Closed-loop tES-non-invasive Stimulation

NCT07671079 | Not Yet Recruiting

• 1 other identifier: F1708
• Study Type: interventional
• Target: 30
• Locations: 1 country
• Sites: 1

Brief Summary

The goal of this study is to establish if non-invasive closed-loop neuromodulation is an effective approach to enhance cognitive function in healthy 18-40 years old volunteers. The main questions it aims to answer are:

• Can closed-loop stimulation increase stimulation effectiveness?
• Can closed-loop focused ultrasound specifically engage with excitatory or inhibitory neural populations in the target structure as measured through MRS?
• Can observed stimulation outcomes for FUS be predicted through connectome analysis and computational models of indirect changes? Researchers will compare different closed-loop options to their open-loop counterpart to see if closed-loop approaches can increase efficacy and reduce the variability of the stimulation compared to open-loop approaches. Participants will:
• Answer some questionnaires at the start of the study and after each intervention session.
• Undertake a MRI scanning session.
• Undertake one open-loop FUS session.
• Undertake one tES session.
• Undertake one closed-loop FUS sessions involving tES and FUS, followed by a MRI scanning
• Undertake one sham FUS session
• Attend one visit in person to assess eligibility through questionnaires and one cognitive task

Conditions

Closed-loop Brain Stimulation

Keywords

neuromodulation; electrical stimulation; transcranial low-intensity focused ultrasound stimulation; closed-loop neuromodulation

Outcome Measures

Primary Outcomes (11)

• Change from Baseline in EEG Power in Alpha Band (8-12Hz)

  Baseline to 10 weeks, measured immediately before, during, and immediately after stimulation

• Change from Baseline in EEG Power in Theta Band (4-7Hz)

  Baseline to 10 weeks, measured immediately before, during, and immediately after stimulation

• Change from Baseline in EEG Power in Beta Band (13-30Hz)

  Baseline to 10 weeks, measured immediately before, during, and immediately after stimulation

• Change from Baseline in EEG Power in Gamma Band (31-45Hz)

  Baseline to 10 weeks, measured immediately before, during, and immediately after stimulation

• Changes from Baseline in EEG-derived spectral power

  Baseline to 10 weeks, measured immediately before, during, and immediately after stimulation

• Changes from Baseline in Functional connectivity (e.g., through changes in Phase-locked value (PLV))

  Baseline to 10 weeks, measured immediately before, during, and immediately after stimulation

• Average Reaction time (ms) measured from the Visual Working memory task

  Baseline to 10 weeks, measured immediately before, during, and immediately after stimulation

• Average Overall accuracy (%) measured from Visual Working Memory task

  Baseline to 10 weeks, measured immediately before, during, and immediately after stimulation

• Change from Baseline in Target-Region metabolite Concentration measured via Magnetic Resonance Spectroscopy (MRS)

  Baseline (Day 1) to immediately after closed-loop post-stimulation intervention

• Changes from Baseline in Functional Connectivity calculated from functional Magnetic Resonance Imaging (fMRI)

  Baseline (Day 1) to immediately after closed-loop post-stimulation intervention

• Changes from Baseline on Structural connectivity metrics derived from multi-shell diffusion MRI (dMRI) tractography

  Baseline (Day 1) to immediately after closed-loop post-stimulation intervention

Secondary Outcomes (1)

• Structured questionnaire assessing adverse effects of the intervention

  Immediately after stimulation, 24 hours after stimulation and 1 week after stimulation

Study Arms (4)

Open-loop transcranial low-intensity FUS

ACTIVE COMPARATOR

Transcranial low intensity focused ultrasound stimulation (FUS) with 500kHz transducer for following either the continuous theta burst or intermittent theta burst protocol using the NeuroFus PRO system

Other: Transcranial low intensity focused ultrasound (FUS); Procedure: Magnetic Resonance Imaging

Closed-loop transcranial low-intensity FUS

EXPERIMENTAL

Closed-loop Transcranial Electrical Stimulation by means of tACS or TI delivered through a Digitimer DS5 for brain entrainment phase-locked on peak or trough to transcranial low intensity FUS delivered to dACC through the NeuroFUS PRO system

Other: Transcranial low intensity focused ultrasound (FUS); Other: transcranial electrical stimulation; Procedure: Magnetic Resonance Imaging

tES alone

ACTIVE COMPARATOR

tACS or TI delivered through a Digitimer DS5 for brain entrainment phase-locked on peak or trough

Other: transcranial electrical stimulation; Procedure: Magnetic Resonance Imaging

Sham FUS

ACTIVE COMPARATOR

FUS delivered to ventricles or FUS and tACS located on head, one of them on or off depending on sham, or active.

Other: Transcranial low intensity focused ultrasound (FUS); Procedure: Magnetic Resonance Imaging

Interventions

Magnetic Resonance Imaging PROCEDURE

We obtain baseline functional, metabolic and structural information through MRI and MRS scanning

Also known as: MRI

Closed-loop transcranial low-intensity FUS; Open-loop transcranial low-intensity FUS; Sham FUS; tES alone

Transcranial low intensity focused ultrasound (FUS) OTHER

Low intensity focused ultrasound stimulation (FUS) with 500kHz transducer for following either the continuous theta burst or intermittent theta burst protocol using the NeuroFus PRO system

Also known as: LIFU, tFUS, TUS

Closed-loop transcranial low-intensity FUS; Open-loop transcranial low-intensity FUS; Sham FUS

transcranial electrical stimulation OTHER

Transcranial electrical stimulation (by means of transcranial alternating current stimulation (tACS) or non-invasive temporal interference (TI) electrical stimulation) using the DS5 isolated bipolar constant current stimulator together connected to a wave generator and with two electrodes for tACS (TI implementation will be carried out with two DS5 systems, separate wave generators and four electrodes).

