Temporal Interference Methods for Non-invasive Deep Brain Stimulation, Study 1.3

Temporal Interference Methods for Non-invasive Deep Brain Stimulation

This grant aims to develop a line of research using temporal interference (TI) electrical neurostimulation technology to understand the causal role of deep brain structures in cognition. In the short term, the investigators aim to validate and characterize the effects of TI on brain activity as measured by fMRI and demonstrate its ability to focally stimulate deep brain regions without affecting overlying cortex. In the longer term, investigators aim to use these data to resolve longstanding debates about the function of deeper brain regions and lay the foundation for future clinical applications of TI for treating addiction, Obsessive-Compulsive Disorder (OCD), Parkinson's disease, and other disorders involving deep brain dysfunction. The grant supports 2 distinct aims, each of which will be evaluated through a series of independent studies.

Study Overview

• Status: Recruiting
• Conditions: Healthy Volunteers
• Intervention / Treatment: Device: Temporal Interference (TI) Electrical Stimulation - dACC 20 Hz TI Active; Device: Temporal Interference (TI) Electrical Stimulation - dACC 20 Hz TI Sham; Device: Temporal Interference (TI) Electrical Stimulation - dACC Comparison Frequency TI Active; Device: Temporal Interference (TI) Electrical Stimulation - dACC Comparison Frequency TI Sham

Detailed Description

Through the grant's duration, the investigators hypothesize that temporal interference (TI) electrical neurostimulation will be well tolerated and effective at focally manipulating deep brain activity as measured by functional MRI (fMRI) BOLD signals. The investigators will investigate whether TI stimulation can increase BOLD activity in targeted deep brain regions including the nucleus accumbens (NAcc) and dorsal anterior cingulate cortex (dACC), and whether this stimulation can influence cognitive functions controlled by these regions. TI works by applying alternating currents of slightly different frequencies through multiple electrode pairs, creating an interference pattern that can stimulate deep brain regions without significantly affecting superficial cortical areas. This method is similar to traditional transcranial direct current stimulation (tDCS), however TI can stimulate deeper brain structures that tDCS cannot reach effectively. The study is broken up into two main aims with multiple sub-studies. In Aim 1, the investigators will characterize the effects of TI on fMRI BOLD signals, test different beat frequencies, and compare TI effects in the nucleus accumbens versus dorsal anterior cingulate cortex. In Aim 2, the investigators will apply TI to the dorsal anterior cingulate cortex to test causal theories about its role in cognitive control, conflict monitoring, risk avoidance, and foraging behavior using established cognitive tasks while subjects undergo fMRI scanning.

Study 1.3 (Aim 1, Study 1.3) will test whether TI can focally modulate activity in the dorsal anterior cingulate cortex, around MNI coordinates 0, 30, 30, as measured by fMRI BOLD signal. Healthy subjects (n=30) will complete a single study visit during which they will undergo fMRI while receiving TI stimulation through carbon fiber electrodes attached to the scalp with conductive gel. Electrode placement may vary by participant to optimize dACC targeting using individualized finite element modeling.

Participants will receive active and sham TI stimulation at a selected beat frequency potentially including 5 Hz, 30 Hz, 40 Hz, or another frequency in the 1-100 Hz range. Stimulation will follow an on/off sequence of 2 minutes on, 2 minutes off, 2 minutes on, and 2 minutes off, with 30-second ramp up and ramp down periods beginning at the start of each 2-minute stimulation period. Study 1.3 will also examine whether increased stimulation intensity improves modulation of BOLD activity in the dACC. Stimulation may be delivered up to ±5 mA per channel, corresponding to 10 mA peak-to-peak, with the second stimulation channel linearly scaled based on individualized modeling to maintain optimal targeting. Active and sham stimulation blocks will be counterbalanced across subjects.

