Theta-burst Stimulation Modulates Criticality, Working Memory and Subjective Effort
Phase: NA
Conditions: Healthy
Sponsor: Brown University

 
 
Theta-burst stimulation modulates criticality, working 
memory and subjective effort  
Protocol Number*: 2106003016 
National Clinical Trial (NCT) Identified Number:  <Number, once assigned by 
CT.gov> 
Principal Investigator*: Andrew Westbrook, PhD 
Sponsor: Brown University 
Grant Title: Subjective Cognitive Effort Indexes Sub-Criticality in the Brain 
Grant Number*: K99MH125021 
Funded by: National Institute of Mental Health 
Version Number: Not applicable; this is the first version of the protocol. 
21 October 2022 
 

 
CONFIDENTIALITY STATEMENT 
This document is confidential communication. Acceptance of this document constitutes agreement by the 
recipient that no unpublished information contained herein will be published or disclosed without prior 
approval of the Principal Investigator or other participating study leadership and as consistent with the 
NIH terms of award.  
 

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Table of Contents 
STATEMENT OF COMPLIANCE ............................................................................................................................ 1 
INVESTIGATOR’S SIGNATURE ............................................................................................................................. 2 
1 
PROTOCOL SUMMARY .............................................................................................................................. 3 
1.1 
Synopsis .............................................................................................................................................. 3 
1.2 
Schema ................................................................................................................................................ 3 
1.3 
Schedule of Activities ......................................................................................................................... 4 
2 
INTRODUCTION ........................................................................................................................................... 6 
2.1 
Study Rationale ................................................................................................................................... 6 
2.2 
Background ......................................................................................................................................... 6 
2.3 
Risk/Benefit Assessment ................................................................................................................... 7 
2.3.1 
Known Potential Risks .................................................................................................... 7 
2.3.2 
Known Potential Benefits ............................................................................................. 10 
2.3.3 
Assessment of Potential Risks and Benefits ............................................................. 10 
3 
OBJECTIVES AND ENDPOINTS ............................................................................................................. 12 
4 
STUDY DESIGN .......................................................................................................................................... 14 
4.1 
Overall Design ................................................................................................................................... 14 
4.2 
Scientific Rationale for Study Design ............................................................................................ 15 
4.3 
Justification for Intervention ............................................................................................................ 15 
4.4 
End-of-Study Definition .................................................................................................................... 16 
5 
STUDY POPULATION ............................................................................................................................... 16 
5.1 
Inclusion Criteria ............................................................................................................................... 16 
5.2 
Exclusion Criteria .............................................................................................................................. 17 
5.3 
Lifestyle Considerations ................................................................................................................... 17 
5.4 
Screen Failures ................................................................................................................................. 18 
5.5 
Strategies for Recruitment and Retention ..................................................................................... 18 
6 
STUDY INTERVENTION(S) OR EXPERIMENTAL MANIPULATION(S) ........................................... 19 
6.1 
Study Intervention(s) or Experimental Manipulation(s) Administration ..................................... 19 
6.1.1 
Study Intervention or Experimental Manipulation Description ................................ 19 
6.1.2 
Administration and/or Dosing ...................................................................................... 20 
6.2 
Fidelity ................................................................................................................................................ 20 
6.2.1 
Interventionist Training and Tracking ......................................................................... 20 
6.3 
Measures to Minimize Bias: Randomization and Blinding .......................................................... 21 
6.4 
Study Intervention/Experimental Manipulation Adherence ......................................................... 21 
6.5 
Concomitant Therapy ....................................................................................................................... 21 
6.5.1 
Rescue Therapy ............................................................................................................ 22 
7 
STUDY INTERVENTION/EXPERIMENTAL MANIPULATION DISCONTINUATION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL ........................................................................................ 22 
7.1 
Discontinuation of Study Intervention/Experimental Manipulation ............................................ 22 
7.2 
Participant Discontinuation/Withdrawal from the Study .............................................................. 22 
7.3 
Lost to Follow-Up .............................................................................................................................. 23 
8 
STUDY ASSESSMENTS AND PROCEDURES .................................................................................... 23 
8.1 
Endpoint and Other Non-Safety Assessments ............................................................................. 23 
8.2 
Safety Assessments ......................................................................................................................... 24 
8.3 
Adverse Events and Serious Adverse Events .............................................................................. 24 
8.3.1 
Definition of Adverse Events ....................................................................................... 24 
8.3.2 
Definition of Serious Adverse Events ......................................................................... 24 

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8.3.3 
Classification of an Adverse Event ............................................................................. 25 
8.3.4 
Time Period and Frequency for Event Assessment and Follow-Up ...................... 26 
8.3.5 
Adverse Event Reporting ............................................................................................. 26 
8.3.6 
Serious Adverse Event Reporting .............................................................................. 28 
8.3.7 
Reporting Events to Participants ................................................................................ 28 
8.3.8 
Events of Special Interest ............................................................................................ 29 
8.3.9 
Reporting of Pregnancy ............................................................................................... 29 
8.4 
Unanticipated Problems ................................................................................................................... 29 
8.4.1 
Definition of Unanticipated Problems ......................................................................... 29 
8.4.2 
Unanticipated Problems Reporting ............................................................................. 30 
8.4.3 
Reporting Unanticipated Problems to Participants .................................................. 30 
9 
STATISTICAL CONSIDERATIONS ......................................................................................................... 31 
9.1 
Statistical Hypotheses ...................................................................................................................... 31 
9.2 
Sample Size Determination ............................................................................................................. 31 
9.3 
Populations for Analyses ................................................................................................................. 32 
9.4 
Statistical Analyses .......................................................................................................................... 32 
9.4.1 
General Approach ......................................................................................................... 32 
9.4.2 
Analysis of the Primary Endpoint(s) ........................................................................... 32 
9.4.3 
Analysis of the Secondary Endpoint(s) ...................................................................... 33 
9.4.4 
Safety Analyses ............................................................................................................. 33 
9.4.5 
Baseline Descriptive Statistics .................................................................................... 34 
9.4.6 
Planned Interim Analyses ............................................................................................ 34 
9.4.7 
Sub-Group Analyses .................................................................................................... 34 
9.4.8 
Tabulation of Individual Participant Data ................................................................... 34 
9.4.9 
Exploratory Analyses .................................................................................................... 34 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ............................. 34 
10.1 
Regulatory, Ethical, and Study Oversight Considerations .......................................................... 34 
10.1.1 
Informed Consent Process .......................................................................................... 34 
10.1.2 
Study Discontinuation and Closure ............................................................................ 35 
10.1.3 
Confidentiality and Privacy .......................................................................................... 36 
10.1.4 
Future Use of Stored Specimens and Data .............................................................. 37 
10.1.5 
Key Roles and Study Governance ............................................................................. 38 
10.1.6 
Safety Oversight ............................................................................................................ 38 
10.1.7 
Clinical Monitoring ......................................................................................................... 40 
10.1.8 
Quality Assurance and Quality Control ...................................................................... 41 
10.1.9 
Data Handling and Record Keeping ........................................................................... 41 
10.1.10 
Protocol Deviations ....................................................................................................... 42 
10.1.11 
Publication and Data Sharing Policy .......................................................................... 43 
10.1.12 
Conflict of Interest Policy ............................................................................................. 43 
10.2 
Additional Considerations ................................................................................................................ 43 
10.3 
Abbreviations and Special Terms .................................................................................................. 43 
10.4 
Protocol Amendment History .......................................................................................................... 46 
11 
REFERENCES ............................................................................................................................................ 47 
 

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STATEMENT OF COMPLIANCE 
 
The trial will be carried out in accordance with International Council on Harmonisation Good Clinical 
Practice (ICH GCP) and the following:  
 
• 
United States (US) Code of Federal Regulations (CFR) applicable to clinical studies (45 CFR Part 
46, 21 CFR Part 50, 21 CFR Part 56, 21 CFR Part 312, and/or 21 CFR Part 812).  
 
National Institutes of Health (NIH)-funded investigators and clinical trial site staff who are responsible for 
the conduct, management, or oversight of NIH-funded clinical trials have completed Human Subjects 
Protection and ICH GCP Training. 
 
The protocol, informed consent form(s), recruitment materials, and all participant materials will be 
submitted to the IRB for review and approval. Approval of both the protocol and the consent form(s) must 
be obtained before any participant is consented. Any amendment to the protocol will require review and 
approval by the IRB before the changes are implemented to the study. All changes to the consent form(s) 
will be IRB approved; a determination will be made regarding whether a new consent needs to be 
obtained from participants who provided consent, using a previously approved consent form. 
 
 

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INVESTIGATOR’S SIGNATURE 
The signature below constitutes the approval of this protocol and provides the necessary assurances 
that this study will be conducted according to all stipulations of the protocol, including all statements 
regarding confidentiality, and according to local legal and regulatory requirements and applicable US 
federal regulations and ICH guidelines, as described in the Statement of Compliance above. 
 
Principal Investigator or Clinical Site Investigator: 
Signed: 
 
Date: 
21 October 2022 
 
Name*:  John Andrew Westbrook 
 
Title*: Principal Investigator 
 
Investigator Contact Information 
Affiliation*:  
Brown University 
Address:  
190 Thayer Street 
Telephone:  
919-360-5399 
Email:   
andrew.westbrook@brown.edu 
 
 
 
 

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1 
PROTOCOL SUMMARY 
1.1 
SYNOPSIS  
 
Title: 
Theta-burst stimulation modulates criticality, working memory and 
subjective effort 
Grant Number: 
K99MH125021 
Study Description: 
In this study we test the hypotheses that critical brain dynamics depend 
on the balance of cortical excitation to inhibition and that sub-criticality 
impacts on subjective cognitive effort and capacity for working memory 
tasks.  
Objectives*: 
 
Primary Objective: Test whether continuous theta burst stimulation can 
alter critical dynamics, working memory, and cognitive effort. 
Secondary Objectives: Test whether the effects of continuous theta burst 
stimulation reflect alterations in the cortical excitation to inhibition 
balance. 
Endpoints*: 
Primary Endpoint: Long-range temporal correlations and avalanche 
branching statistics from EEG signals. Working memory performance. 
Cognitive effort discounting of rewards. 
Secondary Endpoints: Functional E/I ratio estimated from EEG data. 
Study Population: 
We will recruit 30 healthy young adults (15 F and 15 M; all 18-45 years 
old), from the Brown University Community in Providence, Rhode 
Island. 
Phase* or Stage: 
N/A  
Description of 
Sites/Facilities Enrolling 
Participants: 
This single-site study will be conducted at Brown University in the 
Magnetic Research Facility, the Carney Human Testing Space, and the 
Metcalf Research Building. No research will be conducted overseas. 
Description of Study 
Intervention/Experimental 
Manipulation: 
The study will involve two sessions of within-subject, sham-controlled 
continuous theta burst stimulation delivered either at the left dorsolateral 
prefrontal cortex (target) or angular gyrus (sham). 
 
Study Duration*: 
Nine Months 
Participant Duration: 
Participants will complete all components within 4 months of their first 
visit. 
1.2 
SCHEMA  
 
 

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Pre-Screening 
 
 
 
Visit 1, Day 1 
 
 
 
Visit 2 
Day 2 – 113 
 
 
 
Visit 3 
Day 9 – 120 
 
 
 
1.3 
SCHEDULE OF ACTIVITIES  
 
 
Pre-screening 
(Pre-consent) 
 
Visit 1 
Day 1 
Visit 2 
Day 63 ±52 
Visit  3 
 Day 70 ±50 
Review Eligibility 
X 
 
 
 
Informed Consent 
 
X 
 
 
Demographics 
 
X 
 
 
Clinical history 
 
X 
 
 
TMS & MRI compatibility 
 
X 
 
 
Height & Weight 
 
X 
 
 
MRI and Resting State Scans 
 
X 
 
 
Outcome Evaluation 
 
 
 
 
Need for Cognition Scale 
 
 
X 
 
Working Memory performance  
 
 
X 
X 
Effort Discounting 
 
 
X 
X 
Long-range temporal correlations 
 
 
X 
X 
Total N: 30 
Pre-screen potential participants by inclusion and exclusion criteria; schedule Visit 1. 
Conduct informed consent process. Perform baseline health screening. Collect fMRI 
resting state scan and T1 MPRAGE and T2w structural scans for subsequent 
neuronavigation. 
Administer offline theta-burst stimulation to either target (dorsolateral prefrontal 
cortex) or sham location (angular gyrus) and collect EEG data during rest and 
performance of cognitive tasks in counterbalanced Session 1.  
Administer offline theta-burst stimulation to either target (dorsolateral prefrontal 
cortex) or sham location (angular gyrus) and collect EEG data during rest and 
performance of cognitive tasks in counterbalanced Session 2.  

