ANZCTR - Registration

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Trial registered on ANZCTR

Registration number

ACTRN12626001197325

Ethics application status

Approved

Date submitted

7/09/2026

Date registered

28/09/2026

Date last updated

28/09/2026

Date data sharing statement initially provided

28/09/2026

Type of registration

Prospectively registered

Titles & IDs

Public title

Targeting the brain circuit of alcohol craving through ultrasound waves

Scientific title

Evaluating the effects of transcranial focused ultrasound stimulation of the anterior insula on the neural substrates of craving in people with alcohol use disorder

Additional trial identifiers [1]

Therapeutic Goods Association (TGA): CTN:04425-1

Universal Trial Number (UTN)

Trial acronym

Related trial records

Health condition

Health condition(s) studied:

Alcohol Use Disorder (AUD)

Condition category

Condition code

Mental Health

Addiction

Intervention/exposure

Study type

Interventional

Description of the intervention or exposure

Low-intensity transcranial focused ultrasound (tFUS) targeting the left anterior insula, using a facilitatory protocol to modulate neural activity in this region.

Materials: We will use a NeuroFUS system (Sonic Concepts; Bothell, Washington, USA) using CTX-500 transducer (Brainbox Ltd., Cardiff, UK) with a four-element array (64 mm diameter). The system will be utilized in conjunction with Brainsight (Rogue Research Inc.) and k-Wave software to accurately and safely apply the ultrasound to the left anterior insula of each participant.

Mode of delivery: Face-to-face administration, provided individually to each participant.

Procedure: This is a randomised, double blind (participants and assessors), sham-controlled, crossover clinical trial.

Participants will be asked to attend three face-to-face sessions at the Monash Biomedical Imaging facility.

The first session will comprise a baseline MRI scan for neuronavigation and tFUS trajectory planning purposes, alongside a battery of background and characterisation measures. This session will take place within approximately one week (7 days; ±3 days) of the first intervention session.

The two intervention sessions will be separated by a washout period of approximately one week (7 days; ±3 days). The procedure for both intervention sessions will be the same, with the only difference being the type of intervention applied (active or sham; order randomised and counterbalanced).

Each intervention session will consist of:
1) completion of cognitive tasks/surveys before and after tFUS stimulation, to assess craving, impulsivity and interoception;
2) low-intensity tFUS to the left anterior insula, and;
3) two MRI scans (once before and after the tFUS intervention).

The baseline MRI session will take ~1 hour, while the intervention sessions will each take ~3.5 hours. Participants will spend approximately 8 hours total in participation.

Active intervention dosage: A validated facilitatory protocol (Zeng et al., 2024) will be delivered to the left anterior insula with the following parameters: 500 kHz frequency, spatial-peak pulse-average intensity (ISPPA) of 20 W/cm² (free-water), 20 ms bursts repeated at 5 Hz (200ms) for 80 seconds (10% duty cycle), administered twice with a 90 second break in between (160s total sonication duration).

In one session, participants will receive an active dose of the tFUS intervention, and in the other session, they will receive a sham (placebo) dose of the intervention.

Intervention administrators: Interventions will be conducted exclusively by a tFUS clinician. Here, a tFUS clinician is defined as an individual holding a PhD in neuroscience or similar disciplines, or possessing equivalent expertise in neuromodulation, demonstrated by a minimum of one year of relevant experience, or an individual who has undergone specific training and is operating under the direct supervision of the neurostimulation leads, who each have 5+ years of experience in the field.

Intervention code [1]

Treatment: Devices

Description of the comparator or control

Placebo (sham tFUS).

The procedure for the sham intervention session will be the same as the active intervention session (above). However, the intervention will be sham (placebo) tFUS.

Sham intervention dosage: The sham tFUS will mimic the sounds, timing, and procedure of the active tFUS intervention, but with no sonication being applied.

Control group

Placebo

Outcomes

Primary outcome [1]

Alcohol cue reactivity-evoked BOLD activation in the anterior insula

Timepoint [1]

Week 1: T1 (pre-tFUS in intervention session 1), T2 (post-tFUS in intervention session 1). Week 2: T3 (pre-tFUS in intervention session 2), T4 (post-tFUS in intervention session 2).