• Study Type: Interventional
• Enrollment (Estimated): 30
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Joshua W Brown, PhD; Phone Number: 812-855-9282; Email: jwmbrown@iu.edu
• Study Contact Backup: Name: Kendall E Moore, BS; Phone Number: 812-856-1846; Email: cclab@iu.edu

Study Locations

• United States
  • Indiana
    • Bloomington, Indiana, United States, 47408
      • Recruiting
      • Indiana University Bloomington, Imaging Research Facility
      • Contact: Josh W Brown, PhD; Phone Number: 812-856-1846; Email: cclab@iu.edu
      • Contact: Kendall E Moore, BS; Phone Number: (812) 856-1846; Email: cclab@iu.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• 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 Criteria:

• Currently taking psychotropic medications for ADHD, other mental illness, or medications for cancer
• History of epilepsy or seizure disorders
• History of migraines or other neurological syndromes
• History of AIDS (due to potential cognitive deficits)
• History of head trauma or cognitive impairments
• Personal experiences consistent with symptoms of psychosis (e.g., hallucinations, delusions of control or special powers)
• History of skull defects (e.g., holes bored into the skull or known cranial fissures)
• Metal implants in the head or under the scalp
• Does not meet fMRI safety screening criteria (e.g., metal implants in the body, permanent jewelry, tattoos on the head or neck)
• Uses an intrauterine device (IUD) for birth control and cannot provide documentation to verify MRI safety
• Pregnancy (self-reported; no pregnancy test administered)
• Weight over 440 lbs (scanner weight limit)
• Presence of pacemakers

