Clinical trial NCT04683640
Conditions: Chronic Pain
Sponsor: University of Florida
Start date: 2021-04-02; Completion date: 2024-05-30
Enrollment: 33 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Chronic pain is a serious public health problem in older adults depending on the pain condition, and the capacity to sleep properly changes with age. Given the potential mechanistic role of GABA (gamma-aminobutyric acid) in both conditions, based on our preliminary data, this proposal will determine the effect of oral GABA administration in sleep quality and pain in older adults with chronic pain and sleep disorders as well as to characterize the potential neurobiological mechanisms involved in both illnesses.

Detailed description:

Arms: arm 1: You will take, by mouth, 2 pills of GABA (500 mg) (Capsule 250mg) daily at home for 4 weeks arm 2: You will take, by mouth, 2 pills of Placebo daily at home for 4 weeks
Interventions: intervention 1: GABA intervention 2: Placebo
Intervention descriptions: intervention 1: Daily oral GABA for 4 weeks intervention 2: Daily oral Placebo for 4 weeks

Protocol documents:
Prot_SAP_000.pdf: 
 
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. 
 
 
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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 
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[51] Nakamura H., Takishima, T. Kometani, T. Yokogoshi, H. “Psychological stress-reducing effect of 
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[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 
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Inventory (WHYMPI)”, Journal of Pain, vol. 23, no. 4. pp. 345-356, 1985. 

ICF_001.pdf: 
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INFORMED CONSENT FORM 
to Participate in Research, and 
AUTHORIZATION  
to Collect, Use, and Disclose Protected Health Information (PHI) 
INTRODUCTION 
 
Name of person seeking your consent: 
 
 
Place of employment & position:  
 
 
Please read this form, which describes the study in some detail. A member of the research 
team will describe this study to you and answer all of your questions and is available should 
any questions arise at (352) 294-8582. Your participation is entirely voluntary.  If you 
choose to participate you can change your mind at any time and withdraw from the study.  
You will not be penalized in any way or lose any benefits to which you would otherwise be 
entitled if you choose not to participate in this study or to withdraw.  If you have questions 
about your rights as a research subject, please call the University of Florida Institutional 
Review Board (IRB) office at (352) 273-9600 
 
GENERAL INFORMATION ABOUT THIS STUDY 
 
1. Name of Participant ("Study Subject") 
 
___________________________________________________________________  
 
2. What is the Title of this research study (this “Research Study”)? 
Sleep, Pain and Aging: Potential Underlying Mechanisms  
(Short title Latent Aging Mechanisms in Pain and Sleep — LAMPS Study) 
 
3. Whom do you call if you have questions about this Research Study (the “Study 
Team”)? 
Principal Investigator: Yenisel Cruz-Almeida, MSPH, PhD at (352) 294-5845 
Co-Principal Investigator: Soamy Montesino Goicolea, MD at (352) 294-8582 
Other Study Staff: Ben Griffith at (352) 294-8582 
 


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4.   Who is paying for this Research Study? 
The sponsors of this study are the University of Florida Clinical Translational Science 
Institute (CTSI), which is supported in part by the National Institutes for Health (NIH) 
National Center for Advancing Translational Sciences, and the Center for Advancing 
Minority Pain and Aging Science (CAMPAS), which is supported in part by the NIH 
National Institutes of Aging (NIA).  
5.  In general, what do you need to know about this Research Study? 
Agreeing to become involved in any research is always voluntary.  By signing this 
form, you are not waiving any of your legal rights.  If you decide not to participate in 
this research, you will not be penalized in any way and you will not lose any benefits 
to which you are entitled. If you have questions about your rights as a research 
subject, please call the University of Florida Institutional Review Board (IRB) office at 
(352) 273-9600.     
a) In general, what is the purpose of the research, how long will you be 
involved?   
The purpose of the research is to study how sleep and pain are related in older 
adults. 
You are being asked to participate in this research study because you are an older 
adult over 45 years of age experiencing pain of at least moderate intensity on more 
days than not during the past three months, and who also reports poor sleep 
quality.  We are studying how taking the brain chemical, Gamma-Aminobutyric acid 
(GABA), may benefit both conditions. GABA is one of the most important 
chemicals in the brain. GABA has many different effects on the body including 
emotions, sleep and pain. The study takes approximately 3 months, with follow up 
calls 3 months after study completion, for a possible total study duration of up to 6 
months. 
A description of this study will be available on http://www.ClinicalTrials.gov as 
required by U.S. Law. This website will not include information that can identify 
you. At most, the website will include a summary of the results. You can search 
this website at any time. 
b) What is involved with your participation, and what are the procedures to be 
followed in the research?  
Your participation will involve 4 study visits with a medication period. You will 
undergo various testing before and after taking GABA or placebo by mouth. See 
below (#7) for more in depth information on the procedures. 
c) What are the likely risks or discomforts to you? 
Likely risks and discomforts associated with this study include a risk of falling or 
losing your balance while performing the physical performance procedures and 
activity tests. The hot and cold pain testing procedures may also produce 
discomfort at the area of stimulation, which may result in mild reddening of the 


