Transcranial Photobiomodulation to Improve Cognition in Gulf War Illness

Paula I Martin, Linda Chao, Maxine H Krengel, Michael D Ho, Megan Yee, Robert Lew, Jeffrey Knight, Michael R Hamblin, Margaret A Naeser, Paula I Martin, Linda Chao, Maxine H Krengel, Michael D Ho, Megan Yee, Robert Lew, Jeffrey Knight, Michael R Hamblin, Margaret A Naeser

Abstract

Introduction: Approximately 25-30% of veterans deployed to Kuwait, 1990-91, report persistent multi-symptom Gulf War Illness (GWI) likely from neurotoxicant exposures. Photobiomodulation (PBM) in red/near-infrared (NIR) wavelengths is a safe, non-invasive modality shown to help repair hypoxic/stressed cells. Red/NIR wavelengths are absorbed by cytochrome C oxidase in mitochondria, releasing nitric oxide (increasing local vasodilation), and increasing adenosine tri-phosphate production. We investigated whether PBM applied transcranially could improve cognition, and health symptoms in GWI. Materials and Methods: Forty-eight (40 M) participants completed this blinded, randomized, sham-controlled trial using Sham or Real, red/NIR light-emitting diodes (LED) applied transcranially. Fifteen, half-hour transcranial LED (tLED) treatments were twice a week (7.5 weeks, in-office). Goggles worn by participant and assistant maintained blinding for visible red. Pre-/Post- testing was at Entry, 1 week and 1 month post- 15th treatment. Primary outcome measures were neuropsychological (NP) tests; secondary outcomes, Psychosocial Questionnaires, including PTSD. Results: Primary Analyses (all participants), showed improvement for Real vs. Sham, for Digit Span Forwards (p < 0.01); and a trend for Trails 4, Number/Letter Sequencing (p < 0.10). For secondary outcomes, Real group reported more improvement on the SF-36V Plus, Physical Component Score (p < 0.08). Secondary Analyses included only subjects scoring below norm (50%ile) at Entry, on specific NP test/s. Real and Sham improved at 1 week after 15th treatment; however, at 1 month, only those receiving Real improved further: Digit Span Total, Forwards and Backwards; Trails 4, Number/Letter Sequencing; California Verbal Learning Test-II, long delay free recall; Continuous Performance Test-II, False Alarm Rate; and Color-Word Interference, Stroop, Trial 3, Inhibition; Sham group worsened, toward Entry values. Only those with more post-traumatic stress disorder (PTSD) symptomatology at Entry, receiving Real, continued to have additional PTSD reduction at 1 month; Sham regressed. Conclusion: This study was underpowered (n = 48), with large heterogeneity at Entry. This likely contributed to significance or trend to significance, for only two of the NP tests (Digit Span Forwards; Trails 4, Number/Letter Sequencing) and only one general health measure, the SF-36V Plus, Physical Component Score. More subjects receiving Real, self-reported increased concentration, relaxation and sleep. Controlled studies with newer, transcranial LED home treatment devices are warranted; this is expected to increase enrollment. Clinical Trial Registration: www.ClinicalTrials.gov, identifier: NCT01782378.

Keywords: Gulf war illness (GWI); LLLT (low-level laser/light therapy); cognitive function; light-emitting diode (LED); photobiomodulation (PBM).

Conflict of interest statement

MRH declares the following potential conflicts of interest: Scientific Advisory Boards: Transdermal Cap Inc, Cleveland, OH; BeWell Global Inc, Wan Chai, Hong Kong; Hologenix Inc. Santa Monica, CA; LumiThera Inc, Poulsbo, WA; Vielight, Toronto, Canada; Bright Photomedicine, São Paulo, Brazil; Quantum Dynamics LLC, Cambridge, MA; Global Photon Inc, Bee Cave, TX; Medical Coherence, Boston MA; NeuroThera, Newark DE; JOOVV Inc, Minneapolis-St. Paul MN; AIRx Medical, Pleasanton CA; FIR Industries, Inc. Ramsey, NJ; UVLRx Therapeutics, Oldsmar, FL; Ultralux UV Inc, Lansing MI; Illumiheal & Petthera, Shoreline, WA; MB Lasertherapy, Houston, TX; ARRC LED, San Clemente, CA; Varuna Biomedical Corp. Incline Village, NV; Niraxx Light Therapeutics, Inc, Boston, MA. Consulting; Lexington Int, Boca Raton, FL; USHIO Corp, Japan; Merck KGaA, Darmstadt, Germany; Philips Electronics Nederland B.V. Eindhoven, Netherlands; Johnson & Johnson Inc, Philadelphia, PA; Sanofi-Aventis Deutschland GmbH, Frankfurt am Main, Germany. Stockholdings: Global Photon Inc, Bee Cave, TX; Mitonix, Newark, DE. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2021 Martin, Chao, Krengel, Ho, Yee, Lew, Knight, Hamblin and Naeser.

