Non-invasive Deep Brain Stimulation to Improve Spatial Navigation Abilities in Individuals Following Traumatic Brain Injury

Investigation of the Plasticity of Deep Brain Structures in Mild Cognitive Impairment and Healthy Aging (PlasMA)

Impairments in spatial memory and spatial navigation are commonly reported amongst patients presenting post-traumatic brain injury (TBI). In this study, the investigators examine the effect of non-invasive deep brain stimulation of the hippocampal-entorhinal complex (HC-EC), a key region supporting navigation abilities, on spatial navigation performance in TBI patients. Using a virtual reality task where participants must first encode and later recall the location of objects in a virtual arena, the investigators contrast performance while active versus control stimulation is applied to the HC-EC. The investigators additionally record brain activity using electroencephalography (EEG) prior to, during, and after task performance to characterize the neural correlates of spatial navigation abilities in TBI patients, and how they are affected by stimulation.

Study Overview

• Status: Not yet recruiting
• Conditions: Traumatic Brain Injury
• Intervention / Treatment: Other: Transcranial electric stimulation

Detailed Description

Patients will perform a virtual reality spatial navigation task comparable to that used previously by Beanato and colleagues (2024; DOI: 10.1126/sciadv.ado4103). Patients will perform 4 blocks of task, each lasting approximately 10 minutes; during the full duration of each block, either active or control transcranial temporal interference stimulation (tTIS) will be applied in an interleaved manner, and EEG recordings will be collected. Resting-state EEG recordings will also be collected prior to and following task performance.

Structural, diffusion-weighted, and resting-state MRI scans will additionally be performed during a prior baseline session.

• Study Type: Interventional
• Enrollment (Estimated): 25
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Switzerland
  • Canton of Geneva
    • Geneva, Canton of Geneva, Switzerland, 1202
      • EPFL, Campus Biotech
      • Contact: Friedhelm Hummel; Phone Number: +41 27 603 23 59; Email: friedhelm.hummel@epfl.ch
  • Valais
    • Sion, Valais, Switzerland, 1950
      • EPFL Valais, Clinique Romande de readaptation
      • Contact: Friedhelm Hummel; Phone Number: +41 27 603 23 59; Email: friedhelm.hummel@epfl.ch

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Age ≥ 18 years
• Clinical diagnosis of TBI
• No history of other severe neurological or psychiatric disorders

Exclusion Criteria:

• Unable to consent
• Severe neuropsychiatric (e.g., major depression, severe dementia) or unstable systemic diseases (e.g., severe progressive and unstable cancer, life threatening infectious diseases)
• Severe sensory or cognitive impairment or musculoskeletal dysfunctions prohibiting to understand instructions or to perform the experimental tasks
• Inability to follow or non-compliance with the procedures of the study

• Contraindications for NIBS or MRI:

  • Electronic or ferromagnetic medical implants/device, non-MRI compatible metal implant
  • History of seizures
  • Medication that significantly interacts with NIBS being benzodiazepines, tricyclic antidepressants and antipsychotics
• Regular use of narcotic drugs
• Pregnancy
• Request of not being informed in case of incidental findings
• Concomitant participation in another trial involving probing of neuronal plasticity

