Revitalize Cognition: A Proof of Concept Study Using Transcranial Near Infrared Stimulation in Older Adults
Phase: NA
Conditions: Aging
Sponsor: University of Florida

  
 
 
Revitalize Cognition: Near Infrared Stimulation in Older Adults 
NCT02582593 
9/4/2019 
 
IRB Protocol 
 
 

 
IRB Protocol 
 
 
1. Title: 
   
Revitalize Cognition:  A Proof of Concept Study with Transcranial Near Infrared Stimulation in 
Cognitively Normal Older Adults, those with Mild Cognitive Impairment or Parkinson Disease  
 
2. Investigators 
 
Dawn Bowers, Ph.D., Professor, Clinical and Health Psychology (PI) 
Aparna Wagle-Shukla, M.D. Assistant Professor, Neurology    
Neal Weisbrod, M.D., Assistant Professor, Neurology 
Demetrius Maragarone, M.D., Professor, Neurology 
Christopher Hess, M.D., Assistant Professor, Neurology 
Adam Woods, Ph.D., Assistant Professor, Clinical & Health Psychology and Neuroscience  
Michael Marsiske, Ph.D., Professor, Clinical and Health Psychology  
Chris Hass, Ph.D., Professor & Associate Provost, UF 
Francesca Lopez, B.S., Graduate Student, Clinical & Health Psychology 
Brittany Rohl, B.S., Graduate Student, Clinical & Health Psychology 
Sidney Baudenstital, B.S. Graduate Student, APK 
Lauren Kenney, B.S., Graduate Student, Clinical & Health Psychology 
Adrianna Ratajska, B.S., Graduate Student, Clinical & Health Psychology 
Rebecca O’Connell, B.S., Staff 
Alyssa Ray, B.S., Staff 
 
3. Abstract 
 
Cognitive decline and transition to dementia, particularly Alzheimer’s disease, is one of the 
most prominent public health concerns of the 21st century.  Over the past decade, progress has 
been made in identifying subtypes of dementia, preclinical biomarkers and associated risk 
factors, along with strides in understanding the role of various suspected pathophysiologic 
mechanisms.  Even so, there is a dearth of clinically meaningful treatment options at this point 
in time for individuals who are at increased risk for transitioning to dementia, particularly those 
with the amnestic variant of mild cognitive impairment (aMCI).  While waiting for causative 
cures and preventive approaches, we are faced with the task of identifying modifying therapies 
that might alter the course or slow down the transition from aMCI to Alzheimer’s dementia.  
Similar concerns face other neurodegenerative disorders (e.g., Parkinson disease) regarding 
transitions from mild cognitive impairment to dementia. 
 
The proposed study hopes to contribute to this mission by testing the viability of a different 
type of intervention, one involving transcranial delivery of near-infrared (NIR) wavelengths 
(808-904nm).  Near-infrared stimulation is safe, non-invasive and appears to improve 
mitochondrial function by promoting increased production of intracellular ATP and possibly 
improved blood flow.  Perhaps most compelling are recent findings of reduced beta-amyloid 
and neurofibrillary tangles in transgenic Alzheimer’s mouse models after exposure to real vs 
sham transcranial NIR stimulation. Similar observations have emerged in mouse models of 

Parkinson disease.  Preliminary human studies involving TBI, stroke, and young adult 
populations have also been promising in terms of positive effects of NIR on cognition.    
 
The overall goal of the present study is to learn whether this unconventional NIR stimulation 
approach has potential for improving cognition in older adults.  To do so, we will conduct a 
randomized sham controlled pilot trial.  The intervention will involve six sessions, over a 2-week 
period in which real or sham stimulation is transcranially applied using a delivery system that 
has been FDA-approved as a nonsignificant risk since 2003.  We hope to learn whether NIR 
stimulation, relative to sham, has positive effects on:  a) novel tasks of memory that are 
sensitive to hippocampal function and amyloid burden;  b) executive tasks from the NIH 
Examiner, and c) emotion measures, including those from the emotion module of the NIH 
Toolbox.  An exploratory neuroimaging aim will examine pre-post intervention changes in 
resting state connectivity and MRS phosphorus ATP in a subset of participants who are eligible 
to undergo magnetic resonance imaging. A subgroup of participants with Parkinson disease will 
participate and will undergo similar procedures in addition to motor testing.  If findings from 
this study are positive, this may set the stage for more finely tuned trials examining various 
dosage parameters. Transcranial NIR stimulation is an understudied intervention that could 
potentially represent a strategy for enhancing thinking and memory in older adults and those 
with mild cognitive impairment or pre-Alzheimer’s disease.     
 
4. 
Background 
 
The proposed project represents a novel, relatively low cost, low risk, though potentially high 
impact approach for a cognitive/ mood intervention in older adults.  It involves transcranial 
delivery of near infrared (NIR) light via light emitting diodes.   Before describing the study 
design, we will briefly describe the background and rationale for this unconventional approach 
 
By history, current nonsurgical device approaches to brain stimulation primarily involve 
magnetic (rTMS, TMS, deep TMS) or electrical stimulation approaches (transcranial direct 
current stimulation (tDCS) which alter synaptic firing rates and neuronal membrane potentials.    
 
In contrast, a very different type of brain stimulation approach involves near infrared light 
(NIR).  Application of light in red (630-700nm) and near-infrared wavelengths (808-904nm) 
appears to improve mitochondrial function by promoting increased production of intracellular 
ATP, which is important for cellular metabolism, respiration and oxygenation.  It increases 
blood flow and upregulates the expression of neuroprotective genes.   Specifically, it targets the 
cytochrome oxidase c integral membrane protein of the mitochondrial membrane (electron 
transport chain) and leads to: a) increased intracellular levels of ATP (Mochizuka-Oda et al., 
20002, Wong-Riley et al., 2005, Oron et al., 2007), b) increased expression of genes supporting 
cell proliferation and mitochondrial energy metabolism (Zhang et al., 2003), and c) decreased 
genes for pro-inflammatory proteins such as interleukin-1, interleukin10, and cytokine 
receptors (Whelan et al., 2003).   Additionally, near infrared light may increase blood flow 
(Chung et al., 2012; Nawashiro et al., 2012) and up-regulate antioxidant genes (Chen et al., 
2009).  Thus, rather than directly modulating neural networks per se, application of NIR appears 
to create a supportive environment for optimal neuronal functioning.  Its influence on neural 
connectivity is thus indirect rather than direct.    
 
Recent animal and human studies have provided tentative support for positive benefits of this 
NIR approach in terms of “brain and cognitive function”.   Animal studies have included reports 
of reduced beta-amyloid load and neurofibrillary tangles in transgenic mice (APP/PSI and 

K3Tau) expected to develop Alzheimer’s disease after exposure to real vs sham transcranial NIR 
stimulation (Purushothuman et al., 2014, 2015).  Others, using mouse and macaque models of 
Parkinson disease,   have found that leads with NIR- attached diodes implanted into the 
ventricles protected dopaminergic neurons in the substantia nigra from MPTP-induced 
degeneration and also preserved locomotor activity (Moro et al, 2013, 2014).  Still others  have 
reported that NIR light stimulation attenuates post-stroke deficits in rabbits (Lapchak et al., 
2007, 2010) and increases  cortical metabolism and memory retention in healthy rats (Rojas et 
al.,  2012).   
 
In human studies, near infrared stimulation has been applied via diodes directly to the scalp 
and is thought to penetrate 1-3 centimeters deep, with approximately 2-3% of the light 
reaching the cortex (Wan, 1981; Naeser et al., 2014).  Stimulation is carried out using FDA-
cleared devices that are deemed safe, painless and non-invasive.  Studies of NIR stimulation 
typically use lasers, light emitting diodes (LEDs), or superluminous diodes (i.e., an LED variant 
that produces stronger light).   The FDA originally approved the technology in 2003 as a 
nonsignificant risk device and the application of this technology in humans has been shown to 
be safe and effective (Rojas & Gonzalez-Lima, 2013).   
 
In humans, positive effects with NIR stimulation  have been observed in  individuals with 
chronic aphasia due to focal stroke (Naeser et al., 2012, 2013),  in individuals with traumatic 
brain injury  who underwent a six week intervention study (Naeser et al., 2014), and in young 
healthy adults (Barrett et al., 2013).  The latter study was ‘sham controlled’ and with young 
adults undergoing only one session of NIR stimulation,  resulting in changes on tasks of 
executive functioning and processing speed. Patients with TBI showed improvement on tasks of 
executive function and recent memory, with relatively large effect sizes ranging from changes 
on the order of 1-2 standard deviations.    At least one neuroimaging study has reported pre-
post changes in resting state functional connectivity MRI following application of real vs. sham 
NIR.     
 
Summary:  While findings from both animal and human studies are promising, it remains 
unclear whether such a novel, unconventional approach might be viable for enhancing in older 
adults, including those at risk for developing Alzheimer’s disease.  More carefully controlled 
studies are clearly needed.   Currently, we have available NIR instrumentation (MedX, FDA 
cleared as nonsignificant risk device) that was obtained from a McKnight Brain Institute shared 
instrumentation grant.  The current proposal intends to use this system to pilot a randomized 
sham-controlled study in cognitively normal older adults, those with mild cognitive impairment 
(amnestic, nonamnestic), and nondemented individuals with Parkinson disease. 
 
5. 
Specific Aims 
 
1. Aim 1:  To test the hypothesis that NIR stimulation will result in greater pre-post 
intervention improvement on tasks of executive function (co-primary outcome) and recent 
memory (co-primary outcome). Executive function will be tested using individual and 
composite scores from the NIH Examiner, a battery of executive function tests (Kramer et al., 
2014) and an experimental Stroop task.  The co-primary  outcome includes a novel  task of 
recent memory  that is sensitive to hippocampal function and amyloid load,  the Spatial 
Navigation Task which is also known as ARENA (Thomas et al., 2001; Laczo et al., 2011).  
Additional executive and memory measures will serve as secondary cognitive outcomes.. 
 

