MRI-guided continuous theta burst stimulation to reduce craving induced by virtual reality cue exposure in alcohol use disorder

Alcohol Use Disorder (AUD) is common, with craving as a core symptom and a primary predictor of relapse [1]. Craving, defined as an intense desire or urge to use alcohol, can be triggered by alcohol-related cues, emotional states, and social contexts [1]. For craving induction and assessment, Virtual Reality cue exposure (VRCE) has emerged as a powerful tool, bridging the gap between highly controlled laboratory settings and ecologically valid, immersive environments [2]. Given the limited efficacy of current treatment options, there is a critical need for innovative and personalized interventions targeting craving in AUD. Continuous Theta Burst Stimulation (cTBS), a form of transcranial magnetic stimulation (TMS), has shown promising potential to modulate brain activity within key networks associated with addictive behaviour. While most studies have targeted the dorsolateral prefrontal cortex (dlPFC) [3], the frontopolar cortex (Fp1) represents a less explored but mechanistically promising target, as this region has been identified as a key part of a brain network involved in craving and addiction-related behaviour. Study designs of both the cTBS-VR and VR-only study arms are presented, followed by a comparison of treatment effects between cTBS-VR and VR-only.

This comparative study aims A) to validate that VRCE effectively induces craving, and B) to compare the difference in VRCE-induced change of craving between cTBS-VR and VR-only.

Both study arms compare changes in VRCE-induced alcohol craving at two time points approximately one week apart. Directly before and after VRCE, craving is assessed via different Visual Analogue Scales (VAS). In the first arm (n=17), we aim to include 34 patients with an ICD-10 diagnosis of AUD (aged 18–65) to investigate the effects of cTBS over the left frontopolar cortex, consisting of 15 sessions over five consecutive days. Structural MRI scans are acquired prior to TMS to localize the treatment site (Fp1) based on each patient’s individual anatomy. The second study arm (AUD n= 51; control n=16) applies the same VRCE protocol without neuromodulation, aiming to include 132 patients with AUD and 35 control subjects without AUD. Patients with AUD are assessed at two time points, whereas control subjects undergo a single VRCE. This design allows to compare craving responses between VR-only groups at baseline as well as longitudinal changes in patients with AUD. Treatment for all study participants consists of standard inpatient care, including group therapy. Patients with current psychotic or manic symptoms are excluded in both arms.

We hypothesize that VRCE elicits higher craving responses in patients with AUD compared to controls. Furthermore, we expect a reduction in craving during the second VRCE session relative to the first in all AUD patients, with a more pronounced craving reduction in cTBS-VR compared to VR-only. Preliminary data on these outcomes will be presented.

The findings may contribute to the development of personalized, neurobiologically informed interventions for AUD and build the basis for future randomized controlled trials.

References

1. Vafaie, N., Kober, H., 2022. Association of drug cues and craving with drug use and relapse: A systematic review and meta-analysis. JAMA Psychiatry 79 (7), 641–650. https://doi.org/10.1001/jamapsychiatry.2022.1240.
2. Wiebe, A., Kannen, K., Selaskowski, B., Mehren, A., Thöne, A.-K., Pramme, L., et al., 2022. Virtual reality in the diagnostic and therapy for mental disorders: A systematic review. Clin. Psychol. Rev. 98, 102213. https://doi.org/10.1016/j.cpr.2022.102213.
3. Mehta, D.D., Praecht, A., Ward, H.B., et al., 2024. A systematic review and meta-analysis of neuromodulation therapies for substance use disorders. Neuropsychopharmacology 49 (4), 649–680. https://doi.org/10.1038/s41386-023-01776-0.