Figures

Figure 1
Figure 1
Study consort chart (VA Boston healthcare system and San Francisco VA medical center).
Figure 2
Figure 2
LED devices. (A) NIR, LED-lined helmet (PhotoMedex, Horsham, PA). (B) LED cluster head placement configuration inside PhotoMedex helmet. (C) Separate clear plastic liner assigned to each participant to fit inside the PhotoMedex helmet (to protect diodes and for hygiene), and control box where each row could be turned on and off separately. (D) Two NIR, LED cluster heads for placement over the ears (MedX Health, Toronto). (E) Red intranasal LED applicator (Vielight, Toronto; Hayward, CA); note, an identical NIR intranasal was also used in the other nostril. (F) NIR, LED-lined helmet (Thor Photomedicine, London, UK; Hampstead, MD), used if the participant's head had a circumference greater than 24 inches. (G) LED cluster head placement configuration inside the Thor helmet, with both red and NIR diodes in each cluster head. Only the NIR diodes were turned on for this study. During all helmet treatments, the midline row was first treated, then turned off, and then the left and right sides were treated. The fans for each LED cluster head inside the helmet (for cooling) were always turned on. Sham and real treatments felt identical. Participants and assistant wore goggles to block the red intranasal light. NIR, near-infrared wavelength; LED, light-emitting diodes. See Table 3 for LED specifications and treatment parameters. (E) Printed with permission from the Vielight Co.
Figure 3
Figure 3
Graphed results for primary analyses (all participants), mixed design random effects model for primary outcome measures/cognitive measures, for four NP tests over time. (A,B,D) Higher scores indicate better outcome. (C) Continuous performance test, only the real group improved, showing shorter reaction time at 1 month post- treatment; the sham group showed no change. (E) SF-36V plus health questionnaire, physical component score (a secondary outcome measure), only the real group endorsed fewer symptoms at 1 week post- LED, relative to entry; whereas the sham group endorsed more symptoms at 1 week and 1 month. See Tables 4A,B for p-values.
Figure 4
Figure 4
Graphed results for secondary analyses (only subjects who scored below norm at entry, on a specific test), primary outcome/cognitive measures for five NP tests and one domain score. These reflect the same factors as the primary analyses [time (pre-Tx entry, 1-Wk post- Tx, 1-Mo post- Tx); and treatment (sham, real), and their interaction], for each. The domain score for learning and memory reflects a composite score for seven NP tests: the CVLT (total; short and long delay - free and cued recall); and the rey-osterreith complex figure test (immediate and delayed recall). There was a consistent pattern across all graphs, where both groups showed improvement at 1 week post- the final, sham or real LED treatment, but only those who received real LED continued to improve at the 1-month, post- testing time point. Those who received sham, regressed at 1 month, approaching entry values.
Figure 5
Figure 5
Graphed results for secondary analyses, for secondary outcome measures/psychosocial self-report/questionnaires for PTSD (A,B); and depression (C–E). All participants were studied for each secondary outcome measure, but only in subgroups as stratified by level of severity at entry [mild, moderate, severe]. (A) Scores less than 36 (mild or no PTSD) showed little change post-treatment in either group, or at either post- testing time point. (B) In contrast to that, for those entering with PCL-C scores greater than 36 (indicative of PTSD symptoms reported at the clinical level), both groups reported reduced PTSD at 1-week post-treatment. However, at 1-month, only the real LED group continued to report even fewer PTSD symptoms, while those in sham, reported increased symptoms, toward entry values. (C) For depression, on the beck depression inventory, there was no change for those with mild or no depression (BDI scores of only 0–19, at entry) in either treatment condition at any time of post- testing. (D,E) However, for those with moderate or severe depression (BDI scores of 20–29, or >30, respectively), those in the sham and real LED groups both reported less depression at 1 week post- treatment. At 1 month post- treatment, however, both groups began to return slightly toward entry values. No difference between sham and real LED was observed, likely due to small numbers in the subgroups.

