Transcranial, Light-Emitting Diode (LED) Therapy to Improve Cognition in GWVI
Phase: NA
Conditions: Gulf War Veterans Illness, Neurobehavioral Manifestations, Memory Disorders
Sponsor: VA Office of Research and Development

	  
December 2017 Naeser - 1	  
 
 
 
 
 
 
 
 
 
 
 
 
 
Transcranial Light-Emitting Diode (LED) Therapy to Improve Cognition in GWVI 
PIs: Margaret Naeser, PhD, VA Boston Healthcare System, Boston, MA 
Linda Chao, PhD, San Francisco VA Medical Center, San Francisco, CA 
NCT01782378 
December 15, 2017 

	  
December 2017 Naeser - 2	  
Research Plan. 
1.  Rationale  1a.  Statement of the Problem 
Impaired cognition is one of the 3 major problem areas of Gulf War Veterans’ Illnesses (GWVI) 
needing empirically-supported treatments. This sham-controlled study proposes to test the treatment 
effectiveness of red and near-infrared (NIR) light, delivered via painless, non-invasive, light-emitting diodes 
(LED), for improving cognitive symptoms in the areas of Attention, Executive Function, and Memory in 
GWVI veterans. Our pilot data show that red/NIR LED therapy effectively reduces cognitive problems - e.g., 
Executive Function (decision-making, multi-tasking, processing speed) and Verbal Memory-- in chronic, 
traumatic brain injury (TBI; even 7 years post- TBI). Increased regional cerebral blood flow (rCBF) may 
underlie these effects. We provide pilot data showing increased rCBF on functional MRI scans, following a 
series of transcranial, red/NIR LED treatments of chronic stroke, and of neurodegenerative disease (Primary 
Progressive Aphasia, similar to Alzheimer’s Disease). Significantly improved behavior was present post- LED. 
The increase in rCBF (vasodilation) is triggered by release of nitric oxide from hypoxic/compromised 
cells, after exposure to the red/NIR photons. It has been known since 1981, that approximately 3% of NIR 
photons applied at the scalp can penetrate 1cm deep, to reach brain cortex. In hypoxic/compromised cells, 
cytochrome C oxidase (the last complex in the electron transport chain) is saturated with nitric oxide; and there 
is little adenosine tri-phosphate (ATP) production to support needed energy for cellular function. Cytochrome C 
oxidase is a photo-acceptor for red/NIR wavelengths. After exposure to the red/NIR photons, the nitric oxide 
is diffused outside the cell wall where it promotes an increase in vasodilation. At the same time, cytochrome 
C oxidase increases ATP production in the mitochondria. The cellular effects last beyond the exposure to 
the red/NIR photons (Lane, 2006). This is referred to as “photobiomodulation.” 
This second major benefit, improved mitochondrial function with increased ATP production, is 
particularly important for GWVI. Studies have reported the presence of mitochondrial dysfunction in 
veterans with GWVI. The mitochondrial dysfunction is associated with neurotoxicant exposures during 
deployment (Golomb, 2008). These include organophosphate pesticides (OP); and pretreatment nerve agents, 
pyridostigmine bromide (PB) pills (Abu-Qare, Abou-Donia, 2001). Exposures to OP and PB have been shown 
to result in tissue loss in the central nervous system from direct insults to mitochondria (Kaur et al., 
2007), and resultant cellular damage from myelin and neuronal breakdown products (Heaton et al., 2007). 
Other benefits from treatment of hypoxic/compromised cells with red/NIR photons include decrease in 
inflammation, and an increase in angiogenesis, neurogenesis and synaptogenesis. We provide laboratory data 
from one of our consultants (M. Hamblin, PhD, Cell Biologist, Wellman Center for Photomedicine, MGH), 
showing an increase in brain-derived neurotrophic factor (BDNF) in animal studies post- TBI, when treated 
with transcranial NIR photons. BDNF is a major regulator of the formation of new neurons, and connections 
between neurons. His cell studies involved particularly the hippocampus. GWI veterans have reduced size of 
the hippocampus (Chao et al., 2010), a brain area important in forming new memories. A significant increase 
in Verbal Memory was observed in our chronic TBI cases post- red/NIR transcranial LED.  We expect to 
observe similar improvements in GWVI veterans treated with transcranial, red/NIR LED.  
1b.  Hypotheses 
1) After 15 Sham LED treatments, there will be no significant improvement in the cognitive measures, as 
tested within 1 week post- the 15th Sham LED treatment. 
2) After 15 Real LED treatments, there will be significant improvement in the cognitive measures, as tested 
within 1 week post- the 15th Real LED treatment. (Results from 1 and 2 will provide efficacy-of-treatment data.) 
 
3) There will be maintenance of improved cognition at 2 Mo. post- the 15th Real LED treatment. 
1c.  Specific Objectives    
Aim 1:  To significantly improve cognition in veterans with GWVI who have cognitive dysfunction, using 
transcranial, red/NIR LED. The cognitive tests are the Primary Outcome Measures. 
Aim 2:  To study the indirect effects of transcranial, red/NIR LED on other aspects of GWVI, including pain, 
fatigue, and mood. Potential biomarkers in the blood will also be examined (e.g., blood tests for mitochondrial 
function, inflammation, and coagulation), pre- and post- Sham and Real LED treatments. These are Secondary 
Outcome Measures, and are expected to provide directions for future studies.  
1d.  Expected Outcomes and Endpoints 
The primary endpoint is to have data showing that transcranial, red/NIR LED significantly improves 
cognitive function in veterans with GWVI.  
1e.  Impact of Results from the Proposed Research to the VA, and to the Field of GWVI  Over 200,000 
Gulf War Veterans have developed the multi-symptom illness of GWVI. This will be the first study to 
investigate a science- and evidence-based treatment expected to improve cognition in veterans with GWVI. 

	  
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2a.  Background 
2a. 1.  Background 
2a. 1a. i. Gulf War Veterans’ Illnesses 
Approximately 25-30% of the 697,000 Gulf War deployed veterans continue to report persistent multi-
symptom illness (Steele, 2000; RAC, 2008). The Kansas City case definition (Steele, 2000) and Fukuda et al., 
(1998) have characterized Gulf War Veterans’ Illnesses (GWVI) as 1 or more chronic symptoms (lasting >6 
months) from at least 2 of 3 symptom categories: 1) musculoskeletal (muscle pain, or joint pain, stiffness); 2) 
mood-cognition; 3) fatigue. Headaches and/or GI problems may also be present. To date, there are no 
successful treatments to improve cognitive function in GVWI. Treating the mechanistic-based cause of 
GWVI in the 175,000 – 209,000 ill Gulf War veterans, remains a top priority for government agencies and 
advisory panels (RAC, 2008).   
 
This proposal will address treating one potential underlying basis for GWVI - e.g., mitochondrial 
dysfunction, in brain neurons and white matter. This will improve cerebral blood flow, and thus treat one of 
the major symptoms of GWVI - e.g., cognitive dysfunction.  
Transcranial, light-emitting diodes (LED) in the red and near-infrared (NIR) wavelengths, will be used. We 
later present pilot data for improved cognitive function post- transcranial, red/NIR LED therapy in cases with 
chronic, traumatic brain injury.  
 
It has been hypothesized that following the First Gulf War, mitochondrial dysfunction is present in 
veterans who present with multi-symptom illness. Mitochondrial dysfunction may be located in the brain 
(associated with cognitive dysfunction); and in the muscles (associated with pain and fatigue) (Sullivan, 
Krengel et al., 2003; Golomb, 2007 and 2008; GWI RAC, 2008).  
 
Evidence that oxidative stress and mitochondrial dysfunction have a role in GWVI was recently 
provided in a report by Golomb (2011), where the effectiveness of the supplement, coenzyme Q10, an 
antioxidant that plays a role in cellular production of adenosine tri-phosphate (ATP), was investigated. Results 
showed significant improvement across the most common symptoms in GWI for coenzyme Q10 vs. placebo 
(p=0.015 (Golomb, GWI RAC Presentation, 2011). For the 20 top-reported symptoms (those in 50% of 
subjects), each symptom showed a favorable direction difference for coenzyme Q10 vs. placebo (p<0.001). 
Symptoms that improved included headache, attention problems, diarrhea, energy to do things, impatience, 
tiredness, and dry skin. There was a trend-to-benefit for anxiety, tinnitus, memory/recall, reading 
comprehension, and sleep problems. On a 5 point self-rated health scale (poor, fair, good, very good, 
excellent) there was also a trend-to-benefit that increased from a baseline mean of 2.2 “fair,” up 0.7, “good,” 
(p=0.1). Systolic blood pressure (SBP) benefited whether low or high. Low SBP showed a 7 point rise; vs. 6 
point further drop on placebo (13 point benefit = significant). High SBP showed a 23 point drop vs. 13 point 
drop on placebo (10 point benefit = trend). There was a benefit in Physical Function (SPS) (p=0.05), where 
73% of those in the Q10 group improved, and 0% were worse. Among those in the Placebo group, 35% 
improved, and 15% were worse. Dr. Golomb is a consultant on this proposed LED research project. 
 
One potential cause for the mitochondrial dysfunction is neurotoxicant exposures during deployment. 
These include organophosphate pesticides (OP); and pretreatment nerve agents, pyridostigmine bromide (PB) 
pills (Abu-Qare, Abou-Donia, 2001). Exposures to OP and PB have been shown to result in tissue loss in the 
central nervous system from direct insults to mitochondria (Kaur et al., 2007), and resultant cellular 
damage from myelin and neuronal breakdown products (Heaton et al., 2007). Cellular debris activates the 
immune cells of the CNS by glial activation (Milligan and Watkins, 2003, Rivest, 2009). Microglia are 
considered the immune cells of the CNS. Glial activation from foreign invaders to the CNS result in release of 
pro-inflammatory cytokines (IL-1, IL-6, TNF) that result in symptoms including cognitive difficulties, muscle and 
joint pain, and fatigue (Watkins et al., 2008; Fields, 2009). 
 
2a. 1a. ii. Brain Imaging Studies, Brain Abnormalities and Cognitive Dysfunction in GWVI 
Brain imaging studies have observed an association between cognitive dysfunction and brain 
abnormalities in veterans with GWVI. Heaton, et al., (2007) reported that linear trend analyses showed a 
significant association between higher levels of estimated sarin/cyclosarin exposure and reduced white matter 
(WM), and increased right lateral ventricle and increased left lateral ventricle volumes. Their findings suggest a 
subtle but persistent central nervous system pathology in GW veterans potentially exposed to even low 

	  
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levels of sarin/cyclosarin. In another structural MRI study with GW veterans who also have PTSD, the head of 
the hippocampus was observed to be significantly smaller, than in healthy civilians (Vythilingam, et al., 
2005). 
 
Liu et al., (2011) reported significant decreases in cerebral blood flow (CBF) in deep brain structures 
(amygdala, hippocampus and caudate) in GWI cases with cognitive dysfunction. Their study utilized fMRI 
with an infusion of physostigmine, as an inhibitory cholinergic challenge. The rationale to use physostigmine as 
an inhibitory cholinergic challenge was based on the notion that neural damage and cognitive deficits are 
associated with excessive exposure to cholinesterase-inhibiting cholinergic stimulants – e.g., OP, PB, and low-
level sarin nerve gas in fallout from Coalition bombing of Iraqi ammunition storage sites (RAC, 2008; Golomb, 
2008; Henderson et al., 2001). These results with fMRI were similar to their results obtained earlier with 
SPECT brain scans, in the same veterans with GWI and cognitive dysfunction (Haley et al., 2009).   
 
Chao et al., (2010) reported that in studying 40 GW-deployed veterans exposed to sarin/cyclosarin, there 
was significantly reduced total gray matter (GM) and hippocampal volumes (compared to 40 matched 
controls). There was a significant positive correlation between total WM volume and measures of executive 
function and visuospatial abilities in veterans with suspected sarin/cyclosarin exposure. In a later study, with 
64 different veterans exposed to sarin/cyclosarin, binary comparisons revealed significantly reduced GM and 
WM volumes in the exposed veterans (compared to controls). On the Continuous Performance Test (CPT), a 
measure of sustained and selective attention, the exposed veterans had significantly more errors of 
omission and tended to have slower responses. There was an effect of GWI/Chronic Multisymptom Illness 
on both GM and WM volume in the exposed veterans (Chao et al, 2011). 
 
Blood tests may allow biomarkers of mitochondrial damage and neuro-inflammation to be measured. OP 
exposures have been shown to affect indices of mitochondrial health such as lactate and pyruvate (Abu-Qare, 
Abou-Donia, 2001). In addition, chronic neuro-inflammation may be examined by IL-1, IL-6, TNF in the blood. 
Blood tests with GWI veterans have shown a state of hypercoagulation in some cases (Hannan et al., 2000). 
 
 Effective treatments for the symptoms of GWVI have remained elusive. A recent controlled study, 
however, using nasal, continuous positive airway pressure (CPAP), has shown that when the real CPAP mask 
was used at night in cases with sleep disordered breathing, the sleep significantly improved, as well as pain, 
fatigue, cognitive function, physical health and mental health (Amin et al., 2011). These results are 
encouraging, because they suggest that new treatments may be effective to help treat veterans with GWVI.  
 
This proposal will investigate whether the new treatment, transcranial, light-emitting diodes (LED) in the 
red/near-infrared wavelengths, can improve cognition in veterans with GWVI. Later, we provide pilot data with 
chronic, mild TBI cases showing significant improvement in Executive Function and Memory, post- LED. 
 
2a. 1b.  Introduction to Effects of Light-emitting Diode (LED) Therapy 
Scalp application of red and near-infrared (NIR) light/photons, utilizing light-emitting diodes (LED), is a new 
application of LED technology. It has been known since the early 1980's, that approximately 3% of NIR 
photons applied to the scalp, can penetrate 1 cm deep, to reach brain cortex (Wan et al. 1981). Vasodilation 
and increased regional cerebral blood flow (rCBF) at the targeted cortical areas have been observed 
following application of NIR light/photons to the head, along with improved behavior in these human studies 
(Schiffer et al., 2009; Nawashiro et al., 2011). We also provide pilot data in this proposal, showing increase in 
rCBF post- a series of LED treatments in chronic stroke, and in neurodegenerative disease. The effect is  
non-thermal.  
 
After exposure to red/NIR photons, there is improved mitochondrial function - improving cellular 
respiration, oxygenation, and cell function (Eells et al., 2003; Karu et al., 2005; Wong-Riley et al., 2005). The 
putative mechanism by which the improved mitochondrial function occurs is as follows: Photons in the red and 
NIR wavelengths are absorbed by cytochrome C oxidase (e.g., a photo-acceptor). Cytochrome c oxidase is the 
last complex in the electron transport chain located within the inner mitochondrial membrane (Karu et al., 1995; 
Eells et al., 2003; Wong-Riley et al., 2005). In hypoxic/poorly functioning cells, cytochrome C oxidase is 
hypothesized to be saturated with nitric oxide. When the mitochondria (including cytochrome C oxidase) are 
exposed to red/NIR photons, at least two major events occur:  

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1) The nitric oxide is diffused outside the cell wall, where this promotes vasodilation and increased 
rCBF. 
2) The cytochrome C oxidase increases adenosine tri-phosphate (ATP) production, and improves
cellular respiration, oxygenation, and cell function. 
Two published studies have now shown increased rCBF, post- transcranial, near-infrared (NIR) LED 
treatments in humans. These are reviewed briefly, below: 
Nawashiro et al., 2011:  A severe TBI patient (persistent vegetative state for 7 mo.) was treated with 
transcranial, NIR LED for 3 Mo. A NIR LED cluster head was applied to left (L) and right (R) forehead for 30 
min per LED session (850 nm wavelength, power density, 11.4mW/cm2; energy density, 20.5 J/cm2 at the 
skin). Post- LED therapy, the patient showed improv ement in his neurological condition by moving his L 
arm/hand to reach the tracheostomy tube; SPECT scan showed increased rCBF in L frontal lobe. Fig.1.  
Schiffer et al., 2009:  Increased rCBF in the L and R frontal pole regions was observed immediately after 
application of NIR LED to the forehead in 10 chronic, severe depression cases (Fig. 2). There was significant 
reduction in depression and anxiety for 2 weeks, following the single LED treatment (Fig. 3). The LED 
cluster head was applied for 4 min each, at the F3 and F4 locations based on the 10/20 EEG system (810 nm; 
power density, 250 mW/cm2 at 4 mm from skin; 60 J/cm2, estimated 2.1 J/cm2 to two treated areas of brain).  
Fig. 1.  A) CT scan for persistent 
vegetative state case, at 7 Mo. 
post-severe TBI. B) SPECT scan 
also at 7 Mo.; Pre- transcranial 
LED therapy. C) SPECT scan at 
30 min after last LED treatment, 
after 3 Mo. of LED therapy, 
showing focal increase of 20% 
(vs. Pre-LED) for rCBF in the left 
anterior frontal cortex (black 
arrow).      Nawashiro et al., 2011!
Fig. 2.  Red circle shows placement of the 
NIR LED cluster head, at left corner of 
forehead. This location is F3 in the 10/20 
EEG system. 
   Red arrow shows mean increase in 
regional cerebral blood flow (rCBF), at left 
frontal pole, post- scalp application of NIR 
LED cluster head (n=10 Depression Cases).  
   rCBF was measured with pulsed NIR 
spectroscopy (INVOS system), vertical, 
black dotted line on electrode patch (not 
part of the NIR treatment). Schiffer, et al., 2009 

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In pilot studies, the PI and colleagues have also observed increased rCBF on functional MRI scans 
(fMRI) in chronic stroke, and in neurodegenerative disease, post- transcranial LED treatments, compared to 
pre- LED. Our pilot data fMRI scans are shown in Section 2a. 2a. i - iv, Preliminary Studies by the PI. 
 
