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. 2021 Jun 16;16(6):e0252350. doi: 10.1371/journal.pone.0252350

Afraid of the dark: Light acutely suppresses activity in the human amygdala

Elise M McGlashan 1,#, Govinda R Poudel 2,#, Sharna D Jamadar 1, Andrew J K Phillips 1, Sean W Cain 1,*
Editor: Tudor C Badea3
PMCID: PMC8208532  PMID: 34133439

Abstract

Light improves mood. The amygdala plays a critical role in regulating emotion, including fear-related responses. In rodents the amygdala receives direct light input from the retina, and light may play a role in fear-related learning. A direct effect of light on the amygdala represents a plausible mechanism of action for light’s mood-elevating effects in humans. However, the effect of light on activity in the amygdala in humans is not well understood. We examined the effect of passive dim-to-moderate white light exposure on activation of the amygdala in healthy young adults using the BOLD fMRI response (3T Siemens scanner; n = 23). Participants were exposed to alternating 30s blocks of light (10 lux or 100 lux) and dark (<1 lux), with each light intensity being presented separately. Light, compared with dark, suppressed activity in the amygdala. Moderate light exposure resulted in greater suppression of amygdala activity than dim light. Furthermore, functional connectivity between the amygdala and ventro-medial prefrontal cortex was enhanced during light relative to dark. These effects may contribute to light’s mood-elevating effects, via a reduction in negative, fear-related affect and enhanced processing of negative emotion.

Introduction

Beyond vision, light has powerful effects on brain function and human health. Non-visual effects of light include the regulation of the circadian clock [1, 2], alertness, physiological arousal [3], and mood [4]. These effects are likely to be largely driven by intrinsically photosensitive retinal ganglion cells (ipRGCs) containing the photopigment melanopsin, which project to many subcortical brain regions [5, 6]. In rodents, ipRGCs directly innervate the amygdala [7], a neural structure that is central to the regulation of emotion [8]. The amygdala, and connections between the ventro-medial prefrontal cortex (vmPFC) and amygdala, play a role in regulating fear-related responses [8–11]. This circuitry is critical for the regulation of negative affect.

In nocturnal animals, light is aversive. Light acutely enhances fear-related learning [12], and the retina-amygdala pathway is involved in light-related alterations in both mood and learning [13]. In humans, light exposure improves mood [14] and alters function in brain areas that are important for cognition [15]. Light therapy is an effective, rapidly acting intervention for depressive disorders, including major depression and seasonal affective disorder [4, 16]. Pre-clinical work suggests that the amygdala is one of the primary brain areas which may underpin the direct effects of light on mood [13]. However, the mechanism for light therapy in humans remains unknown. Previous work has investigated the impact of light with differing spectral compositions on brain function using fMRI [17–19]. This work has shown that blue light exposure, relative to green light exposure, enhances responses to emotional stimuli, and enhances connectivity between the amygdala and hypothalamus [18], demonstrating a potential effect of light on emotional processing in humans. Here, we investigated the impact of dim-to-moderate white light exposure, relative to dark, on amygdala activity and amygdala-vmPFC effective functional connectivity in healthy adults.

Materials and methods

This study was approved by the Monash University Human Research Ethics Committee. Participants gave written informed consent and were reimbursed for their time.

Participants

A total of 24 young healthy adults completed the study. One participant’s data were excluded due to excessive movement (>3mm) during scans, leaving a final sample of 23 (11 women) aged 18–32 years (M = 22.35, SD = 3.07). Participants were free from major medical conditions, were not taking regular prescription medications, and had no personal history of psychiatric conditions. Participants were largely classed as intermediate types on the Morningness-Eveningness Questionnaire [20] (65% intermediate, M = 54.4, SD = 6.65, no extreme morning or evening types). Mean self-reported bedtime and waketime were 23:25 h, and 7:56 h (SD = 00:52 h and 1:13 h respectively). Participants had minimal depressive symptoms measured by the Beck Depression Inventory II [21] (M = 2.22, SD = 3.38) and minimal levels of daytime sleepiness measured by the Epworth Sleepiness Scale [22] (M = 3.7, SD = 2.74). Data were collected between July and October 2018 in Melbourne, Australia (Winter–Spring).

fMRI scan protocol

Participants were imaged using a 3T Scanner (Siemens Magnetom Skyra) with 20-channel head coils. High-resolution anatomical images of the whole brain were acquired using T1-weighted anatomical scans (TE = 2.07 ms; TR = 2.3 s; field of view: 256×256 mm; slice thickness: 1 mm). Functional images were acquired using echo-planar-imaging (TR = 2.66 s; TE = 30 ms; field of view: 220x220 mm; slice thickness: 2.5 mm; number of slices: 41; flip angle = 80, number of volumes = 180). The first five images of each session were discarded to allow for T1 equilibration.

