Dysfunction of the Locus coeruleus (LC), a small brainstem nucleus which consists of the brain's primary source of norepinephrine, is linked to various neurological and psychiatric disorders. Light exposure influences many non-image-forming (NIF) biological functions including those modulated by LC activity. Yet direct evidence of light-driven modulation of the LC has remained elusive due to the structure's small size and deep location. Using ultra-high-field (7 Tesla) functional MRI during an emotional task under varying illuminances, we demonstrate that light modulates LC activity in an emotion-dependent manner. We show that increased illuminance dampens LC responses to negative emotional stimuli while enhancing responses to neutral stimuli. Furthermore, we provide tentative evidence that within an emotional context, light may affect LC activity through the basomedial nucleus of the amygdala as well as through a region of the hypothalamus encompassing the lateral hypothalamus. These findings open avenues for the development of targeted, non-pharmacological treatments leveraging light to modulate norepinephrine tone and/or LC activity in several neuropsychiatric disorders. Significance Statement:Dysfunction of the Locus Coeruleus (LC), a small nucleus of brain and the main source of norepinephrine, is linked to various brain disorders. Here we provide in vivo evidence that exposure to light can alter the activity of the LC with higher illuminance leading to dampened LC responses to negative emotional stimuli. These findings identify the LC as a key target for the therapeutic effects of light on emotion, offering a biological framework for using light to treat neuropsychiatric disorders.

Introduction Outcomes following vagus nerve stimulation (VNS) are difficult to predict prior to surgery in pediatric drug-resistant epilepsy (DRE). We investigated whether structural brain differences among children may explain variability in VNS response. Methods A pediatric-specific brain-age model was developed using structural MRI from 2,623 healthy individuals aged 1.9 to 90 years, capturing nonlinear neurodevelopmental trajectories. Model accuracy was evaluated using cross-validation and independent validation in a pediatric cohort. The model was then applied to a multicenter cohort of 126 children with DRE treated with VNS. Results The brain-age model demonstrated high accuracy (R2 = 0.93; mean absolute error = 3.5 years) and generalized well to an independent pediatric cohort (mean absolute error = 2.16 years). Applied to the VNS cohort, it revealed significantly elevated brain-age gaps (BrainAGEgap) compared to age- and sex-matched controls (t = 6.27, p < 0.0001), indicating cumulative structural divergence from age-referenced norms. BrainAGEgap correlated with baseline seizure burden and postoperative changes in seizure frequency. Lower pre-surgical BrainAGEgap predicted a significantly higher likelihood of becoming a clinical responder to VNS (p = 0.01). Local age within the cingulate cortex, thalamus, nucleus accumbens, and prefrontal cortex contributed disproportionately to BrainAGEgap differences, aligning with VNS-related circuitry. Conclusion Developmental structural differences can be summarized using a robust, single-metric biomarker that reflects both disease burden and treatment responsiveness. BrainAGEgap may support individualized prognostic assessment and improve clinical decision-making in pediatric DRE undergoing neuromodulation.

Objective Although vagus nerve stimulation (VNS) is the most common implantable therapy for drug-resistant epilepsy (DRE), there is a need to develop novel methods to predict treatment response before surgery. An integrated approach combining structural and functional neuroimaging data to infer biophysical brain features at the mesoscopic scale could provide insights into brain-network differences related to response. The Virtual Brain (TVB) offers a computational framework to simulate individual subject brain dynamics using biophysical neural mass models to estimate synaptic transmission properties in the brain. This study aims to (i) assess the ability of TVB-based modeling to capture individual brain dynamics in pediatric DRE, (ii) evaluate the relationship between predictability of brain dynamics using a biophysical approach and VNS outcome, and (iii) identify regional inhibitory features as potential biomarkers of VNS response. Materials and Methods Preimplantation functional and diffusion magnetic resonance imaging data were acquired and used to construct personalized virtual brains using the reduced Wong-Wang model. The model was optimized for individual participants, and both local and global parameters of the models were compared between responders and nonresponders to VNS. Results A total of 38 children with DRE undergoing VNS implantation were included in this multicenter study, including 16 responders and 22 nonresponders. Predictability of the functional connectivity using the biophysical model was significantly lower in nonresponders, implicating atypical brain dynamics in VNS outcomes. TVB simulations showed stronger inhibitory synaptic weights in critical regions of the vagal afferent network in responders compared with nonresponders, including the thalamus, cingulate, and frontal cortices. Conclusions This study constitutes the first work exploring TVB in pediatric DRE and VNS. Personalized brain dynamics simulations revealed distinct inhibitory patterns between responders and nonresponders, offering new insights into the interindividual variability in VNS outcomes and mechanisms of action of VNS therapy.

