Efficacy of Morning Shorter Wavelength Lighting in the Visible (Blue) Range and Broad-Spectrum or Blue-Enriched Bright White Light in Regulating Sleep, Mood, and Fatigue in Traumatic Brain Injury: A Systematic Review

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

 

Thank you for the opportunity to revie this interesting manuscript.  The authors conducted a systematic review of papers examining the efficacy of morning blue/white light exposure on sleep, mood, and fatigue issues among patients with TBI.  They ultimately included 7 published studies.  Results showed that light exposure therapy was associated with phase advancement in sleep timing, improved daytime sleepiness, increased total sleep time, and improved mood.  Overall, this is an important emerging topic in TBI treatment and the paper is well written, pertinent, and clear.  There were some apparent errors in the data tables, but overall this paper provides a nice summary contribution to the literature.  I outline my concerns and suggestions below:

 

This study provides an important summary of this emerging field.  The authors focus on blue and white light as a means for regulating sleep, fatigue, and mood.  This is very interesting, but they don’t really discuss the neurologic underpinnings that contribute to these effects.  Naïve readers would likely want to know “why blue” or “why white” and “why is amber or red a placebo”.  I think it would be helpful for the authors to devote a paragraph explaining why blue wavelength/white light produces effects on the brain/circadian system in this way (e.g., ipRGCs and the suprachiasmatic nucleus of the hypothalamus, etc).  While there is a sentence alluding to this in the discussion, it would provide a bit more understanding at the outset if this was described in more detail.

 

I found a number of apparent errors in the data that are reported in Table 1.  I would encourage the authors to be sure to check the data in each of these entries a bit more closely before this is published.  For instance, a few errors I noted include:

                  Bajaj et al [15]:  The type of light was stated at “Litebook device” (a white light device) but the authors actually used Blue Light Treatment with a Philips GoLite Blu for the active treatment.  It is not clear where they obtained the wavelength and lux numbers, but other research using this device show the values at λ = 469 nm, at 214 Lux, and an identical amber light version for the placebo condition. 

                  Killgore et al [17]:  The definition listed for mTBI appears to be missing some of the criteria that were used (VA/DoD practice guidelines (VA/DoD Management of Concussion/mTBI Working Group, 2009), as the current authors only state that it was based on GCS score (which is not entirely accurate). 

                  Raikes [19]:  The definition listed for mTBI appears to be missing some of the criteria that were used (VA/DoD practice guidelines (VA/DoD Management of Concussion/mTBI Working Group, 2009), as the current authors only state that it was based on GCS score (which is not entirely accurate).  The table also lists the type of injury as “sports injury” but that was not specifically defined in the Raikes paper. 

 

For Table 2, the findings of the Raikes et al [19] paper suggest that there was no change in ESS and BDI scores but a decline in WASO scores.  However, the original table in the Raikes manuscript shows something different.  Specifically, ESS and BDI were significantly reduced when multiple comparisons were not considered, but became non-significant when corrected for the vast number of outcomes and comparisons included in the analyses.  On the other hand, WASO scores were only marginally significant for the uncorrected and not at all significant for the FDR corrected values.  The large number of outcomes and modest sample size is why the authors emphasized effect size estimates rather than statistical significance.  Thus, the authors of the current manuscript need to check the details in their table, and appropriately discuss the findings in light of the effect sizes.

 

In section 2.4, line132-133, the authors state that in the Killgore et al [17] study, morning blue light exposure led to “shorter nap times observed during multiple sleep latency tests (MSLT), indicative of improved executive function.”  However, it is unclear how improved MSLT directly indicates improved executive function in and of itself.  If it was linked to executive function, that would make sense.  I suggest they re-phrase this a bit more clearly.

 

Line 133 in section 2.4 says that “Bajaj et al. [15] found no significant impact of bright white light therapy….”  However, that study looked at blue versus amber, not white light.