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Active stimulation; Patterned stimulation (intermittent theta-burst) generating temporal interference in the hippocampal-entorhinal complex; see Beanato et al. 2024, Sci Adv (DOI: 10.1126/sciadv.ado4103) for details.	Other: Transcranial electric stimulation; Transcranial temporal interference stimulation (tTIS) is an innovative non-invasive brain stimulation approach, in which two or more independent stimulation channels deliver high-frequency currents in the kHz range (oscillating at f1 and f1 + Δf). These high-frequency currents are assumed to be too high to effectively modulate neuronal activity. Still, by applying a small shift in frequency, they result in a modulated electric field with the envelope oscillating at the low-frequency Δf (target frequency) where the two currents overlap. The peak of the modulated envelope amplitude can be steered towards specific areas located deep in the brain, by tuning the positions of the electrodes and the current ratio across stimulation channels. Here, the investigators apply tTIS via surface electrodes applying a low-intensity, sub-threshold protocol following the safety guidelines for low-intensity transcranial electric stimulation in humans.
Placebo Comparator: Control stimulation; High-frequency (2kHz) electrical stimulation with no frequency shift, generating no temporal interference.	Other: Transcranial electric stimulation; Transcranial temporal interference stimulation (tTIS) is an innovative non-invasive brain stimulation approach, in which two or more independent stimulation channels deliver high-frequency currents in the kHz range (oscillating at f1 and f1 + Δf). These high-frequency currents are assumed to be too high to effectively modulate neuronal activity. Still, by applying a small shift in frequency, they result in a modulated electric field with the envelope oscillating at the low-frequency Δf (target frequency) where the two currents overlap. The peak of the modulated envelope amplitude can be steered towards specific areas located deep in the brain, by tuning the positions of the electrodes and the current ratio across stimulation channels. Here, the investigators apply tTIS via surface electrodes applying a low-intensity, sub-threshold protocol following the safety guidelines for low-intensity transcranial electric stimulation in humans.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Speed in the spatial navigation task	Participant speed (in seconds) of departure to, and reach of, object location in the virtual reality spatial navigation task.	During intervention (approximate duration of intervention = 40 minutes, administered in a single session)
Accuracy in the spatial navigation task	Accuracy (error, in virtual meters, between correct and recalled object location) in the virtual reality spatial navigation task.	During intervention (approximate duration of intervention = 40 minutes, administered in a single session)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Brain oscillatory activity	Resting-state and task-related EEG recordings are collected, and metrics of oscillatory activity are extracted to characterize the neural activity associated to the primary outcome.	Peri-interventional (up to 1 hour; approximate duration of intervention = 40 minutes, administered in a single session)
Brain structure and connectivity	Structural, diffusion-weighted, and resting-state MRI scans are performed during the baseline session and are used to evaluate inter-individual anatomical factors associated to the primary outcome.	Baseline (before the intervention)

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Age (years)	Participant age will be recorded to examine its influence on individual responsiveness to the intervention.	Baseline (before the intervention)
Montreal Cognitive Assessment questionnaire score	Participant score on the Montreal Cognitive Assessment questionnaire will be collected to examine its influence on individual responsiveness to the intervention.	Baseline (before the intervention)
Frontal Assessment Battery questionnaire score	Participant score in the Frontal Assessment Battery questionnaire will be collected to examine its influence on individual responsiveness to the intervention.	Baseline (before the intervention)

Collaborators and Investigators

• Sponsor: Friedhelm Hummel
• Collaborators: The Novartis Foundation; Wyss Center for Bio and Neuroengineering; Clinique Romande de Readaptation; SNF Swiss National Foundation; Fondation Bertarelli; HUG University hospital; Fondation Akiva; Canton du Valais

Study record dates

Study Major Dates

• Study Start (Estimated): December 1, 2025
• Primary Completion (Estimated): December 1, 2027
• Study Completion (Estimated): December 1, 2027

Study Registration Dates

• First Submitted: November 14, 2025
• First Submitted That Met QC Criteria: December 5, 2025
• First Posted (Estimated): December 9, 2025

Study Record Updates

• Last Update Posted (Estimated): December 9, 2025
• Last Update Submitted That Met QC Criteria: December 5, 2025
• Last Verified: November 1, 2025

More Information

Terms related to this study

• Keywords: memory; deep brain stimulation; traumatic brain injury; non-invasive brain stimulation; electroencephalography; spatial navigation; subcortical; neuro-imaging; transcranial temporal interference stimulation
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Wounds and Injuries; Craniocerebral Trauma; Trauma, Nervous System; Brain Injuries; Behavior; Spatial Behavior; Brain Injuries, Traumatic; Spatial Navigation
• Other Study ID Numbers: 2020-00127-wp73t; 2020-00127 (Other Identifier: Commission cantonale d'Éthique de la Recherche sur l'être humain Vaud (CER-VD))

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