Secondary outcome [1]

Alcohol cue reactivity-evoked effective connectivity between brain regions of interest during the Alcohol Cue Reactivity Task, indicated by Dynamic Causal Modelling of neural connectivity (Razi et al., 2024).

Timepoint [1]

Week 1: T1 (pre-tFUS in intervention session 1), T2 (post-tFUS in intervention session 1). Week 2: T3 (pre-tFUS in intervention session 2), T4 (post-tFUS in intervention session 2).

Secondary outcome [2]

Target engagement via metabolite concentration within the left anterior insula.

Timepoint [2]

Week 1: T1 (pre-tFUS in intervention session 1), T2 (post-tFUS in intervention session 1). Week 2: T3 (pre-tFUS in intervention session 2), T4 (post-tFUS in intervention session 2).

Secondary outcome [3]

Self-reported craving during in-scanner cue-reactivity task.

Timepoint [3]

Week 1: T1 (pre-tFUS in intervention session 1), T2 (post-tFUS in intervention session 1). Week 2: T3 (pre-tFUS in intervention session 2), T4 (post-tFUS in intervention session 2).

Secondary outcome [4]

Self-reported craving.

Timepoint [4]

Week 1: T1 (pre-tFUS in intervention session 1), T2 (post-tFUS in intervention session 1). Week 2: T3 (pre-tFUS in intervention session 2), T4 (post-tFUS in intervention session 2).

Secondary outcome [5]

Interoceptive awareness during craving states.

Timepoint [5]

Week 1: T1 (pre-tFUS in intervention session 1), T2 (post-tFUS in intervention session 1). Week 2: T3 (pre-tFUS in intervention session 2), T4 (post-tFUS in intervention session 2).

Secondary outcome [6]

Interoceptive awareness of bodily sensations.

Timepoint [6]

Week 1: T1 (pre-tFUS in intervention session 1), T2 (post-tFUS in intervention session 1). Week 2: T3 (pre-tFUS in intervention session 2), T4 (post-tFUS in intervention session 2).

Secondary outcome [7]

Attentional control

Timepoint [7]

Week 1: T1 (pre-tFUS in intervention session 1), T2 (post-tFUS in intervention session 1). Week 2: T3 (pre-tFUS in intervention session 2), T4 (post-tFUS in intervention session 2).

Secondary outcome [8]

Treatment fidelity and safety.

Timepoint [8]

At the completion of each intervention session. Week 1: T2 (post-tFUS in intervention session 1). Week 2: T4 (post-tFUS in intervention session 2).

Secondary outcome [9]

Target engagement via metabolite concentration within the left anterior insula.

Timepoint [9]

Week 1: T1 (pre-tFUS in intervention session 1), T2 (post-tFUS in intervention session 1). Week 2: T3 (pre-tFUS in intervention session 2), T4 (post-tFUS in intervention session 2).

Secondary outcome [10]

Information sampling

Timepoint [10]

Week 1: T1 (pre-tFUS in intervention session 1), T2 (post-tFUS in intervention session 1). Week 2: T3 (pre-tFUS in intervention session 2), T4 (post-tFUS in intervention session 2).

Secondary outcome [11]

Feedback monitoring

Timepoint [11]

Week 1: T1 (pre-tFUS in intervention session 1), T2 (post-tFUS in intervention session 1). Week 2: T3 (pre-tFUS in intervention session 2), T4 (post-tFUS in intervention session 2).

Eligibility

Key inclusion criteria

- Meet DSM-5 criteria for moderate-severe AUD in past 3 months
- Aged 18-49 years
- Can attend 3 sessions in Clayton, Victoria.
- Willing to abstain from alcohol 36 hours before each session.
- Willing to abstain from recreational drugs 7 days prior to each session.
- Consent to nominate a GP to receive details of any MRI incidental findings.
- Willing to nominate an emergency contact for intervention sessions.
- Have consumed alcoholic beverages in the past 30 days.