2. Aim 2:  To test the hypothesis that NIR stimulation will result in greater pre-post 
intervention improvement, relative to sham, on measures of mood, negative affect and 
wellbeing. This will be tested using indices from the Emotion module of the NIH Toolbox 
(Salsman et al., 2013) and traditional measures of depression, anxiety, and apathy.      
 
3. Aim 3: (exploratory):  To learn whether there are intervention-related changes in 
resting state functional connectivity and/or MRS-based markers of ATP function. This will 
be sampled in a subgroup of participants who undergo structural and functional MRI before 
and after intervention, either NIR treatment or sham conditions. 
 
4. Aim 4: (Parkinson specific):  To learn whether there are intervention-related changes in 
motor skills.  This will be tested using measures of fine motor speed and dexterity (Grooved 
Pegboard), gait and balance, and clinical measures of Parkinson disease severity. 
 
6. 
Research Plan 
 
6.1 Design Overview 
This is a pilot study of the efficacy of NIR stimulation for enhancing cognition and mood in older 
adults including those who are cognitively normal, those with mild cognitive impairment 
(amnestic and nonamnestic), and individuals with Parkinson disease.   The overall hypothesis, 
drawn from previous literature, is that exposure to NIR stimulation will have positive effects on 
brain health and will result in better cognitive and mood performance.   We propose to conduct 
a blinded parallel group sham controlled pilot trial, with half the participants in each group 
randomized to the real NIR treatment and half to the sham treatment condition. The two 
conditions are identical in all respects except that no near-infrared light stimulation will occur 
during the sham condition.  The participants will consist of older adults recruited from the 
community, including The Village, and from UF and other clinics. The study will take place at the 
UF-VITAL lab located on The Village campus or in the Cognitive Neuroscience Laboratory at the 
Fixel Center for Neurologic Disease.  The study design is shown below: 
 

 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.2 Participants 
Participants will include individuals, age 62 years and older, who are independently living and 
willing to undergo a two-week intervention program.  Our study groups will consist of the 
following:   70 cognitively normal individuals (N= 35/group), 20 individuals with amnestic MCI 
(N=10/group), 20 individuals with nonamnestic MCI (N=10/group), and 40 nondemented 
individuals with Parkinson disease (N=20/group).   Based on our previous intervention studies 
with older adults, we anticipate a 20% attrition rate and up to 50 screen failures.  To account 
for screening failures and study attrition, we anticipate consenting 206 individuals.   
 
Informed Consent:  Informed consent will be obtained according to university and federal 
guidelines.  The informed consent process may begin with the initial telephone screening call, 
when a prospective participant is contacted or calls to find out more information about the 
study (See Telephone Script).  After that first phone contact, the participant will be sent a copy 
of the Informed Consent via hardmail or via email if they are interested, and/or scheduled for 
an appointment in the VITAL laboratory or at the Fixel Center for Neurologic Diseases to discuss 
the study in more detail and in person.  
 
Other potential participants, particularly those seen during the clinics of the PI or co-
investigators, will be directly asked about their interest in this study and will be provided a copy 
of the informed consent to review. 
 
During the first study visit, the project will be explained in more detail to the potential 
participant by the study coordinator or approved staff and the Informed Consent will be 
reviewed.  Participants will be informed that this is a randomized trial and that there is 50% 
likelihood they may receive the sham intervention.  The participant will be given the 
opportunity to ask questions.  No study interventions will begin until the Informed Consent 

(ICF) paperwork is signed.  Participant will be given a signed copy of the ICF paperwork, and a 
copy will be kept on file with the Principal Investigator. 
 
6.3 Recruitment 
Participants will be recruited from the Village and the community through advertisements, 
brochures, and flyers (See Appendix A).  Targeted locations might include bulletin boards at 
community grocery stores, physician’s offices, medical centers, retirement homes, etc.   
Occasionally, the project coordinator and investigators will make informational presentations 
about age-related changes in various community venues (e.g. health fairs, socials).   As part of 
these presentations, we will encourage interested individuals to contact the VITAL lab to learn 
more ongoing research. Staff members of The Village who obtain signed permission from 
residents will forward resident names and contact information to the Study Coordinator. 
 
Additional recruitment may occur through the clinics of the PI and co-investigators or other 
clinics at the Fixel Center (via flyers).   These clinics focus on older adults including those with 
Parkinson disease, and potential participants will be directly asked about their interest in this 
study by their clinicians.  Additionally, flyers will be distributed to other physicians at the Fixel 
Center.   
 
Finally, recruitment may occur via IRB approved clinical and research databases.  Thus, 
recruitment of normal older adults may take place via two IRB-approved research databases 
that are maintained by one of the co-investigators, Dr. Marsiske.  These include the Claude D. 
Pepper Recruitment Registry (IRB #201601352, previously 415-2007) and the Participant 
Registry for Aging Research (IRB #201601448, previously 131-2002).   
 
Recruitment of individuals with mild cognitive impairment or Parkinson disease may take place 
via INFORM (IRB #201501166, previously #416-2002), a clinical research database that is 
maintained by the Center for Movement Disorders and Neurorestoration (CMDNR).  The 
INFORM database includes patients with both movement and cognitive disorders, including 
those who are seen in Dr. Weisbrod’s and Maraganore’s Cognitive Disorders and Dementia 
clinics at the Fixel Center. 
     
6.4 Inclusion/Exclusion criteria  
 
6.4a.  General Inclusion Criteria for all Participants 
• Age 62 years or above  
• Able to provide informed consent and perform cognitive and mood measures on a 
computer 
• Willingness to be randomized to Sham or Real intervention 
• Can devote 2 weeks to the intervention, and additional time for pre and post testing 
• 8th grade education and ability to read on 8th grade level based on scores on the 
Wechsler Test of Adult Reading (WTAR) or the Wide Range Achievement Test-IV (WRAT-
IV); or a reading test at 14 pt. text 
• On stable doses of major medications; Since some older adults with memory complaints 
may be prescribed acetylcholinererase inhibitors or related medications by their primary 
care physicians (i.e., donepezil, rivastigmine, galantaominhe, memantime, or other 
potential memory-enhancing agent(s), we will not exclude them as long as they have 
been on stable medications for at least two months and plan to continue this 
medication during study participation.   

• Willingness to allow a study partner (spouse, family member, friend) to answer 
questions about their cognitive, mood, and other behaviors.  This does not apply to 
individuals with Parkinson disease.    
 
6.4b.  General Exclusion Criteria for All Participants   
• Sensory loss (vision, hearing) or motor deficits that would preclude participation in the 
experimental cognitive tasks or neuropsychological assessment   
• Unstable and uncontrolled medical conditions (metabolic encephalopathy,  HIV, 
moderate to severe kidney or liver disease)   
• Previous major strokes or other known significant brain abnormalities or diseases 
affecting cognition (i.e., multiple sclerosis, seizure disorder, brain surgery, moderate TBI, 
etc.).  No history of brain surgery.  Exceptions are a diagnosis of Parkinson’s disease for 
the PD subgroup. 
• Evidence of potential dementia based on cognitive screening (e.g., scores < 5th %ile on 
the Montreal Cognitive Assessement (MoCA) or  the Dementia Rating Scale-2 (DRS-2) 
based on appropriate age, education and sex norms. 
• Current or past history of major psychiatric disturbance including schizophrenia, or 
active psychosis, bipolar disorder, current major depressive episode, current alcohol or 
substance abuse or history thereof within the past six months.  This will be assessed 
using the Mental Health Screen v.3 (Carroll & McGinley), a modification of the 
Structured Clinical Interview for DSM-IV psychiatric disorders. We are not excluding 
individuals who are taking antidepressants or anti-anxiety medications, however, use of 
antidepressants and anxiolytics will be recorded and data will be analyzed in post-hoc 
analyses 
• Use of antipsychotics, sedatives, or other medications with significant anticholinergic 
properties (due to potential influence on memory) 
• Use of photo-sensitive medications such as steroids or retin-A within 15 days of the 
study intervention 
• Diagnosis of active cancer 
• Previous participation in a cognitive training study within the last 6  months   
 
6.4c.  Additional criteria for participants in the cognitively normal,  MCI, and Parkinson groups: 
 
Cognitively Normal Group 
• No evidence of objective cognitive decline based on scores on neuropsychological 
screening measures involving delayed memory (HVLT-R or WMS Story Recall), 
confrontation naming (Boston Naming Test), and executive function (Trails B, Category 
Fluency, Judgement of Line Orientation).  Scores on these measures must be no lower 
than -1 standard deviation below normative values.    
• Lives independently with no impairment in social or occupational function 
• No impairment in social and/or occupational function 
• Does not meet DSM-V criterial for Major or Minor Neurocognitive Disorder 
 
Amnestic MCI Groups – Amnestic and Nonamnestic   
• Subjective memory or cognitive  complaints that are confirmed by a study partner 
• Global Clinical Dementia Rating (CDR) Scale of 0.5 with CDR sum of boxes no greater 
than 2.0 (Morris, 1993) 

• For amnestic MCI, objective memory impairment based on HVLT-R delayed word list 
recall or delayed paragraph recall (WMS) of -1.5 standard deviation or below expected 
levels for age, education, ethnic/culture. Scores on other neuropsychological screening 
or baseline measures can be no more than 1.5 SD below normative values.  Note that an 
amnestic component is necessary but non-amnestic component is not required.  
• For nonamnestic MCI, scores on memory tasks (e.g., delayed recall of stories from 
WMS) must be within normal limits (e.g., at least -1.0 SD or better than normative 
values).  Scores in the executive domain  should be -1.5 SD or below normative values.. 
• No impairment in social and/or occupational function 
• Does not meet DSM-V criteria for Major Neurocognitive Disorder 
 
Parkinson Disease Group 
• Participants must have a diagnosis of idiopathic Parkinsons disease by a movement 
disorders specialist based on UK Brain Bank criteria (Hughes et al., 1992a, 1992b). 
• No previous history of brain surgery (DBS, pallidotomy, thalamotomy, or fetal cell 
implants). 
• No evidence of dementia based on scores on a cognitive screener (e.g., Dementia Rating 
Scale-2 (DRS-2)   and  score on delayed paragraph recall cannot be lower than 1.0 
standard deviation of normative values 
• May have difficulties with activities of daily living, but this is due to physical symptoms 
of Parkinson disease and not because of cognitive problems 
• Unwillingness to undergo baseline and followup visits when they are ‘off’ standard 
dopamine medication 
• Inability to undergo a brain scan 
 
Additional exclusion criteria apply to those individuals who participate in the optional brain 
imaging study.  The brain scan is optional for all participants except those with Parkinson 
disease.  In that case, inability to undergo a brain scan, before and after  intervention, is an 
exclusion.  Exclusion criteria for a brain scan include  
• Presence  of claustrophobia 
• Implants such as pacemakers, heart valves, brain aneurysm clips, orthodontics, non-
removable body jewelry, or shrapnel containing ferromagnetic metal. 
 
