Low Level Light Therapy (LLLT) With Near Infrared Light Emitting Diodes in Patients With Moderate Traumatic Brain Injury (TBI)
Phase: NA
Conditions: Moderate Traumatic Brain Injury (TBI)
Sponsor: Massachusetts General Hospital

 
 
 
 
 
 
 
 
 
 
Light Therapy for Moderate Traumatic Brain Injury 
 
NCT02233413 
 
 
Protocol 

 
 
Page 1 of 22 
Version 3.7_07.13.2018 
  
 
 
 
 
 
 
 
 
 
 
 
 
Low-level light therapy (LLLT) with near infrared light emitting diodes in patients 
with moderate traumatic brain injury 
 
 
 
 
  
 
 
 
Protocol Number: 
 
 
2013P000430 
 
 
 
Principal Investigator: 
 
 
 
Rajiv Gupta, M.D., PhD 
Associate Radiologist, MGH 
Director, Advanced X-ray Imaging Sciences (AXIS) Center 
Assistant Professor, Harvard Medical School 
 
Radiological Associates 
55 Fruit Street 
Boston, MA 02114-2696 
 
Phone:  617-726-0369  
Email: RGUPTA1@PARTNERS.ORG  
 
Date of Issue: 
 
07.13.2018 
 
 
 

 
Page 2 of 24 
Version 3.7_07.13.2018 
 
Protocol Synopsis 
Low-level light therapy (LLLT)  with near infrared light emitting diodes in patients 
with moderate traumatic brain injury 
 
 
Trial Population 
 
Males and females 18 years and older admitted to the Emergency 
Department (ED) or Trauma Service with a head injury requiring hospital 
admission as either an inpatient or for observation. 
 
 
 
Investigational 
Product 
 
 
Custom designed Photomedex helmet with LED cluster heads emitting near 
infrared light. 
 
Control 
 
 
Randomized subjects assigned to the placebo procedure (non-activated 
Photomedex helmet) 
 
 
Trial Design 
 
 
Double-blinded placebo controlled study 
 
Primary 
Objective 
 
 
 
Safety and feasibility of using the Photomedex helmet for LLLT and quantify the 
response to LLLT using magnetic resonance imaging and clinical outcome 
measures. 
 
Number of 
Subjects 
 
 
Up to 90 subjects at Massachusetts General Hospital will be enrolled into 
the trial. 
 
Key Inclusion 
Criteria 
 
• At least 18 years old; 
• Injury within 72 hours at the time of consent; 
• Head injury requiring hospital admission; 
• A Glasgow Coma Scale (GCS) score of 9-12 or 13-15 with 
abnormal imaging.  
 
 
Key Exclusion 
Criteria 
 
• Need for emergency neurosurgical intervention (including placement 
of intracranial pressure monitoring devices or drainage catheters); 
• Hemodynamic instability as determined by the clinician; 
• History of any of the following: (i) brain tumor; (ii) prior TBI 
occurring within the past year and requiring hospital admission; (iii) 
a new diagnosis within the past year of either stroke or epilepsy; (iv) 
an established diagnosis of any of the following neurodegenerative 
diseases: Alzheimer’s, Picks, Parkinson’s, Lewy body dementia, 

 
Page 3 of 24 
Version 3.7_07.13.2018 
 
Huntington’s, amytropic lateral sclerosis, spinocerebellar ataxia, 
vascular dementia, HIZ-associated dementia, dementia due to 
metabolic causes (Addison, Cushing, hypothyroidism, renal failure, 
prophyrias, Wilson, mitochondrial diseases, Wernicke-Korsakoff 
syndrome, and dementia of unknown etiology. 
• Pregnancy (all women of child-bearing age will need to have a 
negative pregnancy test prior to the start of the interventional portion 
of the study); 
• Electrical implants such as cardiac pacemakers or perfusion pumps; 
• Ferromagnetic implants such as aneurysm clips, surgical clips, 
prostheses, artificial hearts, valves with steel parts, metal fragments, 
shrapnel, tattoos near the eye, or steel implants, or any other contra-
indications to MRI. 
• Clinical determination that subject cannot undergo MRI 
• Breastfeeding 
• Unstable cervical fractures 
• Scalp lacerations or surgical wounds severe enough to preclude safe 
application of device 
• Unreliable to follow up  
 
 
Primary 
Endpoint 
 
 
Safety and feasibility of using the Photomedex helmet for LLLT and will be based 
on the number of subjects who successfully complete the study without adverse 
events significantly related to application of the device. 
 
 
Secondary 
Endpoint 
 
 
The secondary endpoint will be quantification of the subject response to LLLT 
using MRI and clinical outcome measures. 
 
 
Regulatory 
Status 
 
 
This trial will be conducted as a Non-Significant Risk device trial in accordance 
with both the Food and Drug Administration’s regulations1 and guidelines2.  
 
1 21 CFR 812.2(b)(1)  
2 U.S. Department of Health and Human Services, Food and Drug Administration, Center 
for Device and Radiological Health (January 2006). Information Sheet Guidance For IRBs, 
Clinical Investigators, and Sponsors: Significant Risk and Non-significant Risk Medical 
Device Studies. 
 

 
Page 4 of 24 
Version 3.7_07.13.2018 
 
Table of Contents 
Protocol Synopsis ....................................................................................................................... 2 
Table of Contents ....................................................................................................................... 4 
1. Background and Significance .............................................................................................. 5 
1.1. Prevalence, Burden, and Treatment of Traumatic Brain Injury (TBI). ........................ 5 
1.2. Low-level laser therapy for TBI ................................................................................... 5 
1.3. Clinical evidence of efficacy and safety supporting a pilot clinical study ................... 6 
2. Specific Aims ...................................................................................................................... 6 
3. Subject Selection ................................................................................................................. 7 
4. Recruitment Procedures ...................................................................................................... 8 
5. Consent Procedures ............................................................................................................. 9 
6. Investigational Device Information ................................................................................... 12 
6.1. Helmet Design ............................................................................................................ 12 
6.2. Helmet Specifications and Use .................................................................................. 13 
7. Research Design and Methods .......................................................................................... 13 
7.1. LLLT Photomedex Helmet Device Application ........................................................ 15 
7.2. Magnetic Resonance Imaging .................................................................................... 15 
7.3. Follow Up .................................................................................................................. 16 
8. Concomitant Medication ................................................................................................... 17 
9. Statistical Methods ............................................................................................................ 17 
10. Adverse Events ................................................................................................................. 17 
11. Risk Benefit Analysis ....................................................................................................... 18 
11.1. Known and Anticipated Risks .................................................................................... 18 
11.2. Risk Minimization ...................................................................................................... 19 
12. Monitoring ........................................................................................................................ 20 
12.1. Data and Safety Monitoring ....................................................................................... 20 
12.2. Monitoring and Quality Assurance ............................................................................ 21 
 
 

 
 
