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

Ultra high-field MRI indications that exposure to blue enriched light increases attention brain responses during an oddball task

With the discovery of a new, non-rod, non-cone, photoreceptor, new research shows that natural and artificial light regimes have the potential to weaken and strengthen cognition, attention and perception. These effects are mediated in part by melanopsin-expressing light-sensitive ganglion cells that, in contrast to the classical photopic system that is maximally sensitive to green light (550 nm), is very sensitive to blue light (470--480 nm). These photoreceptors not only stimulate alertness, attention, vitality, and cognitive performance, but they also influence our biological clock, sleep, thermoregulation and hormonal processes. Using high resolution ultra-high field (7T) functional magnetic resonance imaging (fMRI), we characterized the neural correlates of the alerting effect of light by assessing the reposes to an auditory oddball task. Twenty healthy young subjects (22.95y ± 2.1 women) were requested to detect rare (20%) deviant tones (100Hz) among more frequent (80%) standard (500 Hz) ones by pressing a button with their right index. In this task, participants were exposed to 30s blocks of blue enriched light (4,000K; 3 intensities: 63, 155, 308 melanopic EDI lux) and orange monochromatic light (589nm; .2 melanopic EDI lux) interleaved by ~15s dark periods. Like many previous studies have reported, there have been activations of temporal, parietal, thalamus, intraparietal sulcus (IPS) and occipital lobes (uncorrected p<.001) during oddball task. There was increased activation in the left IPS and thalamus, under blue light in comparison to orange light (p=0.001 uncorrected). This is in line with other studies that report increased activation in cortical and subcortical regions related to attention as thalamus and IPS under blue light. These preliminary results will be confirmed in a larger sample

Impact of light on task-evoked pupil responses during cognitive tasks

Light has many non-image-forming functions including modulation of pupil size and stimulation of alertness and cognition. Part of these non-image-forming effects may be mediated by the brainstem locus coeruleus. The processing of sensory inputs can be associated with a transient pupil dilation that is likely driven in part by the phasic activity of the locus coeruleus. In the present study, we aimed to characterise the task-evoked pupil response associated with auditory inputs under different light levels and across two cognitive tasks. We continuously monitored the pupil of 20 young healthy participants (mean [SD] 24.05?[4.0]?years; 14 women) whilst they completed an attentional and an emotional auditory task whilst exposed to repeated 30-40-s blocks of light interleaved with darkness periods. Blocks could either consist of monochromatic orange light (0.16?melanopic equivalent daylight illuminance (EDI) lux) or blue-enriched white light of three different levels [37, 92, 190?melanopic EDI lux; 6500?K]. For the analysis, 15 and then 14 participants were included in the attentional and emotional tasks, respectively. Generalised linear mixed models showed a significant main effect of light level on the task-evoked pupil responses triggered by the attentional and emotional tasks (p?=?0.0001). The impact of light was different for the target versus non-target stimulus of the attentional task but was not different for the emotional and neutral stimulus of the emotional task. There is a smaller sustained pupil size during brighter light blocks but, a higher light level triggers a stronger task-evoked pupil response to auditory stimulation, presumably through the recruitment of the locus coeruleus