The Development and Human Translation of Temporal Interference Brain Stimulation
Phase: NA
Conditions: Visual Acuity
Sponsor: Beth Israel Deaconess Medical Center

NCT Number:  
NCT03747601 
Official Title: 
Temporal Interference Brain Stimulation (TI) 
Document Type: 
Protocol with Qualitative Analysis Plan  
Document Date: 
09/01/2020 

(CCI) Committee on Clinical Investigations 
Page 1 of 15 
 
Study Description – Part B 
CCI Form:  9-2015 
 
PI Revision Date: 09/01/2020 
 
PART B 
STUDY DESCRIPTION 
 
TITLE OF PROTOCOL 
The Development and Human Translation of Temporal 
Interference Brain Stimulation 
Principal Investigator 
Daniel Press, MD 
 
 
B1. 
PURPOSE OF PROTOCOL 
 
The primary aim of this study is to translate temporal interference (TI) stimulation methodology into 
humans and examine its safety, feasibility, steerability, and focality. In the proposed early phase human 
experiment, we will assess the ability to apply TI stimulation along spatial dimensions to selectively 
modulate neural activity and assess the feasibility of selective targeting deep brain structures without 
exciting overlaying cortex. The overall goal of the study is to advance TI methodology and its translation 
to humans. 
 
The specific aims in this study are to  
 
Assess the safety of TI stimulation. 
 
Assess the feasibility, focality, and steerability of TI stimulation by selectively modulating activity 
in subregions of a cortical area (calcarine cortex) 
 
We hypothesize that TI stimulation can be used to impact different regions of the visual field that are 
represented within the calcarine fissure of the human brain.  
 
We hypothesize that TI stimulation is possible in regions within the calcarine fissure without impacting 
intervening regions. 
 
We hypothesize that TI will be well tolerated by human subjects and side effects will be consistent with 
other forms of transcranial electric current stimulation (tES). 
 
 
 
B2. 
SIGNIFICANCE AND BACKGROUND FOR THE STUDY 
 
Current brain stimulation methods have limitations: 
 
Deep brain stimulation (DBS) has had great impact in disorders such as Parkinson’s disease and 
obsessive-compulsive disorder and has potential for other disorders such as depression and Alzheimer’s 
disease. DBS works by delivering focal electrical stimulation from electrodes surgically implanted in 
deep, often sub-cortical regions. Being a surgical procedure, it bears the potential for serious 
complications that limit adoption and scalability. 
 
Transient non-invasive brain stimulation technologies, such as transcranial magnetic stimulation (TMS) 
and transcranial electrical stimulation (tES), have shown efficacy as a therapeutic option for treatment 
resistant depression and are being investigated for stroke rehabilitation and many other brain disorders. 
However, the ability of TMS or tES to directly stimulate deeper brain structures is obtained at the 
expense of inducing stronger stimulations of overlying cortical areas, and the resulting wider stimulation 
often will push on the limits of safety guidelines. Recently, transcranial focal ultrasound has been shown 
to modulate deep brain regions, but the mechanism is currently unknown, and some results suggest 
cellular damage might result. There is still great hope for a method of brain stimulation that could be 
focal, steerable, selectively deep, and electrical. 
 

(CCI) Committee on Clinical Investigations 
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Study Description – Part B 
CCI Form:  9-2015 
 
PI Revision Date: 09/01/2020 
 
 
Temporal interference (TI) stimulation: 
 
We recently discovered a strategy for sculpting the 
amplitude of electric fields so as to enable focal, yet 
noninvasive, 
electrical 
neural 
stimulation. 
We 
discovered that by delivering multiple electric fields to 
the brain at slightly different carrier frequencies — 
which are themselves too high to recruit effective 
neural firing, but for which the offset frequency is low 
enough to drive neural activity — we can cause 
neurons to be electrically activated at a focus without 
driving neighboring or overlying regions. We call this 
method temporal interference (TI) stimulation, since 
the interference of multiple electric fields is what 
enables the focality: neural stimulation will occur only 
at the region for which the amplitude of the electric 
field envelope, at the offset frequency, is of great 
magnitude. We examined whether the TI concept 
could indeed result in well-defined low frequency 
envelope 
modulated 
electric 
fields 
through 
computational 
modeling 
using 
finite 
element 
methodologies (FEM), and found that indeed we could 
create an electric field with peak low frequency 
envelope at a deep point within a conductive structure, without significant low frequency electric field 
at overlying areas. (See figure) 
 
We here explore and develop this physical principle to make it relevant to the brain, which has not 
been done before. One particularly appealing reason for exploring TI stimulation is the very solid 
scientific premise: it is based upon the laws of physics, and easily validated by computational 
modeling and physics experiments.  However, the precise mechanism is not understood, and a key 
goal of our study will be to understand the mechanism in terms of bioelectric effects within and 
between neurons in neural networks. 
 
Animal studies: 
 
We validated that such interferometrically generated low frequencies could effectively drive neural 
activity by applying the TI stimulation strategy transcranially to anesthetized living mice, and recorded 
the responses using whole-cell patch clamp in current clamp mode, using our autopatching robot, 
finding that indeed neurons would follow the low frequency envelope of the electric field, but not the 
high frequency carrier. 
 