The transcranial LED intervention is expected to improve brain-related functioning (cognition), by 
increasing rCBF in targeted cortical areas in the brain; and increasing ATP. LED therapy is expected to 
improve cellular activity particularly in hypoxic/hypometabolic cells that are present throughout the brain in 
GW veterans with cognitive dysfunction. Our fMRI pilot data support a focal increase in rCBF, post- LED.  
2a. 1c.  Cellular Effects of Red, and Near-infrared (NIR) Photons 
The technology of low-level laser therapy (LLLT) that includes non-thermal lasers (less than 500 mW), or 
even non-coherent light emitting diodes (LEDs) in the red or near-infrared (NIR) wavelength range, is 
commonly known as cold laser, biostimulation or photobiomodulation. All types (coherent lasers or non-
coherent LEDs) have been shown to produce beneficial cellular effects in controlled trials (Desmet et al. 2006, 
review). During LED/LLLT, absorption of red or NIR photons by cytochrome C oxidase in the mitochondrial 
respiratory chain (Lane, 2006) causes an increase in cellular respiration that continues for much longer 
than the light is present when delivered at appropriate fluence and exposure durations. The primary cellular 
effect includes an increase in mitochondrial activity and an increase in ATP levels (Karu et al., 1995; Eells 
et al., 2003; Wong-Riley et al., 2005). See Fig. 4. 
Fig. 3.  Significantly (p=.001) 
reduced Depression scores 
(Hamilton D Rating Scale) at 2 
weeks after one transcranial, 
NIR LED treatment to F3 and 
F4 frontal areas (10/20 EEG 
system) for 4 minutes to each 
area, in 10 severe, chronic 
depression cases. See Fig. 2. 
     A high score suggests more 
depression. Fifteen or above is 
suggestive of a clinical 
depression and below 8 is 
suggestive of a remission. The 
legend numbers correspond to 
patient numbers. 
Schiffer et al., 2009  
Fig. 4.  Increase in ATP 
production occurs when cells are 
exposed to light in the red, and 
near-infrared (NIR) wavelengths.   
Cytochrome C oxidase, in the 
electron transport chain within the 
mitochondria, is the primary 
photo-acceptor for red and NIR 
photons.   
This will increase ATP 
production, and improve cellular 
respiration and oxygenation. 
Wong-Riley et al., J. Biological 
Chemistry, 2005 
Near-Infrared (NIR) 
Wavelengths 
Red 
Wavelengths 

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When the oxygen concentration is low, nanomolar concentrations of nitric oxide (NO) can effectively act 
as a regulator of the mitochondrial respiratory chain. The central hypothesis is that red and NIR photons 
that are specifically absorbed by cytochrome C oxidase, disrupt the weak non-covalent bonds between NO and 
its two binding sites in cytochrome C oxidase, allowing the NO molecule to diffuse away (Karu, Pyatibrat, 
Afanasyeva, 2005; Lane, 2006). Fig. 5. Thus, this primary photon absorption event in the mitochondria leads to 
NO release, that is responsible for the increased blood flow that is measured in the brain shortly after 
illumination, Fig. 2 (Schiffer et al., 2009). 
Since nitric oxide (NO) competes with oxygen for binding to cytC ox, the release of NO will have a greater 
effect, and a long-lasting effect on respiration in hypoxic cells, compared to normoxic cells.  See Fig. 6. 
Fig. 5.  Hypothesis regarding effect 
of red or near-infrared (NIR) light 
on the primary photo-acceptor, 
cytochrome C oxidase (cytC ox, in 
this diagram), located in the 
mitochondrial membrane. Before 
red/NIR LLLT/LED application, the 
CytC ox appears "saturated" with 
nitric oxide (NO). After application 
of red/NIR photons, the mitochon-
dria increase ATP production 
and improve respiration.  
    The NO is diffused outside the 
cell wall, and this promotes 
vasodilation. Our fMRI pilot data 
support this, see Sect. 2a. 2b. i. 
Hamblin; Wellman Center for 
Photomedicine, Mass.General Hospital 
Fig. 6. NIR photons promote a 
greater increase of ATP in hypoxic 
cells (6x increase), than in normoxic 
cells (2x increase). Mean 
luminescence values (+/- SD) from 12 
wells of HeLa cells (a human cervical 
cancer cell line used to demonstrate 
LLLT effects) treated or not, with 1.4 
J/cm2 of NIR 810 nm light in either 
normoxic conditions (regular 
atmosphere) or hypoxic conditions  
(1 hour exposure to pure nitrogen 
after 3 cycles of vacuum).  
M. Hamblin, PhD, Consultant on this project; 
Wellman Center for Photomedicine, MGH!

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2a. 1d.  Promotion of Angiogenesis, Neurogenesis, and Synaptogenesis, from Red/NIR Photons 
Neurogenesis is the generation of neuronal precursors and birth of new neural cells. Two key sites for adult 
neurogenesis include the subventricular zone (SVZ) of the lateral ventricles, and the subgranular layer (SGL) 
of the dentate gyrus in the hippocampus (Eriksson et al., 1998). "Neurogenesis persists in the adult 
mammalian brain, where it can be stimulated by physiological factors, such as growth factors and 
environmental enrichment, and by pathological processes, including ischemia!" (Jin et al., 2006).  
Increased vascular endothelial growth factor (VEGF) has been associated with enhanced post-ischemic 
neurogenesis and neuromigration, in VEGF-over-expressing transgenic mice, consistent with a possible role 
in ischemic brain tissue repair (Wang, Jin, Mao et al., 2007). VEGF could provide a therapeutic target for 
more chronic brain repair. NIR laser therapy has been observed to increase VEGF and angiogenesis 
following myocardial infarction in animal studies (Tuby et al., 2006). Scalp application of red/NIR LED could 
stimulate secretion of VEGF, thus promoting angiogenesis and neurogenesis.  
2a. 1e.  Increase in Brain-Derived Neurotrophic Factor (BDNF), from Red/NIR Photons 
Brain-derived neurotrophic factor (BDNF) is a neurotrophin that is a major regulator of both synaptic 
transmission, and plasticity at adult synapses in the central nervous system (Kaplan, Vasterling, Vedek, 
2010; Kim, Lee & Kim, 2010). BDNF has been observed to increase survival of neurons, increase synaptic 
transmission (Lipsky and Marini, 2007), long-term potentiation and depression, and certain forms of short-
term synaptic plasticity (Desai et al., 1999). Thus, BDNF has implications for the formation of memories in 
patients with impaired memory and cognition (Kaplan et al., 2010).  
Recent animal studies at the Wellman Center for Photomedicine, Mass. General Hospital (M. Hamblin, 
PhD, personal communication, Consultant on this project) have observed increased BDNF expression in the 
injured brain (TBI), at 7 and 28 days after a single application of NIR photons (transcranial, low-level laser 
therapy, 810-nm laser), given 4 hours post- TBI (see Figs. 7 and 8). Increased neurogenesis and 
synaptogenesis in the hippocampus was observed post- transcranial NIR, low-level laser therapy.  
This finding suggests that neurogenesis 
has been stimulated in the subgranular zone 
(SGZ) of the dentate gyrus in the 
hippocampus, by transcranial NIR photons. 
It is unclear if the light actually needs to 
penetrate to the hippocampus, or if 
hippocampal neurogenesis can be 
stimulated by BDNF generated in the 
cortex, in response to exposure of the NIR 
photons applied outside the skull, 
transcranially. 
These increases in BDNF, neurogenesis 
and synaptogenesis explain why 
Fig. 7.   Neurogenesis and synaptogenesis in 
a mouse model of TBI, that received a single 
NIR, 810-nm transcranial laser treatment (18 
J/cm2, at 25 mW/cm2), at 4 hours post- TBI. 
   Day 7 (panels E, G) show increased brain-
derived neurotrophic factor (BDNF) expression 
in the dentate gyrus of the hippocampus (pink, 
panel G) in the TBI laser sample. G indicates 
increased proliferating neuroprogenitor cells; 
vs. E, the sample not treated with NIR laser.  
   Day 7 (panels F, H) show an increase of DAPI 
(purple, panel H) in the TBI laser sample. H 
indicates increased formation of new 
connections between existing neurons, and 
suggesting improved neural plasticity in the 
TBI laser sample; vs. F, the sample not treated 
with NIR laser.  Hamblin, MGH Consultant on this project.  
December 2017 Naeser - 8
Fig. 8.  Neurogenesis and synaptogenesis in a mouse 
model of TBI, that received a single NIR, 810-nm transcranial 
laser treatment (18 J/cm2, at 25 mW/cm2), at 4 hours post-
TBI. 
   Day 28 (panels A, G) show BrdU incorporation (green) in the 
dentate gyrus of the hippocampus. The TBI + Laser sample 
G, indicates increased proliferating neuroprogenitor cells; 
vs. A, the sample not treated with NIR laser.  
   Day 28 (panels F, L) show an increase of synapsin-1 (red) in 
lesion area, indicating the formation of new connections 
between existing neurons, and suggesting improved neural 
plasticity in the TBI + Laser sample L; vs. F, the sample not 
treated with NIR laser.   Hamblin, Consultant on project. 
     This is relevant to GWVI because studies have shown 
decreased size of the hippocampus in GW veterans with 
cognitive dysfunction. Transcranial NIR LED could 
potentially improve hippocampal function.  

	  
December 2017 Naeser - 9	  
transcranial NIR can be beneficial in such a variety of brain diseases, where these processes have been 
shown to be crucial in mediating therapeutic effects (De Taboada et al., 2011). Positive results of transcranial, 
red/NIR photons from LED/LLLT, have now been observed in animal models of TBI (Ando et al., 2011; 
Khuman et al., 2011; Oron et al., 2007), in humans with chronic TBI (Naeser et al., 2011), in humans with 
severe depression (Schiffer et al., 2009), in humans with acute stroke (Lampl et al., 2007; Zivin et al., 2009), 
and in humans with chronic stroke (Naeser, pilot data shown in this proposal), and in neurodegenerative 
disease (Naeser, pilot data shown in this proposal, with Primary Progressive Aphasia). 
 
2a. 1f.  Anti-Inflammatory Effect, from Red/NIR Photons 
Red/NIR photons delivered with LED/LLLT produce transient, low levels of reactive oxygen species (ROS) 
in mitochondria of illuminated cells, and these ROS cause NF-kB activation via the redox sensitive sensor 
enzyme protein kinase D1 (Storz, 2007). Cell research (M. Hamblin, PhD, MGH Consultant on this project) has 
observed that repeated NIR LED/LLLT treatments promote decreased inflammation (less NF-kB).  
 
This is partially explained when one considers the role of genes that respond to ROS-induced activation of 
NF-kB, including antioxidants and up-regulated genes such as superoxide dismutase, glutathione 
peroxidase, and heat shock protein 70 (Storz, 2007; Sompol et al., 2006; Zhang et al., 1994; Avni et al., 
2005). The mitochondrial superoxide dismutase is one of the most upregulated genes after NF-kB 
activation (Sompol et al., 2006). Another highly upregulated gene after NF-kB activation and after LED/LLLT 
is heat-shock protein 70, a molecular chaperone for protein molecules that prevents mis-folding and 
unwanted protein aggregation (Zhang et al., 1994). 
 
Photons in the red/NIR wavelengths reduce oxidative damage and reduce inflammation (Rojas & 
Gonzalez-Lima, 2011, review paper). Many reports (Castano et al., 2007) demonstrate that red/NIR photons 
reduce COX-2 expression levels and reduce prostaglandins in multiple animal models as well as in vitro 
(Aimbire et al., 2005; Albertini et al., 2007; Sakurai et al., 2000).  
 
Another key inflammatory mediator that has been implicated in cell pathogenesis is the cytokine tumor 
necrosis factor alpha (TNFα). There are multiple reports showing that red/NIR photons reduce TNFα levels 
in arthritis (Aimbire et al., 2006). There has been a report (Leung et al., 2002) that in a rat stroke model, 
transcranial LLLT triggered the expression of TGF-β1.  
 
2a. 1g.  Acute Stroke, Transcranial Application of NIR Photons 
 
2a. 1g. i.  Animal Studies:  Acute Stroke, Transcranial Application of NIR Photons  
Transcranial, NIR low-level laser therapy (using NIR photons, 808 nm) has significantly improved recovery 
following ischemic stroke in rats, when treated once, at 24 hours post-stroke (Lampl, 2007; Oron et al., 2006). 
Stroke was induced in rats by two different methods (A) permanent occlusion of the middle cerebral artery 
through a craniotomy or (B) insertion of a filament. A near-infrared (NIR) Ga-As diode laser was used 
transcranially, to illuminate the hemisphere contralateral to the stroke at a power density of 7.5 mW/cm2 to 
brain tissue (Oron et al., 2006).  
 
At 3 weeks poststroke, there was a highly significant (p<.01) reduction of 32% in the neurological 
deficit in the laser-treated rats, relative to control ones. The number of newly formed neuronal cells, 
assessed by double immunoreactivity to BrdU and tubulin isotype III, as well as migrating cells (doublecortin 
immunoactivity) was significantly elevated in the subventricular zone (SVZ) of the hemisphere ipsilateral 
to the induction of stroke when treated by LLLT (which had been applied to the contra-lesional side). There 
was no significant difference in the stroke lesion area between control and laser-irradiated rats. The authors 
suggested that an underlying mechanism for the functional benefit post- LLLT in their study was a possible 
induction of neurogenesis. 
Other studies have also suggested that because improvement in neurologic outcome may not be evident 
for 2–4 weeks in the post-stroke rat model, delayed benefits may be due, in part, from induction of 
neurogenesis and migration of neurons (Shen et al., 2008; Detaboada et al., 2006). In addition, transcranial 
LLLT may prevent apoptosis and improve outcomes by exerting a neuroprotective effect, although these exact 
mechanisms are not well understood (Carnevalli et al., 2003). 
 

December 2017 Naeser - 10!
Cortical ATP increase, post- NIR Low-Level Laser Therapy (LLLT) application in acute, embolized rabbits: 
A direct relationship between level of cortical fluence delivered (in J/cm2) and cortical ATP content has been 
observed in a study with embolized rabbits (Lapchak and De Taboada, 2010). Five minutes following 
embolization (right carotid), rabbits were exposed to 2 minutes of transcranial NIR LLLT (continuous wave, 
CW; or pulsed wave, PW) on the skin surface, posterior to the bregma, at midline. Three hours after 
embolization, the cerebral cortex was excised, and processed for measurement of ATP content. Embolization 
had decreased cortical ATP content in ischemic cortex by 45%, compared to naive rabbits. With CW, NIR 
LLLT (0.9 J/cm2; 7.5 mW/cm2) there was an increase of 41% in cortical ATP in the embolized rabbits. With 
PW, NIR LLLT (100 Hz; 4.5 J/cm2; 37.5 mW/cm2) there was an increase of 157% in cortical ATP. It was 
surprising that following transcranial NIR LLLT in the rabbits with stroke, the increased cortical ATP level of 
157% was higher than that measured in naive rabbits that had never suffered stroke. 
2a. 1g. ii.  Human Studies:  Acute Stroke, Transcranial Application of NIR Photons 
Transcranial, NIR LLLT has been shown to significantly improve outcome in human, acute stroke 
patients, when applied at ~18 hours post-stroke, over the entire surface of the head (20 points in the 10/20 
EEG system) regardless of stroke location (Lampl et al., 2007). Only one LLLT treatment was administered, 
and 5 days later, there was significantly greater improvement in the Real- but not in the Sham-treated 
group (p<.05, NIH Stroke Severity Scale). Fig. 9. This significantly greater improvement was still present at 90 
days poststroke, where 70% of the patients treated with Real LLLT had successful outcome, only 51% of 
controls. A NIR (808 nm) laser was used, delivering a fluence of 0.9 J/cm2 over the entire cortical surface (2 
min. per each of the 20 points; power density of 7.5 mW/cm2). 
 
In a second, similar study with the same transcranial LLLT protocol, with an additional 658 acute stroke 
patients randomized for Real or Sham, transcranial LLLT, similar significant beneficial results (p<.04) 
were observed for those who received the Real laser protocol, for moderate and moderate-severe stroke 
patients (n=434) but not for severe patients (Zivin et al., 2009). When data for both stroke studies were pooled 
(n=778; including 120, Lampl et al., 2007; plus 658, Zivin et al., 2009), there was a highly significant 
beneficial effect for the Real transcranial LLLT group (p=0.003), versus those who received the Sham 
laser treatment (Stemer et al., 2010). There were no negative side effects or adverse events. 
The present, proposed study will be the first study to use transcranial red/NIR LED to improve 
cognition in veterans with GWVI.  
Fig. 9.  Significant improvement at day 5, after 1 Real, transcranial LLLT treatment performed at ~18 
hours post-stroke in acute human stroke patients (but not after 1 Sham LLLT Treatment). Both 
hemispheres were treated, regardless of side of stroke. Energy dose to the brain cortex was estimated to be 
only 1 Joule/cm2. No perceptible heat, Real or Sham. NeuroThera Laser System, PhotoThera Laser, San 
Diego. Class IV, near-infrared laser (>500 mW), 808 nm.  No adverse events.         Lampl et al., 2007, Stroke!

	  
December 2017 Naeser - 11	  
Transcranial, red/NIR LED holds promise for treating other CNS-disorders present in veterans – e.g., 
cognitive dysfunction from traumatic brain injury (TBI); chronic, post-traumatic stress disorder (PTSD); 
depression, anxiety; and neurodegenerative disorders - possibly in the early stages of Alzhiemer’s Disease. 
 
There are no contraindications to transcranial LED therapy, such as metallic implants or pacemakers. 
 
Transcranial LED therapy also has potential for long-term, home treatments. 
 
 
2a. 2.  Preliminary Studies by the PI, using Transcranial, Red/NIR LED 
We present pilot data with 3 patient populations, where we have used transcranial, LED to improve behavior: 
 
i)  Chronic, traumatic brain injury (TBI) cases, to improve cognition 
 
ii)  Chronic, (left-hemisphere) stroke patients who have aphasia, to improve language  
 
iii)  Neurodegenerative disease (Primary Progressive Aphasia), to improve language 
 
We have observed significant improvement in cognition or language post- LED, in each patient type. 
 
In addition, we have observed changes on functional MRI (fMRI) scans, pre- and post- transcranial, LED 
therapy, that parallel changes in language behavior. These fMRI studies show that specific LED placement 
locations on the head are associated with specific effects on language behavior.  
 
Prior to our fMRI studies, this focal effect on brain cortex for NIR light applied outside the skull, was not 
known. Our results suggest a proof of principle for the effect of transcranial LED to affect neural networks, 
and improve behavior. 
 
We also present resting state, functional connectivity MRI scan analyses following either Sham LED, or 
Real LED treatment, in the neurodegenerative disease, Primary Progressive Aphasia. Only following the 
Real LED treatment (at a dose of 13 J/cm2, per LED placement), was there a change in functional 
connectivity between two, left frontal gyrus areas important for language (middle and inferior frontal gyrus).  
 
We believe our pilot data provide a foundation, for a sham-controlled study examining whether transcranial, 
red/NIR LED therapy can improve cognitive function in veterans with GWVI, where cognitive dysfunction has 
been documented to be present. 
 
Our pilot data with these 3 patient populations are summarized, below. 
 
