Regional response to light illuminance across the human hypothalamus

Light exerts multiple non-image-forming (NIF) biological effects that influence the quality of sleep and wakefulness, and higher illuminance is known to stimulate alertness and cognition (Campbell et al., 2023). The biological effects of light primarily rely on a subclass of retinal ganglion cells that are intrinsically photosensitive (ipRGCs) because they express the photopigment melanopsin, which is maximally sensitive to photons with wavelength ~480 nm. IpRGCs combine the light signalling of rods and cones to their intrinsic photosensitivity and, collectively, the biological effects of light present a maximal sensitivity to the shorter blue wavelength of visible light (Do, 2019). IpRGCs project to multiple subcortical brain areas and their denser projections are found within the hypothalamus, particularly in nuclei involved in sleep and wakefulness regulation (Scammell et al., 2017; Do, 2019). The suprachiasmatic nucleus (SCN), which is the site of the principal circadian clock, receives the strongest inputs from ipRGC inputs, over the anterior part of the hypothalamus (Hattar et al., 2006). Other nuclei also receive ipRGC projections: the subparaventricular zone, one of the main output routes of the SCN, the ventrolateral preoptic nucleus (VLPO) and the preoptic nucleus (PON) involved in sleep initiation and also found in the anterior part of the hypothalamus; the lateral hypothalamus (LH), site of the orexinergic wake-promoting neurons and melanin-concentrating hormone sleep-promoting neurons, found in contrast over the lateral and posterior parts of the hypothalamus (Scammell et al., 2017; Do, 2019).

The brain circuitry underlying the biological effects of light has mostly been uncovered in nocturnal rodent models (Campbell et al., 2023; Do, 2019). Translation to diurnal human beings, where the later maturation of the cortex allows for complex cognitive processing (Braak and Del Tredici, 2015), remains scarce. In particular, whether hypothalamus nuclei contribute to the stimulating impact of light on cognition in humans is not established.

We addressed this question using ultra-high-field (UHF) 7 Tesla (7T) functional magnetic resonance imaging (fMRI) in healthy young adults exposed to light of various illuminance while engaged in two different auditory cognitive tasks. We find that higher illuminance increased the activity of the posterior part of the hypothalamus encompassing the mamillary bodies (MB) and parts of the LH and tuberomammillary nucleus (TMN). In contrast, higher illuminance decreased the activity over the anterior and ventral parts of the hypothalamus encapsulating notably the SCN and another part of the TMN. Critically, the pattern of modulation was consistent across the two cognitive tasks. Importantly, the performance of the complex cognitive task was improved under higher illuminance while the activity of the posterior part of the hypothalamus was correlated to task performance. The findings reveal the distinct local dynamics of different hypothalamus areas in response to changing illuminance that may contribute to light’s impact on cognition.

Twenty-six healthy young adults (16 women; 24.3±2.9 y; Supplementary file 1a) completed two auditory cognitive tasks encompassing, respectively, the executive (Collette et al., 2005) and emotional (Grandjean et al., 2005) domains, while alternatively maintained in darkness or exposed to short periods (<1 min) of light of four different illuminances (0.16, 37, 92, 190 melanopic equivalent daylight illuminance - mel EDI- lux; Supplementary file 1b; Figure 1). The hypothalamus of each participant was segmented into five subparts – inferior-anterior, superior-anterior, inferior-tubular, superior-tubular, and posterior (Figure 2A) – so we could consistently extract the regional effect of illuminance change on fMRI blood-oxygen-level-dependent (BOLD) signal over most of the hypothalamus volume.

Figure 1

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Figure 2

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Performance to the executive task is improved by light and related to the activity of the posterior hypothalamus

Following these analyses, we explored whether the changes in activity across illuminances were related to cognitive performance. We first considered the more difficult (2-back) subtask of the executive task as it requires higher cognitive functions (see Materials and methods for a full rationale; Collette et al., 2005). The analysis revealed that accuracy to the executive task was high in all participants, but accuracy to the more difficult subtask (2-back) improved with increasing illuminance (GLMM; main effect of illuminance; F=2.72; p=0.034; Partial R2 215=0.1; Figure 3A), controlling for age, sex, and BMI. Critically, the analysis also showed that performance under each illuminance was significantly related to the activity of the posterior hypothalamus subpart (GLMM; main effect of posterior subpart activity; F=9.43; p=0.0027; Partial R2 219=0.09). Surprisingly, the association was negative (Figure 3B), suggesting that the part of variance explained by the hypothalamus subpart is distinct from the impact of light on performance. In contrast, no significant association was found when considering the activity of the other four subparts (GLMM; main effect of posterior subpart activity; F<0.62; p>0.4; Figure 3C and D; Supplementary file 1g). We went on and found that the accuracy to the simpler control subtask of the executive tasks (0-back, see Materials and methods) was not associated with the activity of the posterior hypothalamus subpart (GLMM controlling for age, sex and BMI; main effect of subpart activity; F=0.57; p=0.45; Figure 3E), suggesting that the association with performance is specific to the 2-back subtask.