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skin. There is a slight chance that the pressure testing may leave a small bruise at 
the area of stimulation. In addition, the Magnetic resonance imaging (MRI), a body 
pictures created by using magnetic energy rather than x-ray energy, may feel 
uncomfortable if you do not like to be in close spaces. The MRI scanner produces 
a loud hammering noise; however, earplugs will be given to reduce any risk. Also, 
the risks of drawing blood from a vein includes discomfort at the site of puncture, 
which can leave a bruise or swelling at the puncture site. Last, you may feel 
uncomfortable answering some of the questions on the questionnaires or become 
stressed or frustrated on the thinking and memory tests. 
d) What are the likely benefits to you or to others from the research?  
The likely benefits to you or to others from the research are listed in depth on 
question (#11). Some participants may experience improved pain and sleep 
quality. Participation in this research study may help advance our understanding 
of sleep and pain as well as help to develop better treatments for individuals with 
pain and sleep problems.  
e) What are the appropriate alternative procedures or courses of treatment, if 
any, that might be helpful to you?   
Only your physician can inform and prescribe you of any alternative treatments 
you qualify for. You have the option not to participate in the present study.  
Additional and more detailed information is provided within the remainder of this 
Informed Consent form, please read before deciding if you wish to participate in this 
study. 
 
WHAT CAN YOU EXPECT IF YOU PARTICIPATE IN THIS STUDY? 
 
6. What will be done as part of your normal clinical care (even if you did not 
participate in this Research Study)?  
Dr. Cruz-Almeida or Dr. Montesino do not provide clinical care. Your clinical care will 
not be affected by your participation in the current study. 
 
7.  What will be done only because you are in this Research Study?  
You will take, by mouth, 2 pills of GABA (500 mg) (Capsule 250mg) or Placebo daily at 
home, at 08:00 pm, over 4 weeks. This study has the following parts:  
• Initial screening 
• 2 baseline study visits (Health and Sensory testing and Neuroimaging visit) 
• 4-week medication phase during which you will take the GABA/PLACEBO 
daily and short weekly phone contact with study staff. 
• 2 study visits after the intervention (Health and Sensory testing and 
Neuroimaging visit) 
• Repeat Follow-up phone contact one week, and 3 months 
• Wear an OURA ring during the entire study  


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All study visits (4 visits in total) will be conducted in the Dental Tower, and the McKnight 
Brain Institute at the University of Florida. Each visit is expected to last between 2 and 
2 ½ hours for a total of 10 hours. You will be taking by mouth the GABA or PLACEBO 
pill in your home for a period of 4 weeks.  
You will be assigned by chance, much like the flip of a coin, to receive either GABA 
or a placebo pills to take. The placebo is a substance that looks like and is given in 
the same way as the GABA but contains no GABA. Neither you nor the research 
assistant will know which type of pill you are getting. This information is coded and 
securely stored away until the data is analyzed. This is called a “double-blind study” 
for that reason, but that information is available if it is needed.  
There is some flexibility on when the following assessments may be conducted and in 
general, questionnaires and other testing may be collected during any session that is 
most convenient for you as long as it is collected before you start taking the study 
treatment. 
Medication Part: 
Screening, Baseline Health Assessment and Sensory testing Visit:  Together with 
the information obtained in the phone pre-screening that we have already conducted, 
the main purpose of the screening visit is to find out if you are eligible to continue in 
the study.  
At the beginning of this visit, after receipt the signed copy of the informed consent, we 
will conduct a physical examination including vitals (blood pressure, temperature, and 
pulse as well as weight, waist circumference, and height) medical, sleep and pain 
history and the review of systems. 
You will be given some questionnaires concerning your health, pain, sleep, and 
feelings and emotions. You do not have to answer any questions that you do not want 
to answer. 
If after this first part of the visit, we determine that you are not eligible for this 
study because you have a condition that interferes with the study or the study would 
put you at risk, you will still be compensated for your time. If you are eligible to continue 
in the study, we will do the second part of the visit that include, the blood draw, Urine 
Test, pregnancy test (if you are women under the oge of 62), and the sensory testing. 
• A blood draw (~3 tablespoonfuls) by a phlebotomist (someone who is trained 
to collect blood samples). The study clinician will review the blood tests. Results 
of blood may indicate that you should not participate in the study (e.g., certain 
test results could be out of normal range). If this is the case, we will give you a 
copy of your lab results, so that you may share them with your own medical 
provider and seek care if appropriate. All samples will be stored in a locked 
space, labelled using a unique ID and without any identifiable information. If 
blood is not fully collected during one session, with your request, the remaining 
blood sample may be collected at a later session. We will also collect a urine 
sample to determine how well your kidneys are working.  