**Note that we are highly experienced in working with older adults who are identified as 
experiencing current major depression or other psychological disturbances or who perform 
below cutoff on standard cognitive screening measures. The PI [Bowers] is a boarded clinical 
neuropsychologist who has been working with this clinical population for over 30 years. The 
clinical Co-I’s (Maraganore, Wagle-Shukla, Weisbrod, Hess) are experienced neurology 
clinicians, and the doctoral students on this protocol are clinical psychologists in training with 
experience in  diagnosis and treatment of mood and cognitive disorders.  Discussions will be 
held with individuals of concern and recommendations will be made to appropriate health care 
providers with permission of the participant and in line with standards of care.   
 
6.5 Screening Interview and Measures    
Participants will be screened for inclusion/exclusion criteria. This will involve review of 
background and demographic information, medical and psychiatric history, current 
medications, and assessment of functional activities, along with screening of current cognitive 

status using the MoCA or DRS-2, the HVLT-R or WMS-III Logical Memory, and other cognitive 
measures.    Screening will be administered by the project coordinator.    
 
Table 1: Screening & Baseline Measures 
Dementia   
Screen 
Montreal Cognitive Assessment (MoCA: Nasreddine et al., 2005) or Dementia Rating 
Scale (DRS); these are widely used cognitive screening measures for dementia;  See text 
for cutoff scores for Cognitively Normal and MCI groups    
Objective 
Memory 
Hopkins Verbal Learning Test-Revised  and  the WMS Logical Memory Stories:   delayed 
recall scores on  these measures  are used to assign participants to Cognitively Normal 
(CN), amnestic and nonamnestic MCI groups, or to exclude Parkinson patients; (see 
text)  
Other Cognitive 
measures 
Executive Function  -  Trailmaking Test (Optional: Wisconsin Card Sort) (optional for PD) 
Visuospatial  – Judgement of Line Orientation (JOLO)  (optional for PD) 
Language -  Boston Naming Test, Category Fluency  (optional for PD) 
Attention & Processing Speed  -  Digit Span, Digit Symbol  (optional for PD) 
Medical 
Background medical history- rule out medical conditions (i.e., neurodegenerative, TBI, 
etc.), 
Charlson Comorbidity: Assesses for variety of comorbid medical conditions, computes 
risk factor score 
List of Medications:   stable medications for 3 months;  rule out use of anticholinergic 
medications; rule out use of photo-sensitive medications within 15 days of intervention 
Psychiatric 
Mental Health Screen V.3 (Carroll & McGinley) - this is modification of Structured Clinical 
Interview for DSM-IV psychiatric disorders, both current and historical (SCID-IV, First, 
Spitzer, Gibbon, & Williams);  Goal is to rule out major depressive disorder, 
schizophrenia, psychosis, current substance abuse, and other Axis 1 disorders             
Reading 
Literacy 
Wechsler Test of Adult Reading (WTAR) or the reading subtest from the Wide Range 
Achievement Test –IV (WRAT-IV);  participant reads aloud single words in order to 
estimate reading level; All must read on at least an  8th grade level    
Vision 
Vision & Color Vision Screening;. Basic visual acuity will be measured using a Snellen 
chart and color vision will be tested using Ishihara color plates. 
 
Participants will require a Study Partner (e.g., spouse, family member, friend) to provide 
independent information about their cognitive and behavioral status.  The study partner will 
complete structured questionnaires about the participant.   Both the participant and the study 
partner must provide independent consent for this to take place.    The requirement for a study 
partner is ‘optional’ for those individuals with Parkinson disease.    
 
It is possible that some participants, particularly those in the MCI or Parkinson groups who are 
recruited through the UF Cognitive Disorders and Dementia clinics or CMNDR, may have 
already had some of the screening measures, cognitive tasks, and rating scales associated with 
the current study.  If so, we will request permission to use these, rather than repeat them, if 
they have been completed within 2 months.  We will also request permission to access relevant 
medical and neuroimaging records.  
 
If a participant does not meet inclusion/exclusion criteria, they will be thanked for their 
participation and given information as to the reason for their screen failure.    There are several 
reasons why a participant might fail inclusion/exclusion criteria.  Some that are of particular 
concern are poor test performance on the dementia screening measures (MoCA or DRS), 
presence of current major depression, substance abuse, or psychosis (i.e., hallucinations, 
delusions).   If any of these scenarios emerge, we will discuss with the participant and, if 
appropriate, we will offer a referral for additional clinical evaluation through their primary 
physician or a specialty health care provider.  Should individuals report suicidal ideation, the PI 
or co-investigators will meet with the participant to assess risk and refer for further evaluation 

or treatment if necessary.   With participant permission, we will provide results of our screening 
to their health care provider and/or them or a family member.  As mentioned above, the 
project team is experienced in diagnosis and treatment of mood/cognitive disorders.  
 
6.6  Pre and Post-Intervention Measures   
 
Participants who meet study criteria and who remain interested in participating in the 2 week 
intervention will be randomized to treatment or sham groups and undergo a baseline/ pre-
intervention testing.   The pre-intervention measures will be administered by a trained 
psychometrist or research assistant who will be blinded to group assignment (sham, real NIR 
stimulation).     
 
The pre-intervention testing will take approximately 3  – 3.5 hours, and will consist of measures 
of executive function, recent memory, and mood.    These same measures will be given after 
the two-week intervention has completed.  
 
Individuals with Parkinson disease will complete the pre and post intervention visits when they 
are “off” their typical dopaminergic medications.  This is identical to what Parkinson patients 
are asked to do as part of standard clinical care when seen at the UF Movement Disorders 
Clinic.  To do so, the Parkinson patients will refrain from taking their parkinsonian medications 
overnight, with no dopa  medication after 10:00 PM the night before.  The theoretical rationale 
for evaluating patients when off dopamine medication is to obtain an index of the true status of 
their disease state.. The remainder of the protocol (i.e., screening, intervention) will be 
completed when participants are on their normal medications.  When tested ‘off medication’, 
patients may experience increased slowness, tremors and stability.  Because of this, they will be 
closely monitored and provided a wheel chair.  If they become too uncomfortable they can take 
their medication and will be withdrawn from the study.     
 
In previous IRB- approved studies, we have tested Parkinson patients off medication while they 
completed an array of cognitive, EEG, and other tasks.  We have found that the tolerability was 
quite good and no participants dropped out of the study for the medication issue.  In the 
current study, we are implementing testing ‘off dopa’ medications at the recommendation of 
the Parkinson Foundation.   
 
 
6.6.1  Executive Measures   [NIH Examiner, Stroop] 
The executive measures include the NIH Examiner, a computerized battery consisting of 9 
individuals subtasks described below, and a measures of cognitive inhibition (Stroop task).  
During post-intervention, an executive measure given as part of screening (Trail Making Test) 
will be repeated.   
 
6.6.1a Description of the NIH Examiner:  The National Institutes of Health Executive abilities: 
Methods for Neurobehavioral Evaluation and Research (Kramer et al., 2012). The NIH Examiner is a 
computer based battery that involves nine tasks of frontal-executive function and takes around 45 
minutes to complete.  Funding for development of the NIH Examiner was provided by NINDS in 2005 to 
develop sensitive, domain-specific tasks of fronto-executive function. The NIH Examiner consists of 9 
individual tasks that can be combined into three domain specific scores: Cognitive Control, Working 
Memory, and Fluency.  An overall Executive Composite score can also be computed (Kramer et al., 2014).   
In the current study, the dependent variable for the primary aim will be the “executive composite” 

