Temporal Interference Methods for Non-invasive Deep Brain Stimulation
Phase: NA
Conditions: Healthy Volunteers
Sponsor: Indiana University

Indiana University, Bloomington, IN 
 
1 
 
 
 
 
 
 
 
 
Temporal interference methods for non-invasive deep brain stimulation 
 
Joshua W. Brown, Indiana University Bloomington 
 
 
 
 
IRB Study # 26941 
 
 
Revised April 22, 2025 
Table of Contents: 
 
 
● 
Objectives: Clearly stated specific aims aligned with well-defined endpoints and 
appropriate study design. 
● 
Scientific Merit/Background and Rationale: Justification for conducting the study; 
results of similar or pilot data; current literature cited. 
● 
Design: Cleary [sic] describes: how stated objectives will be achieved, methods to 
acquire data, and strategies to overcome anticipated barriers. Addresses randomization, 
minimization of bias, patient follow-up, and blinding (if applicable). 
● 
Eligibility Criteria: Specific inclusion/exclusion requirements and stratification factors (if 
applicable). 
● 
Outcome Characteristics and Endpoint Definitions: Clearly defined primary and 
secondary endpoints/outcomes. 
● 
Statistical Analysis and Sample Size: Appropriate and adequate study design 
statistical analysis plan. Prospective analysis plan, including sample size justification to 
achieve study objectives and plans to minimize missing data. 
● 
Data Management: Practices and procedures in order to manage data analysis, quality, 
cleaning, and storage. 
● 
Principal Investigator and Study Site Qualifications and Resources: Has the 
necessary skills, experience, time, and resources to ensure that the study can be 
successfully completed, including identification of personnel to provide statistical 
computations and statistical expertise. A plan to register protocol with clinicaltrials.gov. 
 
 
1.0 
Objective 
 
There is an urgent need for new non-invasive methods of focal deep brain stimulation. Existing 
methods of non-invasive transcranial neurostimulation include transcranial magnetic stimulation 
(TMS), direct current stimulation (tDCS), alternating current stimulation (tACS), and focused 
ultrasound (tFUS). All are limited in that they cannot stimulate deeper brain regions, at least 

Indiana University, Bloomington, IN 
 
2 
without confounding stimulation of the overlying cortex. This leaves unresolved debates about the 
causal roles of various deep brain structures in cognition, in particular the dorsal anterior cingulate 
cortex. Most of what is known about deeper regions in humans comes from fMRI studies, which 
show correlation but not causation between activity and cognition.  
 
Likewise, a non-invasive deep brain stimulation method could open up new ways to treat a 
variety of clinical issues. Invasive stimulation of the nucleus accumbens has caused a dramatic 
loss of addiction in opioid users and those with alcohol dependence. Likewise cingulotomy has 
been used to treat OCD successfully, and Parkinson’s disease can be treated with invasive 
stimulation of the subthalamic nucleus. The surgery required presents a barrier in all of these 
cases, making treatment impractical short of dire illness. 
Temporal interference (TI) electrical neurostimulation is a new method of non-invasive 
deep brain stimulation. It works by applying several pairs of electrodes to the skull, each carrying 
different frequencies of alternating current. The individual currents are typically 2KHz or greater 
and thus are low-pass filtered by neuronal membranes so that they don’t activate neurons. 
However where two different current frequency fields intersect, they create an interference pattern 
that oscillates at a beat frequency equal to the difference between the two applied frequencies. 
This beat frequency can be low enough to activate neurons, and the overlap field can be steered 
deep into the brain. Stil, it is relatively unknown whether TI can increase BOLD activity in deep 
brain regions, nor how TI may influence deeper brain regions involved in cognitive control, 
decision-making, and associated clinical conditions including addiction, schizophrenia, OCD, 
Parkinson’s disease, and others. 
The overall objective of the present application is to develop and test Temporal 
Interference electrical neurostimulation by validating and characterizing its effects on human 
BOLD signals, and by demonstrating its usefulness in resolving longstanding debates about the 
function of a deeper brain region, the dorsal anterior cingulate cortex.  
Aim 1: Test and characterize the effects of TI on the fMRI BOLD signal. We will apply TI to 
human subjects with fMRI. In Study 1.1, we will test the ability to focally activate the nucleus 
accumbens without activating the overlying cortex, and also its effects on functional connectivity. 
In Study 1.2, we vary the beat frequency parameter of TI to characterize its effects on BOLD 
inhibition vs. activation. In Study 1.3, we test the ability to stimulate a different deeper brain 
region, the dorsal ACC, and explore the optimal beat frequency. 
Aim 2: Identify causal effects of dorsal anterior cingulate cortex (dACC) on cognition. We 
will apply TI to the dorsal ACC of human subjects with fMRI. In Study 2.1, we examine whether TI 
can disrupt or enhance the effect of conflict-monitoring signals on subsequent behavior. In Study 
2.2, we test the theory that dACC drives motivation to avoid risk or loss, with subjects performing 
a previously published difficult forced-choice task while given the option to avoid the risk by 
skipping more difficult trials. We will test whether TI to dACC can change the probability of 
choosing to avoid risky choices. As time and resources permit, Extra Study 2.3 will run a foraging 
task to ascertain whether TI to dACC will influence the choice probability to forage vs. influence 
RT when choices are most difficult. 
 