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• We will assess in detail your ability to feel sensations due to touch, vibration, 
and changes in temperature on your skin at several locations, some pre-
selected (i.e., hands and feet) and some unique to you (in an area where you 
experience pain that last a long time). You can stop any of these procedures 
at any time. 
 
• Touch Sense: We will measure your touch sensitivity by applying small, plastic, 
blunt-tipped sticks (filaments) of differing thickness against your skin. The 
larger filament is about the thickness of a toothpick and the smaller is about 
three-quarters that size. We will touch your skin with one filament at a time and 
ask you to tell us if you feel any painful sensation. If you have pain, we will also 
assess your pain response to touch that is normally not painful by using another 
plastic filament about one-third the thickness of a toothpick lightly tapping your 
skin 1 to 10 times. Additionally, we will brush your skin with a soft-bristle 
paintbrush 1 to 10 times. 
 
• Vibration Sense: We will use a small blunt device that vibrates more and more 
vigorously over time, and you will be asked to let us know when you first start 
to feel the vibration. We will repeat this procedure 3 times at each test site 
(hands, feet, and painful areas). 
• Temperature Sense: A small metal heating/cooling surface, about the size of 
two adjacent postage stamps, will be placed on your skin. You will be asked to 
tell us when you first feel coolness, warmth, or pain due to cold or heat. We will 
repeat these 3 or 4 times at each site. The metal heating/cooling surface is not 
able to reach temperatures, or be of a duration, that could cause tissue damage 
to your skin. The machine has built-in safety features and algorithms to ensure 
participant’s safety. 
• Sensitivity to Heat: One type of sensation will be produced by a small heat 
probe, or heated metal plate placed on your skin, that will increase in 
temperature. You will feel several different levels of heat. Some of these 
temperatures might cause you to experience pain. You will be asked to tell the 
researcher how the heat feels to you by rating the sensation using numbers or 
a sliding scale. For your safety, the small heat probe is not able to reach 
temperatures, or be of a duration, that could cause tissue damage to your skin. 
The machine has built-in safety features to ensure this. 
• Sensitivity to Cold: A second type of sensation will be produced by a small cold 
contact placed on your skin that will decrease in temperature. You will feel 
several different levels of cold. Some of these temperatures might cause you 
to experience pain. You will be asked to tell the researcher how the cold feels 
to you by rating the sensation using numbers or a sliding scale. For your safety, 
the small cold contact does not reach temperatures, which would cause tissue 
damage to your skin.  
• Pressure Sense: Another type of sensation will be produced by a device that 
will be pressed against the skin for several seconds. This might produce 
pressure pain, similar to what you would feel if you pressed your finger against 


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your skin. You will be asked to press a button and give a rating to indicate how 
the pressure feels to you. 
 
• Pinprick Pressure: We will also apply a series of weighted pinprick probes. The 
probes will not penetrate your skin. We will ask you to tell us which probes 
produce pain, and then a weighted probe will be applied several times in a row, 
and you will be asked to rate the pain experienced from the probe. In addition, 
we will apply a small, plastic, pinprick device to your hand and foot and you will 
be asked to rate the level of pain you experience at each site. 
 
• Combined Heat and Cold Test:  We will also conduct some heat and cold pain 
testing procedures to assess how the heat pain feels by itself, and then we will 
test how the heat pain feels after you remove your hand from a cold-water bath. 
First, we will have you rate several heat pulses. Then, we will ask you to put 
your hand into the cold water for up to a minute. After you take your hand out 
of the cold water, we will ask you. 
 
• to rate the heat pulses one more time. 
 
Before and after the sensory testing procedures, several physical measures will be     
taken including:   
• Blood Pressure and Heart Rate: We will measure your blood pressure and 
heart rate with a device that attaches to your arm. 
 