Author Response

We greatly appreciate you taking the time to review our manuscript, and we are grateful to have had the opportunity to improve our manuscript with your help.

Comment 1: The authors focus on blue and white light as a means for regulating sleep, fatigue, and mood.  This is very interesting, but they don’t really discuss the neurologic underpinnings that contribute to these effects.

Response: We have now addressed this point (Lines 265-276). Please see below

“Neurological underpinnings may explain some of the benefits of morning blue light exposure. For example, Bajaj et al. [19] provided preliminary evidence suggesting that morning blue light exposure facilitates recovery of brain structure and function following mild traumatic brain injury (mTBI) linked to reduced daytime sleepiness. Their study examined white matter water diffusion in the brain. Killgore et al. [21] further demonstrated exposure to blue light showed stronger connections between a part of the brain called the thalamus and other areas involved in attention, planning, and language (frontal and parietal cortex). This was not seen with the amber light. Stronger connections between these brain areas were linked to better daytime alertness, and executive functioning. Other studies have shown patients with mTBI decreased functional connectivity between the thalamus and cortical regions [30].”

Comment 2: Naïve readers would likely want to know “why blue” or “why white” and “why is amber or red a placebo”.  I think it would be helpful for the authors to devote a paragraph explaining why blue wavelength/white light produces effects on the brain/circadian system in this way (e.g., ipRGCs and the suprachiasmatic nucleus of the hypothalamus, etc).  While there is a sentence alluding to this in the discussion, it would provide a bit more understanding at the outset if this was described in more detail.

Response: We have now addressed this point (Lines 54-67). Please see below.

“White light, consisting of all visible wavelengths (polychromatic), can reset the circadian clock. However, blue light (monochromatic), approximately at 479 nm, is the strongest synchronizing agent for the clock in humans [12]. Amber light (at 570 nm) and red light (at 650 nm) are at the opposite end of the light spectrum. Light entrains the circadian system via the eye, received by intrinsically photosensitive retinal ganglion cells (ipRGC) con-taining the receptor melanopsin [13]. Melanopsin sends signals to the suprachiasmatic nucleus (SCN), which uses this light information to regulate melatonin secretion from the pineal gland. In the presence of light, the SCN uses light information to synchronize its internal clock with the external light-dark cycle. The effectiveness of light exposure de-pends on factors such as spectrum (white vs. blue emphasis), intensity, duration, and timing relative to circadian rhythms [14]. Sunlight, rich in both white and blue light, is particularly effective due to its high intensity (over 100,000 lux). Morning light exposure is most impactful, promoting earlier sleep, alertness, and mood [15,16].”

Comment 3: I found a number of apparent errors in the data that are reported in Table 1.  I would encourage the authors to be sure to check the data in each of these entries a bit more closely before this is published.  

Response: We have made changes to Table 1 following careful review of original articles based on your advice.

 

Comment 4: For Table 2, the findings of the Raikes et al [19] paper suggest that there was no change in ESS and BDI scores but a decline in WASO scores.   Thus, the authors of the current manuscript need to check the details in their table, and appropriately discuss the findings in light of the effect sizes.

Response: We have made changes to Table 2 based on your advice. BDI was removed since this manuscript does not examine depression.   

Comment 5: In section 2.4, line132-133, the authors state that in the Killgore et al [17] study, morning blue light exposure led to “shorter nap times observed during multiple sleep latency tests (MSLT), indicative of improved executive function.  However, it is unclear how improved MSLT directly indicates improved executive function in and of itself.  If it was linked to executive function, that would make sense.  I suggest they re-phrase this a bit more clearly.”

Response: Changes have been made to the Results (Line 184-190), please see below.

“Two studies using the MSLT found adults with mTBI had significantly delayed daytime sleep onset after morning blue light exposure, suggesting reduced daytime sleepiness [19,21]. Interestingly, all four studies showing improved sleepiness used blue light [19,21,23,24], while the two with no significant effect used bright white light [20,22]. Re-garding the two studies that examined mood, only one study by Elliot et al. [25] showed improvement in mood with bright white light exposure in veterans with mTBI.”