Also known as: tES

Closed-loop transcranial low-intensity FUS; tES alone

Eligibility Criteria

• Age: 18 Years - 40 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Participant is willing and able to give informed consent for participation in the study
• Aged between 18 and 40
• Good general health
• Not consume alcohol 48 hours prior study visit
• Not currently taking any medications (except contraceptive pills) or if on long-term medication for a non-neurological/non-psychiatric condition (r.g. inhalers) to be considered otherwise healthy and stable with no symptoms
• Be right handedness

You may not qualify if:

• Inability to complete MRI/FUS/TMS/tES safety questionnaire and / or informed consent process.
• Current or previous diagnosis of a neurological, neurosurgical, psychiatric disorders.
• Currently pregnant, breast feeding, or on planned pregnancy.
• Medication intake (such as beta-blocker, glucocorticoids, anti-depressants, anti-inflammatory drugs in the last 7d).
• Medication intake (such as beta-blocker, glucocorticoids, anti-depressants) in the last 7d that are likely to affect brain function.
• Significant use of medication or recreational drugs that affect the nervous system.
• Excessive consumption of alcohol (\>2 alcohol beverages per day).
• Known allergy to any required consumables (such as aquasonic gel).
• History of anaphylaxis to any substance
• Have tightly coiled, curly or voluminous texture hair type (e.g., hair type 3, 4, or afro hair).
• Having skin disease or sensitive skin on or close to the head.

Sponsors & Collaborators

• University of Nottingham: lead

Study Sites (1)

University of Nottingham

Nottingham, United Kingdom

Location

Related Publications (7)

• Zhai Z, Ren L, Song Z, Xiang Q, Zhuo K, Zhang S, Li X, Zhang Y, Jiao X, Tong S, Sun J, Liu D. The efficacy of low-intensity transcranial ultrasound stimulation on negative symptoms in schizophrenia: A double-blind, randomized sham-controlled study. Brain Stimul. 2023 May-Jun;16(3):790-792. doi: 10.1016/j.brs.2023.04.021. Epub 2023 Apr 29. No abstract available.

  PMID: 37121354 BACKGROUND

• Sarica C, Nankoo JF, Fomenko A, Grippe TC, Yamamoto K, Samuel N, Milano V, Vetkas A, Darmani G, Cizmeci MN, Lozano AM, Chen R. Human Studies of Transcranial Ultrasound neuromodulation: A systematic review of effectiveness and safety. Brain Stimul. 2022 May-Jun;15(3):737-746. doi: 10.1016/j.brs.2022.05.002. Epub 2022 May 6.

  PMID: 35533835 BACKGROUND

• Raco V, Bauer R, Tharsan S, Gharabaghi A. Combining TMS and tACS for Closed-Loop Phase-Dependent Modulation of Corticospinal Excitability: A Feasibility Study. Front Cell Neurosci. 2016 May 25;10:143. doi: 10.3389/fncel.2016.00143. eCollection 2016.

  PMID: 27252625 BACKGROUND

• Briley PM, Boutry C, Webster L, Veniero D, Harvey-Seutcheu C, Jung J, Liddle PF, Morriss R. Intermittent theta burst stimulation with synchronised transcranial alternating current stimulation leads to enhanced frontal theta oscillations and a positive shift in emotional bias. Imaging Neurosci (Camb). 2024 Jan 25;2:imag-2-00073. doi: 10.1162/imag_a_00073. eCollection 2024.

  PMID: 40800403 BACKGROUND

• Nakazono H, Ogata K, Takeda A, Yamada E, Oka S, Tobimatsu S. A specific phase of transcranial alternating current stimulation at the beta frequency boosts repetitive paired-pulse TMS-induced plasticity. Sci Rep. 2021 Jun 23;11(1):13179. doi: 10.1038/s41598-021-92768-x.

  PMID: 34162993 BACKGROUND

• Zrenner C, Desideri D, Belardinelli P, Ziemann U. Real-time EEG-defined excitability states determine efficacy of TMS-induced plasticity in human motor cortex. Brain Stimul. 2018 Mar-Apr;11(2):374-389. doi: 10.1016/j.brs.2017.11.016. Epub 2017 Nov 24.

  PMID: 29191438 BACKGROUND

• Gold JM. Cognitive deficits as treatment targets in schizophrenia. Schizophr Res. 2004 Dec 15;72(1):21-8. doi: 10.1016/j.schres.2004.09.008.

  PMID: 15531404 BACKGROUND

MeSH Terms

Interventions

Transcranial Direct Current Stimulation; TES; Magnetic Resonance Spectroscopy

Intervention Hierarchy (Ancestors)

Electric Stimulation Therapy; Therapeutics; Convulsive Therapy; Psychiatric Somatic Therapies; Behavioral Disciplines and Activities; Electroshock; Psychological Techniques; Spectrum Analysis; Chemistry Techniques, Analytical; Investigative Techniques

Study Officials

• Marcus Kaiser, PhD

  University of Nottingham

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Dr. Falcon Caro

CONTACT

+44 115 823 2866; alicia.falconcaro@nottingham.ac.uk

Dr. Halls

CONTACT

+44 115 823 2866; Daniel.Halls@nottingham.ac.uk

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: PARTICIPANT
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor of Neuroinformatics

Study Record Dates

• First Submitted: June 22, 2026
• First Posted: June 26, 2026
• Study Start: July 1, 2026
• Primary Completion (Estimated): August 1, 2027
• Study Completion (Estimated): December 1, 2027
• Last Updated: June 26, 2026

Record last verified: 2026-06

Locations

GB (1)