An integrated measure of GABA to characterize post-stroke plasticity.

peer reviewedStroke is a major cause of death and chronic neurological disability. Despite the improvements in stroke care, the number of patients affected by stroke keeps increasing and many stroke survivors are left permanently disabled. Current therapies are limited in efficacy. Understanding the neurobiological mechanisms underlying post-stroke recovery is therefore crucial to find new therapeutic options to address this medical burden. Long-lasting and widespread alterations of γ-aminobutyric acid (GABA) neurotransmission seem to play a key role in stroke recovery. In this review we first discuss a possible model of GABAergic modulation of post-stroke plasticity. We then overview the techniques currently available to non-invasively assess GABA in patients and the conclusions drawn from this limited body of work. Finally, we address the remaining open questions to clarify GABAergic changes underlying post-stroke recovery, we briefly review possible ways to modulate GABA post stroke and propose a novel approach to thoroughly quantify GABA in stroke patients, by integrating its concentration, the activity of its receptors and its link with microstructural changes

Brain correlates of perceptual switch during perception rivalry: an ultra-high field 7T functional magnetic resonance imaging study

Introduction Perceptual rivalry while viewing ambiguous stimulus leads to repetitive switches between two perceptions of the same image1. Switches are considered to recruit bottom-up and top-down attentional processes. We aimed to investigate the neural mechanisms of perceptual switch using high resolution ultra-high-field 7-Tesla MRI. Methods 35 healthy subjects (18-70y; 28 women) were recruited. FMRI (voxel size 1.4 mm³) was recorded for 10 minutes while participants viewed a Necker cube 2 (10s breaks every minute). Subjects were instructed to report switch of their perception by pressing a button. Results Perceptual switches were associated with increased activation in the bilateral intraparietal sulcus (which is involved in attention), the insula (part of the salience network), the occipital cortex (including in an area compatible with V4, involved in shape detection), the left motor cortex, and the right cerebellum (whole-brain FWE corrected p<.05) (Fig1). Conclusions We report neural substrates compatible with the top-down and bottom-up attentional processes involved in resolving perceptual rivalry. Our results further suggest that perceptual changes of ambiguous figures are associated with a widespread set of brain activation. Funding: FNRS, ULiège, FEDER, SAO-FRA, Wallonia-Brussels federation References 1. Blake R, Logothetis NK. Visual competition. Nature Reviews Neuroscience. 2002;3(1):13-21. 2. Einhäuser W, Stout J, Koch C, Carter O. Pupil dilation reflects perceptual selection and predicts subsequent stability in perceptual rivalry. Proceedings of the National Academy of Sciences. 2008;105(5):1704-1709

Pitfalls in recording BOLD signal responses to light in small hypothalamic nuclei using Ultra-High-Field 7 Tesla MRI.

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Non-visual Impacts of Light on Effective Connectivity associated to executive brain responses

peer reviewedIntroduction: Beyond vision, light have many non-visual biological effect including the stimulation of alertness and cognition. These effect are considered to be mediated mainly through the recently discovered blue-light-sensitive intrinsically photosensitive retinal ganglion cells i.e. ipRGCs (Warthen, D. M., & Provencio, 2012)⁠⁠⁠ Direct projections of ipRGCs mainly reach subcortical structures, including the hypothalamus and thalamus. However, non-visual impact of light have also been reported on the activity of cortical regions, presumably through an initial subcortical impact. Here, we assessed the impact of blue-enriched light on the connectivity of a brain network sustained the brain activity associated with an ongoing auditory executive task in healthy young adults. We anticipated that blue-enriched light would mainly affect subcortical to cortical connectivity. Method: 20 healthy participants (60% Female, 23.2±4.1 years) who met our inclusion criteria assessing both physical and mental health in addition to having regular sleep habits, were included in the study. Participants started the study protocol by a structural 7T MRI scan in which high resolution T1-weighted structural images of their brain were collected. Following a loose sleep-wake schedule (±1.5h; verified with actigraphy) for 7 days, participants came to the lab, ~2 hours before/after their habitual sleep/wake time to do a functional 7T MRI scan (GRE-EPI sequence, TR = 2340 ms, TE = 24 ms, voxel size = 1.4 × 1.4 × 1.4 mm3). Participant completed an auditory working memory task (N-back: 0-back and 2-back) under different light conditions including an active blue-enriched polychromatic light, to stimulate ipRGCs (6500K; 190, 92 and 37 melanopic Equivalent Daylight Illumination (EDI) lux) and a control monochromatic orange light (590nm; 0.2 mel EDI luc), to which ipRGCs are almost nonresponsive. Based on a standard whole-brain GLM analyses using SPM12, 3 regions significantly involved in the N-back task (p FWE whole-brain < 0.05) were isolated: a dorsoposterior part of the thalamus corresponding to the pulvinar, the Intraparietal sulcus (IPS) and Anterior insula (AI) (Figure.1) Effective connectivity among the 3 region network and the modulatory effect of different light conditions on the inter-region connections were estimated using the Dynamic Causal Modeling as part of SPM12 (Figure.2A). Effects were considered robust for posterior probably (Pp) > .95. Results: The DCM analysis indicated that only the driving inputs of the 2-back task was effective for the IPS and AI) (Pp ≥ .95). The baseline effective connectivity showed that among the connections defined in the initial model, 3 connections were robust (Pp ≥ .95). The pulvinar to IPS and pulvinar to AI connectivity were excitatory while the AI to IPS connectivity was inhibitory (Figure.2B). Evaluation of the modulatory effect of light conditions (blue-enriched and orange) revealed a significant modulation of the connections going from the pulvinar to both the IPS and AI with only blue-enriched light was significantly strengthening the two aforementioned connectivity (Pp ≥ .95) (Figure.2C). Conclusion: These results are in line with an initial impact of non-visual light on the information flow going from subcortical to cortical areas(Vandewalle et al., 2005)⁠. In the context of an executive task, blue-enriched, but not orange light, seems to affect thalamo-cortical loops. Future analyses will considered the different level of blue-enriched light

