Sleep Quality, Heart Rate Variability and Anxiety Following Brain Injury
Conditions: Traumatic Brain Injury, Anxiety
Sponsor: Shirley Ryan AbilityLab

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PROTOCOL TITLE: The association between Sleep, Heart Rate Variability, and Anxiety 
following brain injury. 
PRINCIPAL INVESTIGATOR:
David Ripley, MD, MS
Medical Director, Brain Injury Medicine & Rehabilitation Program
Rehabilitation Institute of Chicago
Phone 312-238-1125
dripley@ric.org
VERSION DATE:
Version 1
STUDY SUMMARY:
Investigational Agent(s) 
(Drugs or Devices)
IND / IDE / HDE # 
Indicate
Special Population(s)
Children 
 Children who are wards of the state 
 Adults Unable to Consent  
 Cognitively Impaired Adults 
 Neonates of Uncertain Viability 
 Pregnant Women 
 Prisoners (or other detained/paroled individuals) 
 Students/Employees 
Sample Size
Funding Source
Indicate the type of consent 
to be obtained
Written 
Verbal/Waiver of Documentation of Informed Consent
Waiver of HIPAA Authorization 
Waiver/Alteration of Consent Process  
Site
 Lead Site ( For A Multiple Site Research Study)
 Data Coordinating Center (DCC)
Research Related 
Radiation Exposure
Yes 
 No 
DSMB / DMC / IDMC
Yes 
No
OBJECTIVES:
Aim: To investigate the association between heart rate variability, anxiety and sleep in 
the Brain Injury population using biosensors. 

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Hypothesis: We predict that decreased heart rate variability and poor sleep quality will 
be significantly correlated with higher self-reported anxiety following BI.
BACKGROUND:
1.1
Anxiety is a common problem after Brain Injury (BI). Anxiety has been 
associated with interference in rehabilitation following BI and worse functional 
outcomes.  Dysregulation of mood, including anxiety are common following 
TBI1. This is a result of the primary neuropathology, as well as secondary 
factors such as sleep disturbances and memory of the inciting trauma.
Depression and anxiety after a TBI are associated with poorer cognitive, 
social, and functional outcomes.4
1.2
The hospital anxiety and depression scale (HADS), is a self-reported scale 
used to measure symptoms of depression and anxiety within the past one 
week. Patients rate the frequency of these symptoms on a 4-point Likert-type 
scale. It has been validated in both medical and general populations, the 
HADS consists of 14 items total and is divided into the Anxiety subscale 
(HADS-A) and Depression subscale (HADS-D). The HADS has strong 
internal validity in the TBI population with good concurrent and discriminant 
validity with other self-report scales.4 In addition, the depression anxiety 
stress scales (DASS-21) is a self-report scale assessing levels of depression, 
anxiety, and stress over the previous week. Items are rated on a 4-point 
Likert-type scale, with higher scores reflecting higher levels of depression, 
anxiety, or stress. The measure displays good-to-excellent reliability and 
validity.5 The association between sleep and anxiety, as assessed by the 
HADS and DASS-21, has not been studied in an inpatient TBI population.
1.3
Sleep Disorders are also common following BI.  Many of the impairments 
demonstrated by individuals following BI may be exacerbated by sleep 
disorders2. Current assessment of sleep in inpatient BI patients is subjective, 
often obtained from patient self-reports or based on gross observation by a 
staff member. The inpatient BI population is frequently in an amnestic state – 
1 Mallya, S., Ornstein, T.J, et. al. 2015. The Manifestation of Anxiety Disorders after Traumatic Brain Injury: A Review. J 
Neurotrauma. 2015 Apr 1;32(7):411-21. doi: 10.1089/neu.2014.3504. Epub 2015 Jan 23.
4 Driskell, L.D., Starosta, A.J., Brenner, L.A. 2016. Clinical Utility and Measurement Characteristics of the Hospital Anxiety and 
Depression Scale for Individuals With Traumatic Brain Injury. Rehabil Psycho 2016 Feb;61(1):112-3. doi: 10.1037/rep0000079. 