Participants were scheduled for a functional magnetic resonance imaging (fMRI) scan beginning between 2 and 6 hours after their habitual waketime, M = 3:54 h, SD = 00:45 h. Scan timing was based on habitual sleep timing, and participants were asked to maintain their typical sleep timing on the night prior to the scan. Sleep was not objectively monitored prior to assessments. Participants arrived at the Monash Biomedical Imaging center ~1 hour before their scheduled scan time, during which they sat in a quiet waiting room and completed questionnaires (in regular room lighting).

Participants each underwent an ~30-min MRI scan to examine brain responses to dim (10 lux) and moderate (100 lux) light intensities, relative to periods of dark (<1 lux). Participants were asked to lay supine in the MRI scanner while a fiber-optic-based light delivery system was fitted on the MRI head coil. Lights in and near the scanner room were switched off during data acquisition, as were those on the scanner (ambient room lighting <1 lux). Foam supports were used for participant comfort and to minimize movement during scans. Participants were exposed to a passive light stimulus paradigm and were asked to keep their eyes open other than normal blinking. The scan consisted of two 8-min exposure blocks with alternating 30-s periods of light and dark, and a 5-min period of darkness separating the two exposure blocks. The 10-lux exposures were always delivered first, and study staff spoke with participants during the 5-min break (in darkness) to avoid participants falling asleep during this period. Due to the binocular nature of the exposure, eye-tracking could not be used to monitor gaze during exposures.

Light stimuli

Light stimuli were delivered in the scanner using a custom-built fiber-optic-based device [described in 23]. This consisted of a halogen light source (DC950H, Dolan-Jenner Industries, MA, USA) and metal-free fiber-optic cables (100-strand cable with 0.75-mm fibers, Optic Fibre Lighting, Sydney, AU) which transmitted light to two circular plastic diffusers (40-mm diameter) positioned ~50 mm above each eye. Light stimuli had a CCT of ~2800K (λp = 655 nm) and were delivered at two intensities: ~10 photopic lux (4.3 μW/cm2) and ~100 photopic lux (42.73 μW/cm2) at the eye (intensity assessed using Tektronix J17 Luma Colour, Oregon, USA; spectral characteristics assessed using a MK350N Spectrometer, UPRTek, Taiwan). Daytime equivalent melanopic illuminance was ~34.67 and ~3.5 lux for the 100 lux and 10 lux conditions, respectively [24]. Tabulated spectral data are available in the (S1 Table).

Data analysis

Images were converted from DICOM to NIFTI format using the dcm2nii tool. The fMRI data were processed and analyzed using Statistical Parametric Mapping (SPM12) in MATLAB 2016a (MathWorks, Natick MA, USA) and the FMRIB Software Library (FSL 6.0).

MRI data pre-processing

Pre-processing performed in SPM12 included motion-correction, slice-time correction, and normalization to a standard template. For normalization, the participant’s T1 image was segmented into 3 tissue classes (grey, white, and CSF) using non-linear transformation implemented in SPM12. The resulting inverse deformation field was applied to the T2* EPIs. Standardized Montreal Neurological Institute (MNI) ICBM152 was used for normalization. Using FSL FEAT, data were spatially smoothed using a 6-mm full-width-at-half-maximum (FWHM) kernel and high-pass filtered with a 75-s filter.