Based on our own pilot data and others previous findings, we hypothesize that TI with a 
20Hz beat frequency will cause increased fMRI BOLD activation in the targeted regions, without 
increasing activity in the overlying cortex. Further, we predict that a lower, 5Hz beat frequency 
may lead to BOLD inhibition as found previously. Moreover in Aim 2, we expect that TI will disrupt 
cognitive control signals in dACC, disrupt motivation to avoid risk or loss, and disrupt the 
probability of choosing to forage. If so, these findings will lay the foundation for testing clinical 
interventions with TI to disrupt addiction, OCD, and schizophrenia symptoms, which are known to 

Indiana University, Bloomington, IN 
 
3 
involve the dACC, as well as further applications of TI outside of dACC, such as non-invasive 
stimulation of the STN for Parkinson’s disease, and the nucleus accumbens for addiction. 
 
 
2.0 
Background 
 
Need for new non-invasive deep brain stimulation. There is an urgent need for deep, focal, 
non-invasive, and cost-effective neurostimulation methods in humans. Both basic science and 
clinical needs are pressing. Much of the basic cognitive neuroscience research in humans focuses 
on fMRI or EEG, which can show neural correlates of behavior but cannot show neural causes of 
behavior, strictly speaking. Likewise clinically, many targets for intervention in addiction (nucleus 
accumbens) and OCD (anterior cingulate) lie deep in the brain, beyond the reach of common 
transcranial electrical neurostimulation methods like tDCS, tACS and standard TMS. Some deep 
TMS methods are now FDA-approved to target deep structures like the ACC, but these lack 
focality and stimulate a range of areas across the prefrontal cortex(Harmelech et al., 2021). 
Transcranial focused ultrasound (tFUS) can provide focal stimulation (sonication) of deep 
structures but requires invasive skull fixation(Webb et al., 2022). A cost-effective method that 
allows deep, focal, non-invasive neurostimulation in humans, without also stimulating the 
overlying superficial cortical regions, would allow answers to many basic questions about the 
causal role of particular deep brain regions in cognition, especially cognitive control. Moreover, it 
may open the door to a number of potential clinical treatments, especially if the equipment can be 
made inexpensive and portable.  
 
Temporal interference (TI) electrical neurostimulation has the potential to provide 
such a non-invasive deep brain stimulation method(Grossman et al., 2017). TI(C. C. Brown, 
1975; Pope et al., 1995) works by administering two or more alternating currents of slightly 
different frequencies (Figure 1). These frequencies are typically too high to cause significant 
neural stimulation, on the order of 2KHz or higher, as they are filtered out by a neurons cell 
membrane, which acts as an electrical low-pass filter. Where two fields of slightly different 
frequencies overlap, they create an interference pattern (the beat frequency), with a frequency 
equal to the difference of the two carrier frequencies. This is analogous to the beat frequency 
created by plucking two guitar strings that are slightly out of tune with each other. This 
interference pattern can be aimed at deep brain regions, where the lower interference pattern 
frequency can cause neural stimulation without stimulating the 
more superficial cortical regions(Grossman et al., 2017). Such 
an effect requires at least four electrodes, with two pairs of 
alternating current electrodes. Early results in rodents showed 
that TI could be administered effectively and without tissue 
damage(Grossman et al., 2017). Subsequent studies also 
showed that high-frequency TI affects the sharp-wave ripples in 
hippocampus and suppresses epileptic biomarkers in mouse 
models(Acerbo et al., 2022) and may influence neural 
activity(Wessel et al., 2023) and memory encoding in 
humans(Acerbo et al., 2022; J. W. Brown, 2023; Violante et al., 
2023).  Theoretical results suggest how TI may activate sodium 
channels, essentially “jiggling” them open, but without activating 
hyperpolarizing currents in individual neurons(Cao et al., 2020). 
Fig. 1.  Temporal interference 
electrical neurostimulation.  
Stimulation occurs where the electric 
fields intersect, but not from either field 
individually12. This allows deep regions 

Indiana University, Bloomington, IN 
 
4 
The potential implications are profound – the method may allow a number of basic science 
questions about the causal role of deeper brain structures to be answered, and moreover, it may 
allow new treatments for a number of clinical disorders that involve dysfunction of deeper brain 
structures (e.g. addiction(Müller et al., 2009; Zhou et al., 2011), OCD(Kim et al., 2003), and 
pain(Corkin et al., 1979) among others). 
 
Developing TI neurostimulation for use in humans. Previous work by us and others has shown 
that TI can be safely used in humans with fMRI and may have modest value as an intervention on 
behavior (Modak et al., 2024; Violante et al., 2023; Wessel et al., 2023). It remains unclear exactly 
how TI may influence neural activity and cognitive function in healthy humans as measured by 
fMRI BOLD responses, and specifically how variations in the TI beat frequency may contribute to 
the effectiveness of TI stimulation (Aim 1), as well as how TI may influence cognitive processes in 
deeper brain regions (Aim 2). The present work will address these directly, showing the nature of 
the effects on both BOLD signals and cognition, the safety of the effects, and will provide a 
foundation for future work both to understand the causal role of deep brain regions in cognitive 
functions and develop new clinical treatments. We will first test the effects of TI on human brain 
activity and then demonstrate the utility of TI to adjudicate long-standing questions about the 
causal role of deeper brain structures in cognition, especially the dorsal anterior cingulate cortex.  
 