Figure 3

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In the last step, we explored the reaction times during the emotional task (accuracy to the lure task is not meaningful). We found that reaction times to the emotional stimuli were not significantly affected by illuminance (GLMM controlling for age, sex and BMI; main effect of illuminance; F=1.01; p=0.41; Figure 3F) and yet, they were significantly associated with the activity of the posterior hypothalamus subpart across each illuminance (GLMM; main effect of subpart activity; F=4.34; p=0.04; Figure 3G). The association was positive meaning that reaction times were longer if activity estimates were higher, which could indicate a reinforcement of the emotional response characterised by longer reaction times (Grandjean et al., 2005). No such significant association was detected when considering reaction times to the neutral items of the task (GLMM controlling for age, sex and BMI; main effect of illuminance; F=1.5; p=0.21; main effect of subpart activity; F=0.28; p=0.6; Figure 3H).

Animal research has established that the biological impact of light illuminance impinges on many subcortical structures, many of which regulate sleep and wakefulness (Campbell et al., 2023; Hattar et al., 2006; Scammell et al., 2017; Do, 2019). How these findings translate to human beings is not established. Here, we took advantage of the relatively high resolution and signal-to-noise ratio of UHF 7T fMRI to determine how illuminance affects the activity of the hypothalamus as, based on animal research, it receives the densest projections from ipRGCs (Hattar et al., 2006; Do, 2019). We find that the activity of the posterior part of the hypothalamus increases with increasing illuminance while, in contrast, the inferior and anterior hypothalamus show a seemingly opposite pattern and see their activity decrease under higher illuminance. The pattern of light-induced changes was consistent across an executive and an emotional task which consisted of a block and an event-related fMRI design, respectively. This suggests that a robust anterior-posterior gradient of activity modulation by illuminance is present in the hypothalamus across cognitive domains. Importantly, performance to the complex cognitive task was improved under higher illuminance and was correlated to the activity of the posterior part of the hypothalamus under the different illuminance, though negatively. The results demonstrate that the human hypothalamus does not respond uniformly to variations in illuminance while engaged in a cognitive challenge and suggest that the posterior part of the hypothalamus may be key in mediating the stimulating impact of light on cognition.

The different nuclei of the hypothalamus do not have clear contrast boundaries based on MRI signals (Billot et al., 2020). As a result, achieving nucleus resolution over the human hypothalamus even using UFH MRI remains out of reach (Sharifpour et al., 2022). Therefore, we cannot assign the effects we report to a specific nucleus. We can only speculate and present a selection of plausible scenarios that would need to be tested. The posterior part of the hypothalamus – delineated in each participant based on an automatic reproducible procedure (Billot et al., 2020) – encompasses the MB as well as parts of the LH and the TMN. All these nuclei could participate to the increased BOLD signal we detect under higher illuminance. The LH and TMN, respectively, produce orexin and histamine, which are both known to promote wakefulness, while animal histology reports direct projection of the ipRGCs to the LH (Hattar et al., 2006; Scammell et al., 2017; Do, 2019). Orexin is a good candidate to constitute the circadian signal that promotes wakefulness and to counter the progressive increase in sleep needs with prolonged wakefulness (Zeitzer, 2013). Our data may therefore be compatible with an increase in orexin release by the LH with increasing illuminance. In line with this assumption, chemoactivation of ipRGCs lead to increase c-fos production, a marker of cellular activation, over several nuclei of the hypothalamus, including the lateral hypothalamus (Milosavljevic et al., 2016). If the initial effect of light we observe over the posterior part of the hypothalamus was maintained over a longer period of exposure, this would stimulate cognition and maintain or increase alertness (Campbell et al., 2023) and may also be part of the mechanisms through which daytime light increases the amplitude in circadian variations of several physiological features (Bano-Otalora et al., 2021; Dijk et al., 2012). It could then also be part of the mechanisms through which evening light may disturb subsequent sleep (Chellappa et al., 2013) when illuminance is higher than the recommended maximum of 10 mel EDI lux for evening light (Brown et al., 2022). If the TMN was the hypothalamus nucleus underlying the regional increase in the BOLD signal we report, it could confer a role to histamine in mediating the stimulating impact of light. Of interest, the TMN receives orexin signal from the LH (Scammell et al., 2019). Alternatively, our findings may suggest a role for the MBs in mediating the impact of light on ongoing cognition, potentially influenced through its innervation by the TMN (Vann, 2010).