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Pre-screening 
(Pre-consent) 
 
Visit 1 
Day 1 
Visit 2 
Day 63 ±52 
Visit  3 
 Day 70 ±50 
Avalanche branching statistics 
 
 
X 
X 
Functional E/I balance 
 
 
X 
X 

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2 
 
INTRODUCTION 
 
2.1 
STUDY RATIONALE  
 
The healthy human brain is a complex, dynamical system which is hypothesized to lie near a phase 
transition at rest – at the boundary between order and chaos. Proximity to this critical point is functionally 
adaptive as it affords maximal flexibility, dynamic range, and information handling capacity, with 
implications for working memory function. Divergence from this critical point has become correlated with 
diverse forms of psychopathology and neuropathy suggesting that distance from a critical point is both a 
potential biomarker of disorder and also a target for intervention in disordered brains. We have further 
hypothesized that subjective cognitive effort is a reflection of sub-criticality induced by engagement with 
demanding tasks. 
 
A key control parameter determining distance from criticality in a resting brain is hypothesized to be the 
balance of cortical excitation to inhibition (the “E/I balance”). Transcranial magnetic stimulation is a widely 
used experimental and clinical tool for neuromodulation and theta-burst stimulation (TBS) protocols are 
thought to modulate the E/I balance. Here we test whether we can systematically modulate cortical 
dynamics away from the critical point with continuous theta-burst stimulation (cTBS), which is thought to 
decrease the E/I balance, and thereby impact on working memory function and subjective cognitive effort 
during performance of the working memory tasks. 
 
2.2 
BACKGROUND  
 
The brain is hypothesized to rest near a critical point and divergence from this critical point is increasingly 
regarded as an important biomarker for psychopathology and neuropathy (O’Byrne et al., 2022). 
Importantly, the brain enters a state of sub-critical dynamics when people engage in tasks versus rest 
(Pfeffer et al. 2018) and becomes even more sub-critical with increasing task demands (Churchill et al., 
2016; Kardan et al., 2020). We thus hypothesize that phenomenological, subjective cognitive effort 
indexes sub-criticality associated with demanding task engagement. Given that deficient cognitive effort 
is a core feature of multiple forms of psychopathology (Patzelt et al. 2019, Westbrook and Braver, 2015), 
it is essential to understand the mechanisms of subjective effort sensitivity. If, as we hypothesize, 
subjective effort reflects sub-critical brain dynamics, we may one day be able to predict subjective effort 
by measuring a brain’s proximity to a critical point, and also develop treatments for targeting the 
mechanisms which underlie sub-criticality in some individuals. 
 

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A key control parameter thought to regulate proximity to criticality is the balance of cortical excitation to 
inhibition or “E/I balance” (Pfeffer et al. 2018; Agrawal et al. 2018). Prior work has shown that 
atomoxetine, a norepinephrine reuptake inhibitor, can modulate brain dynamics making them less sub-
critical and more closely approximate critical dynamics, even when people are engaged a task versus rest, 
consistent with the hypothesis that norepinephrine increases cortical E/I balance (Pfeffer et al. 2018).  
 
Transcranial magnetic stimulation (TMS) is another promising tool for modulating cortical E/I balance and 
may thereby impact on brain criticality. Specifically, theta-burst stimulation (TBS) protocols have been 
shown to alternately increase (using intermittent TBS) or decrease (continuous TBS) cortical E/I balance 
(Desforges et al. 2022; Huang et al. 2005; Chung et al. 2018). TMS is widely used for treatment of 
depression (Cole et al., 2022), yet the mechanisms of action are unclear. It is therefore tempting to 
speculate that modulation of E/I balance and critical dynamics contribute to treatment efficacy – 
especially given that deficient cognitive effort is a defining feature of depression (Westbrook et al. 2022). 
TMS is also an attractive experimental tool by virtue of its capacity to precisely target cortical regions. 
Since working memory and cognitive effort are associated with neural activity in the dorsolateral 
prefrontal cortex (Braver et al. 1997), it is reasonable to posit that modulation of E/I balance and cortical 
dynamics in the dorsolateral prefrontal cortex impact on subjective cognitive effort and working memory 
performance. 
 
Recent studies have demonstrated that it is possible to estimate a functional E/I balance measure from 
EEG data, based on several minutes of resting EEG data (Bruining et al. 2021). In principle, we should thus 
be able to estimate the consequences of TBS on cortical excitability more directly, through intrinsic 
functional dynamics. 
 
2.3 
RISK/BENEFIT ASSESSMENT  
 
2.3.1 KNOWN POTENTIAL RISKS  
 
Information Risks 
 
The potential for loss of electronic and paper records of personal information used for screening may 
place the participant at low risk for loss of privacy. The magnitude of this risk is also low as information 
about an individual participant’s behavioral performance on abstract cognitive control tasks and / or their 
dynamic brain response to task engagement or TMS is of minimal use outside of the context of this 
experiment.  
 
Physical Risks or Harms 
 

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EEG 
EEG Devices are categorized as NSR by FDA (https://www.fda.gov/media/75459/download). 
 
MRI 
The use of the legally marketed MRI system in research mode will be performed under operating 
conditions below each of the limits (field strength, Specific Absorption Rate, time rate of change of 
gradient fields and sound pressure levels) deemed to be significant risk by the FDA as stated in the FDA 
guidance document, Criteria for Significant Risk Investigations of Magnetic Resonance Diagnostic Devices. 
(https://www.fda.gov/media/71385/download). 
 
There are no known significant risks associated with participation in MRI at the levels of magnetic field 
proposed here, beyond those due to the effect of a magnetic field on an implanted metal fragment or 
medical device.  
 
TMS 
Overview:  
Participating in a TMS study provides indirect benefit to the participants in terms of outstanding scientific 
knowledge gained about brain function, but it is low risk given that the stimulation parameters being used 
are within the established safety norms (Table 1; Figures 5-6), and we will only enroll healthy participants 
without contraindication for TMS. In what follows, we detail the specific risks associated with this protocol 
and the steps we will take to protect against risk beyond those already described in relation to the consent 
process. 
 
Risks associated with participation in TMS experiments:  
(1) Heating, induced voltages, and magnetic field effects. The action of the magnetic field on any 
implanted or worn metal in, on, or around the head poses a significant risk. Magnetic fields can move or 
dislodge metal, induce current in conductive metals, cause heating around metal components, and/or 
affect the operation of any metal device. Thus, it is crucial to screen participants for any irremovable metal 
in or around the head. Our health screening includes the relevant screening questions. 
 
(2) Hearing changes. Movement of the TMS coil within its casing when current is passed through it 
produces an audible “click”. Though this click is often not perceived as loud due to the stapedial reflex, it 
can nevertheless reach 140 dB or more of sound pressure. This exceeds OSHA sound level limits and could 
produce changes in hearing levels if exposed repeatedly. Thus, we will require all participants to wear 
earplugs. In addition, we will exclude participants with potential hearing problems. 
 
(3) Induced seizure: Though exceedingly rare even in patients with epilepsy, induction of a “generalized” 
seizure is the most severe adverse event associated with TMS. A seizure is an episode of excessive brain 
activity and stiff muscle activity (often referred to as a “convulsion” or “fit”). Seizure risk increases at high 
stimulator output intensities, at high frequencies of stimulation, with multiple repeated trains of 

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stimulation, with long durations of stimulation, with short inter-train-intervals, and when stimulating 
participants with reduced seizure thresholds. However, the risk of seizure induction is minimal to 
negligible if TMS parameters are kept within the prescribed consensus safety parameters (Rossi et al., 
2009; Rossi et al. 2020), and participants are carefully screened for seizure risk. Indeed, over the past 
decade of experience in both clinical and research domains, this risk has been reduced to the order of one 
1 in 89,000 cases (Rossi et al 2020).  
 
(4) TMS application site (scalp) discomfort/headache: The stimulation itself is felt as a tapping sensation 
on the scalp. The tapping induced by rTMS at high stimulator output intensity can feel sharper and even 
painful. In addition to a tapping or percussion sensation on the head, muscles and peripheral nerves in 
the head and face react to TMS with sensations such as twitching of superficial muscle groups. Depending 
on the location of stimulation, these sensations can be more or less bothersome. The sum of these 
sensations can range from tolerable to irritating to mildly painful. Beyond informing participants of these 
risks explicitly during the consent procedures, we will also ask participants about their comfort level 
throughout the session, and will reduce the stimulator output intensity to their comfort level or stop the 
session entirely depending on the feedback they give us. 
 
Some individuals who undergo TMS experience a headache, though this may be due to the experimental 
set up as much as the TMS itself. Headaches usually start after the session (20 mins to 3 hours). In the 
event of a participant informing us that a headache is coming on during the session, we will allow the 
participant to cope with the headache in their preferred way, including termination of the session if they 
wish. 
 
TMS is considered low risk when protocols use stimulation parameters within established international 
safety norms. Parameters and procedures for all protocols cited here fall within previously published 
international consensus safety guidelines (Rossi et al., 2009; Rossi et al., 2020) which were incorporated 
into FDA’s Class II Special Controls Guidance Document: Repetitive Transcranial Magnetic Stimulation 
(rTMS) Systems in “Table 2. Maximum Safe Train Duration (seconds) Limits for Avoiding Seizures.” 
(https://www.fda.gov/media/81495/download).  
 
(A) Single pulse TMS to primary motor cortex: 
Delivery of single TMS pulses (< 1 Hz) over motor cortex will primarily be used in studies of cortical 
excitability. Single TMS pulses will be delivered at precisely timed points during an experimental trial to 
either motor cortex. When delivered over motor cortex, the elicited response in EMG of the fingers, hand, 
or arm will be recorded. These data can characterize changes in the excitability of motor cortex during 
manipulations of cognitive control due to manipulations of cognitive control or attention. The time 
between pulses will be irregular, as they are determined by the timings of specific trial events that may 
not be spaced at regular intervals. However, the minimum time between any two pulses will be 1 second 
to keep the frequency below 1Hz, and most will be at longer intervals (> 5 seconds). See Figure 5 for 
relevant safety guideline. 

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(B) Offline patterned repetitive TMS: 
We may apply rTMS in patterned bursts, using continuous theta-burst stimulation (cTBS) for up to 40 s 
offline followed by a second train after a timed delay (for a total of 1200 pulses). The pattern consists of 
bursts of three rapid (50 Hz) pulses delivered at a frequency of 5 Hz. In a “spaced” variant of this 
procedure, two trains are delivered, with a 5-15 minute break in between trains. The spaced variant is 
advantageous in that it produces more consistent and reliable effects on cortical E/I balance in a meta-
analysis (Chung et al. 2018). Importantly, a spaced variant is deemed safe, conforming to the standards 
articulated in a consensus statement (Rossi et al. 2020). While spaced TBS procedures increase the overall 
pulse count, they do not increase stimulation intensity or frequency which are of primary concern. At 
present, spaced TBS procedures with higher pulse counts have been used safely in dozens of studies and 
hundreds of participants without incident.  
 