Changes have also been made to the Discussions (Line 307-313), please see below.

“While natural light is the ideal source, all studies used light devices for standardized light exposure to minimize external factors introduced by varying light exposure levels in natural settings. However, sleep-wake timing might influence light therapy effectiveness. Since TBI can cause sleep-wake misalignment with the natural internal clock [6], this misalignment could affect how well light exposure synchronizes the rhythm. Future studies that evaluate sleep-wake patterns, advanced versus delayed, would assist with increasing the understanding of the potential benefits of light therapy in TBI patients.”

Comment 6: Line 133 in section 2.4 says that “Bajaj et al. [15] found no significant impact of bright white light therapy….”  However, that study looked at blue versus amber, not white light.”

Response: Changes have been made to Table 1.

We trust that the issues above have been addressed and clarified sufficiently and we look forward to hearing from you in the near future.

Reviewer 2 Report

Comments and Suggestions for Authors

In this systematic review article Moi Chow and colleagues reviewed the impact of morning blue light and bright white light exposure among TBI patients with various severity. The effects were evaluated with a focus on sleep, mood, and fatigue. The authors nicely discussed the importance of light on circadian rhythms in humans and whether its disruption can affect mood and the sleep/wake cycle.

The impact of light exposure after brain injury and the effects on circadian rhythms seems to be crucial in TBI, however, several factors should be considered when cases are being evaluated. This includes the parameters involved in the protocol of light exposure such as wavelength, intensity, timing, and duration of exposure. The reviewed studies in this manuscript employed different protocols that can affect the outcome of the trials. The effect of monochromatic low intensity blue light versus high intensity polychromatic white light was discussed by the authors. However, differences in light exposure duration, timing of exposure and the individual differences in sleep/wake timing are required for a systematic review of addressed studies.

Size and location of the injury as well as timing after the onset of the injury were not considered in this review. For example, after the TBI, the brain undergoes structural and functional reorganization based on the injury timelines. The included studies ranged from subacute phase to chronic and even several years after the TBI and thus cannot be accurately compared, thus the value of this systematic review is limited.

 

Comments on the Quality of English Language

The English seemed fine.

Author Response

We greatly appreciate you taking the time to review our manuscript, and we are grateful to have had the opportunity to improve our manuscript with your help.

Comment 1: The reviewed studies in this manuscript employed different protocols that can affect the outcome of the trials. The effect of monochromatic low intensity blue light versus high intensity polychromatic white light was discussed by the authors. However, differences in light exposure duration, timing of exposure and the individual differences in sleep/wake timing are required for a systematic review of addressed studies.

Response: We have amended the Discussion to address the points you have raised (Lines 300-313), please see below.

“The use of monochromatic blue light with low intensity versus polychromatic bright white light with higher intensity did not differentiate the study findings, except for sleepiness. This finding is noteworthy since blue light is the dominant light detected by melanopsin receptors [34]. Nevertheless, polychromatic light can be as effective in eliciting circadian responses [35] as seen in the study by Elliott et al. [25]. The reviewed studies used a light exposure range of 30-60 minutes, with most studies (5 out of 7) using 30 minutes. These exposure durations appear practical, yet a dose-response curve has not been constructed. While natural light is the ideal source, all studies used light devices for standardized light exposure to minimize external factors introduced by varying light exposure levels in natural settings. However, sleep-wake timing might influence light therapy effectiveness. Since TBI can cause sleep-wake misalignment with the natural internal clock [6], this misalignment could affect how well light exposure synchronizes the rhythm. Future studies that evaluate sleep-wake patterns, advanced versus delayed, would assist with increasing the understanding of the potential benefits of light therapy in TBI patients.”