score calculated from the tasks within the NIH Examiner. Described below are each of the 9 tasks of the 
battery.    
1. Dot Counting (working memory): Participants look at a mixed array of green circles, blue circles, 
and blue squares. They are asked to count all of the blue circles and remember the final total, 
before counting the blue circles on new displays. The number of new displays increases from two 
to seven over a total of six experimental trials. The dependent variable is total correct score over 
trials 1-6, which contributes to the Executive Composite and the Working Memory factor scores.  
2. N-back (working memory): Participants view a series of white squares that appear in different 
locations on a black screen. In the 1-back trials, participants are required to remember the location 
of squares and compare the location of each new square to the previous square. In the 2- back 
trails, participants are required to compare each new square location to the location of the square 
two trials before. The 2-back will only be administered if sufficient performance is reached on the 
1-back (computerized adaptive testing). The 1-back consists of 30 trials total while the 2-back 
consists of 90 trials. Discriminability (d-prime) is calculated as the difference between the z-
transforms of the hit rate and the false positive rate. The dependent variables are the 1-back and 2-
back d-prime scores and contribute to the Working Memory factor score and the Executive 
Composite.  
3. Flanker (inhibition): In this task, participants view a row of five arrows presented at the center of 
the screen and then indicate the direction of the center arrow using the arrow keyboard keys. In 
some sets of trials, all arrows point in the same direction (congruent); in other sets of trials, the 
center arrow points in the opposite direction of the rest of the arrows (incongruent). Reaction 
times are typically longer on the incongruent trials. A total of 48 trials are administered. Total 
accuracy score and reaction time scores on the incongruent trials are calculated and added 
together to create the total flanker score. The dependent variable is the total flanker score, which 
contributes to the Executive Composite and the Cognitive Control factor score.  
4. Continuous Performance Test (inhibition): Participants are asked to press a button when they see a 
five-pointed start, and not respond when they see any other shape. A total of 100 trials are 
presented, 80% consisting of the five-pointed star. The dependent variable is the total number of 
false alarm errors made on the stimuli. This variable contributes to Executive Composite and 
Cognitive Control factor scores.  
5. Anti-saccades (inhibition): In this task, participants are asked to watch a moving dot on the 
computer screen and move their eyes upon presentation of a laterally presented stimulus. Some 
trials involve moving eyes in the direction of the presented stimulus (prosaccade, 10 trials), and 
some involve moving eyes in the opposite direction (anti-saccade, 40 trials). The dependent 
variable is the total number of correct anti-saccade trials, which contributes to the Executive 
Composite and Cognitive Control factor scores. 
6. Set Shifting (set-shifting): Participants are required to match a stimulus on the top of the screen to 
one of two stimuli located in the lower corners of the screen. Stimuli are matched either based on 
color or shape depending on the cue. There are three tasks: Task A involves matching stimuli based 
on shape (homogenous; 20 trials), Task B involves matching stimuli based on color (homogenous; 
20 trials), and Task C alternates between matching stimuli based on shape and color 
(heterogeneous; 64 trials; 32 shape, 32 color). Both reaction time score and accuracy scores are 
calculated across all blocks. These two scores are summed to create the dependent variable, a total 
set shifting score. This total set shifting score is used to calculate the Executive Composite and the 
Cognitive Control factor scores.  
7. Phonemic Fluency (fluency): In this task, participants are asked to generate as many words that 
begin with a particular letter of the alphabet. The task is timed for one minute and participants are 
given two different letters (F and L) for which they must generate words. The dependent variables 
are the total number of correct words generated on F and L trials, which contribute to the 
Executive Composite and Fluency Factor scores.  
8. Category Fluency (fluency): This task is similar to “phonemic fluency”. However, participants are 

asked to generate as many words possible that belong to a particular category. This task is timed 
for one minute and participants are given two categories (animals and vegetables) for which they 
must name items. The dependent variables are the total number of correct words generated on 
animal and vegetable trials, which contribute to the Executive Composite and Fluency Factor 
scores.  
9. Unstructured Task (planning): In this task, participants are presented with three booklets, each 
containing five pages of puzzles. Puzzles are cognitively simple but may take anywhere from 4 to 60 
seconds to complete, and are associated with a specific point value. Participants are given six 
minutes to complete puzzles and are required to use judgment and planning skills in order to earn 
as many points as possible. The dependent variable is the total number of points earned during the 
6 minutes. The score on this task is not factored in to the Executive Composite or the factor scores.  
  
6.6.1b. Description of the Stroop (Golden version).   This version of the Stroop is a 
standard task given as part of the typical neuropsychological exam and is pre-approved by the 
IRB.  It involves 3 parts:  Word Reading, Color Naming, and Color-Word Interference.  During 
Word Reading, a participant reads the words (red, blue, green) typed in black ink on a white 
page, vertically.  Final trial score is total number of words read in 45”.  During Color Naming, the 
participant rapidly names the color patches (red, green, blue) that are arrayed on a card.  Final 
trial score is total number of patches accurately identified in 45”.  During the Color-Word 
Interference condition, a word (i.e., Red) is printed in color ink that differs in meaning from the 
meaning of the written word.  The participant’s task is to name the ink color of the word, and 
inhibit reading the word.  Final trial score is total number of items identified over 45”.  The 
dependent variable is the cognitive inhibition score, which is based on the Color-Word 
interference score, taking into account performance on the 2 baseline trials.   
6.6.2 Recent Memory Tasks [AVLT, Arena Task, MST] 
The recent memory measures include a verbal word list learning task (AVLT), a spatial 
navigation and learning measure (ARENA), and an object recognition memory task (MST).  
During post-intervention, the memory measure given as part of screening (Logical Memory 
Stories) will be repeated. 
 
6.6.2a.  Description of the Auditory Verbal Learning Test (AVLT):  The AVTL is a word list 
learning task that assesses learning, proactive interference, along with retention and 
recognition over 30 minute delays (Rey, 1964; Schmidt, 1996).  It is   widely used in clinical 
settings and is similar to other word list learning tasks, except that the individual items are not 
semantically related to each other. Thus, participants must impose their own unique strategies 
in order to optimize learning. The AVLT consists of two 15 item lists, with List A given over 5 
trials, followed by one presentation of List B, with subsequent immediate recall of List B, then 
List A.  Later 30 minute recall and recognition of List A are obtained.  The primary dependent 
variables for this task are overall learning, the degree of proactive interference, and delayed 
recall after 30 minutes.    
 
 6.6.2b. Description of Computerized Arena Task (Laurance et al., 2012): This is a task of 
spatial memory and navigation that has been linked to hippocampal function and is a human 
analogue to the Morris water maze used in animal studies. At UF, this task has been used in 
other IRB-approved studies with older adults (the VITAL study), those with Essential tremor, 
those with mild cognitive impairment and Alzheimer’s disease.  
 
 The task is given on a computer and participants are trained in the use of a joystick or direction 
pad before beginning the task.  Participants must navigate in a virtual, 3-D room displayed on a 
computer screen.  They must start from different positions to find an invisible target on the 

floor as quickly and efficiently as possible.  Shown below are sample walls of the virtual room.  
The overall goal is to find a ‘hidden target’ on the floor of the arena. 
 
The participant uses either a 
direction pad or joystick to 
navigate this “arena”.    
Navigation is constrained to a 
circular “arena” designed to 
look like a pool of water (the 
blue on the pictures above). 
The arena is bordered by a low 
wall and is in its entirety 
located in a perfectly square 
room, with each of the four 
walls of the room differentiated from the others by 1-2 unique, fractal-based patterns 
 
Practice and Visible Target Trials. The task begins by providing a participant with a 5-10 minute 
orientation session, in which they   practice using the joystick or direction pad and then 
navigate to visible targets within the environment.  In the figure to 
right the white elliptical circle represents the target.  Performance 
on up to 5 visible-target navigation trials ends the practice session 
and the recorded path length and time to acquire the target will 
serve as a sensorimotor baseline against which invisible target trials will be evaluated. 
 
Hidden target condition.  After subjects have learned the task, they will participate in 8 
invisible-target acquisition trials.  In these trials the target is not visible from afar and is 
discoverable only when the joystick or direct pad icon is hovered over the target.  A trial begins 
with a fixed tour of a new room, where each wall is shown for approximately 2 seconds during 
two sweeps of the room.  Participants are instructed that the hidden target will be in the same 
place on each trial and that their task is to find it as soon as possible.  Participants are typically 
given 120 seconds to find the target.  During the first 2 trials, the examiner takes over after 120 
seconds and assists the participant finding the target.  No assistance is given after the initial two 
trials.   If the target has not been located after 120 seconds in the later trials, the trial ends and 
a 10-second inter-trial interval (ITI) ensues, and the next trial begins.  If the subject acquires the 
target on any trial, it becomes visible and a pleasant auditory signal additionally alerts them to 
target acquisition.  They are allowed to stay on the acquired target for 15 seconds and are 
encouraged to rotate-in-place to survey the environment.  After this, the 10-second ITI ensues 
and the next trial begins at a different compass point.     A final spatial memory probe occurs 
following the 8th trial.   On this final trial, the invisible target is removed unbeknownst to the 
participant.  This means that target acquisition is not possible, but search behavior is evaluated 
with regard to the percent of the 120-second trial that is spent in the quadrant containing the 
target.  On each acquisition trial, path length, time to acquire the target, and target acquisition 
(yes-no) are recorded.  On the probe trial, path length and percent of time spent in each 
quadrant of the Arena is recorded.  A composite score, consisting of mean z-scores on path 
length, time to acquire target, and percent of time spent in the proximal quadrant on the probe 
trial, will also be calculated.  The dependent variable will be this navigational performance 
composite.  
 

6.6.2c. Description of the Mnemonic Similarity Test (MST; Starke et al., 2013, 2015, 
2017):  This task is sensitive to hippocampal dysfunction and the effects of normal aging. It 
relies on process of pattern separation, the process of grouping similar inputs into distinct 
memory representations. The MST measures recognition memory performance for objects 
using traditional targets, novel foils, and other items (“lures”)  that are perceptually and 
semantically related to the targets.  During the learning/encoding phase, participants are 
shown a series of designs/objects.  This is followed by a recognition task in which the items are 
true replications (hits), novel items (foils), or are similar but not identical to the hits (i.e., lures).  
The task is completed on a computer and takes about 15 minutes 
 
6.6.3. Processing Speed  
Processing speed, a potential contributor or mediator of both memory and executive function, 
will be assessed using reaction time subtests from the California Computerized Assessment 
Package  (CALCAP-RT; Miller, 2013). 
 
The CAPCAP is a comprehensive tool for assessing reaction time, speed of information 
processing, rapid visual scanning, form discrimination, brief memory and divided attention.  We 
plan on administering the abbreviated version, which consists of 4 subtests that take 
approximately 8-10 minutes.  All tasks are given on a computer.  The 4 subtests are described 
below. 
 
• 
Simple Reaction Time. Subjects are asked to press a key as soon as they see anything at all on 
the screen. This procedure provides a basal measure of reaction time. 
• 
Choice Reaction Time for Single Digits. Subjects are asked to press a key as soon as they see a 
specific number such as '7', otherwise they are to do nothing. This procedure adds a simple 
element of memory to the task. 
• 
Serial Pattern Matching 1 (Sequential Reaction Time 1). Subjects are asked to press a key only 
when they see two of the same number in sequence, for example, if they see the number '3' 
followed by a second occurrence of the number '3'. This procedure adds a more complex 
element of memory since the subject must keep in mind the last number that was seen.  
• 
Serial Pattern Matching 2 (Sequential Reaction Time 2). Subjects are asked to press a key only 
when they see two numbers in sequence (increasing order). For example, if they see the number 
'3' followed by the number '4', the number '6' followed by '7' and so on. 
 
