Scalp Application of LED Therapy to Improve Thinking and Memory in Veterans With Gulf War Illness

The purpose of this study is to learn if an experimental treatment can help thinking ability, and memory in Veterans with Gulf War Veterans Illnesses (GWVI). The experimental treatment uses light-emitting diodes (LEDs), that are applied outside the skull, to the head using a helmet that is lined with near-infrared diodes. LEDs are also placed in the nostrils (one red diode; and one near-infrared diode), near-infrared photons to the olfactory bulbs located on the orbito-frontal cortex. There are connections between the olfactory bulbs and the hippocampus. A treatment takes about 30 minutes. The participants receive a series of LED treatments which take place as outpatient visits at the VA Boston Healthcare System, Jamaica Plain Campus. The FDA considers the helmet LED device used here, to be a non-significant risk device. The diodes in the device placed in the nose are low-risk devices, within the FDA Category of General Wellness. In addition, a single, 90 mW near-infrared (NIR) LED was placed on each ear. The LEDs do not produce heat.

Rationale: Impaired cognition is one of the 3 major symptom areas of GWVI. Mitochondrial dysfunction is reported in Gulf War Illness (GWI) veterans, associated with neurotoxicant exposures during deployment - e.g., organophosphate pesticides (OP); and pretreatment nerve agents, pyridostigmine bromide (PB) pills. Improved mitochondrial function with increased production of adenosine tri-phosphate (ATP) has been reported in hypoxic/compromised cells treated with red/NIR photons. Recent studies in humans have shown an increase in regional cerebral blood flow subjacent to where the near-infrared LEDs were placed on the scalp (Schiffer et al., 2009; Nawashiro et al., 2012; Chao L.L., 2019). General Explanation of the Light-Emitting Diode Treatment Procedure: LED treatments take place as outpatient visits at the VA Boston Healthcare System (VABHS) Jamaica Plain Campus (JP Campus), 150 South Huntington Ave., Boston, MA, 02130 or a second site, VA Medical Center, San Francisco, San Francisco, CA. The transcranial LED treatment procedure is painless, non-invasive and no heat is generated. Administration of treatment: Three devices were placed at the same time on the participant. All LED devices were approved for use by the VABHS safety committee. Device 1. NIR, LED lined helmet (PhotoMedex, Horsham, PA or Thor Photomedicine, Inc., Hampstead, MD). If a participant's head circumference was larger than 24" circumference a larger LED helmet (Thor Photomedicine) was used to accommodate head size. Device 2. Two intranasal LEDs (red, 633 nm and near-infrared, 810nm, single diodes, Vielight, Inc., Toronto). One Intranasal LED was placed in each nostril, held in place by a plastic clip. Placement of red and NIR Intranasals was alternated by side (left/right) at each session. Intranasal LEDs have an automatic timer, and treatment was administered for 25 minutes, during the ongoing helmet treatment. Device 3. Two cluster heads (MedX Health, Toronto) were used simultaneously on the L and R ears for 4 mins, turned on towards the end of treatment. Each participant wore a clear plastic liner beneath the LED Helmet to protect the LEDs and for hygienic reasons. No liquids or gel are used to hold the LEDs in place on the head. This clear plastic liner was assigned to each participant, and only used by that participant. It was kept in a locked filing cabinet in the treatment room, and discarded after the participant's completion of the study. Sham and Real LED devices were identical in look and feel, except no photons were emitted in the Sham devices. For the purpose of blinding, the participant and the person administering treatments wore goggles (LS-DIO, Phillips Safety Products, Inc.) that blocked 600-900nm wavelengths including red 633 nm wavelength, emitted from the red Intranasal diode. The participant will not feel anything when the LED lights are on; it is a painless, noninvasive treatment procedure. There are small fans built into the LED helmet (to assist in cooling). The participant will always hear the fans, during each LED treatment, whether the LEDs are on, or they are not on. Sequence and Timing of LED treatment, each session: Part 1: The LEDs in the center of the helmet are on for about 14 minutes; then turned off. Part 2: The LEDs in the left and right side of the helmet are on for about 14 minutes; then off. During Parts 1 and 2, the intranasal devices are on for about 25 minutes. Part 3: Two LED cluster heads were used simultaneously on the L and R ears for 4 mins, turned on towards the end of treatment. Approximate treatment time is about 30 minutes, per treatment visit. The participant was treated in a soft recliner chair. Each visit lasts about 35 to 45 minutes, allowing time for record keeping. There were 15 visits in an LED treatment series. Each LED treatment series lasts for 7.5 weeks. Each LED treatment visit is scheduled twice per week, with at least 48 hours between each visit. If the participant needs to miss an appointment, that appointment will be