5 Lovibond, SH, Lovibond PF. 1995. Manual for the Depression Anxiety Stress Scales (DASS), 2nd. Ed. edn. Sydney: Psychology 
Foundation; 1995. 
6 Betthauser, LM, Bahraini, N, Krengel, MH, Brenner, L.A. 2012. Self-Report Measures to Identify Post Traumatic Stress Disorder 
and/or Mild Traumatic Brain Injury and Associated Symptoms in Military Veterans of Operation Enduring Freedom (OEF)/Operation 
Iraqi Freedom (OIF). Neuropsychol Rev (2012) 22:35–53. DOI 10.1007/s11065-012-9191-4
7 Klein, E., Caspi, Y., Gil, S. 2003. The Relation Between Memory of the Traumatic Event and PTSD: Evidence From Studies of 
Traumatic Brain Injury. Can J Psychiatry. 2003 Feb;48(1):28-33. doi: 10.1177/070674370304800106.
1Orff, H., Ayalon, L. and Drummond, S. (2009). Traumatic brain injury and sleep disturbance: a review of current research. The Journal of Head 
Trauma Rehabilitation 24, 155.

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referred to as post-traumatic amnesia. Therefore, these patients have 
difficulty with accurately reporting their recollection of duration and quality of 
sleep. The use of activity monitors, such as the ANNE sensors or 
BiostampRC patch, may be a more accurate way of measuring quality of 
sleep in patients with BI. 
1.4
No study to date has evaluated the association between anxiety and sleep 
quality after BI. In other populations, sleep deprivation results in an increase 
in self-reported feelings of depressed mood, anger, frustration, tension, and 
anxiety3. Manifestation of such behaviors has the potential to impede the 
patient’s recovery by interfering with participation in therapies while 
participating in inpatient rehabilitation. Properly regulating the patient’s sleep-
wake cycle is one way such behaviors can be minimized as much as 
possible. In addition, early identification and treatment of anxiety and post-
traumatic stress disorder (PTSD) may improve functional recovery for these 
patients.
1.5
Similar to self-reports of sleep, BI patients may have difficulty expressing 
their subjective experience of anxiety to clinicians. Reduced heart rate 
variability has been demonstrated to correlate with symptoms of anxiety in the 
general population.8.4 Using biosensors, such as ANNE sensors or 
BiostampRC patch, the ECG component may be used to calculate heart rate 
variability in TBI patients. Heart rate variability is a physiologic measure that 
has been used to indirectly estimate function of the cardiac autonomic 
nervous system. It is comprised of various frequencies that are influenced by 
circadian rhythm, core body temperature, sympathetic and parasympathetic 
activity.9 Heart rate variability and anxiety has been studied in the mild TBI 
population, however it has not yet been assessed in the moderate and severe 
BI population using validated scales such as HADS and DASS-21.10 
STUDY ENDPOINTS:
This study will enroll up to 100 subjects who have had a TBI. Data collection will end after 
enough subjects have enrolled for adequate analysis of the data. 
STUDY INTERVENTION(S)  / INVESTIGATIONAL AGENT(S):
2.1 ANNETMsensor system: A research grade noninvasive sensor system measuring Vital signs 
monitoring system for sleep worn on the chest and finger, providing respiratory, 
3 Orton, D. and Gruzelier, J. (1989). Adverse changes in mood and cognitive performance of house officers after night duty. British Medical 
Journal 298, 6665.
8 Chalmers, JA, Heathers, JAJ, Abbott, MJ, Kemp, AH, Quintana, DS. 2016. Worry Is Associated With Robust Reductions in Heart 
Rate Variability: A Transdiagnostic Study of Anxiety Psychopathology. BMC Psychol. 2016 Jun 3;4(1):32. doi: 10.1186/s40359-016-
0138-z.
9 Stauss, H. 2003. Heart rate variability and circadian rhythm. American Journal of Regul Integr Comp Physiol 285:R927-R931, 
2003; 10.1152/ajpregu.00452.2003. 
