Foundational Elements of an Alternate Scientific Approach to Developing Veteran-centric Precision Cognitive Restoration Interventions
Phase: NA
Conditions: Moderate Cognitive Impairment, Traumatic Brain Injury, Stroke
Sponsor: VA Office of Research and Development

 
 
 
 
 
 
 
 
 
1641897 Foundational Elements of an Alternate Scientific Approach to Developing 
Veteran-Centric Precision Cognitive Restoration Interventions 
Funding Agency: VA SPiRE 
Optional Study:   Infinite Hero Foundation administered through Northwestern University 
Feinberg School of Medicine-Department of Physical Medicine and Rehabilitation.  
Principal Investigator: Theresa Bender Pape, DrPH, MA, CCC-SLP/L, FACRM 
Version 5:  02 August 2022 
 
 
 
 

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Abstract 
The purpose of this SPiRE is to identify the supports and barriers to scalability of 
Veteran-tailored iTBS and APT across neurologic conditions, with the longer-term goal 
of providing an empirical basis for the tailoring of a broader range of cognitive 
rehabilitation strategies to optimize each Veteran’s cognitive function in daily life. After 
Veterans receive standard cognitive rehabilitation, cognitive impairments often persist 
and if they do make gains there is limited carry-over to daily function. The tenets of 
precision neurorehabilitation suggest that tailored interventions will optimize gains and 
carry-over, but precision-tailoring of cognitive rehabilitation will only be possible if 
researchers develop and test scalable approaches for identifying, organizing, and 
analyzing the multitude of Veteran-specific variables driving and influencing treatment 
responsiveness. This project addresses long-standing scientific barriers to 
understanding treatment responsiveness, particularly study sample heterogeneity and 
individual variability. We address study sample heterogeneity by linking Veterans, 
across TBI and ischemic stroke, according to levels of cognitive impairment. We create 
a cohort of Veterans with a homogeneous level of cognitive impairment, thereby 
enabling explication of person-centric factors influencing treatment responsiveness and 
carry-over to daily function. Advancing understanding of the basic study design 
elements will be achieved by leveraging our knowledge of intermittent Theta Burst 
Stimulation (iTBS) and iTBS paired with Attention Processing Training exercises (iTBS 
+ APT). iTBS is advantageous as it robustly improves working memory with just one 
treatment session. These interventions, together, are advantageous as they can each 
be tailored to a Veteran’s unique cognitive challenges and to target the neural site, 
unique to each Veteran’s neuropathology. These two interventions also directly address 
cognitive deficits, while simultaneously inducing neuroplasticity in neural regions 
hampered or impaired by neural injury. We will study Veterans with moderately impaired 
cognition who, after standard cognitive rehabilitation, continue to struggle with daily life 
requiring assistance with complex instrumental activities of daily living (IADL). Veterans 
will participate in a series of two within-subject treatment studies, conducted on two 
separate days, 2-weeks apart. Veterans will be randomly assigned to first receive a 
single session of Active iTBS or Placebo iTBS and then they will receive APT paired 
with their assigned iTBS (Active iTBS + APT vs Placebo iTBS + APT). We will test if 
diagnosis moderates the effects of these interventions on both immediate and persisting 
change in cognition. For immediate effects, we use a novel testing battery and for 
persisting gains we use established and feasible neuropsychological tests as well as an 
established test of cognitive function during IADL. Results will be used to obtain pilot 
data and examine feasibility in terms of study attrition relative to Veteran fatigue, mood, 
and Veteran reports of suitability of key aspects of the study design. These findings will 
be used to develop a future merit within-subject cross-over study examining the over-
arching hypothesis that tailored iTBS and APT applied to a transdiagnostic sample and 
subsequently matched to a Veteran, according to a biotype algorithm, will result in 
better functional performance of Veteran-valued IADL.  
 
 

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List of Abbreviations 
ABS: Agitated Behavioral Scale 
AMPS: Assessment of Motor and Process Skills 
APT: Attention Process Training 
AUDIT-C:  Alcohol Use Disorders Identification Test 
BAI: Beck Anxiety Inventory 
BRIEF-A: Behavior Rating Inventory of Executive Function 
CDW:  Corporate Data Warehouse 
C-SSRS:  Columbia Suicide Severity Rating Scale  
CTI:  Center for Translational Imaging  
DAI: Diffuse Axonal Injury 
DAST-10:  Drug Abuse Screening Test 
DLPFC: Dorsolateral Prefrontal Cortex 
DKEFS: Delis-Kaplan Executive Function System 
ES: Effect Size 
FIM: Functional Independence Measure 
fMRI: Functional Magnetic Resonance Imaging 
FSS: Fatigue Severity Scale 
GIMME:  Group Iterative Multiple Model Estimation 
IADLs: Instrumental Activities of Daily Living 
ImE: Immediate Effects 
iTBS: intermittent Theta Burst Stimulation 
MCG: Maximum Cognitive Gains 
MDS: Modified Digit Span Test 
MLM: Mixed-Effects Linear Regression Model 

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MRI: Magnetic Resonance Imaging 
NURIPS:  Northwestern University Research Imaging Processing System 
PCL: Posttraumatic Stress Disorder Checklist 
PE: Persisting Effects 
RBANS: Repeatable Battery for the Assessment of Neuropsychological Status 
ROI:  Region of Interest 
TBI: Traumatic Brain Injury 
WAIS-IV: Wechsler Adult Intelligence Scale Fourth Edition  
 

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Contents 
1.0 
Study Personnel ...............................................................................................................6 
2.0 
Introduction ......................................................................................................................6 
3.0 
Objectives ........................................................................................................................7 
4.0 
Resources and Personnel ................................................................................................9 
5.0 
Study Procedures .............................................................................................................9 
5.1 Study Design .....................................................................................................................9 
5.2 Recruitment Methods.......................................................................................................21 
5.3 Informed Consent Procedures .........................................................................................22 
5.4 
Inclusion/Exclusion Criteria .........................................................................................23 
5.5 Study Evaluations ............................................................................................................26 
5.6 Data Analysis ..................................................................................................................30 
5.7 Withdrawal of Subjects ....................................................................................................33 
6.0 
Reporting........................................................................................................................33 
7.0 
Privacy and Confidentiality .............................................................................................37 
8.0 
Communication Plan ......................................................................................................37 
9.0 
References .....................................................................................................................38 
 
 
 

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Protocol Title: Foundational Elements of an Alternate 
Scientific Approach to Developing Veteran-Centric Precision 
Cognitive Restoration Interventions 
1.0 
Study Personnel 
• Principle Investigator: Theresa Bender Pape, DrPH, Hines VA, Clinical 
Neuroscientist Research and Development, (151H) 
Theresa.BenderPape@va.gov  
• Co-Principle Investigator: Gwendolyn Kartje, MD, Hines VA, Chief of 
Neuroscience (151H) Gwendolyn.Kartje@va.gov  
• Co-Investigators:  
o Amy Herrold, PhD, Edward Hines Jr VA Hospital 
o Patrick Riordan PhD, Edward Hines Jr VA Hospital 
o Vijaya Patil, MD, Edward Hines Jr VA Hospital 
o Bridget Smith, PhD, Edward Hines Jr VA Hospital 
o Sherri Livengood, PhD, Edward Hines Jr VA Hospital 
o Ann Guernon, PhD, Edward Hines Jr VA Hospital 
o Todd Parrish, PhD, Northwestern University  
• 2 participating sites: Hines VA, Northwestern University CTI 
2.0 
Introduction 
Each year, 15,000 Veterans incur a new ischemic stroke (stroke) with many of the survivors 
(32% - 56%) experiencing persisting cognitive impairments 1 and continued cognitive 
degradation. 2 For the more than 40,0003 service members with moderate to severe TBI, the 
rates are similar with about 65% experiencing long-term cognitive impairments. 4,5 Considering 
the high prevalence of persisting cognitive impairments and that standard stroke and TBI 
rehabilitation have limited impact in mitigating this fundamental barrier to daily function, this 
protocol tests the scalability of an approach to effectively and feasibly tailor iTBS and APT to a 
Veteran’s level of cognitive impairment.  
 
Considering that Veterans with the same neurologic diagnosis are not homogenous by brain 
pathology or recovery patterns 6,7,8,9 and further that Veteran-specific factors such as level of 
cognitive impairment influence recovery, 10-12 studying treatment responsiveness by diagnosis 
alone is unlikely to advance understanding of how to tailor interventions to maximize each 
Veteran’s daily function. Thus, we apply our recent work 13 and ideas from the field of mental 
health 14 to pilot transdiagnostic sampling. More specifically, we create a sample of Veterans 
with either TBI or stroke who are linked across diagnoses by homogeneous levels of cognitive 
impairment. Applying our recent work, 13 we use the Functional Independence Measure (FIM) to 
broadly link Veterans according to the FIM category of moderate cognitive impairment. This 
category includes individuals with short-term memory problems requiring assistance for problem 
solving and shifting attention. As this is a broad link, we refine the link according to 

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neuropsychological tests of cognitive capacity and by testing cognitive function during IADL 
performance.  
 
This protocol also addresses the need for pilot data to provide the empirical basis for future 
within-subject cross-over studies. 15 The pilot data will inform the need to account for practice 
effects while estimating magnitude and duration of treatment effects from a single session of 
iTBS alone and a single session of iTBS + APT. As iTBS can now be tailored to each Veteran’s 
unique neuropathology 16 and because a single iTBS session can create a potentiated neural 
environment, 17-21 iTBS is ideal to study alone. For healthy controls, one session of iTBS to the 
dorsal-lateral-prefrontal cortex (DLPFC), for example, induces gains in executive functioning. 
22,23 These immediate effects enhance feasibility of future cross-over studies explicating the 
constellation of Veteran-specific factors related to a Veteran’s responses to multiple 
interventions. APT is ideal for pairing with iTBS, in part, because APT can be tailored to each 
Veteran’s unique global and domain specific cognitive challenges. The tenets of metaplasticity 
24,25 also suggest that APT is ideal because APT is based on principles of exercise-dependent 
plasticity 26-28where novel training-exercises across five domains are provided to deliver stimuli 
of differing intensity. When APT is provided after iTBS, the provision of targeted APT stimuli 
during the time of iTBS enhanced plasticity is thought to regulate the plasticity ultimately 
optimizing cognitive gains as well as carry over of training-related gains.  
 
Testing the scalability of an approach to feasibly and effectively tailor iTBS and APT for 
Veterans across stroke and TBI, advances rehabilitation research by enabling future research 
addressing the need for an empirical basis to tailor a broad range of cognitive rehabilitation 
strategies for Veterans across neurologic diagnoses. If the scientific basis for determining how-
to feasibly and effectively tailor cognitive restoration interventions remain undeveloped, then 
Veterans with persisting cognitive impairments will continue to have diminished quality of life 
and sub-optimal function, ultimately relying on caregivers for performing daily activities.  
 
Rehabilitation research capabilities for complex chronic populations will be advanced by 
leveraging the study team’s collective expertise developing neuromodulatory interventions 9,29-40 
and developing methods to mitigate scientific barriers (e.g., imaging motion; 29,31 neural 
targeting; 16 differential diagnoses; 41 detecting treatment responsiveness; 42-44 study designs and 
complex analyses 45). As creating a scientific basis for feasible and effective development of 
precision Veteran-tailored cognitive restoration interventions has never been explored, the PI 
has not been funded in this area. Dr. Bender Pape has, however, assembled an interdisciplinary 
team of experts with established collaborations to address this long-standing need.  
3.0 
Objectives 
Aim 1: Elucidate merits of transdiagnostic sampling. Within the two intervention groups 
(Group 1: n = 24, Active iTBS and Active iTBS + APT; Group 2: n = 24, Placebo iTBS and 
Placebo iTBS + APT], we expect that (1i) neurologic diagnosis (stroke, TBI) will not moderate 
the effect of Active iTBS or Active iTBS + APT on Maximum Cognitive Gain as assessed by the 
Modified Digit Span (MDS) and the Streamlined AMPS (AMPS).  
 