Association between locus coeruleus activity during wakefulness and sleep features

editorial reviewedIntroduction The locus coeruleus (LC) is the main source of norepinephrine (NE) in the brain and sends monosynaptic projections to most of the brain (Szabadi, 2013). It contributes to multiple processes such as cognition and arousal (Mather & Harley, 2016). The LC further contributes heavily to the transition between sleep and wakefulness, and between slow wave sleep (SWS) and rapid eye movement sleep (REMS) (Cirelli, Tononi 2005). Through the local release of NE, it governs the synchrony of brain activity and is tightly linked to the oscillatory modes found during sleep, such as sleep spindles and slow waves in animals (Eschenko et al., 2012). While the LC appears to be an important structure for sleep, only limited imaging studies evaluated whether the LC is related to sleep variability due to the difficulty of imaging such a small size nucleus in vivo (Keren et al., 2009). We aimed to investigate the link between LC activity during wakefulness and electroencephalogram (EEG) features of sleep using ultra-high-field 7-Tesla MRI. To trigger a response of the LC, we used a perceptual rivalry task. Subjects saw an ambiguous stimulus which could trigger spontaneous switches between two perceptions of the same image (Blake & Logothetis, 2002). Switches are considered to recruit bottom-up and top-down attentional processes associated with activity of the LC (Einhauser et al., 2008; Murphy et al., 2014). Methods 50 healthy volunteers, including 33 young (age: 22.27y ± 3.21y; 29 women) and 17 late middle-aged (age: 61.35y ± 5.19y; 12 women) individuals completed the protocol. They first underwent a structural 7T MRI session, which allowed collecting high-resolution whole-brain T1-weighted images as well as a sequence dedicated to acquire 6cm LC slab. The latter was used to create in the brain space of each participant an individual LC-mask. All individual LC-masks were gathered into a probabilistic LC-mask in a standardized group brain space. Following 1 week of regular sleep times, participants completed an fMRI session in the morning, 2h to 3h after wake-up time, during which they were administered the perceptual rivalry task (TR= 2.34s; voxel size 1.4x1.4x1.4 mm³). Participant’s habitual and baseline sleep was recorded in-lab under EEG to extract 4 sleep features of interest depicting some of the most canonical characteristics of sleep (i.e., cumulated power of the theta frequency band during REMS, slow wave energy (SWE), sleep onset latency, and REMS percentage). We first conducted a general linear model with the Statistical Parametric Mapping 12 package (SPM12) over the entire brain. We then extracted the activity estimates over individual LC masks and then conducted generalized linear mixed models (GLMMs) to test for associations between the activity of the LC and EEG features of sleep, including age, sex, BMI, and total sleep time as covariates. Results Perceptual switches were associated with increased activation in the left LC after controlling for age, sex, BMI, and total sleep time (whole brain FDR-corrected p 3.055) (Fig1). This supported the extraction of individual LC activity in the individual space to associate with sleep EEG metrics. GLMMs on the LC activity and sleep EEG metrics revealed a positive association between the bilateral LC activity and SWE (cumulated EEG power over the .5-4Hz frequency band) (p = 0.02, F= 5.1), which reflects SWS intensity. A similar positive association was found between the LC activity and EEG cumulated power of the theta frequency band (4-8Hz) during REMS (p = 0.03, F=4.8), which is the dominant oscillatory mode of REMS. No other significant associations were detected. Conclusions These results show that a greater LC activity during wakefulness is associated with a more intense SWS and REMS. Future analyses will consider the relationship between LC activity and sleep microstructure. Funding: FNRS Belgium, ULiège, FEDER, Alzheimer Foundation (SAO-FRA), Wallonia-Brussels federation   References Blake, R., & Logothetis, N. K. (2002). Visual competition. Nature Reviews Neuroscience, 3(1), 13–21. Einhauser, W., Stout, J., Koch, C., & Carter, O. (2008). Pupil dilation reflects perceptual selection and predicts subsequent stability in perceptual rivalry. Proceedings of the National Academy of Sciences, 105(5), 1704–1709. https://doi.org/10.1073/pnas.0707727105 Eschenko, O., Magri, C., Panzeri, S., & Sara, S. J. (2012). Noradrenergic neurons of the locus coeruleus are phase locked to cortical up-down states during sleep. Cerebral Cortex, 22(2), 426–435. https://doi.org/10.1093/cercor/bhr121 Keren, N. I., Lozar, C. T., Harris, K. C., Morgan, P. S., & Eckert, M. A. (2009). In vivo mapping of the human locus coeruleus. NeuroImage, 47(4), 1261–1267. https://doi.org/https://doi.org/10.1016/j.neuroimage.2009.06.012 Mather, M., & Harley, C. W. (2016). The Locus Coeruleus: Essential for Maintaining Cognitive Function and the Aging Brain. Trends in Cognitive Sciences, 20(3), 214–226. https://doi.org/10.1016/j.tics.2016.01.001 Murphy, P. R., O’Connell, R. G., O’Sullivan, M., Robertson, I. H., & Balsters, J. H. (2014). Pupil diameter covaries with BOLD activity in human locus coeruleus. Human Brain Mapping, 35(8), 4140–4154. https://doi.org/10.1002/hbm.22466 Scammell, T. E., Arrigoni, E., & Lipton, J. O. (2017). Neural Circuitry of Wakefulness and Sleep. Neuron, 93(4), 747–765. https://doi.org/10.1016/j.neuron.2017.01.014 Szabadi, E. (2013). Functional neuroanatomy of the central noradrenergic system. Journal of Psychopharmacology, 27(8), 659–693. https://doi.org/10.1177/026988111349032