Previous research indicated that increasing illuminance reduced the activity of the anterior part of the hypothalamus encompassing the SCN, either following the exposure to light (Perrin et al., 2004) or during the exposure (Schoonderwoerd et al., 2022). We extend this finding by showing that the significant decrease in activity extends beyond the inferior anterior hypothalamus and therefore much beyond the SCN. Chemoactivation of ipRGCs in rodents led to an increase activity of the SCN, over the inferior anterior hypothalamus, but had no impact on the activity of the VLPO, over the superior anterior hypothalamus (Milosavljevic et al., 2016). How our findings fit with these fine-grained observations and whether there are species-specific differences in the responses to light over the different part of the hypothalamus remains to be established. The inferior-tubular and inferior-anterior subparts of the hypothalamus – that we isolated also based on an automatic reproducible procedure (Billot et al., 2020) – encompass several nuclei such as notably the SCN, SON, ventromedial nucleus of the hypothalamus, arcuate nucleus and part of the TMN. Again, all these nuclei may be involved in the reduction in BOLD signal we observe at higher illuminance. In terms of chemical communication, these changes in activity could be the results of an inhibitory signal from a subclass of ipRGCs, potentially through the release aminobutyric acid (GABA), as a rodent study found that a subset of ipRGCs release GABA at brain targets including the SCN (and intergeniculate leaflet and ventral lateral geniculate nucleus), leading to a reduction in the ability of light to affect pupil size and circadian photoentrainment (Sonoda et al., 2020). Whatever the signalling of ipRGC, our finding over the anterior hypothalamus could correspond to a modification of GABA signalling of the SCN which has been reported to have excitatory properties, such that the BOLD signal changes we report may correspond to a reduction in excitation arising in part from the SCN (Albers et al., 2017). Likewise, the SCN is also producing other neuropeptides that could affect its downstream targets. As the inferior-tubular subpart of the hypothalamus also includes part of the TMN it may be the TMN and its GABA production that is decreased by higher illuminance (Scammell et al., 2019). The decrease in BOLD signal with increasing illuminance we report could therefore arguably reflect a decreased inhibitory signal arising from the anterior and inferior nuclei of the hypothalamus.

Importantly, none of the scenarios we elaborated on are mutually exclusive and we may have overlooked the potential implication of several nuclei as well as the cellular diversity of the nuclei of the hypothalamus (Adamantidis et al., 2019; Scammell et al., 2017). We further note that the anterior-superior hypothalamus subpart of the hypothalamus encompassing the VLPO and PON sees its activity decreasing under higher illuminance during the emotional task, similarly to the anterior-inferior and inferior-tubular areas. Likewise, similar to the posterior subpart, the activity of the superior-tubular hypothalamus subpart may be increased under higher illuminance during the emotional task. Whether this represents a task-specific effect arising, for instance, from differences in the salience of the auditory stimulus, remains to be determined.

Subcortical structures, and particularly those receiving direct retinal projections, including those of the hypothalamus, are likely to receive light illuminance signal first, before passing on the light modulation to the cortical regions involved in the ongoing cognitive process (Campbell et al., 2023). A critical aspect of our results is that the performance to the 2-back (executive) subtask was significantly increased when exposed to higher illuminance light. The extent of this increase was limited, likely because performance was overall high at all illuminances, but was not detected for the simpler detection letter subtask (0-back). The result contrasts with many previous 3T MRI investigations on the biological effects of light on human brain function which did not report behavioural changes induced by repeated short exposures to light (e.g. Vandewalle et al., 2007a; Vandewalle et al., 2007b; Vandewalle et al., 2011a but see Daneault et al., 2018; Vandewalle et al., 2006). Our 7T MRI study, which includes a sample size larger than many of these previous studies, supports that BOLD fMRI is sensitive in detecting subtle impacts of light on the brain and that these detected changes can arguably contribute to the behavioural changes others reported using longer light exposure and other approaches (e.g. Cajochen et al., 2011; Lockley et al., 2006 but see Smolders et al., 2018).