To test whether the TI stimulation methodology could be used to recruit deep brain structures without 
recruiting overlying neural layers, we transcranially applied TI stimulation and control stimulation 
conditions to the hippocampus of anesthetized living mice and measured the activation profile using 
c-fos staining. We found that 10 Hz transcranial stimulation resulted in very broad c-fos expression 
profiles, with a strong activation in the cortex as well as in the hippocampus. In contrast, transcranial 
application of 2 kHz + 2.01 kHz TI stimulation, with an envelope amplitude peak deeper than the 
cortex, resulted in c-fos expression only in the hippocampus with no significant neural activation in the 
cortex. We found that the TI stimulation did not alter the neuronal and synaptic integrity of the 
underlying tissue 24 h after stimulation, at least as reflected by the stains we used. 
 
 
TI stimulation cartoon.  Two alternating 
current sources are placed on the head.  
Where the two fields converge, a low 
frequency envelope electrical field 
occurs. (Figure 1, from Lozano 2018, 
NEJM) 

(CCI) Committee on Clinical Investigations 
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Study Description – Part B 
CCI Form:  9-2015 
 
PI Revision Date: 09/01/2020 
 
To test whether TI stimulation could evoke behaviorally relevant responses, we stimulated the 
forelimb region of the motor cortex and measured evoked motor activity. We found that simultaneous 
application of currents  and 
 at frequencies 
 did not evoke motor activity. However, 
when 
 was set to 2.001 kHz, 2.005 kHz or 2.01 kHz, while keeping 
 fixed at 2 kHz, the stimulation 
evoked a movement of the contralateral forelimb at the difference frequency of 1 Hz, 5 Hz and 10 Hz, 
respectively. To test whether the evoked movement could be steered without physically moving 
electrodes, we increased the current  above the forelimb area of the motor cortex and decreased 
the current 
 above the whisker area of the contralateral motor cortex, keeping the current sum fixed 
(predicting steering toward the 
 electrodes). We found that the movement amplitude of the 
contralateral paw decreased and the movement amplitude of the contralateral whisker increased. 
When  was larger than 
, the stimulation evoked a movement in the whisker ipsilateral to the  
electrodes, with stronger movements evoked as the amplitude of  increased compared to 
. This 
suggest that the steering anticipated in our modelling can be realized in-vivo. 
 
 
Human pilot testing: 
 
Researchers at MIT have completed relevant pilot testing to assess whether TI stimulation is safe and 
can recruit activity in the human brain. We applied TI stimulation to the motor cortex of nine healthy 
volunteers (three females; mean age 27.5 ±5) and measured BOLD signals concurrently using fMRI. 
The experiment included four sessions consisting of six stimulation blocks - 10 Hz stimulation, 2 kHz 
stimulation, TI stimulation with 1:1 current ratio, TI stimulation with 1:3 current ratio, TI stimulation 
with 3:1 current ratio, and sham. Each stimulation block lasted 25 s with 5 s ramp-up and ramp-down 
periods. All participants tolerated the procedure without any adverse or side effects. No pain, tingling, 
cognitive changes, or sensory-motor difficulties were reported for the TI case by any of the 
participants.  To test whether the TI stimulation changed the BOLD signal at the brain regions that 
were exposed to the electric fields we compared the T-score inside a spherical region of interest 
(ROI) in which activation was predicted by a subject-specific FEM modeling. We found that TI 
stimulation with a current ratio of 1:1 increased the BOLD signal at the center of the ROI. In contrast, 
TI stimulation with a current ratio of 1:3 increased the BOLD signal primarily at the frontal half of the 
spherical ROI, while TI stimulation with a current ratio of 3:1 increased the BOLD signal primarily at 
the dorsal half of the ROI, suggesting that steering might be possible in humans. 
 
TI Validation with Visual Field Stimulation: 
The organization of the human visual system is an ideal model system suited for evaluation of the 
steerability of TI stimulation. The primary methodological advancement of TI is stimulation of deeper 
structures leaving superficial structures near the electrodes unaffected.  The human primary visual 
system is organized “retinotopically”, that is, with respect to the center of gaze.  It is located within the 
calcarine sulcus, located in the occipital lobe at the posterior of the head.  The most posterior part of 
the sulcus represents the center of gaze, and the most anterior part of the sulcus represents the 
periphery.  Using this feature, we will examine if stimulation targeting the anterior calcarine sulcus 
induces a detectable visual change within the peripheral visual field, without impacting the center of 
gaze, located more superficially.  Additional control sessions will evaluate the precision of TI steering. 
 
Visual stimulation has historically been used as a preliminary investigation of non-invasive stimulation, in 
the study of transcranial magnetic stimulation (TMS) and transcranial electrical stimulation (tES). These 
sessions in healthy participants have shown acute effects of stimulation (e.g. brief phosphenes, transient 
scotomas) that are transient. 
 
Clinical significance: 
 
The importance of the problem we are tackling with TI stimulation is enormous, clinically speaking. 

