Target engagement during interleaved iTBS-fMRI predicts subsequent clinical response to connectivity-guided accelerated iTBS: results of the PRISM-TRD trial

Abstract Objective Reliable prognostic biomarkers in depression remain elusive. The objective of this study was to assess whether interleaved intermittent theta-burst stimulation-fMRI (iTBS-fMRI) can measure real-time target engagement, and prospectively test whether target engagement was associated with subsequent response to accelerated, connectivity-guided iTBS in treatment-resistant depression. Methods This single-centre trial ( NCT05813093 ) included 71 patients (42 with treatment-resistant depression [TRD], 29 ultra-treatment-resistant [UTRD]) who received personalized left dorsolateral prefrontal cortex (dlPFC) targeting based on functional connectivity with the subgenual anterior cingulate cortex (sgACC). Participants underwent one sham-controlled iTBS-fMRI session followed by five days of open-label accelerated iTBS (40 sessions; 600 pulses each). The primary outcome was change in HAM-D 17 . Primary imaging analyses examined active-sham interleaved iTBS-fMRI effects in the sgACC and left dlPFC regions, and their relationship with clinical outcomes. Results Accelerated iTBS was associated with rapid, sustained symptom reductions (ΔHAM-D 17 -9.01, p<0.001); overall response and remission rates were 40.8% (TRD: 47.6%, UTRD: 31.0%) and 16.9% (TRD: 16.7%, UTRD: 17.2%), with benefit maintained at 4 and 12 weeks. During interleaved iTBS-fMRI, active stimulation elicited significant target engagement within the sgACC-associated seedmap used for targeting (p=0.029). This brain response correlated with subsequent clinical improvement in depression and anxiety, but not other symptoms, and provided additional prognostic value independent of established clinical and demographic predictors. Conclusions Connectivity-guided accelerated iTBS was associated with rapid antidepressant effects in both TRD and UTRD participants with less pronounced effects in UTRD. Online target engagement measured by interleaved iTBS-fMRI is a candidate mechanistic biomarker that may aid prognosis in the future.