Minimum age

18 Years

Maximum age

49 Years

Sex

Both males and females

Healthy volunteers

Key exclusion criteria

- Any MRI or tFUS contraindication such as ferromagnetic metal in the head, brain surgery or -implanted medical devices
- Body weight of >250 kg (upper limit of MRI scanner)
- Co-occurrence of serious or unstable mental disorders that can substantially interfere with the study protocols and therapeutic goals, such as psychosis, schizophrenia, and bipolar disorders (ascertained with the SCID-5/ QuickSCID-5).
- Self-reported history of brain trauma with loss-of-consciousness >30 minutes or any loss of consciousness in the past 6 months, seizures/epilepsy, neurodegenerative illnesses, fever (>37.5c) on either intervention session, or any other neurological condition associated with severe cognitive impairment as indicated by the Montreal Cognitive Assessment test (MoCA) as these conditions can impact the safety and/or reduce the efficacy of the intervention.
- Currently taking anti-craving medications (e.g., naltrexone, nalmefene, bupropion) that can mask or amplify the effects of the study.
- Currently taking any dosage of medication that may interfere with safety of the intervention (i.e., high-dose diazepam, clozapine).
- Accessing formal treatment for alcohol use disorder currently, or within the past 28 days, or planning to commence formal treatment for alcohol use disorder in the next 28 days.

Study design

Purpose of the study

Treatment

Allocation to intervention

Randomised controlled trial

Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)

Treatment order allocation will be concealed using a central randomisation by computer, created in advance by an independent statistician/ independent researcher.

The randomisation schedule will be held online on a secure university REDCap server, and only accessible by the designated tFUS clinicians after participant eligibility has been confirmed and baseline assessments completed. The researchers responsible for assessing eligibility and enrolling participants will not have access to the allocation schedule at any stage.

Methods used to generate the sequence in which subjects will be randomised (sequence generation)

Treatment order will be determined using permuted block randomisation. Half of the participants will receive active stimulation in the first intervention session followed by sham stimulation in the second session, and the other half will receive sham stimulation first followed by active stimulation.

Masking / blinding

Blinded (masking used)

Who is / are masked / blinded?

The people receiving the treatment/s

The people assessing the outcomes

Intervention assignment

Crossover

Other design features

Phase

Not Applicable

Type of endpoint/s

Safety/efficacy

Statistical methods / analysis

Power analysis was conducted for a 2 × 2 repeated-measures ANOVA, with Condition (active tFUS vs sham) and Time (pre- vs post-stimulation) as within-subject factors.

This design was informed by Zhao et al. (2026), who reported a significant Condition × Time interaction on alcohol cue-induced brain reactivity following a sham-controlled course of neuromodulation in AUD (partial eta² = 0.143), and Legon et al. (2024), who reported that tFUS to the anterior insula produced significant changes in an interoceptive heart rate variability task relative to sham (partial eta² = 0.094). In addition, Schacht et al. (2013), who assessed the stability of alcohol-cue-elicited fMRI activation across two scans in AUD patients (ICC = 0.75-0.81). To ensure a conservative estimate given the absence of tFUS-specific precedent in alcohol cue reactivity, we powered our study to detect an effect size smaller than that reported by Zhao and Legon (d = 0.4, medium effect size), using the more conservative end of Schacht et al.'s reliability range (r = 0.75).
With a two-tailed alpha of 0.05, power (1-ß) of 0.80, and a moderate Pearson correlation coefficient (r = 0.75) between timepoints, a total sample of n = 27 was required.

Descriptive statistics of key demographic and clinical characteristics will be reported at baseline.

The primary analysis will examine anterior insula cue reactivity using a mixed effects model within a frequentist framework. For each participant and timepoint, anterior insula activation during the Alcohol Cue Reactivity Task will be estimated and entered into the model. Fixed effects will include Condition (active vs sham), Time (Pre tFUS vs Post tFUS), their interaction, Condition (Active vs Sham), and treatment order, with a random intercept for participant. The primary contrast of interest is the Condition × Time interaction, reflecting the differential pre to post cue reactivity BOLD signal change in the anterior insula between active and sham tFUS.