(CCI) Committee on Clinical Investigations 
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Study Description – Part B 
CCI Form:  9-2015 
 
PI Revision Date: 09/01/2020 
 
Approximately 100,000 people have had DBS implants, requiring invasive surgery, but the patient 
population that could be helped is potentially in the many millions – and noninvasive stimulation could 
potentially help. While DBS has proven effective for some patients, one critical barrier for its wider 
therapeutic impact is eliminating the serious complications that can result from surgery and making 
the effects more widely available than can be deployed by the relatively small number of 
neurosurgeons. Currently, perhaps 1% of the current tremor population receives DBS due to the high 
risk involved; by making DBS noninvasive, we will help increase the accessibility of this kind of 
treatment by perhaps orders of magnitude. On the other hand, noninvasive brain stimulation 
methods, such as TMS or tCS, could potentially help many more people if we were able to make it 
more steerable and more focal. Thousands of studies have been performed with noninvasive brain 
stimulation, and four different TMS devices have been approved for the treatment of medication-
resistant depression18, raising the question of whether having better focality, precise steerability, and 
depth selectivity, might open up TMS/tCS-like protocols to broader patient populations as well. 
 
The key goal of this proposal is to advance the translation of the TI stimulation methodology to 
humans. At present, TI stimulation cannot match the spatial resolution of implantable DBS at depth. 
We hypothesize that in the future it might be possible to pinpoint smaller regions of the brain using a 
larger number of interfering kHz-frequency electric fields, contingent on a similar neural response to 
those individual fields. TI stimulation has also not been tried with different frequencies (e.g., neural 
drive frequencies) as high as those used in DBS.  We will explore these higher frequencies, e.g. at 
100 Hz and beyond, in this proposal. 
 
 
In conclusion, the proposed project will offer new experimental frontiers to map and modulate the 
brain with a non-invasive alternative to DBS/TMS/tCS with low risk, precise steerable focality, and 
depth selectivity. We will advance the TI methodology and initiate its translation to humans. 
  
 
 
 

(CCI) Committee on Clinical Investigations 
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Study Description – Part B 
CCI Form:  9-2015 
 
PI Revision Date: 09/01/2020 
 
B3. 
DESCRIPTION OF RESEARCH PROTOCOL 
A. 
Study Design – Overview, Methods, Procedures 
 
 
Overview 
This is an investigational early phase testing of temporal interference (TI) stimulation in humans. The 
overall aim of the study is to assess the safety, feasibility, focality, and steerability of TI stimulation by 
selectively modulating activity in subregions of a cortical area (calcarine cortex – the primary visual 
cortex) 
 
Healthy subjects who meet inclusion and exclusion criteria will be entered into the study. The study will 
recruit up to 20 subjects with the aim to complete 12 subjects. 
 
Study Visits: 
The study will consist of up to 6 study visits. The screening and baseline visit, the MRI visit, and up to 
4 TI study. The screening and baseline visit and TI visits will occur at Beth Israel Deaconess Medical 
Center in the Berenson-Allen Center. The MRI visit will take place at the Boston University Cognitive 
Neuroimaging Center. 
  
 
Screening and Baseline visit (Visit 1): 
Subjects will be prescreened over the phone or REDCap and invited in to the Berenson Allen 
Center to complete screening and baseline if they appear eligible and continue to be 
interested in the study. After Informed Consent is obtained, the following screening and 
baseline procedures will be completed: 
 
o Inclusion and exclusion criteria review 
o Subject demographics 
o Handedness assessment 
o Medical history and medication review 
o Physical and Neurological exam conducted by a Neurologist or Neurologic Nurse 
Practitioner 
o Baseline perimetry assessment (may be completed during/after MRI visit at BU) 
o The MINI International Psychiatric Interview Psychiatric assessment  
o All female subjects will undergo a pregnancy test and pregnant women will be 
excluded 
o Screening for retinotropic mapping – assessing the participant’s ability to hold fixation 
with their eyes for experimental trials (may be completed during/after MRI visit at BU) 
o MRI safety review 
 
The baseline and screening visit will take approximately 1.5 hours. 
 
 
MRI session(Visit 2) 
The MRI session will take place at the Boston University Cognitive Neuroimaging Center 
under a Boston University submitted and approved protocol that is specific to this study. An 
MRI scan of the brain will be conducted while the participant views visual stimuli to obtain 
each individual’s retinotopic map. This data will be provided to the study team at BIDMC to 
conduct the study visit and for analysis (Further details in “Data Security”) 
 
This visit will take approximately 1.5-2 hours. 
 
 
Temporal Interference (TI) Sessions (Visits #3-7): 

(CCI) Committee on Clinical Investigations 
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Study Description – Part B 
CCI Form:  9-2015 
 
PI Revision Date: 09/01/2020 
 
Each subject will then undergo up to 4 TI stimulation sessions (2 minimum) separated by at 
least 2 days to minimize the risk of carry over effects of the stimulation. In each visit, the 
participant will receive TI stimulation to a region of retinotopic representation in the calcarine 
fissure. The cortical targets will be defined by electrical field modelling that will be used to 
optimize the electrode placement.  
 
Stimulation visits will consist of TI stimulation combined with a visual discrimination task, with 
any changes in visual perception assessed by collecting behavioural responses (i.e. button 
presses) from the subject in response to visual stimuli presented before, during, and after TI 
stimulation.   
 