2a. 2a. ia.  Chronic, Traumatic Brain Injury:  Improved Cognition post- LED (published cases) 
The PI and colleagues have published two, chronic, mild traumatic brain injury (mTBI) cases where 
significant, improved cognition was observed after scalp application of red/NIR LED therapy (Naeser et al., 
2011). Despite different etiologies, veterans with GWVI share some similarities of patients with chronic 
TBI - i.e., hypoxic/hypometabolic cells that are part of neural networks for higher cortical functions, and 
impaired behavior is present. In chronic TBI cases, for example, this results in poor performance on attention 
and executive function tasks (Kato et al., 2007; Sanchez-Carrion et al., 2008; Strangman et al., 2008; 
McAllister et al., 2006; Scheibel et al., 2007). Poor performance on attention and executive function is also 
present in GW veterans with cognitive dysfunction, as reviewed above, in section 2a. 1a. ii. “Brain Imaging 
Studies, Brain Abnormalities and Cognitive Dysfunction in GWVI” (Heaton et al., 2007; Haley et al., 2009; Liu 
et al., 2011; Chao et al., 2010; 2011). Our pilot studies with transcranial LED have observed improved 
cognition, post- transcranial, red/NIR LED treatments in chronic TBI, as reviewed below.  
 
Published TBI case, P1 (66Yr F) began transcranial, red/NIR LED treatments at 7 years after closed-
head mild TBI (mTBI) from a car accident that occurred at age 59. For 7 years after the accident, and pre- 
transcranial, red/NIR LED therapy, her sustained attention was limited to 20 minutes (computer work). 
She had been a web designer, teaching at the university level. Post- 8 weeks of transcranial LED therapy, her 

December 2017 Naeser - 12!
sustained attention increased to 3 hours (computer work). She has now treated herself at home nightly, 
for almost 7 years, with transcranial LED. She maintains her improved cognition, at age 73. There have been 
no negative side effects, and she reports improved sleep. She owns only 1, red/NIR LED cluster head that 
she uses at home (red/NIR, 500 mW). The cost of this FDA-cleared Home Treatment Device (1 LED cluster 
head) is $1,400 (manufactured by the MedX Health Co., Toronto). 
Published TBI case, P2 (52Yr F) with mTBI+PTSD is an OIF veteran, retired high-ranking military 
officer who had a history of multiple concussions during civilian traumas (rugby, sky diving), and military 
deployment. In 2007, she fell backwards from a swing, hitting the back of her head on concrete (with LOC, 
several minutes). Within 1 year, she required Medical Disability due to cognitive dysfunction. Fronto-parietal 
atrophy was present on her MRI scan (Naeser et al., 2011). There were significant problems with cognition, 
and modulating emotions and behavior (PTSD).  
Pre- transcranial LED, she had been on Medical Disability for 5 months. Post- 4 Mo. of transcranial LED 
treatments at home, she returned to work full-time. She was trained to perform LED treatments at home, 
using the MedX Health LED Device, Model 1100. This FDA-cleared device has 3 LED cluster heads (cost, 
$5,000). One of the LED cluster heads is shown in Fig. 10a,b.  
Neuropsychological testing post- 9 months of transcranial LED therapy, showed significant 
improvement in cognition - e.g., +2 SD, on the Stroop Test for Executive Function (Inhibition and Inhibition 
Accuracy); +1, and +2 SD on the Wechsler Memory Scale R, Immediate and Delayed Recall. See Fig. 11. 
Her PTSD symptoms improved, with better emotional control in family, social and work settings. 
 
Fig. 10a,b,c.  Case P2, mTBI+PTSD.  a.) Sample red and NIR, LED cluster head (2-inch diameter), for transcranial 
LED therapy, used in published TBI cases and in pilot LED studies. b) LED placement on R forehead, for one of the 
LED cluster heads.  c) Graphs showing significant improvement in cognition, post- LED therapy in case, P2 (OIF 
Veteran) on tests of Executive Function (Inhibition, and Inhibition accuracy, +2 SD); and on the next page, Memory 
(Immediate and Delayed Recall +1,+2 SD).  She returned to full-employment, post- 4 Mo. of transcranial LED 
treatments at home.  
"
!"
#"
* +2 SD Improvement, inhibition, inhibition accuracy 
After 4 months of nightly, transcranial LED treatments at home, P2 returned to work full-time 
(executive consultant, international technology); she discontinued medical disability.

December 2017 Naeser - 13!
2a. 2a. ib.  Chronic, Traumatic Brain Injury:  Improved Cognition post- LED (7 Additional TBI Cases)  
Pilot data for seven additional, chronic, mTBI cases (closed-head injury) who also showed significantly 
improved cognition, post- transcranial, red/NIR LED treatments are presented below. These 7 cases (non-
veterans) were treated as part of a pilot, open-protocol study at Spaulding Rehabilitation Hospital, Boston, 
Harvard Medical School (personal communication, R. Zafonte, M. Naeser, M. Krengel, M. Hamblin, P. Martin).  
They were treated with the same LED protocol described in Naeser et al., (2011), using the MedX Health 
LED cluster heads. Patients entered the study at 1-7 years post- closed-head, mTBI. To be eligible for 
enrollment, subjects scored at least 2 SD below the norm on one of the Neuropsychological (NP) cognitive 
tests, or 1 SD below the norm on at least two tests. These are well known, standardized NP tests: Trails A and 
B (Reynolds, 2002); FAS Test (Spreen & Benton, 1977); California Verbal Learning Test II (Delis et al., 2000); 
Stroop test for Executive Function (Delis, Kaplan, 2000).  
Each case received 18 Real red/NIR LED, transcranial treatments; treated 3x per week (M,W,F) for 6 
weeks, as an outpatient. Each LED cluster head had a 2-inch diameter, and was 500 mW; and contained 9 red 
LED diodes, and 52 NIR LED diodes; power density, 22.2 mW/cm2 (Fig. 10a). The LED cluster heads were 
placed bilaterally, on the forehead and scalp areas including frontal, temporal, parietal and occipital areas, and 
on the midline (front-to-back hairline) including at the vertex (10 min. per placement, two sets of placements, 
for a total of 20 min. of LED therapy at each visit). Each treatment visit lasted about 30-40 min. There were  
no negative side effects or complications. A few patients were sleepy after the initial LED treatments. 
Patients received NP testing at Entry, and at 1 Wk., 1 Mo. and 2 Mo. after the 18th LED treatment. 
Results for 7 Additional chronic, TBI Cases:  There was significantly improved cognition, on two tests – 
e.g., Executive Function; and Verbal Memory, at 1 Wk. post- the 18th transcranial LED treatment (Figs. 
12a,b, next page). Percentile scores were used for the pre- vs. post- LED data analyses, adjusting for age, 
gender and level of education. [Two patients have incomplete follow-up Testing at 1 Mo., and 2 Mo. post- LED 
therapy, thus complete statistical analyses could only be performed on the 1 Wk, post- LED data, at this time.]  
On Executive Function (Stroop, Trial 4, Inhibition Accuracy), significant improvement (p<.01 two-tail) 
was observed at the 1-Week post- LED testing. The pre- LED percentile mean was 28.9, SD=26.0; and the  
1-Week post- LED percentile mean was 67.6, SD=35.6 (t=3.825). See Fig. 12a. 
On Verbal Memory, California Verbal Learning Test (CVLT) II, Total Trials 1-5, significant improvement 
(p<.05 two-tail) was also observed. The pre- LED percentile mean was 39.3, SD=26.9; and the 1-Week post- 
LED percentile mean was 58.1, SD=17.9 (t=2.434).  See Fig. 12b. 
Fig. 11.  P2 cont’d.  Significant Improvement in Memory, on Immediate and Delayed Recall, at 9 Mo. post- LED. 
c 
c 

December 2017 Naeser - 14!
0 
20 
40 
60 
80 
100 
Pre-Tx 
1Wk. 
Post- 18 Tx 
1Mo. 
Post- 18 Tx 
2Mo. 
Post- 18 Tx 
Percentile 
Testing Time 
Executive Function  
Stroop Trial 4, Inhibition Accuracy 
** 
** = p<.01 
Relative to Pre-Tx Baseline 
n=7 chronic, mild TBI cases 
Fig. 12a.  Significant improvement (p<.01) on Executive Function for the Stroop Test (Trial 4, Inhibition Accuracy), 
tested at 1 Week, post- the 18th transcranial LED treatment. This test examines selective attention, cognitive flexibility, 
and processing speed. Pilot Data, n=7 chronic, TBI cases, pre- and post- transcranial, red/NIR LED treatments. 
Spaulding Rehabilitation Hospital, Boston. 
 
 
 
 
Zafonte, Naeser, Krengel, Hamblin, Martin 
Fig. 12b.  Significant improvement (p<.05) on Verbal Memory, California Verbal Learning Test, tested at 1 Week, 
post- the 18th transcranial LED treatment.  Pilot Data, n=7 chronic, TBI cases, pre- and post- transcranial, red/NIR 
LED treatments. Spaulding Rehabilitation Hospital, Boston. 
              
Zafonte, Naeser, Krengel, Hamblin, Martin  
0 
20 
40 
60 
80 
100 
Pre-Tx 
1Wk. 
Post- 18 Tx 
1Mo. 
Post- 18 Tx 
2Mo. 
Post- 18 Tx 
Percentile 
Testing Time 
Verbal Memory 
CVLT II Alternate Version,  
Total Trials  1-5 
* 
* = p<.05 
Relative to Pre-Tx Baseline 
n=7 chronic, mild TBI cases 

	  
December 2017 Naeser - 15	  
Seven Additional TBI Cases, Demographics, and Medical History, Spaulding Rehabilitation Hospital  
P001, mTBI: 52 Yr. F, at Entry (5 years post- TBI, MVA). College-educated, and high-ranking position in 
finance field, prior to TBI. On Medical Disability, 5 years, unable to return to work.  Post- LED therapy, able to 
sort bills, write checks, read essays, tasks previously unable to do for 5 years, since the TBI.  
P004, mTBI: 59 Yr. M, at Entry (2.5 years post- TBI, MVA).  PhD degree, and continued to work part-time 
(22 hours/week after TBI, down from 30-34 hours/week before TBI). Post- LED therapy, his headache pain 
was reduced from VAS of 5, down to VAS of 2; and he no longer requires Extra Strength Tylenol or Tylenol, 
for HA pain. He continues to work.  
P005, mTBI: 50 Yr. F, at Entry (20 months post-TBI, where she was a pedestrian running on sidewalk 
when hit by a car). MA degree, had taught English on the college level. She was depressed, and non-talkative 
at Entry, but became quite verbal and talkative after a few weeks of LED treatments. She continues to have 
right shoulder pain, and cannot return to work. Her husband reports that she is "better adjusted" at home. 
P006, mTBI+PTSD:  26 Yr. F, at Entry (16 months post- TBI, four-car MVA, and hit by two cars, from 
behind her car). Two years of college. Unemployed. Also has PTSD post- MVA. PTSD Checklist-Civilian was 
Severe (score of 47) at Entry, and improved to Mild (score of 30) at 1 Week post- the 18th LED treatment.   
P007, mTBI:  58 Yr. M, at Entry (1 year post- TBI, hit in the head at close range, by a baseball that was hit 
by a bat). College educated, high school teacher and baseball coach. On Medical Disability.  At 1 Wk, and at 1 
Mo. post- the 18th LED treatment, he became "more active." He did taxes, and went on a job interview.  
P009, mTBI:  62 Yr. F; 7 Yr. post- MVA.  Lab tech, hair dresser; disabled. 
P011, mTBI:  49 Yr. F; 3 Yr. post- TBI (hit by a snowboarder while standing still). He had a history of 
multiple concussions, and stroke at age 37. B.S. degree, hotel management; disabled. 
 
In summary, our pilot studies with transcranial, red/NIR LED show significant improvement in 
executive function and verbal memory, post- LED treatments in chronic, TBI cases (Naeser et al., 2011, 
where n=2; and pilot data from Spaulding Rehabilitation Hospital, where n=7).  
 
2a. 2a. ii.  Chronic Stroke Patients with Aphasia:  Improved Language post- LED (and fMRI scan data)  
Despite different etiologies, veterans with GWVI share some similarities of patients with chronic 
stroke – i.e., hypoxic/hypometabolic cells that are part of neural networks for higher cortical functions, 
and impaired behavior is present. In chronic stroke patients with left-hemisphere stroke and aphasia, 
hypoxic/hypometabolic cells (in left, peri-lesional areas) are part of the remaining neural networks for language. 
This results in poor performance on language tasks (Naeser Martin et al., 2004; Martin, Naeser et al., 2005; 
2009). Our pilot studies with transcranial, red/NIR LED show significant language improvement, post- 
transcranial, red/NIR LED in chronic stroke patients with aphasia.  
Two chronic stroke patients, with left-hemisphere stroke and aphasia have been treated with transcranial 
LED (at 18, and at 12 years post-stroke). Both had nonfluent aphasia, as tested with the Boston Diagnostic 
Aphasia Exam (BDAE) (Goodglass, Kaplan, Barresi, 2001). They were both treated using two different LED 
Placement Paradigms. They were first treated with a Bilateral, LED Placement Paradigm during Summer 
2011. This was the same as the original, transcranial LED protocol used with the chronic TBI cases (Naeser et 
al., 2011), and explained above, in Section 2a. 2a. “Transcranial LED to treat Chronic, Traumatic Brain Injury.”  
Later, these aphasia patients were treated with a Left Hemisphere Only, LED Placement Paradigm, 
during Fall 2011. We observed different, significant language improvements with each paradigm, and 
different activation patterns on fMRI, after treatment with each of the two LED Placement paradigms. 
Results for each of the two different LED Placement Paradigms are presented below. 
First Transcranial LED Treatment Method for Aphasia due to Stroke:  Bilateral LED Treatments 
The same LED device that had been previously used with the TBI cases (Naeser et al., 2011; and 
Spaulding Rehabilitation Hospital, Boston), was used with the aphasia cases treated at the VA Boston 
Healthcare System (JP campus) – e.g., the MedX Health LED Console Model 1100 (Toronto). Each Model 
1100, has three, 2-inch diameter, LED cluster heads. Two Model 1100 devices were used at the same time (6 
cluster heads were in place on the head, at the same time). Each LED cluster head was 500 mW; and 
contained 9, red 633nm LED diodes; and 52, NIR 870nm LED diodes; the power density, 22.2 mW/cm2.  
These are non-thermal devices; there is no sensation of heat or pain. It is an entirely painless, non-
invasive treatment. The MedX Health LED device is FDA-cleared, as non-significant risk, and used to 
...temporarily increase blood circulation for ...temporary decrease in musculoskeletal pain. The FDA-
clearances date from 2003.  

	  
December 2017 Naeser - 16	  
A dose of 13 Joules/cm2 (12 min 11 sec) was applied to each of the bilateral scalp placement areas (L and 
R forehead areas, L and R perisylvian language areas, and midline LED placement areas including the R and 
L SMAs). The patients were treated in a soft recliner chair. The 6 LED cluster heads were held in place with a 
soft elastic cap, and Velcro bands were used if necessary, to secure the LEDs in place. 
Each stroke patient received 18 transcranial LED treatments (M,W,F) for 6 weeks, with 13 J/cm2 applied at 
each LED placement location using pulsed wave, 146 Hz (12 min 11 sec per LED placement). It was estimated 
that 0.4 J/cm2 reached brain cortex (3%, at 1 cm deep to the skin/scalp application; Wan, Parrish et al., 1981).  
Overt Naming fMRI Scan Paradigm, Pre- and Post- the LED Treatment Series: Prior to any transcranial 
LED treatments, structural MRI scan, and overt naming fMRI scans were obtained using the 3T Philips 
Scanner at the Boston University Center for Biomedical Imaging. The fMRI scans were analyzed using SPM99, 
and the threshold for whole brain analysis was set at p<.001, uncorrected. Our overt naming fMRI protocol 
uses a continuous sample, block design where the hemodynamic delay is utilized to obtain samples for “overt 
picture naming,” during a silent period (viewing patterns), as published in Martin, Naeser et al., (2005); and 
Martin, Naeser, Ho et al., (2009).  
 
Second Transcranial, LED Treatment Method for Aphasia in Stroke:  Left Hemisphere Only, LED Treatments 
The same LED device that had been used for the Bilateral LED Placement Paradigm, was used with the 
Left Hemisphere Only, LED treatments. During this second LED treatment method, the LED cluster heads 
were placed only on the left forehead and left perisylvian language areas on the left side of the head. A 
dose of 39 Joules/cm2 (39 min 33 sec) was applied to each left hemisphere placement area. No LEDs were 
placed on the right hemisphere; and no LED was placed on the R and L SMAs. The same treatment schedule 
was used, 3x per week, for 6 weeks. 
Results, fMRIs and Language Data, Pre- vs. Post- Bilateral, and Left Hemisphere Only, LED Placements  
The results for the first chronic stroke patient, P1 (67 YrM), treated at 18 years post-stroke) are shown in 
Figs. 13 and 14.  

December 2017 Naeser - 17!
Chronic Stroke Patient, Bilateral LED Placements (Less Effective to
Pre- Bilateral LED Tx.               6-1-11 
+2 Wk. Post- 18th Bilateral LED Tx. 8-29-11 
+2 Mo. Pos
Chronic Stroke Patient, Left Hemisphere Only, LED Placements (More Effe
Pre- Left Hemisphere Only, LED Tx. 
Same Scan, as at +2 Mo.  
Post- 18th Bilateral LED Tx.       11-2-11 
December 2017
+2 Wk. Post- 18th Left Hemisphere Only, 
LED Tx.                                         12-21-11 
aeser
17
+1 Mo. Pos
LED Tx.      
er 17
Fig. 13.!Different effects of the Bilateral LED treatments, vs. the Left Hemisphere Only, LED treatments, as studied 
with overt naming fMRI scans (P1, 18 Yrs. poststroke onset, nonfluent aphasia). High activation in the R SMA and R 
frontal areas is compatible with poor Picture Naming. The Left Hemisphere Only, LED treatments, however, 
activated the left hemisphere only, and were thus effective to significantly improve Picture Naming. Figs. 14, 15. 

December 2017 Naeser - 18!
 
