Closed-loop tES-non-invasive Stimulation (CLIBM)

Closed-loop Non-invasive Stimulation for Improving Brain and Mental Health in Healthy Individuals

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

Study Overview

• Status: Not yet recruiting
• Conditions: Closed-loop Brain Stimulation
• Intervention / Treatment: Other: Transcranial low intensity focused ultrasound (FUS); Procedure: Magnetic Resonance Imaging; Other: transcranial electrical stimulation

Detailed Description

Closed-loop approaches may offer greater efficacy and lower variability across individuals compared to current open-loop stimulation approaches, yet they remain a relatively new approach, with no studies evaluating closed-loop transcranial low-intensity focused ultrasound stimulation (FUS) yet.

For this reason, we will collect and evaluate cognitive, biological and metabolic data from healthy participants, before and after closed-loop and open-loop stimulation interventions. This will allow us to compare our proposed closed-loop stimulation approach to stablished non-invasive techniques and to investigate the underlying mechanisms through which FUS can alter brain activity.

For this study, participants will attend multiple visits. To assess eligibility, participants will attend one initial session in-person before the start of the study.

Following safety guidelines, each participant will receive a maximum of two 1-hour MRI scanning sessions in a single week.

This study will be separated into three blocks of stimulation sessions: one block for tACS-FUS phase-locked on peak, and another block for tACS-FUS phase-locked on trough, and another block for TI-FUS. Participants will be randomly allocated to receive one of the blocks.

Before the during recruitment, participants will be asked to complete online some baseline questionnaires such as the O-Life inventory, BECK, MAIA, or STAI. Furthermore, full eligibility will be assessed in person.

At the first appointment, participants will have a brain scan at Sir Peter Mansfield Imaging Centre or Queen's Medical Centre, Nottingham, UK. This will help us to apply the brain stimulation to the right part of the participant's brain, as well as obtain baseline functional, metabolic and structural information.

Participants will be randomly allocated to either receive open-loop FUS, closed-loop FUS, tES, or sham FUS, in the second appointment and the other interventions in the subsequent visits for their assigned block. During all stimulation sessions, we will use an AntNeuro neuronavigation system to guide the location of the transducer.

During either of the stimulation visits, participants will have physiological (EEG) and cognitive markers recorded. Some emotional assessments (i.e., through a short STAI) will be performed before and after stimulation. EEG recordings will be conducted before, during and after stimulation on the same day. Rest-state EEG will be recorded pre-stimulation before the start of the cognitive tasks, and post-stimulation after the end of the cognitive tasks.

The participant will then undergo one cognitive assessment, which will consists on a visual working memory task (delayed-spatial-estimation-task). The task involves visual stimuli, with responses recorded via keyboard. The task is designed to take approximately 5-15 minutes to complete on pre and post-stimulation. The duration of the task during stimulation will be adapted to the duration of the stimulation. Following this, participants will receive the allocated intervention.

Participants will have the same physiological and cognitive assessments recorded during the stimulation and after the stimulation has been completed. For the closed-loop stimulation, participants will also undergo an MRI scanning after the stimulation.

The first visit, consisting of brain scan, will be separated by at least 24 hours from the second visit. Subsequent visits will be separated by at least one week from each other.

During each consecutive appointment, participants will be asked about any changes to their eligibility and continued consent.

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

Contacts and Locations

• Study Contact: Name: Dr. Falcon Caro; Phone Number: +44 115 823 2866; Email: alicia.falconcaro@nottingham.ac.uk
• Study Contact Backup: Name: Dr. Halls; Phone Number: +44 115 823 2866; Email: Daniel.Halls@nottingham.ac.uk

Study Locations

• United Kingdom
  • Nottingham, United Kingdom
    • University of Nottingham
    • Contact: Alicia Dr. Falcon Caro; Email: alicia.falconcaro@nottingham.ac.uk

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• 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

Exclusion Criteria:

• Inability to complete MRI/FUS/TMS/tES safety questionnaire and / or informed consent process.
• Current or previous diagnosis of a neurological, neurosurgical, psychiatric disorders.
• Other significant medical condition (specific details to be reviewed by the CI prior to inclusion).
• 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.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Open-loop transcranial low-intensity FUS; 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); 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 Names: TUS; LIFU; tFUS; Procedure: Magnetic Resonance Imaging; We obtain baseline functional, metabolic and structural information through MRI and MRS scanning; Other Names: MRI
Experimental: Closed-loop transcranial low-intensity FUS; 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); 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 Names: TUS; LIFU; tFUS; Procedure: Magnetic Resonance Imaging; We obtain baseline functional, metabolic and structural information through MRI and MRS scanning; Other Names: MRI; Other: transcranial electrical stimulation; 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).; Other Names: tES
Active Comparator: tES alone; tACS or TI delivered through a Digitimer DS5 for brain entrainment phase-locked on peak or trough	Procedure: Magnetic Resonance Imaging; We obtain baseline functional, metabolic and structural information through MRI and MRS scanning; Other Names: MRI; Other: transcranial electrical stimulation; 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).; Other Names: tES
Active Comparator: Sham FUS; 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); 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 Names: TUS; LIFU; tFUS; Procedure: Magnetic Resonance Imaging; We obtain baseline functional, metabolic and structural information through MRI and MRS scanning; Other Names: MRI

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
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 Outcome Measures

Outcome Measure	Time Frame
Structured questionnaire assessing adverse effects of the intervention	Immediately after stimulation, 24 hours after stimulation and 1 week after stimulation

Collaborators and Investigators

• Sponsor: University of Nottingham
• Investigators: Principal Investigator: Marcus Kaiser, PhD, University of Nottingham

Publications and helpful links

General Publications

• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (Estimated): July 1, 2026
• Primary Completion (Estimated): August 1, 2027
• Study Completion (Estimated): December 1, 2027

Study Registration Dates

• First Submitted: June 22, 2026
• First Submitted That Met QC Criteria: June 22, 2026
• First Posted (Actual): June 26, 2026

Study Record Updates

• Last Update Posted (Actual): June 26, 2026
• Last Update Submitted That Met QC Criteria: June 22, 2026
• Last Verified: June 1, 2026

More Information

Terms related to this study

• Keywords: electrical stimulation; neuromodulation; transcranial low-intensity focused ultrasound stimulation; closed-loop neuromodulation
• Additional Relevant MeSH Terms: Investigative Techniques; Therapeutics; Behavioral Disciplines and Activities; Chemistry Techniques, Analytical; Spectrum Analysis; Electric Stimulation Therapy; Convulsive Therapy; Psychiatric Somatic Therapies; Electroshock; Psychological Techniques; Magnetic Resonance Spectroscopy; Transcranial Direct Current Stimulation; TES
• Other Study ID Numbers: F1708

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