Preliminary results of combined TI and fMRI 
In a set of pilot subjects (Modak et al., 2024), we applied 2mA per 
each channel of TI stimulation using the Soterix Interferential 
Neuromodulation System (Soterix Medical, Inc.), via carbon fiber 
electrodes while subjects were scanned with whole-brain fMRI 
(Fig. 2). Frequencies were 2000 Hz and 2020 Hz, for a 20Hz beat 
frequency. We aimed to target the left nucleus accumbens, and 
our finite element simulations predicted an optimal electrode 
placement with one channel at {F9, F10} in the EEG 10-10 
locations and the other channel at {Fp1, CPz} (Fig. 2 top). Each 
subject received alternating 2 minutes on / 2 minutes off 
stimulation, with 30-second current ramp up and down. Sham 
stimulation consisted of current ramp up followed immediately by 
current ramp down, to control for initial scalp tingling(Gandiga et 
al., 2006). The sham stimulation will be controlled by the 
experiment script on a computer and is designed so that subjects 
will not be able to discern the difference between active and sham 
stimulation; the subject’s experience will be the same, involving 
mild tingling in some subjects. Subjects received four sets of on/off 
stimulation for each of stimulation and sham conditions, with the order of on vs. off first 
counterbalanced. The results (Fig. 2 bottom) show increased BOLD signal in the region predicted 
by the finite element simulation. Moreover, when we changed the frequencies to be the same (i.e. 
2000 Hz in both channels, the high frequencies remained, but the TI beat frequency was 
abolished. In 8 pilot subjects, the BOLD activation seen in Fig. 2 (bottom) was likewise abolished, 
which suggests that TI and not the high frequencies per se are essential for the BOLD activation 
observed. Our pilot subjects tolerated the stimulation well and revealed no substantial safety 
concerns. These pilot results will be tested more fully in Aim 1. 
 
Fig. 2.  Top: Finite element simulation 
prediction of TI effect of 2000Hz vs. 
2020Hz at {F9, F10} and {Fp1, CPz}. 
Bottom: Increased fMRI BOLD effect due 
to TI in our pilot subjects (TI stimulation 
minus sham, Z statistic across n=16 
subjects). 

Indiana University, Bloomington, IN 
 
5 
Characterizing the effect of TI on fMRI BOLD and cognition 
The most fundamental open question here is how TI may influence activity as measured by the 
fMRI BOLD signal. New work suggests TI at 5 Hz beat frequency may suppress BOLD activity 
(Violante et al., 2023), but our pilot data with a 20 Hz beat frequency suggests TI may increase 
BOLD activity. Study 1.1 will test whether a 20Hz beat frequency TI may increase BOLD activity. 
Second, it remains to be established whether the BOLD effects are due to the beat frequency 
rather than an overlap of two high frequency signals of the same frequency. Study 1.1 also 
includes a comparison between 20Hz beat frequency TI vs. a control condition of zero Hz beat 
frequency, i.e. when the two electrode pairs have the same frequency (2000Hz). Third, because 
theoretical work suggests that higher beat frequencies may cause more neural excitation(Cao et 
al., 2020), we will directly compare 5 Hz TI vs. 20 Hz TI in Study 1.2.   Fourth, it remains to be 
established how specifically TI can target various deep brain regions. In preparation for Aim 2, we 
will test how well TI at 20 Hz can focally target the dorsal anterior cingulate cortex (around MNI 0, 
30, 30) (Study 1.3). 
 
Resolving long-standing debates about the role of dorsal anterior cingulate cortex 
The causal role of several deep brain regions in cognition remains unresolved. This is because we 
have lacked a method to temporarily and non-invasively disrupt deep brain regions without also 
disrupting the overlying cortex, which leads to confounds. This limitation applies to transcranial 
direct and alternating current stimulation, and transcranial magnetic stimulation, even with deep 
TMS coils(Harmelech et al., 2021). Transcranial focused ultrasound holds some 
promise(Kubanek, 2018) but can only minimize the superficial stimulation, not eliminate it.  
 
The function of the dorsal anterior cingulate cortex (dACC) in particular, including the 
adjacent medial prefrontal cortex, remains contested and has been the focus of vigorous and 
unresolved debate for nearly three decades(Clairis & Lopez-Persem, 2023). Almost all functional 
arguments are based on measurements of activity rather than manipulations, and so the evidence 
shows functional correlates rather than the causal roles. TI stimulation provides a fresh path 
forward to resolve some of these longstanding debates.  An early theory proposed that dACC 
signaled conflict and thus increased control, as evidenced by the Gratton effect, in which 
response conflict leads to slower responses on subsequent trials(Botvinick et al., 1999). However 
neuropsychological studies have yielded mixed results(Fellows & Farah, 2005; Sheth et al., 2012). 
We will test this in Study 2.1. Other findings suggest a different function, i.e. that dACC drives 
motivation(Parvizi et al., 2013), especially to avoid risk or loss(J. W. Brown & Braver, 2007; 
Magno et al., 2006), which we will test in Study 2.2. Still others have argued that dACC drives 
foraging behavior(Kolling et al., 2012), with ongoing debate on whether apparent foraging value 
represents difficulty instead(Kolling et al., 2016; Shenhav et al., 2014), or perhaps prediction 
errors in service of learning(J. W. Brown & Alexander, 2017). We may test this in Extra Study 2.3. 
The unresolved debates in turn hinder our ability to understand dysfunctions of the dACC and its 
roles in clinical disorders such as addiction(Fishbein et al., 2005; Forster et al., 2016), 
OCD(Fitzgerald et al., 2005), and schizophrenia(Adams & David, 2007). In Aim 2, we apply TI to 
test for causal roles of dACC on behavior, with the goal of adjudicating the ongoing debates. 
 