 
 
 
 
 
 
 
Unexpectedly, after the Bilateral LED treatments in P1, we observed high activation in the R SMA, and 
in the R frontal areas (both areas had been treated with LED). See Fig. 13. Also, our language results showed 
significantly impaired Picture Naming at +1 Mo. post- Bilateral LED treatments, although the naming 
ability returned to Entry Baseline, at +2 Mo. post- Bilateral LED therapy.  
In our previous fMRI aphasia research, we have observed that high, “over-activation” in the R SMA 
(and other R frontal areas) to be compatible with poor performance on Picture Naming (Naeser et al., 
2004; Martin et al., 2005; Martin, Naeser, Ho et al., 2009). High, “over-activation” in the R frontal areas in 
stroke patients with nonfluent aphasia has also been observed to interfere with speech in other functional 
imaging studies by other investigators (Belin et al., 1996; Rosen et al., 2000; Perani et al., 2003; Postman-
Caucheteux, 2010; Weiduschat et al., 2011). It is possible that R frontal “over-activation” is related to 
transcallosal disinhibition suggesting maladaptive plasticity and only partial, or incomplete recovery (Belin et 
al., 1996; Lefaucheur, 2006; Heiss and Thiel, 2006; Saur et al., 2006). The placement of LEDs on the R frontal 
areas and R SMA likely increased the high “over-activation” that was already present there, post-stroke. This 
was temporarily detrimental to speech output and Picture Naming for P1. We also observed this same pattern 
of impaired Picture Naming, post- Bilateral LED Placements, in the second stroke patient, P2 (53 YrM), 
treated at 12 years poststroke (Fig. 15). 
Thus, our fMRI and language data suggest that Bilateral LED placements that include R SMA and R 
frontal lobe, should not be used in chronic stroke patients with aphasia, who have had left hemisphere 
stroke. The LED effect is very focal, and can temporarily impair naming, if the LED placements include R 
SMA and R frontal areas, in aphasia patients.  
Both stroke patients did, however, show significant improvement in sentence-level Auditory 
Comprehension, post- Bilateral LED treatments. This is likely associated with the bilateral, increased 
activation in the right posterior, temporo-parietal areas, as shown in Fig. 13 top row, with stroke patient P1. 
* 
-20 
-10 
0 
10 
20 
 
1 Wk Post- 
 LED Tx 
 
1 Mo. Post- 
 LED Tx 
 
2 Mo. Post- 
 LED Tx 
Percent Change  
from Baseline 
Philadelphia Naming Test 
Post- Bilateral LED Treatments 
0 
-40 
10 
60 
 
1 Wk Post- 
 LED Tx 
 
1 Mo. Post- 
 LED Tx 
 
2 Mo. Post- 
 LED Tx 
Percent Change  
from Baseline 
Philadelphia Naming Test  
Post- Bilateral LED Treatments 
* 
-20 
-10 
0 
10 
20 
1 Wk Post- 
 LED Tx 
1 Mo. Post- 
 LED Tx 
2 Mo. Post- 
 LED Tx 
Percent Change  
from Baseline 
Philadelphia  Naming Test  
Post- Left Hemisphere Only,  
LED Treatments 
* 
-40 
10 
60 
1 Wk Post- 
 LED Tx 
1 Mo. 
Post- 
 LED Tx 
2 Mo. 
Post- 
 LED Tx 
Percent Change  
from Baseline 
Philadelphia Naming Test  
Post- Left Hemisphere Only,  
LED Treatments 
Fig. 14. Different effects of the Bilateral LED 
treatments, vs. the Left Hemisphere Only, LED 
treatments. For stroke patient, P1, significant 
improvement in Picture Naming was present after 
the Left Hemisphere Only, LED treatments.  
Fig. 15. Different effects of the Bilateral LED 
treatments, vs. the Left Hemisphere Only, LED 
treatments. For stroke patient, P2, significant 
improvement in Picture Naming was present after the 
Left Hemisphere Only, LED treatments. 

December 2017 Naeser - 19!
2a. 2a. iii. Neurodegenerative Disease, Primary Progressive Aphasia:  Improved Language post-LED 
Primary Progressive Aphasia is a relentless language impairment without generalized dementia (Mesulam, 
1982). It is associated with progressive cortical thinning in parts of the left perisylvian language areas. One 
chronic PPA case, P3 (76 YrF), with the logopenic variant of PPA (lvPPA) (Gorno-Tempini et al., 2011), was 
treated with the Bilateral LED treatments. She had significant cortical thinning in her left temporo-parietal 
areas. She was treated during Summer 2011. She had a 2-Yr. history of PPA.  
This lvPPA patient participated in overt naming fMRI scans, pre- and post- the Bilateral LED treatments. 
See Fig. 16. Her fMRI results are similar to those observed with the first chronic stroke patient, P1 (Fig. 13 top 
row). Her fMRI scan obtained at +1 Wk. Post- the Bilateral LED placements showed increased bilateral, 
frontal and temporal activation, post-LED. There was significant improvement in Sentence-Level 
Auditory Comprehension at the +2 Week Language testing, but not Picture Naming. There was no 
increased activation in either the L or R SMA (differing from chronic stroke patient, P1, Fig. 13 top row). Her 
follow-up fMRI scans at +1 and +2 Mo. post- LED (Fig. 16) showed the increased activation from the Bilateral 
LED treatments, to wear off within 1 month.  
At +2 Mo. post- the Bilateral LED Placement Paradigm, all of her language scores remained stable 
compared to her Entry Baseline scores; thus there was no overall deterioration. Her language scores 
remained stable, from May 19, 2011 (pre- LED), to October 31, 2011 (+2 Mo. post- LED). The 6 weeks of LED 
therapy occurred in July/August#!She would likely be a good candidate for the Left Hemisphere Only, LED 
treatments, as well as possibly for long-term, Home Treatments with a LED device. 
Fig. 16. P3, Neurodegenerative disease case with lvPPA. The overt naming fMRI scan obtained at +1 Week post- the 
18th Bilateral LED treatment shows bilateral areas of increased activation in the R and L inferior frontal, and superior 
and middle, posterior temporal/inferior parietal areas (green circles). There was significant improvement in Sentence-
Level Auditory Comprehension at the +1 Week Language testing, but not Picture Naming.  
 
* 
-20 
-10 
0 
10 
20 
2 Wk Post- 
 LED Tx 
1 Mo. Post- 
 LED Tx 
2 Mo. Post- 
 LED Tx 
Percent Change  
from Baseline 
Sentence-Level Auditory Comprehension  
for Commands 
Post- Bilateral, LED Treatments 
$!
$!
-20 
-10 
0 
10 
20 
2 Wk Post- 
 LED Tx 
1 Mo. Post- 
 LED Tx 
2 Mo. Post- 
 LED Tx 
Percent Change  
from Baseline 
Philadelphia Naming Test 
Post- Bilateral, LED Treatments 
!
!
R L 
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R L 
+
+1 Mo. Post- 18th Bilateral LED Tx. 
                                              10-4-11 
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+1 Wk. Post- 18th Bilateral LED Tx.
                                                9-9-11 
Pre- Bilateral LED Tx.       
                                          6-7-11 
R L

December 2017 Naeser - 20!
Fig. 17.  Neurodegenerative Disease, P3, Primary Progressive Aphasia (PPA) similar to Alzheimer’s Disease, but 
Language impairment only. Significant improvement in sentence-level Auditory Comprehension, post- LED. Similar 
to both stroke cases (P1, P2) there was impaired Picture Naming after Bilateral LED treatments.  See also Figs. 13-15. 
As mentioned above, P3 (neurodegenerative disease, PPA) had significant cortical thinning in the left 
posterior temporo-parietal area. It is of interest to note that there was increased rCBF to her areas of 
atrophy, on her fMRI scan at 1Wk., post- the 18th bilateral LED treatment, and there was significant 
improvement in sentence-level Auditory Comprehension at that time. These data suggest that the NIR photons 
are entering the brain cortex areas, even in areas where cortical thinning is already present. This suggests that 
additional LED treatments and LED studies are warranted with this type of neurodegenerative disease.  
Her type of neurodegenerative disease, the lvPPA, has recently been studied with 11C-labelled Pittsburgh 
Compound " PET imaging, where 12 of 13 lvPPA cases (92%) showed positive " amyloid uptake (Leyton et 
al., 2011). The effect of transcranial laser therapy (TLT) in the NIR wavelength of 808 nm (Photothera, Inc., 
Carlsbad, CA) was recently examined in an amyloid-" protein precursor (A"PP) transgenic mouse model of 
Alzheimer’s disease (AD). After 6 Mo. of NIR TLT (3x/Wk., initiated age 3 Mo.), numbers of A" plaques (and 
amyloid load) were significantly reduced (vs. controls). NIR TLT mitigated behavioral effects seen with 
advanced amyloid deposition and reduced the expression of inflammatory markers in A"PP transgenic 
mice. The authors suggest that NIR TLT is a potential treatment for AD (De Taboada et al., 2011). The NIR 
LED treatments could also potentially help to treat neurodegenerative disease such as lvPPA, where the 
putative pathology is " amyloid.  
P4 (neurodegenerative disease, with the nonfluent variant PPA, nfvPPA), is currently undergoing Left 
Hemisphere Only, transcranial, NIR LED treatments. She is Tau-positive from lumbar puncture, and has 
atyptical bilateral fronto-parietal atrophy.  
Prior to any LED treatments, however, resting state, functional connectivity fMRI scans were performed 
pre- and post- three different doses of Joules/cm2 applied to the Left Hemisphere Only. The fMRIs were 
obtained, pre- and post- 1 session Sham LED treatment (0 Joules/cm2); and pre- and post- 1 session of Real 
LED treatment (2 Joules/cm2); and pre- and post- 1 session of Real LED treatment (13 Joules/cm2). The 
results shown in Fig. 18, indicate that Sham LED had no effect; and Real LED at a dose of only 2 J/cm2 also 
had no effect. Only the Real LED treatment at 13 Joules/cm2 showed an increase of 1 SD, above 
Baseline/Entry for strengthening the functional connections between two left frontal regions important 
for language, the left middle frontal gyrus and the left inferior frontal gyrus. Both areas treated with LED. 
Fig. 18. Neurodegenerative disease, case P4, resting state fMRI data showing functional connectivity strength between  
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Neurodegenerative Disease        72 Yr. F Primary Progressive Aphasia (PPA), Nonfluent Variant'
  
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Controls - 
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2 cortical  
areas where 
functional  
connections should be 
strong.   
 
They were initially weak 
in the PPA patient, 
but stronger Post- 13 J/
cm2 Real LED. 
where 
nal  

	  
December 2017 Naeser - 21	  
2 left hemisphere cortical areas for language:  L middle frontal gyrus and L inferior frontal gyrus.  Relative to Baseline  
(pre-Sham), functional connectivity data show no change post- Sham LED Treatment, and no change post- 2 J/cm2 
Real LED Treatment  (>2 days between paired sessions.)  Substantial increase (1 SD) in functional connectivity, only 
after higher dose, 13 J/cm2 Real LED Treatment.    Naeser, Dickerson, Ho, Martin, Treglia, Hollenbeck, Krengel, Hamblin, Baker, in prep. 
 

	  
December 2017 Naeser - 22	  
2a. 2a. iv.  Summary of Pilot Data using Transcranial, red/NIR LED to Treat 3 Patient Populations: 
1.  Chronic TBI, 2 published cases:  Post- transcranial, red/NIR LED, there was significant improvement 
in sustained attention; executive Function and verbal memory (Naeser et al., 2011).  The second case 
returned to work, full-time, after 4 months of home treatments (she had been on medical disability for 5 
months.  
2.  Chronic TBI, 7 additional cases:  Post- transcranial, red/NIR LED, there was significant improvement 
in executive function (p<.01), and verbal memory (p<.05). Cases had cognitive dysfunction for 1 – 7 years, 
before entry. 
3.  Chronic (left-hemisphere) stroke patients with aphasia:  Post- Bilateral transcranial, red/NIR LED 
treatments, there was significant improvement in sentence-level Auditory Comprehension (p<.05), but 
temporary impairment in speech (Picture Naming), each of 2 cases. 
4. Chronic (left-hemisphere) stroke patients with aphasia:  Post- Left Hemisphere Only, transcranial, 
red/NIR LED treatments, there was significant improvement in Picture Naming (p<.05), each of 2 cases. 
5. fMRI scans in the chronic (left-hemisphere) stroke patient with aphasia showed that post- Bilateral LED 
treatments, there was bilateral activation in the R and L SMA and the R and L frontal lobe areas. This high 
activation in R (contralesional) frontal regions has previously been observed to interfere with speech output 
and Picture Naming. 
6.  fMRI scans in the chronic (left-hemisphere) stroke patient with aphasia showed that post- Left 
Hemisphere Only LED treatments, there was only L SMA and L peri-lesional activation (L sensori-motor 
cortex area for mouth); and there was significant improvement in Picture Naming (p<05).  
 
Thus, there is a remarkably focal effect for the specific location of LED cluster head placements on 
the head, suggesting a proof of principle, that NIR LED light can penetrate the skin/scalp to affect brain 
cortex, and affect focal neural networks for language. The photons appear to have an effect, where they are 
targeted.  
Bilateral LED Placements (including R and L SMA; and R and L frontal lobe areas) significantly impaired 
Picture Naming. 
Left Hemisphere Only, LED Placements significantly improved Picture Naming. 
 
7.  Neurodegenerative Disease, Primary Progressive Aphasia:  Post- Bilateral transcranial, red/NIR LED 
treatments, there was significant improvement in sentence-level Auditory Comprehension (p<.05) at 2 
weeks post- LED, but the effect was transient, and wore off by 1 Mo. post- LED. Post- Bilateral LED, there was 
no improvement in Picture Naming.  
8. fMRI scans in neurodegenerative disease, Primary Progressive Aphasia (logopenic variant):  Post- 
Bilateral transcranial, red/NIR LED treatments, there was increased activation in the left posterior 
temporo-parietal area, where her significant cortical thinning was present. This suggests that the NIR 
photons reached her primary areas of cortical thinning, and this may have been associated with her improved 
sentence-level Auditory Comprehension, post- Bilateral LED. Or, the increased activation in her right posterior 
temporo-parietal area which was also present, post- Bilateral LED could also have been associated with her 
improved sentence-level Auditory Comprehension.  
However, the increased bilateral frontal lobe activation post- Bilateral LED, may have interfered with her 
Picture Naming, where there was no improvement (similar to the two stroke cases following Bilateral LED). 
9. Resting state, functional connectivity fMRI scans, Neurodegenerative Disease, Primary Progressive 
Aphasia (nonfluent variant):  Within one session of Left Hemisphere Only, red/NIR LED treatment, Sham LED 
had no effect, and Real LED at 2 Joules/cm2 had no effect. However, Real LED at 13 Joules/cm2 
increased the functional connectivity between two left hemisphere language areas by 1 SD (left middle 
frontal gyrus and left inferior frontal gyrus).  
10.  Taken together, the significant improvement in executive function and verbal memory in the 
chronic TBI cases; and the significant improvement in sentence-level Auditory Comprehenson post- 
Bilateral LED treatments in chronic stroke (and 1 neurodegenerative disease/PPA case) suggest that the 
red/NIR photons are reaching brain cortex, to affect improvement in behavior.  
The LEDs have a focal effect, however, ...where they are placed. With Bilateral LED placements in 
chronic stroke, there is increase in bilateral activation (R and L SMA, and R and L frontal); with Left 
Hemisphere Only LED placement, there is increase in left hemisphere only activation (L SMA, and L peri-
lesional activation).  
 

December 2017 Naeser - 23!
11. Resting state, functional connectivity fMRI in neurodegenerative disease, Primary Progressive Aphasia 
showed a dose-response effect with LED to the Left Hemisphere Only, where there was increased functional 
connectivity when 13 Joules/cm2 was applied, not 0 Joules/cm2 (Sham LED), nor 2 Joules/cm2 (Real LED). 
12. The primary, hypothesized mechanism of action is local, increased vasodilation and increased 
rCBF due to diffusion of nitric oxide outside the cell wall, following exposure of the hypoxic/ 
hypometabolic cells to red/NIR photons from transcranial LED. The cytochrome C oxidase in the 
mitochondrial membrane is a photo-acceptor of red/NIR photons; this promotes the diffusion of nitric oxide 
outside the cell wall, and there is increased ATP production for improved cellular energy and function.  
Our fMRI scan data obtained pre- vs. post transcranial LED therapy support this primary, hypothesized 
mechanism of action, because increased activation and rCBF in specific neural networks for language 
was observed post- LED. Our fMRI results are compatible with two previously published reports of increased 
rCBF in humans post- transcranial NIR LED – i.e., 1) with a patient in persistent vegetative state where 
increased rCBF was observed on SPECT scan post- a series of LED treatments (Fig. 1) (Nawashiro et al, 
2011); and with severe depression cases (Fig. 2) (Schiffer et al., 2009).  
These positive effects on cognition and language behavior from our pilot studies support the need for 
sham-controlled studies with transcranial LED. This proposal will conduct a sham-controlled LED study to 
examine whether transcranial, red/NIR LED can be used to improve cognitive function in veterans with GWVI. 
There are currently, no treatments for cognitive dysfunction in veterans with GWVI. 
2a. 3.  Research Design and Methods 
This is a blinded, randomized, sham-controlled study, originally designed as a complete crossover study. 
The study has been red-designed as a partial crossover study. Recruitment has been lower than expected. 
The new design will reduce the burden on participants for the number of visits and this is expected to improve 
enrollment. The new design will not alter the primary, planned statistical comparisons (Real vs. Sham LED 
Treatments) that are based on the 1st Series of Treatments only. The randomization and blinding remain in 
place. 
This study investigates if scalp application of non-invasive, light-emitting diodes (LED) in red and near-
infrared (NIR) wavelengths improves cognition in veterans with Gulf War Veterans’ Illnesses (GWVI). Impaired 
cognition is one of the 3 major symptom areas of GWVI. Prior to entry, all participants will have been 
determined to meet the criteria of having Gulf War Veterans’ Illnesses (GWVI), including cognitive dysfunction. 
The recruitment process and Inclusion/ Exclusion criteria are explained in detail in Section 2a. 3a. i.  
Participant Referral and Recruitment. 
There are two groups, with about 49 participants per group; total 98; see Flowcharts, below. 
Participants in Group 1 receive 15 LED treatments over a 7.5 week period (2x per week, 48 hr. between visits).  
At +1 Week and +1 Month after the 15th Sham LED treatment (when the Post-testing has been completed), the 
subjects are informed that they had received the Sham LED Series of Treatments.  These subjects are then 
offered the option of returning to receive the Real LED Series of Treatments (15 Real LED treatments over a 
7.5 week period (2x per week, 48 hr. between visits), if they wish to do so.  These subjects would then receive 
the additional payments for these extra treatment visits and Post-testing visits, for up to a total of $1,150. 
Participants in Group2 receive 15 Real LED treatments over a 7.5 week period (2x per week). At +1 Week and 
+1 Month, after the 15th Real LED treatment (when the Post-testing has been completed), the subjects are 
informed that they had received the Real LED Series of Treatments.  The participation of these subjects is 
terminated at that time.  They have received up to a total of $710 for their participation. 
Group 1.  Sham LED Series First; Optional Real LED Series Second   
!
Time 1 
Baseline  
Neuro-
psychology 
Testing (1x) 
 
Actigraphy 
(for 1 week) 
 
 
1st Intervention  
15 Sham LED 
Tx.'s   2x/Wk,     
7.5 Wks. 
Times 2 and 3 
Post- Testing within 
1 Wk and at 1 Mo 
after 15th Sham 
LED Tx. (T2 and T3)  
Actigraphy (T2 and 
T3) 
 