Aim 2: Obtain pilot data to inform estimation of treatment and practice effects. We will 
gather pilot data regarding the magnitude and duration of treatment effects as well as MDS and 
AMPS practice effects. As we anticipate (2i) greater immediate gains in IADL performance 
(AMPS) after Active iTBS + APT when compared to Active iTBS alone, we will compare 
Maximum Cognitive Gains (MCG) on MDS with MCG on AMPS between the Active iTBS and 
Active iTBS + APT groups to determine if MCGs differ in magnitude. We will also determine if 

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Active iTBS + APT trend lines indicate an additive treatment effect of APT on MDS and/or 
AMPS. We also anticipate (2ii) some persisting treatment effects and to explicate these effects 
we will examine effects for Active iTBS and Active iTBS + APT in the short-term (post-pre-
treatment), long-term (2 weeks after a session) and cumulatively across treatment sessions. 
Since the AMPS uses a unique task during each testing interval and MDS uses 1 of 6 alternate 
test forms, we will determine (2iii) presence and magnitude of practice effects by testing 
whether prior exposure to MDS or AMPS results in MDS or AMPS gains for Placebo iTBS.  
 
Aim 3: Explicate study attrition by perceived suitability of aspects the study design and 
the relationship between this perceived suitability and fatigue as well as mood. We will 
test the ideas that (3i) Attrition rates do not differ by stroke and TBI groups, (3ii) Veterans across 
stroke and TBI have similar perceptions regarding suitability of the number and type of tests as 
well as number of study-days, and (3iii) perceived suitability is related to Veteran-reported 
fatigue and mood.  
Aligned with VA RR&D's mission to create knowledge and innovations advancing the 
rehabilitative health and care of Veterans, this project will scale-up the scientific basis for 
developing and, ultimately, delivering Veteran-tailored, interventions that improve the aspects of 
function identified by Veterans across neurologic diagnoses as important to their well-being. For 
Veterans with moderately impaired levels of cognition who are struggling with daily life, thereby 
requiring assistance with complex instrumental activities of daily living, this project will explicate 
critical and practical barriers to developing Veteran-tailored interventions that optimize cognitive 
function in daily life. The results will be used to design and conduct future merit research 
examining the over-arching hypothesis that restorative cognitive interventions developed 
according to transdiagnostic sampling and matched with a biotype algorithm, compared to a 
diagnosis-based algorithm, result in better functional performance of Veteran-valued IADL. 
With additional supplemental funds awarded through the Infinite Hero Foundation administered 
through Northwestern University Feinberg School of Medicine Department of Physical Medicine 
and Rehabilitation, two additional aims have been added to this study.   With the provide funds, 
the study will enable all Veteran participants enrolled in the Pilot study to have their baseline 
fMRI to be collected at Northwestern University Clinical Translational Imaging (NU CTI) center 
located at Olson Pavilion at 710 N. Fairbanks, Chicago, IL 60611.   
Secondly, it will provide additional optional treatment for up to 12 enrolled Veterans with a 
diagnosis of Traumatic Brain Injury who have enrolled and completed the main study.   
Participants with the diagnosis of Stroke will not be eligible to participate in the Optional 
Experimental Treatment sessions.   
Additional exploratory aims are: 
Aim 4: Optimal Neural Targets for iTBS using Group Iterative Multiple Model Estimation 
(GIMME) based on ab a priori fixed network structure comprised of 12 anatomical nodes 
associated with cognitive processing. GIMME will be used to identify common, subgroup and 
unique neural circuits of moderately cognitively impaired participants.   For persons with 
moderate cognitive impairment resulting from TBI, we hypothesize that there will be sub-types 
of persons with common brain circuitry important to cognition. 
 
Aim 5: Determine immediate gains in working memory and performance of complex IADL 
after provision of a single session of iTBS targeting to the same location in the L DLPFC that 
was treated and after a single session of iTBS targeting the optimal GIMME brain target. For 
persons with moderate cognitive impairment resulting from TBI, we hypothesize that average 
gains in working memory and functional performance after a single iTBS session site will be 

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significantly different according to site of stimulation (L DLPFC site, GIMME site). 
 
4.0 
Resources and Personnel 
• 
Research will be conducted at the Hines VA Hospital and Northwestern 
University, Clinical Translational Imaging laboratory (CTI), locate at Olsen 
Pavilion 710 North Fairbanks, Chicago, IL  20211 
• 
Theresa Bender Pape is the PI.  Gwendolyn Kartje is the Co-PI. 
• 
Access to protected health information: All study team members from the Hines 
VA will have access to protected health information. Consultants and 
collaborators from outside the VA will not have access to protected heath 
information. 
• 
Recruitment: Drs. Bender Pape and Kartje, along with trained study personnel, 
will be involved in recruitment 
• 
Obtaining informed consent: Dr. Bender Pape and trained study personnel will be 
involved with obtaining informed consent 
• 
Administering procedures: Dr. Bender Pape will administer procedures as well as 
train study team personnel to administer procedures. 
• 
Data analysis: Zhiping Huo is the team statistician and will lead data analysis 
with all investigators contributing to the interpretation.  
• 
Due to recent award from the Infinite Hero Foundation awarded to Dr. Theresa 
Pape, MRIs for this study will be conducted at Northwestern University Clinical 
Translational Imaging (CTI) laboratory. 
5.0 
Study Procedures 
5.1 Study Design 
Recruitment of Veterans will involve a multi-step process to eliminate those who would be at 
highest risk for adverse events related to study procedures and to identify a cohort of Veterans 
who meet inclusion/exclusion criteria (Figure 1). NOTE:  This is for the primary study, the 
optional study participation will be for individuals with primary diagnosis of TBI.  Veterans with 
diagnosis of stroke are excluded.   
 
Screening: Identifying and Recruiting Research Candidates: 
We will identify a cohort of Veterans from the corporate data warehouse (CDW) by using the 
ICD codes in the national inpatient and outpatient files available with VA Informatics and 
Computing Infrastructure. We will identify Veterans with ischemic stroke or TBI admitted to a 
rehabilitation bed and/or seeking outpatient rehabilitation services (i.e. OT, SLP) from Hines VA 
in the previous 10 years. We will filter and sort this list to exclude primary diagnoses other than 
ischemic stroke or TBI, any dementia diagnoses, deaths and enrollment in extended care. We 
will then re-sort the list by primary and co-occurring diagnoses, gender, age, date of most recent 
neurologic event, comorbid medical conditions including seizure disorders, by last date of a VA 
rehabilitation service, and by prescribed medications (by first and last fill date as well as dose). 
To maximize likelihood of medical stability, Veterans with changes in medications and/or dose 
within 3-months of list extraction will be excluded. We will use the sorted list to minimize 
heterogeneity by excluding Veterans with both ischemic stroke and TBI, receiving anti-epileptic 
medications to control seizures or have a documented seizure three months prior to list 
extraction, and Veterans with these comorbid medical conditions: congestive heart failure, 
implanted pacemakers, defibrillators and/or cochlear implants. We anticipate having at least 

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1,500 Veterans remaining on the list from which we will randomly sample 500 males (250 with 
ischemic stroke, 250 with TBI) who will each be sent recruitment letters. We anticipate a smaller 
percentage of female Veterans on the list, therefore we will send a recruitment letter to all 
female Veterans to reduce risk of results being non-representative across biological sex. The 
letter will introduce the study and inform Veterans that researchers will be contacting them by 
telephone, text, and/or email to determine study participation interest. Veterans will be 
contacted up to 5 times. To determine interest in study participation, male Veterans will be 
contacted according to the order of the randomized list. During telephone contact, male 
Veterans expressing interest in study participation will continue with the telephone call to start 
screening. All female Veterans will be contacted and those expressing interest, will also 
continue with the telephone call to start screening.  
Telephone Screening-Part 1: Stabilization of Functional Recovery and Medical Status: 
Considering that the nature, severity and recovery of functional capabilities vary widely within 
and between ischemic stroke and TBI as well as by sex, the Veteran and/or healthcare 
surrogate will be asked to report current rehabilitation services (VA, non-VA) and if they 
experienced a seizure since their last visit to Hines VA. Veterans reporting active rehabilitation 
services, seizures and/or pregnancy will be excluded. Veterans who report any change in 
medical status since last medical evaluation will be advised to seek follow up medical 
evaluation. Veterans remaining eligible will complete a brief iTBS and MRI safety checklist and 
those without contraindications will proceed to Part-2 of the phone screening.  The 
contraindications identified on the MRI screening form, including but not limited to ferromagnetic 
or other magnetic-sensitive metals implanted in their head or 30cm of the treatment coil (e.g. 
implanted electrodes/stimulators, aneurysm clips or coils, stents, medication pumps, 
intracardiac lines, bullet fragments) or implanted stimulator devised in or near the head (e.g. 
cardiac pacemakers, deep brain stimulators, cochlear implants, and vagus nerve stimulators), 
will be excluded.   
 
Telephone Screening-Part 2: Self-Report of Cognitive Impairment: 
Part-2 involves a second broad screening of cognitive function based on the Functional 
Independence Measure (FIM) completed by telephone interview. This incremental cognitive 
screening approach will circumvent potential diluting effects of including Veterans at extremes of 
the functional impairment continuum (mild, severe). For the 6-months prior to screening, 
Veterans requiring minimal or moderate assistance on problem-solving (scores: 3 or 4) and/or 
minimal assistance or supervision on memory (scores: 4 or 5), will remain eligible. These cut-off 
points are based on recent research by the study team6 indicating that Veterans with these 
scores for these items most likely have short-term memory issues, impeding function, but not 
long-term memory issues. Veterans and/or healthcare surrogates will be asked to report 
location of any non-VA emergency room (ER), intensive and post-acute care treatment and for 
consent to collect these medical records for further screening.  
 
Screening Medical Records: 
The VA electronic medical record and any non-VA medical records will be reviewed to confirm 
completion of rehabilitation services as indicated by inpatient/outpatient therapy reports and 
notes. Veterans actively receiving therapy services will be excluded. To examine medical 
stability, we will also confirm that medical status has remained stable for three months (e.g., 
new seizures, new diagnoses) prior to the records review as well as absence of other 
exclusionary conditions (e.g., having both TBI and ischemic stroke). We will also review 
medications to identify Veterans actively receiving pharmacological neurostimulants. These 
cases will be reviewed by the study neurologist who will consult with the prescribing physician to 
determine safe withdrawal, via titration. If there is question about safety, then the Veteran will be 

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excluded. Dictated radiology reports will be reviewed to identify Veterans with ischemic strokes 
bilaterally who will be excluded.  
 
Medication Review:  For participant inclusion and safety, if the participant is prescribed 
medication know to act on the CNS, an evaluation of cumulative seizure risk and appropriate 
risk mitigation for each patient according to their prescribed medication profile and relative to 
self-reported medications, alcohol consumption (AUDIT-C) and substance use (DAST-10) will 
be evaluated prior to enrollment.   In lieu of excluding participants based on the name of any 
particular drugs or drug classes or limit them to a set, we will follow the procedure as described: 
 
• 
Clinical experts (e.g., Research Neuropsychiatrist Dr. Alexandra Aaronson, 
Neuropsychologist Dr. Patrick Riordan, Neurologist and Epileptologist Dr. Vijaya 
Patil, Neurologist and Stroke Expert Dr. Gwendolyn Kartje) and/or scientific 
subject matter experts (e.g., TBI expert Dr. Theresa Pape, AUD and SUD expert 
Dr. Amy Herrold) will review all CNS acting medications for each research 
candidate/participant.  
• 
CNS acting medications will be reviewed for likelihood of seizure risk according 
to purpose for which the medication was prescribed, dose, speed of dose 
change (increase or decrease), combination with other CNS active drugs or 
other factors potentially contributing to lower the seizure threshold (i.e., sleep 
deprivation, alcohol consumption, marijuana therapeutic and recreational use). 
• 
The determination (by clinical and/or scientific subject matter experts) of likely or 
plausible seizure risk will be used to make these decisions:  
o To optimize patient safety and mitigate risk, participant should be titrated off 
a specific medication(s) or receive a lower dose or alternate medication 
during study participation:  
 
If clinical experts determine that the medication(s) can be safely 
withdrawn or changed, then participant remains eligible. 
 
