Combined Regulatory Effects of 40 Hz eTNS and Multisensory Stimulation on Brain Networks

Official title

A Study on the Enhancing Effects of 40 Hz Combined Trigeminal-Sensory Stimulation on Working Memory

Overview

The purpose of this study is to investigate the independent and interactive effects of 40Hz auditory, visual, and external trigeminal nerve stimulation (eTNS) on brain state dynamics and functional connectivity. While 40Hz visual and auditory sensory stimulation have been explored for potential cognitive and therapeutic benefits, the underlying mechanisms on large-scale brain networks and the potential effects of combining multiple modalities remain unclear. This study aims to determine whether multimodal co-stimulation genuinely compounds network-level effects or if targeted dual-pairings are more efficient for brain network reorganization. In this within-subject study, 23 participants will receive all eight possible combinations of 40Hz auditory, visual, and eTNS (targeting the maxillary branch) in a randomized order. Each stimulation condition will last for 5 minutes, separated by 1-minute inter-stimulus intervals. Continuous electroencephalography (EEG) will be recorded throughout the procedures to evaluate brain responses. The collected EEG data will be analyzed using microstate analysis, functional connectivity analysis, and graph-theoretic network analysis. Ultimately, the study seeks to understand how these non-invasive stimulation techniques, independently and together, drive large-scale network reorganization and optimize the balance between local specialization and global integration in the brain.

Detailed description

Physical neuromodulation at 40 Hz has emerged as a promising therapeutic approach, with visual and auditory stimulation demonstrating the capacity to entrain gamma oscillations and confer cognitive benefits. Analogous effects have also been observed with electrical approaches, including external trigeminal nerve stimulation (eTNS). While the prevailing assumption in the field suggests that combining multiple sensory modalities will more comprehensively recruit distributed brain circuitry and yield greater therapeutic effects, the mechanistic foundations of this additive hypothesis remain contested. Furthermore, recent evidence indicates that network-level reorganization, rather than localized gamma entrainment, may represent a more causally relevant substrate for these cognitive improvements.

This study is designed to systematically characterize the independent and interactive effects of 40Hz auditory, visual, and eTNS stimulation on brain state dynamics, functional connectivity, and graph-theoretic network properties. The trial employs a fully crossed 2×2×2 within-subject design. A total of 23 participants will undergo all eight possible combinations of 40Hz stimulation modalities: sham (no stimulation), auditory only, visual only, eTNS only, auditory + visual, auditory + eTNS, visual + eTNS, and the three-way combination of auditory + visual + eTNS.

During the experimental session, the eTNS will specifically target the maxillary branch of the trigeminal nerve. The eight stimulation conditions will be administered in a randomized order for each participant. Each stimulation block will last for 5 minutes, separated by 1-minute inter-stimulus intervals to prevent carry-over effects.

Continuous electroencephalography (EEG) will be recorded throughout the session using a 32-channel eego™ mylab system (ANT Neuro, Netherlands) to capture real-time cortical responses. Following data acquisition, standard preprocessing pipelines will be applied, including notch filtering, 0.5-45Hz bandpass filtering, average re-referencing, ICA-based artifact rejection, and bad channel interpolation.

Interventions

• Device 40 Hz External Trigeminal Nerve Stimulation
  Electrical stimulation targeting the maxillary branch of the trigeminal nerve at a frequency of 40 Hz
• Device 40 Hz Auditory Stimulation
  Auditory sensory stimulation delivered at 40 Hz for 5-minute durations
• Device 40 Hz Visual Stimulation
  Visual sensory stimulation delivered at a frequency of 40 Hz for 5-minute durations
• Other Sham Stimulation
  Inactive control stimulation designed to mimic the sensory experience of the active modalities without delivering actual 40 Hz therapeutic stimulation

Primary outcome measures

• Whole-Brain Functional Connectivity (Phase-Locking Value) [Time frame: Day1 (during the single experimental session)]

Secondary outcome measures (3)

• EEG Microstate Dynamics (Mean Duration and Segment Density) [Time frame: Up to 1 hour (during the single experimental session)]
• EEG Phase-Locking Value (PLV)-Derived Global Efficiency [Time frame: Day1 (during the single experimental session)]
• EEG Phase-Locking Value (PLV)-Derived Small-World Propensity [Time frame: Day 1 (during the single experimental session)]

Eligibility criteria

Inclusion criteria

• Healthy adults aged ≥18 years old.
• Normal or corrected-to-normal vision and hearing (essential for 40Hz visual and auditory stimulation).
• Right-handedness.
• Willing to participate in the study and capable of providing written informed consent.

Exclusion criteria

• Personal or family history of epilepsy or seizures (crucial safety criteria for 40Hz flicker and electrical stimulation).
• History of any neurological or psychiatric disorders.
• Presence of metallic implants in the head, cardiac pacemakers, or other implanted electronic medical devices.
• Skin lesions, infections, or hypersensitivity at the eTNS stimulation site (maxillary branch of the trigeminal nerve).
• Current use of psychoactive medications or substances that may significantly alter EEG signals or brain state dynamics.
• Pregnant or lactating individuals.
• Poor sleep quality or irregular sleep-wake cycles prior to the experiment.

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

Healthy volunteers: Yes

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Basic science

Study locations

China · 1 center

• Xidian University — Xi'an

Identifiers

NCT: NCT07668167 · 20260612

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