 
 
Optional 2nd 
Intervention  
15 Real LED Tx.'s 
2x/Wk, 7.5 Wks.  
Times 4 and 5 
Post- Testing within       
1 Wk and at 1 Mo after 
15th Real LED Tx.  
(T4 and T5) 
Actigraphy (T4 and T5) 
 
 

December 2017 Naeser - 24!
Group 2.  Real LED Series Only 
2a. 3a. i.  Participant Referral and Recruitment 
Only GW veterans will participate; about 98 over the grant period. Potential participants from a Fort Devens 
cohort of veterans were advised in their prior informed consent procedures for previous VA-related GW studies 
that they may be contacted in the future about the possibility of participating in future studies. Veterans will be 
recruited for this study through the Co-Investigator, Maxine Krengel, Ph.D., Clinical Neuropsychologist, VA 
Boston Healthcare System. 
Dr. Krengel is currently funded for a three-year Department of Defense grant (2011-2014) where she will 
re-contact the original 2,123 veterans from the Fort Devens cohort of veterans from the New England region, 
who returned from their 1990-91 Gulf War deployment through Ft. Devens, Massachusetts. This cohort was 
originally evaluated just days after their return from the Gulf War in 1991 and have been resurveyed for health 
symptoms and medical diagnoses multiple times in the past 21 years following their return from the war. 
Approximately 1,500 veterans participated in the most recent surveys of this large, population-based cohort. As 
part of Dr. Krengel's current resurvey of this cohort, recruitment letters will be mailed to all of the original 
surviving Ft. Devens cohort members. It is estimated that a minimum of 600 of these GW veterans will 
participate in Dr. Krengel’s current DoD-funded resurvey.  
These veterans will be invited by Dr. Krengel to participate in a web-based survey regarding their current 
health concerns and medical diagnoses. They are provided with an ID number and therefore all data are de-
identified. As part of the survey, the following questionnaire is used: “Symptom Questions used to Identify Gulf 
War Illness by Kansas Case Definition, and Chronic Multisymptom Illness by Fukuda Case Definition.” Dr. 
Krengel will determine from the answers to this questionnaire, whether the veterans meet the criteria from the 
Kansas GWI definition and the Fukuda CDC multi-symptom illness criteria for GWVI (Steele, 2000; Fukuda et 
al., 1998).  
Additional participants may be recruited through other sources including the following.  
We will submit a data request to the Department of Defense’s Defense Manpower Data Center (DMDC) for the 
names and mailing addresses of Gulf War veterans who reside within a 100 mile radius of the Boston VA Healthcare 
System, JP Campus for the the purposes of study recruitment. Once we obtain the list of GW veterans who reside within a 
100 mile radius, we will send them an IRB-approved recruitment letter and a permission to contact form, with a pre-
addressed, stamped return envelope. These GW veterans will be invited to contact us by phone or by returning the 
permission to contact form if they are interested in participation and/or if they would like more information about the study. 
If they do not contact us or return the permission to contact form within 2 weeks, we will contact them by phone. 
We would like to use CPRS to identify veterans who live locally and who meet our inclusion/exclusion criteria.  
We will also apply for access to the VA VINCI/CDW data, by initiating a DART data request, to obtain a list of GW 
veterans who reside within a 100 mile radius of the Boston VA Healthcare System, JP Campus so we can send them an 
IRB-approved recruitment letter and a permission to contact form, with a pre-addressed, stamped envelope. These GW 
veterans will be invited to contact us by phone or by returning the permission to contact form if they are interested in 
participation and/or if they would like more information about the study. If they do not contact us or return the permission 
to contact form within 2 weeks, we will contact them by phone.  
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.    
For the purposes of this LED study, Dr. Krengel will use the Fukuda et al., 1998 criteria for GWVI - i.e., the 
presence of 1 or more chronic symptoms (lasting >6 months) from at least 2 of 3 symptom categories: 1) 
Time 1 
Baseline  
Neuro-
psychology 
Testing (1x) 
 
Actigraphy 
(for 1 week) 
1st Intervention  
15 Real LED Tx.'s 
2x/Wk, 7.5 Wks.  
Times 2 and 3 
Post- Testing within 
1 Wk and at 1 Mo 
after 15th Real LED 
Tx. (T2 and T3) 
Actigraphy (T2 and 
T3) 
 
 
 
 

	  
December 2017 Naeser - 25	  
musculoskeletal (muscle pain, or joint pain, stiffness); 2) mood-cognition 3) fatigue. (Note, although the Fukuda 
et al., 1998 criteria for GWVI will be used as an Inclusion criterion for this LED study, data for the Kansas Case 
Definition will also be available.) 
Dr. Krengel will refer veterans with GWVI who have also answered ‘Yes’ to the following questions: 1) 
Difficulty concentrating; and/or 2) Difficulty remembering recent information, to Dr. Naeser for further 
neuropsychological screening, and potential participation in this LED research project to improve cognition. 
Additionally, recruitment, screening and data collection will occur at a second site in San Francisco, CA. 
This second site has been added to improve recruitment and enrollment numbers. The goal is to enroll 98 
subjects for the whole study. Enrollment of 50 cases in projected for Sept. 2017 in Boston; and 50 cases is 
projected for March/April 2018 in SF. 
Dr. Linda Chao, at SF VAMC has an active Gulf War Illness research program. In 2011 her group published a MRI 
paper with 64 GW Veterans who participated [NeuroToxicology 32 (2011) 814-822]. Her office will work from their most 
current GWI registry to recruit participants. The same protocol and processes for informed consent, enrollment, inclusion 
and exclusion, currently in place at the Boston VABHS (see below) will be followed. No sleep data, however, will be 
collected at the SF VAMC to save funds. The overall study will be overseen by Dr. Naeser.  
Screening of eligibility will be conducted at the SF VAMC, using our screening criteria. Data collected at SF VAMC 
research site will be transferred to the Dr. Naeser's office at the VABHS, JP campus in the following manner: 
A) A de-identified Data Summary Sheet for each case (will only have randomized participant ID) will be faxed to our 
VA FAX.  It is located in one of our locked offices, and we would then place it in a locked filing cabinet in our locked office.  
On the Data Summary Sheet, Age, Ed., Gender, will be provided and data timepoints will be labeled as  Baseline, 
Testing Time 1 (T1), T2, T3, T4, etc. (no dates on this sheet).    
 
B) We also want to be able to double-check the Data Summary Sheet with the raw data pages, just for redundancy in 
checking. The raw data test sheets will be mailed to us for each subject, for each testing time,  so we have them for our 
files here. They will be kept in a locked filing cabinet, in Dr. Naeser’s locked offices. This will be done through USPS 
Priority mail, with appropriate tracking ability. Linda Chao at the SF VA will keep copies of all the raw data sheets.The 
following information will be on these raw data sheets that will be xeroxed and mailed, for each subject, for each testing 
time: participant Id# and test dates. No name or other identifying information. Data analysis will be completed at the 
Boston VABHS.  
 
 
2a. 3a. ia.  Initial Contact and Informed Consent Process 
Initial Contact. The initial contact following referral of the patient to Dr. Naeser’s office by Dr. Krengel will 
consist of a phone call by Dr. Naeser’s office to the patient. All potential participants referred by Dr. Krengel 
have already agreed to share their contact information regarding the possibility of participating in future GWVI 
studies. A description of the full study protocol, time required, and reimbursement for their time and effort will 
be discussed with the participants. They will be informed that whether or not they participate will have no 
bearing on their medical care and that, if they choose to participate, they may withdraw at any time without 
prejudice. After the initial contact, an appointment for obtaining signed informed consent, and further screening 
with neuropsychological testing at the VABHS, JP campus, will be arranged. 
Informed Consent Process.  If the potential participant chooses to participate in the study, an appointment 
will be scheduled with the PhD Study Coordinator at the VABHS, JP campus. At that time, the participant will 
be presented with the ICF and all questions will be answered. The participant will then be given the ICF for 
signature. After consent is obtained, the participant will have further screening [neuropsychological (NP) 
testing]. At the time of screening, the Word Reading Subtest from the Wide Range Achievement Test-4 will be 
used to estimate the premorbid level of cognitive functioning as a standard score for age, education, and 
gender (converted to SD). This score is then used for comparison to the other standardized NP test scores at 
screening, as follows: Participants must score at least 2 SD below their estimated premorbid cognitive level on 
at least 1 of these NP tests; or 1 SD below on at least 2 of these NP tests at Entry testing, for Inclusion into the 
study. If the participant meets the criteria for entry, based on their estimated premorbid level of cognitive 
functioning at NP screening on the Word Reading Subtest of the Wide Range Achievement Test (WRAT– 4), 
additional tests for pain, fatigue, mood and health questionnaires will be administered.  
The participant will be informed that the PI will mail a letter to his/her primary care provider (PCP), 
informing his/her PCP about the veteran’s participation. Each participant will be asked to provide the name and 
address of his/her PCP. A copy of that letter is provided. This letter includes a short, 2-page summary of the 
study. All subjects will be treated the same, and this procedure will also be followed for the GWI veterans who 
do have a PCP in the VA system. 
 

	  
December 2017 Naeser - 26	  
Neuropsychological Screening.  The neuropsychological tests that will be used in this screening battery are 
taken from a previously validated screening for cognitive dysfunction in Gulf War veterans (Sullivan, Krengel et 
al., 2003; White et al., 2001).  At the time of screening, the Word Reading Subtest from the Wide Range 
Achievement Test-4 will be used to estimate the premorbid level of cognitive functioning as a standard score 
for age, education, and gender (converted to SD). This score is then used for comparison to the other 
standardized NP test scores at screening, as follows: Participants must score at least 2 SD below their 
estimated premorbid cognitive level on at least 1 of these NP tests; or 1 SD below on at least 2 of these NP 
tests at Entry testing, for Inclusion into the study. The following other tests are administered: 1) Trail Making 
Test (Reynolds, 2002); 2) COWAT - FAS Test (Spreen & Benton, 1977; Benton & Hamsher, 1989); California 
Verbal Learning Test II, Alternate Version (Delis et al., 2000); Stroop (“color-Word” test) (Delis, Kaplan, 
Kramer, 2001); and 5) Short Form McGill Pain Questionnaire (1984); 6) Overall VAS pain rating (0-10); Test of 
Memory Malingering (TOMM; 1996). Posttraumatic stress disorder will be assessed at screening using the 
PTSD Checklist –Civilian (C). The PCL-C (for civilians) scores should be >50, with PTSD symptoms exceeding 
clinical diagnostic thresholds for DSM-IV (i.e., 1 B-Criterion; 3 C-Criteria; 2 D-Criteria).  
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.    
 
At screening, the Fitzpatrick Skin Type scale will be used, to determine the skin type, ranging from 1 (very fair 
skin) to 6 (darkest skin). Treatment dose will be adjusted when treating those participants who have the lightest 
(decreased) pigmentation of the skin and darkest (increased) pigmentation of the skin.  See section 2a. 3b.  
 
If screening or neuropsychological testing cannot be completed on the same day, we will complete any 
remaining tests at another visit at the patient’s request to accommodate their schedule. 
 
 
Method of Transcranial LED Treatment 
A sample data entry sheet for the Neuropsychological Screening tests and subtests is provided in Appendix 3. 
 
2a. 3a. ib.  Inclusion Criteria: 
1. Must be a veteran deployed in 1990-1991 Gulf War. 
2. 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, they will be considered to have GWVI (Fukuda et al., 1998).  
3. Participants must have GWVI, and have answered ‘Yes’ to the following questions: 1) Difficulty 
concentrating and/or 2) Difficulty remembering recent information, on the Symptom Questionnaire. 
4. Ages 38 - 65 years. 
5. Must be physically able to travel to the VA Boston Healthcare System, Jamaica Plain, or San Francisco 
VAMC for Neuropsychological testing and transcranial LED treatments 
6.  Must meet screening criteria from the Neuropsychological Screening Tests. 
2a. 3a. ic.  Exclusion Criteria: 
1.  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). 
2. Participant 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. 
3.  Less than age 38, or greater than age 65. 
4.  Presence of a neurodegenerative disease such as ALS, Parkinson's, Dementia. 
5.  Presence of a life-threatening disease such as cancer.  
6.  Presence of a severe mental disorder such as schizophrenia, or severe depression. 
7.  Physical limitations that would prevent traveling to the VA Boston Healthcare System, Jamaica Plain, for 
Neuropsychological testing and transcranial LED treatments 
8.  Current substance abuse or active treatment 
9.  Did not meet screening criteria from the Neuropsychological Screening Tests. 

	  
December 2017 Naeser - 27	  
10. Participants may not have a level of pain greater than 7/10 on VAS or 38/50 on the Short Form McGill pain 
questionnaires at the time of screening. 
11. On the TOMM (1996), a score of less than 45 on either Part 1 or 2 would show evidence of malingering 
and the participant may not be included, with the following exception: If a participant fails Trial 1, but does not 
fail Trial 2, he/she would not be excluded if he/she also show evidence of poor learning on other NP Screening 
tests, such as the CVLT. If they fail Trial 2, alone, or Trial 1 and Trial 2, then this would exclude the participant 
from the study.  
 
Medical records will be obtained to determine history of any surgeries; general medical history; current 
medications; brain CT and MRI scans with full sets of images if available, as well as Radiology reports; history 
of previous treatment interventions. We will request that participants let us know if there are any changes in 
medication type or dosages throughout their participation in this study. They will be asked weekly when they 
come in for treatment if there were any changes.  Measurements (circumference, length from tragus of the R 
ear to tragus of the left ear, and length from glabella to occipital protuberance) will be taken. If the participant's 
head circumference is greater than 24 inches, we will utilize the Thor Helmet (for Real or Sham) to 
accommodate this larger head size and ensure the participant remains comfortable throughout the treatment. 
The treatment will be administered with appropriate timing to ensure output is equivalent.  See Appendix 10. 
Table 1, for specifications of the Photomedex Helmet compared to the Thor Helmet. 
 
Neuropsychological (NP) Tests:  The neuropsychological tests selected as the Primary Outcome 
Measures for this research project measure the primary neurocognitive domains impaired in GW veterans. We 
have grouped them into 3 domains: 1) Attention/ Executive Function; 2) Learning and Memory; and 3) 
Psychomotor/Visual Spatial. Impairments measured by these tests are associated with underlying brain 
dysfunction involving temporal, parietal and frontal brain regions. Executive functioning is a higher-order 
cognitive activity that is built on more fundamental cognitive skills (i.e., attention, language, and perception). 
While multiple cortical regions distributed across the brain contribute to higher-order cognitive processing, the 
prefrontal areas of the frontal lobe (i.e., dorsolateral prefrontal cortex; anterior cingulate cortex; orbitofrontal 
cortex) are very involved in coordinating executive functions. These are cortical areas that are targeted (among 
others) with the transcranial application of red/NIR LEDs in this project. The specific NP tests are below.  
Digit Span (DS):  The forward and backwards span sequences of this subtest from the Wechsler Adult 
Intelligence Scale-IV assess attention, processing speed and working memory. 
 
Trail Making Test (TMT):  The TMT assesses the cognitive flexibility aspects of executive functioning using 
a visual-motor sequencing task format (i.e. connect the dots format). This study will use two variations of the 
TMT; one for screening (Reynolds, 2002) and the other for repeated administrations (D-KEFS Trails). TMT-
Part A primarily assesses visuospatial scanning, motor sequencing skills, rote memory, integration and 
cognitive processing speed. TMT-Part B is more complex than Part A because it requires the examinee to 
connect numbers and letters in an alternating pattern (1-> A-> 2-> B-> 3-> C, etc.) as quickly as possible 
without errors. TMT-B has found to be a useful tool in identifying general frontal lobe dysfunctions (Reitan & 
Wolfson,1985; 1995). Both Part A and B are scored for time to completion and then interpreted using standard 
norms (Bradford, 1992; Tombaugh, 2004). 	  
For repeated administrations of the trailmaking test, the Trails Test from the D-KEFS (trials 1-5) will used.  
The D-KEFS (Delis, Kaplan & Kramer, 2001) is a nationally standardized set of nine tests that measures a 
wide range of verbal and nonverbal executive functions.  Each test is designed to be a stand-alone instrument 
that can be administered individually or along with other D-KEFS tests.  In clinical populations, the D-KEFS can 
be used to assess mild brain damage in general and mild frontal-lobe involvement in particular. 
Stroop Color-Word Interference Test (Stroop):  The Stroop Color-Word Test is a brief, five minute test used 
to evaluate aspects of executive functioning, including cognitive flexibility, resistance to interference from 
outside stimuli, and creativity (Golden, 1978). EEG and functional neuroimaging studies of the Stroop effect 
have consistently revealed activation in the frontal lobe, more specifically in the anterior cingulate cortex and 
dorsolateral prefrontal cortex (Carter & van Veen, 2007). Four trials of the Stroop Test from the D-KFES will be 
administered both as a screening and an outcome measure. If the subject screens into the study based on the 
initial NP screening, the test is not re-administered for Baseline data; and the scores are pulled over from the 
NP screening, and entered as Baseline data. 
California Verbal Learning Test-II (CVLT-II):  The CVLT-II assesses multiple aspects of verbal learning 
(Delis et al., 2000). CVLT-II administration requires that a list of 16 words be presented to the examinee for 
memorization (4 words from 4 categories: furniture, vegetables, ways of traveling, and animals). The CVLT-II 