• Temperature: We will measure the temperature of your skin. This will tell us 
about how stressed you are. We use round flat sensors, about the size of a 
dime, that are taped to the skin in places such as your arm, leg, or finger. You 
will not have any sensation where these sensors are attached to your skin. 
We will also perform tests of your physical ability that include:  
o Standing up from a chair 
o Balance tests 
o Muscle strength tests of your arm and leg 
We will train you on how to use the app you need to have in your cellphone to use an 
OURA ring. You may wear this ring during the entire study period to record your daily 
physical activities (e.g., number of steps you take) throughout the day as well as your 
sleep quality over the night. At the end, you will return the ring to the study 
coordinators.  
 
The OURA ring includes a secure smartphone app that summarizes sensor-monitored 
data. Sleep quality will be captured each day throughout the entire study. Data will be 
downloaded remotely or when the participant reports to the clinic during the 
intervention phase. You will start wearing the device during the baseline weeks and 
at each visit, we will ask you about wearing the ring. 
 
 
 


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Baseline Neuroimaging Visits (up to 2):  
At the beginning of this visit, we will ask to get some information about your general 
health since your last visit, your current grade of pain as well as your feeling and 
emotion at this moment. 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 also receive the GABA or PLACEBO pill you are going to be taking during 
the next 4 weeks since this visit and will be provided with a copy of a medication diary 
log sheet to records the precise date and time of the administration of the 
GABA/Placebo each day. 
We will take pictures of your brain at rest and while at work using magnetic resonance      
imaging (MRI). During the MRI, we will also apply pain since we are also interested in 
examining changes in your brain when you experience pain. MRI is a procedure non-
invasively using magnetic waves to look at soft tissues of the brain-body and is a 
relatively safe and common practice.  
We will also measure chemical changes in your brain at rest using a non-invasive 
technology called magnetic resonance spectroscopy or MRS for short.  
If an obvious gross abnormality is discovered during your MRI scan, the PI will be 
notified immediately. Per the standard protocol of our neuroimaging facility, the on-
call licensed radiologist will receive the scans for review. The radiologist will contact 
you and encourage you to seek further evaluation and follow-up.   
If we cannot finish your imaging session in one visit, we will ask you to come back in 
another visit which will be equally compensated 
Study Medication Period: During the 4-week part when you will take the pill, you will 
also be asked to do the following: 
• You will take either a GABA or Placebo pill by mouth daily at around 08:00 pm, 
over 4 weeks.  
• You will continue to fill in short diary (asking about your bedtime and 
waketimes) that we provided you in your first visit where we ask you about last 
night’s sleep and you will fill it out every day throughout the entire study (3 
months approximately). 
• You will also wear the OURA ring that was shown to you in the previous visit. 
The device will also automatically record your physical activity levels and your 
sleep quality, that information will be updated each day in your OURA 
application we installed in your cell phone in the first visit. We will call you once 
a week during the medication period, to ensure proper remote download of data 
from your ring and also, to ask you whether you experienced any side effects 
or any problems with your health. 
• Every day you will record your pain ratings as well as if you took any pain 
medications.  
 


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We will provide either GABA or Placebo pills and the ring for the duration of the 
medication phase. When the study is complete, you will return both to the study 
coordinator. 
Post-Intervention Health Assessment and Sensory Testing Visit:  You will be 
asked to participate in the following: 
• You will again be physically examined (including vitals) under the supervision 
of the study clinician. 
• We will ask you questions about your health condition since your last visit, your 
current grade of pain as well as your feeling and emotion at this moment.  
• You will be given some questionnaires concerning your pain, sleep, and 
feelings and emotions. These measures will be very similar to the ones you did 
before the intervention phase. You do not have to answer any questions that 
you do not want to answer.   
• Any side effects from the intervention period and recent activities.  
• Another blood draw (~3 tablespoonful) will be conducted by the phlebotomist 
to run blood tests, and another urine sample to measure urine specific gravity. 
The samples will be stored in a locked research space, labeled using a unique 
ID and without any identifiable information. 
• The sensory testing will be the same described before in the intervention 
phase. 
Post-Intervention Neuroimaging Visit: We will ensure that you are eligible and safe 
to participate in the MRI/MRS scanning session on days of testing. This visit will be 
exactly like the Neuroimaging before the intervention. 
Similar to the baseline visits, if brain imaging is not fully collected during one session, 
with your request, the remaining brain images may be collected at a later session and 
you will be compensated for the extra session. 
Upon completion of the study, we will tell you about the general goals of the study and 
answer any questions that you may have. 
Follow-Up Phone Call: We will call you about one week, and 3 months after your last 
study visit to inquire whether you experienced any GABA side effects or any health 
problems. This phone call will consist of questionnaires already exposed to the 
participant. 
If you participate in this research study, as mentioned above, we will collect blood and 
urine for laboratory tests. The samples will be stored in a locked research space at 
the University of Florida. We will use the samples to measure standard clinical 
parameters and the GABA levels in your blood.  
When there is no longer enough amounts of blood samples collected from you for 
analysis, or samples become degraded, or you request in writing that we destroy it, 
any remaining genetic material will be destroyed. The samples will only be accessible 
to the research staff and will be labeled only by an identification number, not your 