6.6.4   Mood Measures   [Emotion module of NIH Toolbox, STAI, POMS, BDI-II, AS] 
 
6.6.4a. Description of NIH Toolbox Emotion Module (Salsman et al., 2013).  The NIH 
Toolbox for the Assessment of Neurological and Behavioral Function (www.nihtoolbox.org) is a 
standardized set of Web-based measures developed through a contract initiated by the NIH 
Blueprint for Neuroscience Research (Gershon et al., 2013). It contains four modules: Motor, 
Sensation, Cognition, and Emotion.   
 
This study will use the Emotion module.  It is a 12 to 22 minute computer administered, self-
report measure of emotional health and psychological function.  It surveys positive and 
negative emotions such as joy, sorrow, fear, etc..  Questions consist of likert-type items that are 
rated by a participant.  The module consists of 4 scales: Psychological Well Being, Negative 
Affect, Social Relationships, and Stress& Self Efficacy.  Each is described below.  The dependent 
variable is the T score from each measure.  The first two scales are the co-primary outcomes 
and the latter are the secondary outcomes:   
 
1. 
Psychological wellbeing (co-primary outcome).  Subscales making up this domain include: general 
life satisfaction, meaning and purpose, and positive affect. Participants rate statements such as “I 

am satisfied with my life”, “I value my activities”, and “there is not enough purpose in my life”. 
There are a total of 76 items on the Psychological Wellbeing scale.  
2. 
Negative affect (co-primary outcome; subscales making up this domain include anger, fear, and 
sadness). Participants rate statements such as “I feel worthless” and “I felt envious of others”. A 
total of 89 items are given on the Negative Affect scale.  
3. 
Social Relationships (exploratory outcome, subscales making up this domain include social 
support, companions, social distress, and positive social development), Participants rate 
statements such as “people in my life act as if they don’t care about me” and “people don’t listen 
when I ask for help”. A total of 26 items will be given on the Social Relationships scale.  
4. 
Stress and Self-efficacy (exploratory outcome; subscales making up this domain include: perceived 
stress and self-efficacy). Participants rate statements and questions such as “I can handle 
whatever comes my way” and “how often in the past month did you feel nervous and ‘stressed’”. 
A total of 20 items will be given on the Stress and Self-efficacy domain.  
6.6.4b. Description of State Trait Anxiety Inventory  (STAI;  Spielberger,1983a; 1983b; 
1989).  The STAI is a 40-item questionnaire that is used to assess current (state) and general 
(trait) levels of anxiety. Higher scores represent higher levels of anxiety, or feelings of worry, 
tensions, and stress. Items on the questionnaire include ratings of statements such as “I feel 
calm”, “I am jittery”, and “I feel nervous”. The STAI has been used extensively in clinical and 
research settings and displays a test-retest reliability of 0.31 to 0.86 and internal consistency 
alpha coefficients of 0.86 to 0.95 (Spielberger et al., 1983a). Further, this measure shows high 
convergent validity with other measures of anxiety (0.72 to 0.86; Spielberger et al. 1989).  
6.6.4c. Description of Profile of Mood States, short form (POMS, Curran et al., 1995).  
This is a 30 item self- report questionnaire of mood states such as “discouraged”, “grouchy”, 
“vigorous”, and “efficient”. The short form version of the POMS is easy to administer, and yields 
information about transient current mood states. The measure is grouped into subscales 
including tension, depression, anger, fatigue, and vigor. Test-retest reliability ranges from 0.65 
to 0.74, internal consistency is 0.93, and the test also features high degrees of construct validity 
(Curran et al., 1995).  
 
6.6.4d. Description of Beck Depression Inventory-II  (BDI-II; Beck et al., 1996).  This is a 21 
item self-report questionnaire of symptoms of depression such as sadness, self-criticalness, loss 
of interest, or somatic changes such as insomnia or increased sleep, increased or decreased 
appetite, and low energy.  This questionnaire allows one to characterize levels of depression as 
mild, moderate, or severe, depending on the total score. The BDI-II has strong convergent 
validity, internal consistency (α=.91) and test-retest reliability (r=.93) and has been used 
extensively in clinical and psychological research. 
 
6.6.4f.  Description of Apathy Scale  (AS, Marin et al., 1991). This is a 14 item self-report 
questionnaire that assesses for symptoms of motivation, drive, and initiative.  Participants 
answer questions on a 5 point likert scale ranging from 0 to 4.  The AS has been subgrouped 
into components reflecting cognitive, affective, and behavioral components of apathy.  Test-
retest reliability is strong, and the AS has strong convergent validity with real world indicators 
of behavior (Ferencz et al., 2012).   
 
6.6.5  Other Measures 
 
6.6.5a. Placebo Control Questionnaire (PCQ): This is a 4-item questionnaire that is given 
after the end of the 2-week intervention. It asks questions regarding which group (real, sham) 
the participant believes they were assigned.      
 

6.6.5b. Adverse Events Log (AE). This is a standard open ended questionnaire regarding   
symptoms or adverse events that the participant has experienced since beginning the 
intervention.  This will be assessed at the end of each intervention session and will prompt for 
symptoms the participant may have experienced during the session and/or since the previous 
intervention session.  It queries for severity, how long the symptoms last, and whether (if 
known) the symptom might be related to the intervention.   This will also be assessed during 
the followup session. 
 
6.6.5c. Fitzpatrick Skin-Type Questionnaire (Fitzpatrick, 1986): This is a 10 item self-report 
form where participants indicate hair, eye, and skin color, as well as rate burning and tanning to 
sun exposure.  This information is being obtained because skin and hair pigmentation may 
impact the penetrance of infrared light through the skin and scalp.  This scale is often used in 
dermatology and will be used to as a covariate in statistical analyses.    
 
6.6.5d.   Cognitive Change Index (CCI)   On this 20 item questionnaire, participants rate 
changes in their own thinking and memory.  They use a 5 point Likert scale that goes from 1 (no 
problem/normal ability) to 5 (much worse/severe problem).  Domains that are covered include 
multi-tasking, learning new things, recalling old memories, thinking quickly, retrieving names, 
etc.  This questionnaire will be given before and after the intervention to assess perceived 
changes.  
 
6.6.5e.  Expectancy Questionnaire:  This measure is given prior to the intervention and 
asks participants to rate their expectations about changes they anticipate will change as a result 
of the intervention. 
 
6.6.5f.  Followup Questionnaire:  This measure is given after the intervention.  It asks 
participants to rate the extent that they experienced changes in particular cognitive and 
functional domains 
 
6.6.5g. Pittsburgh Sleep Quality Index:  This is well-known and well-validated sleep scale 
for detecting insomnia and sleep quality. It will be given before and after the intervention. 
 
6.6.5h.  Fatigue Severity Scale (FSS):   This is standard self-report questionnaire that 
measures degree of fatigue that an individual experiences.  It will be given before and after the 
intervention. 
 
6.6.5i.  Pain Rating Scale.  This is analogue rating scale where participants rates the current 
severity of any ongoing pain.  
 
 
6.6.6  Motor Measures  (UPDRS, Grooved Pegboard, Walking-Balance & GaitRite) 
Individuals with Parkinson disease will receive additional motor measures before and after NIR 
intervention.  These include the Unified Parkinson Disease Rating Scale for rating disease 
severity, a task of manual fine motor speed and dexterity (Grooved Pegboard Task) and walking 
speed and balance that is measured using a Gait Rite mat which has digital sensors that records 
speed and foot placement and other motor measures. 
 
6.7 Near-infrared (NIR) Stimulation Protocol  
 
Overview:  Participants in both the real and sham conditions will participate in a total of six 
intervention sessions, 3 sessions a week, over a two-week period.  Each session will include 40 

minutes of “stimulation” time, followed by completion of a brief adverse events questionnaire 
and a brief mood questionnaire (POMS).   Total session time in the lab may take up to 1.5 
hours.  During each session, the participant will be seated comfortably in a chair. Clusters of 
LED’s will be positioned across various regions of the scalp via a flexible head cap. Onset of the 
NIR light stimulation will be controlled by a MedX Console unit.  During the 40 minutes of NIR 
stimulation or sham stimulation, the participants will view nature documentaries (BBC Life 
documentary series; Gunton, 2009) that are presented during the period of stimulation. This is 
being done in order to standardize cognitive engagement and control for differences in 
cognitive activity during stimulation.    
In addition to stimulation in the laboratory, participants may be asked to do daily intranasal 
stimulation in their home.  They will be provided Vielight intranasal devices (described below) 
and asked to stimulate themselves for 25 minute sessions  on the days they do not come to the 
lab (i.e., 2 days during week 1 and 2 days during week 2).   
6.7.1  Equipment: MedX Rehab Console System. 
Near infrared (NIR) stimulation will be delivered to the cranium via two  MedX 1116 Rehab 
Console Systems (MedX Health, LLC, 
Mississauga, ON, Canada).    See Figure 
2.   The MedX system was FDA-cleared in 
2003 as a Class II medical device 
(K032231, 21 CFR 890.5500) and has 
been freely available on the market 
since that time.  It is not viewed as 
causing harm or injury, and  falls under 
the category of an infrared lamp with 
indicated use for “increase in local blood 
circulation” as well as muscle relaxation 
and relief of muscle and joint aches, 
pains, and stiffness.  It has been used in 
transcranial studies of cognition and mood in humans since 2009, without any known adverse 
side effects (See review by Rojas & Gonzalez-Lima, 2013).   
 
 Each MedX console consists of a control unit and 3 superluminous diodes - a cluster of LED’s  (3 
MedX MCT502).  Each superlumious LED cluster consists of 52 near infrared diodes and 9 visible 
red diodes (see Figure 2).  The energy delivered by the device is 1 Joule/cm2 in 45 seconds at 
treatment wavelength of 870 nm. The LED cluster has an irradiance of 22.2 mW/cm2 and treats 
an area of 22.48 cm2.   
 
In 2013, we were awarded monies from a shared instrumentation grant from the McKnight 
Brain Institute for purchase of two MedX console systems (each approximately $5000).  Since 
then we have acquired additional units, including two units  that are ‘sham’.  