Offline TBS has been shown to be effective at eliciting both disruptive and facilitative effects during tasks 
related to cognitive control and learning. Prior work has shown that TBS effects can last up to 60 minutes 
following stimulation (Opie et al., 2017; Tse et al., 2018). During this time participants will remain in the 
lab as the stimulation would be applied in the beginning of the experimental session. This offline 
technique provides a means of testing the necessity of a brain region for a given task while controlling for 
the potentially distracting nature of the stimulation itself. It is of higher potency and lasts for a longer 
duration than other forms of offline stimulation, yet it uses lower intensities and for shorter total 
durations of stimulation. 
2.3.2 KNOWN POTENTIAL BENEFITS  
 
The proposed research does not guarantee direct benefits to the participants beyond the opportunity to 
participate in a scientific enterprise. There is a potential indirect benefit of this research as it may advance 
understanding of the cognitive control of sequences of tasks, knowledge that may have beneficial clinical 
or societal impact. 
2.3.3 ASSESSMENT OF POTENTIAL RISKS AND BENEFITS  
 
TMS is widely used for both clinical and experimental purposes and has garnered consensus recognition 
as both safe and effective for altering neuromodulation (Rossi et al. 2009; Rossi et al. 2020). Yet, TMS’s 
effects on cortical function are poorly understood. Thus, studies like this are essential for elucidating the 
mechanisms by which TMS alters brain function and cognition. Additionally, correlations between critical 
dynamics and healthy brain functioning, and the use of criticality as a biomarker of psychopathology 
(O’Byrne et al. 2022), imply the need for studies of those factors which regulate critical dynamics. TMS is 
a safe and effective method for modulating cortical E/I balance and thus provides a valuable tool for 
causally testing the role of E/I balance in critical dynamics. The core value of the information to be gained 
in this study is therefore twofold: 1) it will test mechanistic hypotheses about how theta-burst stimulation 

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protocols alter cortical functioning and 2) it will test hypotheses about the role E/I balance in critical 
dynamics with implications for working memory functioning as well as subjective cognitive effort.  
 
To enhance the efficacy and precision of the TMS manipulation, we will collect MRI data for each 
participant prior to their stimulation sessions. The MRI data will provide vital information about brain 
morphology so that we can direct precision neuronavigation for TMS. This data is vital to ensure that we 
can target the cortical locations we intend with TMS so that we can make accurate inferences about their 
respective roles in working memory and subjective effort. MRI-guided neuronavigation is also valuable 
because it will enable us to make precise inferences about the local effects of stimulation to sites which 
are commonly used in clinical TMS protocols. 
 
As noted above, the chief risk of TMS studies is seizure, yet this risk is significantly mitigated by well 
established, consensus guidelines with a proven track record for safe administration (Rossi et al. 2009; 
Rossi et al. 2020). Key methods for minimizing seizure risk include screening against risk factors among 
otherwise healthy young adult participants (e.g. epilepsy, history of brain trauma, the use of anti-
depressants, etc.). Additionally, we will adhere closely to safety consensus guidelines as articulated by 
Rossi et al., which have a proven track record of safe administration. Nevertheless, as we cannot rule out 
seizure risk entirely, every experiment will be run by the PI (Westbrook) and a second experimenter 
trained to respond quickly and effectively in the event of a seizure. All experimenters will be thoroughly 
trained, and closely familiar with the protocol for responding including securing the participant to 
preclude further harm, contacting emergency medical services, remaining with and reassuring the 
participant until emergency medical services arrive, and subsequently documenting and reporting the 
incident to our IRB. 
 
For MRI, there are no known risks beyond interactions between metal and the magnetic field. Hence, all 
participants are extensively screened for implanted metal. Persons at primary or secondary risk based on 
an implanted object or medical device will be excluded according to MRF operating procedures. 
Moreover, no personnel are permitted in the scanner room with any metal on their person. As such, we 
do not anticipate any significant risk from the application of these procedures. In rare cases, a participant 
will become anxious because of lying in an enclosed space. We will exclude participants who report a 
history of anxiety in enclosed spaces, and we will terminate the session of a participant who expresses 
anxiety about lying in the bore. 
 
All participants will be able to stop the session at any time by squeezing a ball held in one hand. The ball 
activates a buzzer in the control room. There is also an intercom voice link with the control room that 
allows verbal communication between participant and experimenters. 
 
To minimize risks around the loss of private information, participant identifiable information will be stored 
separately from individual data and any screening conversations will take place in private. All electronic 
records will be maintained on password protected fileservers in a locked office, further protected by 

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firewalls and other security procedures. Paper records will be maintained in locked file cabinets in locked 
offices. 
 
3 
OBJECTIVES AND ENDPOINTS  
 
OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR 
ENDPOINTS 
PUTATIVE 
MECHANISMS OF 
ACTION 
Primary 
 
 
 
Test whether continuous 
theta-bursts stimulation 
induces sub-critical dynamics 
in the cortex 
Diminished 
markers of critical 
dynamics include 
reduced long-
range temporal 
correlations 
measured by 
detrended 
fluctuation 
analysis, and sub-
critical avalanche 
branching ratios. 
Long-range temporal 
correlations and avalanche 
branching dynamics are 
widely used metrics of 
distance from the critical 
point (degree of sub-
criticality) in EEG studies. 
Long-range 
temporal 
correlations and 
avalanche 
branching ratios of 
1.0 are emergent 
properties of 
dynamical systems 
at a critical point. 
By reducing the E/I 
balance, continuous 
theta burst 
stimulation should 
make the brain 
more sub-critical, 
thus dampening 
these emergent 
properties. 
Test whether continuous 
theta-bursts stimulation to 
dlPFC diminishes working 
memory function relative to 
stimulation to the angular 
gyrus. 
Lower 
discrimination (d’) 
accuracy and 
slower reaction 
times on the N-
back following 
dlPFC stimulation. 
Criticality affords dynamic 
flexibility as needed for 
rapid, reliable updating in 
the N-back task, and also 
flexible task switching. Prior 
work has shown that dlPFC 
continuous theta burst can 
undermine working 
memory function. Here we 
test the specific hypothesis 
that this reflects the effects 
A decrease in the 
E/I balance in the 
dlPFC produced by 
dlPFC theta-burst 
stimulation should 
make the brain 
more sub-critical, 
thus impairing 
functional flexibility 
afforded by a 
critical state. This 
should matter most 

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OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR 
ENDPOINTS 
PUTATIVE 
MECHANISMS OF 
ACTION 
of TMS-induced sub-
criticality in the dlPFC. 
in the dlPFC which 
is a key nexus of 
higher-order 
working memory 
function. 
Test whether continuous 
theta burst stimulation to the 
dlPFC increases subjective 
cognitive effort relative to 
stimulation to the angular 
gyrus. 
Steeper 
discounting of 
rewards 
contingent on the 
expenditure of 
cognitive effort 
following dlPFC 
stimulation versus 
angular gyrus 
stimulation. 
By virtue of dlPFC’s 
involvement in working 
memory and cognitive 
control, it is hypothesized 
to play a key role in 
subjective cognitive effort. 
We specifically predict that 
critical dynamics in the 
dlPFC are what the brain 
tracks as subjective effort. 
 
Secondary 
 
 
 
Test whether continuous 
theta-burst stimulation 
decreases E/I balance 
Decrease in the 
functional E/I (fE/I) 
balance ratio at 
rest, estimated 
from EEG data 
after TMS 
The fE/I measure derived 
from EEG activity has been 
shown to index E/I balance 
in silico, and in vivo with 
humans taking GABAergic 
medication. Thus, in 
principle, a change in E/I 
balance induced by TMS 
should also be apparent in 
the EEG dynamics and 
thereby the fE/I of channels 
near the stimulation site. 
Changes in fE/I should 
moderate effects of theta-
burst stimulation on critical 
dynamics and  
Theta-burst 
stimulation is 
thought to promote 
inhibitory 
neurotransmission, 
at diverse 
timescales, thus 
decreasing E/I 
balance in local 
microcircuits. The 
fE/I measure should 
be sensitive to 
these 
neuromodulatory 
changes. 
Control for session order 
effects on task performance, 
subjective effort. 
Effects of session 
order on accuracy 
(d’) and reaction 
times in working 
memory task, on 
Session order will be 
included as a covariate in all 
analyses since participants 
improve discrimination 
accuracy and response 
Practice improves 
performance, and 
people find tasks 
with which they 
have more practice 

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OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR 
ENDPOINTS 
PUTATIVE 
MECHANISMS OF 
ACTION 
discounting of 
rewards as a 
function of 
subjective effort.  
speed across sessions with 
the working memory task. 
In turn, they find tasks to be 
less effortful across 
sessions. 
to be subjectively 
easier. 
Tertiary/Exploratory  
 
 
 
 
4 
STUDY DESIGN 
 
4.1 
OVERALL DESIGN 
 
The hypothesis to be studied in this Trial is that criticality in the brain depends on the balance of cortical 
excitation to inhibition and that sub-criticality impacts on working memory and subjective cognitive effort. 
This hypothesis leads to predictions including that TMS protocols which decrease the cortical excitation 
to inhibition ratio (like theta burst stimulation) will make the brain more sub-critical. In turn, when theta-
burst stimulation is targeted at regions involved in working memory like the dorsolateral prefrontal cortex, 
this predicts worse, more inflexible working memory performance and greater subjective effort when 
people are engaged in working memory tasks.   
 
We will use a repeated measures design wherein every subject is their own control. Specifically, on 
different days, separated by at least one week, participants will receive continuous theta burst stimulation 
to either their dorsolateral prefrontal cortex (the active condition) or the angular gyrus (the control 
condition). The order of these sessions is pseudo-randomized across participants. Specifically, 15 of our 
target 30 participants will be randomly pre-assigned to complete an active condition session first and 
control condition second and vice versa for the other 15 participants. The pre-assignment will be 
determined by permutation of a list of subject numbers before recruitment starts. Every subject number 
will subsequently be assigned to participants in order of their recruitment. Errors in randomization will be 
documented and session order will be included as a covariate in all analyses. 
 
Participants will come in for three sessions: 1) a first session to complete paperwork and an MRI structural 
scan for subsequent neuronavigation and a resting state scan, 2) one counterbalanced order session for 
dorsolateral prefrontal cortex stimulation and working memory task performance and 3) another 
counterbalanced order session for angular gyrus stimulation and working memory task performance. The 
first stimulation session can happen the day after an MR scan (but no more than 113 days after the MR 

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scan) and the second stimulation session can happen one week after the first stimulation session (but no 
more than 113 days after the first stimulation session).   
 
This is a single-site trial. 
 
The intervention is spaced, continuous theta burst (cTBS) stimulation to either the anatomically-defined 
dorsolateral prefrontal cortex or angular gyrus. This will entail two trains of 50 Hz triplet bursts of 
stimulation delivered at 5 Hz (theta rhythm) continuously for 40 seconds (600 pulses for each train for a 
total of 1200 pulses) at an intensity based on 80% of a participant’s active motor threshold. These two 
trains will be separated by between 5 and 25 minutes of rest, hence the stimulation is “spaced”.   
 
Subjects will be their own controls. The use of subjects as their own controls was selected because it will 
permit within-participant comparisons of the effect of theta burst stimulation on the dorsolateral 
prefrontal cortex versus the angular gyrus. While this approach will avoid many random individual 
difference factors which might confound interpretation of effects relative to a between-participants 
design, the chief limitation of this design is session order effects. Namely every participant will have target 
stimulation occurring either first, or after a control stimulation session, and they will also perform the 
working memory tasks either first, or after another session. Session order will be treated as a covariate in 
all analyses. 
 
The only stratification among participants is gender. There are no expected effects of this stratification. 
 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN 
 
Participants will serve as their own controls in this repeated measures design. This design is ideal for 
avoiding random effects of individual differences unrelated to the constructs of interest and will provide 
maximal power for detected control versus target stimulation effects. All participants will be healthy, 
young adults. This group is ideal for studying normal brain function apart from developmental effects and 
aging effects and without any confounding effects of disease or disorder.  
 
4.3 
JUSTIFICATION FOR INTERVENTION 
 
There are few tools for causally manipulating the cortical balance of excitation to inhibition in humans. 
TMS was chosen as an intervention for modulating E/I balance in the dorsolateral prefrontal cortex to 
alter critical dynamics with consequences for working memory and subjective cognitive effort. 
Transcranial magnetic stimulation has already been shown to modulate cortical E/I balance, with effects 
on working memory performance when targeting the dorsolateral prefrontal cortex. It is widely used, safe 

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and effective. While there are pharmacological means of modulating E/I balance, it is impossible to 
selectively target the dorsolateral prefrontal cortex with pharmacological interventions. 
 
A single train of 600 pulses of continuous theta burst stimulation (cTBS) is a standard cTBS design. We are 
using a modification involving two trains of 600 pulses separated by 5 to 25 minutes of rest in between 
based on a meta-analysis showing that the effects are more reliable and more durable for a spaced cTBS 
design relative to a single train cTBS (Chung et al. 2016).  
 