	  
December 2017 Naeser - 28	  
measures both recall and recognition of the word lists over 5 different trials. It also measures delayed and cued 
recall. The CVLT-II has alternate forms for repeated administrations. The scores from the CVLT-II will be used 
for screening and as a primary outcome measure. If the subject screens into the study based on the initial NP 
screening, the test is not re-administered for Baseline data; and the scores are pulled over from the NP 
screening, and entered as Baseline data. 
Continuous Performance Test-Visual AX version (CPT):  The CPT measures a person's impulsivity, 
selective attention, plus sustained attention and effort in a cognitively demanding context. The computerized 
presentation of the visual CPT-AX version in this study (NES; Letz & Baker, 1988) will require the examinee to 
respond with a right mouse press whenever the letter stimulus on screen is an X that was preceded in the 
sequence by the letter “A”.  The left mouse button is pressed for an X that was not preceded in the sequence 
by the letter ”A”.  Stimuli are presented for 200 msec each. The inter-trial interval varies across trials and may 
be 1.5, 2.0 or 2.5 seconds (this includes the duration of the stimulus), so the average ITI is 2.0 seconds. 
Approximately 20% of the stimuli are targets (A preceding X). Performances will be scored for: % correct target 
detections, % non-target detections, false alarms, reaction times.  The CPT can be repeatedly administered. 
Rey-Osterrieth Complex Figure Test (ROCF):  The Rey–Osterrieth Complex Figure Test (ROCF; 
Osterrieth, 1944; Rey, 1941)is a widely used neuropsychological test for evaluating visuospatial-visuoconstru-
ction ability and visual memory (Knight and Kaplan, 2004). It has also been used for measuring executive 
functions mediated by the prefrontal cortex. Examinees are asked to reproduce a complicated line drawing as 
a direct copy and from memory. The ROCF involves three test conditions: Copy, Immediate Recall and 
Delayed Recall. Each of the three productions generated is scored for accuracy and placement of 18 specific 
design elements according to established scoring rules.  The ROCF test will be used an outcome measure.  
Controlled Oral Word Association Test (COWAT)-FAS Test (Screening only):  The COWAT is a brief and 
sensitive measure of executive function.  The version used in this study appraises verbal fluency by requiring 
the examinee to generate as many words as possible in 60 seconds beginning with a specific letter F, A, or S. 
The examinee’s scores is the Total Number of Words generated across the three letter categories. Both frontal 
and temporal lobe areas of the brain have been implicated by neuropsychological investigations as being 
involved in successful performances (Lezak, 1995).  
2a. 3a. ii.  Primary Outcome Measures, Neuropsychological Tests 
The neuropsychological tests cover 3 cognitive domains: 1) Attention/Executive Function; 2) Learning and 
Memory; and 3) Psychomotor/Visual Spatial. A sample data entry sheet for NP tests is provided in Appendix 4. 
1) Attention/Executive Function 
Digit Span Subtests (WAIS-IV; Wechsler, 2008) 
D-KEF Trails (Delis, Kaplan & Kramer, 2001) 
Stroop Test (“Color-Word” test) (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 laptop computer; RVisual CPT, NES)  
 
(Letz & Baker, 1988; Rosvold et al., 1956)  
Rey Osterrieth Complex Figure Test (ROCFT; Knight & Kaplan, 2004) 
 
2a. 3a. iii.  Secondary Outcome Measures  
These additional tests measure other symptoms associated with GWVI. Sample data entry sheet, App. 4. 
Pain Tests:  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).  
Fatigue:  Multi-Dimensional Fatigue Inventory (Smets et al., 1995). 
Sleep: Pittsburgh Sleep Quality Index (PSQI) (Buysee et al., 1989). Karolinska Sleepiness Scale (KSS). The 
Karolinska Sleepiness Scale will be administered each of the Neuropsychological Testing time points and each 
treatment day, at the end of treatment.  
Actigraphy (Actiwatch): Accelerometer worn on the wrist as a watch used to provide an objective sleep 
measure; worn 1 week at a time, pre- treatment, 1 week and 1 month, post- Real and Sham LED treatment 
series. A sleep log will be filled out each week the Actiwatch is worn. 
Mood:  Beck Depression inventory (BDI; Beck, 2006) 
Data for General Physical Health:  Short Form-36V Plus (Ware et al., 2000); and the Health Symptom 
Checklist (HSC). The HSC is a comprehensive list of 34 frequently reported health and mental health 
symptoms originally adapted from Bartone et al., (1989). It asks how often in the past 30 days each of the 

December 2017 Naeser - 29!
health symptoms was experienced.  Symptoms from nine body systems are assessed (cardiac, pulmonary, 
dermatological, gastrointestinal, genitourinary, musculoskeletal, neurological, and psychological).   
2a. 3b. Method of Transcranial LED Treatment 
After all Pre-testing is complete (including the NP tests), randomization and assignment for LED treatment 
to Group 1 (Sham 1st, Real 2nd), or to Group 2 (Real 1st, only) will take place. A total of 49 cases are treated per 
Group; approximately 98 total across the study. The PhD Study Coordinator will use the free computer 
software program GraphPad (graphpad.com), to assign the participants (10 at a time), using a blocked 
randomization procedure, into the 2 groups. After 10 participants have been assigned, another set of 10 
participants will be randomized into Group 1 or 2 in the same manner. This method will continue to be used, 
until all cases have been treated, across the study period. The study coordinator at the Boston VA is 
responsible for assignment of randomization  at the SF VA as well. 
Participants are treated 2x per week (at least 48 hours between treatments), for 7.5 weeks in each series – 
total of 15 LED Tx.’s per LED series. Blinding is preserved because neither the participant, nor the Neuro-
psychologist doing the Pre- Post- testing is aware of whether the patient has received Sham or Real LED. 
The LED Helmet manufactured by PhotoMedex, Montgomeryville, PA will be used (Fig. 19). This helmet 
contains 18 pods (LED cluster heads). Each pod is 4.5cm x 4.8cm. The helmet is designed with 6 pods to treat 
the midline of the head; 6 pods to treat the right side of the head; and 6 pods to treat the left side of the head.  
The pods have been FDA-cleared as non-significant risk and a single pod is sold over-the-counter as a 
product labeled “OmniLux New U.” This device has been FDA-cleared to apply directly to the face to reduce 
peri-orbital wrinkles. The FDA clearance documents are provided in Appendix 5. Each participant will be 
provided a clear plastic liner in the shape of the helmet, worn on the head beneath the LED Helmet. This is 
stored in the treatment area and labeled with the patients ID number.  
The helmet liner will be re-used (after completion of all treatments for one participant) for another 
participant, throughout that subject’s participation in the LED treatment series. The liner will be cleaned as per 
instructions from Infection Prevention (and the Safety Committee). See Appendix 9. 
CleaningofHelmetLiner6_30_16 

	  
December 2017 Naeser - 30	  
 
While some warmth is produced from the LED pods in the Helmet, the warmth is dissipated by the built-in 
fans (…eighteen fans are used; the voltage of the fans increase from 15V to 24V in both helmets; direction of 
airflow is changed in 10 of the 18 fans in the Real Helmets and 4 of the 18 fans in the Sham Helmets; some 
warmth is applied in the Sham Helmet to make the temperature equivalent between Helmets).  
 
Table 1 showing LED specifications for: 1) red/NIR LED cluster heads already used at VABHS (Dr. Naeser’s 
Lab, for mTBI or stroke projects).  
2)  Photomedex red/NIR Helmet previously approved, January, 2013 by VABHS, Safety Subcommittee and 
IRB (Dr. Naeser’s Lab, for GWI project) 
3)  Photomedex NIR ONLY Helmet, re-designed by Photomedex, June 2014, the red LEDs were removed (to 
reduce warmth). (for Dr. Naeser’s Lab, for Gulf War Illness project) 
* The MedX Health LED Cluster Heads (MedX Health Console Unit Model 1100) are FDA-cleared, as non-
significant risk, “...to temporarily increase blood circulation ...to temporarily decrease pain in musculoskeletal 
conditions.”  The MedX Health FDA-Clearance Documents are provided in Appendix 7.  
On October 13, 2010, the Research Safety Subcommittee, VA Boston Healthcare System, approved the 
use of this MedX Health LED therapy system for use in Dr. Naeser’s, IRB# 2492, “Transcranial LED to Improve 
Naming in Primary Progressive, and other Aphasias.” This research project has been using this LED device 
since Spring, 2011. A total of 5 or 6 LED cluster heads are used on the head at the same time. The energy 
density doses per LED cluster head have been either 13 J/cm2 or 39 J/cm2 (pulsed wave, 146 Hz). There have 
been no negative side effects or adverse events here at the VABHS. This original Research Safety 
Subcommittee, VABHS, Approval document is provided in Appendix 8. 
** The Photomedex LED Cluster Heads (Omnilux New-U) are FDA-cleared, as non-significant risk, “...to 
decrease peri-orbital wrinkles on the face.”  The Photomedex FDA-Clearance Documents are provided in 
Appendix 5. 
 
 
 
 
 
 
 
 
 
 
Specific  
LED Parameters 
Per each LED cluster 
head 
1) 
MedX Health, Toronto, 
Canada. Specifications are for 
each LED Cluster Head. 
 
5-6 used simultaneously,  
     2 Different Placement Sets 
on the head: Midline, R & L 
sides of the head, and on the 
foot. 
2)  
PhotoMedex Inc., Horsham, PA. 
Specifications for Each LED Cluster 
Head (in LED Helmet).   
Based on Omnilux New U, pods (4 
red and 20 NIR diodes per pod) 
embedded into the Helmet.   
 
6, then 12 pods used 
simultaneously in single Tx.  
2 Different Placements Sets:  
   a) Midline Only; then  
   b) L and R sides only 
3)  
 PhotoMedex Inc., Horsham, PA. 
Specifications for Each LED 
Cluster Head/pod (in LED 
Helmet). 
6, then 12 pods used 
simultaneously in single Tx. 2 
Different Placements Sets:  
   a) Midline Only; then  
   b) L and R sides only 
LED cluster head size 
2-inch diameter, 22.48 cm2 
3.9 cm x 4.8 cm, 19 cm2 
4.5 cm x 4.8 cm, 21.6 cm2 
Power output 
500 mW 
692.5 mW 
665.3 mW 
Power density 
22.2 mW/cm2 
36.5 mW/cm2 
30.8 mW/cm2 
Number of red LEDs, 633 
nm 
9 red 
4 red 
No red LEDs 
Number of near-infrared 
LEDs, 830/870 nm 
52 near-infrared (870nm) 
20 near-infrared (830nm) 
20 near-infrared (830nm +/-5)) 
Continuous Wave (CW) 
CW, only 
CW, only 
CW, only 
Total Power 
2.5 W (5 cluster heads on) 
3.0 W (6 cluster heads on) 
4.16 W (6 pods turned on) 
8.3 W (12 pods turned on) 
4 W (6 pods turned on) 
8 W (12 pods turned on) 
CW, number of sec. = 1 
Joule/ cm2 
45 sec. 
27.4 sec. 
32.5 sec. 
Treatment Dose, 
Joules/cm2 
13 Joules/cm2 per Set 
 (2 Different Sets) 
26 Joules/cm2 per Set 
26 Joules/cm2 per Set 
Treatment Time per Set 
9 min. 45 sec. 
per Set (2 Different Sets) 
11 min. 52 sec. per Set  
14 min. 5 sec. per Set  
Total Treatment Time per 
Visit 
19 min 30 sec. (approx. 20 19 
min. 30 sec. 
23 min. 44 sec. 
28 min. 10 sec. 

December 2017 Naeser - 31!
Treatment dose adjustments for Skin Type 
Treatment dose will be adjusted when treating those participants who have lighter (decreased) 
pigmentation or darker (increased) pigmentation of the skin. The Fitzpatrick Skin Type scale will be used, to 
determine the skin type, ranging from 1 (very fair skin) to 6 (darkest skin). The current treatment protocol, using 
26 J/cm2 (14 min. 5 sec.) for each row of LED pods in the Photomedex Helmet, is appropriate to continue to 
use with skin types 2-5. Also, the current treatment protocol, using 1 J/cm2 (4 min 10 sec) on the ears, with the 
MedX Health LED cluster heads is appropriate to continue to use with skin types 2-5. The number of 
Joules/cm2, and the treatment times need to be decreased for skin type 1 and increased for skin type 6. 
1.  
For Part 1, and for Part 2 of the Helmet LED Treatment Protocol, for skin type 1 (very fair skin), the 
treatment time will be decreased by 25%. The new adjusted treatment time, per part, for type 1 will be 
approximately 10 min 34 sec (19.5 J/cm2).  
2. 
For the MedX Health LED placements on the ears, the adjusted treatment time for type 1 (where the 
treatment time will be decreased by 25%), the time will be 3 min 8 sec (.75 J/cm2).  
3. 
For Part 1, and for Part 2 of the Helmet LED Treatment Protocol, for skin type 6 (dark black), the 
treatment time will be increased by 25%. The new adjusted treatment time, per part, for type 6 will be 
approximately 17 min 36 sec (32.5 J/cm2).  
4. 
For the MedX Health LED placements on the ears, the adjusted treatment time for type 6 (where the 
treatment time will be increased by 25%), the time will be 5 min 12 sec (1.25 J/cm2).  
The Sham LED helmet will look and feel the same as the Real LED helmet. The Sham LED helmet will 
contain the same fans activated when the switches are turned on, however no NIR photons will be emitted 
from the Sham LED pods. The NIR wavelength as used in the Real helmet is beyond the visible spectrum, thus 
the participant will not see any light during a Sham LED or a Real LED treatment.  
During a Real LED treatment, a total dose of 26 J/cm2 will be delivered from each pod (approximately 0.8 
J/cm2 ) is expected to reach brain cortex (Wan, Parrish, Anderson et al., 1981). The duration of the total 
treatment with the Sham or Real LED Helmet is about 28 minutes.  
Additional LED placements 
Intranasal LED Placements 
At each treatment session, participants also receive a simultaneous Real or Sham Intranasal LED 
placement. It is hypothesized that these intranasal devices may deliver photons to the inferior temporal lobe, 
and hippocampus. The intranasal LED treatment procedures are painless and noninvasive. There is no risk for 
use of the intranasal LED device, because the LEDs are non-coherent, and thus they cannot cause any ocular 
damage, even if one stares directly into the red/NIR LED. During Sham or Real LED treatment the patient 
wears goggles that will block the red wavelength. A sample of the red LED is shown in the nostril in Fig. 
25b. 
 
The red and near-infrared Intranasal LED devices will be used 
at the same time; one in each nostril, held in place by a plastic clip. 
The placement of the LEDs will be alternated by side (left/right) at 
the next session.  
Each participant is provided with a red LED device and an 
infrared LED device that are labeled with his/her ID number, and 
stored in a separate plastic bag between treatments, onsite at the 
VABHS. It will be wiped down with an alcohol pad every day after use. The LEDs will be stored after the study 
in Dr. Naeser’s office, with the partipant’s ID label, for potential follow-up studies with each individual. The 
devices will not be used on another patient.  
Two Intranasal LED devices (red and near-infrared) will be applied at the same time as the helmet LED 
treatment, Parts 1 and 2 during each LED Tx series (Sham or Real).  The Intranasal placement is applied for 
approximately 25 min. The device has a timer that shuts itself off after 25 min.  The Sham LED Intranasal 
devices will look and feel the same as the Real LED Intranasal devices, however, no light will be emitted. 
Fig. 25b. Sample of one Intranasal, light-emitting diode (LED) 
device clipped in the nostril; 6.5mW. The intranasal LED uses 
one AA battery, and has a built-in timer for a 25 min treatment. 
This device does not heat up.  
www.VieLight.com, Toronto, Canada 

December 2017 Naeser - 32!
Intranasal LED Parameters 
Specifics for parameters of the VieLight, 633 red intranasal, LED device are as follows: 1) single diode; 
total power: 6.5mW; 633nm wavelength; power density, 7.6 mW/cm2; energy delivered to mucosa, 11.4 J/cm2.
Specifics for parameters of the VieLight, 810 near-infrared intranasal, LED device are as follows: 1) single 
diode; total power: 6.5mW (net of 50% pulsed duty cycle), pulsed at 10 Hz; 810nm wavelength; power density 
(net of pulsed duty cycle), 7.6 mW/cm2; energy delivered to mucosa, 11.4 J/cm2.  
See FDA email to Dr. Naeser (7/24/13) stating that the FDA will accept the determination of risk level, as 
assessed by the Boston VA IRB. 
MedX Health LED placements on the ears 
LED cluster heads manufactured by MedX Health (Toronto) will be used for two additional transcranial LED 
placements on the ears. Each MedX Health Home unit contains 1 LED cluster head. Each cluster head has a 
2-inch diameter, with NIR 870nm diodes. The total power is 90 mW. The transcranial LED treatment 
procedures are painless and noninvasive. There is no sensation of heat or pain, during LED application. There 
is a built-in heat-sink, so that the LED cluster heads do not become uncomfortably warm. LED therapy is 
considered to be a non-thermal treatment method. There is no risk for use of the transcranial LED device, 
because the LEDs are non-coherent, and thus they cannot cause any ocular damage, even if one stares 
directly into the red/NIR LED cluster head. 
The MedX Health Home Unit, was FDA-cleared as non-significant risk in 2003 and it was also FDA-
cleared for home treatment use, in 2005, "for ...temporary increase in local blood circulation...for temporary 
relief of minor muscle and joint aches..." (see FDA documents) 
A similar product, that contains 3 cluster heads, The MedX Health Console Units (Model 1100) is already in 
use at the VABHS, in Dr. Naeser’s LED projects: IRB# 2492, “Transcranial LED to Improve Naming in Primary 
Progressive, and other Aphasias” and IRB #2703 “Transcranial LED Therapy to Improve Cognitive and 
Psychosocial Functioning in TBI”. 
During the MedX Health LED treatments, 1 J/cm2 will be applied at each LED cluster head placement.  
This will require 4 min 10 sec min.  
There will be two MedX Health LED cluster head placements:  
1) An LED cluster head is placed centered on the front of the L ear 
2) An LED cluster head is placed centered on the front of the R ear 
Each placement is applied simultaneously with the helmet during the last 4 min of Part 2 (Left and Right) 
and for  
The chinstrap of the LED helmet will hold the LED cluster heads into place on the front of the L and R ear. 
All LED cluster heads are wiped with a disinfectant, after each treatment.  
All appointments are scheduled ahead, for a specific day and time of day, (usually a Mon/Weds or a 
Tues/Thurs schedule). It is necessary to have at least 48 hours, between treatments. 
Fig 24.  MedX Health Console Unit, with 
sample LED cluster heads to be used for 
the transcranial LED treatment 
intervention, in this research study.  
 
Dotted white lines on MRI in  
a. and b., show expected direction of 
NIR (870 nm) photons, into bilateral 
frontal lobes (prefrontal cortex and 
anterior cingulate gyrus areas), with 
forehead placements.  Additional 
placement sites are used, see text.  

	  
December 2017 Naeser - 33	  
If the participant needs to miss an appointment, that appointment will be re-scheduled  so that all 15 LED 
treatments are completed, in each of the two LED treatment series. If a subject misses 2 weeks in a row 
without any treatment, the subject will be given the option to start over or be withdrawn from the study. 
 
 
Statistical Analyses and Power Statement Errol Baker, PhD; Statistician, VA IRB, Consultant on this project 
Participants are likely to show different profiles for performance on individual tests on which they met entry 
criteria. Using all participants to examine efficacy test by test, will create a serious bias. Therefore, following 
the lead of the Neuropsychologists on our team (M.K. and J.K.) we will create 3 cognitive domain scores: 
Attention/Executive Functioning; Learning and Memory; and Psychomotor/Visual Spatial.  
1) Attention/Executive Function: Digit Span Subtests (WAIS-IV; Wechsler, 2008); Trail-Making Test (Delis, 
Kaplan, Kramer, 2001); and Stroop Test (“Color-Word” test) (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) 
 
Each of our individual tests has been standardized, and yields age/education/gender-adjusted z-scores. 
For each domain, we will compute the mean z-score from those tests that load for that factor (i.e., the two tests 
selected for Learning and Memory have a total of 9 standardized scores: the domain score will be the mean of 
these 9 values). 
 