If clinical experts determine that the medication(s) cannot be safely 
withdrawn or changed, then the participant will be excluded. 
 
To optimize patient safety and mitigate risk, participant should remain on medication as 
prescribed and remains eligible for study participation. 
 
For Veterans remaining eligible, medical records will be further reviewed to document biological 
sex, age, time post ischemic stroke or TBI onset and current co-morbid medical conditions. 
Dictated radiology reports, as well as other records, will be reviewed to document right vs left 
cortical and sub cortical ischemic strokes and number of ischemic strokes. Radiology reports as 
well as clinical notes (e.g., History and Physical) will be reviewed to delineate TBI by etiology 
including diffuse axonal injury (DAI) and ≥ 1 contusion (e.g., blast, vehicular, assaults) or DAI + 
≥ 1 contusion + an anoxic event subsequent to TBI (e.g., respiratory, cardiac). These variables 
will be examined for use as covariates in analyses.  
 
In-Person Eligibility Confirmation: 
Veterans who meet all inclusion/exclusion criteria throughout the phone screening process will 
be consented for participation and proceed to in-person eligibility confirmation. The final 
screening step involves in-person testing at Hines VA to confirm that cognitive impairments are 
moderately impaired in capacity and function as determined by a battery of clinician rated tests 
including RBANS, WAIS-V, DKEFS, BRIEF, Dot Counting Test and AMPS. We measure 
cognitive capacity according to neuropsychological tests that correlate with functional 

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disability.46,47 We developed a testing battery that can be used to determine study eligibility and 
that can be feasibly repeated to use as an outcome indicative of persisting cognitive gains 
(Table 2). The Audit C and DAST-10 will be completed at this time. 
 
Alcohol and Substance Use:  As part of eligibility screening, during the in-person screening, the 
participant will complete the following two self-report tests: 
 
The AUDIT-C is a brief alcohol screening instrument that identifies persons who likely to be 
hazardous drinkers or have active AUD (including alcohol abuse or dependence).  The AUDIT-
C has 3 questions and is scored on a scale of 0-12. Each AUDIT-C question has 5 answer 
choices valued from 0 points to 4 points. In men, a score of 4 or more is considered positive, 
optimal for identifying hazardous drinking or active alcohol use disorders. In women, a score of 
3 or more is considered positive. Generally, the higher the score, the more likely it is that a 
person's drinking is affecting his or her safety.  
 
The DAST, a NIDA CTN common data element, is a brief, self-report instrument for population 
screening, clinical case finding and treatment evaluation research.  The DAST-10 is a 10-item 
self-report instrument that has been condensed from the 28-item DAST. Scores range from 0 to 
10 with scores of 1-2 being considered low level problems that should be monitored with re-
assessments periodically whereas further evaluation is indicated with a score of 3 or more.   
 
Persons with alcohol use disorder (AUD) and/or substance use disorder (SUD) diagnoses 
confirmed by clinical and/or scientific experts (e.g., Research Neuropsychiatrist Dr. Alexandra 
Aaronson, Neuropsychologist Dr. Patrick Riordan, Neurologist/Epileptologist Dr. Vijaya Patil) 
and/or scientific subject matter expert (e.g., Dr. Amy Herrold) will be excluded. 
 
Persons who do not have AUD or SUD but do consume alcohol and/or use elicit substances at 
a level, as determined by clinical and/or scientific experts (e.g., Research Neuropsychiatrist Dr. 
Alexandra Aaronson, Neuropsychologist Dr. Patrick Riordan, Neurologist/Epileptologist Dr. 
Vijaya Patil) and/or scientific subject matter expert (e.g., Dr. Amy Herrold), likely to elevate 
seizure risk (i.e., hazardous level plausibly lowering of seizure threshold) will be excluded. 
 
If a participant screens positive on the AUDIT-C (Men score of 4 or more, women score of 3 or 
more), then they will be referred to their clinical care team for further evaluation and clinical 
management. 
 
If a participant scores 1 to 2 on the DAST, then substance use will be monitored by having 
researchers re-administer the DAST on each study day.  
 
If at any time a participant scores a 3 or more on the DAST, then they will be referred to their 
clinical care team for further evaluation and clinical management. 

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For this within-subject placebo-controlled partially-blinded treatment protocol (Fig 2), we will 
enroll 48 medically stable Veterans with stabilized recovery trajectories after a stroke or a TBI 
and who have a homogeneous level of moderately impaired cognitive function persisting after 
standard rehabilitation.  
 
An equal number of Veterans with stroke/TBI (24-stroke; 24-TBI) will be enrolled, but we will 
over-sample females (Figure 2). For each iTBS group to include an equal number of Veterans 
with stroke/TBI, Veterans will be randomly assigned by diagnostic groups, to receive Active 
iTBS or Placebo iTBS. To measure immediate effects (ImE), an equal number of Veterans with 
stroke/TBI within each iTBS group will be randomly assigned to be tested with the Modified Digit 
Span (MDS) or AMPS, three times at 30 min intervals. Persisting effects (PE) tests will be 
administered to all participants at five timepoints including prior to and after Active iTBS or 
Placebo iTBS and 2-weeks later prior to the 2nd intervention, where all Veterans receive APT 
paired with their assigned iTBS (Active iTBS + APT or Placebo iTBS + APT). The alternate ImE 
test is then administered three times at 30 min intervals, followed by re-administration of all PE 
tests. Two weeks later, all PE tests are administered a 5th time (B4). ImE and PE measures are 
used to define magnitude and duration of cognitive change. Randomization (SAS Proc Plan) will 
be managed by one un-blinded researcher who will not provide interventions or conduct testing. 
 
Figure 2. Study Design (ImE = Immediate Effects Tests: AMPS = AMPS or MDS = Modified Digit Span;    PE = 
Persisting Effects Tests for all participants; Study Day-1: Obtain Covariates and Treatment preparation information;  
B0 = Pre-Study-Day-2; B1 = Post-Study-Day-2; After 2-Weeks B2 = Pre-Study-Day-3; B3 = Post-Study-Day-3; After 
2-Weeks B4 = Study-Day 4) 
 
Study-Day 0 (In Person Eligibility Screening) (2-3 hours) 
1. Complete questionnaires and testing 
a. Audit-C and DAST-10 

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b. Testing questionnaires 
c. Demographic information collection 
 
Study-Day 1 (~5 hours) (may occur over 2 days): 
1. Complete tests/questionnaires that are not repeated. Some are collected for use as 
covariates (Table 2) and some are needed for treatment preparation.  
a. Baseline testing battery 
b. APT Baseline 
c. fMRI-to be completed at NU CTI 
d. Motor Threshold 
e. Baseline EEG* 
2. Rating suitability of the number and types of tests 1-3.   
*EEG to be completed prior and reviewed by physician prior to Motor Threshold    
 
Study-Day 2 (4 days after Study Day 1)(~8 hours):  
1. PE testing battery 
2. A single session of Active iTBS or Placebo iTBS  
3. Randomly assigned ImE test (MDS or AMPS), administered 3-times at 30 min intervals, 
each interval includes 5 to 15 min of rest). 
4. PE testing battery 
5. Suitability ratings 1-3  
 
Study-Day 3 (2 weeks after Study Day 2)(~8 hours): 
1. PE testing battery 
2. Single session Active iTBS+ APT or Placebo iTBS+APT  
3. Alternate ImE test (MDS or AMPS) three times at 30min intervals  
4. PE testing battery 
5. Suitability ratings 1-3  
 
 Study-Day 4 (2 weeks after Study-Day 3) (~2.5 hours): 
1. PE testing battery 
2. Suitability rating 1-8 
 
Optional Study for Participants with diagnosis of TBI only- Day 5 (to occur within 2 weeks 
of Day 4, can occur on same day as Day 4) (~2 hours)  
1. Single session of Active iTBS at GIMME site of stimulation 
2. ImE test: MDS, one time only 
3. ImE test: AMPS, one time only 
 

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Interventions. All iTBS sessions will be double-blinded, but APT exercises will not be 
blinded. For Active iTBS and Placebo iTBS, the left DLPFC using the Resting Network Mapping 
algorithm.60,93 . 
fMRI (neuroimaging)- Functional MRI (fMRI) measures will be collected at Baseline.  The fMRI 
measures will include structural imaging, 20 minutes of resting-state fMRI, diffusion tensor 
imaging (DTI) and an Arterial Spin Labelling Sequence (ASL). Participants will be in the MRI for 
approximately 55 minutes. fMRI scanning, for all participants, will take place at Northwestern 
University’s CTI in the Olsen Pavilion located at 710 N Fairbanks, Chicago, IL 60611.   
 
Veterans will be responsible for transportation to the CTI, however parking vouchers will be 
provided at not cost to the participant.   Parking is available at the Northwestern Memorial 
Hospital parking garage located across from the Olsen Pavilion.   Research staff will be present 
on day of scan and available to provide assistance.   
 
Scanning will take place on a Siemens Prisma 3.0 T MRI scanner equipped with a 64-channel 
head/neck coil. A high-resolution 3D MP-RAGE T1-weighted sagittal anatomical scan (voxel 
size = 0.8 mm isotropic resolution; 224 sagittal slices) will be collected for each participant. 
Resting state BOLD data will be collected using T2* weighted EPI with a TR=0.5s, TE=25ms, 
flip angle of 48o, and 2mm isotropic voxels and a multiband factor of 8. Rest data will be 
collected while the subject views a fixation crosshair. The DTI data will use a two shell (64 
directions per shell) acquisition with diffusion values of 1000 mm2/sec. The acquisition will 
collect 1.5mm isotropic voxels with a TR=4500, TE=62ms and a multiband factor of 4, and 96 
slices. 
 
The collection of the fMRI data will be directed by Dr. Todd Parrish. fMRI data collected at CTI 
will be de- identified and uploaded to Northwestern University Research Image Processing 
System (NURIPS), an online collaborative research environment for securely storing, managing, 
analyzing and sharing de-identified medical imaging, associated data (e.g., behavioral), and 
results from advanced customizable processing pipelines. NURIPS is supported by both 
Northwestern University IT and Feinberg School of Medicine IT and takes advantage of the NU 
high performance computing cluster, Quest. NURIPS is a secure environment that supports the 
latest NU policy and procedures for encryption of data during transit and rest, provides granular 
project level access controls with varying permissions based on user groups, and allows non-
NU collaborators access once they obtain an affiliate NetID. All data are backed up and have 
restore points that go back for 30 days. Once the data is uploaded to NURIPS, a copy will be 

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downloaded onto Hines VA secure research servers for storage on \\v12.med.va.gov\v12\hin. 
 
Motor Threshold Testing & Brain Mapping Site of Stimulation 
Stimulation intensity that will be used in iTBS will be determined by collecting each participant’s 
motor threshold (MT) using the finger representations of the motor cortex.  The consensus in 
the literature is that iTBS can be safely provided at 80% of active motor threshold (AMT).  Since 
there is more within and between subject variability with AMT (e.g, different gripping strengths), 
relative to resting motor threshold (RMT), scientifically the RMT is preferred. There is also 
recent evidence that motor threshold estimates using RMT and AMT are equivalent.98 This 
means that treatment intensity, based on these two MT estimation procedures, would be 
equivalent, we will use RMT to estimate MT and compute treatment intensity. Thus, the 
standard iTBS parameters will be used in this trial to maximize safety.  iTBS will be provided at 
80% of RMT. 
 