References

    1. Steele L. Prevalence and patterns of Gulf War illness in kansas veterans: association of symptoms with characteristics of person, place, and time of military service. Am J Epidemiol. (2000) 152:992–1002. 10.1093/aje/152.10.992
    1. Research Advisory Committee on Gulf War Veterans Illnesses Gulf War Illness and the Health of Gulf War Veterans: Research Update and Recommendations, 2009-2013. Boston, MA: US Government Printing Office; (2014).
    1. Fukuda K, Nisenbaum R, Stewart G, Thompson WW, Robin L, Washko RM, et al. . Chronic multisymptom illness affecting air force veterans of the gulf war. JAMA. (1998) 280:981. 10.1001/jama.280.11.981
    1. White RF, Steele L, O'Callaghan JP, Sullivan K, Binns JH, Golomb BA, et al. . Recent research on Gulf War illness and other health problems in veterans of the 1991 Gulf War: effects of toxicant exposures during deployment. Cortex. (2016) 74:449–75. 10.1016/j.cortex.2015.08.022
    1. Janulewicz PA, Krengel MH, Maule A, White RF, Cirillo J, Sisson E, et al. . Neuropsychological characteristics of Gulf War illness: a meta-analysis. PLoS ONE. (2017) 12:e0177121. 10.1371/journal.pone.0177121
    1. Chao LL, Zhang Y, Buckley S. Effects of low-level sarin and cyclosarin exposure on white matter integrity in Gulf War Veterans. NeuroToxicol. (2015) 48:239–48. 10.1016/j.neuro.2015.04.005
    1. Abu-Qare AW, Abou-Donia MB. Combined Exposure To Deet (N,N -Diethyl- M -Toluamide) and permethrin-induced release of rat brain mitochondrial cytochrome C. J Toxicol Env Health A. (2001) 63:243–52. 10.1080/15287390151143640
    1. Kaur P, Radotra B, Minz R, Gill K. Impaired mitochondrial energy metabolism and neuronal apoptotic cell death after chronic dichlorvos (OP) exposure in rat brain. NeuroToxicol. (2007) 28:1208–19. 10.1016/j.neuro.2007.08.001
    1. Golomb BA, Allison M, Koperski S, Koslik HJ, Devaraj S, Ritchie JB. Coenzyme Q10 benefits symptoms in Gulf War veterans: results of a randomized double-blind study. Neural Comp. (2014) 26:2594–651. 10.1162/NECO_a_00659
    1. Shetty GA, Hattiangady B, Upadhya D, Bates A, Attaluri S, Shuai B, et al. . Chronic oxidative stress, mitochondrial dysfunction, Nrf2 Activation and inflammation in the hippocampus accompany heightened systemic inflammation and oxidative stress in an animal model of Gulf War Illness. Front Mol Neurosci. (2017) 10:182. 10.3389/fnmol.2017.00182
    1. Abdullah L, Evans JE, Joshi U, Crynen Reed J, Mouzon B, et al. . Translational potential of long-term decreases in mitochondrial lipids in a mouse model of Gulf War Illness. Toxicol. (2016). 372:22–33. 10.1016/j.tox.2016.10.012
    1. Chen Y, Meyer JN, Hill HZ, Lange G, Condon MR, Klein JC, et al. Role of mitochondrial DNA damage and dysfunction in veterans with Gulf War Illness. PLoS ONE. (2017) 12:e0184832 10.1371/journal.pone.0184832
    1. Sullivan K. Cognitive functioning in treatment seeking gulf war veterans: pyridostigmine bromide use and PTSD. J Psychopath Behl Assess. (2003) 25:95–103. 10.1023/A:1023342915425
    1. Golomb BA. Acetylcholinesterase inhibitors and Gulf War illnesses. Proc Natl Acad Sci USA. (2008) 105:4295–300. 10.1073/pnas.0711986105
    1. Koslik HJ, Hamilton G, Golomb BA. Mitochondrial dysfunction in Gulf War Illness revealed by 31 phosphorus magnetic resonance spectroscopy: a case-control study. PLoS ONE. (2014) 9:e92887. 10.1371/journal.pone.0092887
    1. Rayhan RU, Raksit MP, Timbol CR, Adewuyi O, Vanmeter JW, Baraniuk JN. Prefrontal lactate predicts exercise-induced cognitive dysfunction in Gulf War Illness. Am J Transl Res. (2013) 5:212–23.