Statistical analyses

Normalized fMRI data were analyzed using a general linear model (GLM) in FSL. The first-level GLM included (i) the BOLD activity during light compared with dark (30 s on vs. 30 s off) using a block-design regressor; and (ii) six motion parameters. Block design regressors were convolved with double gamma haemodynamic response functions. Separate first-level GLMs were run for each light intensity (10 and 100 lux). Two contrasts were defined: fMRI activity during light < dark (deactivation) and fMRI activity during light > dark (activation). To estimate the main effect of light, we averaged the contrast parameter estimates associated with 10 and 100 lux. Group-level significance of the parameter estimates was determined using a nonparametric one-sample permutation-based test using the randomise function in FSL (5000 Permutations). Amygdala voxels showing deactivation at p<0.05 were considered to be significantly suppressed by light (voxel-wise corrected for a bilateral amygdala mask obtained from WFU PickAtlas). Areas showing significant activation during light compared with dark (p<0.05, voxel-wise corrected for the whole brain) are shown in the (S1 Fig). To assess whether the 100-lux condition resulted in greater group-level deactivation than the 10-lux condition, we used the randomise function in FSL to conduct a nonparametric paired permutation-based test (5000 permutations). Amygdala voxels showing greater deactivation during 100 lux compared with 10 lux at p<0.05 were considered to be significantly different (one-tailed; cluster corrected using threshold free cluster enhancement [TFCE] for a bilateral amygdala mask).

To investigate whether there was a differential interaction between the amygdala and ventro-medial prefrontal cortex (vmPFC) during light vs. dark, we analyzed functional connectivity using a psycho-physiological interaction (PPI) model in FSL. For the PPI model, the average BOLD fMRI time series in the amygdala within the voxels showing a significant main effect of light was obtained for each participant. Using a subject-specific PPI model, we modeled (i) light vs. dark activity using a block design; (ii) the activity in the amygdala; and (iii) an interaction term between the block task-related regressor and the activity in the amygdala. The PPI model was first estimated at the subject level using separate GLMs for each light level (10 and 100 lux). The contrast parameter estimate corresponding to the interaction term defined the difference in functional connectivity between light and dark conditions. To establish the interaction effect of light vs. dark, we averaged the contrast parameter estimates associated with 10 and 100 lux. To test whether the contrast parameter estimate of the interaction term was significantly different from zero, we used a nonparametric one-sample permutation-based test using the randomise function in FSL (5000 permutation). Any voxels within a vmPFC mask showing an interaction effect at p<0.05 (one-tailed; cluster corrected using threshold free cluster enhancement (TFCE) for the vmPFC mask) were considered significant. The vmPFC mask was defined using the neurosynth tool (https://neurosynth.org/), which identified vmPFC voxels functionally connected to the amygdala (seed MNI: 19, -4, 14) using a resting-state fMRI sample of 1,000 participants [25–27]. The vmPFC mask was identified by thresholding the functional connectivity map identified by neurosynth at r>0.15.

Results

We found a significant (p<0.05, small volume voxels corrected) reduction in amygdala activity during light (averaged across conditions) compared with dark (MNI coordinate of the local maxima: 19, -4, -14; t(22) = 8.35; p = 0.0002; total number of significant voxels: 142, see Fig 1A and 1B). Light also activated the visual cortex and lateral geniculate areas of the thalamus (Fig 1). When considered separately, the 100-lux condition resulted in a significant reduction in amygdala activity (MNI coordinate of the local maxima: 21, -4, -12; t(22) = 5.65; p = 0.0002 corrected; total number of significant voxels: 364), while the 10-lux condition resulted in a below-threshold reduction in amygdala activity (MNI coordinate of the local maxima: 16, -2, -16, t(22) = 3.5; p = 0.065 corrected). There was significantly greater suppression of BOLD activity (p<0.05, small volume cluster corrected) due to 100 lux compared with 10 lux in the right amygdala (MNI coordinate: 25, -7, -19, t(21) = 3.47, p = 0.045, cluster size = 4 voxels, Fig 1C). We additionally found a significant (p<0.05, small volume voxel corrected) psychophysiological interaction effect (light > dark) of amygdala activity in the vmPFC area (local maxima MNI coordinate: 2, 35, -14; t(22) = 3. 98; p = 0.005; cluster size = 53 voxels). During light there was significantly greater functional connectivity between amygdala and vmPFC activity, compared with dark. Voxels with a significant interaction are shown in Fig 1D.

Fig 1. Light, compared with dark, decreased activation in the amygdala and increased functional connectivity between the amygdala and ventro-medial prefrontal cortex.

