Clinical trial NCT01782378: Scalp Application of LED Therapy to Improve Thinking and Memory in Veterans With Gulf War Illness
Official title: Transcranial, Light-Emitting Diode (LED) Therapy to Improve Cognition in GWVI
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Gulf War Veterans Illness
Neurobehavioral Manifestations
Memory Disorders
Keywords: Gulf War Veterans Illness
Veterans Health
Executive Function
Memory
Attention
Cognition
Laser Therapy, Low-Level
Phototherapy
Light Therapy
Depression
Light-Emitting Diodes
Lead sponsor: VA Office of Research and Development
Sponsor class: FED
First posted: 2013-02-01
Enrollment: 96
Sex: ALL
Minimum age (years): 38
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
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.
Primary purpose: TREATMENT

Brief 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.

Eligibility criteria: Inclusion Criteria:

Participants were recruited from the participants in a Department of Defense (DoD) study of a longitudinal cohort of Gulf War Veterans who returned from their deployment in 1991 through Ft. Devens, MA. This cohort has been followed at multiple time points since the end of war (Proctor et al., 1998), and through the VA Informatics and Computing Infrastructure (VINCI)/Corporate Data Warehouse (CDW) database, with approval from NDS. 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.

Participants answered 'Yes' to the following questions: 1) Difficulty concentrating; and/or 2) Difficulty remembering recent information.

* Must be a Veteran deployed in 1990-1991 Gulf War, in the Kuwait Theatre
* Meets criteria for GWVI as defined by "Symptom Questions used to identify Gulf War Illness by Kansas Case Definition, and Chronic Multisymptom Illness by Fukuda Case Definition" (Steele, 2000; Fukuda et al., 1998). Participants must have the presence of 1 or more chronic symptoms (lasting \>6 months) from at least 2 of 3 symptom categories from Fukuda et al., (1998): 1) musculoskeletal (muscle pain, or joint pain, stiffness); 2) mood-cognition 3) fatigue.
* Ages 38 - 65 years
* Must be physically able to travel to the VA Boston Healthcare System, Jamaica Plain or San Francisco VA Medical Center, for Neuropsychological testing and transcranial LED treatments
* Must meet screening criteria from the Eligibility Screening:

The following Neuropsychological (NP) tests were administered at Screening: Trail Making Test A \& B (Reynolds, 2002); Controlled Oral Word Association Test (COWAT (FAS); Spreen \& Benton, 1977; Benton and Hamsher, 1989); California Verbal Learning Test - II (Delis et al., 2000); Color-Word Interference Test (Stroop; Delis, Kaplan, Kramer, 2001). Additional screening tests included: Short Form McGill Pain Questionnaire (Melzac, 1984); Overall VAS current pain rating (0-10); and the PTSD Checklist- Civilian (PCL-C, Weathers et al., 1994).

Participants were required to score at least 2 SD below the standardized norm (age, education, gender) on at least 1 NP screening test or 1 SD below the standardized norm on at least 2 NP screening tests. The Word Reading Subtest from the Wide Range Achievement Test-4 (Wilkinson and Robertson, 2006) was used to estimate premorbid level of cognitive functioning. The SD for each participant on each NP screening test was adjusted by his/her estimated premorbid cognitive level.

The Test of Memory Malingering (TOMM, 1996) was administered. Participants who failed Trial 2, or Trial 1 and 2 were excluded from the study. If a participant failed Trial 1, but did not fail Trial 2, he/she was not excluded if he/she showed evidence of poor learning on other NP screening tests such as the CVLT (Schroeder et al., 2013, Arch Clin Neuropsych) Participants were required to have a level of pain 7/10 or less on the VAS and less than 38/50 on the McGill pain questionnaires at screening, as pain has been shown to influence cognition (Moriarty et al., 2011, Review).

Exclusion Criteria:

* Presence of a neurodegenerative disease such as ALS, Parkinson's, Dementia
* Presence of a life-threatening disease such as cancer
* Presence of a severe mental disorder such as schizophrenia, or bipolar depression (not associated with PTSD)
* Current substance abuse or active treatment within last 6 months