    1. O'Callaghan JP, Kelly KA, Locker AR, Miller DB, Lasley SM. Corticosterone primes the neuroinflammatory response to DFP in mice: potential animal model of Gulf War Illness, J. Neurochem. (2015) 133:708–21. 10.1111/jnc.13088
    1. O'Callaghan JP, Miovicz LT, Kelly KA. Supporting a neuroimmune basis of Gulf War illness. EBioMed. (2016) 13:5–6. 10.1016/j.ebiom.2016.10.037
    1. Georgopoulos AP, James LM, Carpenter AF, Engdahl BE, Leuthold AC, Lewis SM. Gulf War illness (GWI) as a neuroimmune disease. Brain Res. (2017) 235:3217–25. 10.1007/s00221-017-5050-0
    1. Johnson GJ, Slater BC, Leis LA, Rector TS, Bach RR. Blood biomarkers of chronic inflammation in gulf war illness. PLoS ONE. (2016) 11:e0157855. 10.1371/journal.pone.0157855
    1. Mester E, Spiry T, Szende B, Tota JG. Effect of laser rays on wound healing. Am J Surg. (1971) 122:532–5. 10.1016/0002-9610(71)90482-X
    1. Ferraresi C, Parizotto NA, de Sousa MVP, Kaippert B, Huang Y-Y, Koiso T, et al. . Light-emitting diode therapy in exercise-trained mice increases muscle performance, cytochrome c oxidase activity, ATP and cell proliferation. J Biophot. (2015) 8:740–54. 10.1002/jbio.201400087
    1. Karu TI, Pyatibrat LV, Afanasyeva NI. Cellular effects of low power laser therapy can be mediated by nitric oxide. Laseurg Med. (2005) 36:307–14. 10.1002/lsm.20148
    1. Wong-Riley MT, Liang HL, Eells JT, Chance B, Henry MM, Buchmann E, et al. . Photobiomodulation directly benefits primary neurons functionally inactivated by toxins: role of cytochrome C oxidase. J Biol Chem. (2005) 280:4761–71. 10.1074/jbc.M409650200
    1. Desmet KD, Paz DA, C JJ, Eells JT, Wong-Riley MT, Henry MM, et al. . Clinical and experimental applications of NIR-LED photobiomodulation. Photomed Laser Surg. (2006) 24:121–8. 10.1089/pho.2006.24.121
    1. Ayuk SM, Houreld NN, Abrahamse H. Effect of 660 nm visible red light on cell proliferation and viability in diabetic models in vitro under stressed conditions. Lasers Med Sci. (2018) 33:1085–93. 10.1007/s10103-017-2432-2
    1. Karu T, Pyatibrat L, Kalendo G. Irradiation with He-Ne laser increases ATP level in cells cultivated in vitro. Photochem Photobiol B Biol. (1995) 27:219–23. 10.1016/1011-1344(94)07078-3
    1. Eells JT, Henry MM, Summerfelt P, Wong-Riley MT, Buchmann EV, Kane M, et al. . Therapeutic photobiomodulation for methanol-induced retinal toxicity. Proc Natl Acad Sci USA. (2003) 100:3439–44. 10.1073/pnas.0534746100
    1. Hamblin MR. Mechanisms and applications of the anti-inflammatory effects of photobiomodulation. AIMS Biophys. (2017) 4:337–61. 10.3934/biophy.2017.3.337
    1. Wan S, Anderson RR, Parrish JA. Analytical modeling for the optical properties of the skin with in vitro and in vivo applications. PhotochemPhotobiol. (1981) 34:493–9. 10.1111/j.1751-1097.1981.tb09391.x
    1. Tedford CE, DeLapp S, Jacques S, Anders J. Quantitative analysis of transcranial and intraparenchymal light penetration in human cadaver brain tissue: transcranial and intraparenchymal light penetration. Lasers Surg Med. (2015) 47:22 10.1002/lsm.22343
    1. Sun L, Peräkylä J, Kovalainen A, Ogawa KH, Karhunen PJ, Hartikainen KM. Human brain reacts to transcranial extraocular light. PLoS ONE. (2016) 11:e0149525. 10.1371/journal.pone.0149525
    1. Round R, Litscher G, Bahr F. Auricular Acupuncture with Laser. Comp Alt Med. (2013) 2013:984763. 10.1155/2013/984763
    1. Oron A, Oron U, Streeter J, de Taboada L, Alexandrovich A, Trembovler V, et al. . Low-level laser therapy applied transcranially to mice following traumatic brain injury significantly reduces long-term neurological deficits. J Neurotrauma. (2007) 24:651–6. 10.1089/neu.2006.0198