Page 5 of 24 
Version 3.7_07.13.2018 
 
1. Background and Significance 
1.1. Prevalence, Burden, and Treatment of Traumatic Brain Injury (TBI).  
TBIs are common across both military and civilian populations.  In military populations, blast-
induced TBI has become a signature casualty of the Iraq and Afghanistan wars [1]. A study of 
recently deployed personnel estimated that 19% suffered a probable TBI [2]. At this rate, nearly 
320,000 military personnel suffered a blast-related brain injury through 2008 [2]. In civilian 
populations, TBIs from automobile accidents, sports injuries, and other sources rank as one of 
the leading causes of emergency hospitalizations [3]. In the US, the CDC reports an annual TBI 
incidence of 1.7 million, with 580,000 TBI-associated deaths in the decade 1997-2007 [3]. 
Worldwide estimates place the number of annual deaths and hospitalizations associated with TBI 
at 10 million [4].  
For a patient, the burden of TBI extends for months, years, and even a lifetime after the injury. 
Chronic cognitive deficits have been firmly associated with all severities of TBI. Often, 
neurocognitive function improves over the first year after injury but plateaus below pre-injury 
levels [5]. Psychological deficits are also associated with TBI; in a recent study of returning 
military personnel, 43% of patients who met a criteria for mild TBI suffered from PTSD 
compared with 16% with other (non-TBI) injuries [2, 6]. TBI can induce depression within 
months and extending to years after injury [2, 7]. As a result, suicide rates for military personnel 
with a documented TBI are higher than those without [8, 9]. Sleep disruptions, daytime fatigue, 
and irritability have all been associated with mild TBI and are sometimes grouped under the 
label of post-concussive syndrome [10, 11]. Neuromotor impairment is common in severe TBIs; 
a recent study estimated that one third of severe TBI patients retained neuromotor impairment 2 
years following injury [12]. Finally, somatic co-morbidities linked to TBI include pulmonary, 
cardiovascular, and gastrointestinal dysfunction [2]. 
1.2. Low-level laser therapy for TBI 
Low-level light therapy (LLLT), also known by low-level laser therapy, is unique among the 
many therapies tested clinically for TBI. Its mechanism of action is biostimulation by near-
infrared (NIR) light, also known as photobiomodulation (PBM). The advantages of LLLT in the 
brain have been appreciated for over a decade [13]. First, the penetration (~2 cm) of NIR light 
allows a device placed against the scalp to deliver therapeutic levels of light to the cortex. 
Second, LLLT is very well tolerated; reports of adverse events in LLLT clinical and case studies 
are extremely rare [14]. Third, LLLT has a relative short approval pathway because it is 
regulated as a device that is applied noninvasively through the skin overlying the skull. Because 
of these unique advantages of LLLT, it is promising as a near-term solution for the immediate 

 
 
Page 6 of 24 
Version 3.7_07.13.2018 
 
and unmet military and civilian need for TBI therapy. 
Over the past decade, multiple studies have demonstrated that LLLT improves recovery in TBI 
[15-20] and stroke [21-25] models. In parallel to these preclinical efficacy studies, laboratory 
research has partially deciphered LLLT’s mechanisms of action. It is broadly accepted that NIR 
light absorption within the mitochondrial respiratory chain initiates downstream changes in 
neuroprotection and vascular function [13].  
1.3. Clinical evidence of efficacy and safety supporting a pilot clinical study 
Positive preclinical results motivated a first clinical study of LLLT for stroke. The results of that 
study, NEST-1, were published in 2007 [26]. This double-blinded placebo controlled study 
tested the efficacy and safety of LLLT across 120 patients. Light was delivered through a 
handheld device placed against the shaved scalp. The device was moved to 20 predetermined 
locations, and held at each location for a duration of 2 minutes. The treated group received LLLT 
at an average of 16 hours after stroke. Patients were evaluated based on the NIH stroke severity 
(NIHSS) scale at baseline, +5 d, +30 d, +60 d, and +90 d after stroke. The treatment group in this 
study showed improved NIHSS over this time-frame (p = 0.021). In a follow-up study of 660 
patients (NEST-2) [27], a post-hoc analysis of moderate to moderate-severe stroke subpopulation 
(n = 434 patients) showed a statistically significant NIHSS benefit (p = 0.044)[40]. A third study 
(NEST-3) targeting a moderate stroke populations is currently underway.  
In addition to providing clinical evidence that transcranial LLLT is effective in treating brain 
trauma, the NEST-1/2 studies demonstrated a very strong safety profile for the intervention. 
Detailed safety analyses were performed in both studies of over 700 combined subjects and 
concluded that LLLT was not associated with any risks within the stroke population of the 
studies.  
Transcranial PBM has not to date been studied as an adjunctive treatment for acute moderate 
TBI and we would like to conduct a pilot study to assess feasibility.  We see this as the first of a 
series of studies to explore whether LLLT might be useful as a safe and effective treatment for 
moderate TBI. 
2. Specific Aims 
The goal of this research is to assess PBM using LLLT to improve outcomes in subjects with 
moderate traumatic brain injury (TBI). In this study we use the definition of TBI as described by 
the DoD:  GCS between 9-12 or 13-15 with an abnormal head CT.  

 
 
Page 7 of 24 
Version 3.7_07.13.2018 
 
The specific aim of this study is to determine the feasibility of PBM with near infrared light 
emitting diodes (LEDs) using the Photomedex Helmet and to quantify the response to LLLT 
using magnetic resonance imaging (MRI) and clinical outcome measures.  We hypothesize that 
the Photomedex helmet will successfully deliver LLLT and that we will be able to quantify the 
response to LLLT through imaging and clinical outcome measures. 
3. Subject Selection 
In this study, we propose to conduct a double-blinded placebo-controlled trial and enroll 90 
subjects with moderate TBI to confirm the safety and feasibility to: 1) use the Photomedex 
Helmet to deliver low-level laser light through the scalp/skull and 2) track the response of 
delivery through MRI and clinical examinations.   
Only patients presenting to the Emergency Department (ED) and/or admitted to the Trauma 
Service at Massachusetts General Hospital (MGH) will be considered.  The following are the 
inclusion/exclusion criteria for the study. 
Table 1:  Selection Criteria 
Inclusion Criteria 
I1.  At least 18 years old; 
I2. Injury within 72 hours at the time of consent; 
I3. Head injury requiring hospital admission;; 
I4. A Glasgow Coma Scale (GCS) score of 9-12 or 13-15 with abnormal 
imaging. 
 