We will require two separate stimulation sessions for participants so that we can compare the effects of 
stimulation on the target versus a control location. The sessions will be separated by at least one week 
providing sufficient time for normalization of brain function between sessions. 
 
Both sessions are needed for a within-participants comparison of target versus control stimulation effects. 
 
4.4 
END-OF-STUDY DEFINITION 
 
A participant is considered to have completed the study if he or she has completed the MR scan session, 
one target stimulation session, and one control session. 
 
The end of the study is defined as completion of the second stimulation session as shown in the Schedule 
of Activities (SoA), Section 1.3. 
5 
STUDY POPULATION 
 
5.1 
INCLUSION CRITERIA 
 
In order to be eligible to participate in this study, an individual must meet all of the following criteria: 
1. Provision of signed and dated informed consent form 
2. Stated willingness to comply with all study and availability for the duration of the study  
3. Males and females; Ages 18-45 
4. Healthy, neurologically normal with no diagnosed mental or physical illness 
5. Willingness to adhere to the MRI and two session stimulation protocol 
6. Fluent in English 
7. Normal or corrected to normal vision 
8. At least twelve years of education (high school equivalent) 
9. Right-handed 
 

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Participants will report simply whether they meet screening criteria prior to consent and this data will 
not be retained. We will only retain data collected after participants give signed written consent and are 
thus considered enrolled in the study. Participants responding that they do not meet one of the 
screening criteria will not be enrolled. 
5.2 
EXCLUSION CRITERIA 
 
An individual who meets any of the following criteria will be excluded from participation in this study: 
 
1. Ongoing drug or alcohol abuse 
2. Diagnosed psychiatric or mental illness 
3. Currently taking psychoactive medication 
4. Prior brain injury 
5. Metal in body 
6. History of seizures or diagnosis of epilepsy 
7. Claustrophobia  
8. Pregnant or possibly pregnant 
9. Younger than 18 or older than 45 
10. Use of medications which potentially lower the usage threshold 
 
Participants younger than 18 are excluded because there is evidence that cortical excitation to inhibition 
changes throughout childhood and adolescence and has been associated with an increase in critical 
dynamics with development (Smit et al. 2011). There is also evidence of increasing excitation to inhibition 
altering scale-free properties linked to critical dynamics in older adults relative to young adults (Voytek et 
al. 2015). We are restricting our study to young adults aged 18-45 to avoid any confounds associated with 
early development or cognitive aging. 
 
Participants will be asked if they are pregnant or possibly pregnant and excluded from participation if they 
affirm either. 
 
5.3 
LIFESTYLE CONSIDERATIONS 
During this study, participants are asked to: 
 
• 
Come to the study well-rested 
• 
Refrain from using products in their hair to avoid adversely impacting impedance for EEG 
recordings  
• 
Avoid high amounts of caffeine intake the morning of the study 
 

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5.4 
SCREEN FAILURES 
 
Screen failures are defined as participants who consent to participate in this study but are not 
subsequently assigned to the study intervention or entered in the study. Individuals who do not meet the 
criteria for participation in this trial (screen failure) because of meeting one or more exclusion criteria that 
are likely to change over time may be rescreened. Examples include coming back for a stimulation session 
after receiving a full night’s rest, or without products in the participant’s hair. 
 
5.5 
STRATEGIES FOR RECRUITMENT AND RETENTION 
 
Participants will be recruited via flyers and announcements which detail core inclusion / exclusion criteria. 
As such we only anticipate needing to recruit around 40 individuals in order to meet our target (30 
participants; 15 male / 15 female) recruitment. Flyers will be posted around the Brown University 
Community, and announcements will be posted in local periodicals (e.g. the Today @ Brown newsletter), 
which is appropriate for communicating with a sample of young adults in the target age range. This 
recruitment strategy has proven successful in recruiting participants who match community 
demographics in prior study and we anticipate it will remain successful going forward. 
 
Potential participants who see our flyers and announcements will be invited to expressing their interest 
by emailing us. We will respond to this email with a brief description of what is involved in the study and 
inclusion / exclusion criteria. Our email will also instruct potential participants to simply say that yes they 
do or do not meet all of the screening criteria (without specifying which criteria they do / do not meet). If 
they say they meet all criteria, they are invited to a first session for informed consent procedures. After 
they give consent, they then fill out detailed screening forms which we retain as part of the study record. 
 
Our anticipated enrollment will approximate the demographics of Providence, Rhode Island and the 
Brown University community including 26 not Hispanic or Latino and 4 Hispanic or Latino participants. 
Racial breakdown will approximate 2 Asian, 2 Black or African American, 22 White, and 4 More than One 
Race participants. All participants will be between the ages of 18 and 45. 
 
To increase the chances that participants come to all study sessions, we will describe the procedures in 
detail during the recruitment and consenting processes, indicating that we are recruiting participants who 
would be willing to participate in all sessions (though participants can, at any time, decide to no longer 
participate and there will be no penalty if that happens). We will also send participants a calendar invite 
to remind them of their participation and a reminder email the day before their session.  
 
Participants will be paid $20/hour for MRI, or TMS and EEG experiments. Depending on the experiment, 
participants may have the opportunity to earn additional compensation. Specifically, participants will have 

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the opportunity to select among offers of money to repeat various levels of the working memory task for 
money. Based on their choices, participants may receive an additional ($0.50 to $4.00) in each 
experimental TMS sessions. This bonus is part of an experimental design intended to assess how people 
evaluate the subjective costs of cognitive effort.  
 
Participants in MRI are also given an anatomical picture of their brain in digital format if they desire. 
Participants will be paid in cash, at the end of each experimental session. For participants completing the 
three sessions (MRI, active TMS, and control stimulation), their total pay will not exceed $208 across all 
three sessions ($40 for the MRI session, and $84 each for the TMS sessions).  
 
We do not believe these nominal amounts to be coercive and moreover will inform participants that they 
can end their participation in the experiment at any time, and they will receive a pro-rated amount of 
remuneration for their time in the respective session.  
 
6 
STUDY INTERVENTION(S) OR EXPERIMENTAL MANIPULATION(S) 
 
6.1 
STUDY INTERVENTION(S) OR EXPERIMENTAL MANIPULATION(S) ADMINISTRATION 
 
6.1.1 STUDY INTERVENTION OR EXPERIMENTAL MANIPULATION DESCRIPTION 
 
The study intervention is modulation of cortical excitation to inhibition (E/I) balance in the dorsolateral 
prefrontal cortex (dlPFC) by means of 2 trains of spaced continuous theta burst stimulation (cTBS) using a 
transcranial magnetic stimulation device. As prior work (Huang et al 2005; Chung et al. 2018) has shown 
that cTBS reliably decreases the cortical E/I ratio with diverse cortical targets, we expect to replicate a 
reduction in E/I balance when applied to the dlPFC. The mechanism of action is thought to be an increase 
in inhibitory neurotransmission across diverse timescales. The endpoint of this stimulation will be a 
decrease in the local E/I ratio that should last at least 60 minutes post-stimulation (Chung et al., 2018).  
 
We will assess the change in E/I balance by quantifying the functional E/I ratio as previously done in a 
study of the GABA receptor agonist Zolpidem (Bruining et al. 2020). We furthermore anticipate that a 
reduction in dlPFC E/I balance will also make the dynamics of dlPFC neurons more sub-critical (Pfeffer et 
al. 2018; Poil et al. 2012), hence we will test the prediction that cTBS weakens long-range temporal 
correlations otherwise found in the brain in a critical state. Moreover, we will test the prediction that cTBS 
to the dlPFC will undermine working memory performance and amplify subjective effort, given the role 
of the dlPFC in working memory processes. 
 

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Importantly, we will contrast the effects of dlPFC cTBS with control cTBS to the angular gyrus. Active 
stimulation of a control region is preferrable to sham stimulation since the latter is less convincing than 
active control stimulation and may present a confound of participant awareness. Also, the angular gyrus 
is a suitable control region because, unlike the dlPFC, it is not part of the frontoparietal or dorsal attention 
networks which have been implicated in working memory and cognitive control (Power et al. 2011) and 
moreover has a low participation coefficient indicating that it is minimally coupled with these networks 
(Power et al. 2013). 
6.1.2 ADMINISTRATION AND/OR DOSING 
 
As noted, the intervention is spaced, cTBS to either (in alternate sessions) the anatomically-defined dlPFC 
or angular gyrus. Each session will thus entail two trains of 50 Hz triplet bursts of stimulation delivered at 
5 Hz (theta rhythm) continuously for 40 seconds (600 pulses for each train for a total of 1200 pulses) at 
an intensity based on 80% of a participant’s active motor threshold to either the target or control region. 
These two trains will thus constitute the full-dose intervention in either location.  
 
Each participant will have their own personal set of two sessions and will thus not interact with other 
participants during the study. 
6.2 
FIDELITY 
 
6.2.1 INTERVENTIONIST TRAINING AND TRACKING 
 
All TMS operators will receive training on the two key variables which may affect the consistency of cTBS. 
The first is the strength of stimulation intensity. Here, stimulation intensity will be based on participants’ 
active motor threshold, which is diagnosed with the use of TMS-evoked potentials measured by 
electromyography and leads attached to participants’ right hand, pursuant to a single pulse to their motor 
cortex hand knob. Motor thresholding will be based on a semi-automated threshold detection algorithm 
which is given feedback about the efficacy a given pulse for eliciting a motor evoked potential of 100 
microvolts from peak to trough. Thus threshold identification should be standardized across participants, 
as should corresponding stimulation intensities.  
 
The second degree of freedom is the precision of TMS targeting. For both motor threshold detection and 
cTBS, it is important to ensure precise targeting (of the hand knob and dlPFC, respectively). To ensure 
consistent targeting, we will use participant-specific structural MRI scans coupled with 3D vision-based 
neuronavigation systems. The neuronavigation system gives real-time feedback for precision targeting. 
Also, the exact location of every single pulse is recorded during stimulation, to ensure consistency. Finally, 
only two TMS operators will be used for the entirety of the study (the PI and one assistant), and both will 
be thoroughly trained to ensure consistent administration.  

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6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING 
 
All participants will complete both one target and one control stimulation session, but the order of these 
sessions will be pseudo-randomized. Specifically, participants will be assigned participant ID numbers 
based on their order of recruitment, but the participant ID numbers will be pseudo-randomized with 
respect to the order of target versus control stimulation sessions. Pseudo-randomization of IDs will be 
saved in a digital file and included in all subsequent analyses as a covariate of no interest. Any breaking of 
pseudo-randomization will be corrected with subsequent re-pseudo-randomization of unassigned ID 
numbers to ensure balance in session orders across participants. This pseudo-randomization will be 
managed / maintained by the PI.  
 
The specific session that a participant is in (target versus control region) will be known to the experimenter 
(there is no way for the experimenter not to know since they are administering stimulation). To mitigate 
the impact on participants, they will be instructed that we will stimulate the brain on two different days, 
making no reference to possible differential effects across brain regions. The experimental condition will 
not be explained to the participant until the end of their participation, during debriefing. 
 
Any instance of accidental unblinding – e.g. the participant learns that dlPFC stimulation is considered 
target, and angular gyrus is considered control stimulation will be noted and subsequent analysis will be 
conducted both including and excluding these participants to ensure that their inclusion has no effect on 
the conclusions of the study. 
 
While it may be possible for some participants to infer that effects of stimulation at different sites should 
have differential effects, they will not be made aware which sites we expect to impact on working memory 
performance or subjective effort. 
 
6.4 
STUDY INTERVENTION/EXPERIMENTAL MANIPULATION ADHERENCE 
 
Participation in all three sessions (MRI and two stimulation sessions) is mandatory for participants to 
remain active participants in the study. Participation will be tracked across sessions by a single ID number 
associated with all data collected across the three sessions. All study components will be completed within 
one of the three sessions, so there is no issue of adherence beyond those three sessions.  
 