Each visit will consist of up to four, 10 minute blocks of stimulation paired with a visual 
discrimination task. The stimulation blocks will be completed with TI stimulation at a difference 
frequency ranging from 1 to 80Hz, transcranial alternative current stimulation (tACS) 
stimulation with no temporal interference at a frequency ranging from 1 – 80HZ, or a no offset 
stimulation (e.g. matched carrier stimulation frequencies such that no envelope modulation is 
anticipated). The most common signal from visual cortex during wakeful relaxation is in the 
frequency range (8-12 Hz). Due to this feature of visual cortex, we hypothesize that 
stimulation frequencies in and around  are likely to demonstrate TI efficacy. Moreover, since 
visual perception changes have been induced with tACS at 60Hz, we hypothesize that 
stimulation in and around this frequency will associate with detectable visual perception 
changes. We hypothesize that TI with a residual effective stimulation frequency of 1-80 Hz will 
be ideally suited for activation of the targeted visual cortex.  
 
Each block will go as follows: 
1. Baseline visual discrimination task to assess threshold 
2. TI stimulation paired with the visual discrimination task and visual disturbance assessment 
(10 minutes) 
3. Repeat visual discrimination task 
Participants will have a 5 minute break between blocks.  
Participants will be monitored throughout the visit for any adverse effects and a tES side-effect 
questionnaire will be administered at the beginning and end of each stimulation visit to 
additionally track any adverse effects. Although any visual disruption induced by the 
stimulation is expected and anticipated to be transient in nature, at the conclusion of each 
visit, a standard automated visual perimetry assessment will be completed on a Humphrey 
Visual Field analyser to compare to baseline. If there is a change in the perimetry assessment, 
a study MD will evaluate the participant to determine the need for additional follow-up. If there 
are any immediate concerns, the participant will be further evaluated by the study 
ophthalmologist. Overall, each stimulation visit will take approximately 3 hours to complete.  
 
 
Detailed Methods and Procedures: 
 
Mini International Neuropsychiatric Interview (MINI): 
All subjects will be screened as overseen by a board-certified psychiatrist using the Mini International 
Neuropsychiatric Interview, ver. 6.0 (MINI) to identify prospective subjects with exclusion criteria related 
to mental health.  
 
If a subject answers affirmatively to the question “Did you repeatedly consider hurting yourself, feel 
suicidal, or wish that you were dead? Did you attempt suicide or plan a suicide?” within the past 2 weeks, 
a study MD (psychiatrist or neurologist) will be notified and will assess the participant/the participant’s 

(CCI) Committee on Clinical Investigations 
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Study Description – Part B 
CCI Form:  9-2015 
 
PI Revision Date: 09/01/2020 
 
responses. The MD may recommend follow-up with their primary care provider and/or with a mental 
health care provider. Although not anticipated in this study of healthy individuals, if a participant is 
thought to need urgent care, the participant’s healthcare provider may be contacted by one of the study 
clinicians to develop a plan for follow-up. If there is concern for their immediate safety, they will be sent to 
the emergency room at BIDMC.   
 
MRI 
The subject will go to Boston University Cognitive Neuroimaging Center and will have the MRI under 
a Boston University submitted and approved protocol The MRI will include T1 and T2 structural 
images.  Retinotopic mapping and population receptive field mapping (pRF) will be performed using 
T2* weighted EPI (BOLD) images.  Participants will view a computer screen projected within the bore 
of the MRI.  The computer display will consist of visual stimuli presented in regions of the visual field 
to evoke targeted visual responses in the brain. Participants will be asked to make button presses to 
specific stimuli within the display while they keep their eyes still.  Individual MRI runs will be 4-12 
minutes, giving brief breaks to participants between runs for the whole MRI session. 
 
Although the scan will be collected under a separate protocol at Boston University, the data will be 
sent to BIDMC and the study team at BU will alert the BIDMC PI if they note any findings to be 
reviewed. Any suspected incidental findings will be reviewed by a neurologist, who will share the 
findings with the patient in real-time and will recommend follow-up with their primary care provider 
and/or will recommend that they follow-up with a specialist provider. Although not anticipated in this 
study of healthy individuals, if a participant is thought to need urgent attention, the participant’s 
healthcare provider may be contacted by one of the study clinicians to develop a plan for follow-up.   
 
Visual field Testing 
All participants will have a baseline visual field assessment with a computerized visual field device (a 
Humphrey field analyzer – HFA) to be completed in the BIDMC ophthalmology department. This 
assessment will also be completed at the end of each TI visit. The assessment consists of the 
participant being positioned against a forehead and chinrest while being asked to maintain fixation on 
a central target and while providing responses when a light stimulus is noted. One eye will be 
assessed at a time. The testing takes under 10 minutes. If an abnormality is noted at baseline, the 
study ophthalmologist will review the results and will share the findings with the patient in real-time 
and will recommend follow-up with their primary care provider and/or will recommend that they follow-
up with a specialist provider in ophthalmology. They will be excluded from the study if an abnormality 
is discovered at baseline. If a change is noted at the end of a testing session, a study MD will 
evaluate the participant to determine the need for additional follow-up. If there are any immediate 
concerns, the participant will be further evaluated by the study ophthalmologist who will provide 
recommendations for observation or follow-up.  
 