 
Exclusion Criteria 
E1.  Need for emergency neurosurgical intervention (including 
placement of intracranial pressure monitoring devices or drainage 
catheters); 
E2.  Hemodynamic instability as determined by the clinician; 
E3. History of any of the following: (i) brain tumor; (ii) prior TBI 
occurring within the past year and requiring hospital admission; (iii) a 
new diagnosis within the past year of either stroke or epilepsy; (iv) an 
established diagnosis of any of the following neurodegenerative 
diseases: Alzheimer’s, Picks, Parkinson’s, Lewy body dementia, 
Huntington’s, amytropic lateral sclerosis, spinocerebellar ataxia, 
vascular dementia, HIZ-associated dementia, dementia due to metabolic 
causes (Addison, Cushing, hypothyroidism, renal failure, prophyrias, 
Wilson, mitochondrial diseases, Wernicke-Korsakoff syndrome, and 
dementia of unknown etiology. 
E4. Pregnancy (all women of child-bearing age will need to have a 
negative urine pregnancy test prior to the start of the interventional 
portion of the study); 
E5.  Electrical implants such as cardiac pacemakers or perfusion pumps; 
E6.  Ferromagnetic implants such as aneurysm clips, surgical clips, 
prostheses, artificial hearts, valves with steel parts, metal fragments, 

 
 
Page 8 of 24 
Version 3.7_07.13.2018 
 
Table 1:  Selection Criteria 
shrapnel, tattoos near the eye, or steel implants, or any other contra-
indications to MRI.     
E7.  Clinical determination that subject cannot undergo MRI 
E8.  Breastfeeding 
E9.  Unstable cervical fractures 
E10. Scalp lacerations or surgical wounds severe enough to preclude 
safe application of device 
E11.  Unreliable to follow up 
 
4. Recruitment Procedures 
Patients will be approached for enrollment by members of the research team, which include 
clinical research coordinators and research managers in addition to the PI and other study 
physicians.  Recruitment and enrollment will likely occur in the Emergency Department as it is 
preferred that the study procedures begin as soon as possible after consent has been obtained.  
EPIC and other relevant patient databases will be used by qualified research and clinical staff 
(research coordinators, managers, and study physicians) to electronically identify patients who 
may be potential candidates for the study.  The trauma alert/stat pager may also be used to 
identify potential subjects by qualified study staff.  
We will recruit subjects with head injury according to our inclusion/exclusion criteria.  
Depending on the type of head injury patients may be admitted as an inpatient or admitted to the 
ED observation unit. 
Admission as Inpatient 
For patients that are admitted as an inpatient, recruitment may require interaction with a 
surrogate because the patient could have impaired decision-making capacity.  All potential 
subjects are evaluated for the capacity to consent by a physician investigator on the study to 
determine whether or not surrogate consent is required.  When a patient is found to be eligible, a 
member of the clinical team will first ask the surrogate or patient if they are willing to be 
approached about a research study.  If the surrogate or patient declines, no further attempts will 
be made to enroll.  If the surrogate or patient agrees to speak to someone about the research, a 
study staff member will approach him or her for discussion of the trial and informed consent, as 
further outlined in the consent procedures.   
Admission to ED Observation Unit 

 
 
Page 9 of 24 
Version 3.7_07.13.2018 
 
For patients that are admitted to the ED observation unit, a clinician investigator on the study 
will evaluate the patient to determine whether or not he or she has impaired decision-making 
capacity.  If the patient has impaired decision-making capacity, a surrogate will be approached.  
If the patient is not found to have impaired decision-making capacity, they will be asked if they 
are interested in hearing about our research study.  If the surrogate/patient declines, no further 
attempts will be made to enroll.  If the surrogate/patient agrees to speak with someone about the 
research, a study staff member will approach him or her for discussion of the trial and informed 
consent as further outlined in the consent procedures.   
Patients with a strong likelihood of non-adherence as described in the inclusion and exclusion 
criteria will not knowingly be enrolled/randomized. 
Recruitment will not involve restrictions on sociodemographic factors including gender or ethnic 
characteristics. Recruitment will be devoid of any procedures which could be construed as 
coercive. As such, no members of the treating Emergency Medicine teams will be involved in 
obtaining consent.  
5. Consent Procedures 
Consent will be obtained by one of the licensed physician investigators listed on the study.  
The subjects to be enrolled in this study will have confirmed traumatic brain injury (TBI), 
requiring hospital admission either to an inpatient floor or to ED Observation.  Depending on the 
severity of the head injury, these subjects may have diminished capacity to provide informed 
consent at the time of enrollment, and therefore require a surrogate for consent.  All patients will 
be evaluated for the capacity to consent by a physician investigator on the study to determine 
whether or not surrogate consent is required.  If it is found that the patient does have diminished 
capacity, then surrogate consent will be sought by the physician investigator.  Otherwise, the 
physician investigator will obtain written informed consent from the potential subject. 
Surrogate Consent 
 Initial consent must be sought first from a legal guardian if available, then durable power of 
attorney if available, then healthcare proxy if available, or if none of these, then from a spouse or 
other close family member by a physician investigator. However, there may be an opportunity at 
a follow up time-point, when the subject can be re-consented.  During the scheduled follow-up, 
the subject will be evaluated to determine whether or not he/she has the capacity to consent.  If 
the subject regains the capacity to consent at the follow up they will be consented at this time.  If, 
however, the subject still has diminished capacity but is capable of assent at the time of follow-

 
 
Page 10 of 24 
Version 3.7_07.13.2018 
 
up – assent will be obtained.  Written assent is not required but any prospective subject who is 
generally combative or who actively protests about joining the study should not be enrolled, in 
spite of surrogate consent.  Re-consent and/or assent at the time of follow up may be obtained by 
a non-physician investigator trained on the consent process. 
 
The background of the proposed trial and the benefits and risks of the procedures and trial must 
be explained to the surrogate.  The surrogate must sign the current IRB approved consent form 
prior to enrollment.  This form must be presented to and signed by the surrogate as well as by the 
consenting investigator physician. 
 
One of the licensed physician investigators listed on the study responsible for consent will 
approach the surrogate after eligibility has been determined and after the surrogate has agreed to 
hearing about the research study from someone other than the study staff surgeon, such as a 
research fellow or study nurse.  Assurance that participation in this study is completely voluntary 
will be given. The investigator physician obtaining consent will explain in detail the protocol of 
the study, its purpose and potential benefits to society.  The surrogate will be informed about 
minimal risks of routine high magnetic field, non-ionizing RF radiation involved in MR imaging 
and exposure to the Photomedex Helmet. The surrogate will be informed that if he or she feels 
uncomfortable with the study, he/she can choose to terminate the study at any time. The 
surrogate will be informed that their refusal to participate in the study or choosing to terminate it 
at some point will have no effect on care and treatment received by them now or in future. The 
surrogate will be informed that their personal information will be protected as per the HIPAA 
guidelines. Surrogates will typically have less than 12 hours to decide whether or not they wish 
to consider participation since we are looking to apply the light helmet as soon as possible after 
injury.    
Prior to obtaining informed consent, information will be given in a language and at a level of 
complexity understandable to the surrogate in both oral and written form by the investigator or 
assigned designee.  The surrogate will not be coerced, persuaded, or unduly influenced to 
participate or remain in the trial.  The surrogate will be given ample time and opportunity to 
inquire about details of the trial and all questions about the trial should be answered to the 
satisfaction of the representative.   
The subject and his/her surrogate will receive a copy of the signed and dated informed consent 
form(s). 