Animal studies established that the locus coeruleus (LC) plays important roles in sleep and wakefulness regulation. Whether it contributes to sleep variability in humans is not yet established. Here, we investigated if the in vivo activity of the LC is related to the variability in the quality of Rapid Eye Movement (REM) sleep. We assessed the LC activity of 34 healthy younger ( 22y) and 18 older ( 61y) individuals engaged in bottom-up and top-down cognitive tasks using 7-Tesla functional Magnetic Resonance Imaging (fMRI). We further recorded their sleep electroencephalogram (EEG) to evaluate associations between LC fMRI measures and REM sleep EEG metrics. Theta oscillation energy during REM sleep was positively associated with LC response in the top-down task. In contrast, REM sleep theta energy was negatively associated with LC activity in older individuals during the bottom-up task. Importantly, sigma oscillations power immediately preceding a REM sleep episode was positively associated with LC activity in the top-down task. LC activity during wakefulness was related to REM sleep intensity and to a transient EEG change preceding REM sleep, a feature causally related to LC activity in animal studies. The associations depend on the cognitive task, suggesting that a balanced level of LC tonic activity during wakefulness is required for optimal expression of REM sleep. The findings may have implications for the high prevalence of sleep complaints reported in aging and for disorders such as insomnia, Alzheimer’s, and Parkinson’s disease, for which the LC may play pivotal roles through sleep.

OBJECTIVE:Although vagus nerve stimulation (VNS) is a well-established neuromodulation therapy for drug-resistant epilepsy, treatment outcomes remain heterogeneous. One possible source of variability lies in differing interpretations of seizure frequency ratings (SFRs). This study examined interrater reliability (IRR) in SFRs between (1) retrospective clinician-clinician chart reviews and (2) prospective caregiver-clinician reports, and explored sources of disagreement. METHODS:Data were collected from the CONNECTiVOS database. In the retrospective cohort (n = 254), two clinicians independently reviewed medical records and rated seizure frequency across multiple timepoints. In the prospective cohort (n = 214), caregivers and clinicians independently reported SFR in children treated with VNS. IRR was assessed across different measurement thresholds, and potential causes of disagreement were analyzed. RESULTS:Clinician-clinician agreement in retrospective chart reviews was excellent (intraclass correlation coefficient [ICC] > .90, Cohen κ > .80), with 18.8% divergent ratings and 4.8% exceeding the reliable change index. Disagreement was significantly associated with higher mean seizure frequency at baseline (p = .004) and at postoperative timepoints (p < .001). In the prospective caregiver-clinician comparison, agreement for absolute seizure frequency was poor (ICC < .50), with discrepancies in 86.5% of cases, although only 1.8% were statistically significant. When rating pairs diverged, clinicians more often reported lower absolute seizure frequencies (p = .002) and greater relative seizure reductions (p = .023) and were more likely to classify patients as achieving a 90% reduction (p = .043). SIGNIFICANCE:This study highlights interrater variability in both retrospective and prospective SFR assessments, a finding systematically related to baseline seizure frequency. Coarser classifications (e.g., 50% or 90% seizure reduction) may improve agreement but reduce clinical nuance. Future efforts should focus on structured, patient-centered documentation and the development of objective outcome measures in VNS evaluation, particularly for children with high seizure burden.

Background Light can influence several non-image-forming biological effects including the modulation of mood and emotional processing through neural circuitry that remains to be fully established. Rodent data showed that nuclei the amygdala, known to be important to mood regulation and emotional processing, receive direct inputs from the retina and mediate part of the affective impact of light. Here, we wanted to assess whether these animal findings translate to human beings. We determine the dynamics of the impact of light exposure on the activity of the amygdala, and whether the dynamics varied across its volume, during the processing of emotional stimulation. Methods We used 7 Tesla functional magnetic resonance imaging to assess the impact of variations in light illuminance on the regional activity of the amygdala in healthy young adults (N = 29; 18 women; 24 ± 3.1y) during an auditory emotional task. Results We find that several subregions of the amygdala, including the medial nucleus that receives direct retinal projection, showed a marked and linear reduction of activity with increasing illuminance when processing emotionally charged stimuli. Conclusion We speculate that it is through the medial nucleus that light affects the emotional state of healthy individuals. These findings shed more light on the mechanisms that underlie the biological impact of light on the brain and may contribute to the benefits of light therapy in the treatment of mood disorders. ### Competing Interest Statement The authors have declared no competing interest.

Light 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±2.9 y) 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, the 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.