Impact of repeated short light exposures on sustained pupil responses in an fMRI environment

Light triggers numerous non-image forming (NIF), or non-visual, biological effects. The brain correlates of these NIF effects have been investigated, notably using Magnetic Resonance Imaging (MRI) and short light exposures varying in irradiance and spectral quality. However, it is not clear whether having light in subsequent blocks may induce carry over effects of one light block onto the next, thus biasing the study. We reasoned that pupil light reflex (PLR) was an easy readout of one of the NIF effects of light that could be used to address this issue. We characterized the sustained PLR in 13 to 16 healthy young individuals under short light exposures during three distinct cognitive processes (executive, emotional and attentional). Light conditions pseudo-randomly alternated between monochromatic orange light [0.16 melanopic Equivalent Daylight Illuminance (mel EDI) lux] and polychromatic blue-enriched white light of three different levels [37, 92, 190 mel EDI lux]. As expected, higher melanopic irradiance was associated with larger sustained PLR in each cognitive domain. This result was stable over the light block sequence under higher melanopic irradiance levels as compared to lower ones. Exploratory frequency-domain analyses further revealed that PLR was more variable within a light block under lower melanopic irradiance levels. Importantly, PLR varied across tasks independently of the light condition pointing to a potential impact of the light history and/or cognitive context on PLR. Together, our results emphasize that the distinct contribution and adaptation of the different retinal photoreceptors influence the NIF effects of light and therefore potentially their brain correlates

Impact of repeated short light exposures on sustained pupil responses in an fMRI environment.

peer reviewedLight triggers numerous non-image-forming, or non-visual, biological effects. The brain correlates of these non-image-forming effects have been investigated, notably using magnetic resonance imaging and short light exposures varying in irradiance and spectral quality. However, it is not clear whether non-image-forming responses estimation may be biased by having light in sequential blocks, for example, through a potential carryover effect of one light onto the next. We reasoned that pupil light reflex was an easy readout of one of the non-image-forming effects of light that could be used to address this issue. We characterised the sustained pupil light reflex in 13-16 healthy young individuals under short light exposures during three distinct cognitive processes (executive, emotional and attentional). Light conditions pseudo-randomly alternated between monochromatic orange light (0.16 melanopic equivalent daylight illuminance lux) and polychromatic blue-enriched white light of three different levels (37, 92, 190 melanopic equivalent daylight illuminance lux). As expected, higher melanopic irradiance was associated with larger sustained pupil light reflex in each cognitive domain. This result was stable over the light sequence under higher melanopic irradiance levels compared with lower ones. Exploratory frequency-domain analyses further revealed that sustained pupil light reflex was more variable under lower melanopic irradiance levels. Importantly, sustained pupil light reflex varied across tasks independently of the light condition, pointing to a potential impact of light history and/or cognitive context on sustained pupil light reflex. Together, our results emphasise that the distinct contribution and adaptation of the different retinal photoreceptors influence the non-image-forming effects of light and therefore potentially their brain correlates

