Brain-Informed Tailored Interventions for Alcohol Use Disorder

Background: Interventions comprise different non-invasive brain stimulation approaches. The specific intervention each participant receives will be determined by brain imaging analyses. Participants will undergo a functional magnetic resonance imaging (MRI) scan prior to intervention allocation, in which brain network function will be assessed using resting-state fMRI. The fMRI time series will be analyzed using spectral dynamic causal modeling (spDCM) to estimate individual-level features of effective connectivity in a predefined network of interest comprising Dorsolateral Prefrontal Cortex (DLPFC), Ventromedial Prefrontal Cortex (VMPFC), Insula, and Striatum. The resulting parameters will be incorporated into a generative embedding framework to classify participants with AUD into biotypes based on the following subnetworks: 1. ‘Ventromedial stream’: Altered connectivity in the VMPFC subnetwork. 2. ‘Dorsolateral stream’: Altered connectivity in the DLPFC subnetwork. A machine learning derived classification method will then determine the participant's subtype and appropriate biotype-matched intervention. Participants will be biotyped as ‘Ventromedial stream’ or ‘Dorsolateral stream’, and allocated to personalized VMPFC (Arm 1) or DLPFC (Arm 2) brain stimulation interventions, respectively. Duration: Participants will complete 5 consecutive stimulation days. Four intervention doses are provided on each day, with a 50-minute break between each administration. Therefore an intervention day will be 3-4 hours long. Baseline and outcome data will be collected during neurocognitive sessions conducted at three timepoints: baseline, immediately post-intervention, and Day 90. These sessions will run for approximately 6-8 hours, including a lunch break, with total duration dependent on task completion speed and participant preference for additional breaks. The primary alcohol consumption outcome will be assessed separately at Day 30 in a dedicated 1-hour session. The duration for each iTBS dose is approximately 7 minutes, the duration for each cTBS dose is approximately 3 minutes, and the duration for the sham dose is 5 minutes. Mode of delivery: Face-to-face administration, provided individually to each participant. Materials: The interventions will be delivered using Deep Transcranial Magnetic Stimulation (dTMS). As a result, the administration structure in both arms is identical, except for differences in stimulation parameters and resting motor threshold protocol. Arm 1: To modify altered connectivity in the 'Ventromedial stream', continuous theta-burst stimulation (cTBS) over the VMPFC will be applied. cTBS will be administered using the H7 Brainsway coil targeting the vmPFC positioned 4 cm anterior to the motor hotspot using standardized localization procedures (Isserles et al., 2021). Arm 2: To modify altered connectivity in the 'Dorsolateral stream', intermittent theta-burst stimulation (iTBS) over the dlPFC will be applied. iTBS will be administered using the H1 Brainsway coil targeting the dlPFC, positioned 6 cm anterior to the motor hotspot, using standardized localization procedures (Feifel et al., 2016; Pell et al., 2022). Intervention administrators: The administration of these interventions will be conducted exclusively by a dTMS clinician. Here, a dTMS clinician is defined as an individual holding a PhD or possessing equivalent expertise in neuromodulation, demonstrated by a minimum of three years 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 ten years of experience in the field. Intervention dosage: In both arms, before the administration of dTMS, resting motor threshold (RMT) for each participant will be determined. The RMT is the minimum stimulation intensity required to elicit visible motor responses from 3 out of 6 pulses. The site of motor response (foot in Arm 1, hand in Arm 2) is determined by the coil used in each arm per standard Brainsway protocol. The dose of dTMS will be set based on a percentage of each individual's RMT, following standardised procedures. RMT is followed by a short adaptation procedure, to ensure participants are comfortable with the stimulation intensity. The adaptation procedure will involve exposing the participant to a short train (~2 s for iTBS, 4 s for cTBS) of the dTMS protocol at a reduced intensity to acclimate the participant. Arm 1: dTMS will be administered at 80% of foot RMT. The cTBS protocol will consist of two trains of a standard cTBS sequence (per Huang et al., 2005), with a 30-second intertrain interval. Each train will consist of 600 pulses, comprising three-pulse bursts at 50Hz repeated every 200ms (5Hz) for 40 seconds. Arm 2: dTMS will be administered at 100% of hand RMT. The iTBS protocol will consist of three-pulse bursts at 50Hz repeated every 200ms (5Hz) for 2 seconds, with an 8-second intertrain interval, for 40 trains (1200 pulses). Intervention adherence/fidelity and tolerance: Adherence to the interventions will be measured by tracking participants’ attendance across the 20 stimulation doses. We will use standard pre and post stimulation interviews to monitor tolerability, track session attendance, and assess barriers to adherence, such as participant discomfort, through feedback gathered during and after the sessions. Adherance will be monitored via a REDCap tool that is completed for each dose to track dose completion and intensity. Participants must complete a minimum of 4 days of the intervention (this involves 16 sessions), with no more than 3 consecutive days between any two sessions. Participants must receive at least 16 total stimulation doses across all sessions. Treatment intensity must meet the following thresholds: - In Session 1, the average intensity across all doses must be within 30% of the target intensity. - In all subsequent Sessions, the average intensity across doses must be within 10% of the target intensity. - All sessions must be completed within a maximum treatment window of 9 calendar days. - These treatment intensity thresholds were informed by a pilot study, where iTBS (with a target intensity of 100%) was delivered at an average of 95%, and cTBS (with a target intensity of 80%) was delivered at an average of 70%. Therefore, the target of within 10% across sessions should be feasible for both intervention arms, especially considering the capacity to titrate intensity up across doses.