3.0 Design 
Overview. This is a study examining the effects of TI on brain activity as measured by fMRI BOLD 
signals (Aim 1), and the effects of TI-related changes in deeper brain region activity on cognitive 
functions. Both aims build on our preliminary results showing focal changes in BOLD signals 
resulting from TI. In Aim 1, we will first establish the effects of TI on BOLD signals, then show that 

Indiana University, Bloomington, IN 
 
6 
these are not confounded with the high frequency carrier signal effects alone, and then show how 
TI can manipulate activity can propagate across brain networks to influence functionally 
connected brain regions. In Aim 2, we apply TI to stimulate a deeper brain region, the dorsal 
anterior cingulate cortex, to resolve longstanding questions about its causal role in cognition. We 
anticipate recruiting 200 subjects, allowing for attrition to achieve our goal of 30 subjects for each 
individual study below. 
 
Subjects will spend 2-3 hours for the session and be paid $35/hour. 
 
Aim 1: Test and characterize the effects of TI on the fMRI BOLD signal 
In all studies, we will administer the Stimulation experience scale before starting the stimulation 
and after the stimulation session is complete. Subjects will also be asked periodically to rate any 
discomfort on a scale of 1-5 (5=highest discomfort), and indicate the location and qualities of any 
discomfort. 
 
Study 1.1. Test the effect of TI in NAcc, controlling for the effects of high frequency 
stimulation.  Healthy subjects (n=30) will be placed in the fMRI scanner and administered the 
same protocol used to generate our pilot results in Figure 2.  Specifically, subjects will have two 
pairs of carbon fiber electrodes attached with conductive gel, at {F9, F10} and {Fp1, CPz}. They 
will receive one 8-minute block of stimulation at 2mA per electrode pair. The stimulation sequence 
will be 2 minutes on, 2 minutes off, 2 minutes on, and 2 minutes off with 30 second ramp up and 
ramp down beginning at the start of each 2-minute period. The first block will apply active TI 
stimulation with 2000Hz in one channel and 2020Hz in the other channel. The second block will 
be a sham TI stimulation, identical to the first block but with the “on” condition immediately 
ramping down as soon as it reaches 2mA after ramp up. The third and fourth blocks will be 
identical to the first and second blocks, except that both electrode pairs will stimulate at 2000Hz, 
resulting in a “NO-TI active” and “NO-TI sham” conditions. The order of blocks, and whether the 
“on” or “off” condition occurs first within a block, will be counterbalanced across subjects. 
 
Study 1.2. Test effect of varying TI beat frequencies on BOLD inhibition vs. activation.  In 
the same left NAcc region, also with n=30 subjects, we will repeat Study 1.1, but instead of the 
NO-TI condition with a zero Hz beat frequency, we will replace it with a 5Hz beat frequency 
(2000Hz and 2005Hz in the two channels). Likewise the 20 Hz beat frequency condition will be 
replaced with 30 Hz (2000Hz and 2030Hz stimulation). We will then compare the degree of BOLD 
activation for 5 vs. 30 Hz beat frequencies as in Study 1.1. 
 
Study 1.3. Confirm effect of TI on the dorsal ACC, around MNI 0, 30, 30. We will repeat Study 
1.1, but targeting the dorsal ACC (n=30 subjects), to confirm we can activate it with 20Hz TI. 
Instead of zero Hz as in Study 1.1, we will use the frequency from Study 1.2 that is found to 
produce the strongest BOLD activation other than 20 Hz, which will be 5Hz, 30Hz, or 40Hz. We 
may find that certain beat frequencies are futile, we may select an alternative beat frequency in 
the range of 1 to 100 Hz. 
 
Aim 2:  Identify causal effects of dorsal anterior cingulate cortex (dACC) on cognition 
Study 2.1. Test whether 20Hz TI in the dACC enhances or disrupts cognitive control.  For 
this, n=30 human subjects will be placed in the fMRI scanner to perform a flanker task(Eriksen & 
Eriksen, 1974), in which subjects must indicate whether the central arrow points left or right. The 

Indiana University, Bloomington, IN 
 
7 
trials will be 50% congruent (“<<<<<” and “>>>>>”) and 50% incongruent (“<<><<” and “>><>>”) 
trials. Previous work shows not only elevated reaction time and error rates for incongruent trials, 
but also a “Gratton effect” in which RT and error rate (as well as dACC activity) are even more 
elevated for incongruent trials that follow a previous congruent trial (Botvinick et al., 1999). This is 
arguably because cognitive control-related activity in the dACC prior to the start of the trial was 
lower, thus requiring more cognitive control-related activation as a reaction to the incongruent task 
stimulus(Botvinick et al., 1999). We will test whether the Gratton effect is reduced by TI to the 
dACC in the scanner, and whether this is accompanied by increased baseline dACC activity due 
to TI. Subjects will be divided into two groups. One will receive 2 consecutive eight-minute blocks 
of TI stimulation (2000 and 2020 Hz in the two electrode pairs, or alternatively the most effective 
beat frequency identified in Aim 1) to dorsal ACC, followed by 2 eight-minute blocks with no-TI 
stimulation, as subjects perform the flanker task in the fMRI scanner. The second group of 
subjects will undergo an identical procedure, except that the first two blocks will be no-TI 
stimulation, followed by 2 eight-minute blocks of TI stimulation. In all subjects, blocks 1 and 3 will 
include the Flanker task, and blocks 2 and 4 will include the visual search task of Magno et al., 
(2006). The visual search task will provide the data needed for Study 2.2. 
 