Model estimates will be reported as mean differences with 95% confidence intervals and corresponding p-values. Standardised effect sizes will also be presented.

Secondary and exploratory outcomes will be evaluated within a consistent multilevel modelling framework. For related families of outcomes (e.g., MRS-derived GABA and glutamate), multiplicity will be addressed using within-family control procedures such as Holm correction or multivariate estimation.

Recruitment

Recruitment status

Not yet recruiting

Date of first participant enrolment

Anticipated

5/10/2026

Actual

Date of last participant enrolment

Anticipated

29/03/2027

Actual

Date of last data collection

Anticipated

19/04/2027

Actual

Sample size

Target

Accrual to date

Final

Recruitment in Australia

Recruitment state(s)

VIC

Funding & Sponsors

Funding source category [1]

Government body

Name [1]

National Health and Medical Research Council (NHMRC GNT2009464)

Address [1]

Country [1]

Australia

Funding source category [2]

University

Name [2]

Monash University Academic Support Funds

Address [2]

Country [2]

Australia

Primary sponsor type

University

Name

Monash University

Address

Country

Australia

Secondary sponsor category [1]

None

Name [1]

Address [1]

Country [1]

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Monash University Human Research Ethics Committee

Ethics committee address [1]

https://www.monash.edu/researchoffice/ethics

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

21/07/2026

Approval date [1]

28/07/2026

Ethics approval number [1]

48963

Summary

Brief summary

This study aims to examine possible changes in brain activity in people with alcohol use disorder after receiving focused ultrasound stimulation guided by brain imaging. Stimulation will be applied to the anterior insula, a brain region involved in craving.
We will assess changes in brain activation, connections and chemistry, self-reported craving, and cognition and behaviour. We will also assess emotional awareness to better understand how the intervention works.
We hypothesise that applying focused ultrasound stimulation to the left anterior insula will facilitate insula connections with the prefrontal cortex, which is a brain region involved in craving regulation.

Trial website

Trial related presentations / publications

Public notes

References:
Anton et al., (1996). The obsessive compulsive drinking scale: A new method of assessing outcome in alcoholism treatment studies. Arch Gen Psychiatry, 53(3), 225-231. https://doi.org/10.1001/archpsyc.1996.01830030047008

Bohn et al., (1995). Development and initial validation of a measure of drinking urges in abstinent alcoholics. Alcoholism: clinical and experimental research, 19(3), 600-606.

Cabrera, A. et al. Assessing body awareness and autonomic reactivity: Factor structure and psychometric properties of the Body Perception Questionnaire-Short Form (BPQ-SF). Int J Methods Psychiatr Res 27, e1596 (2018). https://doi.org/10.1002/mpr.1596

Cyders et al., (2014). Examination of a short English version of the UPPS-P Impulsive Behavior Scale. Addictive behaviors, 39(9), 1372-1376. https://doi.org/10.1016/j.addbeh.2014.02.013

Flannery et al., (1999). Psychometric properties of the Penn Alcohol Craving Scale. Alcohol Clin Exp Res 23, 1289-1295.

Henry, J. D. & Crawford, J. R. The short-form version of the Depression Anxiety Stress Scales (DASS-21): construct validity and normative data in a large non-clinical sample. Br J Clin Psychol 44, 227-239 (2005). https://doi.org/10.1348/014466505X29657

Herman et al., (2022). The utility of the emBODY tool as a novel method of studying complex phenomena-related emotions. Scientific Reports, 12(1), 19884. https://doi.org/10.1038/s41598-022-23734-4

Mehling et al., (2018). The Multidimensional Assessment of Interoceptive Awareness, Version 2 (MAIA-2). PLoS ONE, 13(12). https://doi.org/10.1371/journal.pone.0208034

Mellick et al., (2023). Alcohol Cue
Processing in Co-Occurring Bipolar Disorder and Alcohol Use Disorder. JAMA
Psychiatry. 80(11), 1150-1159. https://doi.org/10.1001/jamapsychiatry.2023.2726