6.5 
CONCOMITANT THERAPY 
 

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6.5.1 RESCUE THERAPY 
 
N/A 
 
7 
STUDY INTERVENTION/EXPERIMENTAL MANIPULATION DISCONTINUATION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL 
 
7.1 
DISCONTINUATION OF STUDY INTERVENTION/EXPERIMENTAL MANIPULATION 
 
Reasons for discontinuation of a stimulation (TMS) session include discomfort or expressed desired to 
discontinue a TMS session. Some individuals receiving TMS, for example, have reported headaches 
associated with stimulation and may request discontinuation.  
  
When a subject discontinues from a TMS session, and a clinically significant finding is identified after 
enrollment, the investigator will determine if any change in participant management is needed. Any new 
clinically relevant finding will be reported as an adverse event (AE). 
 
The data to be collected at the time of study intervention discontinuation will include the following: 
• 
The reason(s) for discontinuing the participant from the intervention 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY 
 
Participants are free to withdraw from participation in the study at any time upon request. 
An investigator may discontinue a participant from the study for the following reasons: 
 
• 
Identification of brain abnormalities during the MRI scan 
• 
Non-compliance with regards to cognitive task instructions 
• 
Lost-to-follow up; unable to contact subject (see Section 7.3, Lost to Follow-Up) 
• 
Any event or medical condition or situation occurs such that continued collection of follow-up 
study data would not be in the best interest of the participant or might require an additional 
treatment that would confound the interpretation of the study; With TMS an unlikely but possible 
medical condition would be onset of a seizure 
• 
The participant meets an exclusion criterion (either newly developed or not previously 
recognized) that precludes further study participation 

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The reason for participant discontinuation or withdrawal from the study will be recorded on the Case 
Report Form (CRF). Subjects who sign the informed consent form and are randomized but do not receive 
the study intervention may be replaced. Subjects who sign the informed consent form, and are 
randomized and receive the study intervention, and subsequently withdraw, or are discontinued from the 
study, will be replaced. 
 
7.3 
LOST TO FOLLOW-UP 
 
A participant will be considered lost to follow-up if he or she fails to appear for the MRI session, or appear 
or return for two scheduled stimulation sessions and study staff are unable to contact the participant after 
at least 3 attempts.  
 
The following actions must be taken if a participant fails to return for a required study visit: 
 
• 
The site will attempt to contact the participant, reschedule the missed visit within one week, 
counsel the participant on the importance of maintaining the assigned visit schedule and ascertain 
if the participant wishes to and/or should continue in the study 
• 
Before a participant is deemed lost to follow-up, the investigator or designee will make every 
effort to regain contact with the participant (3 emails). These contact attempts will be 
documented in the participant’s medical record or study file.  
• 
Should the participant continue to be unreachable, he or she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up 
 
8 
STUDY ASSESSMENTS AND PROCEDURES 
 
8.1 
ENDPOINT AND OTHER NON-SAFETY ASSESSMENTS 
 
 
During the screening process, participants will be informed about basic inclusion / exclusion criteria after 
they first contact us, by email. We will then ask participants questions, by phone, on the MRI and TMS 
screening forms in detail and indicate whether they meet criteria or not. Although we will not yet ask 
participants to fill out these forms (i.e. no data will be recorded at this stage), we will ask them to confirm 

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that they meet all criteria on the forms, prior to scheduling their first visit. Within two weeks of this 
confirmation, we will invite participants for their first session visit.  
 
At the first visit, participants will complete the informed consent process and then be asked to fill out the 
screening forms, after giving consent. These data will include information about psychiatric or 
psychological history, presence or absence of metal in the body, history of physical trauma to the brain, 
current alcohol or drug abuse, current use of psychoactive medications, and use of other medications 
which may lower the seizure threshold. We will also collect basic demographic and handedness 
information.  
 
 Following the informed consent process the following data will be collected during the study 
• 
Performance-based assessments: Working memory task performance, decision-making task 
performance 
• 
Questionnaires: The Need for Cognition Scale 
• 
Imaging assessments: Using a 64-channel EEG system, we will record brain waves at the scalp 
throughout all procedures during the stimulation session. In the MRI scanner we will collect 
several types of scans. For the purposes of TMS neuro-navigation, we will collect T1 MPRAGE 
sequences, structural localizer scans, and a field map scan. We will also collect 10-12 minutes of 
resting state fMRI data. These data will be collected on a 3T MRI. 
8.2 
SAFETY ASSESSMENTS 
 
N/A 
8.3 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
 
8.3.1 DEFINITION OF ADVERSE EVENTS 
 
This protocol uses the definition of adverse event from 21 CFR 312.32 (a): any untoward medical 
occurrence associated with the use of an intervention in humans, whether or not considered intervention-
related. 
 
8.3.2 DEFINITION OF SERIOUS ADVERSE EVENTS 
 

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Any adverse event that (i) results in death; (ii) is life-threatening (places the subject at immediate risk of 
death from the event as it occurred); (iii) results in inpatient hospitalization or prolongation of existing 
hospitalization; (iv) results in persistent or significant disability/incapacity; (v) results in congenital 
anomaly/birth defect; or (vi) based upon appropriate medical judgement, may jeopardize the subject’s 
health and may require medical or surgical intervention to prevent one of the other outcomes listed in 
this definition. 
8.3.3 CLASSIFICATION OF AN ADVERSE EVENT 
8.3.3.1 SEVERITY OF EVENT 
 
For adverse events (AEs) not included in the protocol defined grading system, the following guidelines will 
be used to describe severity.  
 
• 
Mild – Events require minimal or no treatment and do not interfere with the participant’s daily 
activities.  
• 
Moderate – Events result in a low level of inconvenience or concern with the therapeutic 
measures. Moderate events may cause some interference with functioning. 
• 
Severe – Events interrupt a participant’s usual daily activity and may require systemic drug 
therapy or other treatment. Severe events are usually potentially life-threatening or 
incapacitating.  Of note, the term “severe” does not necessarily equate to “serious”. 
 
8.3.3.2 RELATIONSHIP TO STUDY INTERVENTION/EXPERIMENTAL MANIPULATION 
 
All adverse events (AEs) will have their relationship to study procedures, including the intervention, 
assessed by an appropriately-trained clinician based on temporal relationship and his/her clinical 
judgment. The degree of certainty about causality will be graded using the categories below.  
 
• 
Related – The AE is known to occur with the study procedures, there is a reasonable possibility 
that the study procedures caused the AE, or there is a temporal relationship between the study 
procedures and the event. Reasonable possibility means that there is evidence to suggest a causal 
relationship between the study procedures and the AE. 
• 
Not Related – There is not a reasonable possibility that the study procedures caused the event, 
there is no temporal relationship between the study procedures and event onset, or an alternate 
etiology has been established. 
 
8.3.3.3 EXPECTEDNESS  

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A clinician with appropriate expertise in transcranial magnetic stimulation will be responsible for 
determining whether an adverse event (AE) is expected or unexpected. An AE will be considered 
unexpected if the nature, severity, or frequency of the event is not consistent with the risk information 
previously described for the study procedures. 
 
8.3.4 TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND FOLLOW-UP 
 
The occurrence of an adverse event (AE) or serious adverse event (SAE) may come to the attention of 
study personnel during study visits and interviews of a study participant presenting for medical care, or 
upon review by a study monitor. 
 
All AEs, not otherwise precluded per the protocol, will be captured on the appropriate case report form 
(CRF). Information to be collected includes event description, time of onset, clinician’s assessment of 
severity, relationship to study procedures (assessed only by those with the training and authority to make 
a diagnosis), and time of resolution/stabilization of the event. All AEs occurring while on study will be 
documented appropriately regardless of relationship. All AEs will be followed to adequate resolution. 
 
Any medical or psychiatric condition that is present at the time that the participant is screened will be 
considered as baseline and not reported as an AE. However, if the study participant’s condition 
deteriorates at any time during the study, it will be recorded as an AE.  
 
Changes in the severity of an AE will be documented to allow an assessment of the duration of the event 
at each level of severity to be performed. Documentation of onset and duration of each episode will be 
maintained for AEs characterized as intermittent. 
 
The Principal Investigator will record events with start dates occurring any time after informed consent is 
obtained until 7 (for non-serious AEs) or 30 days (for SAEs) after the last day of study participation.  At 
each study visit, the investigator will inquire about the occurrence of AE/SAEs since the last visit.  Events 
will be followed for outcome information until resolution or stabilization. 
 
8.3.5 ADVERSE EVENT REPORTING  
 
Reportable Events 

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Principal Investigators must report to Brown’s HRPP the occurrence of any of the events described below, 
collectively referred to as Reportable Events: 
• 
Any Adverse Event (AE) that (1) is a UAE and (2) is related or possibly related to participation in 
the research. 
• 
Any UP. 
• 
Any breach of Privacy or Confidentiality, including lost or stolen confidential information of a 
research participant. 
• 
Any medical, procedural, or laboratory error potentially increasing risk to participants (e.g., errors 
in drug administration or dosing, surgical or other procedures, testing of samples, or test results). 
• 
Any interim analysis, safety monitoring report, publication in a peer-reviewed journal, or other 
finding indicating that there are new or increased risks to subjects or others, or that subjects are 
less likely to receive any direct benefits from the research study than as initially presented to the 
IRB or HRPP. 
• 
Any complaint by or on behalf of a subject indicating that the rights, welfare, or safety of the 
subject have been adversely affected. 
• 
Any change in the Food and Drug Administration (FDA) labeling; any change in the status of an 
Investigational New Drug Application (IND) or Investigational Device Exemption (IDE); any 
withdrawal from market; any manufacturer alert from the sponsor of the research study; or any 
recall of an FDA-approved drug, device, or biologic under investigation in the research study. 
• 
Any event that requires prompt reporting to the sponsor of the research study, when applicable. 
• 
A Suspension or Termination of a research study or of a study’s enrollment, including by the FDA 
or the sponsor of the research study, based on information indicating that the research study 
places subjects at an increased risk of harm than was previously known or recognized. 
• 
Any other event that is unanticipated (irrespective of any “relatedness” to the research) and 
indicates that the research study places subjects or others (e.g., other investigators, research 
assistants, students, the public, family members or partners of subjects) at an increased risk of 
harm or otherwise adversely affects the rights, welfare, or safety of subjects or others. 
 
Reporting Timeframes 
Principal Investigators must report Reportable Events to the HRPP in accordance with the following 
timeframes: 
• 
Reportable Events that are either life-threatening or have resulted in death must be reported to 
the HRPP via telephone, or email if phone is not possible, within one business day from the date 
the PI is notified of or discovers the Reportable Event. The PI must ensure that Research Personnel 
are trained to report any Reportable Event to the PI promptly upon discovery, and no later than 

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24 hours following its discovery or occurrence. A Reportable Events Form must be submitted to 
the HRPP within 48 hours of the PI’s initial verbal or email notification to the HRPP of the 
Reportable Event. 
• 
Reportable Events that are not life-threatening and have not resulted in death must be reported 
to the HRPP in writing as soon as possible, and no later than 7 business days from the date the PI 
is notified of or discovers the Reportable Event. 
• 
Minor Protocol Deviations must be reported to the HRPP in writing at the time of continuing 
review when continuing review is applicable to the study protocol, and must be reported during 
any quality assurance/quality improvement assessment by the HRPP. If continuing review is not 
applicable to the study protocol, the PI must maintain Minor Protocol Deviations as part of the 
study record and make the study record available upon request to the IRB, HRPP, and/or any 
federal sponsor or regulatory agency, as applicable. 
 
Reporting Reportable Events 
In accordance with the timeframes outlined above, PIs must submit to the HRPP a Reportable Events Form 
and include the following information: 
• 
Identifying information for the research study, including the study title, the PI’s name, and the IRB 
protocol number; 
• 
A detailed description of the Reportable Event, including relevant dates and times; 
• 
A detailed description of any corrective action or change to the protocol, planned or already 
taken, to ensure that the Reportable Event is corrected and will not occur again; 
• 
An assessment of whether any research participants or others were placed at risk as a result of 
the Reportable Event, or suffered any physical, social, or psychological harm and any plan to 
address these consequences; and 
• 
Any other information deemed relevant by the PI 
 
8.3.6 SERIOUS ADVERSE EVENT REPORTING  
 
The PI will be responsible for conducting an evaluation of a serious adverse event and shall report the 
results of such evaluation to the NIH and the reviewing Institutional Review Board (IRB) as soon as 
possible, but in no event later than 7 working days after the event. 
 
