Scalp Application of LED Therapy to Improve Thinking and Memory in Veterans With Gulf War Illness
Condition: Gulf War Veterans Illness; Neurobehavioral Manifestations; Memory Disorders
MeSH terms: Memory Disorders; Neurobehavioral Manifestations
Study type: Interventional

Summary: 
      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.
    

Detailed description: 
      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.
    

Intervention name(s): Real LED Treatment; Sham LED Treatment
Intervention type(s): Device; Device
Intervention description(s): PhotoMedex Helmet: 12 Pods, 4.5 x 4.8cm (21.6 cm2); 20 diodes; 830nm; Power Output (PO) 665.3 mW; Power Density (PD)/LED 30.8 mW/cm2; CW; Time/session 28m 10s*; Dose: Energy Density 26 J/cm2.
MedX Device: 1 Cluster Head/ear, 2 inch diameter (22.48 cm2); 870nm; PO 90 mW; PD/LED 4 mW/cm2; CW; Time/session 4m; Energy Density 4 J/cm2; 2 Vielight Intranasal Devices: Red, 633nm diode; PO 6.5 mW; PD/LED 7.6 mW/cm2; CW; Time/session 25m; Energy Density 11.4 J/cm2 and NIR, 810nm diode; PO 6.5 mW; PD/LED 7.6 mW/cm2; Pulse frequency 10Hz; Duty Cycle 50%; Time/session 25m; Energy Density 11.4 J/cm2 Thor Photomedicine Helmet: 10 Pods, 6cm diameter (28.3 cm2); 35 diodes; Wavelength 850nm; PO 1050 mW; PD/LED 50 mW/cm2; CW; Time/session 23m, 24s; Energy Density 26 J/cm2 2 Placement sets: 1) midline, 6 cluster heads; 2) L&R side of head 12 cluster heads (14m, 5s, each set); 1) midline, 5 cluster heads; 2) L&R side of head 10 cluster heads (11m, 42s, each set) CW, Continuous Wave; Intervention for Real and Sham are Identical, but sham has power output of 0, no photons emitted.
Other intervention name(s): Photomedex Helmet, Thor Photomedicine Helmet, MedX LED cluster heads, Vielight Intranasal
Allocation: Randomized
Intervention model: Crossover Assignment
Intervention model description: This was a blinded, randomized, sham-controlled partial crossover study, with 2 Groups. Group 1: Sham LED Series First followed by optional Real LED Series Second. Group 2: One Real LED Series, only. Neuropsychological (NP) tests were completed at Entry (T1), within 1 week post- (T2) and at 1 month post- the 15th treatment (T3) (First series). NP testing was administered after the optional Second Real Series within 1 week post- (T4) and at 1 month post- the 15th treatment (T5). Primary Outcome Measures included NP tests in 3 domains: 1) Attention/Executive Function; 2) Learning and Memory; 3) Psychomotor/Visual Spatial. The Secondary Outcome Measures included sleep, pain, fatigue, and mood.
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Gulf War Veterans Illness; Veterans Health; Executive Function; Memory; Attention; Cognition; Laser Therapy, Low-Level; Phototherapy; Light Therapy; Depression; Light-Emitting Diodes