Visual Discrimination and Disruption Testing  
Participants will be asked to perform a visual discrimination task within the targeted region of visual 
space and within a control region prior to, concurrently, and following TI stimulation. 
Adaptive thresholds will be computed for orientation discrimination and contrast discrimination using 
an algorithmic approach. Discrimination thresholds for stimulated and unstimulated regions will be 
assessed using a within-subjects design using a repeated-measures ANOVA. Subjects will be asked 
to fixate at different locations on a screen and press a button, for example, to indicate where they see 
a visual stimulus. 
 
TI Stimulation 
 
TI stimulation will be generated by our prototype device and applied to the head via standard, carbon 

(CCI) Committee on Clinical Investigations 
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Study Description – Part B 
CCI Form:  9-2015 
 
PI Revision Date: 09/01/2020 
 
electrode pads. Similar to other forms of tES, TI will be delivered using a low amplitude (4mA or 
lower) electric current via a minimum of two and a maximum of 24 scalp electrodes. We will use 
computer simulations to optimize the location of the electrodes to maximize the amplitude of the 
envelope modulation in the targeted area (calcarine cortex subregions) while minimizing its amplitude 
in the neighboring or overlying cortex. Electrodes will be fitted with fiducial markers for post-
processing localization of the electrodes in MRI.  TI stimulation will be applied for up to 10 min (with 
5-10s ramping-up and ramping-down periods) with a difference frequency of 1-80Hz.   
As compared to modern tES, these values are reduced in duration, frequency and intensity relative to 
tES guidelines (“up to 60 minutes”, frequencies up to 10kHZ), but follow overall guidance for ramping-
up and ramping down periods (Antal et al 2017, Clin Neurophysiology). 
Control conditions will include non-TI controls (i.e. stimulation at a single frequency equal to the 
difference frequency of TI stimulation, thus no envelope of stimulation). TI delivered at the carrier 
frequency only, or TI with alternative difference frequencies expected to be suboptimal.  The carrier 
frequency, as well as the current amplitude,  will be selected according to the animal data, scaled 
according to the computer models, and governed by safety guidelines and considerations. 
 
 
B. 
Statistical Considerations 
 
a. Sample Size Justification: This study aims to assess the feasibility, focality, and 
steerability of TI stimulation in humans. Pilot testing with 9 healthy participants 
demonstrated the feasibility and safety of this study, and 9 participants were sufficient 
to identify a neurophysiological effect upon BOLD signal.  
 
We aim to complete at least 12 subjects, but up to 20 will be entered to allow for 
attrition. 
 
b. Data Analysis: This study has a primary aim of assessing visual discrimination 
thresholds before, during and after TI stimulation.  These values will be entered into a 
repeated measures ANOVA to assess the impact of TI stimulation, with the primary 
outcome being an interaction between TIME factors (before, during and after TI) and 
visual field location (stimulated with TI vs unstimulated).   All analysis will be conducted 
in either SPSS or R. 
 
Safety information will be tabulated as frequency of expected events (e.g. headache), 
and non-conforming safety information will similarly be tabulated and reported. 
 
 
 

(CCI) Committee on Clinical Investigations 
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Study Description – Part B 
CCI Form:  9-2015 
 
PI Revision Date: 09/01/2020 
 
C. 
Subject Selection 
The population of the Greater Boston area is 84% Caucasian, 9% African-American, 5% Hispanic 
and 2% Asian, with relatively similar numbers of men and women. Participants of any gender, race, 
ethnicity, religion, and sexual orientation will be included. All efforts will be made to include equal 
numbers of both genders and to include minorities in the studies in equal proportions to the Boston 
area. 
 
Inclusion Criteria: 
 
 
Normal healthy volunteer  
 
18-45 years of age 
 
Normal or corrected-to-normal vision 
 
Right handed 
 
Exclusion Criteria: 
 
 
Visual impairment that may interfere with eye tracking equipment (for example glasses with 
high reflection) 
 
Any current or past history of a psychiatric disorder  
 
Any current or past history of neurological disorders or acquired neurological disease (e.g. 
stroke, traumatic brain injury), including intracranial lesions 
 
History of head trauma resulting in prolonged loss of consciousness; or a history of >3 grade I 
concussions 
 
Current history of poorly controlled headaches including intractable or poorly controlled 
migraines 
 
Any systemic illness or unstable medical condition that may cause a medical emergency in 
case of a provoked seizure (cardiac malformation, cardiac dysrhythmia, asthma, etc.) 
 
History of fainting spells of unknown or undetermined etiology that might constitute seizures 
 
History of seizures, diagnosis of epilepsy, history of abnormal (epileptiform) EEG, or family 
history of treatment resistant epilepsy with the exception of a single seizure of benign etiology 
(e.g. febrile seizures) in the judgment of a board-certified neurologist 
 
Possible pregnancy. All female participants of child bearing age are required to have a 
pregnancy test 
 
Any metal in the brain, skull or elsewhere unless approved by the responsible MD  
 
Any medical devices (i.e. cardiac pacemaker, deep brain stimulator, medication infusion 
pump, cochlear implant, vagal nerve stimulator) unless otherwise approved by the responsible 
MD 
 
Substance abuse or dependence within the past six months 
 
Pregnancy; all female participants of child bearing age will be required to have a pregnancy 
test; any participant who is pregnant will not be enrolled in the study.  
 
