Induction and Stabilization of Gamma Oscillations With 40 Hz External Brain Stimulation

NCT06680154 | Completed DMC

• 1 other identifier: IfADo_196
• Study Type: interventional
• Target: 30
• Locations: 1 country
• Sites: 1

Brief Summary

The goal of the present studies is to develop and validate novel stimulation protocols for the entrainment of gamma oscillations, which are associated with many cognitive functions and critically involved in cognitive impairment such as Alzheimer's disease. In this proposal, combination of repetitive transcranial magnetic stimulation (rTMS) and transcranial alternating current stimulation (tACS), which has been shown effective for the induction, and stabilisation of alpha and theta frequencies in our forgoing studies, will be adopted to the gamma frequency range and applied on prefrontal regions as well as model-based cortical areas to enhance and stabilize gamma oscillations, thereby facilitating cognition

Conditions

Alzheimer Disease; Working Memory; EEG Brain Oscillations

Keywords

Alzheimer's disease; Gamma oscillations; EEG; Transcranial alternating current stimulation, tACS; Intermittent theta burst stimulation

Outcome Measures

Primary Outcomes (3)

• Working Memory behavioral performance

  Participants view a continuous sequence of alphabet letters, presented as stimuli in Arial font, size 120pt, on a tube screen positioned at 60cm eye distance. The stimuli are shown with a time interval of two seconds between them. The task consisted of six blocks with 70 stimuli, including 12 possible hit trials. Participants were instructed to press the left key on a response box if the presented stimulus matched either the one presented one trial prior (1-Back) or three trials prior (3-Back). In all other cases, participants press the right key. The left button is pressed with the index finger, while the right button is pressed with the middle finger of the right hand, with buttons aligned horizontally. The response condition varied by block, with three blocks for 3-Back and three for 1-Back, and the order was counterbalanced across participants and sessions.

  During procedure (20 minutes)

• electroencephalogram (EEG) oscillatory power

  Change in the EEG power in alpha, delta, theta and beta bands

  up to 2 hours after the intervention

• electroencephalogram (EEG) functional connectivity

  Change in EEG functional connectivity, specifically global efficiency, coherence, and phase-locking value.

  up to 2 hours after the intervention

Study Arms (5)

Transcranial alternating current stimulation

ACTIVE COMPARATOR

During tACS, an alternating electrical current with a 1 milliamp peak-to-peak amplitude will be delivered, featuring a 15-second ramp-up at the start and a 15-second ramp-down at the end. The stimulation duration is 20 minutes and four channels are used for delivering sinusoidal alternating currents to the head. The alternating current was delivered to the prefrontal cortex bilaterally with the electrodes at F3 and F4 and the return electrodes were placed at the ipsilateral mastoids at TP9 and TP10 (international 10-20 EEG electrode placement system).

Device: Transcranial alternating current stimulation

intermittent theta burst stimulation

ACTIVE COMPARATOR

The intermittent theta burst stimulation (iTBS) is regarded as safe for high-frequency neuromodulation. The pulse bursts are applied for two seconds in 5Hz intervals followed by an eight-second break before the next bursts are applied. This pattern is repeated for 190 seconds resulting in 600 pulses per protocol. 80% of the individual subjects' active motor threshold (AMT) are used for stimulation intensity and will be applied four times within a 20-minute time frame starting at 0 minutes, 5 minutes, 10 minutes, and 15 minutes from the beginning of the intervention resulting in 2400 delivered pulses for the whole intervention

Device: Theta burst stimulation

combited iTBS- tACS peak

ACTIVE COMPARATOR

To combine tACS and the iTBS protocol, a customized circuit is developed in-house to phase-lock the TMS pulses to the waveform generated by tACS. TMS pulses were delivered using two figure-of-eight shaped coils (double 70 mm, PMD coil type; Mag and More GmbH, Munich, Germany). For the stimulation, the center of the TMS coils are placed over the two prefrontal tACS electrodes (F3 and F4 electrode positions) with an orientation of 45 degrees to the midline and the handles pointing backward. Using the customized circuit, TMS pulses will be delivered at the peak of the tACS wave.