    1. Xuan W, Vatansever F, Huang L, Wu Q, Xuan Y, Dai T, et al. . Transcranial low-level laser therapy improves neurological performance in traumatic brain injury in mice: effect of treatment repetition regimen. PLoS ONE. (2013) 8:e53454. 10.1371/journal.pone.0053454
    1. De Taboada L J, El-Amouri S, Gattoni-Celli S, Richieri S, McCarthy T, et al. . Transcranial laser therapy attenuates amyloid-β peptide neuropathology in amyloid-β protein precursor transgenic Mice. J Alz Dis. (2011) 23:521–35. 10.3233/JAD-2010-100894
    1. Grillo SL, Duggett NA, Ennaceur A, Chazot PL. Non-invasive infra-red therapy (1072nm) reduces β-amyloid protein levels in the brain of an Alzheimers disease mouse model, TASTPM. J Photochem Photobiol B Biol. (2013) 123:13–22. 10.1016/j.jphotobiol.2013.02.015
    1. Purushothuman S, Johnstone DM, Nandasena C, Mitrofanis J, Stone J. Photobiomodulation with near infrared light mitigates Alzheimers disease-related pathology in cerebral cortex – evidence from two transgenic mouse models. Alz Res Therapy. (2014) 6:2. 10.1186/alzrt232
    1. Purushothuman S, Johnstone DM, Nandasena C, van Eersel J, Ittner LM, Mitrofanis J, et al. . Near infrared light mitigates cerebellar pathology in transgenic mouse models of dementia. Neurosci Lett. (2015) 591:155–9. 10.1016/j.neulet.2015.02.037
    1. Reinhart F, Massri NE, Darlot F, Torres N, Johnstone DM, Chabrol C, et al. . 810 nm near-infrared light offers neuroprotection and improves locomotor activity in MPTP-treated mice. Neurosci Res. (2015) 92:86–90. 10.1016/j.neures.2014.11.005
    1. Johnstone DM, Moro C, Stone J, Benabid AL, Mitrofanis J. Turning on lights to stop neurodegeneration: the potential of near infrared light therapy in Alzheimers and Parkinsons disease. Front Neurosci. (2016) 9:500. 10.3389/fnins.2015.00500
    1. Darlot F, Moro C, El Massri N, Chabrol C, Johnstone DM, Reinhart F, et al. . Near-infrared light is neuroprotective in a monkey model of Parkinson disease: neuroprotection. Ann Neurol. (2016) 79:59–75. 10.1002/ana.24542
    1. Wang X, Tian F, Soni S, Gonzalez-Lima F, Liu H. Interplay between up-regulation of cytochrome-c-oxidase and hemoglobin oxygenation induced by near-infrared laser. Sci Rep. (2016) 6:30540. 10.1038/srep30540
    1. Tian F, Hase SN, Gonzalez-Lima F, Liu H. Transcranial laser stimulation improves human cerebral oxygenation: human cerebral oxygenation by laser stimulation. Lasers Surg Med. (2016) 48:343–9. 10.1002/lsm.22471
    1. Schiffer F, Johnston AL, Ravichandran C, Poi A, Teicher MH, Webb RH, et al. . Psychological benefits 2 and 4 weeks after a single treatment with near infrared light to the forehead: a pilot study of 10 patients with major depression and anxiety. Beh Brain Funct. (2009) 5:46. 10.1186/1744-9081-5-46
    1. Nawashiro H, Wada K, Nakai K, Sato S. Focal Increase in cerebral blood flow after treatment with near-infrared light to the forehead in a patient in a persistent vegetative state. Photomed Laser Surg. (2012) 30:231–3. 10.1089/pho.2011.3044
    1. Hipskind SG, Grover FL, Fort TR, Helffenstein D, Burke TJ, Quint SA, et al. . Pulsed transcranial red/near-infrared light therapy using light-emitting diodes improves cerebral blood flow and cognitive function in veterans with chronic traumatic brain injury: a case series. Photobiomod Photomed Laser Surg. (2019) 37:77–84. 10.1089/photob.2018.4489
    1. Naeser MA, Saltmarche A, Krengel MH, Hamblin MR, Knight JA. Improved cognitive function after transcranial, light-emitting diode treatments in chronic, traumatic brain injury: two case reports. Photomed Laser Surg. (2011) 29:351–8. 10.1089/pho.2010.2814