re-scheduled. However, if the participant only made 1 appointment, over a two-week period, he/she was withdrawn from the study. The length of time for participation in this study is 2-4 months including pre- testing, and final follow-up testing after the last LED treatment visit. This study is sponsored by the Department of Veterans Affairs, Clinical Science Research and Development, Office of Research \& Development (ORD). There are no potential conflicts of interest associated with this research. Referral and Screening of Potential Participants: Participants were recruited through a Fort Devens, MA, cohort of Gulf War Veterans (Proctor et al., 1998), and through the VA Informatics and Computing Infrastructure (VINCI)/Corporate Data Warehouse (CDW) database, with approval from VINCI. The San Francisco VA Medical Center (SF VAMC) was a second site on the study (35 Veterans were run in Boston; 12 were run in San Francisco on the same protocol.) Those recruited from the VINCI/CDW database, resided within a 25 mile radius of the Boston VA Healthcare System (VABHS) or 25 miles of the SF VA Medical Center (VAMC). The Institutional Review Board at the VA BHS and the SF VAMC (University of California, San Francisco) approved the study. In accordance with the Declaration of Helsinki, Informed Consent and HIPAA authorization was obtained from all participants. All study visits take place at the VA BHS, JP Campus or San Francisco VA Medical Center. After referral to this study, the potential participant was contacted by telephone, and a description of the full study protocol is explained, including time required, and reimbursement for time and effort. After the initial contact by telephone, an initial visit to the VABHS, JP campus was scheduled. At this time, the entire study was explained and questions answered. After the informed consent form (ICF) has been signed, an appointment is then scheduled for Neuropsychological (NP) Screening testing. These tests measure the ability to think and remember recent information. If results from the Neuropsychological Screening tests show that the potential participant is eligible for entry into this study, an additional appointment is scheduled where Additional Neuropsychological Testing is performed, and Additional Health Information is obtained. NP Assessments before and after LED Intervention Series NP testing was completed within 1 week before (T1), and at 1 week (T2) and 1 month (T3) after the intervention series. For those who received Sham First, there was an optional, second Real Series. NP testing was also completed within 1 week (T4) and 1 month (T5) after the second optional, intervention series. Each NP Testing session was completed in 1-1/2 hours. Primary Outcome Measures assessed 3 neurocognitive domains impaired in GW veterans: 1\) Attention/Executive Function: Digit Span Forward and Backward (WAIS-IV; Wechsler, 2008), Delis-Kaplan Executive Function (D-KEF) Trails and Color-Word Interference (Stroop) (Delis, Kaplan \& Kramer, 2001); 2) Learning and Memory: California Verbal Learning Test-II (CVLT-II; Delis, Kramer, Kaplan, \& Ober, 2000); and 3) Attention/Visual Spatial: Conner's Continuous Performance Test II (Administered on laptop computer; CPT) (Letz \& Baker, 1988; Rosvold et al., 1956); Rey Osterrieth Complex Figure Test (ROCFT; Knight \& Kaplan, 2004; Osterrieth, 1944; Rey, 1941). An alternate version of the CVLT was administered at every other testing session to avoid practice effects. Secondary Measures were assessed for: 1) Pain: Visual Analog Scale (VAS) Pain Scale (0-10) (Farrar et al., 2001); Short Form McGill Pain Questionnaire (Melzack, 1984) and the West Haven-Yale Multi-dimensional Pain Inventory (WHYMPI, Kerns et al., 1985). ; 2) Fatigue: Multi-Dimensional Fatigue Inventory (Smets et al., 1995); 3) Sleep: Pittsburgh Sleep Quality Index (PSQI) (Buysee et al., 1989), Karolinska Sleepiness Scale (KSS); 4) Mood: Beck Depression inventory (BDI; Beck, 2006); and 5) General Physical Health: Short Form-36V Plus (Ware et al., 2000); and the Health Symptom Checklist (HSC) adapted from Bartone et al., (1989); PTSD Checklist PCL-C (Weathers et al., 1994). There were a total of 59 tests/subtests. Statistical Analyses and Power Statement: Tests and subtests within each cognitive domain were analyzed pre- and post- LED intervention. 1. Attention/Executive Function: Digit Span Subtests (WAIS-IV; Wechsler, 2008); Trail-Making Test (Delis, Kaplan, Kramer, 2001); and Color Word Interference Test (Stroop) (Delis, Kaplan, Kramer, 2001) 2. Learning and Memory: California Verbal Learning Test-II (CVLT-II; Delis, Kramer, Kaplan, \& Ober, 2000) 3. Psychomotor/Visual Spatial; Continuous Performance Test (Administered on computer; CPT-R) (Letz \& Baker, 1988; Rosvold et al., 1956); Rey Osterrieth Complex Figure Test (ROCFT) (Knight \& Kaplan, 2004) Power Analysis: Power was computed under the following assumptions for ANOVA: a) alpha = .05 (2-tail); b) to establish clinical relevance, Cohen's large effect size (.25) was used. Power = .86 to detect a significant between-group difference in change from Baseline to end of Treatment for an interim analysis.