 
 
Page 11 of 24 
Version 3.7_07.13.2018 
 
The surrogate will also provide screening information about the subject for MR compatibility 
and will give written informed consent prior to the MR imaging study.  Informed consent clearly 
states that the subject and surrogate may choose to terminate the study at any time. 
Subject Consent 
If the potential subject is admitted to the ED observation unit and found to have full capacity for 
informed consent, then surrogate consent will not be obtained.  Rather, the background of the 
proposed trial and the benefits and risks of the procedures and trial must be explained to the 
potential subject.  The potential subject must sign the current IRB approved consent form prior to 
enrollment.  This form must be presented to and signed by the potential subject as well as by the 
consenting investigator physician.   
One of the licensed physician investigators listed on the study responsible for consent will 
approach the potential subject after eligibility has been determined and after the potential subject 
has agreed to hearing about the research study from someone other than the study staff physician, 
such as a research fellow or study nurse.  Assurance that participation in this study is completely 
voluntary will be given. The investigator physician obtaining consent will explain in detail the 
protocol of the study, its purpose and potential benefits to society.  The potential subject will be 
informed about minimal risks of routine high magnetic field, non-ionizing RF radiation involved 
in MR imaging and exposure to the Photomedex Helmet. The potential subject will be informed 
that if he or she feels uncomfortable with the study, he/she can choose to terminate the study at 
any time. The potential subject will be informed that their refusal to participate in the study or 
choosing to terminate it at some point will have no effect on care and treatment received by them 
now or in future. The potential subject will be informed that their personal information will be 
protected as per the HIPAA guidelines. Potential subjects will typically have less than 12 hours 
to decide whether or not they wish to consider participation since we are looking to apply the 
light helmet as soon as possible after injury.    
Prior to obtaining informed consent, information will be given in a language and at a level of 
complexity understandable to the potential subject in both oral and written form by the 
investigator or assigned designee.  The potential subject will not be coerced, persuaded, or 
unduly influenced to participate or remain in the trial.  The potential subject will be given ample 
time and opportunity to inquire about details of the trial and all questions about the trial should 
be answered to the satisfaction of the representative.   
The subject will receive a copy of the signed and dated informed consent form(s). 

 
 
Page 12 of 24 
Version 3.7_07.13.2018 
 
The subject will also provide screening information about the subject for MR compatibility and 
will give written informed consent prior to the MR imaging study.  Informed consent clearly 
states that the subject may choose to terminate the study at any time. 
6. Investigational Device Information 
6.1. Helmet Design 
To deliver LLLT acutely to a population of moderate TBI patients, we will acquire two LLLT 
delivery helmets that are custom manufactured with light-emitting diodes (LEDs) cluster heads 
arranged uniformly over the inner surface. We will work with Photomedex, Inc. 
(Montgomeryville, PA) to acquire two LLLT helmet devices (one will serve as a backup device). 
These helmets will be modified versions of existing prototype devices Figure 1.  The 
Photomedex helmet will sit comfortably on the head and will emit light based energy through 
multiple LED cluster-heads that are contained inside the custom designed helmet.  
 
 
Figure 1:  Photomedex Helmet Prototype 
 
An array of 360 LED light sources will be located within the helmet. The energy that is 
generated by the LED sources is photothermal and therefore does not have cumulative mutagenic 
potential like that of ultraviolet (UV) light.  Over the 20 minute procedure, this provides an 
incident fluence of approximately 43 J/cm2 (0.036 W/cm2 x 20 minutes x 60 seconds/minute = 

 
 
Page 13 of 24 
Version 3.7_07.13.2018 
 
43.2 J/cm2) to the scalp.  Of this energy only approximately 3% or 1.3 J/cm2 will reach the 
cortical surface based on known scalp/skull transmission of NIR light in cadavers [28]. Heat 
generated by the LEDs themselves and by the control electronics will be dissipated by fans 
located on the exterior of the helmet (see Figure 1). The core temperature of the subject will be 
monitored during exposure to ensure that there is not an increase of more than 0.5 C during the 
study procedure.  A control unit will be connected to the helmet by a 5 ft cable, and will be used 
to control the helmet state (on/off/sham).  
 
6.2. Helmet Specifications and Use 
The Photomedex Helmet will be used by experienced study staff members who have undergone 
training and it will undergo and pass initial electrical safety and quality assurance testing.  In 
addition, the unit will be calibrated once every six months or every ten subjects, whichever 
happens first, to ensure the intensity does not exceed the specified intensity of 36mW/cm2 +/- 
20%.  This is to ensure we are within our power density specifications to maintain data quality 
and consistency.  This testing frequency is based on our confirmation by weekly testing that the 
LEDs are extremely consistent and reliable in output parameters. 
The exposure generated by the Photomedex Helmet is well below the accepted ANSI standard 
for the safe use of lasers and laser systems (ANSI Z136.1).  The accepted maximum permissible 
exposure (MPE) for skin exposure between 10s-10,000s is 332 mW/cm2.  The Photomedex 
Helmet will be applied for approximately 1200s (20 minutes) at a power density of 36 mW/cm2 
which is approximately 10 times below the accepted standard.  In addition, the fluence of the 
Photomedex Helmet that will reach the cortex is approximately the same as the reported fluence 
of the Photothera device used in the NEST-1/2 trials  (1.3 J/cm2 vs. ~1J/cm2, respectively).  
The LED sources will emit at a center wavelength of 810 nm with a bandwidth of 30 nm. The 
intensity on the scalp will be approximately 36 mW/cm2 and will be confirmed by a custom-
built light monitoring tool to vary by less than 20% across the illumination field. 
7. Research Design and Methods 
A member of the study staff familiar with the subject population will evaluate eligibility based 
on the approved inclusion/exclusion criteria, using patient charts.  If a subject is eligible a 
physician on the study staff will approach the subject and/or surrogate for informed consent 
(please see consent procedures for more details).  Demographic and clinical data will be 
collected during the acute hospitalization in accordance with the common data elements 
proposed by the TBI Common Data Element Project [29].  A drop point for deterioration for 

 
 
Page 14 of 24 
Version 3.7_07.13.2018 
 
withdrawing a subject will be a change in the GCS of greater than 2 from the previous exam.  
After informed consent has been obtained, the subject will be randomized.  All subjects will 
undergo either treatment or sham (placebo) procedures.  In the sham procedure, the helmet will 
be placed on the patient but the LEDs will not be activated. The randomization will be set up so 
subjects are assigned sequentially into one of 9 groups with 10 subjects in each group.  Within 
each group, the subject will be assigned randomly to either treatment or sham with an allocation 
ratio of 1:1.  Once the first 10 subjects have been enrolled and have finished treatment (or sham) 
a DSMB (see detailed description under data safety and monitoring) will go over all of the safety 
data presented and make a recommendation on the continuation of the study.  Subsequent DSMB 
meetings will take place once per year   
If the subject is admitted to the ICU, he/she, will be treated according to the ICU standard of care 
procedures.   
Standard of care procedures include: 
Monitoring of O2/CO2 levels; 
Avoiding hypotension; 
Maintaining temperature within normative range; 
Adjusting cervical collar placement if necessary; 
Repeat CT scan if necessary; 
Bed placement at > 30 degrees while in the ICU 
Sedation and analgesia using recommended agents 
 