Not on any medications with the exception of birth control unless approved by the responsible 
MD. 
 
Inability to hold gaze on a central visual stimulus  
 
Abnormal automated perimetry results at baseline  
 
Data Safety Monitoring Plan 
The DSMP consists of a comprehensive plan for monitoring the participant throughout the study. This will 
be accomplished by daily assessments of adverse effects, both expected and unexpected. The study will 
be monitored both by a Data Safety Monitoring Board (DSMB).  
 
Ongoing Assessment: 

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Study Description – Part B 
CCI Form:  9-2015 
 
PI Revision Date: 09/01/2020 
 
The application of tES in the form of temporal interference (TI) stimulation has been minimally 
studied. Prior tES studies have not reported negative effects, including a study applying multi-day 
stimulation in healthy subjects (Polania, Nitsche, Korman, Batsikadze, & Paulus, 2012; Santarnecchi 
et al., 2016).  
 
Previous studies using TMS have evoked phosphenes from the single pulse stimulation, from a 
number of cortical regions.  Electrical stimulation often evokes phosphenes, believed to be of retinal 
origin (Kar and Krekelberg 2012).  Repetitive TMS has been used to induce transient scotomas in 
healthy participants, which overlap with single-pulse evoked phopshenes (Kammer 1999).   Despite a 
history of transient effects from non-invasive brain stimulation resolving, we will conduct the baseline 
visual field assessment that will be repeated at the end of each stimulation visit as described above.  
 
Adverse Event Monitoring 
Adverse effects will be collected from the start of the experimental protocol to the end of study 
participation. All adverse events, regardless of attribution to TI or pre/post assessments, will be 
collected and recorded using a standard adverse event form. Participants will be asked, in an open-
ended way, about the presence of any such events on a daily basis. Additionally, a standard 
questionnaire for tES-related adverse effects will be completed in the period after every TI session. 
Intensity of each adverse event will be graded as mild, moderate or severe. If an event occurs that is 
not expected (e.g. is not described in the research protocol or consent form), that indicates a change 
from baseline in cognition, and/or requires immediate attention, such as a seizure, the PI (or covering 
investigator) will be informed in real time to assess the event, advise on immediate care of the 
participant and to determine the necessary reporting steps. Any events that are serious or unexpected 
in nature, severity or frequency as compared to the risks described in the study plan will be reviewed 
by the principal investigator or designee (e.g. a co-investigator) to determine the relationship of the 
event to the study. Reportable events will be submitted to the IRB per determined policies and will be 
reported to the DSMB as described below. 
 
Adverse Event Communication with Boston University for the MRI protocol 
Adverse events related to the MRI imaging protocol at BU will be monitored and collected by study 
staff at BU. Following the completion of each subject, the staff at BU will share adverse events that 
were captured by their study team with the BIDMC study team. This information will be included in the 
summaries provided to the DSMB. A serious or unexpected adverse event that requires reporting to 
the BU IRB per the BU PI will be reported to the BIDMC study staff in parallel with the BU reporting 
procedures. These events will be shared with the DSMB in real time as will any local reportable 
events.  
 
DSMB 
A DSMB will be appointed for this study as described in Part P.  A report will be provided to the DSMB at 
least every 6 months for review. The report will include enrollment information, a summary of adverse 
events, a summary of the ongoing visual assessments and any other data that the group determines to 
be necessary. Serious and unexpected adverse events will be reported to the DSMB simultaneously with 
reporting to the BIDMC IRB within the designated IRB guidelines. For example, a serious adverse event 
will be reported by fax or e-mail within 1 business day, followed by a written report within 7 days. The 
DSMB reports will be shared with the IRB during continuing review or sooner if the DSMB requests 
action, such as pausing the study or amending the protocol.  
 
General Safety Plan 
A licensed physician, credentialed at BIDMC will be available by pager during all tACS and TI visits at 
BIDMC. Furthermore, the person applying tACS and TI will have training in basic life support (BLS) with 
the availability of emergency equipment. We will monitor patients in detail during and after delivery of 
tACS, and TI using an approach drawn directly from suggested guidelines.  

(CCI) Committee on Clinical Investigations 
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Study Description – Part B 
CCI Form:  9-2015 
 
PI Revision Date: 09/01/2020 
 
 
Withdrawal Criteria 
Subjects may be withdrawn from the trial if: 
 
A serious adverse event occurs. 
 
The investigator considers it, for safety reasons, in the best interest of the subject that he/she be 
withdrawn. 
 
 
  
 
 
B4. 
POSSIBLE BENEFITS 
As with any study focusing on basic research, the subjects will derive no immediate direct benefit. 
This will be made clear in the informed consent process. This study could advance the translation of 
TI stimulation methodology to humans and provide new experimental frontiers to map and modulate 
the brain with a non-invasive alternative to DBS/TMS/tES with low risk, precise steerable focality, and 
depth selectivity. 
 
