual imagery of autobiographical memories to take their relative's perspective. This strategy may help AD patients to cope with episodic memory impairment even if it does not prevent them from making some mind-reading errors.

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 processing of auditory and noxious stimuli in severely brain injured patients: differences between VS and MCS.

We review cerebral processing of auditory and noxious stimuli in minimally conscious state (MCS) and vegetative state (VS) patients. In contrast with limited brain activation found in VS patients, MCS patients show activation similar to controls in response to auditory, emotional and noxious stimuli. Despite an apparent clinical similarity between MCS and VS patients, functional imaging data show striking differences in cortical segregation and integration between these two conditions. However, in the absence of a generally accepted neural correlate of consciousness as measured by functional neuroimaging, clinical assessment remains the gold standard for the evaluation and management of severely brain damaged patients.

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.

Nonvisual responses to light exposure in the human brain during the circadian night.

The brain processes light information to visually represent the environment but also to detect changes in ambient light level. The latter information induces non-image-forming responses and exerts powerful effects on physiology such as synchronization of the circadian clock and suppression of melatonin. In rodents, irradiance information is transduced from a discrete subset of photosensitive retinal ganglion cells via the retinohypothalamic tract to various hypothalamic and brainstem regulatory structures including the hypothalamic suprachiasmatic nuclei, the master circadian pacemaker. In humans, light also acutely modulates alertness, but the cerebral correlates of this effect are unknown. We assessed regional cerebral blood flow in 13 subjects attending to auditory and visual stimuli in near darkness following light exposures (>8000 lux) of different durations (0.5, 17, 16.5, and 0 min) during the biological night. The bright broadband polychromatic light suppressed melatonin and enhanced alertness. Functional imaging revealed that a large-scale occipito-parietal attention network, including the right intraparietal sulcus, was more active in proportion to the duration of light exposures preceding the scans. Activity in the hypothalamus decreased in proportion to previous illumination. These findings have important implications for understanding the effects of light on human behavior.

Auditory processing in severely brain injured patients: differences between the minimally conscious state and the persistent vegetative state.

BACKGROUND: The minimally conscious state (MCS) is a recently defined clinical condition; it differs from the persistent vegetative state (PVS) by the presence of inconsistent, but clearly discernible, behavioral evidence of consciousness. OBJECTIVE: To study auditory processing among patients who are in an MCS, patients who are in a PVS, and healthy control subjects. METHODS: By means of (15)O-radiolabeled water-positron emission tomography, we measured changes in regional cerebral blood flow induced by auditory click stimuli in 5 patients in an MCS, 15 patients in a PVS, and 18 healthy controls. RESULTS: In both patients in an MCS and the healthy controls, auditory stimulation activated bilateral superior temporal gyri (Brodmann areas 41, 42, and 22). In patients in a PVS, the activation was restricted to Brodmann areas 41 and 42 bilaterally. We also showed that, compared with patients in a PVS, patients in an MCS demonstrated a stronger functional connectivity between the secondary auditory cortex and temporal and prefrontal association cortices. CONCLUSIONS: Although assumptions about the level of consciousness in severely brain injured patients are difficult to make, our findings suggest that the cerebral activity observed in patients in an MCS is more likely to lead to higher-order integrative processes, thought to be necessary for the gain of conscious auditory perception.

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.

Phonological short-term memory networks following recovery from Landau and Kleffner syndrome.

Landau-Kleffner syndrome (LKS) is a rare acquired aphasia occurring in otherwise healthy children, together with spike-wave discharges predominating over superior temporal regions and activated by sleep. Although the outcome of language abilities is variable, a residual impairment in verbal short-term memory (STM) is frequent. This STM deficit might be related to the persistent dysfunction of those temporal lobe regions where epileptic discharges were observed during the active phase of the disorder. We tested this hypothesis by measuring brain activation during immediate serial recall of lists of 4 words, compared to single word repetition, using H(2) (15)O positron emission tomography (PET), in 3 LKS patients after recovery and in 14 healthy controls. The patients (TG, JPH, and DC) had shown abnormally increased or decreased glucose metabolism in left or right superior temporal gyrus (STG) at different stages during the active phase of their disease. At the time of this study, the patients were 6-10 years from the active phase of LKS. Results showed that Patients JPH and DC had impaired performance in the STM condition, whereas TG showed near normal performance. PET data showed that JPH and DC activated significantly less than controls left and right posterior STG. TG, having near normal STM performance, showed increased activity in the posterior part of the right STG. These data suggest that impaired verbal STM at late outcome of LKS might indeed be related to a persistent decrease of activity in those posterior superior temporal gyri that were involved in the epileptic focus during the active phase.

Neural correlates of "hot" and "cold" emotional processing: a multilevel approach to the functional anatomy of emotion.

The neural correlates of two hypothesized emotional processing modes, i.e., schematic and propositional modes, were investigated with positron emission tomography. Nineteen subjects performed an emotional mental imagery task while mentally repeating sentences linked to the meaning of the imagery script. In the schematic conditions, participants repeated metaphoric sentences, whereas in the propositional conditions, the sentences were explicit questions about specific emotional appraisals of the imagery scenario. Five types of emotional scripts were proposed to the subjects (happiness, anger, affection, sadness, and a neutral scenario). The results supported the hypothesized distinction between schematic and propositional emotional processing modes. Specifically, schematic mode was associated with increased activity in the ventromedial prefrontal cortex whereas propositional mode was associated with activation of the anterolateral prefrontal cortex. In addition, interaction analyses showed that schematic versus propositional processing of happiness (compared with the neutral scenario) was associated with increased activity in the ventral striatum whereas "schematic anger" was tentatively associated with activation of the ventral pallidum.

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.