Analysis Plan:  
Preliminary Analyses:  Before testing any of the stated hypotheses, the frequency distributions for all study 
variables will be examined, and appropriate transformations will be carried out whenever violations of normality 
are determined. Descriptive statistics and bivariate correlations will be computed. This will be necessary in 
order to test for colinearity among dependent variables. The number of variables will be constrained when  
r >.75. In addition, each variable will be tested for leptokurtosis to insure that there is a sufficient range of 
scores. Variables found to be significantly leptokurtic will be converted into dichotomous outcomes.  
 
Tests of Hypotheses:  All participants will be evaluated at Entry (Baseline) and within one week of completing 
either Sham Intervention or Real Intervention The main hypothesis will be tested by two-way mixed-design 
analysis of variance, with a trend analysis with treatment conditions as the between-groups variable and time 
of testing as the repeated-measures variable. To control for the fact that the dependent variables can co-vary 
and for the large number of F-tests to be computed, these analyses will be carried out by Multivariate Analysis 
of Variance (MANOVA) utilizing PASW v.18. Subsequent to the MANOVA, a series of univariate ANOVAs will 
be conducted for each dependent variable. Empirical effect sizes will be computed by partial eta2. Headsize 
measurements will be used as covariates. 
 
Power Analysis:  
Primary Analysis: The primary analysis is between Real Only and Sham 1st. This comparison will be between 
groups. It is a parallel design for this primary analysis. 
Power and sample size were computed for only the primary, between-group analysis using a moderate effect 
size appropriate to ANOVA. 
The following computer software was used: Borenstein M, Rothstein H and Cohen J.  Power and Precision 
(2004). Englewood, NJ, Biostat. We solved for sample size in order to obtain power = .80 given the following 
assumptions: alpha =  .05 (1-tailed); power = .80; moderate effect size. ANOVA is always a 1-tailed test. 
Cohen recommends that readers of his book who consider the ES range defined as ‘Large” to be too small 
(or too large) to meet the appropriate standards of his/her area, should define alternative operational definitions 
(p.79).  See table created below by the PIs from the content in Cohen (1988). 
 
Statistic 
ES Index 
Small 
Medium 
Large 
Correlation 
r 
.10 
.30 
.50 
Difference Between Correlations 
q 
.10 
.30 
.50 
Proportion equal to .50 
g 
.05 
.15 
.25 
Difference Between Proportions 
h 
.20 
.50 
.80 

	  
December 2017 Naeser - 34	  
Chi-Square 
w 
.10 
.30 
.50 
F Test on Means (ANOVA/ANCOVA) * 
f 
.10 
.25 
.40 
Multiple Regression 
f2 
.02 
.15 
.35 
 
* Please note, we used f as the ES Index for the power calculations submitted to the DMC. 
	  
Cohen, J. (1988).	  Statistical	  Power	  Analysis	  for	  the	  Behavioral	  Sciences	  (2nd	  Ed.).	  Lawrence Erlbaum 
Associates. 
 
Secondary Analysis: 
The Sham 1st shifted to Real will be a second test of efficacy of treatment, and subjects will be compared 
only within-subject. 
In the secondary analyses the two groups will not be compared to one another. 
 
Drop-Outs: In any longitudinal intervention study there will be participants who do not complete the protocol 
(missing data). The issue of missing data was addressed in a recent special report in the New England Journal 
of Medicine by an expert panel convened by the National Research Council (Little et al., 2012). Analyses 
utilizing only data from completers, even when intent-to-treat analyses have established no differences 
between these samples at Baseline, at best will yield an underestimation of standard errors and, at worst, can 
lead to biased results. They recommend using an acceptable multiple imputation (MI) procedure to “replace” 
missing values. Since the data are missing, in all likelihood, Not-At-Random (NAR), this will require generating 
a model accounting for missingness. Following the recommendations of Moon (Moon et al., 2006) we will 
utilize a flexible MI procedure known as MICE (multiple imputation by chained equations) on S+ and which will 
utilize the outcome for imputation of missing predictor values. Completers and non-Completers will be first 
compared on socio-demographic variables to predict the likelihood of completion by discriminant analysis. Any 
variables that discriminate Completers from non-Completers will be entered into our models as weighted 
covariates. 
 
Interim Analyses:  For both ethical and pragmatic reasons, we have a planned interim analysis at exactly the 
halfway point of the study, regardless of drop-out rate. To be conservative we will employ the O’Brien-Fleming 
alpha spending function to establish stopping boundaries. If the MANOVA is significant at p<.022, efficacy will 
be considered to be reliably established.  
 
 
Tentative Sequence or Timetable 
Yr 1: Hire personnel, purchase equipment/supplies. Recruit and screen veterans. Begin treatment of 40 cases.   
Yr 2: Continue to recruit and treat 40 GWVI cases. Perform interim analyses. Present papers.  
Yrs 3, 4: Recruit, treat 40 GWVI cases per year. Present papers and prepare final report and manuscripts. 
 
k.  Human Studies Section 
k.1. Risk to Subjects 
k.1.a.  Human Subjects Involvement and Characteristics 
Only GW veterans will participate; about 98 over the grant period. All potential treatment study participants 
were advised in their prior informed consent procedures for previous VA-related GW studies that they may be 
contacted in the future about the possibility of participating in future studies. Veterans will be recruited for this 
study through the Co-Investigator, Maxine Krengel, Ph.D., Clinical Neuropsychologist, VA Boston Healthcare 
System. 
 
Dr. Krengel is currently funded for a three-year Department of Defense grant (2011-2014) where she will 
re-contact the original 2,123 veterans from the Fort Devens cohort of veterans from the New England region, 
who returned from their 1990-91 Gulf War deployment through Ft. Devens, Massachusetts. This cohort was 
originally evaluated just days after their return from the Gulf War in 1991 and have been resurveyed for health 
symptoms and medical diagnoses multiple times in the past 21 years following their return from the war. 
Approximately 1,500 veterans participated in the most recent surveys of this large, population-based cohort. As 
part of Dr. Krengel's current resurvey of this cohort, recruitment letters will be mailed to all of the original 

	  
December 2017 Naeser - 35	  
surviving Ft. Devens cohort members. It is estimated that a minimum of 600 of these GW veterans will 
participate in Dr. Krengel’s current DoD-funded resurvey.  
 
These veterans will be invited by Dr. Krengel to participate in a web-based survey regarding their current 
health concerns and medical diagnoses. They are provided with an ID number and therefore all data are de-
identified. As part of the web-based survey, the following questionnaire is used: “Symptom Questions used to 
Identify Gulf War Illness by Kansas Case Definition, and Chronic Multisymptom Illness by Fukuda Case 
Definition.” Dr. Krengel will determine from the answers to this questionnaire, whether the veterans meet the 
criteria from the Kansas GWI definition and the Fukuda CDC multi-symptom illness criteria for GWVI (Steele, 
2000; Fukuda et al., 1998).  
 
For the purposes of this LED study, Dr. Krengel will use the Fukuda et al., 1998 criteria for GWVI - i.e., the 
presence of 1 or more chronic symptoms (lasting >6 months) from at least 2 of 3 symptom categories: 1) 
musculoskeletal (muscle pain, or joint pain, stiffness); 2) mood-cognition 3) fatigue.  
 
Dr. Krengel will refer veterans with GWVI who have also answered ‘Yes’ to the following questions: 1) 
Difficulty concentrating; and/or 2) Difficulty remembering recent information, to Dr. Naeser for further 
neuropsychological screening, and potential participation in this proposed transcranial, LED research project to 
improve cognition. 
Additional participants may be recruited through other sources including the following.  
We will submit a data request to the Department of Defense’s Defense Manpower Data Center (DMDC) for the 
names and mailing addresses of Gulf War veterans who reside within a 100 mile radius of the Boston VA Healthcare 
System, JP Campus for the the purposes of study recruitment. Once we obtain the list of GW veterans who reside within a 
100 mile radius, we will send them an IRB-approved recruitment letter and a permission to contact form, with a pre-
addressed, stamped return envelope. These GW veterans will be invited to contact us by phone or by returning the 
permission to contact form if they are interested in participation and/or if they would like more information about the study. 
If they do not contact us or return the permission to contact form within 2 weeks, we will contact them by phone. 
 
We would like to use CPRS to identify veterans who live locally and who meet our inclusion/exclusion criteria.  
We will also apply for access to the VA VINCI/CDW data, by initiating a DART data request, to obtain a list of GW 
veterans who reside within a 100 mile radius of the Boston VA Healthcare System, JP Campus so we can send them an 
IRB-approved recruitment letter and a permission to contact form, with a pre-addressed, stamped envelope. These GW 
veterans will be invited to contact us by phone or by returning the permission to contact form if they are interested in 
participation and/or if they would like more information about the study. If they do not contact us or return the permission 
to contact form within 2 weeks, we will contact them by phone.  
 
Additionally, recruitment, screening and data collection will occur at a second site in San Francisco, CA. 
This second site has been added to improve recruitment and enrollment numbers. The goal is to enroll 98 
subjects for the whole study. Enrollment of 50 cases in projected for Sept. 2017 in Boston; and 50 cases is 
projected for March/April 2018 in SF. 
Dr. Linda Chao, at SF VAMC has an active Gulf War Illness research program. In 2011 her group published a MRI 
paper with 64 GW Veterans who participated [NeuroToxicology 32 (2011) 814-822]. Her office will work from their most 
current GWI registry to recruit participants. The same protocol and processes for informed consent, enrollment, inclusion 
and exclusion, currently in place at the Boston VABHS (see below) will be followed. No sleep data, however, will be 
collected at the SF VAMC to save funds. The overall study will be overseen by Dr. Naeser.  
Screening of eligibility will be conducted at the SF VAMC, using our screening criteria. Data collected at SF VAMC 
research site will be transferred to the Dr. Naeser's office at the VABHS, JP campus in the following manner: 
A) A de-identified Data Summary Sheet for each case (will only have randomized participant ID) will be faxed to our 
VA FAX.  It is located in one of our locked offices, and we would then place it in a locked filing cabinet in our locked office.  
We have approval to receive Quest blood sample data this way.  
On the Data Summary Sheet, Age, Ed., Gender, will be provided and data timepoints will be labeled as  Baseline, 
Testing Time 1 (T1), T2, T3, T4, etc. (no dates on this sheet).    
 
B) We also want to be able to double-check the Data Summary Sheet with the raw data pages, just for redundancy in 
checking. The raw data test sheets will be mailed to us for each subject, for each testing time,  so we have them for our 
files here. They will be kept in a locked filing cabinet, in Dr. Naeser’s locked offices. This will be done through USPS 
Priority mail, with appropriate tracking ability. The following information will be on these raw data sheets that will be 
xeroxed and mailed, for each subject, for each testing time: participant Id# and test dates. No name or other identifying 
information. Data analysis will be completed at the Boston VABHS. Linda Chao at the SF VA will keep copies of all raw 
data. 

	  
December 2017 Naeser - 36	  
 
Neuropsychological Screening 
The neuropsychological tests that will be used in this screening battery are taken from a previously 
validated screening for cognitive dysfunction in Gulf War veterans (Sullivan, Krengel et al., 2003; White et al., 
2001). At the time of screening, the Word Reading Subtest from the Wide Range Achievement Test-4 will be 
used to estimate the premorbid level of cognitive functioning as a standard score for age, education, and 
gender (converted to SD). This score is then used for comparison to the other standardized NP test scores at 
screening, as follows: Participants must score at least 2 SD below their estimated premorbid cognitive level on 
at least 1 of these NP tests; or 1 SD below on at least 2 of these NP tests at Entry testing, for Inclusion into the 
study. The following tests are administered: 1) Trail Making Test (Reynolds, 2002); 2) FAS Test (Spreen & 
Benton, 1977; Benton & Hamsher, 1989); California Verbal Learning Test II, Alternate Version (Delis et al., 
2000); and Stroop (“color-Word” test) (Delis, Kaplan, Kramer, 2001). ). A sample data entry sheet for the 
Neuropsychological Screening tests and subtests is provided in Appendix 3. Headsize measurements 
(circumference, length from R tragus of the ear to L tragus of the ear, and length from glabella to occipital 
protuberance) will be taken. If the participant's head circumference is greater than 24 inches, we will utilize the 
Thor Helmet (for Real or Sham) to accommodate this larger head size and ensure the participant remains 
comfortable throughout the treatment. The treatment will be administered with appropriate timing to ensure 
output is equivalent.  See Appendix 10. Table 1, for specifications of the Photomedex Helmet compared to the 
Thor Helmet. 
 
If screening or neuropsychological testing cannot be completed on the same day, we will complete any 
remaining tests at another visit at the patient’s request to accommodate their schedule. 
 
k.1.b  Sources of Materials: 
All research material will be obtained specifically for research purposes, and no existing specimens, 
records, or data will be used. The sources of research material obtained from individually identifiable living 
human subjects in the form of specimens, records, or data will be obtained specifically for this research project.  
This includes the cognitive tests, pain questionnaires, Multi-Dimensional Fatigue Inventory; Beck Depression 
Inventory; Health Symptom Checklist; Short Form-36V Plus;  
All subjects will be assigned a random ID number; and all records for each case will be retained in files for 
this research project, using that subject's ID number. All data will be kept in locked file cabinets or desks, and 
encrypted, password-protected computers, within locked offices. Only Dr. Naeser’s co-investigators, and 
laboratory members associated with the study, will have access to individually identifiable private information 
about living human subjects.  
 
k.1.c  Potential Risks:   
There is minimal risk for participating in this study. There is no risk for the paper and pencil tests for the 
cognitive tests, pain questionnaires, Multi-Dimensional Fatigue Inventory; Beck Depression Inventory; Health 
Symptom Checklist; Short Form-36V Plus. The participants may be frustrated by the difficulty of some of the 
neuropsychological tasks. They will receive assistance with these tasks and they can stop the session if they 
want to.  
Actiwatch 
There is no known risk of actigraphy for participants. The only potential risk may be the discomfort 
associated with wearing a monitor on your wrist for a continuous week. We hope to minimize this discomfort by 
providing comfortable bands that allow for breathability of the material while still remaining secure on the wrist. 
 
There is a small possibility that there could be a temporary increase in symptoms, lasting up to 2 or 3 days, 
that are associated with Gulf War Veterans’ Illnesses – these include, for example, muscle aches and pains, 
headache, fatigue or gastro-intestinal disorders. 
 
 
There is no risk for use of the LED device, because the light-emitting diodes are non-coherent, and thus 
they cannot cause any ocular damage, even if one stares directly into the LED. 
The participants may be sleepy after the LED treatment session for the first 2 weeks. This has been reported, 
especially after the first treatment. Participants will be escorted to and from the first 4 treatments (2 weeks) and 
advised to exercise care in going about their daily activities, immediately after the LED treatment. We will ask 

	  
December 2017 Naeser - 37	  
the participant if they feel sleepy. The length of sleepiness may vary from case to case, and an escort will be 
requested, until the patient no longer exhibits excess sleepiness following an LED treatment. They will not be 
excluded from the study if they cannot bring an escort as requested. If they do not bring an escort and they 
report feeling sleepy, they will be asked to remain for an hour. If the participant prefers to leave that will be their 
choice. 
Transcranial LED treatment.  
The PhotoMedex helmet manufactured by PhotoMedex, Montgomeryville, PA will be used. This helmet 
contains 18 pods (LED cluster heads). Each pod is 4.5cm x 4.8cm. The helmet is designed with 6 pods to treat 
the midline of the head; 6 pods to treat the right side of the head; and 6 pods to treat the left side of the head.  
See Fig. 19 in the Research Plan. The specifications for each LED pod are as follows: Power output 665.3 
mW; power density, 30.8 mW/cm2; each pod contains 24 diodes (20 NIR diodes, 830nm); 1 J/cm2 = 32.5 sec, 
26 J/cm2 = 14 min, 5 sec; total treatment time is approximately 28 min, 10 sec. 
The pods have been FDA-cleared as non-significant risk and a single pod is sold over-the-counter as a 
product labeled “OmniLux New U.” This device has been FDA-cleared to apply directly to the face to reduce 
peri-orbital wrinkles. The FDA clearance documents are provided in Appendix 5.  
Each participant will be provided a clear plastic liner in the shape of the helmet, worn on the head beneath 
the LED helmet. This is stored in the treatment area and labeled with the patients ID number.  
The helmet liner will be re-used (after completion of all treatments for one participant) for another 
participant, throughout that subject’s participation in the LED treatment series. The liner will be cleaned as per 
instructions from Infection Prevention (and the Safety Committee). See Appendix 9. 
CleaningofHelmetLiner6_30_16 
 
Two LED helmets will be manufactured by PhotoMedex- e.g. one Real LED helmet and one Sham LED 
helmet. The Sham LED helmet will look and feel the same as the Real LED helmet. The Sham LED helmet will 
contain the same fans activated when the switches are turned on, however no NIR photons will be emitted 
from the Sham LED pods. The NIR wavelength is beyond the visible spectrum, thus the participant will not see 
any light during a Sham LED or a Real LED treatment. During a Real LED treatment, a total dose of 26 J/cm2 
will be delivered from each pod (approximately 0.8 J/cm2 is expected to reach brain cortex (Wan, Parrish, 
Anderson et al., 1981). The total duration of the treatment with the Sham or Real LED helmet is about 28 
minutes. The patient is treated in a recliner chair; goggles are put into place before the device is turned on. 
 
Treatment dose adjustments for Skin Type 
Treatment dose will be adjusted when treating those participants who have lighter (decreased) 
pigmentation or darker (increased) pigmentation of the skin. The Fitzpatrick Skin Type scale will be used, to 
determine the skin type, ranging from 1 (very fair skin) to 6 (darkest skin). The current treatment protocol, using 
26 J/cm2 (14 min 5 sec) for each row of LED pods in the Photomedex Helmet, is appropriate to continue to use 
with skin types 2-5. Also, the current treatment protocol, using 1 J/cm2 (4 min 10 sec) on the ears, with the 
MedX Health LED cluster heads is appropriate to continue to use with skin types 2-5. The number of 
Joules/cm2, and the treatment times need to be decreased for skin type 1 and increased for skin type 6. 
1.  
For Part 1, and for Part 2 of the Helmet LED Treatment Protocol, for skin type 1 (very fair skin), the 
treatment time will be decreased by 25%. The new adjusted treatment time, per part, for type 1 will be 
approximately 10 min 34 sec (19.5 J/cm2).  
2. 
For the MedX Health LED placements on the ears, the adjusted treatment time for type 1 (where the 
treatment time will be decreased by 25%), the time will be 3 min 8 sec (.75 J/cm2).  
3. 
For Part 1, and for Part 2 of the Helmet LED Treatment Protocol, for skin type 6 (dark black), the 
treatment time will be increased by 25%. The new adjusted treatment time, per part, for type 6 will be 
approximately 17 min 36 sec (32.5 J/cm2).  
4. 
For the MedX Health LED placements on the ears, the adjusted treatment time for type 6 (where the 
treatment time will be increased by 25%), the time will be 5 min 12 sec (1.25 J/cm2).  
 
