Temporal Interference Methods for Non-invasive Deep Brain Stimulation, Study 1.2

Official title

Temporal Interference Methods for Non-invasive Deep Brain Stimulation

Overview

In its totality, 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.

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 1.2 (Aim 1, Study 12) will test the ability to focally activate the nucleus accumbens without activating the overlying cortex, and also its effects on functional connectivity. Healthy subjects (n=30) will present for a single study visit during which they will be placed in the fMRI scanner and administered a temporal interference protocol. Specifically, subjects will have four pairs of carbon fiber electrodes attached to the scalp with conductive gel. 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. For Study 1.2, two TI beat frequencies will be evaluated: 5 Hz (produced by channels at 2000 Hz and 2005 Hz) and 10 Hz (produced by channels at 2000 Hz and 2010 Hz). Each beat frequency will have an Active block (30-second ramp to 2 mA, 2 min on / 2 min off cycles) and a matching Sham block where the stimulation immediately ramps down as soon as it reaches 2 mA after ramp up. The order of blocks and whether the "on" or "off" condition occurs first will be counterbalanced across subjects.

Interventions

• Device Temporal Interference (TI) Electrical Stimulation - NAcc 5 Hz TI Active
  Non-invasive electrical brain stimulation delivered through two sets of scalp electrodes using alternating current frequencies at up to 2 mA per electrode. For the NAcc 5 Hz TI Active condition, one channel will deliver 2000 Hz and the other 2005 Hz, producing a 5 Hz beat frequency that focally stimulates deep brain regions without activating overlying 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-
• Device Temporal Interference (TI) Electrical Stimulation - NAcc 5 Hz TI Sham
  Same setup as the 5 Hz TI Active condition, except that the stimulation immediately ramps down as soon as it reaches 2 mA after ramp up, producing a sham condition.
• Device Temporal Interference (TI) Electrical Stimulation - NAcc 10 Hz TI Active
  Non-invasive electrical brain stimulation delivered through two sets of scalp electrodes using alternating current frequencies at up to 2 mA per electrode. For the NAcc 10 Hz TI Active condition, one channel will deliver 2000 Hz and the other 2010 Hz, producing a 10 Hz beat frequency that focally stimulates deep brain regions without activating overlying 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
• Device Temporal Interference (TI) Electrical Stimulation - NAcc 10 Hz TI Sham
  Same setup as the 10 Hz TI Active condition, except that the stimulation immediately ramps down as soon as it reaches 2 mA after ramp up, producing a sham condition.

Primary outcome measures

• Change in brain activity in the nucleus accumbens during 5 Hz versus 10 Hz temporal interference stimulation [Time frame: During fMRI scan on study day (approximately 60 minutes)]

Secondary outcome measures (3)

• Change in brain activity in the nucleus accumbens during active versus sham stimulation at 5 Hz [Time frame: During fMRI scan on study day (approximately 60 minutes)]
• Change in brain activity in the nucleus accumbens during active versus sham stimulation at 10 Hz [Time frame: During fMRI scan on study day (approximately 60 minutes)]
• Change in brain connectivity between the nucleus accumbens and other brain regions during temporal interference stimulation [Time frame: During fMRI scan on study day (approximately 60 minutes)]

Eligibility criteria

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

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: Yes

Study design

Allocation

Randomized

Model

Crossover

Masking

Single blind

Primary purpose

Basic science

Study locations

United States · 1 center

• Indiana University Bloomington, Imaging Research Facility — Bloomington

Publications

• 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. PMID 37857775
• 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. PMID 39059712
• 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. PMID 28575667

Identifiers

NCT: NCT07339072 · 26941, Study 1.2 · 1R21MH140210-01

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