Sleep, Pain and Aging: Potential Underlying Mechanisms
Phase: PHASE2
Conditions: Chronic Pain
Sponsor: University of Florida

 
Latent Aging Mechanisms in Pain and Sleep (LAMPS) 
ClinicalTrials.gov Identifier: NCT04683640 
Date: 5/10/2022 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

1. 
Project Title 
 Sleep, Pain, and Aging: Potential Underlying Mechanisms (Latent Aging Mechanisms in Pain and Sleep 
— LAMPS Study) 
2. Investigators: 
 
Yenisel Cruz-Almeida, PhD (PI) 
Soamy Montesino Goicolea, MD (PI Proxy) 
Pedro Antonio Valdes Hernandez, PhD (Co-I) 
Eric Porges, PhD (Co-I) 
Zhiguang Huo, PhD (Co-I) 
Olga Nin, MD (Co-I) 
Cameron Smith, MD-PhD (Co-I) 
3. Abstract: 
 
Chronic pain is a serious public health problem peaking at older age depending on the pain condition [1]. 
Similarly, the capacity to sleep properly changes with age with nearly half of older adults complaining of 
difficulty sleeping [2][3]. Although the bidirectional link between sleep and pain is widely established, the 
common underlying neurobiological mechanisms have yet to be fully elucidated, especially in aging. As 
currently available sleep and chronic pain therapies are only partially effective, novel treatment 
approaches are urgently needed. Given the potential mechanistic role of GABA in both conditions, based 
on our preliminary data and the availability of GABA supplements over the counter, the present proposal 
will determine the effect of oral GABA administration in sleep quality and pain in middle to older aged 
adults with chronic pain and sleep disorders as well as to characterize the potential neurobiological 
mechanisms involved in both conditions. Results from the present investigation using a parallel, double-
blinded, placebo-controlled study will provide novel and the preliminary information needed for future 
translational pain and sleep research.  
4. Background: 
Chronic pain is a serious public health problem affecting all age groups peaking at older ages depending 
of the pain condition [1]. Similarly, the capacity to sleep properly changes with age with nearly half of 
older adults complaining of difficulty sleeping, changes which start around middle age [2][3]. Although 
the bidirectional link between sleep and pain is widely established, the common underlying 
neurobiological mechanisms have yet to be fully elucidated, especially in aging. As currently available 
sleep and chronic pain therapies are only partially effective, novel treatment approaches targeting 
shared potential mechanisms underlying both conditions simultaneously are urgently needed. 
 
A shared mechanism linking poor sleep and chronic pain in aging is GABA deficiency. Gamma-
Aminobutyric Acid or γ-aminobutyric acid (GABA) is the most important inhibitory neurotransmitter of 
the central nervous system (CNS). GABA has a broad range of effects on the body with lower levels of 
GABA being implicated in the modulation of stress, mood, sleep and pain [4][5][6]. Specifically, previous 
studies have shown negative associations between brain GABA concentrations with sleep disorders 

and chronic pain independently 
(see 
Figure 
1 
for 
model) 
[7][8][10][11][12][13][14]. 
Our 
preliminary data suggest that 1) 
brain GABA concentrations are 
lowest 
in 
older 
adults 
that 
experience chronic pain using 
single-voxel 
proton 
magnetic 
spectroscopy (1H-MRS), and 2) 
those with the worse chronic pain 
reports have the worse self-
reported sleep quality. 
Specific Aims: 
Our study aims to examine associations between sleep and pain in middle to older aged individuals in 
two separate phases. These phases are independent from each other, although interested individuals 
may take part in one or both of the phases if they wish and qualify.  
In the first phase of the study, middle to older aged individuals (n=100) and (n=50) younger controls, 
will provide 4 weeks of self-reported sleep and pain measures (i.e., validated sleep and pain 
questionnaires) as well as objective measures of sleep at home (i.e., by wearing a ring).  
Specific Aim 1: To determine the associations between pain and sleep quality in middle to older 
aged adults. We will assess self-reported and objective sleep quality and a standardized, validated self-
reported pain battery to community-dwelling older adults. Based on the literature, we hypothesize (H1a) 
that self-reported and objective sleep measures will significantly predict subsequent self-reported pain 
measures. We also hypothesize (H1b) that objective sleep quality measures will be better predictors of 
self-reported pain over the study period.  
During the second phase, we will enroll a subset of middle to older aged adults with poor sleep and 
chronic pain who will self-administer oral GABA or placebo (P) over four weeks using a randomized, 
parallel group design (n=28). Before and after the intervention, participants will undergo clinical and 
experimental pain, as well as self-reported and objective sleep assessments. Proposed mechanisms 
will be evaluated using Magnetic Resonance Spectroscopy (MRS) for brain GABA, and HPLC for 
plasma GABA concentrations.   
Specific Aim 2: To determine the effect of oral GABA administration on sleep quality as well as 
clinical and experimental pain in middle to older aged adults with poor sleep quality and severe 
pain. We will assess self-reported sleep and a standardized, multi-modal experimental pain battery 
measures. Informed by our pilot data, we hypothesize that compared to P, GABA treatment will result 
in significant improvements in: H2a) self-reported sleep quality; H2b) self-reported pain intensity H2c); 
objective sleep measures derived from OURA ring, and H2d) experimental pain sensitivity.  
Specific Aim 3: To characterize the neurobiological mechanisms contributing to the 
interindividual variability in both sleep restoration and pain relief. Based on our preliminary data, 
we hypothesize that compared to P, GABA administration will result in significant: H3a) increases in 
brain GABA levels; and H3b) increases in plasma GABA levels. Further, H3c) increases in GABA 
concentrations will be significantly associated with improvements in sleep quality and pain.  

Each phase of our study will advance our understanding of the interaction between sleep and pain in 
aging. The comprehensive evaluation of self-reported and objective sleep measures are highly relevant 
to function in the home and community, and will thus contribute to the ecological validity of our study. 
5. Research Plan: 
Our study aims to examine associations between sleep and pain in middle to older aged individuals in 
two separate phases. These phases are independent from each other, although interested individuals 
may take part in one or both of the phases if they wish and qualify. To reduce participant burden, portions 
of the study (including the ICF) may be conducted remotely via phone calls, UF Zoom, and/or online 
(REDCap). 
 
First Phase of the Study 
 
5.1. Participants, Recruitment and Compensation. We propose to enroll and screen 100 older adults 
over 45 years of age who up to 70% are expected to experience musculoskeletal pain and 50 younger 
controls between 18 and 30 years of age. All study visits during Phase 1 will be conducted via UF Zoom. 
Potential participants will be asked about subjective musculoskeletal complaints in the neck, shoulders, 
hands, lower back, knees and feet during the preceding 12 months and 7 days. We will attempt to recruit 
equivalent numbers of males and females and include minority adults. Recruitment of participants will 
also be accomplished using newspaper and a flyer that will be distributed electronically. We will also 
contact individuals in various IRB-approved registries. 
Interested individuals will call our laboratory to learn about the study and complete a telephone or UF 
Zoom screening to establish preliminary eligibility. Participants will be compensated $50 once the study 
is completed and the ring is received by the study staff. 
Study Exclusions: 1) ;  history of alcohol/drug abuse in the past; 2) known intra-cerebral pathology or 
epilepsy; 3) significant cognitive impairment as evidenced by the TICS; 4) hospitalizations for mental 
health reasons in the past year; 5) chronic/current use of narcotic  medications; and 6) inability to provide 
consent for study participation. If participants are excluded because of a TICS score < 30, the PI will 
attempt to contact the participants by phone and if unsuccessful by mail to explain that we are unable 
to include them at this time because their score(s) on a thinking/memory test, fell below the level we 
needed for eligible participants.The PI will also explain there can be many reasons why they did not 
reach the score level we needed, including difficulties with hearing, visual acuity, and lack of sleep. 
However, based on this score, they could also be experiencing other thinking, memory, and problem-
solving changes that they might wish to discuss with their primary care provider. The PI will explain that 
this should not be a source of concern or alarm. However, we recommend that they share this 
information with their primary care provider. If the participant or their physician have any questions they 
are also welcome to contact the study PI for more information. 
Initial Phone/Remote Pre-Screening. Interested individuals will call in using provided phone number 
and one of the study team members will complete a telephone interview. This will provide the individuals 
information about the study and if they are interested a pre-screening will be conducted. After the phone 
pre-screening, if participants are eligible and still interested in participation, we will send them the link to 
provide an electronic consent. Participants will be given the opportunity to read the consent on their own 
or share with others and we will reschedule a time to perform the electronic consenting process using 
REDCAP via UF Zoom. Once consent is obtained, the study team will either mail the participant the 
study binder with the questionnaires and the ring, as well as return-labels and mailing materials, or will 