In order to determine motor threshold, a structural brain image of the participant is needed.  
Therefore, eligible participants will undergo an fMRI scan in order to obtain a structural brain 
image also referred to as the participant’s 3D-MPRAGE T1 volume. This T1 image will be 
loaded into the Localite TMS Neural Navigator system which is a Magventure compatible and 
portable neuronavigational system.  Based on the T1 image, the right motor cortex will be 
initially targeted to determine MT. Single pulse TMS will be applied to the optimal scalp location 
(‘hot spot’) to activate the abductor pollicis brevis (APB) in the hand, that functions as an 
abductor of the thumb, on the left hand to determine the RMT, or the lowest stimulus intensity 
necessary to produce MEPs of peak-to-peak amplitude ≥50µV in 5 of 10 subsequent trials.  MT 
is lowest in intrinsic hand muscles and higher in more proximal muscles.  The same data will be 
collected on the opposite hemisphere for comparison measures.  MEPs will be recorded using 
surface EMG electrodes.  Data will be stored on the computer for offline analysis. The 
Magventure C-B60 coil will be used to deliver single TMS pulses for MT determination.  All 
participants, regardless of group randomization will receive MT testing and thus will receive 
some stimulation.  The motor threshold will be measured only at Baseline. 
 
We will use each Veteran’s MT, an indicator of cortical excitability, as the benchmark for 
determining iTBS intensity for each participant ( iTBS intensity will be 80% of each subject’s RMT). 
This intensity will be maintained throughout study participation. 
 
 iTBS will be delivered with the Magventure MagProX100 with MagOption stimulator and Cool 
Coil B65. Active iTBS will be provided using active setting (A) at 80% of each Veteran’s resting 
motor threshold. Placebo iTBS participants will not receive any stimulation as the coil will be 
switched to placebo (P) setting. To maintain double-blind in A and P settings, Veterans and 
researchers wear headphones connected to a sham noise generator.   
 
For APT: 30 min of training exercises, 10 min metacognitive training, and 5 min of functional goal 
setting. Study-Days 2 or 3 sessions will each include novel exercises.  For metacognitive training, 
the Veteran will be instructed on how to use strategies to self-regulate or to “think about his or her 
own thinking” and to self-monitor while performing an activity and efficiently allocate his or her 
cognitive resources. Goals will then be set to implement the strategy in the Veteran’s daily life.     
 
iTBS will be delivered with the Magventure MagProX100 with MagOption stimulator and Cool 
Coil B65. Active iTBS will be provided using active setting (A) at 80% of each Veteran’s resting 
motor threshold. Participants randomized to active iTBS will receive stimulation at the left 
DLPFC at 80% RMT. 80% RMT is the intensity most commonly used and cited in the literature 
and has been shown to be safe26.  The right DLPFC will be marked in the TMS Localite 

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Navigation system for each participant.  The navigation system will provide target guidance and 
will help the researcher to position the coil very precisely in reference to the participant’s brain. 
The neuronavigation system will be used every iTBS session to ensure reproducibility and 
consistency at the stimulation site. 
 
For the Optional Study:  The site of stimulation will be determined by the GIMME modeling.  
Optimal brain target is identified through GIMME modeling, which is a directed functional 
connectivity modeling approach based on iterative model optimization.96,97    
 
Potential Risks: 
 
Physical: The experimental intervention of iTBS being provided is a patterned form of rTMS. 
The biggest concern for transcranial magnetic stimulation (TMS) is seizure induction. Other 
known side effects of rTMS include headache, dizziness, tinnitus, nausea, neck pain, or scalp 
burns.52 Side effects reported to date for iTBS include sweating, feeling dizzy, 53 neck pain, mild 
decrease in diastolic blood pressure, headache, 54 discomfort/mild tingling sensation, 55 
occasional local pain or discomfort during stimulation, and isolated, transient, non-pulsatile, left-
sided tinnitus.56 Additionally, there is risk of equipment malfunction. The Magventure 
MagProX100 with MagOption stimulator and Magpro Cool Coil B65 or one of the coils may 
malfunction which may result in harm to the patient.  
 
Participation in the AMPS requires the Veteran to complete a variety of physical tasks that may 
be challenging to complete. There is a risk of injury depending on the type of task the Veteran 
identifies as valuable to complete (e.g. burns, laceration, falls).  
 
Psychological: Participation in the study outcome measures, including self-report (i.e. PCL), 
observational (i.e. ABS), neuropsychological (i.e. DKEFS, WAIS-IV), cognitive capacity and 
function outcomes (i.e. AMPS, RBANS), effort testing (i.e. DCT) structured interview data 
(AMPS) and safety outcomes (Data Safety Monitoring Scale), involves minimal risks and 
discomforts. The risks for the Veteran include frustration, agitation, anxiety, fatigue, and 
possible trigger of PTSD symptoms.  
 
fMRI: There are no known risks associated with fMRI when individuals are appropriately 
screened, except some people have experienced discomfort in trying to remain still. MRI is not 
safe when specific ferromagnetic materials are present in the body (i.e. metal fragments in 
brain/skull, metal surgical clips, etc). Some people have been noted to be anxious or 
claustrophobic during the scan. The MRI scanner makes loud banging noises during scanning. 
 
EEG:  The self-adhesive used with surface EEG electrodes may produce minor irritation of the 
skin.  The possibility of irritation will be minimized by applying gel to the skin prior to electrode 
placement and by cleaning the skin with alcohol before and after the application of the 
electrodes.  If there is irritation, then additional gel will be used on future applications.  There is 
also the possibility of an allergic reaction to the electrode gel.  If the participant is allergic to the 
gel, then the response plan is to use an alternative gel.  If the scalp is red to the extent beyond 
minor irritation, then the response will be to substitute the standard EEG electrode placement 
with conductive plastic electrodes and the standard electrode placement will still be used. 
 
Protection Against Risk:  
 
Physical: In order to minimize the risk of harm from seizure should one occur during iTBS, motor 
thresholding and all treatments will be provided in a room within the hospital’s Rapid Response 

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area. If Veterans show any signs of seizure or other adverse reaction, study team will contact 
the Hines Rapid Response Team via Rapid Response call button or via phone. Once the Rapid 
Response Team arrives, they will assume responsibility for carrying out all emergency 
procedures.  
 
The treatment room is equipped with a crash cart, defibrillator, pyxis machine and all equipment 
needed to monitor vital signs. The Rapid Response team is triggered via phone call using the 
phone physically located in this room. There is also an accessible code button within 20 feet of 
this room. Researchers have completed training with the Rapid Response and Code teams on 
activating these emergency systems as well as monitoring and caring for the subject while 
awaiting arrival of the Rapid Response or Code teams. 
 
To prevent hearing loss, all Veterans will wear headphones during the iTBS intervention. For 
Veterans who are receiving placebo iTBS, the sham noise generator will be set to a sound level 
that is within the normal hearing range to prevent hearing damage.  
 
The following safety indicators will be tracked at each study day: blood pressure, heart rate, 
fatigue, tinnitus, sleep, dizziness, nausea, vomiting, confusion, seizure, headache, and neck 
pain. Change from baseline is rated according to severity and for each severity rating there is a 
specified medical response to be followed. The ratings are on a scale of 1 to 5 with a higher 
number indicating more deleterious change.  
 
To minimize the risks of iTBS, the following rules will apply for pausing, stopping or rescheduling 
iTBS:  
 
Rules for Pausing treatment to Evaluate Need to Change iTBS Treatment Protocol: 
1) Any seizure  
2) Skin break-down on scalp at site of TMS  
3) Constant headaches that do not resolve with acetaminophen 
4) Suicidality response  on C-SSRS is 2 or higher   
5) A composite score of visuomotor processing speed assessments that falls below 2 
standard deviations from the mean. 
Rules for Stopping iTBS Treatment/Study Participation: 
1) Shock (of any etiology), 
2) Any seizure activity that study epileptologist deems as categorizing someone as unsafe 
to continue iTBS   
3) A participant who previously agreed during consenting procedures to stop taking 
amphetamine and non-amphetamine/methylphenidate CNS stimulant medications 
reports initiating taking these medications, and does not wish to forgo CNS stimulants 
for remainder of study participation  
4) Any participant experiences a change to their prescribed medications, either initiating a 
new mental health medication or experiencing a prescribed change in dose for mental 
health reasons during study participation  
5) Participants with a positive urine pregnancy screen or report new pregnancy (for 
females)  

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Rules for Rescheduling Treatment Session 
1) Participant reports taking CNS stimulants (non-amphetamine/methylphenidate and/or 
amphetamine-based stimulants), but express willingness to  discontinue CNS 
stimulants to enable continued study participation  
2) Subject reports sleep disruption and epileptologists determine that iTBS should not be 
provided during scheduled visit, but could be provided after sufficient sleep is 
achieved.  
 
To prevent equipment malfunction, the equipment will be inspected before and after each iTBS 
session. Manufacturer guidelines will be followed according to maintenance and useful life of 
the device. Should any equipment appear broken or have loss of integrity, the equipment will 
not be used until it is inspected by the biomedical engineering department at Hines VA Hospital 
and the Magventure service representatives.  
 
Dr. Theresa Bender Pape has secured an FDA Investigational Device Exemption (#G150119) 
for the intended use of this device (Magventrue MagPro X100) for persons with mild TBI. Safety 
protocols and total amount of stimulation are the same as the currently approved FDA IDE. An 
FDA Investigational Device Exemption has been secured dated 1.12.2022., G210364. The FDA 
has found that iTBS does not present a risk to the health, safety, or welfare of individuals with 
brain injuries, and does not cause seizures at a rate of stimulation used in the current research 
design for persons without brain injury. However, it is noted that the risk of causing a seizure in 
persons with brain injuries or ischemic stroke is not known but it is possible that iTBS could 
cause one or more seizures.  
 
In event of a seizure, the following response will be administered: 
• 
Within 0-5 Minutes: Stabilization phase, initiated immediately upon patient 
demonstrating seizure-like activity 
o Stop stimulation 
o Notify RRT (Rapid response team) and MD experienced in seizure 
management 
o Basic Seizure First Aid will be provided by research staff until RRT 
arrives: 
 
Ensure patient in safe position 
 
Stabilize patient (airway, circulation, breathing, neurologic exam) 
 
Track time 
 
Obtain vital signs (BP, HR, RR and SpO2) 
 
Vast majority of seizures are self-limited within 5 minutes1 
• 
Within 5-20 minutes: Initial therapy phase 
o RRT arrives within 5-10 minutes of seizure onset and assumes 
responsibility for carrying out all emergency procedures. Research team 
will notify RRT of intervention and patient’s vital signs thus far to facilitate 
coordination of care. RRT initiates the tasks below; the time frame for 
these tasks may run into next phase. 
 
O2 administration if SpO2 <90% 
 
Cardiac monitoring 
 
Glucose assessment 
o MD will assess the situation and prescribed benzodiazepine will be 
administered by RRT if indicated. Respiratory support will be provided by 
RRT if necessary. 
• 
Within 20-40 minutes-Second therapy phase 

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o Emergency medical services continues individualized care. 
o Following termination of seizure activity, medical evaluation completed by 
emergency room physician, Dr. Patil, covering MD or on call Epilepsy 
physician 
RRT will determine timing of transportation to ER once subject is determined to be 
stable for transport. 
 
The stimulating coil will be used on multiple Veterans. To prevent the spread of contamination 
from one Veteran to the next, the coil will be disinfected and sanitized after every iTBS session. 
  
To further ensure participant safety, all female Veterans will submit to a urine pregnancy screen 
at baseline. If the urine screen is positive for pregnancy, the Veteran will be excluded from 
participation.  
 
To prevent injury during participation in AMPS assessment, all Veterans will be supervised by 
an AMPS certified Occupational Therapist.  
 