If the subject is admitted to the ED Observation Unit, he/she will be treated according to the ED 
standard of care procedures. 
The application of the Photomedex helmet will be in addition to but will not change the standard 
of care.   
The following table summarizes the timing and specific assessments to be conducted in this 
study: 
 
ASSESSMENTS 
PRE-PROCEDURE  
PROCEDURE 
FOLLOW UP 
Eligibility Assessment 
X 
 
 
Informed Consent Forma 
X 
 
 
Demographics, including date of birth, 
gender, and race and ethnicity 
X 
 
 
Medical History  
X 
 
 
Pregnancy Testb 
X 
 
X 
Investigational LLLT using the Photomedex 
 
X 
 

 
 
Page 15 of 24 
Version 3.7_07.13.2018 
 
Helmet 
Neuroimaging using Magnetic Resonance 
 
X 
X 
Clinical Outcomes Assessment 
 
X 
X 
AE, SAE, UADE Assessment 
 
X 
X 
 
a If the subject regains capacity they will be re-consented at the time of follow up. 
b Exclusion criteria (E4.) specific for female subjects of childbearing age. 
 
7.1. LLLT Photomedex Helmet Device Application 
In order to maintain blinding, a study staff member not associated with analysis of the study will 
create a randomization code and assign treatment via an envelopment randomization system.  
The study staff member in charge of applying the Photomedex helmet will open each 
randomization envelop and once the clinician deems it is acceptable, subjects will undergo 
approximately 20 minutes of exposure to the Photomedex helmet within 72 hours after injury. If 
the subject is assigned to the sham group the LEDs will not be activated.  Because the helmet 
uses NIR light that is invisible to the human eye, clinical staff within the room will not be able to 
detect whether the LEDs are activated.  
The Photomedex helmet will be used up to 3 times for each subject. The first application will be 
as soon as possible after injury, within 72 hours.  Follow up applications of the Photomedex 
helmet will be applied for up to 2 additional time points no sooner than 12 hours after the 
previous helmet application.  If the subject is discharged from the hospital prior to the second 
helmet application, a follow up helmet application will be scheduled. If the subject wishes to 
have the option to complete in-person visits at his/her place of residence or another location, they 
will indicate this by signing the LLLT Out of Hospital Follow Up Consent Form at the time they 
enroll in the study. 
7.2. Magnetic Resonance Imaging 
Following the 1st Photomedex helmet application, a baseline MRI will be performed, at the 
earliest opportunity, as soon as the subject is able to lay flat for 1 hour and the scanner is 
available for use.  If the subject is admitted as an inpatient the scan will take place at Lunder 6 on 
the MGH Main Campus.  If the subject is discharged from ED Observation prior to the first 
MRI, then the baseline MRI will take place at the Martinos Center at the Charlestown Campus.  
It is anticipated that the MRI will take place within 24-48h hours after enrollment and the 
scanning protocols themselves will take approximately 60 minutes to perform.  Taking into 
account any necessary set up time before, during and after scanning the total time for the MRI 
will be approximately 60-90 minutes.  If the subject is unable to undergo research-related 
imaging, this will be deferred until it is safe and feasible. This baseline MRI is performed 

 
 
Page 16 of 24 
Version 3.7_07.13.2018 
 
following the first application of light therapy because of the need to deliver light therapy as 
soon as possible after injury, and the clinical challenges of performing MRI within the first 12 
hours. A designated study staff member will be responsible for gathering post-procedure follow-
up data on the subject.  The subjects will be followed until discharge.   
Imaging protocol (for baseline and post-treatment imaging): 
Subjects will be asked to lie still in a supine position for the duration of the imaging session. 
Head motion will be minimized during image acquisition by the use of a dedicated head coil with 
holder. 
The MRI protocol may include the following sequences: 
1) Localizer/Auto-aligned scout  
2) High resolution T2 weighted imaging 
3) FLAIR (Fluid attenuated inversion recovery) imaging 
4) High resolution 3D T1 weighted isotropic imaging 
5) Susceptibility-weighted imaging (SWI) 
6) Diffusion tensor imaging (60 encoding directions) 
7) BOLD EPI functional MRI for the evaluation of resting state functional connectivity (FC) 
within and between motor, visual, auditory, dorsal attention, executive control, salience and 
default mode networks.  
8) Arterial Spin Labeling (ASL) brain perfusion imaging. 
 
No contrast agent or other pharmacological substance other than ones clinically required for the 
subject will be given. 
 
7.3. Follow Up  
Follow up visits will be coordinated by the study staff with the subject and/or surrogate. 
Additional MRI scans will be performed at approximately 14-21 days and 3 months after injury 
for image analysis (see Section 7.2 for Imaging Protocol).  At day 7 a follow-up phone call will 
be made to check on the subject after discharge for symptoms reporting. Clinical follow-up visits 
will take place at approximately 14-21 days, 3 months and 6 months post-injury.  The 6 month 
follow up can be completed in person or over the phone since it does not require in person 
physical evaluation.  A follow-up phone call will also be performed at day 7 and at 12 months.  
For subjects who are discharged from the ED’s 24-hour Observation Unit, the same follow up 
procedures will apply.  Additionally, subjects in ED Observation who only received 1 helmet 
application will have up to 2 additional helmet application(s) performed by study staff at a 
follow up appointment.  Throughout the study duration, subjects may be contacted by phone, 
email or mail by clinical research staff for study related reasons. 
 

 
 
Page 17 of 24 
Version 3.7_07.13.2018 
 
8. Concomitant Medication  
Each subject’s concomitant medication regimen before the start of the trial is to be documented.  
Concomitant medications are to be recorded on the appropriate case report form (CRF).  
9. Statistical Methods 
In this pilot study, the study size is limited by number of recruitable patients admitted to MGH 
emergency department. Based on prior-year admission records, the itemized inclusion/exclusion 
criteria, and an assumed 80% consent rate, we estimate an average enrollment of 1 patient per 
week.  
The sufficiency of these enrollments toward powering the primary hypothesis (DTI outcome 
measure) is presented below. These calculations require an assumption of the acute LLLT 
therapeutic effect size, which is unknown and cannot reasonably be estimated from either the 
preclinical data or the clinical stroke studies. Our analysis is based on an assumed effect size of 
25%. 
The coefficient of variation for fractional anisotropy (FA) is based on data from a cohort of 12 
mild to moderate TBI patients scanned using quantitative MRI [30]. For this cohort, FA was 
measured in 16 regions of the brain. The coefficient of variation (CV), defined as the ratio of 
mean to the standard deviation, was 53.45%. However, this study included mild to moderate. 
With the more narrow inclusion of moderate TBI, we estimate a FA CV of 40% (based on 
clinical and research experience of the investigators, and knowing that the CV for healthy 
volunteers is 25%).  The required sample size for detecting changes in FA associated with acute 
LLLT [31] is then 82 (41 patients in each group).  We note that other diffusion parameters (mean 
diffusivity, axial diffusivity, and radial diffusivity) featured much lower CV, and would be 
sufficiently powered with this sample size. 
10. Adverse Events 
Adverse events will be reviewed by the Principal Investigator, Research Monitor and the DSMB 
and will be reported to the Human Research Committee within the required time frame and to all 
participating investigators according to the Partners Human Research Committee guidelines. 
Underlying diseases or conditions are not reported as AEs unless there is an increase in severity 
or frequency during the course of the investigation.  Death should not be recorded as an adverse 
event, but should only be reflected as an outcome to the applicable AE that led to the death.  