Fig 1

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(a) Voxels with significantly decreased activity in the amygdala during light relative to dark (p<0.05, small volume correction using bilateral amygdala mask); (b) average time-course of the baseline-corrected BOLD signal across individuals (shaded areas represent SEM). Time-courses were obtained by averaging the normalized BOLD signal for the 8 cycles each of light and dark periods from significant voxels within the amygdala; (c) BOLD signal % change in the cluster (4 voxels) showing greater deactivation during 100 lux compared with 10 lux (p<0.05, cluster corrected within the bilateral amygdala mask). The peak voxel was located at MNI: 25, -7, 19. Individual responses are represented by circles, and dashed and dotted lines represent the median and upper/lower quartiles, respectively; and (d) voxels (53 voxels) within the vmPFC mask showing a significant interaction effect for light vs. dark for functional connectivity with the amygdala (p<0.05, cluster corrected within the vmPFC mask). The peak voxel was located at MNI: 2, 35, -14. Note: Slice labels in panels a, c, and d denote MNI slice numbers. Activation maps are shown on an MNI template and visualized using MRICroGL software using radiological orientation.

Discussion

We studied the acute effect of light on amygdala activity in humans using fMRI. Our results show that light acutely suppresses activity in the amygdala and enhances connectivity between the amygdala and vmPFC. Moderate light (100 lux) resulted in greater suppression of amygdala activity than dim light (10 lux). These findings demonstrate a potential mechanism for improved mood with exposure to light in humans.

The amygdala and vmPFC together play a key role in the expression and regulation of fear. The amygdala is involved in the acquisition and expression of fear-related conditioning, while the vmPFC is required for effective fear extinction [28, 29]. Amygdala-vmPFC connectivity is involved in the regulation of negative affect [9], and dysfunction in this circuitry is associated with higher anxiety [30]. In nocturnal rodents, light enhances learned fear responses, both when present during acquisition and during the expression of fear responses that were learned in darkness [12]. In humans, who are diurnal, we found that light, relative to dark, is associated with an enhanced connective relationship between the vmPFC and amygdala. This suggests that light exposure may facilitate fear extinction in humans via enhanced vmPFC-amygdala connectivity. As we tested the passive response to light, accompanying behavioral and cognitive data will provide further insight regarding the role of light in fear-related learning in humans.

There are reciprocal connections between the amygdala and vmPFC [29], and the amygdala receives direct retinal innervation in rodents [7]. Therefore, suppression of activity in the amygdala by light may permit increased prefrontal control via enhanced amygdala-vmPFC connectivity, resulting in improved regulation of affect. The potential for ipRGCs to be inhibitory is consistent with recent evidence that subtypes of ipRGCs release GABA [31]. Light interventions can be more efficacious in the treatment of depression than standard antidepressant medications [32]. Despite this, the neural mechanism for light therapy efficacy remains largely unknown. Our finding that light suppresses activation in the amygdala and enhances vmPFC connectivity, in combination with other subcortical ipRGC targets, may underpin the mechanism of action for light therapy. Assessments of brain function before and after therapeutic light interventions are needed to determine any lasting effects of increased regular exposure to bright light on mood-related brain areas.

It was previously thought that very bright light was required to elicit many of the non-visual effects of light. This was in part driven by our understanding that melanopsin has a relatively high threshold for activation [33], both in terms of intensity and duration of exposure. Previous human imaging work has shown preferential activation of cognitive brain areas in response to ‘blue’ light, suggesting a role of melanopsin-containing ipRGCs in mediating these responses [17, 18]. However, ipRGCs receive additional input from rods and cones (visual photoreceptors), which are sensitive to even very low levels of light [34]. Behavioral and physiological data in humans indicate that non-visual light responses can occur very rapidly, and with very dim light [35, 36]. These effects are likely due to a combination of rod, cone, and melanopsin activation. Furthermore, there are several subtypes of human ipRGCs, some of which exhibit rapid and short-lived responses [37]. Our findings and other human imaging findings [15] are consistent with rapid onset changes in brain function, which may have important implications for subsequent behavior. As we studied effects of relatively short duration stimuli, it is possible that the appearance of light (i.e., the change in visual experience) also contributed to our observed effects. It is not possible from our data to distinguish between the visual and non-visual components that may have contributed to our findings. This could be achieved by manipulating the spectral quality of the light. Further work will be needed to begin to understand the unique contribution of different subsets of ipRGCs, and other photoreceptors, to both the visual and non-visual aspects of light responses.