 
Vielight 810 Infrared Light will be delivered intranasally 
using a Vielight 810 Infrared system (Vielight, Inc., 
Toronto, ON, Canada).  The Vielight 810 Infrared 
System uses light that is considered safe and painless, 
and does not require FDA clearance (considered a low-
risk device). The Vielight 810 consists of an infrared 
diode that delivers light at a wavelength of 810 nm, 
with an irradiance of 7.6 mW/cm2 and a pulse 
frequency of 10 Hz.    
 
6.7.2   Duration of Treatment, Dosage Parameters, 
and Placement of LED Clusters   
The intervention protocol will span 2 weeks and will include laboratory (six sessions) that 
involves transcranial plus intranasal stimulation and an optional four  ‘at home’  sessions 
involving intranasal stimulation (.  For Parkinson patients, we may add  up to four at home 
sessions with intranasal stimulation (25 minutes/session).  Both the duration of treatment (6 
sessions over two weeks) and the dosage of stimulation were originally adapted from prior 
investigations in TBI patients  (Naeser et al., 2014), young adults (Barrett & Gonzalez-Lima, 
2013), and individuals with Alzheimer’s disease (Saltmarche et al., 2017),  showing that NIR 
stimulation was safe, well tolerated and had no side effects.  In our pilot work using the 
laboratory based protocol with older adults, we found positive effect sizes with this dosing for 
memory and executive function, along with increased ATP and neural connectivity.  In a parallel 
IRB study with older adults we have increased the duration of treatment to 8 weeks, based on 
recent findings by Saltemarche et al. (2017) with Alzheimer’s patients.  However, we continue 
to keep the current protocol brief as it is designed to determine potential effect sizes and 
feasibility.      
Placement of Clusters and Dosage.  During each laboratory session, actual stimulation via the 
LED clusters will occur for a total of 40 
minutes.  Six LED clusters will be applied in 
2 distinct configurations.  There will be 20 
minutes of stimulation at each of these 
configurations.   Each configuration will 
target 8 sites (6 cranial + 2 intranasal), for a 
total of 16 sites over the course of the 40 
minute session.   Placement of LED clusters 
on the scalp follows the recommendations 
of Naeser (personal communication, 2014, 
2015, and 2016).   See Figure 3 for site placement.   
 
The power density used will be 500 mW with a cumulative fluence (energy density) of 336 
J/cm2 (26 J/cm2 applied at 12 cranial sites + 12 J/cm2 at 2 nasal sites).  It is estimated that 
approximately 6 J/cm2 will reach the cortex with each daily treatment. At this energy level, the 
MedX MCT502 accessory does not cause tissue damage or physical damage and emits negligible 
heat.  There is no nominal ocular hazard distance (NOHD) for the LED accessory, as LEDs do not 
pose a serious risk to vision.  
 
Parameters for stimulation such as energy density and length of application were adapted from 
Figure 3:  Placement of LED Clusters in 2 
Configurations  

parameters used in Naeser et al., 2014 as well as personal correspondence in September 2015.  
In 2013, Naeser and colleagues demonstrated that an energy density of 13.3 J/cm2 resulted in 
changes in resting state- connectivity, whereas an energy density of 2 J/cm2 did not. Current 
studies conducted by the Naeser group involve an energy density of 26 J/cm2. 
6.7.3   Stimulation Session Procedure 
 
In Lab Sessions:  All participants will attend six NIR stimulation sessions.  During each session, 
the participant will be seated comfortably in a chair.  Clusters of LED’s will be positioned across 
various regions of the scalp via a flexible nylon head cap that is appropriate to the participants 
head size.  Onset of the NIR light stimulation will be controlled by the MEDX Console.  Twenty 
minutes of stimulation will occur during each Set, for a total of 40 minutes NIR light application, 
with LEDs repositioned to a new position for each set.  During the session, the 810 nm 
intranasal Vielight will be placed in each nostril and turned on once per session for 25 minutes 
(one dose) and subsequently removed. 
 
During the actual stimulation period, participants will view nature documentaries (BBC Life 
documentary series; Gunton, 2009) that are shown on a monitor during the duration of 
stimulation.  This is being done in order to standardize cognitive engagement and control for 
differences in cognitive activity during stimulation.  This will also be done to reduce 
conversation between the examiners and the participant during the period of stimulation, 
which could differ between participants.  Six episodes of the BBC Documentary will be 
presented in the same order for each participant, with a different episode played at each 
stimulation session. A brief description of each episode is provided below: 
1. “Challenges of Life”: This episode is the series opener and features stories of animal 
behavior such as feeding, hunting, and courting from around the world. Animals 
featured include killer whales, poison-dart frogs, and penguins. 
2. “Mammals”: This episode features the life of mammals from around the globe.  Stories 
feature animals such as reindeer, polar bears, African elephants, and humpback whales.   
3. “Birds”: This episode features stories of birds from across the globe.  Nesting, parenting, 
and migratory behaviors are described from animals such as humming birds, pelicans, 
grouses, and bowerbirds. 
4. “Creatures of the Deep”: This episode features an exploration of life in the deep ocean.  
Deep-sea creatures such as jellyfish, spider crabs, sea urchins, octopus, and coral reefs 
are described. 
5. “Plants”: This episode utilized time-lapse photography and videography to explore the 
behavior of plants.  Featured plants include Venus flytraps, sundews, milkweeds, 
dragons blood trees and mangrove trees. 
6. “Primates”: This episode features stories of primates and the attributes that have made 
them a highly successful group of mammals.  Animals featured include lemurs, gibbons, 
orangutans, and macaques. 
 
Other episodes include “Reptiles and Amphibians”, “Fish”, “Insects”, and “Hunters and 
Hunted”.  These videos may be played if there is reason to need an extra video. 
 
At Home Intranasal Sessions (optional).  Each participant will be loaned an intranasal device, 
that is identical to the one used during the laboratory session. Participants will be asked to use 
the intransal device for 25 minutes each day, except for days they visit the laboratory.  The 
participants are trained to use the device during the initial lab visit and shown that the device 

automatically cuts off after 25 minutes.  Participants will be asked  to keep a log of usage and to 
return the device at the completion of the study. 
  
Equipment Sterilization 
Following each session, the 6 MedX LED clusters and 2 Vielight intranasal leads will be sterilized 
with disinfectant wipes (PDI Super Sani-Cloth Germicidal Disposable Wipes) before storage.   
The manufacturer’s recommendations are to clean equipment with sterilizing swabs in between 
sessions.  In addition, a new flexible net caps will be used for each participant. 
 
Questionnaires: Following the 40-minute stimulation period all participants will fill out 
the POMS short form and will be queried for adverse events (using the Adverse Events log).  
Completion of these questionnaires will take place at the end of each session.    
 
 
6.7.4  SHAM NIR Condition and Blinding 
Participants in the sham control group will undergo identical procedures as the intervention 
group  -  screening, baseline testing, and LED cluster placement procedures.  We have sham 
devices that look similar in all respects to the active devices, both transcranial and infranasal.  
The sham and active devices are coded and only one of the Investigators knows the code.   The 
research assistant administering the stimulation sessions will not be aware of the participant’s 
treatment status, and  will have no role in post-intervention assessments.  The research 
assistant administering post-intervention testing will be blinded to the treatment status of the 
participant. 
 
6.8. Optional Research MRI:  Exploratory Aim 
A subset of participants, from the Real and Sham Intervention groups will participate in 
collection of neuroimaging data, obtained before and after the intervention.  This is an 
exploratory aim and designed to obtain pilot data.  This portion of the study will be coordinated 
by Dr. Woods, an expert in multimodal imaging with older adults. We plan to obtain: 
• structural MRI 
• resting state fMRI.  This will allow us to examine intervention changes in functional 
connectivity. 
• Blood flow.   This will allow us to examine changes in brain perfusion 
• 
spectroscopy data using a newly acquired  MRI/S head coil.  The latter will allow us to 
assess for region-specific changes in phosphorous MRS-based markers of ATP function, 
one of the presumed mechanisms of NIR stimulation.   
After giving informed consent and undergoing the appropriate prescreening measures, eligible 
participants will receive  pre-intervention  and post-intervention brain scans at the McKnight 
Brain Institute on the AMRIS 3T Philips scanner utilizing a dual tuned 31P-1H MRS coil. 
Structural MRI scans are also acquired as part of this scanning protocol.  Inside the brain 
scanner, participants will like on a padded table with foam pads used to hold the participants 
head in place. During this portion of the study, participants will be asked to lie as still as 
possible.  There will be no specific task or behavior that the participant must engage in.  We 
anticipate that this protocol will take 1 hour.  Specifics are shown below. 
 

 
Neuroimaging Methods. We will conduct neuroimaging on a 3.0 Tesla Philips research 
dedicated scanners with a research agreement supporting all scanner sequences. We will use a 
Rapid MR International dual tuned 31P-1H MRI/S head coil for data acquisition. 
 
MRI protocol. The scanning sequences will take 1.5 hour to acquire: 1) Structural MRI 
(MPRAGE), 2) Phosphorous MR Spectroscopy (31P-MRS) and 3) FMRI (EPI-BOLD).  
 
