C. B. Pople, M. Vasileiadi, A. Zaidi, D. Silver, L. Musa, A. J. Nyman, A. Baskaran, E. Collins-Rivera, F.-H. Lin, R. F. H. Cash, A. Zalesky, A. Mollica, M. Goubran, K. Dunlop, R. Chen, J. Near, M. I. Husain, J. S. Rabin, D. M. Blumberger, B. Davidson, C. Hamani, P. Giacobbe, N. Lipsman, M. Tik, S. Nestor
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-D17. 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 ({Delta}HAM-D17 -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.