Primary outcomes:
measure: Digit Span Forwards
timeFrame: within 1-2 weeks before LED treatment series, within 1 Week and 1 Month after the last LED treatment
measure: Digit Span Backwards
timeFrame: within 1-2 weeks before LED treatment series, within 1 Week and 1 Month after the last LED treatment
measure: Digit Span Total Forward + Backwards
timeFrame: within 1-2 weeks before LED treatment series, within 1 Week and 1 Month after the last LED treatment
measure: Trails Condition 2
timeFrame: within 1-2 weeks before LED treatment series, within 1 Week and 1 Month after the last LED treatment
measure: Trails Condition 4
timeFrame: within 1-2 weeks before LED treatment series, within 1 Week and 1 Month after the last LED treatment
measure: Stroop Inhibition (Trial 3)
timeFrame: Within 1-2 weeks before LED treatment series, within 1 week and 1 month after LED treatment series
measure: Stroop Inhibition/Switching
timeFrame: Within 1-2 weeks before LED treatment series, within 1 week and 1 month after LED treatment series
measure: California Verbal Learning Test -II (CVLT-II) Total Trials 1-5
timeFrame: within 1-2 weeks before LED treatment series; within 1 Week and 1 Month after the last LED treatment
measure: CVLT-II, Short Delay Free Recall
timeFrame: within 1-2 weeks before LED treatment series; within 1 Week and 1 Month after the last LED treatment
measure: CVLT-II, Short Delay Cued Recall
timeFrame: within 1-2 weeks before LED treatment series; within 1 Week and 1 Month after the last LED treatment
measure: CVLT-II Long Delay Free Recall
timeFrame: within 1-2 weeks before LED treatment series; within 1 Week and 1 Month after the last LED treatment
measure: CVLT-II Long Delay Cued Recall
timeFrame: within 1-2 weeks before LED treatment series; within 1 Week and 1 Month after the last LED treatment
measure: Conner's Continuous Performance Test II (CPT) False Alarms
timeFrame: within 1 week before LED treatment series, within 1 Week and 1 Month after the last LED treatment
measure: CPT Correct Detections, Reaction Time (RT)
timeFrame: within 1 week before LED treatment series, within 1 Week and 1 Month after the last LED treatment
measure: Conner's Continuous Performance Test II (CPT), D'
timeFrame: within 1 week before LED treatment series, within 1 Week and 1 Month after the last LED treatment
measure: Rey Osterrieth Complex Figure Test (ROCFT); Immediate Recall
timeFrame: within 1-2 weeks before LED treatment series, within 1 Week and 1 Month after the last LED treatment
measure: ROCFT, Delayed Recall
timeFrame: within 1-2 weeks before LED treatment series, within 1 Week and 1 Month after the last LED treatment
Secondary outcomes:
measure: Beck Depression Inventory (BDI)
timeFrame: within 1-2 weeks before LED treatment series, within 1 Week and 1 Month after the last LED treatment
measure: PCL-Civilian Survey
timeFrame: within 1-2 weeks before LED treatment series, within 1 Week and 1 Month after the last LED treatment
measure: Visual Analog Pain Rating
timeFrame: within 1-2 weeks of LED treatment, within 1 Week and 1 Month after the last LED treatment
measure: Short Form McGill Pain Questionnaire
timeFrame: within 1-2 weeks before LED treatment series, within 1 Week and 1 Month after the last LED treatment
measure: Pittsburgh Sleep Quality Index (PSQI)
timeFrame: 1-2 weeks before LED treatment series, within 1 Week and 1 Month after the last LED treatment
measure: Karolinska Sleepiness Scale
timeFrame: 1-2 weeks before LED treatment series, within 1 Week and 1 Month after the last LED treatment
measure: Short Form-36V Plus (PCS)
timeFrame: within 1-2 weeks before LED treatment series; within 1 Week and 1 Month after the last LED treatment
measure: Short Form-36V Plus (MCS)
timeFrame: within 1-2 weeks before LED treatment series; within 1 Week and 1 Month after the last LED treatment
measure: Multidimensional Fatigue Inventory (MFI), General Score
timeFrame: 1-2 weeks before LED treatment series, within 1 Week and 1 Month after the last LED treatment
measure: Multidimensional Fatigue Inventory, Physical Score
timeFrame: 1-2 weeks before LED treatment series, within 1 Week and 1 Month after the last LED treatment
measure: Multidimensional Fatigue Inventory, Reduced Activity Score
timeFrame: 1-2 weeks before LED treatment series, within 1 Week and 1 Month after the last LED treatment
measure: Multidimensional Fatigue Inventory, Reduced Motivation Activity
timeFrame: 1-2 weeks before LED treatment series, within 1 Week and 1 Month after the last LED treatment
measure: Multidimensional Fatigue Inventory, Mental Fatigue
timeFrame: 1-2 weeks before LED treatment series, within 1 Week and 1 Month after the last LED treatment
Other outcomes:
Locations:
city: San Francisco
country: United States
facility: San Francisco VA Medical Center, San Francisco, CA
state: California
city: Boston
country: United States
facility: VA Boston Healthcare System Jamaica Plain Campus, Jamaica Plain, MA
state: Massachusetts
Study officials:
affiliation: VA Boston Healthcare System Jamaica Plain Campus, Jamaica Plain, MA
name: Margaret Naeser, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: San Francisco VA Medical Center, San Francisco, CA
name: Linda L Chao, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Martin PI, Chao L, Krengel MH, Ho MD, Yee M, Lew R, Knight J, Hamblin MR, Naeser MA. Transcranial Photobiomodulation to Improve Cognition in Gulf War Illness. Front Neurol. 2021 Jan 21;11:574386. doi: 10.3389/fneur.2020.574386. eCollection 2020.