Study 2.2. Test the causal role of dorsal anterior cingulate in avoidance. We will apply TI 
stimulation as in Study 2.1 to the dorsal ACC with subjects in the fMRI scanner, and for efficiency, 
we will run this task on the same subjects as Study 2.1 concurrently and without leaving the 
scanner. Subjects will perform the task of Magno et al. (2006), during blocks 2 and 4 of the 
sessions described in Study 2.1. Specifically, subjects will perform a visual search task, identifying 
“target present” or “target absent” within a short deadline. There are two trial types, easy (few non-
targets) and hard (many non-targets). They gain +1 reward for correct responses (converted to 
cash after the session), -1 reward for errors, and they can also skip the trial for 0 reward to avoid 
risk. Previous work shows dorsal ACC activity only when subjects skip the trial to avoid the risk of 
an error, but anterior insula activity occurs instead when subjects choose to respond and then 
make an error (Magno et al., 2006).  
 
Study 2.3. Test the causal role of the dorsal ACC in foraging decisions. Using the TI 
stimulation of Study 2.1 with humans subjects in the scanner (n=30), subjects will perform a 
foraging and difficulty task(Shenhav et al., 2014) to adjudicate between competing theories of 
dorsal ACC, whether it drives foraging or reflects task difficulty. Subjects will be divided into two 
groups as in Study 2.1 and will perform the task of Shenhav et al. (2014)(Shenhav et al., 2014) 
during 4 eight-minute blocks, with TI and no-TI conditions in the scanner as in Study 2.1 for each 
of the two groups. In the task, subjects must decide whether to accept playing a gamble with 
known probabilities or forage to find a better gamble with more favorable probabilities. The relative 
value of foraging (RVF), i.e. the difference in expected value for playing the gamble vs. foraging, 
varies between an easy decision (large positive or negative RVF) or a difficult decision (near-zero 
RVF).  
 
Risks of participation and mitigation of risks: 
Subjects may feel uncomfortable completing the interview. For instance, there are questions 
about whether they may be pregnant, surgical history, and about the existence of tattoos and 
piercings on the body. They may decline to answer specific questions or decline to continue 
participating. 
 
This MRI scan is not a medical test.  It is designed to address research questions and it is not a 

Indiana University, Bloomington, IN 
 
8 
complete scan for any clinical purpose.  If there is an abnormality, the scan, the MRI technician, or 
the researcher may not detect it.  If the technician or researcher suspects a possible abnormality, 
the scan will be sent without any participant identifiers to a neuroradiologist for further review.  If 
the neuroradiologist recommends further action, the subject will be notified.    
 
MR imager: MRI has not been shown to produce health problems in normal, healthy individuals. 
The imager DOES NOT produce ionizing radiation, which is radiation associated with 
conventional radioactive sources, such as x-rays, radioactive iodine, uranium, or other 
substances. No medication, needle stick, or injections of drug or contrast agents are involved. 
There are hundreds of imagers of this type used in the U.S. and abroad, both to assist doctors in 
clinical diagnoses and for research. To view a copy of the Food and Drug Administration safety 
guidelines for MR imagers, subjects may simply ask the MRI operator. 
 
Because of the strong magnetic fields used for MR imagers, persons who have magnetic life-
support devices (e.g., pacemakers and aneurysm clips), metal prostheses or other metallic 
objects (e.g. cochlear implants, steel pins implanted to help repair and strengthen broken bones, 
metal fragments from previous injuries) cannot participate in this research. Subjects will be 
screened for MR contraindications 
 
The radio frequency energy used in this exam has produced burns (most of them minor) in about 
one in a million cases.  If subjects feel any burning sensation they will immediately inform the 
staff, so that the scan can be stopped. 
 
MRI may be harmful to an unborn child. If subjects are of childbearing potential (that is, if subject 
is a woman with sexual partner(s) and do not use an adequate birth control method), they must be 
excluded. Reliable birth control (i.e. oral, implanted, or barrier methods) should be used by all 
participants and/or their sexual partner to prevent pregnancy while participating in MR imaging. If 
subjects find that they were pregnant while participating and undergoing MRI, you should notify 
their physician immediately. If subjects use an IUD for birth control they will be excluded unless 
they can document the model of the IUD and we can verify its safety for the MRI environment.  
Pregnancy should be self-reported, and a pregnancy test will not be administered. 
 
While there is no evidence of increased risk with multiple scans, the risks associated with multiple 
scans are not known.  The IUB imaging center is adopting an arbitrary maximum of 40 hours of 
scanning time per individual per year and the time involved in the present study is well below that 
limit. 
 
Though uncommon, there is also the risk that the imaging procedure may result in nausea, 
dizziness, sweating, or headaches. Individuals who suffer from migraines may be more 
susceptible to these side effects as a result of the noise level inside the scanner. These symptoms 
are generally temporary, and the scan can be stopped at any time if you begin experiencing 
discomfort. 
 