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name. The University of Florida will not sell the samples and will not use the DNA for 
cloning.  
Once this research study is completed, any information that could identify you might 
be removed from any identifiable private information or identifiable biospecimens 
collected. After such removal, the information or biospecimens could be used for 
future research studies or distributed to another investigator for future research 
studies without additional informed consent from you or your legally authorized 
representative. You can stop any procedure or test at any time by simply telling us to 
stop. Furthermore, if you have any questions now or at any time during the study, or 
if you have any discomfort or concerns during or after the study, you are encouraged 
to get in contact with the Principal Investigators listed in question 3 of this form. 
 
8. What identifiable health information will be collected about you and how will it be 
used? 
 
The Research Team will also collect: 
• Your contact information 
• Information you provide regarding your demographic, health history, medical 
conditions, and treatments. 
• List of medications you are taking 
• Email and home address  
• Information obtained from the questionnaires 
• Information related to diagnosis of a mental health condition as provided by 
you. 
• Your social security number for compensation purposes. 
• Your responses to study procedures including sensory testing procedures. 
• Results of assessment of your physical abilities  
• Results of imaging by MRI  
• Results of laboratory tests assessing chemical markers related to pain 
perception  
This information will be stored in locked filing cabinets or on computer servers with 
secure passwords or encrypted electronic storage devices until the completion of the 
study.  All data entered into computers or electronic storage files are assigned subject 
ID numbers that are de-identified to ensure that all information is protected.  
Some of the information collected could be included in a "limited data set" to be used 
for other research purposes. If so, the limited data set will only include information that 
does not directly identify you. For example, the limited data set cannot include your 
name, address, telephone number, SSN, photographs, or other codes that link you to 
the information in the limited data set. If limited data sets are created and used, 
agreements between the parties creating and receiving the limited data set are 
required in order to protect your identity, confidentiality and privacy 
The Research Team may collect this information from other healthcare providers, 
such as laboratories, which are a part of this research, as well as healthcare 


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providers that are not part of this research (other doctors, hospitals or clinics). Other 
professionals at the University of Florida or Shands Hospital who provide study-
related care, and the University of Florida Institutional Review Board (IRB), may also 
collect your health information.  
The Research Team listed in question 3 above will use or share your health 
information as described below to carry out this research study.  
 
9.  With whom will this health information be shared? 
This health information may be shared with: 
• the study sponsor (listed in Question 4 of this form); 
• United States governmental agencies which are responsible for overseeing 
research, such as the Food and Drug Administration, the Department of Health 
and Human Services, and the Office of Human Research Protections;  
• Government agencies which are responsible for overseeing public health 
concerns such as the Centers for Disease Control and federal, state and local 
health departments. 
• The IRB that reviewed this Research Study and ensures your rights as a Study 
Subject are protected  
Otherwise, your identifiable health information will not be shared without your 
permission unless required by law or a court order. Once your health information is 
shared with those listed above, it is possible that they could share it without your 
permission because it would no longer be protected by the federal privacy law.  
  
10. How long will you be in this Research Study? 
The entire study is roughly 3 months, over the course of 4 separate visits with follow up 
calls during the study and 3 months after study completion.  
This Authorization to use and share your health information expires at the end of the 
study, unless you revoke it (take it back) sooner. 
 
11. How many people are expected to take part in this Research Study? 
We anticipate that we will need to enroll and screen 50 people to achieve the targeted 
number of participants needed for study completion of 28. 
 
WHAT ARE THE RISKS AND BENEFITS OF THIS STUDY AND  
WHAT ARE YOUR OPTIONS? 
 
