Scalp Application of Red and Near-Infrared Light, From Light-Emitting Diodes (LED) to Improve Thinking and Memory in Veterans With Gulf War Illnesses

Rationale:

The rational for using red and near-infrared LEDs is two-fold: 1) These wavelengths have been
shown to improve ATP production, especially in hypoxic or compromised cells. 2) Recent
studies in humans have also 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).

General Explanation of the Light-Emitting Diode (LED) Treatment Procedure:

The 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.

The Transcranial LED treatment procedure is painless, non-invasive and no heat is generated.
It involves placing a lightweight helmet on the head and intranasal devices in the nostrils.
The helmet contains some light-emitting diodes (LEDs). Some of the LEDs are in the visible
range of light that one can see (red wavelengths of light); some of the LEDs are not visible
(near-infrared wavelengths of light). The participant will be asked to wear some
goggles/glasses during each LED treatment. These goggles/glasses will block out the red
wavelengths of light, so that the participant will not be aware of when the lights are on, or
off.

During some of the LED treatments, the lights are turned on. During some of the LED
treatments, the lights are not turned on. All participants who are part of this study will
receive some LED treatments when the LED lights are turned on.

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.

There are 2 sequential parts to each LED treatment visit, while the LED helmet is on the
head:

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.

The entire treatment with the LED helmet in place on the head is about 30 minutes, per
treatment visit. There is no potential for eye damage, because LED light is not a laser
light.

The participant will remain in street clothes, and will be treated in a soft recliner chair.
Each visit lasts about 35 to 45 minutes, allowing time for record keeping.

No liquids or gel are used to hold the LEDs in place on the head. Each participant will be
provided with his/her own clear plastic liner for the LED helmet. This clear plastic liner
will be assigned to each participant, and only used by that participant. It will be kept in a
locked filing cabinet in the treatment room, and discarded after the participant's completion
of the study.

There are 15 visits in each LED treatment series; and each participant will participate in
two 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.

All appointments are scheduled ahead, for a specific day and time of day, at the convenience
of the participant. If the participant needs to miss an appointment, that appointment will be
re-scheduled. However, if the participant misses more than 1 appointment in a row, over a
two-week period, he/she will be withdrawn from the study. This is because it is very
important to treat at least two times per week for the 7.5 weeks, until all 15 LED treatments
have been completed, in each of the two LED treatment series.

The length of time for participation in the actual treatment portion of this study is four
months (two treatment periods of about two months, each). The total time of participation
including pre- testing, and final follow-up testing at 2 months after the last LED treatment
visit, is about 6 months.

This study is sponsored by the Department of Veterans Affairs, Clinical Science Research and
Development. There are no potential conflicts of interest associated with this research.

Referral and Screening of Potential Participants:

As mentioned in a separate section on Subjects and Inclusion Criteria, the participants for
this study are referred by a Neuropsychologist who has been following Veterans in the New
England region who had been deployed to Kuwait in 1990-91. Additional participants may be
recruited through other sources. After signing the ICF, at the time of neuropsychological
screening, the Gulf War Veterans who are not part of the Fort Devens cohort will be given the
"Symptom Questions used to Identify Gulf War Illness by Kansas Case Definition, and Chronic
Multisymptom Illness by Fukuda Case Definition" questionnaire. Qualified participants will
have answered 'Yes' to the following questions: 1) Difficulty concentrating; and/or 2)
Difficulty remembering recent information.

After referral to this study, the potential participant is contacted by telephone, and a
description of the full study protocol is explained, including that three blood draws are
involved, as well as the time required, and reimbursement for time and effort. After the
initial contact by telephone, an initial visit to the VABHS, JP campus may be scheduled with
the PI, or someone on her staff. At this time, the entire study will be explained and
questions answered. If the potential participant wishes to do so, he/she may sign the
Informed Consent Form (ICF) at this first visit.

After the ICF has been signed, an appointment is then scheduled for Neuropsychological
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.

The Additional Neuropsychological Tests also measure the ability to think and remember recent
information. These tests take place at the VABHS, JP. They are administered by the
neuropsychologist or her staff, and they require a two-hour visit.

During the same two-hour visit, Additional Health Information (paper and pencil) is acquired
in the following areas: 1) any pain experienced on a regular basis; 2) fatigue that is
experienced on a regular basis; 3) mood (including depression); and 4) questions regarding
health - for example, how often in the past 30 days symptoms may have been present from each
of nine body systems: cardiac, pulmonary, dermatological, gastrointestinal, genitourinary,
musculoskeletal, neurological, and psychological.

The Additional Neuropsychological Tests (and the Additional Health Information) are each
acquired four times during participation in the study:

Time 1) Within 1 or 2 weeks before the 1st LED Treatment

Time 2) Within 1 week after the 15th LED treatment in the First Series of LED Treatments

Time 3) Within 1 week after the 15th LED treatment in the Second Series of LED Treatments

Time 4) At 2 months after the 15th LED treatment in the Second Series of LED Treatments

Three Blood Draws

Blood samples (venipuncture from the participant's arm) will be taken at three time points
during participation in the study. Each blood draw involves one visit to a Quest Lab located
near the participant's home or place of work.

Time Schedule for Blood Draws:

Time 1) Within 1 or 2 weeks before the 1st LED Treatment

Time 2) Within 1 week after the 15th LED treatment, in the 1st LED Treatment Series (7.5
Weeks)

Time 3) Within 1 week after the 15th LED treatment, in the 2nd LED Treatment Series (7.5
Weeks)

In summary, there are a total of 4 visits for the areas of "Additional Neuropsychological
Tests and Additional Health Information," and 3 visits to a Quest Lab for the Blood Tests.

Statistical Analyses and Power Statement:

There will be two groups of participants, 80 participants per group.

A score for each of 3 cognitive domains will be 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;
RVisual CPT, NES3) (Letz & Baker, 1988; Rosvold et al., 1956); Rey Osterrieth Complex
Figure Test (ROCF) (Knight & Kaplan, 2004)

Power Analysis:

Power was computed under the following assumptions for ANOVA: a) alpha = .05 (1-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.

Inclusion Criteria:

The participants for this study will be 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.

Participants will have answered 'Yes' to the following questions completed on the cohort
survey: 1) Difficulty concentrating; and/or 2) Difficulty remembering recent information.

- Must be a Veteran deployed in 1990-1991 Gulf War

- 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,
for Neuropsychological testing and transcranial LED treatments

- Must meet screening criteria from the Neuropsychological Screening Tests

Exclusion Criteria:

- Not meeting 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).

- Had GWVI, but did not answer 'Yes' to the following questions: 1) Difficulty
concentrating and/or 2) Difficulty remembering recent information, on the Symptom
Questionnaire

- Less than age 38, or greater than age 65

- 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 severe depression

- Physical limitations that would prevent traveling to the VA Boston Healthcare System,
Jamaica Plain, for Neuropsychological testing and transcranial LED treatments

- Current substance abuse or active treatment

- Did not meet screening criteria from the Neuropsychological Screening Tests