Brain stimulation: 
1. Mild physical discomforts: Approximately 66% of participants who receive this kind of 
stimulation experience mild physical discomforts that are short-lived, such as tingling, 
itching, redness, or mild burning sensations on the skin under the pads. Some participants 
have also reported occasional mild headaches and fatigue. There is also a risk of seeing 
flashing lights.  
 
These effects are mild, short lived, and benign. The electric current is very mild and is 
approximately 1000 times smaller than the average static electric shock one might 
receive touching a door knob or light switch after walking on a carpet with socks. While it 
is rare, some participants may experience a stronger unpleasant sensation.  If subjects 

Indiana University, Bloomington, IN 
 
9 
experience any discomfort or wish to stop the experiment, subjects will let the 
experimenter know and the procedure will be stopped immediately. 
 
2. Long term effects: Long term effects of exposure are largely unknown, though no long term 
adverse effects have been reported from any previous study.  As a precaution, the 
stimulation will not last longer than 20 minutes continuously at one time. 
 
3. Medical precautions: Though a significant adverse event has never been reported with 
similar brain stimulation procedures, there theoretically may be a risk to persons with 
conductive metal (i.e. implants) in their head, and to persons who suffer from migraines, 
epilepsy, or other neurological syndromes.  If subjects have any of these conditions they 
may be ineligible to participate in this study. Also, subjects may be ineligible to participate 
in the study if they have a history of seizure disorder, history of cognitive impairment, 
symptoms of psychosis or if you are taking medications for cancer, attention deficit 
hyperactivity disorder (ADHD), autoimmune deficiency syndrome (AIDS), or other mental 
illness. 
 
These risks will be managed by trained researchers; at least one will always be present when 
the machine is operating. The researcher will stop the experiment if they experience 
discomfort that you do not wish to tolerate. Furthermore, the stimulator does not transfer 
current greater than 3 mA per electrode pair, which is still, relatively, a very small current. 
 
Other risks 
There is a small risk of boredom during the session. Subjects can withdraw themselves if they do 
not wish to continue. 
 
There is also a small risk of loss of confidentiality. We will minimize that risk by storing the records 
in secure (locked or password-protected) locations, Electronic data will be identified only by the 
subject's study ID number, with the master list linking the subject ID to identifiable information 
stored on paper. Electronic data will be stored on the PI's servers or on Indiana University servers. 
All systems will have at least password protection. Paper data will be stored in locked cabinets 
inside a locked room. 
 
Study procedure summary 
 
Days before the session: 
• 
Recruitment (via paper flyers and digital ads) 
• 
Pre-screening (via phone) 
 
Day of session: 
• 
Consent  
• 
Fill out questionnaires 
o MR safety screening 
o Demographic form 
o Edinburgh handedness inventory 
o WHODAS 2.0 
o PHQ-9 
o GAD-7 
o Stimulation experience scale (SES) 
• 
Subjects randomized to receive active vs. sham stimulation first, using an alternating list, 
in which supccessive subjects are assigned to the conditions of active first, then sham first, 
then active first etc. 
• 
Brief cognitive task explanation and practice (Aim 2 only) 
• 
Attach electrodes (day of session, in MR facility) 
• 
Scanning while undergoing TI (and if Aim 2, performing cognitive tasks) (day of session) 
o Brief stimulation scale 

Indiana University, Bloomington, IN 
 
10 
o Multiple scanning and stimulation runs, where each stimulation run is followed by 
administering the brief stimulation scale 
• 
Subject removed from scanner, electrodes removed 
• 
SES repeated 
• 
Subject paid and dismissed 
 
 
 
4.0 Eligibility Criteria 
Inclusion: 
• 
between the ages of 18 and 50, must have at least a 6th grade education, ability to 
speak and read English for all phases. 
 
Exclusion: 
• 
Medical - if they are on psychotropic medications for ADHD, other mental illness or 
medication for cancer, epilepsy (i.e. individuals with any history of seizure disorder), migraines, 
or other neurological syndromes, or AIDS (which can cause cognitive deficits (Watkins & 
Treisman, 2015), history of head trauma, history of cognitive impairments, metal implants in the 
head or under the scalp, personal experiences consistent with symptoms of psychosis (i.e. 
hearing or seeing things that aren't there, being secretly controlled, or having special powers, 
seeing or hearing things that aren’t really there), history of holes bored into skull or known 
fissures in cranial bones 
• 
MRI Safety - Subjects will be excluded if they do not meet fMRI safety screening criteria 
(i.e. metal implants in their body, tattoo on head or neck, permanent jewelry, etc.) or if a 
participants uses an IUD for birth control they will be excluded unless the subject can document 
the model of the IUD and we can verify its safety for the MRI environment. Pregnancy should be 
self-reported, and a pregnant test will not be administered. Participants must weigh less than 
440 lbs. Presence of pacemakers 
 
5.0 Outcome Characteristics and Endpoint Definitions: 
 
For Study 2.1, Behaviorally, we predict that the Gratton effect on both RT and error rate will be 
reduced in active TI vs. sham stimulation conditions. We will perform an ANOVA test with factors 
of on vs. off TI stimulation, previous trial congruent/incongruent, and current trial 
congruent/incongruent. We expect to find a significant interaction, with post-hoc tests showing 
reduced effects of previous trial congruency, and reduced interactions of previous trail congruency 
with current trial congruency.  Neurally, we expect to find that the BOLD signal shows a main 
effect of increase during the TI stimulation vs. sham. Also, we expect to find that the contrast of 
dACC responses to incongruent minus congruent trials is attenuated in the active TI stimulation 
condition vs. no-TI. If so, we will conclude that TI disrupts cognitive control by attenuating the 
monitoring function of dorsal ACC. Potential problems and alternate approaches It is possible that 
TI stimulation here may enhance rather than disrupt neural function, in which case we may find 
larger rather than smaller Gratton effects with TI. In that case, we will ask whether the contrast of 
BOLD activity for incongruent minus congruent trials in dorsal ACC is correspondingly increased 
during active TI vs. sham stimulation. 
 