12. What are the possible discomforts and risks from taking part in this Research 
Study? 
Equipment used in this research meets all current safety standards and research staff 
is highly trained in the use of all equipment. There are no known physical or economic 


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risks to participants and minimal, if any, known psychological risk from any of the 
procedures. This study may include risks that are unknown at this time. The reported 
side effects in relation to the intake of GABA supplements include dizziness, anxiety, 
drowsiness, dry mouth, balance problems, constipation, blurred vision, itchiness, 
irritation and stomach pain. Despite these being the most common side effects, only 
a small number of users appear to be affected by GABA. The use of GABA oral 
supplement produces no consistent side effects and provides no known risk to 
participants who meet the study’s eligibility criteria.  
During the intervention phase and one week and three months after study completion, 
you will respond to questions to detect any possible side effects or discomfort related 
to drug administration. Throughout the study, the researchers will notify you of new 
information that may become available and might affect your decision to remain in the 
study. 
Magnetic Resonance Imaging (MRI)/Magnetic Resonance Spectroscopy (MRS): MRI 
and MRS are non-invasive procedures that allow study of the brain and body non-
invasively using magnetic fields and radio waves. These procedures are used 
routinely for medical care and are very safe for most people, but you will be monitored 
during the MRI/MRS scans in case any problems occur.  
The risks of MRI/MRS are: 
o The MRI/MRS scanner contains a very strong magnet. Therefore, you may not 
be able to have the MRI/MRS if you have any type of metal implanted in your 
body, for example, any pacing device (such as a heart pacer), any metal in 
your eyes, or certain types of heart valves or brain aneurysm clips. The 
research staff will ask you questions about this every time before you have the 
MRI/MRS. 
o There is not much room inside the scanner. You may be uncomfortable if you 
do not like to be in close spaces ("claustrophobia"). During the procedure, you 
will be able to talk with the research staff through a speaker system, and, in 
the event of an emergency, you can tell them to stop the scan.  
o The scanner produces a loud hammering noise, which has produced hearing 
loss in a very small number of people. You will be given foam earplugs that will 
be placed inside your ear canal and headphones that cover your ears entirely, 
to reduce this risk.  
o If an obvious gross abnormality is discovered during your MRI scan, the PIs 
will be notified immediately. Per the standard protocol of our neuroimaging 
facility, the on-call licensed radiologist will receive the scans for review. The 
radiologist will share his/her findings with the PI, and the PI will contact you 
within a day of receiving the findings and encourage you to seek further 
evaluation and follow-up.   
o You will be monitored very carefully while in the scanner, and repeatedly 
checked upon to ensure comfort. At the end of the MRI/MRS scan, you will 
respond to a questionnaire to detect any possible discomfort related to the 
MRI/MRS scanning. 


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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: Placing a blood pressure cuff on your arm may cause 
pinching or slight bruising.   
Physical Tests: There is a risk of losing your balance and falling, development of chest 
discomfort due to spasm of heart vessels, or being short of breath, due to heart failure 
or lung disease, that could be associated with the physical ability testing (e.g., the ¼ 
mile walk test, balance tests, rising from a chair). We will minimize this risk by: (i) 
safely escorting you to chairs located along the walking course should you become 
unsteady; (ii) following you at a close distance; and, (iii) being at your side should you 
need assistance. Additionally, you may experience very minor muscle soreness 
following some of the physical testing. This soreness usually disappears completely 
after 2 days. To minimize risk, only trained study team members will oversee the 
physical performance tests. 
Questionnaires: You may feel uncomfortable about answering some of the questions 
on the questionnaires. You are free not to answer those questions. 
Sensory Testing: The sensory testing procedures may be uncomfortable or 
unpleasant, in that you may experience some temporary discomfort from the thermal, 
pressure, and mechanical stimulation. However, if you feel the sensation is greater 
than you wish to tolerate, you can stop any of the procedures at any time 
Heat probe: Several things may occur in the area of skin (1 inch square) after the 
heated probe contacts your skin: (1) It may turn red like a mild sunburn, and (2) there 
may be a slight burning feeling after the heat is removed.  For most people this is gone 
in 1-2 minutes.  It may take up to 1-2 hours for all the symptoms to disappear.  It is 
very unlikely (less than 1% chance) that you will get a burn serious enough to cause 
a blister and it depends on the skin susceptibility of each participant.  In addition, you 
can stop any testing at any time if the pain becomes intense.  The risk of an electrical 
injury as a result of your contact with the test equipment is very small and comparable 
to the electrical shock risk of a common household appliance. 
Pressure: There is a slight chance that a small bruise may form as a result of the testing 
your sensitivity to pressure.  If a bruise should appear it is usually short lasting and not 
painful.  
The OURA ring: Wearing the OURA ring has the same physical risks of wearing a 
normal ring. You can wear your Oura Ring 24/7; It's built for all day comfort. It is 
waterproof up to 100m/328 ft.  While unlikely, if you experience skin irritation/redness 
on your finger, remove the product immediately. In case the ring gets stuck on your 
finger: Use cold water and a small amount of soap, wet your finger, and slowly twist 
the ring to remove it. Hold your hand up above your heart until the blood pressure gets 
lower, and then try the removal. In case of emergency, cut the ring with a ring cutter 
from the palm side of the finger - the ring’s thinnest point. Do not cut the ridge of the 
Balance or the plain of Heritage. This prevents the battery from being cut. The lithium-