10 Liao, K-H, Sung, C-W, Chu, S-F, et al. 2016. Reduced Power Spectra of Heart Rate Variability Are Correlated With Anxiety in 
Patients With Mild Traumatic Brain Injury. Psychiatry Res 2016 Sep 30;243:349-56. doi: 10.1016/j.psychres.2016.07.001. Epub 
2016 Jul 1.

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Photoplethysmograph (SpO2), Temperature (+/- 0.1 ºC), Continuous Blood Pressure from 
Pulse Arrival Time (PAT) and Pulse Transit Time (PTT) and sleep quality. 
2.2 ActiGraphy: Participants will be asked to wear the Actiwatch for 7 consecutive days in 
conjunction with the sleep and wake diary described below. They will be given the Actiwatch 
to wear at the time of clinical examination. Participants will also be required to wear 
Actigraph during in-clinic sleep visit. Actigraphy is established as a valid and objective 
method of assessing sleep-wake parameters in natural settings3. In addition, the actigraphy 
data can be used to determine the duration and timing of naps, the phase of the rest/activity 
cycle, amplitude of the rest/activity rhythm and activity levels during the day and sleep 
period. Of particular interest is the timing and stability of the sleep and wake (rest/activity) 
rhythm in this older adult population because of the age related changes in circadian timing. 
It is designed for long-term monitoring of gross motor activity in humans and has an 
accelerometer capable of sensing motion with a minimal resultant force of 0.01 x g3. 
Actigraphy has been used on a variety of population, including older adults.  Study 
Participants are instructed to wear an actigraph around the clock (except when bathing) for 
7 consecutive days, on the nondominant wrist. We set the recording parameters as follow: 
epoch length, 0.5 minutes, and threshold automatic sensitivity (the algorithm automatically 
scores an epoch as sleep if the total activity value is equal to or less than the threshold
sensitivity value calculated from the mean score in the active period multiplied by K 
[constant=0.888) and divided by epoch length.
2.3 Biostamp Npoint: Small flexible sensor that contours to the skin. This sensor will be used to 
measure additional physical activity and heart rate. 
PROCEDURES INVOLVED:
Following admission to the inpatient brain injury service, patients will be screened in 
order to determine whether or not they meet all of the inclusion or any of the exclusion 
criteria as outlined above. If a subject is deemed to be a candidate for the research 
protocol, they will be approached in order to obtain informed consent for the study. 
Wearable Biosensors and the ActiGraph will be placed on the subject’s non-dominant 
wrist. If the non-dominant wrist has motor impairment due to brain injury, then the 
ActiGraph will be placed on the dominant wrist. If both arms have motor weakness due 
to the brain injury, then the ActiGraph will be placed on the least affected extremity. The 
ANNETMsensor system set will be placed on the patient’s chest and finger. Sleep data 
will be obtained for seven consecutive nights. For anxiety, we will have a daytime, 5-10 
minute epoch to measure heart rate variability, using ANNE ECG and skin temperature 
sensors, or manual temperature. We will measure overnight sleep, not during the day, 
with ANNE sensor accelerometer and ECG. Sleep log data will be extracted from the 
medical record.
Each subject will be randomly assigned a coded identifier. A list of the subjects’ names 
and respective coded identifiers will be stored in a secure location on one of the co-
investigator’s encrypted and password protected computers at the Shirley Ryan 
AbilityLab. The data collected will be associated with the coded identifiers on a Microsoft 
Excel spreadsheet on one of the co-investigator’s encrypted and password protected 
computer at the Shirley Ryan AbilityLab. Data will consist of sleep and heart rate 
variability data from the wearable biosensors, and sleep logs by nursing staff, self-
reported sleep quality, anxiety and PTSD scales. The scales, HAD, DASS-21 and PCL-
S, will be obtained on five separate occasions.

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The subject will be monitored to ensure they are not experiencing an allergic 
reaction/skin irritation from the wearable biosensor system. If this is the case, the 
treating physician will be notified and they will determine whether or not the patient 
should continue with the study.
Sleep log data will be extracted from the Cerner electronic medical record of each 
patient and recorded in a Microsoft Excel spreadsheet with associated coded identifier. 
Data will be stored on one of the co-investigator’s password protected and encrypted 
computer at the Shirley Ryan AbilityLab. 