mail just the ring and administer the questionnaires via REDCap. At this time, we will also schedule the 
first visit within a week.  
Baseline Remote Visit. In a UF Zoom visit within a week of consent, participants will be walked through 
the use of the ring, in particular, issues related to proper fit (i.e., which finger is a better fit), application 
and when/how to charge it. Traditional self-report measures of sleep cannot capture real-time data under 
naturalistic conditions or measure fluctuations on a daily or hourly basis. Data collection on the ring 
offers several advantages including the capability of long-term continuous data collection, ecological 
validity, and cost-effectiveness. Sleep quality will be captured each day throughout 30 days. Data will 
be downloaded remotely during the study. Participants will start wearing the device during this remote 
visit, and   their proficiency and use will be ascertained during weekly check-in remote visits. 
We will then go thru the following baseline sleep and pain questionnaires that was mailed to them in the 
study binder via Zoom:  
Self-Reported Sleep quality will be assessed with the Pittsburgh Sleep Quality Index (PSQI) [39] and 
PSQI total score will be our primary sleep outcome measure to compare to the sleep quality measured 
by the ring. Secondary sleep measures include Berlin Questionnaire[40], Epworth Sleepiness Scale[41], 
PROMIS-Sleep Related Impairment Short Form 8a[47], and FOSQ-10: A Short Version of the Functional 
Outcomes of Sleep Questionnaire [48].  
Self-Reported Pain will be assessed according to location, overall pain severity, and pain interference 
with daily activities using our pain history. Self-reported pain intensity will be our primary outcome 
measure for specific aim 1. We will also administer the Western Ontario and McMaster Universities 
Osteoarthritis Index (WOMAC)[31] a reliable, well-validated measure of lower extremity pain and 
function in aging, the Owestry Low Back Pain Disability questionnaire and the NIH Low Back Pain 
Minimal Dataset as secondary outcomes to characterize sleep with self-reported knee/back pain and 
physical function. Pain-DETECT will be used to assess the degree of neuropathic pain experienced by 
our participants. Participants will also be issued a brief pain questionnaire as it relates to the ongoing 
COVID-19 pandemic to assess how it has affected their pain and access to care for it. 
At the end of this visit, we will explain how to fill out the sleep diary, which provides an assessment of 
habitual bedtimes and waketimes in a single administration questionnaire format. We will also schedule 
2 additional brief check-in remote visits and a final visit to be completed in approximately 30 days. The 
baseline remote visit will last no longer than 3 hours and we will take breaks as needed and will be held 
over UF Zoom.  
Weekly Check-in Remote Visits. During these brief visits completed under 30 minutes, we will confirm 
completion of sleep diaries where participants provide an assessment of habitual bedtimes and waketimes 
in a single questionnaire. We will also ask one question regarding rating of pain, mood and sleep during 
the past 7 days, and we will confirm the correct use of the ring. 
If you are a female under the age of 62 years old, we will ask you to self-report whether you are currently 
pregnant during the online visits.  
 
Final Remote Visit. During this UF Zoom visit, the questionnaires from the baseline visit will be 
readministered and the visit will not last longer than 3 hours taking breaks as needed. We will also 
provide instructions for returning the ring and charger via mail including how the compensation will be 
processed once the ring is received. We will also provide the participant with their ring data if they want 
to. 

Second Phase of the Study 
We propose a double-blinded, randomized parallel group study that will randomize older adults with 
musculoskeletal pain and poor sleep quality to oral self-administration of either GABA (two 250mg 
capsules for a total of 500mg daily) or Placebo during four weeks. Our study design was guided by 
recommendations by the IMMPACT group for clinical pain trials [23][24][25][26] see table 1. After initial 
screening, eligible participants will undergo two 2.5-hour baseline sessions (health, sensory, and 
neuroimaging) for the collection of clinical information, QST, and brain imaging data. During the entire 
study, participants will wear a OURA ring to objectively measure sleep quality. During the intervention, 
participants will receive a phone call once a week for an assessment of adverse effects and compliance. 
During the last week of the intervention period, two assessment sessions will follow, these will be 
identical to the baseline sessions. (Figure 5.) 
To reduce participant burden and exposure risk to COVID-19, the ICF may be conducted remotely via 
phone calls, UF Zoom and/or online (REDCap). A copy of the signed ICF will be provided to the 
participant.  
 
Participants: Older adults over 45 years of age who have a smartphone and have experienced pain of 
at least moderate intensity (>5/10 pain intensity ratings) on more days than not during the past three 
months, and who also reported poor sleep quality (>5 PSQI scores) will be considered for participation. 
Community-based recruitment methods established in Dr. Cruz-Almeida’s lab will be utilized. 
Exclusion criteria will align with study and safety requirements broadly related to GABA administration, 
pain and MRI : 1) serious psychiatric conditions (e.g., schizophrenia, major depression, bipolar disorder;  
Table 1. Study measures consistent with core 
outcome domains recommended by IMMPACT-
www.immpact.org 
IMMPACT 
Core 
Outcome 
Domain 
Proposed Study Measures 
Pain 
Verbal Descriptor Scale (VDS) 
WOMAC-Pain 
Physical 
functioning 
WOMAC-Physical Function 
 
Socio-
emotional 
functioning 
BDI-II 
PANAS 
 
Sleep 
Pittsburgh Sleep Quality Index 
Berlin Questionnaire 
Epworth Sleepiness Scale  
Oura Ring 
Sleep Diary 
Improvement 
and 
satisfaction 
with 
treatment 
Multidimensional Patient 
Impression of Change 