    1. Naeser MA, Zafonte R, Krengel MH, Martin PI, Frazier J, Hamblin MR, et al. . Significant improvements in cognitive performance post-transcranial, red/near-infrared light-emitting diode treatments in chronic, mild traumatic brain injury: open-protocol study. J Neurotrauma. (2014) 31:117. 10.1089/neu.2013.3244
    1. Naeser MA, Martin PI, Ho MD, Krengel MH, Bogdanova Y, Knight JA, et al. . Transcranial, red/near-infrared light-emitting diode therapy to improve cognition in chronic traumatic brain injury. Photomed Laser Surg. (2016) 34:610–26. 10.1089/pho.2015.4037
    1. Martin PI, Ho MD, Bogdanova Y, Krengel MH, Knight JA, Hamblin MR, et al. LED therapy improves functional connectivity and cognition in professional football player with TBI: case study. Arch Phys Med Rehab. (2018) 99:e104–5. 10.1016/j.apmr.2018.07.374
    1. Bogdanova Y, Martin PI, Ho MD, Yee MK, Ho VT, Knight JA, et al. Improved sleep and cognition post transcranial or intranasal, red/near-infrared LED treatments in chronic TBI: Pilot case series. J Head Trauma Rehab. (2015) 30:e101–2.
    1. Lampl Y, Zivin JA, Fisher M, Lew R, Welin L, Dahlof B, et al. . Infrared laser therapy for ischemic stroke: a new treatment strategy: results of the NeuroThera Effectiveness and Safety Trial-1 (NEST-1). Stroke. (2007) 38:1843–9. 10.1161/STROKEAHA.106.478230
    1. Zivin JA, Albers GW, Bornstein N, Chippendale T, Dahlof B, Devlin T, et al. . Effectiveness and safety of transcranial laser therapy for acute ischemic stroke. Stroke. (2009) 40:1359–64. 10.1161/STROKEAHA.109.547547
    1. Naeser MA, Ho MD, Martin PI, Hamblin MR, Koo BB. Increased functional connectivity within intrinsic neural networks in chronic stroke following treatment with red/near-infrared transcranial photobiomodulation: case series with improved naming in aphasia. PhotobiomodPhotomed Laser Surg. (2020) 38:115–31. 10.1089/photob.2019.4630
    1. Saltmarche AE, Naeser MA, Ho KF, Hamblin MR, Lim L. Significant improvement in cognition in mild to moderately severe dementia cases treated with transcranial plus intranasal photobiomodulation: case series report. Photomed Laser Surg. (2017) 35:432–41. 10.1089/pho.2016.4227
    1. Chao LL. Effects of home photobiomodulation treatments on cognitive and Behavioral function, cerebral perfusion, and resting-state functional connectivity in patients with dementia: a pilot trial. Photobiomod Photomed Laser Surg. (2019) 37:133–41. 10.1089/photob.2018.4555
    1. Naeser MA, Martin PI, Ho MD, Krengel MH, Bogdanova Y, Knight JA, et al. Transcranial, near-infrared photobiomodulation to improve cognition in two, retired professional football players possibly developing CTE (0386) abstract from The international brain injury associations 13th world congress on brain injury: march 13 – 16, 2019 Toronto, Canada. Brain Inj. (2019) 33(Supp.1): 1–337. 10.1080/02699052.2019.1608749
    1. Chao LL, Barlow C, Karimpoor M, Lim L. Changes in brain function and structure after self-administered home photobiomodulation treatment in a concussion case. Front Neurol. (2020) 11:952. 10.3389/fneur.2020.00952
    1. Dmochowski GM, Shereen AD, Berisha D, Dmochowski JP. Near-infrared light increases functional connectivity with a non-thermal mechanism. Cereb. Cortex Comm. (2020) 1:tgaa004 10.1093/texcom/tgaa004
    1. Zomorrodi R, Loheswaran G, Pushparaj B, Lim L. Pulsed Near Infrared Transcranial and Intranasal Photobiomodulation Significantly Modulates Neural Oscillations: a pilot exploratory study. Sci. Rep. (2019) 9:6309. 10.1038/s41598-019-42693-x
    1. Biella G, de Curtis M. Olfactory inputs activate the medial entorhinal cortex via the hippocampus. J Neurophysiol. (2000) 83:1924–31. 10.1152/jn.2000.83.4.1924