8.3.7 REPORTING EVENTS TO PARTICIPANTS  

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Incidental findings related to the structural MRI scans are possible. MRIs are collected by the Brown MRF 
(Magnetic Resonance Facility) and staff MD who will review the images for any reportable anomalies and 
contact participants directly if any are identified.  
 
8.3.8 EVENTS OF SPECIAL INTEREST  
 
N/A 
 
8.3.9 REPORTING OF PREGNANCY  
 
If participants indicate during screening that there is a chance they may be pregnant, we supply and ask 
participants to take a pregnancy test to ensure that they are not pregnant. If they are pregnant they will 
be withdrawn from the study and all procedures (MRI, TMS) for safety reasons. 
 
8.4 
UNANTICIPATED PROBLEMS 
 
8.4.1 DEFINITION OF UNANTICIPATED PROBLEMS 
 
This protocol uses the definition of Unanticipated Problems as defined by the Office for Human Research 
Protections (OHRP).  OHRP considers unanticipated problems involving risks to participants or others to 
include, in general, any incident, experience, or outcome that meets all of the following criteria: 
 
• 
Unexpected in terms of nature, severity, or frequency given (a) the research procedures that are 
described in the protocol-related documents, such as the Institutional Review Board (IRB)-
approved research protocol and informed consent document; and (b) the characteristics of the 
participant population being studied; 
• 
Related or possibly related to participation in the research (“possibly related” means there is a 
reasonable possibility that the incident, experience, or outcome may have been caused by the 
procedures involved in the research); and 
• 
Suggests that the research places participants or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or recognized. 
 
UPs may warrant corrective actions. Examples of corrective actions or changes that might need to be 
considered in response to an UP include: 

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• 
Modification of inclusion or exclusion criteria to mitigate the newly identified risks 
• 
Implementation of additional safety monitoring procedures 
• 
Suspension of consenting/enrollment of new participants or halting of study procedures for 
consented/enrolled participants  
• 
Modification of informed consent documents to include a description of newly recognized risks 
• 
Provision 
of 
additional 
information 
about 
newly 
recognized 
risks 
to 
previously 
consented/enrolled participants. 
 
8.4.2  UNANTICIPATED PROBLEMS REPORTING  
 
The principal investigator (PI) will report unanticipated problems (UPs) to the reviewing Institutional 
Review Board (IRB). The UP report will include the following information: 
 
• 
Protocol identifying information: protocol title and number, PI’s name, and the IRB project 
number 
• 
A detailed description of the event, incident, experience, or outcome  
• 
An explanation of the basis for determining that the event, incident, experience, or outcome 
represents an UP 
• 
A description of any changes to the protocol or other corrective actions that have been taken or 
are proposed in response to the UP 
 
To satisfy the requirement for prompt reporting, UPs will be reported using the following timeline:   
 
• 
UPs that are serious adverse events (SAEs) will be reported to the IRB and to the DCC/study 
sponsor/funding agency within 1 business day of the investigator becoming aware of the event  
• 
Any other UP will be reported to the IRB and to the DCC/study sponsor/funding agency within 7 
business days of the investigator becoming aware of the problem  
• 
All UPs should be reported to appropriate institutional officials (as required by an institution’s 
written reporting procedures), the supporting agency head (or designee), and the Office for 
Human Research Protections (OHRP) within one month of the IRB’s receipt of the report of the 
problem from the investigator 
 
8.4.3 REPORTING UNANTICIPATED PROBLEMS TO PARTICIPANTS  
 
For UPs that impact on all participants, all participants will be notified within two weeks, in writing, of the 
UP and corrective actions which have been taken. 
 

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9 
STATISTICAL CONSIDERATIONS  
 
There will not be a formal Statistical Analysis Plan (SAP). Also, no statistical plan will be posted publicly or 
registered before the study begins. 
9.1 
STATISTICAL HYPOTHESES 
 
• 
Primary Endpoint(s):  
We predict that, relative to pre-stimulation rest, continuous theta burst stimulation (cTBS) will result in a 
reduction of the local balance of cortical excitation to inhibition as reflected in the functional E/I balance 
in proximity to stimulated targets. 
 
We also predict that, relative to pre-stimulation rest, cTBS will result in a reduction in markers of critical 
dynamics (including, e.g., long-range temporal correlations) in proximity to stimulation targets. 
 
Finally, we predict that, relative to angular gyrus stimulation, cTBS to the dorsolateral prefrontal cortex 
will increase subjective cognitive effort. 
 
• 
Secondary Endpoint(s): 
 
We hypothesize that subjective effort reflects divergence from a critical state and that criticality depends 
on the E/I balance. As such, we predict that there will be individual difference correlations in the degree 
to which TMS perturbs E/I balance, alters measures of criticality including long-range temporal 
correlations, and ultimately amplifies subjective effort. 
 
9.2 
SAMPLE SIZE DETERMINATION 
 
While studies on the effects of continuous theta-burst stimulation (cTBS) on critical dynamics have never 
been conducted, power calculations are based on prior work showing that cTBS can alter E/I balance and 
working memory function. Specifically, Schicktanz et al. (2015) found that a single train of cTBS to the left 
dorsolateral prefrontal cortex reduced N-back task accuracy (the same working memory task we will use 
in the present study) with an effect size on accuracy of d = 1.39, 3—21 minutes post-stimulation. This 
performance effect was established for the 2-back which is our mid-difficulty level. Using g*Power (Faul 
et al., 2007), we estimate that if the true effect size remains the same, we will have a 95% chance of 
detecting a cTBS effect on 2-back performance with 30 participants at p < 0.05. Importantly, with 30 
participants, we will still have 80% power to detect a group difference in performance even if the true 

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effect size is less than half as large (d = 0.53). As such, our target recruitment is set at 30 participants (but 
will run additional to reach 30 complete participant-session sets, as needed, due to drop-out).  
 
While effect sizes can vary in cTBS owing to considerable inter-individual differences in response to 
stimulation, we are taking additional measures to reduce reliability including participant-specific brain 
images and neuronavigation, and also the use of two, rather than one train of cTBS. As such, if anything, 
we expect the prior estimates to be a lower bound on what we observe. 
 
While this estimate is based on working memory performance alone, this outcome is arguably the most 
important because it is the one measure that has been linked with E/I balance, with subjective effort, and 
with critical dynamics in other studies. As such, this measure was selected because it is also informative 
about all primary and secondary outcomes. 
 
9.3 
POPULATIONS FOR ANALYSES 
 
All participants will be included in all analyses because we are using a within-participant design. 
 
9.4 
STATISTICAL ANALYSES 
 
9.4.1 GENERAL APPROACH 
 
There are no categorical outcomes. Key measures are all continuous outcomes, and are described in detail 
in the next section. They will be analyzed according to pre- versus post-stimulation means. We will also 
report standard errors for each outcome. Key outcomes have multiple associated measures. Multiple 
measures will be used to assess reliability by parallel forms.  
 
We will use standard frequentist cut-offs of p < 0.05 for all statistical tests, correcting for multiple 
comparisons. Key t-tests will include pre-post distinctions in E/I balance measures, working memory 
performance measures, and measures of criticality.  
 
Covariates of no interest to be included are sex and age which we will incorporate via multiple regression 
to ask whether cTBS alters key outcomes (described in the next session).  
 
9.4.2 ANALYSIS OF THE PRIMARY ENDPOINT(S) 
 

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The following key outcomes will be assessed in this study. All measures are interval with the exception of 
the categorical covariate of sex. 
• 
Subjective effort 
o Likert scale ratings (ranging from 1-10) of task-induced effort, demand, time pressure, 
and stress  
o subjective values as estimated from an indifference point discounting procedure 
o self-reported motivation to engage in demanding tasks on a set of Likert scales with 
continuous values ranging from 0-20  
• 
E/I balance  
o fEI derived measure with exponents ranging approximately from 0.0-2.0 
o power-law exponents with exponents approximating -2.0 
• 
Critical dynamics 
o Long range temporal correlations – a derived measure with exponents ranging 
approximately from 0.5-1.0 
o Avalanche size and duration distribution exponents approximating -2.0 and -1.5, 
respectively 
• 
N-back working memory performance 
o overall accuracy rate as a percentage 
o median correct reaction times by trial type: lures versus targets versus regular trials 
o the discrimination index d’ 
 
Primary analyses of these outcomes will entail multiple regression models in which outcomes will be 
regressed on cTBS condition (target versus sham), controlling for sex and age.  
 
9.4.3 ANALYSIS OF THE SECONDARY ENDPOINT(S) 
 
Secondary endpoints will be inter-correlations among the primary endpoint measures. Namely, these 
correlations will test whether the degree to which cTBS alters one measure correlates with stimulation 
effects on other measures. Given the large number of possible correlations, we will only test for 
correlations among those measures which show a reliable stimulation effect in the first place. We will 
then correct for multiple comparisons among these correlations by the false discovery rate method to 
control for Type I errors, limiting them to no more than 5% chance. 
 
We will use Pearson’s correlations for all tests since our outcome measures are continuous, interval 
measures. 
 
9.4.4 SAFETY ANALYSES 

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N/A 
 
9.4.5 BASELINE DESCRIPTIVE STATISTICS 
 
N/A 
 
9.4.6 PLANNED INTERIM ANALYSES  
 
N/A 
9.4.7 SUB-GROUP ANALYSES 
 
N/A 
9.4.8 TABULATION OF INDIVIDUAL PARTICIPANT DATA 
 
We will report individual participant data in terms of their pre- and post- stimulation values for primary 
outcomes. 
 
9.4.9 EXPLORATORY ANALYSES 
 
Exploratory analyses we may pursue include testing whether stimulation targeting predicts individual 
differences in the strength of stimulation effects. We will pursue this question through E-field modeling – 
a method which estimates the strength of local stimulation based on the actual coil placement and 
individual participants’ brain morphology. We may also ask whether the area in which actual stimulation 
intensity was the strongest lies within functional connectivity network parcellations and whether that 
relates to the strength of stimulation effects on behavior. 
10 SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS 
 
10.1 REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS 
 
10.1.1 INFORMED CONSENT PROCESS 
 

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10.1.1.1 CONSENT/ASSENT 
AND 
OTHER 
INFORMATIONAL 
DOCUMENTS 
PROVIDED 
TO 
PARTICIPANTS 
 
Consent forms describing in detail the study intervention, study procedures, and risks will be given to the 
participant and written documentation of informed consent will be completed prior to starting the study 
intervention. The following consent materials are submitted with this protocol: Informed Consent 
Document. 
 
10.1.1.2 CONSENT PROCEDURES AND DOCUMENTATION 
 
In a private room, participants will be given a verbal description of basic study procedures and asked if 
they have any questions. Next, participants will be given the Informed Consent Document and instructed 
to read through it carefully, taking as much time as they need, and asking any questions that arise. Finally, 
if participants and the experimenter are satisfied with the participants’ understanding of the procedures, 
participants will be instructed to sign to indicate their consent to participate. 
 
We are only recruiting fluent English speakers for this study and there is no need to plan for obtaining 
consent from those who do not speak English. Likewise, as we are only recruiting healthy young adult 
participants, there is no need to plan for special accommodation to obtain consent for those who are 
unable to consent on their own behalf. 
 
10.1.2 STUDY DISCONTINUATION AND CLOSURE 
 
This study may be temporarily suspended or prematurely terminated if there is sufficient reasonable 
cause. Written notification, documenting the reason for study suspension or termination, will be provided 
by the suspending or terminating party to study participants, the funding agency, and regulatory 
authorities. If the study is prematurely terminated or suspended, the Principal Investigator (PI) will 
promptly inform study participants, the Institutional Review Board (IRB), and sponsor/funding agency and 
will provide the reason(s) for the termination or suspension. Study participants will be contacted, as 
applicable, and be informed of changes to study visit schedule. 
 