Importantly, we find that activity of the posterior hypothalamus subpart is negatively related to the performance to the executive task, making it unlikely that it mediates directly the positive impact of light on performance. The activity of the posterior hypothalamus was, however, associated with an increased behavioural response to emotional stimuli. The association between behaviour and the posterior hypothalamus is therefore likely to be complex and may depend on the context, with for instance different nuclei or neuronal populations contributing in some instances but not in others (Adamantidis et al., 2019; Scammell et al., 2019). It is likely also to work jointly with the decreased activity of the anterior/inferior hypothalamus we detected as well as with other non-hypothalamus subcortical structures regulating wakefulness to influence behaviour, which intrinsically primarily depends on cortical activity.

Future research may consider data-driven analyses of hypothalamus voxels time series as an alternative to the parcellation approach we adopted here. This may refine the delineation of the subparts of the hypothalamus undergoing decreased or increased activity with increasing illuminance. Future research should also assess the impact of light on other subcortical structures and on the entire subcortical network to determine how illuminance modifies their crosstalk as well as their interaction with the cortex, to eventually lead to behavioural impacts. These analyses could for instance address whether the regional changes in activity of the hypothalamus we find are upstream of the repeatedly reported impact of light illuminance on the activity of the pulvinar in the thalamus (Paparella et al., 2023; Vandewalle et al., 2006). Although it does not receive direct dense input from ipRGCs, it is likely to indirectly mediate the biological impact of light on ongoing cognitive activity (Paparella et al., 2023).

We based our rationale and part of our interpretations on ipRGC projections, which have been demonstrated in rodents to channel the NIF biological impact of light and incorporate the inputs from rods and cones with their intrinsic photosensitivity into a light signal that can impact the brain (Güler et al., 2008; Do, 2019). Given the polychromatic nature of the light we used, classical photoreceptors and their projections to visual brain areas are, however, very likely to have directly or indirectly contributed to the modulation by light of the regional activity of the hypothalamus. Furthermore, we cannot exclude that colour and/or spectral differences between the orange and three blue-enriched light conditions may have contributed to our findings. Research in rodent models demonstrated that variation in the spectral composition of light was perceived by the suprachiasmatic nucleus to set circadian timing (Walmsley et al., 2015). No such demonstration has, however, been reported yet for the acute impact of light on alertness, attention, cognition or affective state. Future human studies could isolate the contribution of each photoreceptor class to the impact of light on cognitive brain functions by manipulating prior light history (Chellappa et al., 2014) or through the use of silent substitutions between metameric light exposures (Viénot et al., 2012).

All these knowledge gaps are important to address because acting on light stands as a promising means to reduce high sleepiness and improve cognitive deficits during wakefulness as well as to facilitate sleep in the few hours preceding bedtime (Brown et al., 2022; Didikoglu et al., 2023; Gooley et al., 2011; Münch et al., 2016; Riemersma-van der Lek et al., 2008; Scheuermaier et al., 2018; Wirz-Justice et al., 2021). Light therapy is also a validated means to improve mood and treat mood disorders (Glickman et al., 2006; Lam et al., 2016). Light administration can also be considered a simple means to disturb the brain circuitry regulating sleep and wakefulness such that it can provide insights about novel means to improve their quality. For instance, if orexin and histamine were part of the mechanism through which natural light affects brain functions, their administration may be the most ecological and/or natural means to affect alertness and cognition. Likewise, as both orexin and histamine are targets for the treatment of brain disorders, our findings could suggest that light may constitute a non-pharmacological complementary intervention to compounds that are being developed to treat arousal, sleep, or cognitive dysfunction in brain disorders (Ma et al., 2018). It remains, however, premature in our view to base recommendations on the therapeutic use of light based on the MRI findings gathered to date. Targeted lighting for interventions or for precise interference of subcortical circuits will require a full understanding of how light affects the brain, particularly at the subcortical level. Our findings represent an important step towards this goal, at the level of the hypothalamus.

The data used in this paper arise from a large study that is leading to several publications and part of the methods have been published previously (Beckers et al., 2024; Campbell et al., 2024a; Paparella et al., 2023). The protocol was approved by the Ethics Committee of the Faculty of Medicine at the University of Liège (ref 2020/11). Participants gave their written informed consent to take part in the study and received monetary compensation for their participation.

The processed version of the data (consisting of the contrast of interest maps in MNI space) are available on ULiège Open Data Repository. The data tables and analysis scripts supporting the results included in this manuscript are publicly available via GitLab (copy archived at Campbell et al., 2024b). We used Matlab and Python scripts for MRI data processing and to compute performance metrics, while we used SAS for statistical analyses. The data cannot be used for commercial purposes without prior agreement of the corresponding author. The raw data could be identified and linked to a single subject and represent a huge amount of data (>200 Gb). Researchers willing to access to the raw should send a request to the corresponding author (GV). Data sharing will require evaluation of the request by the local Research Ethics Board and the signature of a data transfer agreement (DTA).