 
 
Page 18 of 24 
Version 3.7_07.13.2018 
 
11. Risk Benefit Analysis 
11.1. Known and Anticipated Risks  
We anticipate the risk to the subjects due to participation in this study to be low.  Subjects who 
have satisfied the inclusion/exclusion criteria as outlined in the protocol will be eligible for 
enrollment.  All subjects will be treated according to the standard of care guidelines for their 
condition according to the medical staff.  For the experimental portion of the procedure, after 
consent has been obtained, subjects will undergo approximately 20 minutes of exposure to the 
Photomedex Helmet for at least 2 time points and up to 3 time points.  The first helmet 
application will take place in the inpatient unit or in the ED observation unit.  If the subject is 
admitted as an inpatient he/she may have up to 2 additional helmet applications no sooner than 
12 hours after the previous helmet application.  If the subject is discharged from either the 
inpatient unit or the ED observation unit prior to his/her 2nd helmet application, he/she will have 
up to 2 additional helmet applications no sooner than 12 hours after the previous helmet 
application arranged either through a follow up visit.  
In order to optimize the LLLT, we would like to shave the head.  This will be optional to the 
surrogate/subject and will be explained at the time of informed consent.  There is a slight 
potential risk of a small cut to the head during shaving of the head.  In addition, there is a small 
amount of radiant heat that is generated by the Photomedex helmet.  The helmet will be 
efficiently cooled with fans but depending on the skin and hair color of the subject the 
temperature of the scalp may be raised enough to be perceived as warmth. In addition, the 
subject’s core temperature will be monitored and in the unlikely event that the temperature 
increases more than 0.5 C the helmet will be removed. 
Following initial exposure to the Photomedex Helmet, a baseline MRI will be performed at the 
earliest opportunity as soon as the patient is able to lay flat for 1 hour and the scanner is available 
for scheduling.   If the subject is admitted to an inpatient unit, he/she will have the first MRI scan 
in Lunder 6 at the MGH Main Campus.  If the subject is discharged from the ED Observation 
unit, he/she will have the first MRI scan at the Martinos Center in Charlestown. 
For subjects admitted to the inpatient unit, there is a small risk of complication associated with 
moving the subject from the ICU to radiology for MRI.  The most common complications are 
related to inadvertent dislodgement of tubes and lines or related to temporary disconnection from 
the mechanical ventilator.  These complications are inherent in any travel out of the ICU.  If the 
risk of travel complications is deemed by the clinical (non-study) team to be too high, MRI for 
the purposes of this study will be deferred until a later date.    The FDA considers investigations 
using MRI software and hardware to be non-significant risk, as long as they are operated within 

 
 
Page 19 of 24 
Version 3.7_07.13.2018 
 
FDA specified parameters.  All MRI studies will adhere to the FDA approved for the Siemens 
3T system used in this research.  These safety parameters include static magnetic field, time 
varying magnetic fields (dB/dt), specific absorption rate (SAR), and acoustic noise levels. 
11.2. Risk Minimization  
This study involves the application of the Photomedex helmet for delivery of low-level laser 
light using LED cluster heads.  The risks to the subject have been minimized by choosing an 
exposure that has been shown to be effective but does not exceed accepted standards.  The 
exposure generated by the Photomedex Helmet is well below the accepted ANSI standard for the 
safe use of lasers and laser systems [ANSI Z136.1].  The accepted maximum permissible 
exposure (MPE) between 10s-10,000s is 332 mW/cm2.  The Photomedex helmet will be 
operating for approximately 1200s and has a power density of 36mW/cm2 which is 
approximately 10 times below the accepted standard.  In addition, the output fluence of our 
device per treatment session (43 J/cm2) is at approximately half of that used in the NEST-1 trial  
(82 J/cm2) with the Photothera device by Lampl et al in stroke patients.  In this study there were 
no adverse events found to be significantly related to the application of the Photothera device  
[26].  We will also monitor the temperature of the subjects during application of the Photomedex 
helmet to ensure that application of the LLLT does not increase the temperature of the subject 
more than 0.5 C.  If a temperature above this is reached the Photomedex helmet will be removed. 
This study also involves MRI of the brain without intravenous contrast.  There is no additional 
risk to the subject associated with these proposed MRI sequences, above those of a conventional 
MRI that is routinely performed on these patients for clinical workup. The FDA considers 
investigations using MRI software and hardware to be non-significant risk, as long as they are 
operated within FDA specified parameters.  We will ensure all imaging will take place according 
to the FDA specified parameters for the Siemens 3T system. 
We will employ measures throughout the course of this study to minimize risks to subjects 
choosing to participate.  All efforts will be made to minimize potential risks by: 
• 
Providing training on the investigational equipment prior to use 
• 
Defining inclusion/exclusion criteria clearly to ensure only appropriate 
subjects are enrolled.  
• 
Ensuring that the treatment of the subject is consistent with current 
medical practices. 