The ability to easily control our light environment is a very recent development in our evolutionary history. Prior to the invention of electric lighting, light exposure was largely determined by the rise and fall of the sun. The prevalence of our self-exposure to light at night in modern society may be partly motivated by the rewarding and mood-elevating effects of light. Parallel to our own findings, it has been shown that the habenula, a brain structure involved in reward regulation [38, 39], is acutely suppressed by light in humans [40]. Decreased habenula activity is associated with increased expectation of reward [38]. Our findings dovetail with pre-clinical evidence that the amygdala and habenula are critical to light-related mood and learning effects [41, 42]. In humans, increased mood and reward sensitivity could lead to increased light-seeking behavior at times of day when light is disruptive to the circadian system (e.g., in the evening/night). This disruption may be more severe in populations who are hypersensitive to the non-visual effects of light, including those taking medications that increase light sensitivity [43], or with certain sleep [44] or mood disorders [e.g., bipolar disorder; 45]. Conversely, low light sensitivity, which is reported in other mood disorders [e.g., unipolar or seasonal depression; 46, 47], may directly contribute to negative affect via a decreased ability of light to suppress amygdala activity.

Light is an effective therapeutic tool for mood problems. We have shown that dim-to-moderate light suppresses amygdala activation and enhances amygdala-vmPFC connectivity. These effects may contribute directly to the mood-elevating effects of light via improved emotional processing, and a reduction in fear-related emotion.

Supporting information

S1 Fig. Light, compared with dark, increases activity in the visual cortex and lateral geniculate.

Increased activity (p<0.05, voxel-wise corrected) during light compared to dark was observed in the visual cortex (local maxima MNI coordinate: 14, -90, 2, tmax = 8.98) and right lateral geniculate area (tmax = 6.3, MNI coordinate: 26, -25, -2). Bilateral lateral geniculate area showed activation at p<0.001. However, this did not survive whole-brain correction for significance. Voxels with increased activity in the visual cortex and lateral geniculate area of the thalamus are shown. Green voxels represent the voxels significant at p<0.05 (voxel-wise corrected). Red-yellow color represent increased activity at p<0.001, uncorrected. The brain images are presented on a radiological orientation.

(TIFF)

Click here for additional data file. (4.1MB, tiff)
S1 Table. Spectral power distribution for the light source.

Data are shown for a measure of the light source at ~100 photopic lux in 1 nm bins from 360nm to 760nm. Data are reported in μW/cm2, measured using a MK350N Spectrometer (UPRTek, Taiwan).

(XLSX)

Click here for additional data file. (19KB, xlsx)
S1 Data

(XLSX)

Click here for additional data file. (18.9KB, xlsx)

Acknowledgments

We thank the Monash Instrumentation Facility for their assistance with the construction of our light delivery system. We also thank the staff and students of the Monash Biomedical Imaging center for their help with imaging data acquisition, and our participants for their time and effort.

Data Availability

The first-level model outputs and scripts supporting our findings are available at https://osf.io/6ep4t/.

Funding Statement

This work was funded by a Turner Institute Strategic Project Grant awarded to SWC, SDJ, EMM and AJKP and a Medicine Nursing and Health Sciences Platform Access Grant awarded to SWC and GRP. GRP is supported by an ACURF Program Grant. SDJ is supported by an Australian National Health and Medical Research Council Fellowship (APP1174164). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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Decision Letter 0

Tudor C Badea

1 Mar 2021

PONE-D-21-01352

Afraid of the dark: Light acutely suppresses activity the human amygdala

PLOS ONE

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Tudor C Badea, M.D., M.A., Ph.D.

Academic Editor

PLOS ONE

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Reviewers' comments:

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Comments to the Author

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Reviewer #1: Yes

Reviewer #2: Yes

**********

2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: I Don't Know

**********

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Reviewer #1: Yes

Reviewer #2: Yes

**********

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Reviewer #2: Yes

**********

5. Review Comments to the Author

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Reviewer #1: McGlashan and colleagues explore the relationship between light and mood by examining the effects of light on the amgydala using BOLD fMRI in healthy human participants. They find that light suppresses the activity of the amygdala (compared with dark), and enhances the functional connectivity between the amygdala and VMPFC. The study appears to be well designed, has been performed and analysed appropriately. I don’t have any major concerns with the manuscript, though there are some areas where I believe further discussion/interpretation is required. These are highlighted below:

Does 10lux actually drive a significant reduction in BOLD signal? Figure 1c suggests not (I cannot seem to find associated stats to compare light and dark for only 10lux/100lux). It is important to know whether 10lux drives a lower amplitude response; or whether 10lux is below threshold.

I appreciate there are differences in methodologies etc., but how do the authors reconcile their data and the findings of Vanderwalle (2007), who I believe show an activatory - rather than inhibitory - role for (blue) light?