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Single

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: dACC 20Hz Active then Sham; Comparison frequency Active then Sham; Participants in this arm receive temporal interference (TI) electrical stimulation targeting the dorsal anterior cingulate cortex using two pairs of carbon fiber electrodes in the following order: 20 Hz TI Active, 20 Hz TI Sham, selected comparison frequency TI Active, then selected comparison frequency TI Sham. The comparison frequency will be within the 1-100 Hz range.	Device: Temporal Interference (TI) Electrical Stimulation - dACC 20 Hz TI Active; Non-invasive electrical brain stimulation delivered through two sets of scalp electrodes using alternating current frequencies at up to ±5 mA per channel, corresponding to 10 mA peak-to-peak. For the dACC 20 Hz TI Active condition, one channel will deliver 2000 Hz and the other 2020 Hz, producing a 20 Hz beat frequency targeting the dorsal anterior cingulate cortex. Stimulation is administered in 2-minute on / 2-minute off cycles with a 30-second ramp up and ramp down beginning at the start of each 2-minute period.; Other Names: TI Electrical Neurostimulation; TI Neurostimulation; Device: Temporal Interference (TI) Electrical Stimulation - dACC 20 Hz TI Sham; Same setup as the dACC 20 Hz TI Active condition, except that stimulation immediately ramps down after reaching the target intensity following ramp up, producing a sham condition.; Other Names: TI Electrical Neurostimulation; TI Neurostimulation; Device: Temporal Interference (TI) Electrical Stimulation - dACC Comparison Frequency TI Active; Non-invasive electrical brain stimulation delivered through two sets of scalp electrodes using alternating current frequencies at up to ±5 mA per channel, corresponding to 10 mA peak-to-peak. For the dACC comparison frequency TI Active condition, stimulation will be delivered using a selected beat frequency in the 1-100 Hz range. Stimulation is administered in 2-minute on / 2-minute off cycles with a 30-second ramp up and ramp down beginning at the start of each 2-minute period.; Other Names: TI Electrical Neurostimulation; TI Neurostimulation; Device: Temporal Interference (TI) Electrical Stimulation - dACC Comparison Frequency TI Sham; Same setup as the dACC comparison frequency TI Active condition, except that stimulation immediately ramps down after reaching the target intensity following ramp up, producing a sham condition.; Other Names: TI Electrical Neurostimulation; TI Neurostimulation
Active Comparator: dACC 20Hz Sham then Active; Comparison Frequency Sham then Active; Participants in this arm receive temporal interference (TI) electrical stimulation targeting the dorsal anterior cingulate cortex using scalp electrodes. The stimulation order is: 20 Hz TI Sham, 20 Hz TI Active, selected comparison frequency TI Sham, then selected comparison frequency TI Active. The comparison frequency will be in the 1-100 Hz range.	Device: Temporal Interference (TI) Electrical Stimulation - dACC 20 Hz TI Active; Non-invasive electrical brain stimulation delivered through two sets of scalp electrodes using alternating current frequencies at up to ±5 mA per channel, corresponding to 10 mA peak-to-peak. For the dACC 20 Hz TI Active condition, one channel will deliver 2000 Hz and the other 2020 Hz, producing a 20 Hz beat frequency targeting the dorsal anterior cingulate cortex. Stimulation is administered in 2-minute on / 2-minute off cycles with a 30-second ramp up and ramp down beginning at the start of each 2-minute period.; Other Names: TI Electrical Neurostimulation; TI Neurostimulation; Device: Temporal Interference (TI) Electrical Stimulation - dACC 20 Hz TI Sham; Same setup as the dACC 20 Hz TI Active condition, except that stimulation immediately ramps down after reaching the target intensity following ramp up, producing a sham condition.; Other Names: TI Electrical Neurostimulation; TI Neurostimulation; Device: Temporal Interference (TI) Electrical Stimulation - dACC Comparison Frequency TI Active; Non-invasive electrical brain stimulation delivered through two sets of scalp electrodes using alternating current frequencies at up to ±5 mA per channel, corresponding to 10 mA peak-to-peak. For the dACC comparison frequency TI Active condition, stimulation will be delivered using a selected beat frequency in the 1-100 Hz range. Stimulation is administered in 2-minute on / 2-minute off cycles with a 30-second ramp up and ramp down beginning at the start of each 2-minute period.; Other Names: TI Electrical Neurostimulation; TI Neurostimulation; Device: Temporal Interference (TI) Electrical Stimulation - dACC Comparison Frequency TI Sham; Same setup as the dACC comparison frequency TI Active condition, except that stimulation immediately ramps down after reaching the target intensity following ramp up, producing a sham condition.; Other Names: TI Electrical Neurostimulation; TI Neurostimulation
Active Comparator: dACC Comparison Frequency Sham then Active; 20Hz Sham then Active; Participants in this arm receive temporal interference (TI) electrical stimulation targeting the dorsal anterior cingulate cortex using scalp electrodes. The stimulation order is: selected comparison frequency TI Sham, selected comparison frequency TI Active, 20 Hz TI Sham, then 20 Hz TI Active. The comparison frequency will be in the 1-100 Hz range.	Device: Temporal Interference (TI) Electrical Stimulation - dACC 20 Hz TI Active; Non-invasive electrical brain stimulation delivered through two sets of scalp electrodes using alternating current frequencies at up to ±5 mA per channel, corresponding to 10 mA peak-to-peak. For the dACC 20 Hz TI Active condition, one channel will deliver 2000 Hz and the other 2020 Hz, producing a 20 Hz beat frequency targeting the dorsal anterior cingulate cortex. Stimulation is administered in 2-minute on / 2-minute off cycles with a 30-second ramp up and ramp down beginning at the start of each 2-minute period.; Other Names: TI Electrical Neurostimulation; TI Neurostimulation; Device: Temporal Interference (TI) Electrical Stimulation - dACC 20 Hz TI Sham; Same setup as the dACC 20 Hz TI Active condition, except that stimulation immediately ramps down after reaching the target intensity following ramp up, producing a sham condition.; Other Names: TI Electrical Neurostimulation; TI Neurostimulation; Device: Temporal Interference (TI) Electrical Stimulation - dACC Comparison Frequency TI Active; Non-invasive electrical brain stimulation delivered through two sets of scalp electrodes using alternating current frequencies at up to ±5 mA per channel, corresponding to 10 mA peak-to-peak. For the dACC comparison frequency TI Active condition, stimulation will be delivered using a selected beat frequency in the 1-100 Hz range. Stimulation is administered in 2-minute on / 2-minute off cycles with a 30-second ramp up and ramp down beginning at the start of each 2-minute period.; Other Names: TI Electrical Neurostimulation; TI Neurostimulation; Device: Temporal Interference (TI) Electrical Stimulation - dACC Comparison Frequency TI Sham; Same setup as the dACC comparison frequency TI Active condition, except that stimulation immediately ramps down after reaching the target intensity following ramp up, producing a sham condition.; Other Names: TI Electrical Neurostimulation; TI Neurostimulation
Active Comparator: dACC Comparison Frequency Active then Sham; 20Hz Active then Sham; Participants in this arm receive temporal interference (TI) electrical stimulation targeting the dorsal anterior cingulate cortex using scalp electrodes. The stimulation order is: selected comparison frequency TI Active, selected comparison frequency TI Sham, 20 Hz TI Active, then 20 Hz TI Sham. The comparison frequency will be in the 1-100 Hz range.	Device: Temporal Interference (TI) Electrical Stimulation - dACC 20 Hz TI Active; Non-invasive electrical brain stimulation delivered through two sets of scalp electrodes using alternating current frequencies at up to ±5 mA per channel, corresponding to 10 mA peak-to-peak. For the dACC 20 Hz TI Active condition, one channel will deliver 2000 Hz and the other 2020 Hz, producing a 20 Hz beat frequency targeting the dorsal anterior cingulate cortex. Stimulation is administered in 2-minute on / 2-minute off cycles with a 30-second ramp up and ramp down beginning at the start of each 2-minute period.; Other Names: TI Electrical Neurostimulation; TI Neurostimulation; Device: Temporal Interference (TI) Electrical Stimulation - dACC 20 Hz TI Sham; Same setup as the dACC 20 Hz TI Active condition, except that stimulation immediately ramps down after reaching the target intensity following ramp up, producing a sham condition.; Other Names: TI Electrical Neurostimulation; TI Neurostimulation; Device: Temporal Interference (TI) Electrical Stimulation - dACC Comparison Frequency TI Active; Non-invasive electrical brain stimulation delivered through two sets of scalp electrodes using alternating current frequencies at up to ±5 mA per channel, corresponding to 10 mA peak-to-peak. For the dACC comparison frequency TI Active condition, stimulation will be delivered using a selected beat frequency in the 1-100 Hz range. Stimulation is administered in 2-minute on / 2-minute off cycles with a 30-second ramp up and ramp down beginning at the start of each 2-minute period.; Other Names: TI Electrical Neurostimulation; TI Neurostimulation; Device: Temporal Interference (TI) Electrical Stimulation - dACC Comparison Frequency TI Sham; Same setup as the dACC comparison frequency TI Active condition, except that stimulation immediately ramps down after reaching the target intensity following ramp up, producing a sham condition.; Other Names: TI Electrical Neurostimulation; TI Neurostimulation