 
Structural MRI. Whole brain axial gradient-echo MPRAGE T1-weighted images will be 
acquired for 31P and FMRI localization (TE/TR 3.57/2730ms, flip angle = 7 degrees, slice 
thickness=1mm, Gap=0 (contiguous slices), FOV=25.6cm, 256×256 matrix size & 2.0×2.0mm 
resolution; 5 minutes duration).  2D/3D FLAIR imaging will be acquired, time allowing within the 
1.5 hour scan, to assess white matter hyper-intensity load (~6 minutes duration). High 
resolution hippocampal imaging will be performed, time allowing within the 1.5  hour scan, to 
allow localization of functional connectivity analysis seeds in the hippocampus and frontal 
regions  and assessment of possible structural improvements related to intervention (~5 
minutes duration).  3D PASL sequence (TE/TR=10.5/4885ms, PLDelay=2000ms, 1.9x1.9x4mm 
resolution,  FOV = 240 x 240 x 160mm) will enable quantification of changes in cerebral 
perfusion related to intervention. Data will be analyzed using AFNI to compute regional and 
whole brain estimates of resting cerebral perfusion pre and post intervention.    
 Phosphorous MRS. A 31P-MRS pulse-acquired sequence will be acquired from two 6-
cm3 voxels centered in prefrontal cortex and temporal cortex to assess region-specific change in 
phosphorous MRS-based markers of ATP function and brain health. Parameters: TE 0.1ms; TR 
4500ms; Spectral resolution 2.4 Hz/point; Spectral bandwidth 3000 Hz; 7 minutes duration). 
Analyses: Spectra will be analyzed using Tarquin to give concentrations for the following 
phosphorous metabolites: nucleoside di- and tri-phosphate (gamma, alpha, beta-NTP), 
phosphoethanolamine (PEtn), phosphocholine (PCho), glycerophosphoethanolamine (GPEtn), 
glycerophosphocholine (GPCho), 2,3 diphospho-glyceride (DPG), inorganic-phosphate (Pi), 
membrane-bound phospholipid (MP), and phosphocreatine (PCr). The signal amplitudes of 
brain tissue and CSF will be derived (corrected for T2 decay), with brain water signal used to 
correct for partial CSF volume. MRS Quality Assurance: The concentration measures for the 
metabolites will be accepted with Cramer-Rao lower bounds (%SD) of less than 20%, a reliable 
estimate for a particular metabolite for group comparisons. Scans resulting in spectra that do 
not meet quality criteria will be repeated. Line width and signal-to-noise resonance ratios are 
plotted over time (brain, phantom) to monitor spectral quality; inter- and intra-subject 
variability assessed by correlation and Bland and Altman plots.  
 
 
fMRI. We will perform an fMRI resting state block using echoplanar BOLD imaging (EPI) 
methods, with a TR of 2500ms, TE 16ms, field of view = 1922mm, matrix = 642 and voxel size of 
3.5mm3. FMRI processing and analyses will use Statistical Parametric Mapping 12 (SPM12). We will 
present one ten minute block of resting state FMRI before and after intervention to provide 
insight into stimulation related change in functional networks. We will construct time series 
datasets implementing preprocessing methods to minimize physiological and motion artifact, with 
each volume assigned a condition based on task sequence. Whole-brain voxel-wise multiple 
regression analysis will verify activation patterns in resting state networks. Appropriate covariates, 
such as movement, for each participant’s brain voxels will be included using the variation in BOLD 
signal over time. The REST toolbox and local specialized software will be used to obtain total 
interdependence (TI) values to assess functional connectivity between nodes in the resting state 
network, with particular focus on change in hippocampal connectivity. Primary dependent measures 

will TI between each resting state ROI’s per participant (FWE threshold p<.05). TI values will compare 
intervention-related changes in functional connectivity.  
 
 
Shown below is an overview of the temporal overview of the procedures.    
 
Table 2: Overview of Procedures and Protocol 
 
Measures 
Pre-
sceen 
Screening 
Base-
line   
Pre-
MRI* Intervention 
Follow-
up 
Post-
MRI* 
Telephone Screening 
X 
X 
  
  
  
  
  
Inclusion / Exclusion 
  
X 
  
  
  
  
  
Informed Consent 
  
X 
  
  
  
  
  
Demographic Info 
  
X 
  
  
  
  
  
Medical History  
 
X 
 
 
 
 
 
MoCA or DRS-2 
  
X 
  
  
  
  
  
HVLT-R or WMS-III LM 
  
X 
  
  
  
X  
  
Mental Health Screen 
V.3 
  
X 
  
  
  
  
  
Charleson 
  
X 
  
  
  
  
  
Medications 
  
X 
  
  
  
  
  
WTAR or WRAT-IV 
  
X 
  
  
  
  
  
Vision Screen 
  
X 
  
  
  
  
  
Digit Span (WIT) 
 
X 
 
 
 
 
 
TrailMaking Test 
 
  
X 
 
 
X 
 
Wisconsin Card Sort 
 
 
x 
 
 
x 
 
Digit Symbol (WIT) 
 
 
X 
 
 
X 
 
Category Fluency 
 
X 
  
 
 
 
 
JLO  
 
X 
 
 
 
 
 
Functional Activity 
Questionnaire (FAQ) 
 
X 
 
 
 
 
 
Cognitive Function 
Inventory  (CFI) 
 
X 
 
 
 
x   
 
Cognitive Function 
Inventory –Study 
Partner  (not PD) 
 
X 
 
 
 
  
 
Clinical Dementia 
Rating Scale  -Study 
Partner (MCI group 
only) 
 
X 
 
 
 
 
 
Demographic Info -
Study Partner (Not PD) 
 
X 
 
 
 
 
 
MRI Screener** 
  
X* 
  
X* 
  
  
X* 
Cognitive Change Index 
(CCI) 
 
 
X 
 
 
X 
 

Skintype Questionnaire 
  
  
X 
  
  
  
  
Arena Task 
  
  
X 
  
  
X 
  
AVTL 
  
  
X 
  
  
X 
  
MST 
 
 
X 
 
 
X 
 
NIH Examiner 
  
  
X 
  
  
X 
  
Stroop 
  
  
X 
  
  
X 
  
CalCap (processing 
speed) 
 
 
X 
 
 
X 
 
UPDRS (PD only) 
 
 
X 
 
 
X 
 
Grooved Pegboard (PD 
only) 
 
 
X 
 
 
X 
 
Walking-Balance (PD 
only) 
 
 
X 
 
 
X 
 
BDI-II 
  
  
X 
  
  
X 
  
STAI 
  
  
X 
  
  
X 
  
Apathy Scale 
 
 
X 
 
 
X 
 
NIH Toolbox Emotion 
  
  
X 
  
  
X 
  
POMS 
  
  
X 
  
X 
X 
  
Fatigue Severity Scale 
 
 
X 
 
 
X 
 
Pittsburgh Sleep 
Quality Index 
 
 
X 
 
 
X 
 
Pain Rating Scale 
 
 
X 
 
 
X 
 
Adverse Events Log 
  
  
  
  
X 
X 
  
Expectation Quest 
 
 
X 
 
 
 
 
Placebo Control Quest 
  
  
  
  
  
X 
  
 
*MRI, only a subset of participants will be asked to undergo pre and post-MRI; these will be screened for eligibility 
using a standard MRI screener**. MoCA=Montreal Cognitive Assessment; HVLT-R=Hopkins Verbal Learning Test – 
Revised; WMS-III LM = Wechsler Memory Scale, Logical Memory subtest; Charlson = Charleson Comorbidity Index; 
WTAR=Wechsler Test of Adult Reading; JLO = Judgement of Line Orientation; Skin type Questionnaire =Fitzpatrick 
Skin-Type Questionnaire; AVT=Auditory Verbal Learning Test; MST = Mneumonic Similarity Test; CalCap = 
California Computerized Assessment Package; UPDRS = Unified Parkinson Disease Rating Scale; BDI-II=Beck 
Depression Inventory, 2nd edition; STAI=State Trait Anxiety Inventory; POMS=Profile of Mood States, Short Form;   
PCQ=Placebo Control Questionnaire; ;    Daily journal = completed by participant for recording time of daily 
intranasal treatment.   
 
• Note that individuals with Parkinson disease will receive the Unified Parkinson Disease Rating 
Scale, Grooved Pegboard Test, and Gait Rite analysis before and after intervention.  Other 
participants will not. 
 
7 
Outcome and Statistical Approaches 
 
7.1. Outcome Measures 
Aim 1 examines executive function and memory using sensitive cognitive measures. 
• Co-Primary Executive Outcome:   Changes in pre-post treatment scores on: a) executive 
composite and domain scores derived from the NIH Examiner and b) the Stroop 
interference score.   

 
• Co-Primary Memory Outcomes:  Changes in pre-post treatment scores on memory 
measures including a) delayed recall scores and composite from the Arena and b) 
delayed recall score from the AVLT.  Secondary outcomes include other executive and 
memory measures as well as potential mediator and moderator variables such as 
processing speed. 
 Aim 2 examines well-being and mood variables. 
• Co-Primary outcome:  Changes in pre-post treatment scores on the Negative Affect 
and Psychological Wellbeing scales from the NIH Toolbox emotion module.      
 
• Secondary outcomes:  Changes in pre-post treatment scores on traditional mood 
measures including the 1) State-Trait Anxiety Inventory (STAI; Spielberg, 1989), the 
2) Profile of Mood States (POMS; Curan et al., 1995), 3) Beck Depression Inventory-II 
(BDI-II; Beck et al., 1996), and 4) Apathy Scale.  
 
Aim 3 is an exploratory neuroimaging aim that will examine changes in resting state functional 
connectivity as a function of group status (NIR stimulation vs Control).  We are particularly 
interested in potential changes in MRS spectroscopy, particularly those elements associated 
with phosphorous ATP 
Aim 4 pertains to motor variables that are being examined in patients with Parkinson disease 
• Outcomes include:  Changes in pre-post intervention scores on the Grooved Pegboard 
Task,  scores on the UPDRS rating scale, and gait and balance measures on the GAIT-Rite 
scale. 
7.2.  Randomization and Statistical Methods 
7.2.a. Randomization.  Participants in the Cognitively Normal, the MCI, and Parkinson groups 
will be independently assigned to  Sham and Treatment groups on a 1:1 ratio.  For the 
Cognitively Normal group, we anticipate an N of 35 in each treatment group.  For each MCI 
group, we anticipate an N of 10 per treatment group.  For the PD group, we anticipate an N of 
20 per treatment group.   Randomization will be stratified according to age and MoCA/MMSE 
scores so as to prevent different average ages or cognitive status scores between the treatment 
groups.  Treatment assignment will be pseudorandomized in order to have comparable 
distributions of age and cognitive screening scores across Sham and Treatment interventions.  
Procedures will be followed so that group assignments are not available to individuals 
administering and scoring baseline/pre-intervention and post-intervention cognitive/mood 
data.  
 