Razi et al., (2024). Construct validation of a DCM for
resting state fMRI. Neuroimage. 10,1-14. https://doi.org/10.1016/j.neuroimage.2014.11.027

Schacht et al., (2013). Functional neuroimaging studies of alcohol cue reactivity: a quantitative meta-analysis and systematic review. Addiction Biology, 18: 121-133. https://doi.org/10.1111/j.1369-1600.2012.00464.x

Skevington et al., (2004). The World Health Organization's WHOQOL-BREF quality of life assessment: psychometric properties and results of the international field trial. A report from the WHOQOL group. Qual Life Res 13, 299-310. https://doi.org/10.1023/B:QURE.0000018486.91360.00

Smith et al., (2020). A Bayesian computational model reveals a failure to adapt interoceptive precision estimates across depression, anxiety, eating, and substance use disorders. PLOS Computational Biology, 16(12), e1008484. https://doi.org/10.1371/journal.pcbi.1008484

Sobell, L. C., & Sobell, M. B. (1992). Timeline follow-back: A technique for assessing a self-reported alcohol consumption. In R. Z. Litten & J. P. Allen (Eds.), Measuring alcohol consumption: Psychosocial and biochemical methods (pp. 41–72). Humana Press. https://doi.org/10.1007/978-1-4612-0357-5_3

Legon et al., (2024). Noninvasive neuromodulation of subregions of the human insula differentially affect pain processing and heart-rate variability: a within-subjects pseudo-randomized trial.Pain 165(7): 1625-1641. https://doi.org/10.1523/JNEUROSCI.1011-23.2023

Verdejo-Garcia et al., (2021). A unified online test battery for cognitive impulsivity reveals relationships with real-world impulsive behaviours. Nature Human Behaviour, 5(11), 1562-1577. https://doi.org/10.1097/j.pain.0000000000003171

Zeng et al., (2024). Effects of different sonication parameters of theta burst transcranial ultrasound stimulation on human motor cortex. Brain Stimulation, 17(2), 258–268. https://doi.org/10.1016/j.brs.2024.03.001

Zhao et al., (2026). Neural Response to Theta-Burst Stimulation Predicts Long-Term Relapse in Patients With Alcohol Use Disorder: A Pilot fMRI Study. Addiction Biology 31(1). https://doi.org/10.1111/adb.70109

Contacts

Principal investigator

Name

Prof Antonio Verdejo-Garcia

Address

18 Innovation Walk, Monash University, Clayton, VIC, Australia, 3168

Country

Australia

Phone

+61 3 9905 5374

Fax

[email protected]

Contact person for public queries

Name

Antonio Verdejo-Garcia

Address

18 Innovation Walk, Monash University, Clayton, VIC, Australia, 3168

Country

Australia

Phone

+61 3 9905 5374

Fax

[email protected]

Contact person for scientific queries

Name

Antonio Verdejo-Garcia

Address

18 Innovation Walk, Monash University, Clayton, VIC, Australia, 3168

Country

Australia

Phone

+61 3 9905 5374

Fax

[email protected]

Data sharing statement

Will the study consider sharing individual participant data?

Yes

Will there be any conditions when requesting access to individual participant data?

Persons/groups eligible to request access:
• Researchers
Conditions for requesting access:
• Yes, conditions apply:
• Requires review on a case-by-case basis by the trial custodian, sponsor or data sharing committee

What individual participant data might be shared?

• All de-identified individual participant data

What types of analyses could be done with individual participant data?

• Any type of analysis (i.e. no restrictions on data re-use)

When can requests for individual participant data be made (start and end dates)?

From:
After publication of main results
To:
No end date

Where can requests to access individual participant data be made, or data be obtained directly?

• Data repository: Monash University Bridges - open source data repository.
Until the data repository is publicly available, researchers may contact the principal investigator via email (Prof. Antonio Verdejo-Garcia; [email protected]).

Are there extra considerations when requesting access to individual participant data?

What supporting documents are/will be available?

No Supporting Document Provided

Results publications and other study-related documents

Documents added manually

No documents have been uploaded by study researchers.

Documents added automatically

No additional documents have been identified.

Trial Review

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