For Study 2.2, behaviorally, we predict that TI will disrupt the dACC, leading to a smaller 
likelihood of skipping difficult trials. We will perform a logistic regression to determine how TI 
stimulation (on vs. off) and trial difficulty (easy vs. hard), and their interaction, predict the 
probability of skipping a trial. Neurally, we expect to find increased BOLD signal both for TI 
stimulation and for skipping a trial, in overlapping regions. Potential problems and alternate 
approaches As with Study 2.1, it is possible that TI stimulation here may enhance rather than 

Indiana University, Bloomington, IN 
 
11 
disrupt neural function, in which case we may find an increase rather than decrease in the 
probability of skipping with TI stimulation. We will use two-tailed statistical tests to detect this 
possibility. 
 
For Study 2.3, we will test whether TI to dorsal ACC increases or decreases foraging probability, 
or alternatively, whether TI reduces the reaction time differences of easy vs difficult decisions. 
 
6.0 
Statistical Analysis and Sample Size: 
 
Power Analysis: From the pilot data shown in Fig. 2, we used the effect size of the stim-sham 
contrast to calculate the number of subjects required to detect a significant cluster of activity in the 
region shown. We assumed p<0.001 as the cluster defining threshold and required 90% power. 
The required number of subjects is 25, and we budget for 30 subjects per study to allow for 
attrition. We do not have effect size estimates for the behavioral effects of Aim 2. 
 
7.0 
Data Management 
 
Electronic data will at all times be stored and transmitted securely, using encryption such as TLS 
or SSH/SFTP protocols. We will use subject ID numbers to key the data. The data will be stored 
and processed on PI Brown’s internal lab server cluster, which gives secure nightly incremental 
backups to a separate location. We will use standard software tools for analysis, including PI 
Brown’s existing fMRI processing software for the neuroimaging and temporal interference 
studies. The final archival data will be preserved in the IU Scholarly Data Archive. 
 
There will also be a DSMB from IUSM (chaired by Sean O’Conner) to review the data collection 
and the subject safety. The DSMB will monitor the study quarterly or biannually, as the DSMB 
sees fit, and will consist of two medical doctors/engineers and one physician that works with 
TMS, a similar form of brain stimulation. In the case of an event, with regard to participant safety, 
occurs before 3 months after any DSMB meeting and the DSMB would otherwise wait 6 months 
until the next review, the PI will alert the DSMB and have that event reviewed within 3 
months/quarterly.  
 
The PI will monitor the quality of data, the number of subjects recruited, any adverse events, 
and any new information that comes to light that may impact the assessment of risk to the 
subjects. The PI will monitor the research as it is carried out, on a day-to-day basis. Formal 
monitoring evaluation will take place annually prior to continuing review or close-out, and 
quarterly or semi-annually by the DSMB, as the DSMB sees fit.  
 
There are no statistical criteria that would lead to a premature end to the study, because a 
minimum sample size is necessary given the unknown statistical power. The study may be 
ended early if adverse events were to occur.  
 
8.0 
Principal Investigator and Study Site Qualifications and Resources 
 
The PI Joshua Brown has published previous research on combined fMRI and temporal 
interference methods (Modak et al., 2024), as well as a number of papers on computational 
neural models and fMRI. Current research in his lab focuses on understanding real-time neural 
mechanisms of drug use decisions, in which heavy smokers gamble for drugs and are allowed to 
inhale from an e-cigarette briefly when they win a gamble -- all while in the fMRI scanner. He 
also has a degree in engineering with the expertise necessary to implement and use 
neurostimulation technology.  
 