Data recorded will include: sleep data as measured by sleep logs, ActiGraph, 
ANNETMsensor system; scores of the HAD, DASS-21 and PCL-S on five separate 
occasions. No long-term follow-up data will be collected. Post-hoc analyses will be 
performed on biometric data collected by the ANNETMsensor system – including heart 
rate, temperature and movement.
Questionnaires
1.
Karolinska Sleep and wake diaries: Participants will be asked to maintain daily sleep logs 
for 7 consecutive days and to note bedtime, wake-up time, total sleep time, sleep latency, 
wake after sleep onset, naps, any unusual events during the day or night, any hot flashes 
per day (if female), and rating of overall sleep quality. The sleep diary will provide more 
detailed information of sleep quality.
2.
The Pittsburgh Sleep Quality Index (PSQI): This self-rated 21 item questionnaire assesses 
individual sleep habits (bedtime, morning rising time, sleep-onset latency, and night sleep 
duration), insomnia, and hypnotic use over a 1-month time interval. The PSQI has internal 
consistency and a reliability coefficient (Cronbach’s alpha) of 0.83 for its seven 
components. The PSQI has been widely applied in a variety of clinical settings and 
epidemiological studies in many countries, because of its satisfactory 
3.
The Berlin Questionnaire: These questions were designed to identify adult patients who are 
likely to have sleep apnea. It asks about snoring behavior, wake time sleepiness or fatigue, 
and the presence of obesity or hypertension. 
4.
Post-traumatic Stress Disorder Checklist: To evaluate for symptoms of PTSD in our BI 
population, we will use the Post-traumatic Stress Disorder Checklist (PCL) which assesses 
self-reported PTSD symptoms within the past 1 month that correspond with the DSM-IV 
criteria and the Davidson Trauma Scale (DTS). These scales have been researched and 
validated for use in civilian and veteran populations.6 The PCL-S, “S” for specific, is a 17-
item self-report measure covering the 17 DSM-IV symptoms of PTSD that specifies date 
and event of trauma.
5.
The Hospital Anxiety and Depression Scale (HADS): It is a self-reported scale used to 
measure symptoms of depression and anxiety within the past one week. Patients rate the 
frequency of these symptoms on a 4-point Likert-type scale. It has been validated in both 
medical and general populations, the HADS consists of 14 items total and is divided into 
the Anxiety subscale (HADS-A) and Depression subscale (HADS-D). The HADS has strong 
internal validity in the TBI population with good concurrent and discriminant validity with 
other self-report scales.4 
6.
The Depression Anxiety Stress Scale (DASS-21): It is a self-report scale assessing levels 
of depression, anxiety, and stress over the previous week. Items are rated on a 4-point 

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Likert-type scale, with higher scores reflecting higher levels of depression, anxiety, or 
stress. The measure displays good-to-excellent reliability and validity.5
DATA AND SPECIMEN BANKING
Subjects will be assigned confidential codes for data collection.  Code assignment will be kept 
separate from data information; subject code will be kept in a secure room under lock and key.  
No personal information will be stored with their data.  Any data, photos or video will be stored 
for 7 years and stored on a secure, password protected computer at Shirley Ryan AbilityLab.  
The data stored includes all information pertaining to the performance based outcomes 
measures and evaluations.
In the event this study will be published, data may be released to report the outcomes of this 
study.  No released data will include identifiable information.
SHARING RESULTS WITH PARTICIPANTS
Results will be shared with participants if they request the information, but only after data 
analysis is complete. Results will only be shared among qualified research staff within Shirley 
Ryan AbilityLab and/or other Northwestern research labs. If the participant is interested in 
seeing the data collected, he/she will be given a summary of analyzed data. Research staff will 
explain and interpret the observations
INCLUSION AND EXCLUSION CRITERIA
Every patient admitted to the Shirley Ryan AbilityLab for rehabilitation following brain 
injury will be screened for the inclusion and exclusion criteria in order to assess their 
candidacy to participate in the study
Inclusion criteria:
Subject must have had a brain injury
Subject must be at least 18 years of age at the time of the injury
The injury must have occurred in the past 6 months
Subject must be medically stable – as determined by their ability to participate in 
acute inpatient rehabilitation
Exclusion criteria:
Current use of beta blockers 
History of sensitivity or previous skin reactions to skin adhesives
Non-English speaking
Pregnant women
Prisoners
This study will not exclude members of the following special populations: adults unable 
to consent.
