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

Gamma Oscillations and Working Memory Following Combined 40Hz tACS and iTBS

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

Study Overview

• Status: Completed
• Conditions: Alzheimer Disease; Working Memory; EEG Brain Oscillations
• Intervention / Treatment: Device: Transcranial alternating current stimulation; Device: Theta burst stimulation; Device: Sham (No Treatment)

Detailed Description

Neuropsychiatric disorders are a leading cause of global disability-adjusted life years, and treatment solutions are lacking. Recent findings suggest that non-invasive brain stimulation may be a valuable option in conditions such as epilepsy or Alzheimer's disease (AD). Still, a better understanding of mechanisms and patient-specific factors is needed. Personalized hybrid brain models uniting the physics of electromagnetism with physiology - NeuroTwins (NeTs) - are poised to play a fundamental role in understanding and optimizing the effects of stimulation at the individual level. The purpose of this project is to deliver solutions through model-driven, individualized therapy. A computational framework - weaved and validated across scales and levels of detail - will be proposed to represent the mechanisms of interaction of electric fields with brain networks and assimilate neuroimaging data. This will allow us to characterize the dynamical landscape of the individual brain and define strategies to restore healthy dynamics. The work package, which will take place at IfADo, is part of the consortium collaborating with labs across Europe and USA, aiming to validate and optimize the realistic hybrid brain models developed by NeTs. The targeted subject groups of the IfADo project will be healthy young and old participants. Non-invasive brain stimulation including repetitive transcranial magnetic stimulation and transcranial alternating current stimulation will be applied with electroencephalography, and magnetic resonance spectroscopy as outcome measures. The results are to be translated into a technology pipeline for the design of new personalized neuromodulation protocols which will further be tested in a cohort of AD patients by another clinical consortium member, delivering model-driven breakthroughs in basic and clinical neuroscience, with patients ultimately benefiting from safe, individualized therapy solutions.

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

Contacts and Locations

Study Locations

• Germany
  • North Rhine-Westphalia
    • Dortmund, North Rhine-Westphalia, Germany, 44139
      • Leibniz-Institut für Arbeitsforschung

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

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

Exclusion Criteria:

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Transcranial alternating current stimulation; 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; 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
Active Comparator: intermittent theta burst stimulation; 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; 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.
Active Comparator: combited iTBS- tACS peak; 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; 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; Device: Theta burst stimulation; 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.
Active Comparator: Combined iTBS-tACS trough; 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; 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; Device: Theta burst stimulation; 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.
Sham Comparator: sham; 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); 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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

Collaborators and Investigators

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

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start (Actual): July 13, 2021
• Primary Completion (Actual): November 30, 2023
• Study Completion (Actual): November 30, 2023

Study Registration Dates

• First Submitted: November 5, 2024
• First Submitted That Met QC Criteria: November 7, 2024
• First Posted (Actual): November 8, 2024

Study Record Updates

• Last Update Posted (Actual): March 18, 2026
• Last Update Submitted That Met QC Criteria: March 15, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Keywords: Alzheimer's disease; EEG; Gamma oscillations; Intermittent theta burst stimulation; Transcranial alternating current stimulation, tACS
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Mental Disorders; Neurocognitive Disorders; Dementia; Tauopathies; Neurodegenerative Diseases; Alzheimer Disease; Therapeutics; Behavioral Disciplines and Activities; Electric Stimulation Therapy; Convulsive Therapy; Psychiatric Somatic Therapies; Electroshock; Psychological Techniques; Transcranial Direct Current Stimulation
• Other Study ID Numbers: IfADo_196

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No