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Author details

1. Islay Campbell

   GIGA-CRC Human Imaging, University of Liège, Liège, Belgium

   Contribution

   Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Writing - original draft

   Contributed equally with

   Roya Sharifpour

   Competing interests

   No competing interests declared

2. Roya Sharifpour

   GIGA-CRC Human Imaging, University of Liège, Liège, Belgium

   Contribution

   Data curation, Formal analysis, Investigation, Methodology, Writing - original draft

   Contributed equally with

   Islay Campbell

   Competing interests

   No competing interests declared

3. Jose Fermin Balda Aizpurua

   GIGA-CRC Human Imaging, University of Liège, Liège, Belgium

   Contribution

   Data curation, Formal analysis, Writing – review and editing

   Competing interests

   No competing interests declared

4. Elise Beckers

   1. GIGA-CRC Human Imaging, University of Liège, Liège, Belgium
   2. Faculty of Health, Medicine and Life Sciences, School for Mental Health and Neuroscience, Alzheimer Centre Limburg, Maastricht University, Maastricht, Netherlands

   Contribution

   Data curation, Formal analysis, Writing – review and editing

   Competing interests

   No competing interests declared

5. Ilenia Paparella

   GIGA-CRC Human Imaging, University of Liège, Liège, Belgium

   Contribution

   Data curation, Formal analysis, Writing – review and editing

   Competing interests

   No competing interests declared

6. Alexandre Berger

   1. GIGA-CRC Human Imaging, University of Liège, Liège, Belgium
   2. Synergia Medical SA, Mont-Saint-Guibert, Belgium
   3. Institute of Neuroscience (IoNS), Department of Clinical Neuroscience, Université Catholique de Louvain (UCLouvain), Woluwe-Saint-Lambert, Belgium

   Contribution

   Data curation, Formal analysis, Writing – review and editing

   Competing interests

   No competing interests declared

7. Ekaterina Koshmanova

   GIGA-CRC Human Imaging, University of Liège, Liège, Belgium

   Contribution

   Data curation, Formal analysis, Writing – review and editing

   Competing interests

   No competing interests declared

8. Nasrin Mortazavi

   GIGA-CRC Human Imaging, University of Liège, Liège, Belgium

   Contribution

   Data curation, Formal analysis, Writing – review and editing

   Competing interests

   No competing interests declared

9. John Read

   GIGA-CRC Human Imaging, University of Liège, Liège, Belgium

   Contribution

   Resources, Project administration, Writing – review and editing

   Competing interests

   No competing interests declared

10. Mikhail Zubkov

    GIGA-CRC Human Imaging, University of Liège, Liège, Belgium

    Contribution

    Resources, Software, Validation, Writing – review and editing

    Competing interests

    No competing interests declared

11. Puneet Talwar

    GIGA-CRC Human Imaging, University of Liège, Liège, Belgium

    Contribution

    Resources, Software, Writing – review and editing

    Competing interests

    No competing interests declared

    "This ORCID iD identifies the author of this article:" 0000-0001-7631-7926

12. Fabienne Collette

    GIGA-CRC Human Imaging, University of Liège, Liège, Belgium

    Contribution

    Funding acquisition, Project administration, Writing – review and editing

    Competing interests

    No competing interests declared

13. Siya Sherif

    GIGA-CRC Human Imaging, University of Liège, Liège, Belgium

    Contribution

    Resources, Software, Writing – review and editing

    Competing interests

    No competing interests declared

14. Christophe Phillips

    GIGA-CRC Human Imaging, University of Liège, Liège, Belgium

    Contribution

    Resources, Software, Validation, Writing – review and editing

    Competing interests

    No competing interests declared

    "This ORCID iD identifies the author of this article:" 0000-0002-4990-425X

15. Laurent Lamalle

    GIGA-CRC Human Imaging, University of Liège, Liège, Belgium

    Contribution

    Resources, Software, Validation, Writing – review and editing

    Competing interests

    No competing interests declared

    "This ORCID iD identifies the author of this article:" 0000-0002-8930-7337

16. Gilles Vandewalle

    GIGA-CRC Human Imaging, University of Liège, Liège, Belgium

    Contribution

    Conceptualization, Supervision, Investigation, Methodology, Writing - original draft, Project administration, Writing – review and editing

    For correspondence

    gilles.vandewalle@uliege.be

    Competing interests

    No competing interests declared

    "This ORCID iD identifies the author of this article:" 0000-0003-2483-2752

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