The response time-course is relatively swift. Is there evidence that adjustments in emotional responses can occur in these time frames? Relatedly, do the authors observe any cumulative effects of light stimulation over the repeated presentations?

Can the authors comment on the circuitry by which light may suppress activity in the amygdala – ipRGCs are typically thought of showing excitatory responses following light activation.

The final sentence - perhaps a little too much conjecture (!).

Reviewer #2: Referee’s comments for authors:

McGlashan et al report results of an fMRI study assessing changes in BOLD activity in the amygdala over repeated exposures to 30s exposure to dim or moderate light. They report a dose-dependent reduction in activity in amygdala by light across this range. They also report an increase in connectivity between amygdala and ventro-medial prefrontal cortex. The results are interpreted in the context of evidence of light-dependent modulations in mood and the retinal projection to the amygdala reported in non-human species.

I am poorly qualified to comment on the quality of the fMRI data or its analysis and interpretation. I restrict my comments to those aspects relating to the light stimulus and in its application. The light stimulus is poorly described. The authors should provide details of the type of light source used, and also its color (in color coordinates or correlated color temperature). The authors correctly describe their stimulus in terms of melanopic illuminance, but the precise measure used and associated unit are missing (I assume they report ‘melanopic equivalent daytime illuminance’ with the unit of lux?).

Implicit in the interpretation of the outcome is that the effects observed are response to the presence of light. Given the timeframes involved it is at least a likely that they are a response to the appearance of light (suddenly switching on a light for a subject previously in the dark is a particular event in itself). This distinction may seem esoteric, but it has important consequences for the relationship between the current light stimulus and light regulation of mood. If the amygdala response is elicited by light appearance then it is not obviously related to light therapy impacts on mood. The timecourse of BOLD if anything supports the light appearance origin (although other explanations are possible). I would like to see the paper re-written with this distinction in mind. The findings here are consistent with vision impacting amygdala in humans, but content relating to light effects on mood should be toned down (including in the abstract). I recommend replacing

‘light’ with ‘light pulses’ in the title and abstract to make the nature of the stimulus clearer. Also the authors should include a discussion of the distinction between the presence vs appearance of light as an origin for their effects and the implications for interpretation.

Minor:

There is a word (‘in’ or ‘of’) missing in the title.

**********

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PLoS One. 2021 Jun 16;16(6):e0252350. doi: 10.1371/journal.pone.0252350.r002

Author response to Decision Letter 0

6 Apr 2021

Reviewer #1:

Does 10lux actually drive a significant reduction in BOLD signal? Figure 1c suggests not (I cannot seem to find associated stats to compare light and dark for only 10lux/100lux). It is important to know whether 10lux drives a lower amplitude response; or whether 10lux is below threshold.

The main findings in the paper are reported for the main effect of light (averaged 10 lux and 100 lux data), we have also conducted a voxel-wise analysis of the effect of light at 10 lux and 100 lux separately. For the 100 lux condition alone, activity was significantly suppressed (p=.0002, small volume corrected for bilateral amygdala). For the 10 lux condition, the suppression was significant only at an uncorrected level (p=0.01), corrected p=.065. These findings are now included in the manuscript (line 177 onwards).

I appreciate there are differences in methodologies etc., but how do the authors reconcile their data and the findings of Vanderwalle (2007), who I believe show an activatory - rather than inhibitory - role for (blue) light?

As the reviewer states, there are methodological differences between our work and that of Vandewalle et al., (2007, PLOS ONE). In that paper, the authors compare responses to different monochromatic light sources, rather than between broad spectrum light and dark. Furthermore, the light sources they used were all quite visually dim. In terms of photopic illuminance, our 10-lux condition is the most comparable, and our result was below threshold at that light level.

Vandewwalle et al., (2007) reported increased activation in the right amygdala only with the onset of blue light relative to green. This was not observed when the onset of blue light was compared to other monochromatic sources. This effect was transient in nature, that is, occurred only with the onset of the light stimuli and not as a sustained effect during blue light exposures. The authors suggest that this may reflect differences in response latencies between photoreceptors, where melanopsin expressing RGCs may be involved in regulating transient responses, while other photoreceptors contribute to the sustained effects. We observed a persistent rather than transient effect, at a light intensity which was visually much brighter. Given the significant differences in design (comparing different colours rather than light and dark) and light intensity, speculation on the mechanisms that may underly our results is difficult. However, this likely is primarily related to the contribution of different photoreceptors to different aspects of the response (transient vs. sustained), and it may be that effect observed by Vandewalle and colleagues is specific to blue light.