2)  history of alcohol/drug abuse; 3) Alzheimer, 
Parkinson, Epilepsy and other known intra-
cerebral pathology and neurological conditions; 4) 
significant cognitive impairment as evidenced by 
the Modified Mini-Mental State Examination [3MS] 
score ≤ 77; 5) hospitalizations for mental health 
reasons in the past year; 6) chronic/current use of 
narcotic  medications; 7) serious systemic 
(uncontrolled diabetes self-reported HA1C>7), 
(uncontrolled hypertension > 155/90 mm Hg) and 
rheumatic disorders (i.e., rheumatoid arthritis, systemic lupus erythematosus, fibromyalgia, HIV); 8) 
arterial hypotension; 9) digestive tract diseases; 10) major medical surgery in the past two months, 
history of brain surgery or any serious brain condition like aneurysm, stroke, or seizures; 11) excessive 
anxiety regarding protocol procedures; 12) Inability to consent for study participation; 13) Ingestion of 
sleep medications including those with zolpidem (Ambien and others) and eszopiclone (Lunesta and 
others); 14) Neuropathic pain medications including anticonvulsants and antidepressants;  15)  Allergies 
or sensitivity to GABA or its ingredients cellulose‚ gelatin (capsule)‚ magnesium silicate‚ vegetable 
stearate and silica or to the placebo or its ingredients: calcium laurate, hypromellose capsule, 
magnesium (citrate), microcrystalline cellulose; 16) currently taking barbiturate and benzodiazepine and 
baclofen; 17) MRI contraindications including large pieces of metal in the body/face/neck and 
claustrophobia; 18) current cancer diagnosis unless determined no evidence of disease or in remission 
for at least two years, and 19) pregnancy 
Initial screening: Interested individuals will call in using the provided phone number and after the phone 
consent that provides the individual information about the study and if they are interested, a pre-
screening will be conducted. This screening procedure will include two questions regarding general body 
pain, two questions regarding back pain and seven questions regarding sleep quality in the past month. 
Will also assess age, gender, and additional health history information, as well as a questionnaire to 
assess MRI eligibility. After the phone pre-screening, if participants are eligible and still interested in 
participation, the baseline orientation visit will be scheduled. Baseline Health & Sensory Assessment 
Session: After receipt the signed copy of the informed consent previously obtained using REDCap, 
participants will provide a fasting blood sample to evaluate standard clinical parameters (Comprehensive 
Metabolic Panel (CMP-14) Blood Test) and a Urine sample to measure urine specific gravity, which will 
be reviewed by a physician to determine study continuation. For women under the age of 62, pregnancy 
tests will also be conducted.This session will take place in the mornings to accommodate for fasting and 
to control for circadian fluctuations.  
Physical examination. Height and weight will be measured as well as vital signs. Participants will 
complete a thorough Medical and Pain History Questionnaire, including a review of bodily systems 
assessing the reported duration of their pain, comorbid conditions, and current medication use.  
Symptoms 
and adverse 
events 
Passive capture of 
spontaneously reported adverse 
events and symptoms, with the 
use of open-ended prompts 
Disposition 
Detailed information regarding 
participant recruitment and 
progress throughout the trial 
Self-reported evaluation of 
blinding  

Sleep quality will be assessed with the Pittsburgh 
Sleep Quality Index (PSQI) [39] and PSQI total 
score will be our primary sleep outcome measure. 
Secondary 
sleep 
measures 
include 
Berlin 
Questionnaire[40], Epworth Sleepiness Scale[41], 
PROMIS-Sleep Related Impairment Short Form 
8a[47],  and FOSQ-10: A Short Version of the 
Functional Outcomes of Sleep Questionnaire [48]. 
Clinical pain will be assessed according to location, 
overall pain severity, and pain interference with daily 
activities using our pain history and the short form of 
the brief pain inventory. These measurements will 
encompass the key dimensions for pain assessment 
as recommended by the American Geriatrics 
Society[27] and according to the pain taxonomy by 
the Analgesic, Anesthetic, and Addiction Clinical 
Trial Translations, Innovations, Opportunities, and 
Networks and the American Pain Society group 
(AAPT)[28][29]. Self-reported pain intensity will be 
our 
primary 
clinical 
outcome 
measure 
to 
characterize treatment effects in pain using the 
Verbal Descriptor Scale. We will also administer the 
Western 
Ontario 
and 
McMaster 
Universities 
Osteoarthritis Index (WOMAC),[31] a reliable, well-
validated measure of lower extremity pain and 
function in aging, the Owestry Low Back Pain 
Disability questionnaire and the NIH Low Back Pain 
Minimal Dataset as secondary outcomes to 
characterize oral GABA effects in self-reported 
knee/back pain and physical function. Pain-
DETECT will be used to assess the degree of neuropathic pain experienced by our participants. Short-
form McGill Pain Questionnaire (SF-MPQ-2) to rate the extent to which they experienced each of 22 
pain descriptors in the past week using an 11-point numeric rating scale (0 = “none” to 10 = “worst 
possible”). The West Haven-Yale Multidimensional Pain Inventory (WHY-MPI) questionnaire will also 
be issued to assess the participant’s chronic pain experience through several key dimensions, including 
the extent of the psychological and behavioral aspects of how the participant’s pain experience is 
impacted and communicated to others through their daily routines[53]. Emotional function will be 
assessed using The Beck Depression Inventory, 2nd Edition[34] is a widely used depression scale that 
assesses affective (e.g., sadness, loss of interest), cognitive (e.g., worthlessness, guilty feelings), and 
somatic (e.g., changes in sleep, tiredness or fatigue) symptoms common amongst depressed 
individuals. It contains 21 self-report items assessing the frequency and severity of depressive 
symptoms over the previous two weeks. Since item # 9 from the Beck Depression Inventory refers to 
suicidality, the experimenter will, before the end of the test session, review the participant's response to 
this item, and if the participant has chosen response option 2 = “I would like to kill myself “or 3 = “I would 
kill myself if I had the chance”, the experimenter will contact the PIs immediately and the PIs or their 
designee will contact Dr. Ronald Cohen at the University of Florida Psychology Clinic (352-265-0294) 

who will make recommendations. In the unexpected event that the clinic personnel are not available, 
the Alachua County Crisis Center will be contacted. The same procedure will be implemented for the 
post-intervention assessment. The Positive and Negative Affect Scale (PANAS) is a 20-item scale that 
assesses positive and negative affect [35]. The PANAS has demonstrated adequate reliability and 
validity [36]. For this study, participants will be requested to provide “state” information by responding to 
items “at the present moment.” Cognitive function will be assessed via the NIH Toolbox 
(www.nihtoolbox.org) [49]. This battery comprises measures of executive function, attention, episodic 
memory, language, processing speed, and working memory. Following NIH scoring guidelines, 
administering this battery will yield the Cognitive Function Composite Score and the Crystallized 
Cognition Composite Score (e.g., Picture Vocabulary and Reading Recognition), in addition to subtest 
scores. We will also administered The Montreal Cognitive Assessment (MoCA) to screen for dementia. 
The Edinburgh Handedness Inventory will also be administered to determine handedness. As part of 
this visit, we will measure the flicker fusion threshold, which is defined as the frequency at which an 
intermittent light stimulus appears to be completely steady to the observer. Participants will also be 
issued a brief pain questionnaire as it relates to the ongoing COVID-19 pandemic to assess how it has 
affected their pain and access to care for it. 
Real-time assessment of sleep. During the baseline sessions, participants will be trained by study staff 
in the use of the OURA ring. Traditional self-report measures of sleep cannot capture real-time data 
under naturalistic conditions or measure fluctuations on a daily or hourly basis. Data collection on the 
ring offers several advantages including the capability of long-term continuous data collection, ecological 
validity, and cost-effectiveness. Sleep quality will be captured each day throughout the entire study. 
Data will be downloaded remotely or when the individual reports to the clinic during the intervention 
phase. Participants will start wearing the device during the baseline weeks and at each visit, their 
proficiency and use will be ascertained. 
At the end of the session, subjects will be provided a copy of the following questionnaires for them to fill 
out at their convenience and bring back to their next visit:  
• Sleep Diary: provides an assessment of habitual 
bedtimes and waketimes in a single administration 
questionnaire format. 
• Medication Diary log sheet: records the precise date 
and 
time 
of 
the 
administration 
of 
the 
GABA/PLACEBO each day.  
• Oswestry Low Back Pain Disability Questionnaire 
• Report of the Task Force on Research Standards 
for Chronic Low-Back Pain 
• Berlin Questionnaire 
• Epworth Sleepiness Scale 
• FOSQ-10 
• PROMIS-Sleep Related Impairment 
Quantitative Sensory Testing (QST). Participants will 
undergo QST to determine responses to mechanical and 