Psychological: If the participant exhibits frustration or fatigue, then the response plan is to pause 
testing and comfort them. Testing will be resumed after the Veteran exhibits signs of reduced 
frustration. Should the Veteran experience PTSD symptom trigger during any treatment or 
testing, the response plan will be to immediately consult with the Hines Mental Health Service 
and follow their recommendation.  
 
To monitor depression, specifically suicide ideation, the C-SSRS will be administered at 
baseline and repeated as part of each battery assessment.  Administration of the C-SSRS will 
be as defined: 
 
At each C-SSRS administration, all participants will complete the first two questions, #1 
‘wish to be dead’ and # 2 non-specific active suicidal thoughts’ 
 
For participants answering questions 1 and 2 affirmatively, then researchers will 
administer the entire C-SSRS and 
 
For Lifetime: If the C-SSRS results indicate that a participant endorses having 
had suicidal ideation or a suicide attempt in the past, then the participant will be 
asked if their mental health provider(s) are aware of this. 
o  If provider(s) are aware, and patient denies all suicidal ideation/behavior 
at the present time (i.e., past month), participant will be allowed to 
proceed in the study. 
o If the participant is not actively engaged in mental health treatment, then 
the research psychiatrist will be contacted to determine what form of 
psychiatric care is warranted at this time (e.g., contacting of emergency 
authorities, escorting participant to intake for scheduling an outpatient 
evaluation).  
o If they are engaged in mental health treatment and their mental health 
providers are not aware of past suicidality, then researchers will inform 
the mental health provider(s) of past suicidality and the determination of 
study eligibility will be made based on the recommendations of these 
mental health providers 
 
For Past Month: If at any point during the C-SSRS subject endorses passive 
suicidal ideation at the present time (wish to be dead in past month), then: 
o The study team’s psychiatrist will be contacted to evaluate subject 
symptom acuity, and:  

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 
If the participant is actively engaged in mental health treatment, 
then the study team’s psychiatrist will discuss the case with the 
participant’s mental health provider who will determine the safety 
of subject continuing in the study. 
 
If the participant is not actively engaged in mental health 
treatment, then the research psychiatrist determine what form of 
psychiatric care is warranted at this time (e.g., contacting of 
emergency authorities, escorting participant to  intake for 
scheduling an outpatient evaluation).  
If subject endorses any active suicidal ideation (C-SSRS questions 3 through 5) OR recent 
suicidal behavior (i.e., preparatory behaviors, self-harm, recent suicide attempt) subject will be 
excluded from study AND study team psychiatrist will be contacted to evaluate subject and 
determine what form of urgent psychiatric care is warranted at this time (e.g., contacting of 
emergency authorities, contacting of subject's mental health provider(s)). 
fMRI: Prior to enrollment into the study, prescreening is completed with research staff to 
evaluate the Veteran’s compatibility and safety for having an MRI related to the presence of 
ferromagnetic material in the body (i.e. metal fragments in brain/skull, metal surgical clips, etc). 
Prior to the MRI, the MRI safety checklist is repeated (from screening) and reviewed for 
contraindications.  Some people have been noted to be anxious or claustrophobic during the 
scan. In the pre-screening process, it is asked and reviewed if the Veteran has any issues with 
claustrophobia or anxiety in closed spaces. The Veteran may be recommended to not 
participate in the study if it is unknown. The MRI scanner makes loud banging noises while 
taking a measurement, so either ear plugs, or specially designed headphones will be used to 
reduce the noise. The researchers will be in communication with the participant through an 
intercom system to ask how the participant is doing. The earplugs should not get in the way of 
communicating with the researchers. The participant can speak to the technician by talking out 
loud. If at any time, or for any reason, the participant wishes to stop the exam, he may do so by 
squeezing a rubber ball. 
This protocol will involve the vulnerable population of persons with cognitive disabilities and may 
involve persons lacking decisional capacity. Due to the nature of the medical condition of the 
Veterans recruited, the healthcare surrogate (legally authorized representative) may be the 
person providing informed consent for research participation. All Veterans will provide assent in 
addition to the informed consent if necessary to obtain consent from the healthcare surrogate. In 
order to develop treatments to improve cognitive function, individuals with cognitive impairment 
related to ischemic stroke or TBI must participate in the current study design. 
5.2 Recruitment Methods 
48 Veterans will be enrolled.  
We will identify a cohort of Veterans from the corporate data warehouse (CDW) by using the 
ICD codes in the national inpatient and outpatient files available with VA Informatics and 
Computing Infrastructure. We will identify Veterans with ischemic stroke or TBI admitted to a 
rehabilitation bed and/or seeking outpatient rehabilitation services (i.e. OT, SLP) from Hines VA 
in the previous 10 years. We will filter and sort this list to exclude primary diagnoses other than 
ischemic stroke or TBI, any dementia diagnoses, deaths and enrollment in extended care. We 
will then re-sort the list by primary and co-occurring diagnoses, gender, age, date of most recent 
neurologic event, comorbid medical conditions including seizure disorders, by last date of a VA 
rehabilitation service, and by prescribed medications (by first and last fill date as well as dose). 
Once a list of possible participants is generated, a chart review encompassing CPRS, JVL and 

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CAPRI will be conducted to review for pre-screening of eligibility, including, but not limited to, 
medication (and recent changes (and recent inpatient services for medical stability.   We will use 
the sorted list to minimize heterogeneity by excluding Veterans with both ischemic stroke and 
TBI, receiving anti-epileptic medications to control seizures or have a documented seizure three 
months prior to list extraction, and Veterans with these comorbid medical conditions: congestive 
heart failure, implanted pacemakers, defibrillators and/or cochlear implants. We anticipate 
having at least 1,500 Veterans remaining on the list from which we will randomly sample 500 
males (250 with ischemic stroke, 250 with TBI) who will each be sent recruitment letters. We 
anticipate a smaller percentage of female Veterans on the list, therefore we will send a 
recruitment letter to all female Veterans to reduce risk of results being non-representative 
across biological sex. The letter will introduce the study and inform Veterans that researchers 
will be contacting them by telephone, text, and/or email to determine study participation interest. 
Veterans will be contacted up to 5 times. To determine interest in study participation, male 
Veterans will be contacted according to the order of the randomized list. During telephone 
contact, male Veterans expressing interest in study participation will continue with the telephone 
call to start screening. All female Veterans will be contacted and those expressing interest, will 
also continue with the telephone call to start screening. 
 
A flyer will be created to provide to VA clinicians to provide to potential candidates or caregivers 
and post in approved common areas. We will also screen medical records of Veterans in 
relevant clinics, such as Neurology, which will be accessed through CPRS. 
Veterans will receive $100 compensation for completed participation in the study protocol. 
Compensation will be disbursed via Electronic Funds Transfer (EFT) using the veteran’s 
preferred method (ex. Direct Deposit or Direct Express Debit card, etc.). Veterans who are 
unable to utilize this option may not be able to receive compensation. Participants will have an 
opportunity to discuss this option prior to consenting to participate in the study.  The participant 
will be advised payment will take up to 10-14 days to show on their provided account. 
There is no additional compensation for participation in the optional study treatments.   
Parking vouchers will be provided at the time of visit to Northwestern University CTI.   As long 
as participant parks in designated Northwestern Memorial parking garage, they will receive a 
voucher for the parking.   Map and directions to the appropriate lot will be provided prior to the 
appointment.  
5.3 Informed Consent Procedures 
No informed consent waivers will be obtained. 
A partial HIPAA waiver will be requested for recruitment and initial screening.  
The consent process will be conducted in English by trained research staff at Hines VA in a 
designated, private treatment room. Because some of the assessments used are currently only 
validated in English, the Veteran, and as necessary, the healthcare surrogate must be fluent in 
written and verbal English. If either of these individuals cannot speak English, the Veteran will 
be excluded from the study. The Principal Investigator will be available for further discussion or 
questions regarding research participation as needed during the informed consent meeting.  
Informed consent documents will be made available to potential participants, and as applicable 
the healthcare surrogate, prior to the informed consent meeting. Research participants have 

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access to research staff to assist with any questions or concerns until understanding is achieved 
to the judgment of the individual asking the question. If a potential participant refuses, no further 
contact will be made. If the Veteran, or healthcare surrogate with assent of the Veteran, 
consents to the study, a copy of the signed consent is provided, a copy is filed with the Hines 
IRB, and the original Informed Consent is placed in a research binder and maintained in a 
locked file cabinet at Hines VA. Once the informed consent process is completed, a note will be 
documented in CPRS (Hines Electronic medical record system) and the Veteran will be flagged 
as a research participant. 
The optional study procedures will be included in the informed consent, if the participant is 
eligible to participate in the optional procedures, the researcher will provide information about 
the additional treatment sessions.   The participants will initial their assent or dissent to 
participation in the optional study treatments.   It will be communicated in the informed consent 
process that they can change their mind in participation of the additional treatments and 
participation at any time.   If they chose to opt out of the participation, documentation will be 
made in the participants study binder and CPRS.   If they chose to opt in after initially declining, 
a new Informed consent will be signed and dated, and documentation will be made in 
participants study binder and CPRS. Participation in the optional study procedures will not have 
impact in the participation in the primary study.    
 
Northwestern Specific Procedures:  All participants will sign a Northwestern IRB approved 
consent form and a VA approved consent acknowledging participation in a VA sponsored study.  
Copies of the Northwestern signed consent forms and original VA consent forms will be mailed 
via chain of mail custody to the Clinical Research Coordinator at the Hines VA.  Copies of the 
VA consent will be provided to the Hines IRB.  Consent documents will be stored in locked file 
cabinet, behind a locked door at the Hines VA Building 1, Room B317. A copy of the signed 
Northwestern consent form will be provided to NU through the Study Tracker system. 
 
5.4 Inclusion/Exclusion Criteria 
Table 1. Inclusion/Exclusion Criteria 
Inclusion Criteria 
Exclusion Criteria 
• 
Diagnosis of TBI or 
Ischemic Stroke 
• 
2-10 years post 
neurologic event 
having completed 
rehabilitation 
• 
Age 18 - 80 years old  
• 
Medically stable 
• 
Fluent in English 
• 
Moderately impaired 
cognitive function as 
defined by AMPS 
Processing sub-scale 
measures falling 
below 1.0 logits 
• 
Moderately impaired 
cognitive capacity as 
• 
Have BOTH TBI and Ischemic Stroke 
• 
Intracranial lesions or hemorrhagic 
stroke 
• 
Other primary neurologic diagnosis 
• 
Any dementia diagnosis 
• 
History of/or symptoms of psychotic 
spectrum disorders (i.e., bipolar, 
schizophrenia) 
• 
Persons with alcohol use disorder 
(AUD) and/or substance use disorder 
(SUD) diagnoses confirmed by 
clinical and/or scientific experts 
• 
Reside in an extended care facility 
• 
Less than 2 years post TBI or 
ischemic stroke 
• 
Anti-epileptic medications for seizure 
activity 