Comment 2: Size and location of the injury as well as timing after the onset of the injury were not considered in this review. For example, after the TBI, the brain undergoes structural and functional reorganization based on the injury timelines. The included studies ranged from subacute phase to chronic and even several years after the TBI and thus cannot be accurately compared, thus the value of this systematic review is limited.”

Response: We thank you for this feedback. We have amended the Discussion to address the points you have raised (Lines 223-231), please see below.

“Our review reveals diverse effects of blue or bright white light on sleep, mood, and fatigue, depending on TBI severity and specific outcome measures. Notably, reporting the size and location of TBI in the reviewed papers proved challenging, as not all patients received medical diagnostic imaging. Furthermore, the timing of injuries ranged widely, from subacute to chronic stages, spanning several years post-TBI. Such heterogeneity means that studies cannot be accurately compared. Therefore, we focused on the severity of TBI, a common denominator for injuries. Consequently, we made comparisons of light exposure outcomes according to the severity of TBI based on the VA/DoD practice guidelines and Glasgow Coma Scale scores.”

We trust that the issues above have been addressed and clarified sufficiently and we look forward to hearing from you in the near future.

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

Thank you for the opportunity to re-review this manuscript.  The authors were generally responsive to my suggestions and the revisions have definitely improved the quality of the paper.  I only have a couple of minor suggestions:

 

In the first paragraph of the discussion, the authors have added new text stating “reporting the size and location of TBI in the reviewed papers proved challenging…not all patients received medical diagnostic imaging.”  The use of the term TBI here seems a bit vague, as it is not clear whether they are referring to the impact site, the brain lesion, the form of injury, etc.  I would suggest replacing the term “TBI” here with something more specific, such as “the site of impact or brain lesion” or something similar.  It might also be worthwhile to clarify that this lack of specificity and diffuse nature of injury is the norm for mild traumatic brain injuries.  By definition, there is no identifiable brain lesion in an mTBI—and so medical diagnostic imaging does not show anything in an mTBI.

 

On line 275 in the Discussion, the authors state that other studies have shown “decreased functional connectivity between the thalamus and cortical regions [30].”  Since they are referring to the changes in brain structure to light exposure, I might suggest adding an additional clarifying phrase at the end of that sentence that says, “…, a pattern which was reversed by 6-weeks of daily morning blue light exposure [21].”

 

Author Response

We are grateful for your further feedback.

In the first paragraph of the discussion, the authors have added new text stating “reporting the size and location of TBI in the reviewed papers proved challenging…not all patients received medical diagnostic imaging.”  The use of the term TBI here seems a bit vague, as it is not clear whether they are referring to the impact site, the brain lesion, the form of injury, etc.  I would suggest replacing the term “TBI” here with something more specific, such as “the site of impact or brain lesion” or something similar.  It might also be worthwhile to clarify that this lack of specificity and diffuse nature of injury is the norm for mild traumatic brain injuries.  By definition, there is no identifiable brain lesion in an mTBI—and so medical diagnostic imaging does not show anything in an mTBI.

Response:

We have made the corrections on line 224-227:

“Notably, reporting the location of brain lesions in the reviewed studies was challenging. Not all patients received medical diagnostic imaging (MDI), and MDI is often impractical for mTBI due to the diffuse nature of the injury and the common lack of specific findings.”

On line 275 in the Discussion, the authors state that other studies have shown “decreased functional connectivity between the thalamus and cortical regions [30].”  Since they are referring to the changes in brain structure to light exposure, I might suggest adding an additional clarifying phrase at the end of that sentence that says, “…, a pattern which was reversed by 6-weeks of daily morning blue light exposure [21].”

Response:

We’ve made the corrections on line 276-278:

Other studies have shown patients with mTBI decreased functional connectivity between the thalamus and cortical regions [30], a pattern which was reversed by 6-weeks of daily morning blue light exposure [21].

Reviewer 2 Report

Comments and Suggestions for Authors

The authors have adequately responded to my previous comments.

Comments on the Quality of English Language

Minor editing required.

Author Response

We thank you for your feedback.