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ion polymer battery should not have electrolyte flowing, but in case electrolyte comes 
in contact with your skin or eyes, flush it out with water and seek immediate medical 
attention. 
Finally, there is a minor risk that the ring could be stolen, if this happened, there is no 
way to get information from the ring because it is associated with the OURA application 
we installed in your phone. Only authorized personnel have access to research 
information, and no names, social security numbers, or personal information will be 
stored on the OURA application.  
Your Personal Information: Some of the questions you will be asked may be personal 
in nature and may make you uncomfortable. Time will be made to talk with you if you 
appear to be distressed. In addition, we will be asking you for information about sensitive 
issues which may make you feel uncomfortable. If you are uncomfortable answering 
these questions, you can choose not to answer and discontinue participation in the 
study.  Research staff will explain what to do during your clinic visits. There is no right 
or wrong answer on these tests.  
Researchers will take appropriate steps to protect any information they collect about 
you.  However, there is a slight risk that information about you could be revealed 
inappropriately or accidentally.  Depending on the nature of the information, such a 
release could upset or embarrass you, or possibly affect your insurability or 
employability. 
Please note, participating in more than one research study or project may further 
increase the risks to you.  If you are already enrolled in a research study, please inform 
one of the Research Team members listed in question 3 of this form or the person 
reviewing this consent with you before enrolling in this or any other research study or 
project. 
During the study, the Research Team will notify you of new information that may 
become available and might affect your decision to remain in the study.  
The University of Florida is required by law to protect your health information. Your 
health information will be stored in locked filing cabinets or on computer servers with 
secure passwords, or encrypted electronic storage devices, as required by University 
policy. However, there is a slight risk that information about you could be released 
inappropriately or accidentally. Depending on the type of information, a release could 
upset or embarrass you, or possibly affect your ability to get insurance or a job.  
If you wish to discuss the information above or any discomforts you may experience, 
please ask questions now or call one of the Research Team members listed in question 
3 in this form. 
 
13a. What are the potential benefits to you for taking part in this Research Study? 
You may or may not benefit from participating in this study. It is possible, but not 
promised, that some participants may experience improved sleep and/or experience 
some pain relief. 


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13b. How could others possibly benefit from this Research Study? 
Study results will increase our understanding of sleep disorder and chronic pain in aging 
and the role of GABA as a treatment. This would benefit future patients. 
 
13c. How could the Research Team members benefit from this Research Study? 
In general, presenting research results helps the career of a researcher. Therefore, the 
Principal Investigator may benefit if the results of this Research Study are presented at 
scientific meetings or in scientific journals. 
 
13d. Will you be allowed to see the research information collected about you for this 
Research Study?  
You may not be allowed to see the research information collected about you for this 
Research Study, including the research information in your medical record, until after 
the study is completed. When this Research Study is over, you will be allowed to see 
any research information collected and placed in your medical record.  
 
14. What other choices do you have if you do not want to be in this study?  
Participation in this study is entirely voluntary. You are free to refuse to be in the study, 
and your refusal will not influence current or future health care you receive at this 
institution. If you do not want to take part in this study, tell the Principal Investigator and 
do not sign this Informed Consent Form. You have the option to participate in either the 
first or the second part of the study, or both of them. 
You may also refuse to authorize the use of your health information, but if you refuse, 
you may not be allowed to be in this research study or receive any research-related 
treatment that is only available in this research study. However, your decision not to 
sign this Authorization will not affect any other treatment you may be eligible to receive. 
 