thermal stimuli and conditioned pain modulation (CPM) (Figure 6). QST will be performed on 
standardized sites using anatomical landmarks. All tests will be demonstrated and explained before 
being performed. All participants will be tested on the hands and feet with additional standardized testing 
sites chosen to include painful areas. We will randomize the order of thermal and mechanical testing. 
Cold pressor assessment, including conditioned pain modulation, will always occur last to avoid 
carryover effects. Patients’ medications and current clinical pain will also be confirmed. All pain 
procedures are summarized in Figure 6 and will be successfully implemented as in our previous 
studies,[42][43][44] using a Medoc Pathway Thermal Sensory Analyzer (Ramat Yishai, Israel), and 
Algomed Algometer. 
Mechanical testing procedures. Pressure pain threshold (PPT) will be assessed at the ipsilateral 
quadriceps and trapezius muscles. For all PPT measurements, after an initial practice trial, three trials 
will be conducted, and their average will be computed for data analysis. Using a digital, handheld, clinical 
grade pressure algometer (Algomed, Medoc, Ramat Yishai, Israel), the examiner will apply a constant 
rate (30 kPa/second) of pressure and the participant will press a button when the sensation first becomes 
painful, at which time the device records the pressure. Punctate Mechanical Pain will be assessed at 
the left thenar eminence and the left foot 2nd metatarsal head using a nylon monofilament (Touchtest 
Sensory Evaluator 6.65) calibrated to bend at 300g of pressure. As in our previous studies, participants 
will provide a pain rating following a single contact, after which they will provide another pain rating 
following a series of ten contacts at a rate of one contact per second. The difference between the pain 
rating for the single versus multiple contacts reflects temporal summation of mechanical pain. Thermal 
testing procedures. Thermal stimuli will be delivered to the left thenar eminence and the left foot 2nd 
metatarsal head, in randomized order, using a Medoc Pathway Thermal Sensory Analyzer (Ramat 
Yishai, Israel). Heat pain threshold will be assessed at each site, followed by heat pain tolerance and 
temporal summation. Heat pain thresholds and tolerances will be assessed using an ascending method 
of limits as in previous studies. Temporal summation of thermal pain will be assessed using the same 
stimulus parameters as previously reported by us and others.  
Conditioned Pain Modulation (CPM) will be used to assess pain-inhibitory function. The conditioning 
stimulus will be the cold pressor task applied to the left hand, which will be tailored for each participant 
to achieve a stimulus that produces moderate pain (i.e., a rating of 40-60 on the 0-100 scale) and can 
be tolerated for a 60-second period. The test stimulus will be heat pain applied to the opposite ventral 
forearm, at a stimulus intensity which produces moderate but tolerable pain. First, baseline heat pain 
responses will be assessed, after which the participant will immerse their hand in the cold-water bath 
for 60 seconds. Immediately afterwards the heat pain will again be applied to the opposite arm and pain 
ratings will be obtained.  
Short Physical Performance Battery (SPPB). We will use this brief assessment consisting of four 
lower-extremity function measures: standing, balance, walking speed, and ability to rise from a chair. 
These measures have been standardized and are widely used in older populations and have been used 
in our labs.  

Baseline Neuroimaging Assessment: At the beginning of this visit, subjects will complete the following 
questionnaires: The state version of PANAS, the state version of the STAI, the Graded Chronic Pain 
Scale (GCPS), a modified version of a disability instrument called the Pepper Assessment Tool for 
Disability (PAT-D) as well as listing of all the current medications taken and food eaten within the past 
2-4 hours and we will ask to get some information about participant’s general health and sleep quality 
since the last visit. During this session, we will also collect a small blood sample to quantify circulating 
GABA concentrations. We will also take your vital signs again,and you will receive the GABA or 
PLACEBO capsule you are going to be taking during the next 4 
weeks since this visit. 
We will use a state-of-the-art 3T Siemens Prisma MR system 
group at the McKnight Brain Institute (MBI). Anatomical image 
acquisition will involve a T1-weighted structural scan using a 
magnetization-prepared 
rapid 
gradient 
echo 
(MPRAGE) 
sequence, which provides good contrast between gray and white 
matter, and cerebrospinal fluid based on tissue T1 differences. 
Proton MRS: In line with procedures established in our studies 
(Figure 7), we will acquire single-voxel water suppressed 1H 
spectra (TE/TR = 35/3000ms, bandwidth =2500 Hz, 128 
averages, NEX=8) using a Siemens sequence, with water T2 measurement. 1.5 cc voxels will be 
prescribed in two regions (frontal, insular), with voxels laterality alternated across successive patients. 
GABA will be extracted from frontal and insular regions of interest (ROIs) based on our previous work. 
Neuroimaging analysis: GABA will be quantified using the Gannet program (version 2.0) [33]. All time-
domain data will be frequency- and phase-corrected using spectral registration [34], filtered with a 3-Hz 
exponential line broadening and zero-filled by a factor of 16. The 3-ppm GABA peak in the difference 
spectrum was fit using a five-parameter Gaussian model and will be quantified relative to water in 
institutional units. We will correct for cerebrospinal fluid (CSF) content in the voxel. Additionally, we will 
apply pain using quantitative sensory testing procedure during the MRI. MRI data will be used to 
measure the structural and functional integrity of the brain. Specific items of interest include, but are not 
limited to, descending sensory and motor tract integrity (fiber tractography), intracranial volume, whole 
brain volume, lacunae as well as metabolite concentrations. 
Intervention Period: During the 4-week intervention, participants will self-administer via oral GABA 500 
mg (capsule 250mg) or a placebo daily at home, at 08:00 pm. The utilized synthetic GABA is a 
formulation developed by “Thorne”. We chose this brand as it has high-quality standards that include 
NSF, TGA, and cGMP certifications. The capsules are compounded free from major allergens like 
gluten, eggs, tree nuts, and peanuts. They also do not contain soy, dairy, yeast, shellfish, or fish. The 
inactive placebo will be compounded by the UF IDS Pharmacy to ensure the same capsule size and 
color is used for both the GABA and the placebo. Compliance will be monitored by measuring the 
number of capsules left in the bottle after the treatment period and through a record that participants 
complete each day during the intervention after the treatment period and via a log participant fill in each 
day during the intervention. If at any time during the treatment it is determined that the participant should 
not continue due to adverse events, the participant will be discontinued. Furthermore, at baseline and 
the end of each intervention, blood samples including renal and hepatic function will be checked to 
ensure that no adverse changes have occurred during the study intervention. Over the 4-week 
intervention period, participants will be contacted once a week to assess side effects. Any symptom 
reported as moderate or severe will be brought to the PI’s attention and will be discussed with the study 