 
 
Page 20 of 24 
Version 3.7_07.13.2018 
 
12. Monitoring  
The Principal Investigator will make necessary efforts to ensure that this trial is conducted in 
compliance with GCPs and all applicable regulatory requirements. 
12.1. Data and Safety Monitoring 
The PI will be responsible for overseeing all aspects of the study including: ensuring that the 
study is conducted according to the IRB-approved protocol, performing monitoring and 
confirming compliance of the study, and protecting the rights, safety and welfare of the subjects.  
Should the PI at any point feel that the health and well being of the subject is compromised the 
study procedures will be immediately suspended.   
Data will be collected by the appropriate study staff, such as research fellows from the 
Department of Trauma, Emergency Surgery and Surgical Critical Care.  Case report forms will 
be kept securely in the electronic Partners Redcap Database. In addition, electronic data will be 
stored on a Password Protected computer system and backed up onto a secure server location.  
Only the PI and research team will have access to the database, and identifying information will 
not be released.  The data will be reviewed regularly by the designated study staff and the PI will 
regularly review the data and findings with the study staff during a regularly held research 
meeting. Throughout the duration of the study, the PI will perform ongoing evaluation of subject 
safety data in order to identify AEs and trends as soon as possible.  The PI will be responsible for 
determining whether the research should be altered or stopped.  In addition, de identified image 
MRI image data will be shared with external collaborators in order to perform quantitative image 
analysis through a customized computational algorithm.  The data will have all identifiers 
removed and will be transferred to the collaborator by a study staff member.  
A designated study staff member will be responsible for gathering post-procedure follow-up data 
on the subject.  The subjects will be followed until discharge.  We will also follow-up with the 
patient 3 and 6 months after injury.  A follow up phone call will be completed at 12 months.  
In order to review the data in an unblinded fashion, we will establish a DSMB of experienced 
specialists from Trauma, Neurology, Radiology, Rehabilitation at MGH and Spaulding, and the 
Wellman Center at MGH who are not conflicted or study staff members to review the safety 
data.   The DSMB will review the data collected after the first 10 subjects have been enrolled.  
The DSMB will make a recommendation as to whether or not the study should continue.  If the 
DSMB recommends continuation of the study, subsequent DSMB review of data once per year. 
Additionally, John Chen MD, a neurologist at MGH and member of the DSMB will serve as an 
independent research monitor for the study.  He will review the research protocol with the 

 
 
Page 21 of 24 
Version 3.7_07.13.2018 
 
investigators, review the monitoring plan, and review study data.  If the research monitor is 
concerned for the safety and well-being of the subjects he/she will have the authority to stop the 
research protocol in progress, remove individual human subjects from a research protocol, and 
take whatever steps are necessary to protect the safety and well-being of human subjects until the 
IRB can assess the monitor’s assessment. The research monitor will review all unanticipated 
problems involving risk to subjects or others, device-related serious adverse events and all 
subject deaths associated with the protocol.  At a minimum, the research monitor must comment 
on the outcomes of the event or problem and in case of a device-related serious adverse event or 
death, comment on the relationship to participation in the study.  The research monitor must also 
indicate whether he/she concurs with the details of the report provided by the principal 
investigator.  The research monitor will provide an unbiased written report Reports for events 
determined by either the investigator or research monitor to be possibly or definitely related to 
participation and reports of events resulting in death will be promptly forwarded to the 
USAMRMC ORP HRPO. 
12.2. Monitoring and Quality Assurance 
Monitoring of the study data will be made to ensure that all aspects of the current, approved 
protocol/amendment(s) are followed.  Original source documents will be reviewed for 
verification of data.  A monitoring log will be completed for proper documentation.  A device 
accountability will also be kept for the Photomedex Helmet used in the study. 
Subject data will be collected via case report forms and will be recorded in a Partners RedCap 
Database designed specifically for the study.  The PI will ensure the accuracy and completeness 
of the recorded data and will provide his/her signature to verify.  If any discrepancies are found 
during monitoring of the data, confirmation of the correct information will be made by the PI by 
signature and a note to file description will be generated. 
13. References 
[1] 
D. Warden, "Military TBI During the Iraq and Afghanistan Wars," The Journal of Head 
Trauma Rehabilitation, vol. 21, 2006. 
[2] 
"Invisible Wounds of War," RAND Center for Military Health Policy Research, 2008. 
[3] 
V. G. Coronado, L. Xu, S. V. Basavaraju, L. C. McGuire, M. M. Wald, M. D. Faul, B. R. 
Guzman, and J. D. Hemphill, "Surveillance for traumatic brain injury-related deaths–-
United States, 1997-2007.," MMWR Surveillance summaries:Morbidity and mortality 
weekly report Surveillance summaries/CDC, pp. 1-32, 2011. 

 
 
Page 22 of 24 
Version 3.7_07.13.2018 
 
[4] 
A. A. Hyder, C. A. Wunderlich, P. Puvanachandra, G. Gururaj, and O. C. Kobusingye, 
"The impact of traumatic brain injuries: A global perspective," NeuroRehabilitation, vol. 
22, pp. 341-353, Feb 01 2007. 
[5] 
L. Ruttan, K. Martin, A. Liu, B. Colella, and R. E. Green, "Long-Term Cognitive 
Outcome in Moderate to Severe Traumatic Brain Injury: A Meta-Analysis Examining 
Timed and Untimed Tests at 1 and 4.5 or More Years After Injury," in Archives of 
physical medicine and rehabilitation, 2008, pp. S69-S76. 
[6] 
C. W. Hoge, D. McGurk, J. L. Thomas, A. L. Cox, C. C. Engel, and C. A. Castro, "Mild 
Traumatic Brain Injury in U.S. Soldiers Returning from Iraq," New England Journal Of 
Medicine, vol. 358, pp. 453-463, Feb 21 2012. 
[7] 
M. D. Kim Edward, M. D. Lauterbach Edward, M. D. Reeve Alya, M. D. Arciniegas 
David, P. D. Coburn Kerry, M. D. P. D. M. Mendez, M. D. Rummans Teresa, and M. D. 
Coffey Edward, "Neuropsychiatric Complications of Traumatic Brain InjuryA Critical 
Review of the Literature (A Report by the ANPA Committee on Research)," The Journal 
of Neuropsychiatry and Clinical Neurosciences, vol. 19, pp. 106-127. 
[8] 
G. Simpson and R. Tate, "Suicidality after traumatic brain injury: demographic, injury 
and clinical correlates.," Psychol Med, vol. 32, pp. 687-697, Jun 01 2002. 
[9] 
G. Simpson and R. Tate, "Clinical Features of Suicide Attempts After Traumatic Brain 
Injury," The Journal of Nervous and Mental Disease, vol. 193, 2005. 
[10] 
E. D. Bigler, "Distinguished Neuropsychologist Award Lecture 1999. The lesion(s) in 
traumatic brain injury: implications for clinical neuropsychology.," Archives of clinical 
neuropsychology : the official journal of the National Academy of Neuropsychologists, 
vol. 16, pp. 95-131, Mar 2001. 
[11] 
E. R. Peskind, E. C. Petrie, D. J. Cross, K. Pagulayan, K. McCraw, D. Hoff, K. Hart, C.-
E. Yu, M. A. Raskind, D. G. Cook, and S. Minoshima, "Cerebrocerebellar 
hypometabolism associated with repetitive blast exposure mild traumatic brain injury in 
12 Iraq war Veterans with persistent post-concussive symptoms," NeuroImage, vol. 54, 
Supplement 1, pp. S76-S82, Feb 01 2011. 
[12] 
W. C. Walker and T. C. Pickett, "Motor impairment after severe traumatic brain injury: A 
longitudinal multicenter study," J Rehabil Res Dev, vol. 44, pp. 975-982, 2007. 
[13] 
H. Chung, T. Dai, S. Sharma, Y.-Y. Huang, J. Carroll, and M. Hamblin, "The Nuts and 
Bolts of Low-level Laser (Light) Therapy," Annals of Biomedical Engineering, vol. 40, 
pp. 516-533, Feb 01 2012. 
[14] 
Y.-Y. Huang, A. Gupta, D. Vecchio, V. J. Bil de Arce, S.-F. Huang, W. Xuan, and M. R. 
Hamblin, "Transcranial low level laser (light) therapy for traumatic brain injury," J. 
Biophotonics, vol. (in press), 2012. 
[15] 
T. Ando, W. Xuan, T. Xu, T. Dai, S. K. Sharma, G. B. Kharkwal, Y.-Y. Huang, Q. Wu, 
M. J. Whalen, S. Sato, M. Obara, and M. R. Hamblin, "Comparison of therapeutic effects 