    1. Liu TC-Y, Cheng L, Su W-J, Zhang Y-W, Shi Y, Liu A-H, et al. Randomized, double-blind, and placebo-controlled clinic report of intranasal low-intensity laser therapy on vascular diseases. Int J Phot. (2012) 2012:489713 10.1155/2012/489713
    1. Saour F, Gholipour-Khalili S, Farajdokht F, Kamari F, Walski T, Hamblin MR, et al. Therapeutic potential of intranasal photobiomodulation therapy for neurological and neuropsychiatric disorders: a narrative review. Rev Neurosci. (2020) 31:269–86. 10.1515/revneuro-2019-0063
    1. Conboy L, Gerke T, Hsu KY, St John M, Goldstein M, Schnyer R. The effectiveness of individualized acupuncture protocols in the treatment of gulf war illness: a pragmatic randomized clinical trial. PLoS ONE. (2016) 11:e0149161. 10.1371/journal.pone.0149161
    1. Chao LL. Improvements in Gulf War illness symptoms after near-infrared transcranial and intranasal photobiomodulation: two case reports. Mil Med. (2019) 184:e568–74. 10.1093/milmed/usz037
    1. Proctor SP, Heeren T, White RF, Wolfe Jrgos MS, Davis JD, et al. . Health status of Persian Gulf War veterans: self-reported symptoms, environmental exposures and the effect of stress. Int J Epidemiol. (1998) 27:1000–10. 10.1093/ije/27.6.1000
    1. Reynolds C. R. Comprehensive Trail-Maiking Test (CTMT). Examiners Manual. Austin, TX: PRO-E; (2002).
    1. Tombaugh TN. Trail making test A and B: normative data stratified by age and education. Arch Clin Neuropsychol. (2004) 19:203–14. 10.1016/S0887-6177(03)00039-8
    1. Spreen O, Benton A. Neurosensory Centre Comprehensive Examination for Aphasia: Manual of Instructions. Victoria, BC: University of Victoria; (1977).
    1. Benton AL, Hamsher K. Multilingual Aphasia Examination. Iowa City, IA: AJA Associates, Inc; (1989).
    1. Delis DC, Kramer JH, Kaplan E, Ober BA. California Verbal Learning Test – Second Edition. Adult Version. 2nd Edn. San Antonio, TX: Psychological Corporation; (2007).
    1. Delis DC, Kaplan E, Kramer JH. Delis-Kaplan Executive Function System: Technical Manual. San Antonio, TX: Harcourt Assessment Company; (2001).
    1. Wilkinson G, Robertson G. WRAT4 Wide Range Achievement Test. Lutz, FL: Psychological Assessment Resources; (2006).
    1. Tombaugh T. Test of Memory Malingering (TOMM). New York, NY: Multi-Health Systems, Inc. (1996).
    1. Schroeder RW, Buddin WH, Hargrave DD, VonDran EJ, Campbell EB, Brockman CJ, et al. . Efficacy of test of memory malingering trial 1, trial 2, the retention trial, and the albany consistency index in a criterion group forensic neuropsychological sample. Arch Clin Neuropsych. (2013) 28:21–9. 10.1093/arclin/acs094
    1. Melzack R. The short-form McGill pain questionnaire. Pain. (1987) 30:191–7. 10.1016/0304-3959(87)91074-8
    1. Weathers FW, Litz BT, Herman D, Huska J, Keane T. The PTSD Checklist-Civilian Version (PCL-C). Boston, MA: National Center for PTSD; (1994).
    1. Moriarty O, McGuire BE, Finn DP. The effect of pain on cognitive function: a review of clinical and preclinical research. Prog Neurobiol. (2011) 93:385–404. 10.1016/j.pneurobio.2011.01.002
    1. Weschler D. WAIS-IV-Wechsler Adult Intelligence Scale-Fourth Edition. 4th Edn. San Antonio, Pearson Education, Inc. (2008). 10.1037/t15169-000
    1. Rosvold HE, Mirsky AF, Sarason I, Bransome ED, Beck LH. A continuous performance test of brain damage. J Consult Psych. (1956) 20:343–50. 10.1037/h0043220
    1. Letz R, Baker E. L. Neurobehavioral Evaluation System: NES Users Manual. Winchester, MA: Neurobehavioral Systems, Inc; (1988).
    1. Rey A. L'examen psychologique dans les cas dencephalopathie traumatique (Les problems). Arch Psychol. (1941) 28:215–85.