MD as needed on a case by case basis. These weekly calls will also ensure regimen compliance and 
will assist participants in the download of the OURA ring data to a secure research server.  
Post-Intervention Assessments: In the last week of the intervention phase, participants will be 
scheduled to return for their two post-intervention visits, which will be identical to the baseline visits. 
Importantly, at the follow-up Health and Sensory Assessment, we will assess changes in health status 
and their global impression of change since starting the intervention.  
At study closure, participants will also be asked to guess what study medication they were taking to 
assess the effectiveness of blinding, followed by a full debriefing regarding the study aims. All study 
participants will be financially compensated for study participation. Finally, one week and three months 
after the last treatment phase, participants will receive a follow-up phone call to determine if any side 
effects occurred as well as answer a pain history, the short form of the Brief Pain Inventory, the WOMAC, 
PANAS and the PSQI to inquire about pain and sleep respectively. During these calls, if symptoms that 
indicate imminent danger to the participant are reported such as dizziness, anxiety, drowsiness, balance 
problems, blurred vision, itchiness, irritation or stomach pain, staff will immediately advise participants 
to contact emergency medical services. Simultaneously, this matter will be immediately escalated to the 
study physician and PI and the physician or his proxy will be in immediate contact with the participant to 
determine appropriate steps for follow-up. 
Subjects will participate in 4 separate sessions although to reduce participant burden additional sessions 
may be scheduled. 
Sample essays: Blood samples will be collected from the subject’s antecubital vein using a butterfly 
catheter and EDTA-coated lavender tubes (no more than 3 tbsp collected). The samples will be 
separated and aliquoted in Dr. Cruz-Almeida’s PAIN lab (Dental Tower). Assays will be performed in 
the Quest Diagnostics lab to evaluate standard clinical parameters (Comprehensive Metabolic Panel 
(CMP-14) while high sensitivity plasma GABA concentrations will be done using HPLC by 
Interdisciplinary Center for Biotechnology Research (ICBR) at UF.   
Power and sample size considerations: For phase one, the estimated sample size was derived from 
the literature in sleep and pain studies assuming a medium effect size to achieve 80% power. For phase 
two of the study, we plan to recruit 28 participants, i.e., 14 participants in each of the randomly assigned 
treatment groups for the neuroimaging visits, this will provide effect sizes to determine the estimates of 
variability needed to calculate the sample size needed for future larger proposals working together with 
Dr. Huo. 
Data Analysis: Dr. Huo will work with the study team to perform data analytic procedures for both 
phases. For phase one, we will employ general linear model approaches to determine associations 
between pain and sleep measures while controlling for relevant covariates. For phase two we will employ 
a repeated pre-post analysis of variance to provide the basis for future estimations of effects including 
multiple comparisons corrections. 
Recruitment Strategy: Recruitment of participants will be accomplished using newspapers and flyers, 
as well as community methods similar to our previous studies and social media advertisements on 
Facebook that direct the user to call a lab-controlled phone number. We will also contact individuals in 
the PRICE registry. 
6. Possible Discomforts and Risks: 

Equipment used in this research meets all current safety standards, and all research staff will be highly 
trained in the use of all equipment. This study may include risks that are unknown at this time. Potential 
risks for this study are related to using of study product, neuroimaging, blood draw procedure, blood 
pressure measurement, the physical performance tests, the cognitive function tests, the sensory testing, 
and potential loss of confidentiality related to study participation, as discussed in detail below.  
All assessments will be conducted in Dr. Cruz-Almeida’s PAIN laboratory (Dental Tower) and the 
McKnight Brain Institute and all sessions will be conducted by trained and certified research staff, which 
will monitor potential adverse experiences and symptoms. During the testing sessions, a fully equipped 
defibrillator is available along with a semi-automated ECG cart. All personnel associated with the study 
have received CPR training and training on management of acute events including syncope, chest pain, 
acute dyspnea, focal neurological symptoms, and abnormal vital signs. Portable defibrillators are 
available at the assessment site. Additionally, a study physician is available on call and contact numbers 
for emergency services are posted. Institutional and community EMS services will be activated if 
needed. If participants develop chest pain, shortness of breath, or dizziness at any point during a 
screening or assessment visit, they will be instructed to rest and to contact the center and their 
physicians if these symptoms persist or recur.  
Participants will be instructed to talk with the investigators about any discomforts that occur during the 
study. If for any reason the participant reports an injury, dizziness, anxiety, drowsiness, dry mouth, 
balance problems, constipation, blurred vision, itchiness, irritation or stomach pain, staff will immediately 
advise participants to contact emergency medical, they will be referred to their doctor, or the PI will call 
the doctor or other health care provider.  
Before beginning data collection, all study coordinators undergo standardized training on all study 
procedures. A detailed checklist for each data collection element is in place to ensure all study 
coordinators are appropriately trained and able to conduct study procedures. Research coordinators will 
be certified in each element of the study visit including obtaining informed consent, administering 
questionnaires, protecting the confidentiality of collected data, performing the test batteries. Any study 
coordinator who is found to not adhere to all aspects of the protocol will be required to complete 
additional training followed by re-certification.  
All research staff complete human subjects training required by The University of Florida institutional 
review board (IRB) and the National Institutes of Health (NIH). This training includes education about 
the importance of maintaining the confidentiality of personal health information. The study principal 
investigators or a co-investigator will be available to answer questions that arise during the informed 
consent process as needed. More information about specific protective measures against risk is outlined 
below. 
GABA oral supplement administration  
Gamma-aminobutyric acid (GABA) has become widely available as a food supplement. In the United 
States, GABA is considered a “food constituent” and a “dietary supplement,” respectively. These GABA 
food supplements can be purchased online via numerous websites, including webshop giants such as 
Amazon.com, with often very positive customer reviews. Hundreds of people report that these 
supplements have helped them alleviate anxiety and/or improve sleep quality, in addition to other 
beneficial effects.  
Physiological Effects of GABA. In recent years researchers have reported several placebo-controlled 
studies in which GABA was administered as a food supplement to healthy participants and participants 
with a history of acrophobia. One study found an increase in alpha waves in healthy participants and 

increased levels of immunoglobulin A (IgA; an indicator of immune system functioning) in participants 
with a history of acrophobia when they were exposed to heights [50]. Another study reported reduced 
heart rate variability and salivary chromogranin A (CgA) during an arithmetic task compared to a 
control group after the administration of GABA-enriched chocolate [51]. Additionally, participants who 
received 50 mg of GABA dissolved in a beverage reported less psychological fatigue after completion 
of the task [52]. 
Safety of GABA oral supplement. No significant adverse events were reported in the above studies, 
indicating that GABA oral supplements are generally safe. Currently, there is no established dose for 
GABA as a dietary supplement, and doses in the literature range from 500 to 750 milligrams taken up 
to two times a day. As a precaution in our preliminary study,  we decided to administer the lower dose 
of 500 mg daily.  
Excluded Medical Conditions. As a precaution, we will exclude participants who take hypertension 
medications since GABA can reduce blood pressure levels. We will exclude participants that ingest 
neuropathic pain medication as well as anticonvulsants and antidepressants.  
Drug-Interactions. It does not have any known drug interactions. However, we should know about any 
other medications or supplements participants are taking, including prescription drugs, nonprescription 
drugs, vitamins, and dietary or herbal supplements. Even though there are currently no known 
interactions, it is important to understand that gamma-aminobutyric acid supplementation has been 
studied very little in humans.  
 
Placebo oral administration 
This study compares an active drug (GABA) to a placebo. A placebo is an inactive substance made 
to look/taste like an active medicine. 
Laboratory tests. Participants will have blood drawn at screening and during the post-intervention visit 
for both intervention periods to measure their blood chemistry. Abnormal results will be brought to the 
principal investigator’s attention immediately. The results will be reviewed and signed by the study 
clinician and Dr. Cruz-Almeida. 
Assessment of Adverse Events. A standard operating procedure will be established which is followed 
to collect and deal with adverse events during the research project. In particular, adverse events will 
be systematically monitored both during the treatment phases, as well as 3 months following study 
completion. In particular, participants will respond to a side effect checklist to detect any possible 
physiological reactions related to the drug administration. This will include a series of open-ended 
questions asked by trained research staff regarding any adverse events that have occurred since the 
last visit or phone contact. Additionally, during the 3 months follow up, participants will be asked to the 
WOMAC PANAS and PSQI questionnaires to assess pain, feelings, and sleep respectively. This report 
will be reviewed by the principal investigator and study physician in a timely fashion. Any serious 
untoward event, whether related or unrelated to the study drug or procedures, will be reported to the 
UF IRB.  
Adverse events will be defined as any physical symptoms or side effects that began following the 
administration of the study drug. All reported and observed adverse events will be tracked in a running 
adverse events participant log, which will contain information regarding dates, description, and 
severity. All adverse events will be coded using the most current version of the Medical Dictionary for 
Regulatory Activities (MedDRA). The number and percentage of participants reporting treatment-