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in brain activity in the dorsal anterior cingulate cortex during 20 Hz versus selected comparison frequency temporal interference stimulation	Brain activity in the dorsal anterior cingulate cortex will be measured using functional magnetic resonance imaging (fMRI) during temporal interference (TI) stimulation at 20 Hz compared to a selected comparison beat frequency. The comparison frequency will be in the 1-100 Hz range. Activity will be reported as the percent change in blood-oxygen-level-dependent (BOLD) signal, which reflects changes in neural activity. Higher BOLD values indicate stronger brain activation.	During fMRI scan on study day (approximately 60 minutes)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in brain activity in the dorsal anterior cingulate cortex during active versus sham stimulation at 20 Hz	Brain activity in the dorsal anterior cingulate cortex will be measured using fMRI during active versus sham temporal interference stimulation at a 20 Hz beat frequency. Activity will be reported as the percent change in blood-oxygen-level-dependent (BOLD) signal.	During fMRI scan on study day (approximately 60 minutes)
Change in brain activity in the dorsal anterior cingulate cortex during active versus sham stimulation at the selected comparison frequency	Brain activity in the dorsal anterior cingulate cortex will be measured using fMRI during active versus sham temporal interference stimulation at the selected comparison beat frequency. The comparison frequency will be within the 1-100 Hz range. Activity will be reported as the percent change in blood-oxygen-level-dependent (BOLD) signal.	During fMRI scan on study day (approximately 60 minutes)
Change in brain connectivity between the dorsal anterior cingulate cortex and other brain regions during temporal interference stimulation	Functional connectivity between the dorsal anterior cingulate cortex and other brain regions will be measured using fMRI-based analyses during active versus sham temporal interference stimulation. Higher correlation values indicate stronger communication between brain regions. The primary test statistic will be the whole-brain psychophysiological interaction (PPI) between dorsal anterior cingulate cortex BOLD activity and stimulation condition.	During fMRI scan on study day (approximately 60 minutes)