7.2.b. Missingness and Intent to Treat.  
All data will be checked for missingness, out-of-range values, and distributional form (i.e., 
normality, homogeneity of variance).  Decisions regarding use of parametric vs. nonparametric 
statistics will be based on the results of those analyses.  Standard summary statistics will be 
provided for pre- and post-stimulation.  Intent to treat analysis will be used to reduce selective 
attrition bias;  participants who are unwilling/unable to continue with intervention will be 
encouraged to attend the post intervention testing, if possible.  Thus, statistical analyses will be  
performed on two data sets: 1) on all subjects who were successfully screened, randomized and 
able to participate in at least 1 week of the assigned intervention, regardless of study 

completion (intention-to-treat analysis); and 2) on subjects who were successfully screened, 
randomized and able to complete at least 80% of the treatment assignment. 
 
7.3.   Statistical Analyses   
Data for each group (Cognitively Normal, MCI, Parkinson) will be analyzed separately.  However 
the same analytic approach will be taken for each, as described below. Some analyses will be 
truncated for the MCI groups due to the smaller sample size. 
 
Aim 1:  Aim1 will test the hypothesis that individuals in the active stimulation group will show 
improved cognitive function compared to the sham group. Separate mixed model ANOVAs (2 
[Group: Active Stimulation, Sham stimulation] x 2 [Occasion: Pre-testing, Post-testing]) will be 
conducted using the executive and Memory outcome variables.  When significant, appropriate 
post-hoc analyses will be conducted.  Additional analytic techniques will involve ‘change score’ 
analyses, as well as analyses examining predictors of changes (i.e., age, education, gender).    
Aim 2: Aim 2 will test the hypothesis that individuals in the active stimulation group will show 
improved emotion/psychological function compared to the sham group. Separate mixed model 
ANOVAs (2 [Group: Active Stimulation, Sham stimulation] x 2 [Occasion: Pre-testing, Post-
testing]) will be conducted using the mood outcome variables (mood modules NIH Toolbox, 
STAI, POMS, BDI-II).   When significant, appropriate post-hoc analyses will be conducted.  
Additional analytic techniques will involve ‘change score’ analyses, as well as analyses 
examining predictors of changes (i.e., age, education, gender).   
Aim 3:  This neuroimaging aim is exploratory and  will test the hypothesis NIR intervention will 
produce pre-post increases in frontal and temporal brain markers of MRS ATP function and pre-
post increases in connectivity in frontal and medial temporal lobe mediated resting state brain 
networks (resting state fMRI).  Although this aim will require extensive data reduction, the 
overall data analytic plan is similar to that of Aims 1 and 2. 
Aim 4:  This is aim is specific to Parkinson disease and will test the hypothesis that active NIR 
stimulation will result in greater pre-post intervention improvement in motor parameters  
(UPDRS, fine motor speed, gait, balance) than sham.  Separate mixed model ANOVA’s will be 
conducted similar to those described in Aims 1 and 2. 
Finally, we plan to examine whether various ‘factors’ might potentially be moderators or 
mediators to intervention success.  WE plan to examine age, education, gender, health 
comorbidities, processing speed and mood. 
8. Methodological Limitations 
Only two previous human studies have conducted sham controlled trials.  Thus, there is a  
potential impact of placebo in producing positive effects on cognition.  The current study 
attempts to control for this.   Another issue pertains to the penetrance of near infrared light 
through the skull.  Most transcranial NIR light applied to the human cranium penetrates 1 cm 
into the tissue, reaching cortical tissue but not white matter or subcortical structures. As a 
result the dosage reaching particular brain structures depends on a variety of factors such as 
cranium thickness, degree of cortical atrophy, penetrance, source of light, and duration of 
treatment/energy density of light.  
9. Study Time Line Schedule of Activities 
The Schedule of Participant Activities for this study is as follows: 
 

• Call #1- Telephone Prescreening to review the study details, and inclusion/exclusions.  
 
• Informed Consent Process and Screening Visit- Informed Consent Process begins with 
the participant per UF, state and federal guidelines.  Once the participant has signed the 
informed consent, complete medical history, inclusion/exclusion criteria, concomitant 
medications, and cognitive and mood questionnaires will be administered (listed in 
section C). If participant formally meets study criteria, then he or she is invited to 
participate in the intervention phase of the student consisting of baseline, NIR 
stimulation, and post-baseline testing. 
 
• Baseline Visit -   This assessment involves a series of computer based measures and 
other questionnaires.  This visit may take approximately 3-3.5 hours.   If participants 
undergo MRI, this will take an additional 1.5 hours. 
 
• NIR  Invention (six in lab sessions over two weeks - After completing baseline testing, 
participants will undergo a series of six interventions in the lab over a period of two 
weeks.  The six treatment visits will be scheduled at the baseline visit to ensure 
availability of the participant.  The treatment will be applied over the head and is 
detailed in section C. During each treatment visit, participants will fill out mood 
questionnaires such the POMS.  . 
 
• Post-Treatment Visit- Following the final day of stimulation, the participant will be 
scheduled for a post-testing assessment of cognitive and emotional function identical to 
the baseline visit.  Participants will also fill out other questionnaires such as the adverse 
events and placebo control questionnaires. 
 
10. Data Safety Monitoring Plan 
The PI, Co-Is, or project coordinator will meet with each participant to review the adverse 
events questionnaires and assess for negative effects on the safety of participants.  This 
questionnaire will be reviewed after every intervention session and at the follow up evaluation. 
As this intervention involves an infrared lamp that has been FDA approved as a non-significant 
risk, we do not anticipate adverse events or side effects.  However, should a participant 
experience any adverse event of sufficient concern at any point during the intervention or at 
follow up, we will report to the IRB as directed.  The PI and/or project coordinator will send via 
email a monthly report to the investigative team indicating the nature of any adverse 
events.   If there are no reported adverse events, then an email summary will not be sent that 
month. The PI will take primary responsibility of the Data Safety and Monitoring Plan.  
 
11. Data Management Plan 
Data will be kept in a password protected encrypted database which can only be accessed by 
the investigator and her staff.  All surveys and assessments will be under the direction of the 
Principal and 3.nvestigators who will supervise Research Assistants.  Recruitment, screening, 
and project implementation will be coordinated by the co-investigator and/or research 
assistants. The existing data management group, supported by the IT department of the College 
of Public Health and Health Professions, will manage the database, monitor subject recruitment 
and distribute monthly enrollment reports, and produce reports summarizing the status of data 
acquisition, the baseline characteristics and the blinded primary variables.  
 
The password protected encrypted database mentioned above is the storage place for all 
participants who call and wish to be pre-screened for the study.  In many instances, the 

prospective participant no longer wants to enroll in the study, once they learn of the time 
commitment and details involved in participating.  At this point, they often ask if they could be 
contacted for other studies in the future. We will keep a column noting verbal consent to call in 
the future for short term, easier studies to participate in.  If participants do not wish to be 
contacted in the future for other studies, that will be noted as well.  This information will only 
be used by Dr. Dawn Bowers’ laboratory for future research.   
12.  Possible Discomforts and Risks  
The risks are minimal for individuals who participate in this study.  Light is applied using light 
emitting diodes, which do not present as a serious ocular hazard.  Near infrared light is non-
thermal, painless, and was designated as a non-significant risk by the FDA in 2003. It is 
estimated that approximately 6 J/cm2 is expected to reach the cortex with each daily 
treatment. At this energy level, the MedX MCT502 and Vielight 810 accessories do not cause 
tissue damage or physical damage.. As part of normal operation, the LED clusters may warm up 
during the application of light. The temperature of the MedX Clusters does not exceed 45° C 
(113 ° F) during operation. 
There are four types of potential risks for participants in this study.   
 
First, the completion of various screening and cognitive probes could potentially become boring 
or tiresome.  To minimize fatigue associated with completion of screening and baseline tasks, 
participants will be given frequent breaks and the opportunity to rest. 
 
Second, there is potential risk of loss of confidentiality.  This will be minimized through 
assigning all data collection instruments a unique code without individual identifying 
information. All HIPAA regulations pertaining to protection of participants and eliminating 
identification will be followed.   
 
Third, a subset of participants will undergo MRI.  This is perhaps poses the greatest discomfort.  
Because the MRI scanner has a strong magnet, individuals with metal implanted in their body 
cannot participate.  The scanner produces a loud hammering noise, which has produced 
hearing loss in a very small number of participants.  All participants are provided with ear 
protection while in the scanner.  There is not much room in the scanner and it can be 
uncomfortable to remain still for the scan.  Individuals with known claustrophobia will be 
excluded from participating.   
 
Fourth, it is also possible that incidental findings may emerge on the MRI.  In this situation, the 
participant will be informed and recommendation/referrals will be made with the participant’s 
permission. This could include provision of information to the participant’s primary care 
physician and/or referral to another health care professional for followup.     
 
For individuals with Parkinson disease, there is an additional potential discomfort.  The PD 
participants may experience some increase in their symptoms (i.e., increased slowness, tremor, 
rigidity) when they are tested during the “off medication” state.  This is similar to what occurs 
during their routine clinical evaluation at the Movement Disorders Clinic, when they are asked 
to come to their clinic appointment after being off their Parkinson medication overnight.   For 
our research study, care will be taken to ensure that the Parkinson patients are transported by 
wheelchair when necessary and that they are accompanied by a member of the study team.  
They will be told that if they become too uncomfortable, then they should go ahead and take 
their medication. 

 
It is possible that there are unknown risks for participating in this study.  Individuals will be 
asked about side effects at each visit and encouraged to share information about subjective 
changes. 
  
13.   Possible Benefits   
Cognitive and mood benefits cannot be guaranteed.  However, it is possible that some 
participants may experience cognitive and mood benefits that may include improved memory, 
executive function, and mood.  It is possible that individuals may experience some 
improvements solely due to expectations.   
  
14.   Conflict of Interest 
 
No conflict of interest exists for the investigators of this protocol. 
 
 
 
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