Device: Transcranial alternating current stimulation; Device: Theta burst stimulation

Combined iTBS-tACS trough

ACTIVE COMPARATOR

To combine tACS and the iTBS protocol, a customized circuit is developed in-house to phase-lock the TMS pulses to the waveform generated by tACS. TMS pulses were delivered using two figure-of-eight shaped coils (double 70 mm, PMD coil type; Mag and More GmbH, Munich, Germany). For the stimulation, the center of the TMS coils are placed over the two prefrontal tACS electrodes (F3 and F4 electrode positions) with an orientation of 45 degrees to the midline and the handles pointing backward. Using the customized circuit, TMS pulses will be delivered at the trough of the tACS wave.

Device: Transcranial alternating current stimulation; Device: Theta burst stimulation

sham

SHAM COMPARATOR

80% of the individual subjects' active motor threshold (AMT) four times within a 20-minute time frame starting at 0 minutes, 5 minutes, 10 minutes, and 15 minutes from the beginning of the intervention resulting in 2400 delivered pulses for the whole intervention

Device: Sham (No Treatment)

Interventions

Transcranial alternating current stimulation DEVICE

Transcranial alternating current was delivered utilizing a Starstim 8-channel constant current, battery-powered electric stimulator (Neuroelectrics, Barcelona, Spain). Circular carbon rubber electrodes (2cm radius, 12,57 cm2) were used throughout the stimulation. Before placing the electrodes on the head, the subject's hair was moved to the side

Combined iTBS-tACS trough; Transcranial alternating current stimulation; combited iTBS- tACS peak

Theta burst stimulation DEVICE

the intermittent theta burst stimulation (iTBS) which is regarded as safe for high-frequency neuromodulation. Compared to classical rTMS, where pulses are applied repeatedly at a fixed frequency, iTBS consists of bursts of pulse triplets. In the classical protocol, the bursts are applied for two seconds in 5Hz intervals followed by an eight-second break, before the next bursts are applied. This pattern is repeated for 190 seconds resulting in 600 pulses per protocol.

Combined iTBS-tACS trough; combited iTBS- tACS peak; intermittent theta burst stimulation

Sham (No Treatment) DEVICE

In the case of sham TMS, two different sham coils (double 70mm pCool-SHAM coil, Mag\&More GmbH, Munich, Germany) will produce audible clicks at the decibel intensity corresponding to an active coil without the induction of an electromagnetic pulse. Sham tACS will be applied by only ramping the current for 15 seconds up and 15 seconds down at the beginning and end of the stimulation respectively.

sham

Eligibility Criteria

• Age: 18 Years - 60 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• normal or corrected to normal eye vision
• right-handed
• non-smokers
• being 18-60 years old
• providing written informed consent

You may not qualify if:

• history of neurological or psychiatric disorders including seizures or epilepsy,
• Taking CNS medication
• having metal implants
• current pregnancy

Sponsors & Collaborators

• The National Brain Mapping Laboratory (NBML): lead
• Leibniz Research Centre for Working Environment and Human Factors: collaborator

Study Sites (1)

Leibniz-Institut für Arbeitsforschung

Dortmund, North Rhine-Westphalia, 44139, Germany

Location

Related Publications (1)

• Glinski B, Salehinejad MA, Takahashi K, Jamil A, Yavari F, Kuo MF, Nitsche MA. Phase-synchronized 40 Hz tACS and iTBS effects on gamma oscillations. Imaging Neurosci (Camb). 2025 Sep 10;3:IMAG.a.140. doi: 10.1162/IMAG.a.140. eCollection 2025.

  PMID: 40948603 RESULT

MeSH Terms

Conditions

Alzheimer Disease

Interventions

Transcranial Direct Current Stimulation

Condition Hierarchy (Ancestors)

Dementia; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Tauopathies; Neurodegenerative Diseases; Neurocognitive Disorders; Mental Disorders

Intervention Hierarchy (Ancestors)

Electric Stimulation Therapy; Therapeutics; Convulsive Therapy; Psychiatric Somatic Therapies; Behavioral Disciplines and Activities; Electroshock; Psychological Techniques

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: PARTICIPANT
• Purpose: BASIC SCIENCE
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Dr Mohammad Ali Salehinejad

Study Record Dates

• First Submitted: November 5, 2024
• First Posted: November 8, 2024
• Study Start: July 13, 2021
• Primary Completion: November 30, 2023
• Study Completion: November 30, 2023
• Last Updated: March 18, 2026

Record last verified: 2026-03

Locations

DE (1)