This study will exclude individuals who are not yet adults, pregnant women, and 
prisoners.

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VULNERABLE POPULATIONS
“ 
“CHECKLIST: Cognitively Impaired Adults (HRP-417)”
PARTICIPANT POPULATION(S)
Accrual 
Number:
Category/Group:
(Adults/Children 
Special/Vulnerable 
Populations)
Consented:
Maximum Number to be 
Consented or 
Reviewed/Collected/Screened
Enrolled:
Number to Complete 
the Study or Needed 
to Address the 
Research Question
cognitive impaired 
adults
40 patients
15 patients
Local
cognitive impaired 
adults
40 patients
15 patients
Study-wide
Total:
cognitive impaired 
adults
40
15
RECRUITMENT METHODS
Subjects will be approached for enrollment into the study following admission to 
the Shirley Ryan AbilityLab. A co-investigator will explain the purpose of the 
research to the subject (and medical proxy if applicable) and obtain informed 
consent for participation in the study.
The source of subjects is admission to the Shirley Ryan AbilityLab for 
rehabilitation following brain injury. 
Admissions to the brain injury service will be assessed to determine if they meet 
all of the inclusion criteria or any of the exclusion criteria as outlined above. 
No advertisements will be used for recruitment
Subjects will not be paid for their participation in the study
WITHDRAWAL OF PARTICIPANTS
Subjects will be withdrawn from the study in the event of a medical event or complication (i.e. 
hospitalization) that may alter the inclusion/exclusion criteria or which limits the patient from 
safely completing the remainder of the study, or at the discretion of the PI. 
Subjects can voluntarily discontinue the study at any time. The participant will then be requested
to notify the Principal Investigator, Dr. David Ripley, in writing or call at 312-238-4745, if 
assistance is needed in this process. Information collected prior to the study discontinuation by 
a participant may still be used by the research team.  
The researchers reserve the right to discontinue study participation for any individual or for the 
study as a whole at their discretion.

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RISKS TO PARTICIPANTS
a.
Participation will be voluntary and participants may terminate participation at any time. The 
alternative to this study is to not participate.
b.
Skin irritation where the wearable sensor monitors or electrodes are attached. This risk will 
be reduced by minimized by excluding people who have a known allergy and discontinued 
use if skin irritation occurs. 
c.
Potential risk of breach of confidentiality. There is potential risk of breach of privacy and 
confidentiality of which will be minimized by having computer based data records identifiable 
only by a participant number. Names will not be stored with the participant data. Identifying 
information will be stored separately in a password protected file that will be linked to a 
participant number. 
POTENTIAL BENEFITS TO PARTICIPANTS
There is no direct benefit for the subject. However this information will be used to develop better 
sleeping surfaces/conditions.
DATA MANAGEMENT AND CONFIDENTIALITY
All personal information (names, addresses, email or phone numbers, etc.) gathered for this 
study that can identify participants will be kept secure to protect their privacy and will never be 
shared at any time with any person or entity. Data collected during the study and shared with 
others will reference participants only by an alphanumeric code. The “master list” linking 
personal information to the alphanumeric code will not be shared, and will be kept by the study 
PI in a secure location. De-identified information gathered from participants will be used by the 
Sponsor of this study.
PROVISIONS TO MONITOR THE DATA TO ENSURE THE SAFETY OF PARTICIPANTS
Participants will be notified if any new information concerning the safety of the study device 
becomes available which may affect their decision to remain in the study. Participants will 
however be asked to perform all activities under the supervision of a trained research staff 
member.
PROVISIONS TO PROTECT THE PRIVACY INTERESTS OF PARTICIPANTS
Every possible precaution will be taken to protect the privacy interests of subjects. To begin with 
participation in this is completely voluntary. Trained research personnel will explain the purpose 
of the study and intended use of subject’s personal health information and precautions taken to 
keep the study information and data confidential.