The response time-course is relatively swift. Is there evidence that adjustments in emotional responses can occur in these time frames? Relatedly, do the authors observe any cumulative effects of light stimulation over the repeated presentations?

Unfortunately, it is not possible to assess whether there are cumulative effects of light across the repeated presentations. fMRI signals are always subject to drift over time, and so they require detrending before analysis is performed at the block level. Any cumulative effects of repeated presentations therefore cannot be distinguished from drift in the fMRI signal.

To our knowledge, there are no studies looking at changes in subjective mood with light exposures this short, but many non-visual responses such as changes in heartrate, temperature and arousal do occur very rapidly (Prayag, Jost, Avouac, Dumortier, & Gronfier, 2019). We suggest that our observed changes represent a non-conscious change which may ultimately lead to differences in affective experiences. Although limited, there are findings from fMRI studies showing that acute, short time-scale changes in amygdala activity do relate to real-world experience of emotion. For example, persistence in amygdala activity following the presentation of negative affective stimuli is associated with decreased positive affect and increased negative affect in daily life (Puccetti et al., 2021).

Prayag, A. S., Jost, S., Avouac, P., Dumortier, D., & Gronfier, C. (2019). Dynamics of Non-visual Responses in Humans: As Fast as Lightning? Frontiers in Neuroscience, 13(126). doi:10.3389/fnins.2019.00126

Puccetti, N. A., Schaefer, S. M., van Reekum, C. M., Ong, A. D., Almeida, D. M., Ryff, C. D., . . . Heller, A. S. (2021). Linking Amygdala Persistence to Real-World Emotional Experience and Psychological Well-Being. The Journal of neuroscience, JN-RM-1637-1620. doi:10.1523/JNEUROSCI.1637-20.2021

Can the authors comment on the circuitry by which light may suppress activity in the amygdala – ipRGCs are typically thought of showing excitatory responses following light activation.

Although ipRGCs have traditionally been thought to be excitatory, recent evidence demonstrates that there is a subtype of ipRGCs which release inhibitory GABA (Sonoda et al., 2020). Furthermore, it has been shown that distinct populations of ipRGCs project to distinct brain areas to control different non-visual effects of light (Rupp et al., 2019). Therefore, it is plausible that there is a subtype of ipRGCs which project to the amygdala in humans and are inhibitory. In line with our findings, a recent paper found that light exposure suppressed activity in the human habenula, a brain area involved in mood and reward regulation (Kaiser et al., 2019). Although specific retina-brain pathways have not been as well characterised in humans as in animal models, it is highly likely that some projections are inhibitory in nature, and that this explains our finding. We have commented on this potential circuitry in the paper from line 230.

Kaiser, C., Kaufmann, C., Leutritz, T., Arnold, Y. L., Speck, O., & Ullsperger, M. (2019). The human habenula is responsive to changes in luminance and circadian rhythm. Neuroimage, 189, 581-588.

Rupp, A. C., Ren, M., Altimus, C. M., Fernandez, D. C., Richardson, M., Turek, F., . . . Schmidt, T. M. (2019). Distinct ipRGC subpopulations mediate light’s acute and circadian effects on body temperature and sleep. eLife, 8. doi:10.7554/elife.44358

Sonoda, T., Li, J. Y., Hayes, N. W., Chan, J. C., Okabe, Y., Belin, S., . . . Schmidt, T. M. (2020). A noncanonical inhibitory circuit dampens behavioral sensitivity to light. Science, 368(6490), 527-531. doi:10.1126/science.aay3152

The final sentence - perhaps a little too much conjecture (!).

We have removed this sentence.

Reviewer #2:

The light stimulus is poorly described. The authors should provide details of the type of light source used, and also its color (in color coordinates or correlated color temperature). The authors correctly describe their stimulus in terms of melanopic illuminance, but the precise measure used and associated unit are missing (I assume they report ‘melanopic equivalent daytime illuminance’ with the unit of lux?).

We had described the light source in detail, but this appears to have been missed by the reviewer. The light source is a Halogen bulb, with a CCT of 2800K (included in line 109 onward). Light was delivered using a fibre optic system and controlled using custom a MatLab script. Intensity of the light source was described in terms of photopic illuminance, and irradiance (in µW/cm²), and we supplied tabulated spectral data as a supplement.