Collaborators and Investigators

• Sponsor: Indiana University
• Collaborators: National Institute of Mental Health (NIMH)
• Investigators: Principal Investigator: Joshua W Brown, PhD, Indiana University, Bloomington

Publications and helpful links

General Publications

• Grossman N, Bono D, Dedic N, Kodandaramaiah SB, Rudenko A, Suk HJ, Cassara AM, Neufeld E, Kuster N, Tsai LH, Pascual-Leone A, Boyden ES. Noninvasive Deep Brain Stimulation via Temporally Interfering Electric Fields. Cell. 2017 Jun 1;169(6):1029-1041.e16. doi: 10.1016/j.cell.2017.05.024.
• Violante IR, Alania K, Cassara AM, Neufeld E, Acerbo E, Carron R, Williamson A, Kurtin DL, Rhodes E, Hampshire A, Kuster N, Boyden ES, Pascual-Leone A, Grossman N. Non-invasive temporal interference electrical stimulation of the human hippocampus. Nat Neurosci. 2023 Nov;26(11):1994-2004. doi: 10.1038/s41593-023-01456-8. Epub 2023 Oct 19.
• Modak P, Fine J, Colon B, Need E, Cheng H, Hulvershorn L, Finn P, Brown JW. Temporal interference electrical neurostimulation at 20 Hz beat frequency leads to increased fMRI BOLD activation in orbitofrontal cortex in humans. Brain Stimul. 2024 Jul-Aug;17(4):867-875. doi: 10.1016/j.brs.2024.07.014. Epub 2024 Jul 24.

Helpful Links

• Lab website for study. The Cognitive Control Lab aims to understand the neural mechanisms of goal-directed behavior, using a combination of fMRI, computational neural modeling, and neurostimulation methods in healthy and clinical human populations.
• Project details for the NIMH-funded study on temporal interference stimulation, including abstract, funding, and key personnel.

Study record dates

Study Major Dates

• Study Start (Estimated): May 30, 2026
• Primary Completion (Estimated): July 31, 2026
• Study Completion (Estimated): July 31, 2026

Study Registration Dates

• First Submitted: May 11, 2026
• First Submitted That Met QC Criteria: May 11, 2026
• First Posted (Actual): May 19, 2026

Study Record Updates

• Last Update Posted (Actual): May 19, 2026
• Last Update Submitted That Met QC Criteria: May 11, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: fMRI; Cognitive Control; Neurostimulation; Non-invasive deep brain stimulation; BOLD Signal; Temporal Interference; Dorsal Anterior Cingulate Cortex
• Other Study ID Numbers: 26941, Study 1.3; 1R21MH140210-01 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: Yes
• product manufactured in and exported from the U.S.: No