Circumstances that may warrant termination or suspension include, but are not limited to: 
• 
Determination of unexpected, significant, or unacceptable risk to participants 

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• 
Insufficient compliance of study staff to the protocol (i.e., significant protocol violations) 
• 
Data that are not sufficiently complete and/or evaluable 
 
The study may resume once concerns about safety, protocol compliance, and data quality are addressed, 
and satisfy the funding agency, sponsor, IRB, Food and Drug Administration (FDA), or other relevant 
regulatory or oversight bodies (OHRP). 
 
10.1.3 CONFIDENTIALITY AND PRIVACY  
 
Participant confidentiality and privacy is strictly held in trust by the participating investigators, their staff, 
the safety and oversight monitor(s), and the sponsor(s) and funding agency. This confidentiality is 
extended to the data being collected as part of this study. Data that could be used to identify a specific 
study participant will be held in strict confidence within the research team. No personally-identifiable 
information from the study will be released to any unauthorized third party without prior written approval 
of the sponsor/funding agency.  
 
All research activities will be conducted in as private a setting as possible. 
 
The study monitor, other authorized representatives of the sponsor or funding agency, representatives of 
the Institutional Review Board (IRB), regulatory agencies or representatives from companies or 
organizations supplying the product, may inspect all documents and records required to be maintained 
by the investigator. The study site will permit access to such records. 
 
The study participant’s contact information will be securely stored at each site for internal use during the 
study. At the end of the study, all records will continue to be kept in a secure location for as long a period 
as dictated by the reviewing IRB, Institutional policies, or sponsor/funding agency requirements. 
 
Study participant research data, which is for purposes of statistical analysis and scientific reporting, will 
be transmitted to and stored on secure, password protected University-run data servers which are only 
accessible to lab members. This will not include participants’ contact or identifying information. Rather, 
individual participants and their research data will be identified by a unique study identification number. 
The study data entry and study management systems used by sites and by research staff will be secured 
and password protected. At the end of the study, all study databases will be de-identified and archived 
digitally. 
 

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Although age and sex will be collected, these data are insufficient to identify participants. 
 
Participants’ identities will not be conveyed to any third parties. 
 
Measures Taken to Ensure Confidentiality of Data Shared per the NIH Data Sharing Policies  
It is NIH policy that the results and accomplishments of the activities that it funds should be made available 
to the public (see https://grants.nih.gov/policy/sharing.htm). The PI will ensure all mechanisms used to 
share data will include proper plans and safeguards for the protection of privacy, confidentiality, and 
security for data dissemination and reuse (e.g., all data will be thoroughly de-identified and will not be 
traceable to a specific study participant). Plans for archiving and long-term preservation of the data will 
be implemented, as appropriate.  
 
Certificate of Confidentiality  
To further protect the privacy of study participants, the Secretary, Health and Human Services (HHS), has 
issued a Certificate of Confidentiality (CoC) to all researchers engaged in biomedical, behavioral, clinical 
or other human subjects research funded wholly or in part by the federal government.  Recipients of NIH 
funding for human subjects research are required to protect identifiable research information from forced 
disclosure per the terms of the NIH Policy (see https://humansubjects.nih.gov/coc/index). As set forth 
in 45 CFR Part 75.303(a) and NIHGPS Chapter 8.3, recipients conducting NIH-supported research covered 
by this Policy are required to establish and maintain effective internal controls (e.g., policies and 
procedures) that provide reasonable assurance that the award is managed in compliance with Federal 
statutes, regulations, and the terms and conditions of award. It is the NIH policy that investigators and 
others who have access to research records will not disclose identifying information except when the 
participant consents or in certain instances when federal, state, or local law or regulation requires 
disclosure. NIH expects investigators to inform research participants of the protections and the limits to 
protections provided by a Certificate issued by this Policy. 
 
10.1.4 FUTURE USE OF STORED SPECIMENS AND DATA  
 
Data collected for this study will be analyzed and stored on password-protected research-dedicated 
servers at Brown and Rutgers University. After the study is completed, the de-identified, archived data 
will be transmitted to and stored at the RUresearch Data Portal hosted by Rutgers University, for use by 
other researchers including those outside of the study. When the study is completed, access to study data 
will be provided through the RUresearch Data Portal. 

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10.1.5 KEY ROLES AND STUDY GOVERNANCE 
 
Principal Investigator 
Co-Sponsor 
Co-Sponsor 
Andrew Westbrook, PhD, PI 
Theresa Desrochers, PhD 
Michael Frank, PhD 
Brown University  
Brown University 
Brown University 
190 Thayer Street 
Providence, RI 02906 
185 Meeting Street 
Providence, RI 02912 
190 Thayer Street 
Providence, RI 02906 
(919) 360-5399 
(401) 863-7126 
(401) 863-6872 
andrew.westbrook@brown.edu 
theresa_desrochers@brown.edu 
michael_frank@brown.edu 
 
As the PI, Dr. Westbrook will oversee the planning and implementation of the study, ensuring that all staff 
and assistants are properly in safety procedures related to the EEG, MRI, and TMS and that all safety 
training requirements and protocols are met in consultation with Dr. Theresa Desrochers, who oversees 
TMS safety protocols in the Carney Human Testing Space at Brown University. Dr. Westbrook will also 
report any UP or AE to the IRB. Furthermore, Dr. Westbrook will conduct regular reviews of incoming data 
for Quality Assurance. 
 
10.1.6 SAFETY OVERSIGHT 
Safety Monitoring 
Participants will be monitored for adverse events by study staff. Significant as well as mild adverse effects 
of TMS stimulation (seizures, headache) and MRI scanning (claustrophobic reaction, and movement of 
ferromagnetic objects) will be monitored through questionnaires (e.g. TMS monitoring questionnaire) 
before and after each TMS and MRI session. 
 
Risk mitigation plan and Trial stopping rules  
Three outcomes will be monitored throughout the study as safety endpoints associated with a stop rule.  
 
1. Number of TMS-induced seizures: As described above, we will track TMS-induced seizures and 
clinically significant adverse events requiring outside evaluation. Each stop rule is described in 
detail below:  
a. More than 1 TMS-induced seizure resulting in hospitalization within any 10 consecutive 
participants who receive TMS will result in a protocol hold until further evaluation by the 
PI and Co-Sponsor Dr. Theresa Desrochers. Dr. Desrochers has extensive experience with 

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TMS and overseas safety and training compliance at Brown’s TMS facility. We will also 
consult Dr. Noah Phillip, M.D., Professor of Psychiatry and Human Behavior at the Alpert 
Medical School of Brown University, founding Section Chief of Psychiatric 
Neuromodulation at VA Providence, and Lead for Mental Health Research at the VA RR&D 
Center for Neurorestoration and Neurotechnology. Dr. Phillip possesses the necessary 
clinical expertise to evaluate the proposed safety endpoints. No new TMS sessions will be 
administered to any participant once this stop rule is enacted until evaluation of the 
events is concluded and it is deemed appropriate to proceed. However, participants who 
have completed their TMS treatments may be scheduled for follow-up visits.  
 
2. Clinically significant adverse events (i.e. adverse events that require referral for further 
evaluation) likely related to TMS. For example, a mild headache after TMS that resolves 
spontaneously or with over-the-counter medication will not be considered clinically significant. A 
severe headache that starts during or shortly after TMS and fails to resolve with time and/or OTC 
intervention would prompt referral to an Emergency Department and will be considered clinically 
significant.  
a. If more than 1 clinically significant adverse event related to TMS administration and 
having similar clinical features is seen within any 10 consecutive participants, the protocol 
will be put on hold until further evaluation by the PI and Dr. Desrochers. As above, Dr. 
Phillip will be consulted for his evaluation of the stop rule. Follow up EEG visits may 
continue but TMS will not be administered until the hold is resolved.  
 
3. Adverse events related to MRI: Risks associated with MRI scanning will be minimized in the 
following manner. First, subjects will be screened for contraindications to MRI. In particular, 
subjects will be excluded from the MRI studies who have a history of moderate or severe 
claustrophobia, or a history or possible history of any intra-ocular, intracranial, intra-thorax, or 
intra-abdominal metal or cardiac pace makers. Subjects will be screened twice prior to the study, 
once at the time of initial contact, and a second time when they arrive at the MRI facility prior to 
the study. Anxiety will be minimized by thoroughly explaining the procedures and the nature of 
the magnetic resonance scanner to subjects prior to study. During the scanning procedures, the 
subjects are continually monitored visually and auditory for any potential problems, and subjects 
are assured that they can be removed from the scanner at any time if problems should arise or 
they are experiencing discomfort. Emergency medical equipment and pharmaceuticals are 
present at all of the MRI facilities to be used in this project. The development of muscle aches and 
pains is minimized by providing appropriate cushions at pressure points and beneath the knees 
as desired by the subject. The appearance of claustrophobia on entering the MRI scanner usually 
results in termination of the experiment. Earphones and/or earplugs will be used to dampen the 
sound of the MRI procedure (with a minimum 30 dB dampening effect as per FDA guidelines). 
 

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Process of AE/SAE collection, assessing by PI and reporting  
The PI will receive access to information on any adverse events that have occurred from study visits and 
the results of follow-up assessments to assess post-participation changes The PI will report all adverse 
events according to established IRB guidelines. The study does not involve any invasive procedures. The 
PI will report findings and recommendations to the IRB. A written report will be provided by the PI to the 
SO confirming their review of the data and summarizing any recommendations. Furthermore, the PI will 
be required to report on any significant trends in the data that are indicative of negative or adverse events 
to the office of the SO.  
AE/SAE follow up plan  
Participants will be contacted and will again be asked the questions from the TMS monitoring 
questionnaire. The PI will confirm that AE’s have been appropriately reported and determine whether the 
risk to benefit ratio has changed. 
Data Safety Monitoring  
Safety oversight will be under the direction of the PI. Along with Dr. Desrochers and Dr. Frank who have 
expertise in EEG, TMS, MRI and combined methods like concurrent TMS-EEG. Safety information will be 
conveyed in the annual progress report to the Sponsor (NIMH). 
 
1. Content of report  
a. Brief description of the trial and progress  
b. Enrollment update and baseline sociodemographic characteristics  
c. Retention 
and 
disposition 
of 
study 
participants 
(active, 
completed, 
and 
terminated/withdrawn)  
d. Regulatory Issues (amendment, deviations, IRB report, QA issues)  
e. AEs and SAEs listings  
f. Efficacy (at the end of data collection) 
2. Monitoring activities (initial and ongoing study review)  
Progress reports, including patient recruitment, retention/attrition, and SAEs, will be provided in 
the Annual Progress Report submitted to the PO at the NIMH. The Annual Report will be compiled 
and will include a list and summary of SAEs. In addition, the Annual Report will address (1) 
whether SAE rates are consistent with pre-study assumptions; (2) reason for dropouts from the 
study; (3) whether all participants met entry criteria; (4) whether continuation of the study is 
justified on the basis that additional data are needed to accomplish the stated aims of the study; 
and (5) conditions whereby the study might be terminated prematurely.  
 
10.1.7 CLINICAL MONITORING 
 
N/A 

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10.1.8 QUALITY ASSURANCE AND QUALITY CONTROL 
 
The PI will perform internal quality management of study conduct, and data collection, documentation 
and completion. 
 
Quality control (QC) procedures will be implemented as follows: 
 
Informed consent --- Study staff will review both the documentation of the consenting process as well as 
a percentage of the completed consent documents.  This review will evaluate compliance with GCP, 
accuracy, and completeness.  Feedback will be provided to the study team to ensure proper consenting 
procedures are followed.  
 
Source documents and the electronic data --- Data will be initially captured on source documents (see 
Section 10.1.9, Data Handling and Record Keeping) and will ultimately be entered into the study 
database.  To ensure accuracy site staff will compare a representative sample of source data against the 
database, targeting key data points in that review.  
 
Protocol Deviations – The study team will review protocol deviations on an ongoing basis and will 
implement corrective actions when the quantity or nature of deviations are deemed to be at a level of 
concern. 
 
Should independent monitoring become necessary, the PI will provide direct access to all trial related 
sites, source data/documents, and reports for the purpose of monitoring and auditing by the 
sponsor/funding agency, and inspection by local and regulatory authorities. 
 
Staff training The PI will be responsible for ensuring that all staff receive proper training with respect to 
their roles on the study team.  
 