 
 
Page 23 of 24 
Version 3.7_07.13.2018 
 
between pulsed and continuous wave 810-nm wavelength laser irradiation for traumatic 
brain injury in mice.," PLoS ONE, vol. 6, p. e26212, 2011. 
[16] 
J. Khuman, J. Zhang, J. Park, J. D. Carroll, C. Donahue, and M. J. Whalen, "Low-level 
laser light therapy improves cognitive deficits and inhibits microglial activation after 
controlled cortical impact in mice.," Journal of Neurotrauma, vol. 29, pp. 408-417, Feb 
20 2012. 
[17] 
A. Oron, U. Oron, J. Streeter, L. de Taboada, A. Alexandrovich, V. Trembovler, and E. 
Shohami, "low-level laser therapy applied transcranially to mice following traumatic 
brain injury significantly reduces long-term neurological deficits.," Journal of 
Neurotrauma, vol. 24, pp. 651-656, May 2007. 
[18] 
A. Oron, U. Oron, J. Streeter, L. de Taboada, A. Alexandrovich, V. Trembovler, and E. 
Shohami, "Near infrared transcranial laser therapy applied at various modes to mice 
following traumatic brain injury significantly reduces long-term neurological deficits.," 
Journal of Neurotrauma, vol. 29, pp. 401-407, Feb 20 2012. 
[19] 
B. J. Quirk, M. Torbey, E. Buchmann, S. Verma, and H. T. Whelan, "Near-infrared 
photobiomodulation in an animal model of traumatic brain injury: improvements at the 
behavioral and biochemical levels.," Photomedicine and Laser Surgery, vol. 30, pp. 523-
529, Sep 2012. 
[20] 
Q. Wu, W. Xuan, T. Ando, T. Xu, L. Huang, Y.-Y. Huang, T. Dai, S. Dhital, S. K. 
Sharma, M. J. Whalen, and M. R. Hamblin, "Low-Level Laser Therapy for Closed-Head 
Traumatic Brain Injury in Mice: Effect of Different Wavelengths," Lasers Surg. Med, 
vol. 44, pp. 218-226, Feb 24 2012. 
[21] 
L. DeTaboada, S. Ilic, S. Leichliter-Martha, U. Oron, A. Oron, and J. Streeter, 
"Transcranial application of low-energy laser irradiation improves neurological deficits in 
rats following acute stroke," Lasers Surg. Med, vol. 38, pp. 70-73, 2006. 
[22] 
P. A. Lapchak, K. F. Salgado, C. H. Chao, and J. A. Zivin, "Transcranial near-infrared 
light therapy improves motor function following embolic strokes in rabbits: An extended 
therapeutic window study using continuous and pulse frequency delivery modes," 
Neuroscience, vol. 148, pp. 907-914. 
[23] 
P. A. Lapchak, J. Wei, and J. A. Zivin, "Transcranial Infrared Laser Therapy Improves 
Clinical Rating Scores After Embolic Strokes in Rabbits," Stroke, vol. 35, pp. 1985-1988, 
Feb 01 2004. 
[24] 
M. C. P. Leung, S. C. L. Lo, F. K. W. Siu, and K. F. So, "Treatment of experimentally 
induced transient cerebral ischemia with low energy laser inhibits nitric oxide synthase 
activity and up-regulates the expression of transforming growth factor-beta 1," Lasers 
Surg. Med, vol. 31, pp. 283-288, Sep 25 2002. 
[25] 
A. Oron, U. Oron, J. Chen, A. Eilam, C. Zhang, M. Sadeh, Y. Lampl, J. Streeter, L. 
DeTaboada, and M. Chopp, "Low-Level Laser Therapy Applied Transcranially to Rats 

 
 
Page 24 of 24 
Version 3.7_07.13.2018 
 
After Induction of Stroke Significantly Reduces Long-Term Neurological Deficits," 
Stroke, vol. 37, pp. 2620-2624, Feb 01 2006. 
[26] 
Y. Lampl, J. A. Zivin, M. Fisher, R. Lew, L. Welin, B. Dahlof, P. Borenstein, B. 
Andersson, J. Perez, C. Caparo, S. Ilic, and U. Oron, "Infrared Laser Therapy for 
Ischemic Stroke: A New Treatment Strategy," Stroke, vol. 38, pp. 1843-1849, Feb 01 
2007. 
[27] 
J. A. Zivin, G. W. Albers, N. Bornstein, T. Chippendale, B. Dahlof, T. Devlin, M. Fisher, 
W. Hacke, W. Holt, S. Ilic, S. Kasner, R. Lew, M. Nash, J. Perez, M. Rymer, P. 
Schellinger, D. Schneider, S. Schwab, R. Veltkamp, M. Walker, J. Streeter, and f. t. N.-. 
Investigators, "Effectiveness and Safety of Transcranial Laser Therapy for Acute 
Ischemic Stroke," Stroke, vol. 40, pp. 1359-1364, Feb 01 2009. 
[28] 
S. S. Wan, J. A. J. Parrish, R. R. R. Anderson, and M. M. Madden, "Transmittance of 
nonionizing radiation in human tissues.," Photochemistry and Photobiology, vol. 34, pp. 
679-681, Dec 01 1981. 
[29] 
A. I. Maas, C. L. Harrison-Felix, D. Menon, P. D. Adelson, T. Balkin, R. Bullock, D. C. 
Engel, W. Gordon, J. Langlois Orman, H. L. Lew, C. Robertson, N. Temkin, A. Valadka, 
M. Verfaellie, M. Wainwright, D. W. Wright, and K. Schwab, "Common Data Elements 
for Traumatic Brain Injury: Recommendations From the Interagency Working Group on 
Demographics and Clinical Assessment," in Archives of physical medicine and 
rehabilitation, 2010, pp. 1641-1649. 
[30] 
M. Singh, J. Jeong, D. Hwang, W. Sungkarat, and P. Gruen, "Novel diffusion tensor 
imaging methodology to detect and quantify injured regions and affected brain pathways 
in traumatic brain injury.," Magnetic resonance imaging, vol. 28, pp. 22-40, Feb 2010. 
[31] 
G. van BELLE, "Statistical rules of thumb (Series in probability and statistics)," 
Recherche, 2008.