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defined by having two 
or more scores falling 
≥1 standard deviation 
below age normed 
expectations on: the 
RBANS index scores, 
DKEFS Color-Word 
Trials 3 and 4 scale 
scores, and/or WAIS-
IV Digit Span scaled 
score 
• 
Seizure within the past 3 months or 
active seizure 
• 
Contraindications to MRI/iTBS such 
as ferromagnetic or other magnetic 
sensitive metals implanted in their 
head or with in 30cm of the treatment 
coil or implanted devices in or near 
the head 
• 
Medication changes within 3 months 
of starting participation 
• 
Currently receiving therapy services 
• 
Pregnancy 
• 
FIM scores for problem solving <3 or 
>4 OR memory <4 or >5, or changes 
in FIM scores during screening 
process 
• 
Neurostimulants that cannot be 
safely withdrawn 
• 
Bilateral ischemic stroke 
• 
Mild or severe impairments in 
cognitive capacity or cognitive 
function 
• 
CHF, implanted pacemakers or 
defibrillators, or cochlear implants 
• 
Heart valve with metallic materials 
• 
Questionable test validity as 
indicated by DOT (E-score ≥ 17) or 
BRIEF (Negativity ≥ 6; Infrequency ≥ 
3; Inconsistency ≥ 8) 
• 
RBANS Total Scale < 70 
OPTIONAL STUDY INCLUSION/EXCLUSION CRITERIA 
Inclusion Criteria 
Exclusion Criteria 
• 
Diagnosis of TBI 
• 
2-10 years post 
neurologic event 
having completed 
rehabilitation 
• 
Age 18 - 80 years old  
• 
Medically stable 
• 
Fluent in English 
• 
Moderately impaired 
cognitive function as 
defined by AMPS 
Processing sub-scale 
measures falling 
below 1.0 logits 
• 
Moderately impaired 
cognitive capacity as 
defined by having two 
or more scores falling 
≥1 standard deviation 
below age normed 
• 
Have BOTH TBI and Ischemic Stroke 
• 
Intracranial lesions or hemorrhagic 
stroke 
• 
Other primary neurologic diagnosis 
• 
Any dementia diagnosis 
• 
History of/or symptoms of psychotic 
spectrum disorders (i.e., bipolar, 
schizophrenia) 
• 
Persons with alcohol use disorder 
(AUD) and/or substance use disorder 
(SUD) diagnoses confirmed by 
clinical and/or scientific experts 
• 
Reside in an extended care facility 
• 
Less than 2 years post TBI or 
ischemic stroke 
• 
Anti-epileptic medications for seizure 
activity 
• 
Seizure within the past 3 months or 
active seizure 

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expectations on: the 
RBANS index scores, 
DKEFS Color-Word 
Trials 3 and 4 scale 
scores, and/or WAIS-
IV Digit Span scaled 
score 
• 
Contraindications to MRI/iTBS such 
as ferromagnetic or other magnetic 
sensitive metals implanted in their 
head or with in 30cm of the treatment 
coil or implanted devices in or near 
the head 
• 
Medication changes within 3 months 
of starting participation 
• 
Currently receiving therapy services 
• 
Pregnancy 
• 
FIM scores for problem solving <3 or 
>4 OR memory <4 or >5, or changes 
in FIM scores during screening 
process 
• 
Neurostimulants that cannot be 
safely withdrawn 
• 
Bilateral ischemic stroke 
• 
Mild or severe impairments in 
cognitive capacity or cognitive 
function 
• 
CHF, implanted pacemakers or 
defibrillators, or cochlear implants 
• 
Heart valve with metallic materials 
• 
Questionable test validity as 
indicated by DOT (E-score ≥ 17) or 
BRIEF (Negativity ≥ 6; Infrequency ≥ 
3; Inconsistency ≥ 8) 
• 
RBANS Total Scale < 70 

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5.5 Study Evaluations 
Data collected will include data related to safety in the administration of the experimental 
intervention, iTBS, immediate and persisting effects of the intervention, and acceptability of the 
intervention based on Veteran fatigue ratings, mood, agitation, and measures of Veteran-
perceived suitability.  
 
Electronic Medical Records: Screening procedures involving a review of the Veteran’s medical 
records to screen for eligibility and safety to participate. A HIPAA waiver will be requested to 
provide the research clinician access to the Veteran’s medical record to screen for study 
eligibility based on the approved inclusion/exclusion criteria. If a Veteran is receiving care 
outside the VA, a medical records request will be initiated to obtain necessary records to 
support inclusion/exclusion criteria screening. Medical records will also be screened for 
documentation by a physician that the Veteran lacks decision making capacity. If the Veteran 
continues to meet all inclusion/exclusion criteria after telephone screening and medical record 
review, the Veteran will be scheduled for in person eligibility screening and either the Veteran or 
healthcare surrogate with assent of the Veteran will provide informed consent.  
 
Self-report, Observational, Neuropsychological, Cognitive Capacity and Functional Outcomes, 
Effort Testing, and Structured Interview Data: In person eligibility confirmation testing, study 
outcomes and covariate data will be collected for each Veteran during screening, at enrollment, 
and throughout their participation in the study.  
 
The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) will be used 
to broadly assess a range of cognitive domains (e.g., Learning/Immediate Memory, Language, 
Attention) whereas the Wechsler Adult Intelligence Scale (WAIS-IV) Digit Span subtest10 will be 
used to measure working memory. The Delis-Kaplan Executive Functioning System (DKEFS) 
Color-Word Interference subtest will be used to measure processing speed and executive 
function11 whereas the Behavior Rating Inventory of Executive Function (BRIEF)57,1 will be 
used to measure the Veteran’s perception of executive function across nine domains as well as 
overall executive functioning, behavioral regulation, and metacognition. 57,1 We will also examine 
testing validity in terms of inadequate effort using the Dot Counting Test2 and response validity 
using the BRIEF. 57,1  
 
We define moderately impaired cognitive capacity as having two or more scores falling ≥1 
standard deviation below age normed expectations on: the RBANS58 index scores, DKEFS11 
Color-Word Trials 3 and 4 scale scores, and/or WAIS-IV59 Digit Span scaled score. Any Veteran 
with a RBANS Total Scale < 70 will be excluded as this cut-off point suggests likely presence of 
severe cognitive impairment or major neurocognitive disorder.60 Any Veteran with DOT (E-score: 
≥ 17 ) or BRIEF-A scores (Negativity ≥ 6; Infrequency ≥ 3; Inconsistency ≥ 8) indicative of 
questionable testing validity will be excluded. The use of these test performance criteria will 
identify Veterans who are not employable and are struggling with day to day life requiring 
assistance with complex Independent Activities of Daily Living due to cognitive impairments.  
 
For Veterans remaining eligible, we seek to link cognitive capacity with cognitive function in 
daily life as measured with the Assessment of Motor and Process Skills (AMPS) Processing 
sub-scale, which is a reliable and valid measure of cognitive function16 defined according to the 
quality of performance of daily tasks dependent on cognitive abilities (Independent Activities of 
Daily Living or IADL).61 The AMPS IADL tasks are selected according to patient profiles and the 
value placed on the task by the patient, which is determined through a structured interview. We 
will utilize the streamlined AMPS (AMPS), which will examine the quality of performance of 1 

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unique IADL while adhering to all administration and scoring procedures. Scoring on the AMPS 
is not continuous, rather scores may indicate varying levels of impairment depending on the skill 
of the task examined. All raw AMPS scores are, using AMPS dedicated analytic software, 
transformed to interval level measures (on a logit scale) and calibrated to neutralize any 
potential bias due to rater severity or leniency.62 These calibrations define the boundaries of the 
five categories of difficulty. We define moderately impaired cognitive function as AMPS 
Processing sub-scale measures falling below 1.0 logits. This cut-off indicates the Veteran 
cannot live independently as they have difficulty performing cognitive-based tasks/ADL 
effectively. 63, 64-66  
 
This AMPS sub-scale includes IADL items calibrated by difficulty and grouped by five categories 
(Easiest, Much Easier than Average, Easier than Average, Average and Hardest). The easiest 
items fall within the ‘Uses” domain, which includes tasks requiring use of tools and materials 
relative to intended uses (e.g., pencil sharpener for pencils but not crayons). The hardest items 
fall within the ‘Accommodates’ domain where preventing ineffective task performance requires 
accommodation (e.g., ironing multiple garments, putting garments away). Across the average 
difficulty category, there are 45 IADL within five cognitive domains (terminates, navigates, 
handles, adjusts, continues). The ‘terminates’ domain, for example, involves appropriate task 
cessation (e.g., no premature cessation, no persistence) whereas the ‘continues’ domain 
involves continuing a task without pauses or delays until task completion.  
 
Veterans who progress to enrollment will create a set of 11 IADL AMPS tasks according to 
meaningfulness, reported difficulty with performance and as indicated/agreed upon by the 
researcher according to whether they can be carried out in a clinic setting. To be valid, test 
items/IADL used in the assessment are not standardized across patients, rather they are 
selected on the basis of patient profiles and the value/importance placed on the task by the 
patient. The selected IADL are then setup to accommodate the different ways a person 
completes the task or equipment/item variations they may use. IADL tasks from this set of 11 
tasks will be selected, without replacement, each time the AMPS is administered (Table 2) 
meaning that a unique task is used with each AMPS administration.  
 
Immediate Effects (ImE) Measures. For TBI and stroke, magnitude of cognitive gains 
immediately after a single session of iTBS to the DLPFC are unknown. For healthy controls, 
however, working memory shows the most consistent and largest effects  (g=.938).23,67,68 
Thus, we will measure immediate change in cognitive capacity according to the domain of 
working memory using the MDS, which is based on the WAIS-IV Digit Span 69 as it enables 
repeated administration and has an extensive research base and a structure that lends itself to 
adaptation with less theoretical likelihood of alternate form reliability issues. To minimize 
potential reliability issues, the study Neuropsychologist created 6 alternate forms that each 
retain the underlying WAIS-IV Digit Span subtest structure as closely as possible. Each form 
uses identical instructions, number of practice and test items, and discontinuation and scoring 
criteria. Each form also includes a unique systematic randomization of digits where number 
strings follow the same internal structure including minimization of the digits ‘9’ and ‘5’ in a 
single string (i.e., ‘phonetic similarity’), exclusion of repeated digits and ‘0’ for forward/backward 
trials, consistent placement of repeated digits and ‘0’s as they occur in the original sequencing 
trials, and introduction of the sequencing trials with a ‘no manipulation’ item. Further, no more 
than two sequential digits are used in any trial, and any instances of sequential digits in the 
original item content are reflected in the adapted trials.  As each alternate MDS form will be 
administered three times in 30 min intervals, we will minimize practice effects by doing an 
initial randomization of the ordering for administration of the alternate forms. Thus, each Veteran 

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across all interventions will be tested with the alternate forms in identical order.  Since we are 
not actually testing and establishing the validity of each form, it is critical that the test conditions 
be identical across participants. If the alternate forms are not perfectly equivalent, then this 
identical order allows us to control for this issue across participants.  
 
For measuring immediate changes in cognitive function, we will use the aforementioned AMPS. 
For each of the three administrations, in 30-min intervals, a unique task will be randomly 
selected (without replacement) from the set of tasks developed during Step 4 (Fig 1). Thus, the 
same IADL is never repeated for the same Veteran.  
 