emergent adverse events will be tabulated by treatment, system organ class, and MedDRA-preferred 
term. Treatment-emergent adverse events will be those adverse events that begin or worsened 
following the first dose of study drug. Adverse events will be further classified by severity and 
investigator-assigned relationship to study drug. All reported and observed adverse events will be 
tracked on a running adverse events log (specific to each subject and maintained in his/her study file) 
and will contain information regarding onset/offset dates, time course (i.e., single, sporadic), severity, 
action taken regarding study drug, relationship to study drug, and whether it meets FDA criteria for 
“Serious.” Each reported event is reviewed by the principal investigator and the study physician in a 
timely fashion. Additionally, the principal investigator reviews all adverse events recorded in each 
participant’s log after study participation.   
In Case of Emergency. Participants will have 24-hour access to emergency care and will be provided 
with a means of contacting the on-call study doctor and research staff. Participants will be informed and 
encouraged to contact the study physician and study staff immediately with medical concerns or unusual 
reactions. Participants will also be informed of the closest Emergency Department location to their 
residence.  
Data and Safety Monitoring Plan. A Data Safety Monitoring Plan will be in place. In particular, the 
following procedures will be implemented to ensure data and participant safety. Study progress and 
safety will be reviewed by the principal investigators in collaboration with a physician, and the study MD. 
We will stop the intervention if 30% or more of the participants in the GABA condition report seven or 
more (out of forty-four) of the side effects at moderate to severe levels over more than 3 days as acquired 
during the weekly check-in phone calls during the intervention phase. Data collected before the stop of 
intervention will be used for analysis. All participants who went through the intervention phase of the 
study will be followed up by phone calls for 7 days to ensure safety. Progress reports, including 
participant recruitment, retention/attrition, and adverse events will be provided to an Independent Safety 
Monitor for reviews on a bi-annual basis. The Independent Safety Monitor for this study will consist of 
an established senior investigator not associated with our study. A study end report will be compiled and 
will include a list and summary of adverse events. Also, this report will address: (1) whether adverse 
event rates are consistent with pre-study assumptions; (2) reason for dropouts from the study; 
(3)whether all participants met entry criteria; (4) whether continuation of the study is justified on the basis 
that additional data are needed to accomplish the stated aims of the study; and (5) conditions whereby 
the study might be terminated prematurely. The annual report will be signed by the Independent Safety 
Monitor and will be forwarded to the IRB, NIH, and FDA. The Data Safety Monitoring Plan will also 
require that all significant serious adverse events that may be possibly related to the study participants 
will be reported to the IRB, FDA, and NIH within 48 hours of the principal investigator's learning of the 
event. Besides, any unanticipated serious adverse events that may increase the risk of the research for 
participants or potential participants will be reported to the IRB and the NIH within 48 hours of the 
principal investigators being informed about the event. This study will be stopped before its completion 
if: (1) the intervention is associated with adverse effects that significantly impact the risk-benefit ratio, 
(2) study recruitment or retention becomes futile, (3) any new information becomes available during the 
trial that necessitates stopping the trial; or (4) if independent safety monitor indicates stopping trial is 
necessary due to adverse event frequency or severity. 
ClinicalTrials.gov Requirements. Under Public Law 110-85 and NIH guidelines, the proposed research 
will be registered with ClinicalTrials.gov before the commencement of study procedures involving 
participants 
Magnetic Resonance Imaging (MRI)/ Magnetic Resonance Spectroscopy (MRS) 

MRI and MRS are used routinely for medical care and are very safe for most people, but participants will 
be monitored during the entire scan in case any problems occur. The risks of MRI/MRS are: 
• The scanner contains a very strong magnet. Participants may not be able to have the MRI/MRS if 
they have any type of metal implanted in their body, for example, any pacing device (such as a heart 
pacer), any metal in their eyes, or certain types of heart valves or brain aneurysm clips. Therefore, 
participants will be extensively screened. Participants who would normally be excluded from getting 
an MRI/MRS for safety reasons will be excluded, applying criteria for an exclusion that are more 
stringent than those imposed for standard clinical MRI/MRS scans.  
• There is not much room inside the scanner. Participants may be uncomfortable if they do not like to 
be in close spaces ("claustrophobia"). Participants will be screened for known claustrophobia.  
The scanner produces a loud hammering noise, which has produced hearing loss in a very small number 
of people. Participants will be given earplugs to reduce this risk. Also, they will be informed of this 
possibility in the inform consent form and that they may immediately withdraw from the study at any 
time. During the procedure, participants will be able to talk with the staff through a speaker system, and, 
in the event of an emergency, participants can tell them to stop the scan. 
During neuroimaging, participants will be situated comfortably on the scanner table, with a head-
mounted. Brain image acquisition will take place on a 3T Siemens Prisma human imaging system at 
AMRIS, at the McKnight Brain Institute, employing pulse sequences and hardware that have been 
approved by the FDA for human clinical use. All MRI/MRS safety guidelines and precautionary steps 
established by the AMRIS will be strictly followed. At the end of the session, a post-scan debriefing 
questionnaire will be administered that examines discomfort during and after the scanning. 
 
Blood Draw 
The risks of drawing blood from a vein include discomfort at the site of puncture; possible bruising and 
swelling around the puncture site; rarely an infection; and, uncommonly, faintness from the procedure. 
 
Blood Pressure Measurement 
The risks of placing a blood pressure cuff on a participant’s arms are that it may cause pinching or slight 
bruising. 
Physical Tests 
There is a risk of losing balance and falling or development of chest discomfort due to coronary ischemia 
or dyspnea due to heart failure or lung disease associated with the physical performance-based testing 
(e.g., the ¼ mile walk test, balance tests, rising from a chair). We will minimize this risk by: (1) safely 
escorting participants to chairs located along the walking course should they become unsteady; (2) 
following participants at a close distance; and, (3) being at participants’ side should they need 
assistance. Research staff members will be trained in the conduct of the physical performance tests 
before they work with study participants. Study staff members are trained not to perform these tests if 
they feel that testing is unsafe. Besides, participants will be asked whether they feel the test is safe. 
Those who state it may be unsafe will not be allowed to complete the test. Staff members will be trained 
to protect against falling and will be trained in CPR. They will be trained in activating the emergency 
response system at the research facility.   
 
Sensory Testing 

The sensory testing procedures may be uncomfortable or unpleasant, in that participants may 
experience 
some 
temporary 
discomfort 
from 
the 
thermal, 
pressure, 
and 
mechanical 
stimulation. However, if the participants feel the sensation is greater than they wish to tolerate, they can 
stop any of the procedures at any time. 
 
Personal Information 
Some of the question’s participants will be asked may be personal and may make participants feel 
uncomfortable. Time will be made to talk with the participant if they appear to be distressed. We will be 
asking for information about sensitive issues, such as mood which may make participants feel 
uncomfortable. If they are uncomfortable answering these questions, they can choose not to answer and 
discontinue participation in the study. Some people, when asked such questions, experience strong 
emotional reactions that may require counseling. If they do, they are strongly encouraged to tell the 
Principal Investigator, who can make an appropriate referral to the Psychology Clinic or the UF Counseling 
& Wellness Center at (352) 392-1575. If we should discover, based on the questionnaires or formal clinical 
interview, that the participant experiences marked depression or suffer from another psychiatric condition, 
we will offer to make an appropriate medical, psychiatric, and/or psychological referral. 
  