Additional LED placements 
Intranasal LED Placement 
At each treatment session, participants also receive a simultaneous Real or Sham Intranasal LED 
placement. It is hypothesized that these intranasal devices may deliver photons to the inferior temporal lobe, 
and hippocampus. The intranasal LED treatment procedures are painless and noninvasive. There is no risk for 
use of the intranasal LED device, because the LEDs are non-coherent, and thus they cannot cause any ocular 

	  
December 2017 Naeser - 38	  
damage, even if one stares directly into the red/NIR LED. During Sham or Real LED treatment the patient 
wears goggles that will block the red wavelength. 
The red and near-infrared Intranasal LED devices will be used at the same time; one in each nostril, held in 
place by a plastic clip. The placement of the LEDs will be alternated by side (left/right) at the next session.  
Each participant is provided with a red LED device and an infrared LED device that are labeled with his/her 
ID number, and stored in a separate plastic bag between treatments, onsite at the VABHS. It will be wiped 
down with an alcohol pad every day after use. The LEDs will be stored after the study in Dr. Naeser’s office, 
with the partipant’s ID label, for potential follow-up studies with each individual. The devices will not be used on 
another patient.  
Two Intranasal LED devices (red and near-infrared) will be applied at the same time as the helmet LED 
treatment, Parts 1 and 2 during each LED Tx series (Sham or Real).  The Intranasal placement is applied for 
approximately 25 min. The device has a timer that shuts itself off after 25 min.  The Sham LED Intranasal 
devices will look and feel the same as the Real LED Intranasal devices, however, no light will be emitted. 
 
Intranasal LED Parameters 
Specifics for parameters of the VieLight, 633 red intranasal, LED device are as follows: 1) single diode; 
total power: 6.5mW; 633nm wavelength; power density, 7.6 mW/cm2; energy delivered to mucosa, 11.4 J/cm2. 
Specifics for parameters of the VieLight, 810 near-infrared intranasal, LED device are as follows: 1) single 
diode; total power: 6.5mW (net of 50% pulsed duty cycle), pulsed at 10 Hz; 810nm wavelength; power density 
(net of pulsed duty cycle), 7.6 mW/cm2; energy delivered to mucosa, 11.4 J/cm2.  
See FDA email to Dr. Naeser (7/24/13) stating that the FDA will accept the determination of risk level, as 
assessed by the Boston VA IRB. 
 
MedX LED placements 
LED cluster heads manufactured by MedX Health (Toronto) will be used for two additional transcranial LED 
placements on the ears. Each MedX Health Home unit contains 1 LED cluster head. Each cluster head has a 
2-inch diameter, with NIR 870nm diodes. The total power is 90 mW. The transcranial LED treatment 
procedures are painless and noninvasive. There is no sensation of heat or pain, during LED application. There 
is a built-in heat-sink, so that the LED cluster heads do not become uncomfortably warm. LED therapy is 
considered to be a non-thermal treatment method. There is no risk for use of the transcranial LED device, 
because the LEDs are non-coherent, and thus they cannot cause any ocular damage, even if one stares 
directly into the red/NIR LED cluster head. 
The MedX Health Home Unit, was FDA-cleared as non-significant risk in 2003 and it was also FDA-
cleared for home treatment use, in 2005, "for ...temporary increase in local blood circulation...for temporary 
relief of minor muscle and joint aches..." (see FDA documents) 
A similar product, that contains 3 cluster heads, The MedX Health Console Units (Model 1100) is already in 
use at the VABHS, in Dr. Naeser’s LED projects: IRB# 2492, “Transcranial LED to Improve Naming in Primary 
Progressive, and other Aphasias” and IRB #2703 “Transcranial LED Therapy to Improve Cognitive and 
Psychosocial Functioning in TBI”. 
During the MedX Health LED treatments, 1 J/cm2 will be applied at each LED cluster head placement on 
each ear.  This will require 4 min 10 sec.  
There will be two MedX Health LED cluster head placements:  
1) An LED cluster head is placed centered on the front of the L ear 
2) An LED cluster head is placed centered on the front of the R ear 
Each placement is applied simultaneously with the helmet during the last 4 min of Part 1 (Midline). The 
chinstrap of the LED helmet will hold the LED cluster heads into place on the front of the L and R ear. All LED 
cluster heads are wiped with a disinfectant, after each treatment.  
 
All appointments are scheduled ahead, for a specific day and time of day, (usually a Mon/Weds or a 
Tues/Thurs schedule). It is necessary to have at least 48 hours, between treatments. 
If the participant needs to miss an appointment, that appointment will be re-scheduledso that all 15 LED 
Treatments are completed, in each of the two LED Treatment Series. If	  a	  subject	  misses	  2	  weeks	  in	  a	  row	  without	  
any	  treatment,	  the	  subject	  given	  the	  option	  to	  start	  over,	  or	  be	  withdrawn	  from	  the	  study. 
 
k.1.c.1. Therapeutic Risk:   
 
There is no therapeutic risk involved with this project.  

	  
December 2017 Naeser - 39	  
 
k.1.c.2  Research Risk:   
 
There is potential for sleepiness immediately following the first 4 LED treatments. The length of 
sleepiness may vary from case to case, and if possible an escort will be required, until the patient no longer 
exhibits excess sleepiness following an LED treatment. We will ask the participant if they feel sleepy. The 
length of sleepiness may vary from case to case, and an escort will be requested, until the patient no longer 
exhibits excess sleepiness following an LED treatment. They will not be excluded from the study if they cannot 
bring an escort as requested. If they do not bring an escort and they report feeling sleepy, they will be asked to 
remain for an hour. If the participant prefers to leave that will be their choice. 
 
 
k.2  Adequacy of Protection from Risk 
 
k.2.a Recruitment and Informed Consent 
 
Only GW veterans will participate; 98 over the grant period. All potential treatment study participants were 
advised in their prior informed consent procedures for previous VA-related GW studies that they may be 
contacted in the future about the possibility of participating in future studies. Veterans will be recruited for this 
study through the Co-Investigator, Maxine Krengel, Ph.D., Clinical Neuropsychologist, VA Boston Healthcare 
System. 
 
Dr. Krengel is currently funded for a three-year Department of Defense grant (2011-2014) where she will 
re-contact the original 2,123 veterans from the Fort Devens cohort of veterans from the New England region, 
who returned from their 1990-91 Gulf War deployment through Ft. Devens, Massachusetts. This cohort was 
originally evaluated just days after their return from the Gulf War in 1991 and have been resurveyed for health 
symptoms and medical diagnoses multiple times in the past 21 years following their return from the war. 
Approximately 1,500 veterans participated in the most recent surveys of this large, population-based cohort. As 
part of Dr. Krengel's current resurvey of this cohort, recruitment letters will be mailed to all of the original 
surviving Ft. Devens cohort members. It is estimated that a minimum of 600 of these GW veterans will 
participate in Dr. Krengel’s current DoD-funded resurvey.  
 
These veterans will be invited by Dr. Krengel to participate in a web-based survey regarding their current 
health concerns and medical diagnoses. They are provided with an ID number and therefore all data are de-
identified. As part of the web-based survey, the following questionnaire is used: “Symptom Questions used to 
Identify Gulf War Illness by Kansas Case Definition, and Chronic Multisymptom Illness by Fukuda Case 
Definition.” Dr. Krengel will determine from the answers to this questionnaire, whether the veterans meet the 
criteria from the Kansas GWI definition and the Fukuda CDC multi-symptom illness criteria for GWVI (Steele, 
2000; Fukuda et al., 1998).  
 
For the purposes of this LED study, Dr. Krengel will use the Fukuda et al., 1998 criteria for GWVI - i.e., the 
presence of 1 or more chronic symptoms (lasting >6 months) from at least 2 of 3 symptom categories: 1) 
musculoskeletal (muscle pain, or joint pain, stiffness); 2) mood-cognition 3) fatigue.  
 
Dr. Krengel will refer veterans with GWVI who have also answered ‘Yes’ to the following questions: 1) 
Difficulty concentrating; and/or 2) Difficulty remembering recent information, to Dr. Naeser for further 
neuropsychological screening, and potential participation in this proposed transcranial, LED research project to 
improve cognition. 
Additionally, recruitment, screening and data collection will occur at a second site in San Francisco, CA. 
This second site has been added to improve recruitment and enrollment numbers. The goal is to enroll 98 
subjects for the whole study. Enrollment of 50 cases in projected for Sept. 2017 in Boston; and 50 cases is 
projected for March/April 2018 in SF. 
Dr. Linda Chao, at SF VAMC has an active Gulf War Illness research program. In 2011 her group published a MRI 
paper with 64 GW Veterans who participated [NeuroToxicology 32 (2011) 814-822]. Her office will work from their most 
current GWI registry to recruit participants. The same protocol and processes for informed consent, enrollment, inclusion 
and exclusion, currently in place at the Boston VABHS (see below) will be followed. No sleep data, however, will be 
collected at the SF VAMC to save funds. The overall study will be overseen by Dr. Naeser.  
Screening of eligibility will be conducted at the SF VAMC, using our screening criteria. Data collected at SF VAMC 

	  
December 2017 Naeser - 40	  
research site will be transferred to the Dr. Naeser's office at the VABHS, JP campus in the following manner: 
A) A de-identified Data Summary Sheet for each case (will only have randomized participant ID) will be faxed to our 
VA FAX.  It is located in one of our locked offices, and we would then place it in a locked filing cabinet in our locked office.  
We have approval to receive Quest blood sample data this way.  
On the Data Summary Sheet, Age, Ed., Gender, will be provided and data timepoints will be labeled as  Baseline, 
Testing Time 1 (T1), T2, T3, T4, etc. (no dates on this sheet).    
 
B) We also want to be able to double-check the Data Summary Sheet with the raw data pages, just for redundancy in 
checking. The raw data test sheets will be mailed to us for each subject, for each testing time,  so we have them for our 
files here. They will be kept in a locked filing cabinet, in Dr. Naeser’s locked offices. This will be done through USPS 
Priority mail, with appropriate tracking ability. The following information will be on these raw data sheets that will be 
xeroxed and mailed, for each subject, for each testing time: participant Id# and test dates. No name or other identifying 
information. Data analysis will be completed at the Boston VABHS. Linda Chao at the SF VA will keep copies of all raw 
data sheets.  
 
Recruitment Methodology and description of informed consent process 
Participants will be recruited until 98 participants have completed the treatment trial. 
Initial Contact. The initial contact following referral of the patient to Dr. Naeser’s office by Dr. Krengel will 
consist of a phone call by Dr. Naeser’s office to the patient. All potential participants referred by Dr. Krengel 
have already agreed to share their contact information regarding the possibility of participating in future GWVI 
studies. A description of the full study protocol, time required, and reimbursement for their time and effort will 
be discussed with the participants. They will be informed that whether or not they participate will have no 
bearing on their medical care and that, if they choose to participate, they may withdraw at any time without 
prejudice. After the initial contact, an appointment for obtaining signed informed consent, and further screening 
with neuropsychological testing at the VABHS, JP campus, will be arranged. 
Informed Consent Process.  If the potential participant chooses to participate in the study, an appointment 
will be scheduled with the PhD Study Coordinator at the VABHS, JP campus. At that time, the participant will 
be presented with the ICF and all questions will be answered. The participant will then be given the ICF for 
signature. After consent is obtained, the participant will have further screening [neuropsychological (NP) 
testing]. At the time of screening, the Word Reading Subtest from the Wide Range Achievement Test-4 will be 
used to estimate the premorbid level of cognitive functioning as a standard score for age, education, and 
gender (converted to SD). This score is then used for comparison to the other standardized NP test scores at 
screening, as follows: Participants must score at least 2 SD below their estimated premorbid cognitive level on 
at least 1 of these NP tests; or 1 SD below on at least 2 of these NP tests at Entry testing, for Inclusion into the 
study. If the participant meets the criteria for entry, additional tests for pain, fatigue, mood and health 
questionnaires will be administered.  
Neuropsychological Screening.  The neuropsychological tests that will be used in this screening battery are 
taken from a previously validated screening for cognitive dysfunction in Gulf War veterans (Sullivan, Krengel et 
al., 2003; White et al., 2001). At the time of screening, the Word Reading Subtest from the Wide Range 
Achievement Test-4 will be used to estimate the premorbid level of cognitive functioning as a standard score 
for age, education, and gender (converted to SD). This score is then used for comparison to the other 
standardized NP test scores at screening, as follows: Participants must score at least 2 SD below their 
estimated premorbid cognitive level on at least 1 of these NP tests; or 1 SD below on at least 2 of these NP 
tests at Entry testing, for Inclusion into the study. The following tests are administered: 1) Trail Making Test 
(Reynolds, 2002); 2) FAS Test (Spreen & Benton, 1977; Benton & Hamsher, 1989); California Verbal Learning 
Test II, Alternate Version (Delis et al., 2000); and Stroop (“color-Word” test) (Delis, Kaplan, Kramer, 2001). A 
sample data entry sheet for the Neuropsychological Screening tests and subtests is provided in Appendix 3.  
 
k.2.b  Protection Against Risk 
The protections against the minimal risks involved in this study were explained in detail, above.  These 
include advising the patient to come for the LED treatments with an escort, for at least the first 4 LED 
treatments or remain for an extra hour because the patient may have excess sleepiness after treatment.  
 
The risks to confidentiality for the data in the study will be secured by the assignment of a subject ID 
number, for each participant, for the files kept at the VABHS, JP campus. These files will be kept in a locked 
filing cabinet, in the locked office, of the Study Coordinator at the VABHS, JP campus.  All data entered into 
the computer will be de-identified, using only the patient's subject ID number. 

	  
December 2017 Naeser - 41	  
 
Most of the GWVI cases who will be participating in this study, do not have their medical care managed at 
the VABHS, JP campus.  If there is a medical emergency during the LED treatment, emergency services would 
be called immediately, in the event of a serious emergency. There have been no negative side effects or 
adverse events with any of the LED treatment methods proposed for use in this study. 
 
Adverse events, not previously identified, will be documented and reported to the VA Boston Healthcare 
System, IRB in a timely manner. 
 
Each patient will be provided with his/her own clear plastic liner for the helmet. This is labeled with their ID 
and stored in a separate plastic bag between treatments. The bag is stored onsite at VABHS, JP campus. 
The helmet liner will be re-used (after completion of all treatments for one participant) for another 
participant, throughout that subject’s participation in the LED treatment series. The liner will be cleaned as per 
instructions from Infection Prevention (and the Safety Committee). See Appendix 9. 
CleaningofHelmetLiner6_30_16 
 
 
k.3.  Potential benefits of the Proposed research to the Subjects and Others 
 
 
There are no known benefits of this research for subjects with GWVI, who wish to participate. Recent case 
report studies have observed that when red/NIR laser or LED was applied transcranially (through forehead and 
scalp), there was reduced severity in acute and chronic stroke patients; reduced severity in major depression 
cases; and significantly improved cognition in chronic, mild traumatic brain injury cases. Given that there have 
been no reports of negative side effects, or adverse events, in cases treated with transcranial, low-level laser, 
or light-emitting diode therapies, the possible benefits for the GWVI cases who have cognitive dysfunction 
outweigh any potential risks (the LEDs are FDA-cleared and nonsignficant risk). Results from this LED study 
are anticipated to benefit the GW veterans, as well as others.  
 
k.4.  Importance of knowledge to be gained 
 
There are currently no known treatments for the cognitive dysfunction in veterans with GWVI. This pilot, 
clinical trial treatment study investigates a new light-emitting diode (LED) therapy to improve cognition in 
veterans with GWI. Approximately 175,000 – 209,000 of the 697,000 Gulf War deployed veterans report 
persistent, multi-symptom illnesses. These symptoms accord closely with those of mitochondrial 
dysfunction. LED therapies in the red and near infrared (NIR) wavelengths improve mitochondrial function 
by increasing adenosine tri-phosphate (ATP) production for energy metabolism, and improving cellular 
respiration. Treating a mechanistic-based cause (mitochondrial dysfunction), as well as symptoms, in the 
nearly 175,000 – 209,000 ill Gulf War veterans remains a top priority for government agencies and advisory 
panels (RAC 2008). The results from this study may have application to improving cognition in other central 
nervous system disorders, such as traumatic brain injury and stroke. 	  
 
k.5.  Resources 
 
 k.5.a.  Research Space 
Two additional treatment rooms will be necessary located near Dr. Naeser’s offices, on the 12th Floor, D-
Wing. A request to the Space Committee has been made; Rooms D12-97B and D12-97D are possibilities.  
This proposed project requires the use of two additional treatment rooms, so that two patients can be 
treated at the same time, in separate rooms. Each treatment room would have 1 medical recliner chair, and 1 
utility cart. One treatment room will have the Photomedex, Real LED Helmet, and one will have the 
Photomedex, Sham LED Helmet. The Photomedex, LED Helmet will be stored on the utility cart. Each utility 
cart has shelves, and wheels, so that it can be placed in close proximity to the participant in the medical 
recliner chair, for each transcranial LED treatment. 
 
k.5.b.  Other Research Resources 
 
Location: VA Boston Healthcare System, Jamaica Plain campus:   

	  
December 2017 Naeser - 42	  
 
Margaret Naeser, Ph.D., PD/PI, has an office located at the VA Boston Healthcare System, Jamaica Plain 
Campus, 12th Floor, D-Wing (12D-87). 
 
Maxine Krengel, Ph.D., Co-investigator (Health Science Specialist, Clinical Neuropsychologist), would need 
temporary office space, one day a week. 
 
Jeffrey Knight, Ph.D., Co-investigator, has an office located at the VA Boston Healthcare System, Jamaica 
Plain Campus, 12th Floor, B-Wing, in the National Center for PTSD. 
 
Paula Martin, Study Coordinator, has office space at this time, within Dr. Naeser’s offices.  
 
Michael Ho, Ph.D., Co-investigator, has office space at this time, within Dr. Naeser’s offices.  
 
There is space for a research assistant, within Dr. Naeser’s offices.   
 
Additional office furniture (locked desk, locked filing cabinet), for placement of the laptop computer (encrypted 
and dedicated to this research project), and the patient records and data files will be necessary, however, to 
have in each of the two additional treatment rooms. 

 
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