Melanopic equivalent daytime illuminance is now reported in the text, having been determined using the updated CIE guidelines (Commission Internationale de l'Eclairage [CIE], 2018).

Implicit in the interpretation of the outcome is that the effects observed are response to the presence of light. Given the timeframes involved it is at least a likely that they are a response to the appearance of light (suddenly switching on a light for a subject previously in the dark is a particular event in itself). This distinction may seem esoteric, but it has important consequences for the relationship between the current light stimulus and light regulation of mood. If the amygdala response is elicited by light appearance then it is not obviously related to light therapy impacts on mood. The timecourse of BOLD if anything supports the light appearance origin (although other explanations are possible). I would like to see the paper re-written with this distinction in mind. The findings here are consistent with vision impacting amygdala in humans, but content relating to light effects on mood should be toned down (including in the abstract). I recommend replacing ‘light’ with ‘light pulses’ in the title and abstract to make the nature of the stimulus clearer. Also the authors should include a discussion of the distinction between the presence vs appearance of light as an origin for their effects and the implications for interpretation.

We thank the reviewer for this point and agree that it is reasonable to suggest that our result is also related to the change in visual experience which is inherent in the presentation of light. We note that previous work has observed transient effects related to the onset of light (discussed above), as distinct from sustained effects across light exposure periods of similar durations (~30 seconds). Therefore, although our light exposure durations are relatively short, they are likely sufficient to produce responses which are due to the presence of light, rather than only the appearance of light. Nonetheless, we have edited the paper to acknowledge this alternate interpretation and agree that investigating these effects under different stimulus durations will be an important thing to consider in future research (line 249 onwards).

Regarding the reviewers point about ‘light pulses’, we have elected not to make this change. This is because we do not feel that this would add clarity about the nature of the stimuli. Depending on the field, the term ‘light pulse’ can convey a very different meaning. For example, in circadian rhythms a 6.5-hour light exposure may be described as a light pulse, whereas if we are considering pupil responses, a light pulse may be as short as milliseconds. Therefore, we do not feel that the word “pulse” would aid the reader. We have reported the duration of the exposures in the abstract for clarity, and the timescale is outlined in the methods.

There is a word (‘in’ or ‘of’) missing in the title.

This typo has been corrected, thank you.

Attachment

Submitted filename: Response to Reviewers.docx

Click here for additional data file. (25.2KB, docx)

Decision Letter 1

Tudor C Badea

14 May 2021

Afraid of the dark: Light acutely suppresses activity in the human amygdala

PONE-D-21-01352R1

Dear Dr. Cain,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

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Kind regards,

Tudor C Badea, M.D., M.A., Ph.D.

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

Reviewer #2: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: Thanks to the authors for addressing my previous comments. I have no further queries with the manuscript.

Reviewer #2: The authors have addressed my comments adequately. This work is now suitable for publication in my opinion.

**********

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Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: No

Associated Data

    This section collects any data citations, data availability statements, or supplementary materials included in this article.

    Supplementary Materials

    S1 Fig. Light, compared with dark, increases activity in the visual cortex and lateral geniculate.

    Increased activity (p<0.05, voxel-wise corrected) during light compared to dark was observed in the visual cortex (local maxima MNI coordinate: 14, -90, 2, tmax = 8.98) and right lateral geniculate area (tmax = 6.3, MNI coordinate: 26, -25, -2). Bilateral lateral geniculate area showed activation at p<0.001. However, this did not survive whole-brain correction for significance. Voxels with increased activity in the visual cortex and lateral geniculate area of the thalamus are shown. Green voxels represent the voxels significant at p<0.05 (voxel-wise corrected). Red-yellow color represent increased activity at p<0.001, uncorrected. The brain images are presented on a radiological orientation.

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    S1 Table. Spectral power distribution for the light source.

    Data are shown for a measure of the light source at ~100 photopic lux in 1 nm bins from 360nm to 760nm. Data are reported in μW/cm2, measured using a MK350N Spectrometer (UPRTek, Taiwan).

    (XLSX)

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    S1 Data

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    Attachment

    Submitted filename: Response to Reviewers.docx

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    Data Availability Statement

    The first-level model outputs and scripts supporting our findings are available at https://osf.io/6ep4t/.

    Articles from PLoS ONE are provided here courtesy of PLOS

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