 
 
B5. 
POSSIBLE RISKS AND ANALYSIS OF RISK/BENEFIT RATIO 
 
MRI:  
The MRI studies will be performed on a 3-Tesla Siemens magnet, which has been FDA approved. There 
are no known or foreseeable risks or side effects associated with conventional MRI procedures except to 
those people who have electrically, magnetically or mechanically activated implants (such as cardiac 
pacemakers) or to those who have clips on blood vessels in their brain. Participants will therefore be 
screened very carefully prior to referring to BU for the MRI study to exclude the possibility that they have 
any such devices and/or implants and will be excluded from participation in the event that they do. 
 
A magnetic resonance scan might be uncomfortable if participants are a) prone to claustrophobia (fear of 
enclosed spaces); b) do not like to lie still for a period of time, or c) do not like banging or beeping 
sounds. The researcher will explain the procedure and if a potential participant expresses any doubt 
about a), b), or c), he/she will not be included in the study. 
 
Temporal Interferential (TI) brain stimulation: 
The proposed experiment represents an early-phase experiment of a novel technique in humans. The 
purpose of the experiment is to capture potential risks and adverse effects. We can extrapolate from 
the rather extensive experience gathered in the past several decades using transcranial electric 
current stimulation (tES) in the forms of transcranial direct current stimulation (tDCS), transcranial 
alternating current stimulation (tACS) and transcranial random noise stimulation (tRNS) in humans. 
All these techniques have been shown to have an extremely beneficial side-effect/risk profile. In the 

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present study, all recommended safety precautions for transcranial current stimulation will be strictly 
adhered to by the investigators. 
 
This study uses alternating currents which results in less net charge being applied than in tDCS. There is 
limited reporting of side effects from tES using alternating currents in the literature. Studies that have 
used tACS, have reported adverse effects that are similar in nature to effects described in the tDCS 
literature, for example, headache, sensations under the electrodes and visual sensations (Antal et al. 
2008;Brignani et al. 2013;Feurra et al. 2011a). Adverse effects that have been described in the tDCS 
literature are described here in addition to the tACS reports to offer a conservative assessment of 
possible adverse effects. 
 
Based on the experience with transcranial current stimulation, the following side effects (although 
unlikely) are possible: 
- Sensations reported by subjects under the electrode: (These sensations can sometimes 
continue throughout and for a brief period following completion of the tES but usually resolve shortly 
after the initiation of tES) 
 
Mild tingling (20-70%) 
 
Light itching (30-40%) 
 
Slight burning (10-22%) 
 
Discomfort or mild pain (10-18%) 
 
- Effects reported that occur only during tES: 
 
Visual sensation during switching on and off the stimulation (11%),  
 
- Other effects that can occur both during and after tES include: 
 
Moderate fatigue (35%) 
 
Skin redness (30%) 
 
Headache (10-15%) 
 
Difficulties in concentration (11%) 
 
- Additionally the following rare side effects have been described: 
 
Nausea (3%) 
 
Nervousness (<5%) 
 
Ringing in the ear (<1%) 
 
Changes in the activity of the prefrontal region have the potential to induce acute 
changes in mood. Hypomania has been reported in a few patients receiving tDCS 
for bipolar disorder (Loo et al., 2012) and depression (Arul-Anandam et al., 2010) 
but never in normal controls. Subjects with a history of a psychiatric disorder will be 
excluded from the study. 
 
Transient Visual Disturbance (2%)  
 
- Although it has never been reported in tES, seizures are a theoretical risk. 
 
Visual Discrimination and Periphery Testing: 
Subjects may feel frustrated during the visual tasks.  They will have breaks between the tasks to 
reduce the potential for frustration. 
 
Confidentiality: 
All data will be stored within secure BIDMC databases. The data will be stored without identifying 
information, with a code name assigned to the study participant.  Data will be transferred with code 
names between BU and BIDMC via secure email and secure file transfer for MRI portion of the 

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PI Revision Date: 09/01/2020 
 
experiment. 
 
Risk/Benefit Ratio  
The above stated risks are weighted with the potential application of non-invasive brain stimulation 
methods to impact brain function in healthy participants and various patient populations.  Preliminary 
investigations as described here are necessary to validate the technique.  We believe the balance of 
future application of brain stimulation exceeds the documented risks of transcranial electrical 
stimulation, and the protocol outlines procedures in place to mitigate potential risks of participation.  
 
 
 
B6. 
RECRUITMENT AND CONSENT PROCEDURES 
 
Recruitment 
We will recruit subjects by using targeted flyers, internet postings, and databases of prior subjects 
(IRB approved data repository IRB #2010-P-000169) expressing an interest in future studies. Past 
study subjects will be approached by e-mail or by phone. Individuals interested in participating in the 
study will be instructed to contact a study investigator by telephone or e-mail. Individuals who 
respond to flyers, recruitment e-mails, or phone messages will be contacted by telephone. Study 
details will be discussed and preliminary screening will be done if the potential subject expresses 
interest. If the subject continues to express interest and appears to qualify, the first visit will be 
scheduled for consent and complete screening. 
 