Indiana University, Bloomington, IN 
 
1 
References 
 
Bullen, C., H. McRobbie, et al. (2010). "Effect of an electronic nicotine delivery device (e 
cigarette) on desire to smoke and withdrawal, user preferences and nicotine delivery: 
randomised cross-over trial." Tob Control 19(2): 98-103. 
Chander Bankim S., Witkowski Matthias, Braun Christoph, Robinson Stephen E., Born Jan, 
Cohen Leonardo G., Birbaumer Niels, Soekadar Surjo R. (2016) tACS Phase Locking of 
Frontal Midline Theta Oscillations Disrupts Working Memory Performance. Frontiers in 
Cellular Neuroscience 10:120.   
Cohen Kadosh R, Soskic S, Iuculano T, Kanai R, Walsh V (2010) Modulating Neuronal Activity 
Produces Specific and Long-Lasting Changes in Numerical Competence. Current Biol. 
20(22):2016-2020. 
CentersforDiseaseControlandPrevention (2005). "Annual Smoking-Attributable Mortality, Years 
of Potential Life Lost, and Productivity Losses–United States, 1997–2001." Morbidity and 
Mortality Weekly Report 54(25): 625-628. 
Devinsky, O., Morrell, M. J., & Vogt, B. A. (1995). Contributions of anterior cingulate cortex 
to behaviour. Brain, 118(1), 279-306. 
Eissenberg, T. (2010). "Electronic nicotine delivery devices: ineffective nicotine delivery and 
craving suppression after acute administration." Tob Control 19(1): 87-8. 
Enoch, M. A. (2008). "The role of GABA(A) receptors in the development of alcoholism." 
Pharmacol Biochem Behav 90(1): 95-104. 
Fishbein, D. H., D. L. Eldreth, et al. (2005). "Risky decision making and the anterior cingulate 
cortex in abstinent drug abusers and nonusers." Brain Res Cogn Brain Res 23(1): 119-36. 
Fregni, F., Liguori, F., et al. (2008). "Cortical stimulation of the prefrontal cortex with transcranial 
direct stimulation reduces cue-provoked smoking craving: A randomized, sham controlled 
study." J Clin Psychiatry 69(1): 32-40. 
Goldstein, R. Z., D. Tomasi, et al. (2007). "Subjective sensitivity to monetary gradients is 
associated with frontolimbic activation to reward in cocaine abusers." Drug Alcohol 
Depend 87(2-3): 233-40. 
Hester, R. and H. Garavan (2004). "Executive dysfunction in cocaine addiction: evidence for 
discordant frontal, cingulate, and cerebellar activity." J Neurosci 24(49): 11017-22. 
Huff, W., Lenartz, D., Schormann, M., Lee, S. H., Kuhn, J., Koulousakis, A., ... & Sturm, V. (2010). 
Unilateral deep brain stimulation of the nucleus accumbens in patients with treatment-
resistant obsessive-compulsive disorder: Outcomes after one year. Clinical neurology and 
neurosurgery, 112(2), 137-143. 
Koob, G. F. and F. E. Bloom (1988). "Cellular and molecular mechanisms of drug dependence." 
Science 242(4879): 715-23. 
Koob, G. F. and M. Le Moal (2001). "Drug addiction, dysregulation of reward, and allostasis." 
Neuropsychopharmacology 24(2): 97-129. 
Kufahl, P. R., Z. Li, et al. (2005). "Neural responses to acute cocaine administration in the 
human brain detected by fMRI." Neuroimage 28(4): 904-14. 
Kuhn, J., Lenartz, D., Huff, W., Lee, S. H., Koulousakis, A., Klosterkoetter, J., & Sturm, V. 
(2009). Remission of alcohol dependency following deep brain stimulation of the 
nucleus accumbens: valuable therapeutic implications?. Case Reports, 2009, 
bcr0720080539. 
Matsumoto, H., & Ugawa, Y. (2017). Adverse events of tDCS and tACS: a review. Clinical 
neurophysiology practice, 2, 19-25. 
Nachev, P., Lopez-Sosa, F., Gonzalez-Rosa, J. J., Galarza, A., Avecillas, J., Pineda-

Indiana University, Bloomington, IN 
 
2 
Pardo, J. A., ... & Strange, B. (2015). Dynamic risk control by human nucleus 
accumbens. Brain, 138(12), 3496-3502. 
Onoda, K., Kawagoe, T., Zheng, H., & Yamaguchi, S. (2017). Theta band transcranial 
alternating current stimulations modulates network behavior of dorsal anterior 
cingulate cortex. Scientific reports, 7(1), 3607. 
Redish, A. D. (2004). "Addiction as a computational process gone awry." Science 306(5703): 
1944-7. 
Risinger, R. C., B. J. Salmeron, et al. (2005). "Neural correlates of high and craving during 
cocaine self-administration using BOLD fMRI." Neuroimage 26(4): 1097-108. 
Starr, C. J., Sawaki, L., Wittenberg, G. F., Burdette, J. H., Oshiro, Y., Quevedo, A. S., & 
Coghill, R. C. (2009). Roles of the insular cortex in the modulation of pain: insights 
from brain lesions. Journal of Neuroscience, 29(9), 2684-2694. 
Vanneste S, Walsh V, Van de Heyning P, De Ridder D (2013) Comparing immediate 
transient tinnitus suppression using tACS and tDCS: a placebo-controlled study. 
Exp Brain Res 226(1):25-31. 
Vansickel, A. R., C. O. Cobb, et al. (2010). "A clinical laboratory model for evaluating the acute 
effects of electronic "cigarettes": nicotine delivery profile and cardiovascular and subjective 
effects." Cancer Epidemiol Biomarkers Prev 19(8): 1945-53. 
Varjačić, A., Mantini, D., Levenstein, J., Slavkova, E. D., Demeyere, N., & Gillebert, C. R. (2018). 
The role of left insula in executive set-switching: Lesion evidence from an acute stroke 
cohort. cortex, 107, 92-101. 
Venancio, R. C., Pelegrini, S., Gomes, D. Q., Nakano, E. Y. & Liebano, R. E. (2013) Effects of 
Carrier Frequency of Interferential Current on Pressure Pain Threshold and Sensory 
Comfort in Humans. Arch. Phys. Med. Rehabil. 94, 95–102. 
Watkins C, Treisman G (2015) Cognitive impairment in patients with AIDS – prevalence and 
severity. HIV AIDS (Auckl) 7:35-47. 
Xu, J., A. Mendrek, et al. (2007). "Effect of cigarette smoking on prefrontal cortical function in 
nondeprived smokers performing the Stroop Task." Neuropsychopharmacology 32(6): 
1421-8.