COMPENSATION FOR RESEARCH-RELATED INJURY
If the subject gets an injury or illness as a result of study, the subject is required to promptly 
notify the PI of the study about the illness or injury. The hospital [Researchers, Shirley Ryan 
AbilityLab, Northwestern University and all affiliated clinical sites] will not pay for medical care 
required because of a bad outcome resulting from participation in this research study. However, 

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this does not keep a subject from seeking to be paid back for care required because of a bad 
outcome.
ECONOMIC BURDEN TO PARTICIPANTS
Subjects will not be compensated for their participation in the study.
CONSENT PROCESS
Informed consent will take place at the Shirley Ryan AbilityLab with authorized study personnel. 
Trained research personnel will guide the participant or authorized guardian through consenting 
process. Participant or authorized guardian will be given detailed explanation of the purpose, 
time line, commitment, procedures, data handling and privacy and confidentiality of information 
pertaining to the study.
Before recruitment and enrollment onto this study, the participant or authorized guardian will be 
given a full explanation of the study and will be given the opportunity to review the consent form. 
Each consent form must include all the relevant elements as approved by the Northwestern 
University Institutional Review Board. Once this essential information has been provided to
the participant or authorized guardian and the investigator is assured that the participant or
authorized guardian understands the implications of participating in the study, the participant or 
authorized guardian will be asked to give consent to participate in the study by signing an IRB 
approved consent form. Subjects will be consented with a new consent form if changes are 
made to the protocol. 
Prior to a participation in the trial, the written informed consent form must be signed and 
personally dated by the participant or authorized guardian and by the person who conducted the 
informed consent discussion. The consent process will take place at the Shirley Ryan 
AbilityLab.
Cognitively Impaired Adults
Cognitive impairments will be determined by the physician, family and if needed, a speech 
language pathologist or psychologist to determine fit for consenting for the study. 
PROTECTED HEALTH INFORMATION (PHI AND HIPAA)
Subjects records will be kept completely confidential: Every possible precaution will be taken to 
protect the privacy interests of subjects. Participation in this study is completely voluntary. 
Trained research personnel will explain the purpose of the study and intended use of a subject’s 
medical information and the precautions taken to keep the study information and data 
confidential. Data will be collected and kept confidential and compliant with HIPAA standards. 
Participants will be assigned an alphabetical or numerical study ID. Identifying data will be kept 
in locked cabinets and password protected servers completely separate from de-identified data.
Research data will be de-identified and stored in locked cabinets in the lab accessible only by 
authorized research personnel. Electronic data will be de-identified and kept on secure, 
password protected servers at the Shirley Ryan Ability Lab. Only authorized research staff will 
be able to access any of the formerly mentioned data. De-identified data will be kept indefinitely. 
Study documentation will be collected and stored and kept confidential and compliant with 
HIPAA requirements. Identifying data will be held for 7 years after the study is completed and 
published.

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All personal information (names, addresses, email or phone numbers, etc.) gathered for this 
study that can identify participants will be kept secure to protect their privacy and will never be 
shared at any time with any person or entity. Data collected during the study and shared with 
others will reference participants only by an alphanumeric code. The “master list” linking 
personal information to the alphanumeric code will not be shared, and will be kept by the study 
PI in a secure location. All personal information linking participants to their data will be 
destroyed after 7 years following the completion of the study.
QUALIFICATIONS TO CONDUCT RESEARCH AND RESOURCES AVAILABLE
Research will be conducted in the Shirley Ryan AbilityLab, a 1.2 million square foot Inpatient 
rehabilitation hospital affiliated with Northwestern University.  The facility houses a full 
contingency of staff and resources for the conduction of translational research, including IT, 
biostatistical support, and clinical care resources.  Dr. David Ripley, the Principal Investigator, is 
an Associate Professor in the Department of PM&R at Northwestern University, with 20 years’ 
experience caring for individuals and conducting clinical research in Brain Injury.  Dr. Arun 
Jayaraman, the Co-Investigator, is Director of the Max Näder Center for Rehabilitation 
Technologies & Outcomes Research at the Shirley Ryan AbilityLab and is an Associate 
Professor of PM&R, Medical Social Science, PTHMS, at Northwestern University.