There are currently no established biomarkers for predicting the therapeutic effectiveness of Vagus Nerve Stimulation (VNS). Given that neural desynchronization is a pivotal mechanism underlying VNS action, EEG synchronization measures could potentially serve as predictive biomarkers of VNS response. Notably, an increased brain synchronization in delta band has been observed during sleep-potentially due to an activation of thalamocortical circuitry, and interictal epileptiform discharges are more frequently observed during sleep. Therefore, investigation of EEG synchronization metrics during sleep could provide a valuable insight into the excitatory-inhibitory balance in a pro-epileptogenic state, that could be pathological in patients exhibiting a poor response to VNS. A 19-channel-standard EEG system was used to collect data from 38 individuals with Drug-Resistant Epilepsy (DRE) who were candidates for VNS implantation. An EEG synchronization metric-the Weighted Phase Lag Index (wPLI)-was extracted before VNS implantation and compared between sleep and wakefulness, and between responders (R) and non-responders (NR). In the delta band, a higher wPLI was found during wakefulness compared to sleep in NR only. However, in this band, no synchronization difference in any state was found between R and NR. During sleep and within the alpha band, a negative correlation was found between wPLI and the percentage of seizure reduction after VNS implantation. Overall, our results suggest that patients exhibiting a poor VNS efficacy may present a more pathological thalamocortical circuitry before VNS implantation. EEG synchronization measures could provide interesting insights into the prerequisites for responding to VNS, in order to avoid unnecessary implantations in patients showing a poor therapeutic efficacy.

The mechanisms of action of Vagus Nerve Stimulation (VNS) and the biological prerequisites to respond to the treatment are currently under investigation. It is hypothesized that thalamocortical tracts play a central role in the antiseizure effects of VNS by disrupting the genesis of pathological activity in the brain. This pilot study explored whether in vivo microstructural features of thalamocortical tracts may differentiate Drug-Resistant Epilepsy (DRE) patients responding and not responding to VNS treatment. Eighteen patients with DRE (37.11 ​± ​10.13 years, 10 females), including 11 responders or partial responders and 7 non-responders to VNS, were recruited for this high-gradient multi-shell diffusion Magnetic Resonance Imaging (MRI) study. Using Diffusion Tensor Imaging (DTI) and multi-compartment models - Neurite Orientation Dispersion and Density Imaging (NODDI) and Microstructure Fingerprinting (MF), we extracted microstructural features in 12 subsegments of thalamocortical tracts. These characteristics were compared between responders/partial responders and non-responders. Subsequently, a Support Vector Machine (SVM) classifier was built, incorporating microstructural features and 12 clinical covariates (including age, sex, duration of VNS therapy, number of antiseizure medications, benzodiazepine intake, epilepsy duration, epilepsy onset age, epilepsy type - focal or generalized, presence of an epileptic syndrome - no syndrome or Lennox-Gastaut syndrome, etiology of epilepsy - structural, genetic, viral, or unknown, history of brain surgery, and presence of a brain lesion detected on structural MRI images). Multiple diffusion metrics consistently demonstrated significantly higher white matter fiber integrity in patients with a better response to VNS (pFDR < 0.05) in different subsegments of thalamocortical tracts. The SVM model achieved a classification accuracy of 94.12%. The inclusion of clinical covariates did not improve the classification performance. The results suggest that the structural integrity of thalamocortical tracts may be linked to therapeutic effectiveness of VNS. This study reveals the great potential of diffusion MRI in improving our understanding of the biological factors associated with the response to VNS therapy.

The locus coeruleus–norepinephrine system is thought to be involved in the clinical effects of vagus nerve stimulation. This system is known to prevent seizure development and induce long-term plastic changes, particularly with the release of norepinephrine in the hippocampus. However, the requisites to become responder to the therapy and the mechanisms of action are still under investigation. Using MRI, we assessed the structural and functional characteristics of the locus coeruleus and microstructural properties of locus coeruleus-hippocampus white matter tracts in patients with drug-resistant epilepsy responding or not to the therapy. Twenty-three drug-resistant epileptic patients with cervical vagus nerve stimulation were recruited for this pilot study, including 13 responders or partial responders and 10 non-responders. A dedicated structural MRI acquisition allowed in vivo localization of the locus coeruleus and computation of its contrast (an accepted marker of LC integrity). Locus coeruleus activity was estimated using functional MRI during an auditory oddball task. Finally, multi-shell diffusion MRI was used to estimate the structural properties of locus coeruleus-hippocampus tracts. These characteristics were compared between responders/partial responders and non-responders and their association with therapy duration was also explored. In patients with a better response to the therapy, trends toward a lower activity and a higher contrast were found in the left medial and right caudal portions of the locus coeruleus, respectively. An increased locus coeruleus contrast, bilaterally over its medial portions, correlated with duration of the treatment. Finally, a higher integrity of locus coeruleus-hippocampus connections was found in patients with a better response to the treatment. These new insights into the neurobiology of vagus nerve stimulation may provide novel markers of the response to the treatment and may reflect neuroplasticity effects occurring in the brain following the implantation.