Confidentiality 
Data that will be collected from human subjects for this project will include behavioral performance 
measures, rating scales assessed through interviews and patients’ responses to self-rated scales, 
physiological, and neuroimaging data. Data will be collected specifically for the proposed research 
project. Access to individually identifiable private information about human subjects will be limited to 
research staff affiliated with the project. Research records will be kept confidential to the extent provided 
by law. The collection and submission of medical information will be accomplished with strict adherence 
to professional standards of confidentiality. Participants’ medical information will be kept in a secure 
location accessible only to research staff associated with this study. Participants will only be identifiable 
by ID number, and any published findings resulting from the study will not refer to or identify individuals. 
Several methods will be employed to maintain the confidentiality of participants. First, data will be 
collected in secure spaces where the session cannot be overheard. Secondly, only study investigators 
and key research staff (i.e. data manager and study programmers) will have access to the study 
database. Third, participants will be assigned a unique study identifier. Individual names are not linked 
with collected data in the password-protected study database and only the unique study identifier will 
be used. A file linking the participant name and contact information and their specific study identifier will 
be kept separately and will be password protected and only accessible to study team members. Fourth, 
collected data will be maintained in locked computer files and file cabinets to which only study team 
members have access. Collected data will be used only for research purposes. Published data will not 
contain any individual identifiers. Finally, all research staff members have to retake refresher course 
certification exams every year. 
 
Informed Consent 
Before entry in the trial, the investigator(s) or study coordinator(s) will explain to potential participants 
the aims, methods, reasonably anticipated benefits, and potential hazards of the trial and any discomfort 
it may entail. Subjects will be informed that their participation in the study is entirely voluntary and that 
they may withdraw consent to participate at any time. They will be told that competent physicians/lab 
personnel will examine their records but that personal information will be treated as strictly confidential 
and will not be publicly available. Subjects will be allowed to ask questions and will be given sufficient 

time to review all of the relevant information associated with the study. After this explanation and before 
entry to the trial, the subject’s consent will be obtained and documented via the signature of an informed 
consent form by both the subject and the person conducting the informed consent discussion. If signed 
informed consent cannot be obtained, the subject will not be included in the trial. 
7. Possible Benefits: 
There are no direct benefits for study participation. There may be benefits that we are not yet aware of. 
The report about the results of the study will be made available to study participants as well as others 
in the community. However, the greatest benefit will be to the society as a whole. Scientific knowledge 
advances slowly, but study results will increase our understanding of the underlying neurobiological 
mechanisms in sleep disorder and chronic pain in aging. Such knowledge may be implemented in 
intervention programs that may have the potential to increase function and personal well-being.  
8. Conflict of Interest: 
There are no conflicts of interest in this project. 
 
 
References 
[1] J. L. Riley, C. D. King, F. Wong, R. B. Fillingim, and A. P. Mauderli, “Lack of endogenous modulation 
and reduced decay of prolonged heat pain in older adults,” Pain, vol. 150, no. 1, pp. 153–160, Jul. 2010.  
[2] A. B. Neikrug and S. Ancoli-Israel, “Sleep disorders in the older adult - A mini-review,” Gerontology, 
vol. 56, no. 2, pp. 181–189, 2010.  
[3] S. K. Roepke and S. Ancoli-Israel, “Sleep Disorders in the elderly,” Indian J Med Res 131, 2010.  
[4] S. J. Enna and K. E. McCarson, “The Role of GABA in the Mediation and Perception of Pain,” 
Advances in Pharmacology, vol. 54. pp. 1– 27, 2006.  
[5] M. Jessica VanArsdale, MD, “Self-Care Wellness Toolkit Depression and Anxiety,” 2015.  
[6] S. R. Dash, “The Microbiome and Brain Health : What ’ s the Connection ?,” Medscape Psychiatry 
Ment. Heal., pp. 1–6, 2015.  
[7] R. E. Harris and D. J. Clauw, “Imaging central neurochemical alterations in chronic pain with proton 
magnetic resonance spectroscopy.,” Neurosci. Lett., vol. 520, no. 2, pp. 192–6, Jun. 2012.  
[8] M. Thiaucourt et al., “Posterior Insular GABA Levels Inversely Correlate with the Intensity of 
Experimental Mechanical Pain in Healthy Subjects.,” Neuroscience, vol. 387, pp. 116–122, 2018 
[9] Evert Boonst, Roy de Kleijn,Lorenza S. Colzato, Anneke Alkemade, Birte U. Forstmann,Sander 
Nieuwenhuis, " Neurotransmitters as food supplements: the effects of GABA on brain and behavior", 
Frontiers in Psychology, Vol 6, Oct. 2015.  
[10] H. M. Alshuft, L. A. Condon, R. A. Dineen, and D. P. Auer, “Cerebral cortical thickness in chronic 
pain due to knee osteoarthritis: The effect of pain duration and pain sensitization,” PLoS One, vol. 11, 
no. 9, pp. 1–16, 2016.  
[11] D. T. Plante, J. E. Jensen, and J. W. Winkelman, “The Role of GABA in Primary Insomnia,” Sleep, 
vol. 35, no. 6, pp. 741–742, 2012.  
[12] J. W. Winkelman et al., “Reduced brain GABA in primary insomnia: Preliminary data from 4T proton 
magnetic resonance spectroscopy (1HMRS),” Sleep, vol. 31, no. 11, pp. 1499–1506, Nov. 2008.  
[13] C. B. Saper, T. E. Scammell, and J. Lu, “Hypothalamic regulation of sleep and circadian rhythms,” 
Nature, vol. 437, no. 7063. Nature Publishing Group, pp. 1257–1263, 27-Oct-2005.  

[14] N. K. Sharma, K. McCarson, L. Van Dillen, A. Lentz, T. Khan, and C. M. Cirstea, “Primary 
somatosensory cortex in chronic low back pain - A1H-MRS study,” J. Pain Res., vol. 4, pp. 143–150, 
2011. 
 [15] N. Tzourio-Mazoyer et al., “Automated anatomical labeling of activations in SPM using a 
macroscopic anatomical parcellation of the MNI MRI single-subject brain,” Neuroimage, vol. 15, no. 1, 
pp. 273–289, 2002.  
[16] A. Zalesky, A. Fornito, and E. T. Bullmore, “Network-based statistic: Identifying differences in brain 
networks,” Neuroimage, vol. 53, no. 4, pp. 1197–1207, Dec. 2010. [17] A. Di Martino et al., “Functional 
connectivity of human striatum: A resting state fMRI study,” Cereb. Cortex, vol. 18, no. 12, pp. 2735–
2747, 2008.  
[18] D. Borsook, J. Upadhyay, E. H. Chudler, and L. Becerra, “A key role of the basal ganglia in pain 
and analgesia--insights gained through human functional imaging.,” Mol. Pain, vol. 6, p. 27, May 2010.  
[19] L. Wang, K. Wang, J.-H. Liu, and Y.-P. Wang, “Altered Default Mode and Sensorimotor Network 
Connectivity With Striatal Subregions in Primary Insomnia: A Resting-State Multi-Band fMRI Study,” 
Front. Neurosci., vol. 12, no. December, pp. 1–8, 2018.  
[20] C. Li, M. Dong, Y. Yin, K. Hua, S. Fu, and G. Jiang, “Abnormal whole-brain functional connectivity 
in patients with primary insomnia,” Neuropsychiatr. Dis. Treat., vol. 13, pp. 427–435, 2017.  
[21] C. J. Starr et al., “The contribution of the putamen to sensory aspects of pain: Insights from structural 
connectivity and brain lesions,” Brain, vol. 134, no. 7, pp. 1987–2004, 2011.  
[22] L. Amorim et al., “Poor Sleep Quality Associates With Decreased Functional and Structural Brain 
Connectivity in Normative Aging: A MRI Multimodal Approach,” Front. Aging Neurosci., vol. 10, p. 375, 
2018.  
[23] D. C. Turk et al., “Core outcome domains for chronic pain clinical trials: IMMPACT 
recommendations,” Pain, vol. 106, no. 3, pp. 337–345, 2003.  
[24] R. H. Dworkin et al., “Core outcome measures for chronic pain clinical trials: IMMPACT 
recommendations,” Pain, vol. 113, no. 1–2. pp. 9– 19, Jan-2005.  
[25] R. H. Dworkin et al., “Interpreting the clinical importance of treatment outcomes in chronic pain 
clinical trials: IMMPACT recommendations.,” J. Pain, vol. 9, no. 2, pp. 105–21, Feb. 2008.  
[26] J. S. Gewandter et al., “Research design considerations for chronic pain prevention clinical trials: 
IMMPACT recommendations.,” Pain, vol. 156, no. 7, pp. 1184–97, Jul. 2015. [27] T. Hadjistavropoulos 
et al., “An interdisciplinary expert consensus statement on assessment of pain in older persons.,” Clin. 
J. Pain, vol. 23, no. 1 Suppl, pp. S1-43, Jan. 2007.  
[28] R. B. Fillingim et al., “The ACTTION-American Pain Society Pain Taxonomy (AAPT): an evidence-
based and multidimensional approach to classifying chronic pain conditions.,” J. Pain, vol. 15, no. 3, pp. 
241–9, Mar. 2014.  
[29] R. H. Dworkin, S. Bruehl, R. B. Fillingim, J. D. Loeser, G. W. Terman, and D. C. Turk, 
“Multidimensional Diagnostic Criteria for Chronic Pain: Introduction to the ACTTION–American Pain 
Society Pain Taxonomy (AAPT),” Journal of Pain, vol. 17, no. 9. pp. T1–T9, 2016. 
[30] L. J. Ware, C. D. Epps, K. Herr, and A. Packard, “Evaluation of the Revised Faces Pain Scale, 
Verbal Descriptor Scale, Numeric Rating Scale, and Iowa Pain Thermometer in older minority adults.,” 
Pain Manag. Nurs., vol. 7, no. 3, pp. 117–25, Sep. 2006.  
[31] N. Bellamy, W. W. Buchanan, C. H. Goldsmith, J. Campbell, and L. W. Stitt, “Validation study of 
WOMAC: A health status instrument for measuring clinically important patient relevant outcomes to 
antirheumatic drug therapy in patients with osteoarthritis of the hip or knee,” J. Rheumatol., vol. 15, no. 
12, pp. 1833–1840, 1988.  