Persisting Effects (PE) Measures. This battery includes the same five tests/sub-tests 
administered during screening (Fig 1, Step-4: AMPS, RBANS, WAIS-IV Digit Span, DKEFS 
subtests and BRIEF-A). As the BRIEF-A will be re-administered, the study Neuropsychologist 
will review BRIEF-A scores and, if there are compelling reasons, Veterans with scores 
suggesting atypical validity will be withdrawn.  This battery also includes tests to measure 
change in mood: Columbia Suicide Severity Rating Scale (C-SSRS) Beck Anxiety Inventory 
(BAI),71,72  and the Posttraumatic Stress Disorder Checklist (PCL).73 To assess fatigue, we will 
use the Fatigue Severity Scale (FSS),74,75 which is a self-report measure of prior-week fatigue 
during nine activities and current fatigue. To measure behavioral features of agitation, we will 
use the Agitated Behavioral  Scale (ABS). 76-78 
 
Table 2:  Instrumentation:   Testing Battery 
Immediate Outcome Effects (ImE) 
Hrs/Admin 
Aims 
Variable Types 
# 
Reps 
AMPS 
1.5 
1 & 2 
Continuous (logit) 
3 
Modified Digit Span (MDS 
0.2 
1 & 2 
Proportional (% correct) 
3 
Persisting Effects Testing Battery (PE) 
Hrs/Admin 
Aims 
Variable Types  
# 
Reps 
Repeatable Battery for Assessment of Neuropsych 
Status (RBANS) 
1.0 
2 
Continuous (normed 
score) 
5 
Weschler Adult Intelligence Scale (WAIS-IV) Digit 
Span 
Proportional (% correct) 
5 
Delis-Kaplan Executive Functioning System (DKEFS):  
Color-Word 
Continuous (normed 
score) 
5 
Behavior Rating Inventory of Executive Function 
(BRIEF) 
Continuous 
(normed score) 
5 
AMPS 
1.5 
2 
Continuous (logit) 
5 
PTSD Checklist (PCL) 
0.1 
2 & 3 
Mean # symptoms/ 
severity 
5 
Columbia Suicide Severity Rating Scale (C-SSRS) 
0.1 
2 & 3 
Raw score (Veteran 
rating) 
5 
Beck Anxiety Inventory (BAI) 
0.1 
2 & 3 
Raw score (Veteran 
rating) 
5 
Agitated Behavior Scale (ABS) 
0.1 
2 & 3 
Raw score (research 
clinician rating) 
5 
Fatigue Severity Scale (FSS): Prior Week Daily Living 
Score 
0.1 
2 & 3 
Raw score (Veteran 
rating) 
5 
Fatigue Severity Scale (FSS)L  VASF Current Fatigue 
Rating  
0.1 
2 & 3 
Raw score (Veteran 
rating) 
5 
 
 
 
 

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Covariates. To inform the need for stratified sampling in future research, we will collect a small 
set of Veteran-specific factors (Table 3) known or strongly thought to influence treatment 
responsiveness. Given evidence of positive correlations between age and stroke recovery as 
well as likelihood of further cognitive degradation 79,80 and because prevalence rates dictate use 
of a wide age range, we will use average age. As comorbid conditions impede recovery or 
contribute to progressive cognitive degradation for both TBI and stroke, 81,82 we have developed 
preliminary strata for comorbidities as well as time post event. 83-86 These strata will be revised, 
as indicated by the sample distribution. For etiology, we will classify stroke as right or left 
hemisphere  and TBI as: injuries resulting in diffuse axonal injury (DAI) and ≥ 1 contusion (e.g., 
blast, vehicular, assaults) or  DAI + ≥ 1 contusion + an anoxic event subsequent to TBI  (e.g., 
respiratory, cardiac). We will include pre-disability intellectual function, as measured with the 
Test of Premorbid Function, 87 and  likelihood of having any type of Aphasia, 88 self-reported  
marijuana use and Lifetime TBI exposure. 89 Measures obtained during PE testing will also be 
used to mood changes according to PTSD symptoms, depression, anxiety, and agitation. 
 
*Suitability Measures. To advance understanding of each Veteran’s perspective of the 
appropriateness or suitability of that the number and type of tests and number of study-days, 
Veterans will rate the extent of their agreement to eight statements (Table 4). 
 
 
 
 
 
 
 
 
 
Neuroimaging Data:  
Functional MRI measures will be collected at Baseline.  Functional MRI measures will include 
structural imaging, 20 minutes of resting-state fMRI, diffusion tensor imaging (DTI) and an 
Table 3 Potential Covariates 
Variable/Test 
Operational Definition 
Age at Study Enrollment  
Mean or Median by diagnosis 
Time post neurologic event  
2 to 5 yrs. OR  > 5 to 10 yrs. 
# Comorbidities  
≤ 3   or > 3 
Etiology 
Stroke: R/L hemisphere 
TBI: DAI + Contusion OR DAI + Contusion + Anoxia 
Western Aphasia Battery-Screen 
Likely OR Unlikely to have Aphasia 
Boston Assessment of TBI -Lifetime 
Lifetime score 
Test of Pre-morbid Function 
Normed Score 
Marijuana 
Medical, Recreational, None 
Mood: Change in Anxiety 
Mean Change 
Mood: Change in PTSD symptoms  
Mean Change by # and Mean Change in Severity 
Mood: Change in Agitation 
Mean Change 
Table 4.  Indices of Suitability  
1. The tests were all appropriate. 
2. The number (#) of tests were just right. 
3. There were too many tests. 
4. I enjoyed participating in this study. 
5. I disliked participating in this study. 
6. I would recommend the study to a friend.
7. The # of study visits were just right. 
8. There were too many study visits. 
Scale: 1-Completely Disagree; 2- Disagree; 3- 
Neutral; 4-Agree; 5- Completely Agree 

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Arterial Spin Labelling Sequence (ASL).  Participants will be in the MRI for approximately 55 
minutes.  MRI scanning, for all participants, will take place at Northwestern University’s CTI in 
the Olsen Pavilion located at 710 N Fairbanks, Chicago, IL 60611.    
 
fMRI/Image Acquisition:  Scanning will take place on a Siemens Prisma 3.0 T MRI scanner 
equipped with a 64-channel head/neck coil. A high-resolution 3D MP-RAGE T1-weighted 
sagittal anatomical scan (voxel size = 0.8 mm isotropic resolution; 224 sagittal slices) will be 
collected for each participant. Resting state BOLD data will be collected using T2* weighted EPI 
with a TR=0.5s, TE=25ms, flip angle of 48o, and 2mm isotropic voxels and a multiband factor of 
8. Rest data will be collected while the subject views a fixation crosshair. The DTI data will use a 
two shell (64 directions per shell) acquisition with diffusion values of 1000 mm2/sec. The 
acquisition will collect 1.5mm isotropic voxels with a TR=4500, TE=62ms and a multiband factor 
of 4, and 96 slices.  
 
The collection of the fMRI data will be directed by Dr. Todd Parrish.  fMRI data collected at CTI 
will be de-identified and uploaded to Northwestern University Research Image Processing 
System (NURIPS), an online collaborative research environment for securely storing, managing, 
analyzing and sharing de-identified medical imaging, associated data (e.g. behavioral), and 
results from advanced customizable processing pipelines. NURIPS is supported by both 
Northwestern University IT and Feinberg School of Medicine IT and takes advantage of the NU 
high performance computing cluster, Quest. NURIPS is a secure environment that supports the 
latest NU policy and procedures for encryption of data during transit and rest, provides granular 
project level access controls with varying permissions based on user groups, and allows non-
NU collaborators access once they obtain an affiliate NetID. All data are backed up and have 
restore points that go back for 30 days.  Once the data is uploaded to NURIPS, a copy will be 
downloaded onto Hines VA secure research servers for storage on \\v12.med.va.gov\v12\hin 
 
EEG: For participant safety, all participants will complete a 30-minute baseline EEG sampling. 
EEG will not be routinely repeated unless clinically indicated.  The EEGs will be interpreted by 
Epileptologists to confirm absence of seizure activity (i.e., epileptiform discharges). 
5.6 Data Analysis 
Sample Size to Estimate Effect Sizes.  Our total sample size of 48 participants is based on 
80% power to detect  an Effect Size (ES) of .90.  For 80% power, sample size per group to 
detect a small ES (0.35) is 130, for  a medium ES (0.60) it is 42 and to detect a large ES (0.90) 
it is 21 per group.  To estimate a large ES of 0.90, 42 subjects are required to achieve 80% 
power. Thus, we plan for 48 participants and 12% attrition. 
 
Published methods 90 will be used to examine the merits of transdiagnostic sampling (Aim 1i). 
Specifically, we will use MLM to determine if  neurologic diagnosis (stroke, TBI) moderates the 
effects of the Active intervention (Group 1: n = 24, Active iTBS and Active iTBS + APT;  Group 
2: n = 24, Placebo iTBS and Placebo iTBS + APT) on Maximum Cognitve Gain (MCG) as 
measured with the MDS and the AMPS.  
 
For Aim 2, we will inform estimates of effect sizes by testing the idea (2i) that MDS gains and 
AMPS gains differ for Active iTBS and  Active iTBS + APT.  As specified in Table 1, we will 
examine if gains differ in magnitude by computing the MCGs for each  outcome (MDS and 
AMPS) by each intervention.  For each outcome, we will compare the Average Active iTBS 
MCG with the Average Placebo iTBS MCG and  the Average Active iTBS + APT MCG  with the 

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Average Placebo iTBS + APT MCG using t-tests for continuous data and z-tests for binary data.  
Using MLM, we will also determine if Active iTBS is related to more MDS or more AMPS gains. 
The group (Active iTBS or Placebo iTBS) by time interaction parameter will be used to examine 
if Active iTBS  has a differential trend compared to Placebo iTBS.  For 2i, we will also use MLM 
to identify presence of an additive effect of APT by examining Active iTBS + APT trend lines. 
For both the AMPS and the MDS outcomes, the group (Active iTBS + APT or Placebo iTBS + 
APT)  by time interaction parameter will be used to examine if the  Active iTBS + APT has a 
differential trend compared to Placebo iTBS + APT.  For each intervention  we will also 
determine (2ii) presence of persisting effects of Active iTBS and Active iTBS + APT in the short-
term, long-term  and cumulatively.  Using the PE measures specified in Table 1 and t-tests, we 
will compare each PE measure for Active iTBS with Placebo iTBS and for Active iTBS + APT 
with Placebo iTBS + APT. Significant results will be reported.   For (2iii), we will  use one-tailed 
t-tests to identify presence of practice effects for MDS and AMPS. We will compare MDS and 
AMPS average peak gains after Placebo iTBS with average peak gains after Active iTBS. If the 
average Placebo iTBS peak gain is greater than the average Active iTBS peak  gain for either 
MDS or AMPS, then we will repeat analyses above (for 2i and 2ii) using ImE and PE measures 
after adjusting them for the detected practice effects.   
 
For Aim 3, we will compute study attrition as percent of participants dropping out after Study-
Day 2 and after Study-Day 3. We will examine whether or not these attrition rates differ (3i) by 
stroke and TBI groups using chi-square. To examine if Veteran’s with stroke and TBI have (3ii) 
different perceptions regarding the suitability of the number and type of tests and number of 
study-days, we will compare each group’s average ratings, by suitability index, using t-tests. To 
explore the relationship between perceived suitability and fatigue as well as mood (3iii), we will 
compute  Pearson correlations at each of the 5-timepoints (B0 through B4) between average 
ratings of suitability indices 1 through 3 and averages for each of the two fatigue measures and 
each of the five mood measures [5x (3x2) + 5x (3x5) =  105 correlations]. We will also compute 
correlations for average suitability indices 7 through 8 collected on Study-Day 4 (B4) with the 
averages from that same day for  each of the two fatigue measures and each of the five mood 
measures  [1x (2x2) + 1x (2x5) = 14 correlations). We will test the significance of each 
correlation using Fisher Z test and results will be interpreted accordingly.   
 
Aims 2 and 3 involve multiple comparisons. Bonferroni correction of type I error rate is very 
conservative, and, at this early research stage, it could mask important findings. Thus, we will 
control for false discovery rate (FDR)91,92 using an FDR level of .05.   
 