Light 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.

The locus coeruleus (LC) is the primary source of norepinephrine (NE) in the brain, and the LC-NE system is involved in regulating arousal and sleep. It plays key roles in the transition between sleep and wakefulness, and between slow wave sleep (SWS) and rapid eye movement sleep (REMS). However, it is not clear whether the LC activity during the day predicts sleep quality and sleep properties during the night, and how this varies as a function of age. Here, we used 7 Tesla functional Magnetic Resonance Imaging (7T fMRI), sleep electroencephalography (EEG) and a sleep questionnaire to test whether the LC activity during wakefulness was associated with sleep quality in 52 healthy younger (N=33; ~22y; 28 women) and older (N=19; ~61y; 14 women) individuals. We find that, in older, but not in younger participants, higher LC activity, as probed during an auditory mismatch negativity task, is associated with worse subjective sleep quality and with lower power over the EEG theta band during REMS (4-8Hz), which are two sleep parameters significantly correlated in our sample of older individuals. The results remain robust even when accounting for the age-related changes in the integrity of the LC. These findings suggest that the activity of the LC may contribute to the perception of the sleep quality and to an essential oscillatory mode of REMS, and that the LC may be an important target in the treatment of sleep disorders and age-related diseases.

The brainstem locus coeruleus (LC) influences a broad range of brain processes and is suspected to be involved in many neurological disorders. The LC contrast is an accepted marker of the integrity and can be assessed with specific Magnetic Resonance Imaging (MRI) structural sequences. The small size of the LC has rendered its functional characterization difficult. A full characterization of the LC in healthy young and late middle-aged individuals is needed to determine to potential roles of the LC in different medical conditions. Here, we wanted to determine whether the activation of the LC in a mismatch negativity task changes in aging and whether the LC functional response was associated to the LC contrast. We used Ultra-High Field (UHF) 7-Tesla functional MRI (fMRI) during an auditory oddball task in 53 healthy volunteers, including 34 younger (age: 22.15y ± 3.27; 29 women) and 19 late middle-aged (age: 61.05y ± 5.3; 14 women) individuals. Whole-brain analyses confirmed brain responses in the typical regions previously associated with mismatch negativity. When focusing on the brainstem, we found a significant response in the rostral part of the LC (and most extensively in the left LC). Individual LC activity was not significantly different between young and late middle-aged individuals. Critically, while the LC contrast was higher in older individuals, the functional response of the LC was not associated with its contrast. These findings show that the age-related alterations of the LC structural integrity may not necessarily be related to changes in its functional response.

IntroductionThe brainstem locus coeruleus (LC) influences a broad range of brain processes, including cognition. The so-called LC contrast is an accepted marker of the integrity of the LC that consists of a local hyperintensity on specific Magnetic Resonance Imaging (MRI) structural images. The small size of the LC has, however, rendered its functional characterization difficult in humans, including in aging. A full characterization of the structural and functional characteristics of the LC in healthy young and late middle-aged individuals is needed to determine the potential roles of the LC in different medical conditions. Here, we wanted to determine whether the activation of the LC in a mismatch negativity task changes in aging and whether the LC functional response was associated to the LC contrast.MethodsWe used Ultra-High Field (UHF) 7-Tesla functional MRI (fMRI) to record brain response during an auditory oddball task in 53 healthy volunteers, including 34 younger (age: 22.15y ± 3.27; 29 women) and 19 late middle-aged (age: 61.05y ± 5.3; 14 women) individuals.ResultsWhole-brain analyses confirmed brain responses in the typical cortical and subcortical regions previously associated with mismatch negativity. When focusing on the brainstem, we found a significant response in the rostral part of the LC probability mask generated based on individual LC images. Although bilateral, the activation was more extensive in the left LC. Individual LC activity was not significantly different between young and late middle-aged individuals. Importantly, while the LC contrast was higher in older individuals, the functional response of the LC was not significantly associated with its contrast.DiscussionThese findings may suggest that the age-related alterations of the LC structural integrity may not be related to changes in its functional response. The results further suggest that LC responses may remain stable in healthy individuals aged 20 to 70.

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. Here, 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 (24.05y ±4.0; 14 women) while they completed an attentional and an emotional auditory task whilst exposed to repeated 30-to-40s-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; 6500K]. For the analysis 15 and then 14 participants were included in the attentional and emotional tasks respectively. Generalized 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 ≤.0001). The impact of light was different for the target vs. non-target stimulus of the attentional task but was not different for the emotional and neutral stimulus of the emotional task. Despite a smaller sustained pupil size during brighter light blocks, a higher light level triggers a stronger task-evoked pupil response to auditory stimulation, presumably through the recruitment of the locus coeruleus.