[32] S. Nair et al., “ROAMM: A software infrastructure for real-time monitoring of personal health,” in 
2016 IEEE 18th International Conference on e-Health Networking, Applications, and Services, 
Healthcom 2016, 2016.  
[33] J. L. Riley, M. E. Robinson, and M. E. Geisser, “Empirical subgroups of the Coping Strategies 
Questionnaire-Revised: a multisample study.,” Clin. J. Pain, vol. 15, no. 2, pp. 111–6, Jun. 1999.  
[34] B. G. Beck AT, Steer RA, “Beck Depression Inventory-Second Edition (BDI-II) Men’s Health 
Initiative.” 1996.  
[35] J. R. Crawford and J. D. Henry, “The positive and negative affect schedule (PANAS): construct 
validity, measurement properties and normative data in a large non-clinical sample.,” Br. J. Clin. 
Psychol., vol. 43, no. Pt 3, pp. 245–65, Sep. 2004.  
[36] D. Watson, L. A. Clark, and A. Tellegen, “Development and Validation of Brief Measures of Positive 
and Negative Affect: The PANAS Scales,” J. Pers. Soc. Psychol., vol. 54, no. 6, pp. 1063–1070, 1988.  
[37] G. M. Kiebzak, L. M. Pierson, M. Campbell, and J. W. Cook, “Use of the SF36 general health status 
survey to document the health-related quality of life in patients with coronary artery disease: Effect of 
disease and response to coronary artery bypass graft surgery,” Hear. Lung J. Acute Crit. Care, vol. 31, 
no. 3, pp. 207–213, 2002.  
[38] E. Diener, R. A. Emmons, R. J. Larsem, and S. Griffin, “The Satisfaction With Life Scale,” J. Pers. 
Assess., vol. 49, no. 1, pp. 71–75, 1985.  
[39] D. J. Buysse Charles F Reynolds Ill, T. H. Monk, S. R. Berman, and D. J. Kupfer, “The Pittsburgh 
Sleep Quality Index: A New Instrument for Psychiatric Practice and Research,” 1988.  
[40] N. C. Netzer, R. A. Stoohs, C. M. Netzer, K. Clark, and K. P. Strohl, “Using the Berlin Questionnaire 
to identify patients at risk for the sleep apnea syndrome,” Ann. Intern. Med., vol. 131, no. 7, pp. 485–
491, Oct. 1999.  
[41] M. W. Johns, “A new method for measuring daytime sleepiness: The Epworth sleepiness scale,” 
Sleep, vol. 14, no. 6, pp. 540–545, 1991.  
[42] Y. Cruz-Almeida et al., “Psychological profiles and pain characteristics of older adults with knee 
osteoarthritis,” Arthritis Care Res., vol. 65, no. 11, pp. 1786–1794, Nov. 2013. [43] J. S. Cardoso et al., 
“Experimental pain phenotyping in community-dwelling individuals with knee osteoarthritis,” Pain, vol. 
157, no. 9, pp. 2104–2114, 2016.  
[44] Y. Cruz-Almeida et al., “Racial and ethnic differences in older adults with knee osteoarthritis,” 
Arthritis Rheumatol., vol. 66, no. 7, pp. 1800– 1810, Jul. 2014. 
[45] Y. Cruz-Almeida, M. L. Black L., E. A. Christou A., and D. J. Clark J., “Site-specific differences in 
the association between plantar tactile perception and mobility function in older adults,” Front. Aging 
Neurosci., vol. 6, no. APR, p. 68, 2014.  
[46] Y. Cruz-Almeida et al., “Physical performance and movement-evoked pain profiles in community-
dwelling individuals at risk for knee osteoarthritis.,” Exp. Gerontol., vol. 98, pp. 186–191, 2017. 
[47] Lan Yu, Buysse, Daniel J, Germain, Anne, Moul, Douglas E, Stover, Angela Dodds, Nathan E, 
“Development of Short Forms from the PROMIS Sleep Disturbance and Sleep-Related Impairment Item 
Banks”, Behav Sleep Med.; 10(1): 6–24. December 28, 2011. 
[48] Chasens, Eileen R., Ratcliffe, Sarah J., Weaver, Terri E., “Development of the FOSQ-10: A short 
version of the functional outcomes of sleep questionnaire”, Sleep; Vol 32, pp 915-919, 2009. 
[49] Weintraub S, Dikmen SS, Heaton RK, et al. “The cognition battery of the NIH toolbox for assessment 
of neurological and behavioral function: validation in an adult sample”. J Int Neuropsychol 
Soc.;20(6):567-578, 2014 

[50] Abdou AM1, Higashiguchi S, Horie K, Kim M, Hatta H, Yokogoshi H. “Relaxation and immunity 
enhancement effects of gamma-aminobutyric acid (GABA) administration in humans”. Biofactors, 
26(3):201-8, 2006 
[51] Nakamura H., Takishima, T. Kometani, T. Yokogoshi, H. “Psychological stress-reducing effect of 
chocolate enriched with γ-aminobutyric acid (GABA) in humans: Assessment of stress using heart rate 
variability and salivary chromogranin A”. International Journal of Food Sciences and Nutrition, 106-113, 
2009. 
[52] Boonstra, Evert de Kleijn, Roy Colzato, Lorenza S. Alkemade, Anneke Forstmann, Birte U. 
Nieuwenhuis, Sander, “Neurotransmitters as food supplements: the effects of GABA on brain and 
behavior”, Frontiers in Psychology, 6-11, 2015. 
[53] Kerns, Robert D., Turk, Dennis C., Rudy, Thomas E, “The West Haven-Yale Multidimensional Pain 
Inventory (WHYMPI)”, Journal of Pain, vol. 23, no. 4. pp. 345-356, 1985.