10.1.9 DATA HANDLING AND RECORD KEEPING  
 
10.1.9.1 DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES  
 

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Data collection will be the responsibility of the clinical trial staff under the supervision of the PI. The 
investigator will be responsible for ensuring the accuracy, completeness, legibility, and timeliness of the 
data reported. 
 
All source documents will be completed in a neat, legible manner to ensure accurate interpretation of 
data.   
 
Hardcopies of the study visit worksheets will be provided for use as source document worksheets for 
recording data for each participant consented/enrolled in the study.  
 
Recorded data including transcribed hardcopy data, digital behavioral data, and EEG data will be saved in 
a password-protected, research-dedicated server at Brown University. Raw MR images will be stored in 
BIDS data format on Brown University’s XNAT server managed by the Behavioral Neuroimaging Core. 
 
10.1.9.2 STUDY RECORDS RETENTION  
 
Study documents will be retained for a minimum of 3 years after the date of Federal Financial Report (FFR) 
submission. These documents should be retained for a longer period, however, if required by local 
regulations. No records will be destroyed without the written consent of the sponsor/funding agency, if 
applicable. It is the responsibility of the sponsor/funding agency to inform the investigator when these 
documents no longer need to be retained. 
 
10.1.10 
PROTOCOL DEVIATIONS   
 
This protocol defines a protocol deviation as any noncompliance with the clinical trial protocol, 
International Council on Harmonisation Good Clinical Practice (ICH GCP) requirements. The 
noncompliance may be either on the part of the participant, the investigator, or the study site staff. As a 
result of deviations, corrective actions will be developed by the site and implemented promptly.  
 
These practices are consistent with ICH GCP:  
• 
Section 4.5 Compliance with Protocol, subsections 4.5.1, 4.5.2, and 4.5.3  
• 
Section 5.1 Quality Assurance and Quality Control, subsection 5.1.1  
• 
Section 5.20 Noncompliance, subsections 5.20.1, and 5.20.2.  
 

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It will be the responsibility of the PI to use continuous vigilance to identify and document deviations within 
5 working days of identification of the protocol deviation. All deviations will be addressed in study source 
documents. Protocol deviations will be sent to the reviewing Institutional Review Board (IRB) per their 
policies. The PI will be responsible for knowing and adhering to the reviewing IRB requirements.  
 
10.1.11 
PUBLICATION AND DATA SHARING POLICY  
 
This study will be conducted in accordance with the following publication and data sharing policies and 
regulations: 
 
National Institutes of Health (NIH) Public Access Policy, which ensures that the public has access to the 
published results of NIH funded research. It requires scientists to submit final peer-reviewed journal 
manuscripts that arise from NIH funds to the digital archive PubMed Central upon acceptance for 
publication. 
 
This study will comply with the NIH Data Sharing Policy and Policy on the Dissemination of NIH-Funded 
Clinical Trial Information and the Clinical Trials Registration and Results Information Submission rule. As 
such, this trial will be registered at ClinicalTrials.gov, and results information from this trial will be 
submitted to ClinicalTrials.gov. In addition, every attempt will be made to publish results in peer-reviewed 
journals.  Data from this study may be requested from other researchers 4 years after the completion of 
the primary endpoint by contacting the PI.  Considerations for ensuring confidentiality of these shared 
data are described in Section 10.1.3. 
10.1.12 
CONFLICT OF INTEREST POLICY 
 
The independence of this study from any actual or perceived influence, such as by the pharmaceutical 
industry, is critical. Therefore, any actual conflict of interest of persons who have a role in the design, 
conduct, analysis, publication, or any aspect of this trial will be disclosed and managed. Furthermore, 
persons who have a perceived conflict of interest will be required to have such conflicts managed in a way 
that is appropriate to their participation in the design and conduct of this trial.  
 
10.2 ADDITIONAL CONSIDERATIONS 
 
N/A 

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10.3 ABBREVIATIONS AND SPECIAL TERMS 
The list below includes abbreviations utilized in this template. However, this list should be customized for 
each protocol (i.e., abbreviations not used should be removed and new abbreviations used should be 
added to this list). Special terms are those terms used in a specific way in the protocol. For instance, if the 
protocol has therapist-participants and patient-participants, those terms could be included here for 
purposes of consistency and specificity.  
 
AE 
Adverse Event 
ANCOVA 
Analysis of Covariance 
CFR 
Code of Federal Regulations 
CLIA 
Clinical Laboratory Improvement Amendments 
CMP 
Clinical Monitoring Plan 
COC 
Certificate of Confidentiality 
CONSORT 
Consolidated Standards of Reporting Trials 
CRF 
Case Report Form 
DCC 
Data Coordinating Center 
DHHS 
Department of Health and Human Services 
DSMB 
Data Safety Monitoring Board 
DRE 
Disease-Related Event 
EC 
Ethics Committee 
eCRF 
Electronic Case Report Forms 
FDA 
Food and Drug Administration 
FDAAA 
Food and Drug Administration Amendments Act of 2007 
FFR 
Federal Financial Report 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practices 
GMP 
Good Manufacturing Practices 
GWAS 
Genome-Wide Association Studies 
HIPAA 
Health Insurance Portability and Accountability Act  
HRPP 
Human Research Protection Program 
IB 
Investigator’s Brochure 
ICH 
International Council on Harmonisation  
ICMJE 
International Committee of Medical Journal Editors 
IDE 
Investigational Device Exemption 
IND 
Investigational New Drug Application 
IRB 
Institutional Review Board 
ISM 
Independent Safety Monitor 
ITT 
Intention-To-Treat 
LSMEANS 
Least-squares Means 
MedDRA 
Medical Dictionary for Regulatory Activities 

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MOP 
Manual of Procedures 
NCT 
National Clinical Trial 
NIH  
National Institutes of Health 
NIH IC 
NIH Institute or Center 
OHRP 
Office for Human Research Protections 
PI 
Principal Investigator 
QA 
Quality Assurance 
QC 
Quality Control 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SMC 
Safety Monitoring Committee 
SOA 
Schedule of Activities 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
UP 
Unanticipated Problem 
US 
United States 
 
 
 

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10.4 PROTOCOL AMENDMENT HISTORY 
The table below is intended to capture changes of IRB-approved versions of the protocol, including a 
description of the change and rationale. A Summary of Changes table for the current amendment is 
located in the Protocol Title Page.  
 
Version 
Date 
Description of Change  
Brief Rationale 
1 
07/09/21 
Original version 
NA 
1.1 
1/21/22 
Change recruitment methods 
Increase study visibility at 
project site 
1.2 
10/11/22 
Changed from 1 to 2 trains of theta-
burst stimulation 
Meta-analyses showing more 
robust and lasting effects on 
plasticity to span a full session 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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11 REFERENCES  
 
• Agrawal, V. et al. Robust entropy requires strong and balanced excitatory and inhibitory 
synapses. Chaos: An Interdisciplinary Journal of Nonlinear Science 28, 103115–9 
(2018).  
• Braver, T. S. et al. A Parametric Study of Prefrontal Cortex Involvement in Human 
Working Memory. Neuroimage 5, 49–62 (1997).  
• Bruining, H. et al. Measurement of excitation-inhibition ratio in autism spectrum disorder 
using critical brain dynamics. Sci Rep-uk 10, 9195 (2020). 
• Chung, S. W., Hill, A. T., Rogasch, N. C., Hoy, K. E. & Fitzgerald, P. B. Use of theta-
burst stimulation in changing excitability of motor cortex: A systematic review and meta-
analysis. Neurosci Biobehav Rev 63, 43–64 (2016).  
• Chung, S. W., Rogasch, N. C., Hoy, K. E. & Fitzgerald, P. B. The effect of single and 
repeated prefrontal intermittent theta burst stimulation on cortical reactivity and working 
memory. Brain Stimul 11, 566–574 (2018).  
• Churchill, N. W. et al. The suppression of scale-free fMRI brain dynamics across three 
different sources of effort: aging, task novelty and task difficulty. Scientific Reports 6, 
30895 (2016). 
• Cole, E. J. et al. Stanford Neuromodulation Therapy (SNT): A Double-Blind 
Randomized Controlled Trial. Am J Psychiat 179, 132–141 (2022).  
• Desforges, M. et al. Dose-response of intermittent theta burst stimulation of the 
prefrontal cortex: A TMS-EEG study. Clin Neurophysiol 136, 158–172 (2022).  
• Faul, F., Erdfelder, E., Lang, A.-G. & Buchner, A. G*Power 3: A flexible statistical 
power analysis program for the social, behavioral, and biomedical sciences. Behav Res 
Methods 39, 175–191 (2007).  
• Huang, Y.-Z., Edwards, M. J., Rounis, E., Bhatia, K. P. & Rothwell, J. C. Theta Burst 
Stimulation of the Human Motor Cortex. Neuron 45, 201–206 (2005).  
• Kardan, O. et al. Distinguishing cognitive effort and working memory load using scale-
invariance and alpha suppression in EEG. NeuroImage 211, 116622 (2020).  
• Opie, G. M., Vosnakis, E., Ridding, M. C., Ziemann, U. & Semmler, J. G. Priming theta 
burst stimulation enhances motor cortex plasticity in young but not old adults. Brain 
Stimul 10, 298–304 (2017).  
• O’Byrne, J. & Jerbi, K. How critical is brain criticality? Trends Neurosci (2022) 
doi:10.1016/j.tins.2022.08.007.  
• Patzelt, E. H., Kool, W., Millner, A. J. & Gershman, S. J. Incentives Boost Model-Based 
Control Across a Range of Severity on Several Psychiatric Constructs. Biol Psychiat 85, 
425–433 (2019).  

Criticality, working memory, and effort  
 
Version N/A  
Protocol 2106003016 
 
21 October 2022 
 
 
 
 
 
48 
 
 
• Pfeffer, T. et al. Catecholamines alter the intrinsic variability of cortical population 
activity and perception. PLoS Biology 16, e2003453-32 (2018). 
• Poil, S.-S., Hardstone, R., Mansvelder, H. D. & Linkenkaer-Hansen, K. Critical-State 
Dynamics of Avalanches and Oscillations Jointly Emerge from Balanced 
Excitation/Inhibition in Neuronal Networks. J Neurosci 32, 9817–9823 (2012).  
• Power, J. D. et al. Functional Network Organization of the Human Brain. Neuron 72, 
665–678 (2011).  
• Power, J. D., Schlaggar, B. L., Lessov-Schlaggar, C. N. & Petersen, S. E. Evidence for 
Hubs in Human Functional Brain Networks. Neuron 79, 798–813 (2013). 
• Rossi, S., Hallett, M., Rossini, P. M., Pascual-Leone, A. & Group, T. S. of T. C. Safety, 
ethical considerations, and application guidelines for the use of transcranial magnetic 
stimulation in clinical practice and research. Clinical Neurophysiology 120, 2008–2039 
(2009).  
• Rossi, S. et al. Safety and recommendations for TMS use in healthy subjects and patient 
populations, with updates on training, ethical and regulatory issues: Expert Guidelines. 
Clin Neurophysiol 132, 269–306 (2020). 
• Schicktanz, N. et al. Continuous Theta Burst Stimulation over the Left Dorsolateral 
Prefrontal Cortex Decreases Medium Load Working Memory Performance in Healthy 
Humans. PLoS ONE 10, e0120640-10 (2015).  
• Smit, D. J. A. et al. Scale-Free Modulation of Resting-State Neuronal Oscillations 
Reflects Prolonged Brain Maturation in Humans. J Neurosci 31, 13128–13136 (2011).  
• Tse, N. Y. et al. The effect of stimulation interval on plasticity following repeated blocks 
of intermittent theta burst stimulation. Sci Rep-uk 8, 8526 (2018).  
• Voytek, B. et al. Age-Related Changes in 1/f Neural Electrophysiological Noise. J 
Neurosci 35, 13257–13265 (2015).  
• Westbrook, A. & Braver, T. S. Cognitive effort: A neuroeconomic approach. Cognitive, 
Affective, & Behavioral Neuroscience 15, 395–415 (2015). 
• Westbrook, A. et al. Economic choice and heart rate fractal scaling indicate that cognitive 
effort is reduced by depression and boosted by sad mood. Biological Psychiatry 
Cognitive Neurosci Neuroimaging (2022) doi:10.1016/j.bpsc.2022.07.008.