For Aim 4 we will identify the optimal iTBS Neural Targets using GIMME, which is a directed 
functional connectivity modeling approach based on iterative model optimization.  The optimal 
brain target is the region that, when modulated, communicates effectively with the neural 
systems supporting cognition such that it leads to improved cognitive abilities. This target could 
be a brain region defined at the group level (i.e., generalizable to mild TBI+PTSD population), 
the subgroup level (specific to mild TBI+PTSD persons with shared features), or at the 
individual level. GIMME is based on a feed forward method of adding paths among the pre-
specified brain Regions of Interest (ROIs) that serve as a fixed anatomical structure.  
Considering that GIMME models have included  7 to 20 97,102,103 ROIs,  the fixed GIMME 
anatomical structure will include a set of 12 ROIs implicated in cognition and that serve as 
nodes in neural networks based on a parcellation atlas101 will be used  in all GIMME models to 
as the fixed anatomical structure. (Table 5). The threshold for a group-level or sub-group-level  
pathway connection can be manipulated but we will use 75% as it has been determined to work 
well.97   Based on the fixed anatomical structure, GIMME first produces a group-level model of 
the ROI structure common to at least 75% of the persons in the full dataset/sample.  96,100  

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After the group model has 
been developed it is used as 
a fixed component in the 
determination of each 
individual’s model that then 
delineate sub-
types/subgroups of persons 
sharing a common (75% 
threshold) ROI structure.  
The goal is to identify the 
optimal GIMME brain region 
(ROI) for stimulating with 
iTBS. To identify this ROI, we 
will first identify the best 
representative pathway (e.g., 
a pathway is comprised of 
two ROIs).  
To identify the best representative pathway, we will first identify a pathway from each model 
level (group, sub-types and individual) by using the average the betas (mean betas, µß), for all 
of the group-level pathways subgroup-level pathways, and individual pathways for each person 
comprising each model.  From all the µß weights from each model level, we will select the 
pathway with the maximum µß weight. Now that the pathway-level (group, subgroup or 
individual) has been selected, the path within this collection having the max ß weight will be 
selected as the pathway most important to cognitive function for this specific participant.   
Since we seek to identify one ROI as the optimal iTBS GIMME target and as each pathway is 
comprised of two ROIs, we will select one of the two ROIs comprising the pathway selected as 
the most important to cognitive function. This ROI is the ROI with the highest total degree. The 
graph theory metric of total degree quantifies the sum of in-degree (number of connections 
coming into the ROI) and out degree (outbound connections).  As both in and out degree reflect 
importance of the ROI to cognition, we will use total degree to select the optimal brain region.   If 
the total degree between the brain regions is equal, we will base the decision on TMS ac-
accessibility, Gray Matter Density and/or structural integrity. 
Regarding testing Aim 4, the results from above GIMME modeling and decision criteria will, 
ultimately, test hypothesis that, within our study population of persons with moderate cognitive 
impairment from TBI, there are sub-types/sub-groups of persons with common brain circuitry 
important to cognition. 
Past GIMME work indicates that a minimum of 7 persons with moderate cognitive impairment 
from TBI  will be sufficient to identify an optimal group-level model as well as sub-
types/subgroups.97 That is, 7 participants per diagnosis, here moderate cognitive impairment 
from TBI, has consistently identified an optimal group-level model as well as subgroups within 
this diagnosis. Thus, we will strive to enroll at least 7 participants into these optional studies. 
AIM 5: Determine immediate gains in working memory and performance of complex IADL after 
provision of a single session of iTBS targeting to the same location in the L DLPFC after a 
single session of iTBS targeting the optimal GIMME brain target.  We hypothesize that average 
gains in working memory and functional performance after a single iTBS session site will be 
Table 5:  ROIs for Fixed Anatomical Structure (i.e., 
Critical Network Nodes for Most Cognitive Skills) 
Networks  Network Nodes/Regions of Interest (ROI) 
VAN- 
Salience 
1. right ventral frontal cortex/anterior insula (R 
VFC/AI) 
2. right temporal-parietal junction (R TPJ) 
DAN 
 
3. right frontal eye fields (FEF) 
4. left FEF 
5. right intraparietal sulcus (IPS) 
6. left IPS 
DMN 
 
7. medial prefrontal cortex (mPFC) 
8. posterior cingulate cortex (PCC) (also in FPCN) 
FPCN or 
ECN 
9. Left dorsolateral prefrontal cortex (DLPFC) 
10. Right DLPFC 
11. Parietal association region (PAR) 
12. Posterior cuneus (pCUN) 
VAN = Ventral Attention Network; including salience network; DAN = 
Dorsal Attention Network; DMN = Default Mode Network; FPCN or ECN = 
Frontal Parietal Cortical Network also referred to as the  Executive Control 
Network   

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significantly different according to site of stimulation (GIMME site). For each iTBS session, we 
will compute pre and post iTBS MDS and AMPS scores to be used to compute change in 
working memory and functional performance of IADL. For each outcome and each treatment 
site, the mean change will be computed. Using student t-tests, we will compare mean change in 
working memory and mean change in functional performance between the L DLPFC vs GIMME 
sites. This will allow us to examine the concept that treatment sites personalized by ROI 
structure is or is not important for optimizing clinical benefits of iTBS. 
 
5.7 Withdrawal of Subjects 
Study participants will be informed during the consent process that their participation in the 
study protocol is voluntary, and they may choose to discontinue research participation at any 
time.  Discontinuation of research participation will not impact medical care received outside of 
the research study.  Individuals may choose to withdraw from the study for medical or non-
medical reasons.  If withdrawal from the study occurs during the provision of iTBS, regardless of 
whether this withdrawal is related or unrelated to the protocol, participants will be evaluated by 
the study physician and a medically appropriate plan for follow up will be established in a 
manner that maintains the safety of the research participant.   The PI may also choose to 
withdraw a participant from the study if by the PI’s judgment continuation in the study is not in 
the best interest of the participant for health or safety reasons, non-compliance with study 
procedures or loss of funding for the project. 
 
Every attempt will be made to retain research participants in this study.  Research participants 
who do not complete their study participation will be replaced only if they withdraw prior to any 
research procedures past the baseline measures.  Unless a research participant revokes his/her 
consent to use their health information (i.e. revocation of HIPAA Authorization), any data 
collected prior to study withdrawal will be used in data analysis. 
6.0 
Reporting 
• 
Theresa Bender Pape will be responsible for training other research staff of the 
protocol set forth in this IRB application.  If unanticipated problem occurs such as 
deviation to this protocol that involve risks or has the potential to recur, this 
information will be reported by the investigator, in writing, to the IRB no longer than 
5 business days of the investigator or staff becoming aware of the event.  
 
• 
If the there is an unanticipated, serious adverse event related to this study such as a 
loss of confidentiality or emotional trauma requiring an intervention (e.g., call to 911, 
transfer to VA Crisis Hotline), study personnel will notify the IRB within 2 business 
days but no longer than 5 business days of the investigator or staff becoming aware 
of the event.  Furthermore, if unauthorized access to VA sensitive information 
related to research including but not limited to protected health information (as 
defined in 38 CFR 16.102(f)(2)), and confidential information protected by HIPAA, or 
by Federal records requirements at 38 U.S.C. §§5701, 5705, and 7332, occurs will 
be reported to the ACOS/Research, Facility Information Security Officer and facility 
Privacy Officer within 1 hour.  Also, if any incident occurs that impacts, inhibits or 
compromises the network security operations center, this will be reported within 1 
hour to the ACOS/Research, Facility Information Security Officer and facility Privacy 
Officer. 
 

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• 
Any human subject death which is believed to be both unexpected and related or 
possibly related to participation in research will be verbally reported to the IRB and 
ACOS/Research within 1 hour and written notification to the IRB within 1 business 
day. Any SAEs which are believed to be both unexpected and related or possibly 
related to participation in research will be reported to the IRB within 5 business 
days. All other AEs will be reported at continuing review. All reports of non-
compliance, protocol deviations, information security and privacy incidents will be 
reported to the IRB within 5 business days.  
 
Five (5) Day Reporting Rules:  
• Reports of local SAEs and unanticipated problems involving risk to subjects or 
others are reported to IRB no later than 5 business days after becoming aware of 
the problem. 
• VA Policy – Within 5 business days local unanticipated SAE’s, unanticipated 
problems involving risks to subjects or others, and unanticipated plus related 
deaths must be reported to the IRB. Deaths that are unanticipated problem and 
related to the research must also be reported to the IRB within 5 business days. 
• Local Policy – In addition to VA policy the Hines/FHCC IRB requires the reporting 
of all local serious adverse events. The IRB recognizes that subjects enrolled in 
non-interventional minimal risk studies have common life-time events such as 
hospitalization and early mortality that are unlikely to be unanticipated and are 
unlikely to be related to the research. In these cases, the requirement for IRB 
notification may be waived. 
• Initial Review – The IRB reviews the protocol and submission documents for 
reporting of serious adverse events and unanticipated problems involving risks to 
subjects or others. As with all studies the investigator must follow reporting 
procedures described in the IRB approved protocol. 
• Determinations – Reports are reviewed, findings documented in IRB minutes and 
written notification provided to the Principal Investigator. 
• IRB Reporting to ORO regarding review of serious unanticipated problems and 
unanticipated SAEs: 
• If the convened IRB or the qualified IRB member-reviewer determines that the 
problem or event is serious and unanticipated and related to the research, the 
IRB Chair or designee must notify ORO via telephone or e-mail within 48 hours 
and report the problem or event directly (without intermediaries) to the Facility 
Director within 5 business days after the determination. The report must be made 
in writing, with a simultaneous copy to the ACOS/R and the R&D Committee. The 
Facility Director must report the problem or event to ORO within 5 business days 
after receiving such notification. A simultaneous determination is required 
regarding the need for any action necessary to prevent an immediate hazard to 
subjects including whether or not a protocol or informed consent modification is 
warranted and if previously enrolled subjects need to be notified. 
Non-Five (5) Day Reporting Rules 
• 
Reports of sponsor SAEs, protocol deviations or other issues that do not significantly 
affect the rights, safety or welfare of subjects, or the integrity of the research data, in the 

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investigator’s judgment. Reports are reviewed, findings documented in IRB minutes and 
written notification provided to the Principal Investigator. 

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7.0 
Privacy and Confidentiality 
All data collected in this protocol, are for research purposes only and only IRB-approved 
research personnel will have access to this information. Only those investigators and study 
analysts identified in the study protocol will have access to study data files. There are multiple 
levels of security to ensure the integrity and confidentiality of all data stored on the system. The 
computer system operates entirely within the VA network, which is protected by firewalls 
maintained by the VA Central Office. Cyber security awareness training and privacy training are 
required annually of all VA employees.  
Any breach in security will be reported to ACOS/Research, facility Information Security Officer 
(ISO), and facility Privacy Officer within one hour. To protect from breach of confidentiality, each 
Veteran will be assigned a unique identification number by the study personnel and the only 
place where this identification number will be linked to identifying information (e.g., name, 
address, phone number, date of birth, social security number) will be on a cross-walk file within 
secure Hines VA servers that only authorized research staff will be able to access.  
All research data is de-identified and stored on a VA protected server 
(\\v12.med.va.gov\v12\HIN\Research\ResearchLab) with the exception of data collected that will 
be entered into the electronic REDCap database. This data will be housed on a VA secured 
server and paper files will be maintained at Hines VA in Bldg 1 in a locked filing cabinet behind 
a locked door. Only authorized personnel will have access to this data.  
All raw and source data will be de-identified and stored in Dr. Bender-Pape’s research lab 
located at Hines VAH (Building 1, Room 317) behind a locked door in locked file cabinets and 
maintained in compliance set forth by VA and Office of Research Oversight record retention 
guidelines. Access to the data will be limited to authorized research personnel. If research 
personnel leave the study, then they will be removed from the study protocol and will not be 
able to access any research data. Data will be disposed of according to VA policy and in 
accordance with the applicable VA Records Control Schedule (RCS)  
If the 3T Skyra upgrade is not completed at time of study start up, data from each Veteran’s T1 
anatomical scan will be moved via encrypted USB drive to VA protected server and will be 
loaded into the Localite TMS Neural Navigator system which is a Magventure compatible and 
portable neuronavigational system. Based on the T1 image, the left motor cortex will be initially 
targeted and we will map 5cm anterior of the location to determine motor threshold.  
If the 3T Skyra is upgraded at time of study start up, then we will locate the neural target use our 
Resting State Network Mapping algorithm,60,93 customized for the Northwestern imaging 
processing pipeline that we use in our ongoing iTBS studies.93-95  
Any finding of noncompliance, other deficiencies that substantively compromise the 
effectiveness of the facility’s research information protection program, or suspensions or 
terminations will be reported to the ACOS/ACME/Research, facility Information Security Officer 
(ISO), and facility Privacy Officer within 5 days of becoming aware. Any loss of confidentiality 
falls under immediate reporting requirements and will be reported within the hour of becoming 
aware.  
The information obtained from research analyses may be reported at scientific meetings or in 
other professional articles, but at no time will the Veteran, his/her family or healthcare surrogate 
be mentioned by name or any other identifying information. 
8.0 
Communication Plan 

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Not applicable 
9.0 
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