Consent 
Initially, subjects will be pre-screened over the phone, thus initiating the consenting process.  If they 
appear to be eligible for the study following the telephone screening, they will be scheduled to come 
in for the study if they are interested Due to concerns related to COVID-19, the consent process will 
begin remotely over telephone or secure video. During the consent session, the investigator will begin 
by discussing the study purpose, requirements, procedures, possible benefits, potential risks and 
alternatives. If subjects remain interested in participation, they will review the informed consent 
document and will be allowed to complete reviewing the information in the informed consent form for 
as much time as they need. The potential subject will have the chance to ask any questions before 
giving consent. Investigators will emphasize to each potential participant that his or her participation is 
voluntary and that there is no consequence for refusing participation. Only when they declare that 
they are comfortable with all aspects, will they be allowed to offer consent. Upon arrival for the first in-
person visit, the informed consent will be signed in person by the subject and a member of the study 
staff. All subjects will be provided with copies of the signed consent form. 
 
Subject Protection 
This study uses healthy controls.  It is not anticipated that these subjects would be considered 
vulnerable. To the best of our ability, we will minimize any possibility of coercion or undue influence 
placed on subjects. 
 
 
 
 

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B7. 
STUDY LOCATION 
Privacy  
 
Phone conversations will be limited to providing information about the study and to pre-screening 
questions. If potential subjects are more comfortable answering questions in person, they will be 
invited to come in for the screening.   At the screening visit, informed consent and details of the study 
will be discussed in a private room in the Berenson-Allen Center to encourage free exchange of 
information and only questions pertinent to study participation will be asked.  
 
Physical Setting 
 
Recruitment and screening procedures will take place by study staff at the Beth Israel Deaconess 
Medical Center. Data will be stored at BIDMC and data analysis will occur at BIDMC or Boston 
University. In the event that some specialized processing algorithms are run on computers outside 
BIDMC only de-identified data will be transmitted. MRI scanning will take place at Boston University 
Cognitive Neuroimaging Center under a separate protocol. All TI stimulation experimental sessions 
will take place in the Berenson-Allen Center at BIDMC. 
 
B8. 
DATA SECURITY 
All data will be de-identified with the use of unique subject identifiers per HIPAA guidelines.  Names 
will not be provided to external sources, nor will any identifying marker be published in which a 
participant could be distinguished.  All paper records regarding this research project will be stored in 
the locked offices of the research study team, located within the BA-CNBS at BIDMC. De-identified 
data will be stored on computers protected by individual user passwords to restrict access, using 
available secure data basing suites of REDCap and XNAT when possible. The XNAT will be hosted 
and managed by BIDMC and will be kept behind the firewall for security purposes. 
 
MRI scan images will be sent to BIDMC from BU using a secure file transfer. Any paper forms from BU 
(e.g. adverse event forms) will be scanned and sent to BIDMC via encrypted email. Medical records 
from outside providers will be requested and obtained via secure email or fax.  
 
Information that will be shared with BU for the MRI study will include PHI that is required to contact 
the participant for scheduling. All information will be provided via secured email and/or secure file 
transfer. 
 
Data will be shared with McLean Hospital. As a co-investigator and collaborator at McLean Hospital, 
Mark Halko, PhD will be on BIDMC premises during study visits to help collect data and will have in-
person access to the participants. He will have all data collected by the BIDMC research staff. This 
data includes PHI.  
 
De-identified data will be sent to the National Institute of Mental Health Data Archive (NDA). All data 
will be labeled with a Global Unique Identifier (GUID) that is obtained through a system provided by 
the NDA. Participants will have the option of opting in or out of having their data shared with the 
NDA. 
 

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B9 
Multi-Site Studies 
 
Is the BIDMC the coordinating site?       
 Yes    
 No  
 
Is the BIDMC PI the lead investigator of the multi-site study?     
 Yes    
 No  
 
Research teams from both locations will communicate via phone, email or conference calls on a 
monthly basis or more, as needed. In these interactions, teams will assess safety and review study 
progress.  
 
Adverse events that occur at BU will be communicated to BIDMC study staff for completion of DSMB, 
and IRB communication as described above in the “Data Safety Monitoring Plan”.  
 
All data analysis will be managed by BIDMC although MRI and visual discrimination analysis will be 
completed in a collaborative manner between the sites. Regular meetings will be scheduled as 
described above with ad hoc meetings scheduled as needed. BIDMC will manage protocol 
amendments that affect the overall study aims. Recommended changes that affect the MRI imaging 
protocol will be communicated to the BU study team either in the monthly meeting or via phone 
and/or email in real time. Any amendment needs that are identified by the BU team for the MRI 
imaging protocol will be communicated to the BIDMC team in the same manner.  
 
Data will be shared with a collaborator at Hebrew Senior Life, specifically, Dr. Alvaro Pascual-Leone.  
De-identified MRI data will be shared with a collaborator at Northeastern University, specifically, 
Sumientra Rampersand, PhD. Any data that is sent to HSL and Northeastern University will be de-
identified and sent via encrypted procedures per BIDMC policy.  
 
 
B10 
Dissemination of Research Results 
 
We will send a follow-up e-mail thanking subjects for their participation in the study.  In this follow-up 
e-mail, we will inform subjects that results of the study will be available on our website tmslab.org as 
all publications are available on the website.