Investigating the effects of low-intensity ultrasound stimulation on depression in young adults.

Summary: Low-intensity transcranial focused ultrasound stimulation (TUS), a novel non-invasive deep brain stimulation approach, will be applied to the subgenual anterior cingulate cortex (sgACC), a brain region implicated in depression and linked to the efficacy of another brain stimulation approach, transcranial magnetic stimulation (TMS). This intervention will be provided to healthy young adults to pilot the approach, and then to young adults experiencing depression. Rationale: TMS has been shown previously to improve depression symptoms and is available for clinical use for some Australians who meet criteria. It exerts its effects by stimulating the left dorsolateral prefrontal cortex (lDLPFC), indirectly inducing effects across subcortical networks. Its efficacy is variable, though, and some research has linked this variability in response to variability in the strength of connection between the lDLPFC and sgACC. Unlike TMS, TUS is able to directly stimulate subcortical structures (such as the sgACC), removing any reliance on cortical-subcortical connection strength. Design: Participants will undergo an initial MRI and then the remainder of the study follows a within-participant crossover design (TUS & sham in counterbalanced order) - i.e., within-participant placebo controlled and between-participant depression vs control (healthy). Procedures: After expressing interest, participants will complete the screening questionnaire and participants deemed eligible will engage in a screening phone call to confirm details. Recruitment flyers will link to an explanatory statement which describes the intervention, procedures, risks and benefits, and data security. This explanatory statement will be provided again to participants deemed eligible after the screening call. Participants will attend a baseline session where they are administered the Quick Structured Clinical Interview for DSM-5 (QuickSCID-5). If this inventory reveals any confounding diagnoses or symptoms, they will be excluded from the study but paid for their time up until exclusion. Participants will be required to attend up to three experimental sessions at either Monash Biomedical Imaging or Turner Institute laboratories at Monash University, Clayton. Sessions involving TUS will be separated by a one week interval. Each TUS testing session will run for approximately 1.5 hours. These sessions will include application of TUS, behavioural assessments and neuroimaging. Participants will complete a 45-minute baseline MRI scan at the beginning of the study which will involve a T1-weighted structural scan, a PETRA scan to allow neuronavigation of stimulation targets (details below), functional MRI, and an MR spectroscopy sequence to measure changes to key brain neurometabolites (e.g., gamma aminobutyric acid; GABA). Participants will be randomised into a TUS condition where they will either receive a single dose of TUS to a brain region implicated in depression (e.g., anterior cingulate cortex), or will receive 'sham stimulation' in which noise mimicking the ultrasound will be played to the participant through headphones. Participants will be blinded as to which condition they are in. TUS will applied in accordance with iTRUSST safety guidelines to induce transient modulations of synaptic function (short-lasting effects, less than 3 hours). Importantly, several studies have demonstrated that these protocols are safe and result in minimal thermal heating of targeted tissue (i.e. less than 2 degrees thermal rise - less than that see in mild fever). To localise the stimulation targets, we will be using neuronavigation, a method which ensures accurate positioning of the TUS transducer in relation to brain regions of interest. 3D brain images obtained with MRI are used to locate specific regions, and this is linked to the participant in the lab in real-time via infrared emitters/sensors. Before and after administration of TUS (or sham), self-report mood questionnaires will be administered and resting-state electroencephalography (EEG) recordings will be taken. After administration of TUS (or sham), participants will complete computerised behavioural tasks assessing processes compromised in depression and implicated in associated circuits (e.g., reward and effort sensitivity, appraisals, emotion regulation). It is anticipated that these tasks will take ~30-45 minutes to complete. After a 1-week washout period, participants will undergo the process again under the alternative condition (i.e., sham stimulation if previously received true stimulation, or true stimulation if previously received sham stimulation). Delivery of intervention: A single session of TUS will be administered in-person, individually, at the Neurophysiology Suite within the Turner Institute for Brain and Mental Health. TUS will primarily be applied by A/Prof Coxon & Dr Hendrikse who hold a doctoral qualification involving use of these techniques. Ms Hosler will receive comprehensive training in the use of TUS and will also apply TUS under supervision by A/Prof Coxon and Dr Hendrikse following completion of the training. The specific device used is NeuroFUS Pro from SonicConcepts. TUS parameters: 4-element transducer (DPX-500, Sonic concepts) with fundamental frequency of 500kHz. 30 ms pulses at 10Hz pulse repetition frequency (30% duty cycle), for 40 seconds (doi.org/10.7554/eLife.40541; https://www.cell.com/cell-reports/fulltext/S2211-1247(22)01014-2). For the TUS session, the intensity spatial peak pulse average (ISPPA) will be set to be between 5-8 W/cm2 in-situ at the target (derived from kWave simulations using individual skull morphometry information). This approach is aligned with current best practice from leading international laboratories (https://doi.org/10.1101/2024.07.25.605068; https://doi.org/10.1101/2025.08.14.670358). We will ensure that the TUS protocol falls within iTRUSST safety limits (mechanical index less than 1.9 and less than 2 cumulative effective minutes at 43 degrees, i.e. less than 2 CEM43 (https://arxiv.org/abs/2311.05359). For the Sham session, the device will be set to it's lowest power output setting possible, for an effective ISPPA of 0 W/cm2 in-situ at the target.