15a. Can you withdraw from this study? 
You may withdraw your consent and stop participating in this Research Study at any 
time.  If you do withdraw your consent, there will be no penalty to you, and you will not 
lose any benefits to which you are otherwise entitled. If you decide to withdraw your 
consent to participate in this Research Study for any reason, please contact the 
Research Team listed in question 3 of this form. They will tell you how to safely stop 
your participation. 
You can also change your mind and take back this Authorization at any time by sending 
a written notice to the Research Team listed in question 3 of this form to let them know 
your decision. If you take back this Authorization, the Research Team may only use and 
disclose your health information already collected for this research study. No additional 
health information about you will be collected or disclosed to the Research Team. 
However, if you take back this Authorization, you may not be able to continue in this 
study. Please discuss this with a member of the Research Team listed in question #3. 
 


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15b. Can the Principal Investigator withdraw you from this Research Study?  
You may be withdrawn from this Research Study without your consent for the following 
reasons: 
• You do not follow the instructions given to you by the study team  
• It is not safe for you to continue your study participation 
• Unforeseen administrative reasons 
Ask the Principal Investigators listed in question (#3) of this form if you would like more 
information about this. 
WHAT ARE THE FINANCIAL ISSUES IF YOU PARTICIPATE? 
 
16. If you choose to take part in this Research Study, will it cost you anything? 
Study Services 
The Sponsor will pay for or provide all study services/activities required as part of your 
participation in this study. There will be no cost to you. If you receive a bill related to this 
study, please contact Yenisel Cruz-Almeida, MSPH, PhD, at (352) 294-8584. 
Items/Services Not Paid for by the Sponsor  
Any other medical services provided to you that are not directly required by this study 
will be billed to you or your insurance company in the usual manner. 
 
17. Will you be paid for taking part in this Research Study? 
Yes. You will be compensated in the amount of $35 for each non-MRI session and 
$40 for each MRI session that you attend, and $10 per weekly phone follow up for 4 
weeks; for a total of up to $190 in cash.  
Your payment for participation in this research study is handled through the University 
of Florida’s Human Subject Payment (HSP) Program. Your information which will 
include your name, address, date of birth, and SSN (depending on amount of money 
you are paid) is protected. Access to the (HSP) Program site is limited to certain staff 
with the assigned security role. You will be randomly assigned a specific identification 
(ID) number to protect your identity. If you have any problems regarding your payment 
contact the study coordinator 
If you are paid more than $75 for taking part in this study, your name and social security 
number will be reported to the appropriate University employees for purposes of making 
and recording the payment as required by law. You are responsible for paying income 
taxes on any payments provided by the study. Payments to nonresident aliens must be 
processed through the University of Florida Payroll and Tax Services department. If the 
payments total $600 or more in a calendar year, the University must report the amount 
you received to the Internal Revenue Service (IRS). The IRS is not provided with the 


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study name or its purpose. If you have questions about the collection and use of your 
Social Security Number, please visit: http://privacy.ufl.edu/SSNPrivacy.html. 
 
18.  What if you are injured while in this Research Study?   
If you are injured as a direct result of your participation in this study, only the 
professional services that you receive from any University of Florida Health Science 
Center healthcare provider will be provided without charge. These healthcare 
providers include physicians, physician assistants, nurse practitioners, dentists, or 
psychologists. Any other expenses, including Shand’s hospital expenses, will be billed 
to you or your insurance provider.  
You will be responsible for any deductible, co-insurance, or co-payments. Some 
insurance companies may not cover costs associated with research studies or 
research-related injuries. Please contact your insurance company for additional 
information.  
The Principal Investigator will determine whether your injury is related to your 
participation in this study.  
No additional compensation is offered. The Principal Investigator and others involved 
in this study may be University of Florida employees. As employees of the University, 
they are protected under state law, which limits financial recovery for negligence. 
Please contact Dr. Yenisel Cruz-Almeida at 352-294-5845 if you experience an injury 
or have questions about any discomforts that you experience while participating in this 
study.  
 
 
 


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SIGNATURES 
 
As an investigator or the investigator’s representative, I have explained to the participant 
the purpose, the procedures, the possible benefits, and the risks of this Research Study; 
the alternative to being in the study; and how the participant’s protected health information 
will be collected, used, and shared with others:  
 
 
 
 
 
Signature of Person Obtaining Consent and Authorization  
Date 
 
 
You have been informed about this study’s purpose, procedures, possible benefits, and 
risks; the alternatives to being in the study; and how your protected health information will 
be collected, used and shared with others. You have received a copy of this Form. You 
have been given the opportunity to ask questions before you sign, and you have been told 
that you can ask questions at any time.   
 
 
You voluntarily agree to participate in this study. You hereby authorize the collection, use 
and sharing of your protected health information as described above. By signing this form, 
you are not waiving any of your legal rights. 
 
 
 
 
 
Signature of Person Consenting and Authorizing 
 
Date