    1. Knight JA, Kaplan E. (eds). Handbook of Rey-Osterrieth Complex Figure Usage: Clinical and Research Applications. Odessa, FL: Psychological Assessment Resources; (2004).
    1. Osterrieth PA. Filetest de copie dune figure complex: Contribution a letude de la perception et de la memoire [The test of copying a complex figure: a contribution to the study of perception and memory]. Arch Psychol. (1944) 30:286–395.
    1. Farrar JT, Young JP, LaMoreaux L, Werth JL, Poole MR. Clinical importance of changes in chronic pain intensity measured on an 11-point numerical pain rating scale: Pain. (2001) 94:149–58. 10.1016/S0304-3959(01)00349-9
    1. Kerns RD, Turk DC, Rudy TE. The west haven-yale multidimensional pain inventory (WHYMPI). Pain. (1985) 23:345–56. 10.1016/0304-3959(85)90004-1
    1. Smets EM, Garssen B, Bonke B, De Haes JC. The Multidimensional Fatigue Inventory (MFI) psychometric qualities of an instrument to assess fatigue. J Psychosom Res. (1995) 39:315–25. 10.1016/0022-3999(94)00125-O
    1. Beck AT, Steer RA, Brown GK. (1996). Manual for Beck Depression Inventory. 2nd Edn. San Antonio, TX: The Psychological Corp.
    1. Ware J, Kosinski M, Dewey JE. How to Score Version 2 of the SF-36 Health Survey. Lincoln, NE: Quality Metrics, Inc; (2001).
    1. Jones D, Kazis L, Lee A, Rogers W, Skinner K, Cassar L, et al. . Health status assessments using the Veterans SF-36 and SF-12. Methods for evaluating outcomes in the Veterans Health administration. J Ambul Care Manag. (2001) 24:68–86. 10.1097/00004479-200107000-00011
    1. Buysse DJ, Reynolds CF, Monk TH, Berman SR, Kupfer DJ. The Pittsburgh sleep quality index: a new instrument for psychiatric practice and research. Psych Res. (1989) 28:193–213. 10.1016/0165-1781(89)90047-4
    1. Johns MW. A new method for measuring daytime sleepiness. the epsworth sleepiness scale. J Sleep Res. (1991) 14:540–5 10.1093/sleep/14.6.540
    1. Shahid A, Shen J, Shapiro CM. Measurements of sleepiness and fatigue. J Psychosom Res. (2010) 69:81–9. 10.1016/j.jpsychores.2010.04.001
    1. Fitzpatrick TB. The validity and practicality of sun-reactive skin types I through VI. Arch Derm. (1988) 124:869–71. 10.1001/archderm.124.6.869
    1. Monson CM, Gradus JL, Young-Xu Y, Schnurr PP, Price JL, Schumm JA. Change in posttraumatic stress disorder symptoms: do clinicians and patients agree? Psychol Assess. (2008) 20:131–8. 10.1037/1040-3590.20.2.131
    1. Using the PTSD Checklist (PCL) National Center for PTSD. (2012). Available online at: (accessed November 29, 2020).
    1. Beck A. T. Depression: Causes and Treatment. Philadelphia, PA: University of Pennsylvania Press; (2006).
    1. Gupta SK. Intention-to-treat concept: a review. Pers Clin Res. (2011) 2:109–12. 10.4103/2229-3485.83221
    1. Kaptchuk TJ, Kelley JM, Conboy LA, Davis RB, Kerr CE, Jacobson EE, et al. . Components of placebo effect: randomised controlled trial in patients with irritable bowel syndrome. BMJ. (2008) 336:999–1003. 10.1136/bmj.39524.439618.25
    1. Huang J, Zong X, Wilkins A, Jenkins B, Bozoki A, Cao Y. fMRI evidence that precision ophthalmic tints reduce cortical hyperactivation in migraine. Cephal. (2011) 31:925–36. 10.1177/0333102411409076
    1. Noseda R, Bernstein CA, Nir RR, Lee AJ, Fulton AB, Bertisch SM, et al. . Migraine photophobia originating in cone-driven retinal pathways. Brain. (2016) 139:1971–86. 10.1093/brain/aww119
    1. Ibrahim MM, Patwardhan A, Gaith KB, Moutal A, Yang X, Chew LA, et al. . Long-lasting antinociceptive effects of green light in acute and chronic pain in rats. Pain. (2017) 158:347–60. 10.1097/j.pain.0000000000000767

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