Regional response to light illuminance across the human hypothalamus

peer reviewedLight exerts multiple non-image-forming biological effects on physiology including the stimulation of alertness and cognition. However, the subcortical circuitry underlying the stimulating impact of light is not established in humans. We used 7 Tesla functional magnetic resonance imaging to assess the impact of variations in light illuminance on the regional activity of the hypothalamus while healthy young adults (N=26; 16 women; 24.3 ± 2.9y) were completing two auditory cognitive tasks. We find that, during both the executive and emotional tasks, higher illuminance triggered an activity increase over the posterior part of the hypothalamus, which includes part of the tuberomamillary nucleus and the posterior part of the lateral hypothalamus. In contrast, increasing illuminance evoked a decrease in activity over the anterior and ventral parts of the hypothalamus, encompassing notably the suprachiasmatic nucleus and another part of the tuberomammillary nucleus. Critically, performance of the executive task was improved under higher illuminance and was negatively correlated with the activity of the posterior hypothalamus area. These findings reveal the distinct local dynamics of different hypothalamus regions that underlie the impact of light on cognition. They may suggest that light acts on the orexin and histamine system to affect the quality of wakefulness

Psycho-social factors associated with mental resilience in the Corona lockdown.

The SARS-CoV-2 pandemic is not only a threat to physical health but is also having severe impacts on mental health. Although increases in stress-related symptomatology and other adverse psycho-social outcomes, as well as their most important risk factors have been described, hardly anything is known about potential protective factors. Resilience refers to the maintenance of mental health despite adversity. To gain mechanistic insights about the relationship between described psycho-social resilience factors and resilience specifically in the current crisis, we assessed resilience factors, exposure to Corona crisis-specific and general stressors, as well as internalizing symptoms in a cross-sectional online survey conducted in 24 languages during the most intense phase of the lockdown in Europe (22 March to 19 April) in a convenience sample of N = 15,970 adults. Resilience, as an outcome, was conceptualized as good mental health despite stressor exposure and measured as the inverse residual between actual and predicted symptom total score. Preregistered hypotheses (osf.io/r6btn) were tested with multiple regression models and mediation analyses. Results confirmed our primary hypothesis that positive appraisal style (PAS) is positively associated with resilience (p < 0.0001). The resilience factor PAS also partly mediated the positive association between perceived social support and resilience, and its association with resilience was in turn partly mediated by the ability to easily recover from stress (both p < 0.0001). In comparison with other resilience factors, good stress response recovery and positive appraisal specifically of the consequences of the Corona crisis were the strongest factors. Preregistered exploratory subgroup analyses (osf.io/thka9) showed that all tested resilience factors generalize across major socio-demographic categories. This research identifies modifiable protective factors that can be targeted by public mental health efforts in this and in future pandemics

Social chunking in working memory

Working memory (WM) uses knowledge and relations to organize and store multiple individual items in a smaller set of structured units, or chunks. We investigated whether a crowd of individuals that exceeds the WM is retained and, therefore, recognized more accurately, if individuals are represented as interacting with one another –i.e., they form social chunks. Further, we asked what counts as a social chunk in WM: two individuals involved in a meaningful interaction or just spatially close and face-to-face. In three experiments with a delayed change-detection task, participants had to report whether a probe-array was the same of, or different from a sample-array featuring two or three dyads of bodies either face-to-face (facing array) or back-to-back (non-facing array). In Experiment 1, where facing dyads depicted coherent, meaningful interactions, participants were more accurate to detect changes in facing (vs. non-facing) arrays. A similar advantage was found in Experiment 2, even though facing dyads depicted no meaningful interaction. In Experiment 3, we introduced a secondary task (verbal shadowing) to increase WM load. This manipulation abolished the advantage of facing (vs. non-facing) arrays, only when facing dyads depicted no meaningful interactions. These results show that WM uses representation of interaction to chunk crowds in social groups. The mere facingness of bodies is sufficient on its own to evoke representation of interaction, thus defining a social chunk in WM; although the lack of semantic anchor makes chunking fainter and more susceptible to interference of a secondary tas