Individualizing rTMS in treatment-resistant depression from patient-specific perfusion abnormalities a proof-of-concept randomized trial in comparison to standard rTMS and tDCS.

Background: Studies examining treatment-resistant depression (TRD) as a group implicitly assume that these conditions share similar pathophysiological features, like left prefrontal hypoactivity, and should respond to standardized treatments like repetitive transcranial magnetic stimulation (S-rTMS) or transcranial direct current stimulation (tDCS). Recent advances in arterial spin labeling functional MRI (ASL-fMRI) revealed that subject-specific perfusion abnormalities may be more heterogeneous than expected. Individualized rTMS protocols (I-rTMS) could alleviate such abnormalities and establish their relevance.

Methods: iADAPT was a randomized, cross-over trial comparing I-rTMS with active comparators (S-rTMS and tDCS) on brain perfusion, assessed with ASL-fMRI, and single blind clinical evaluation. Patient-specific abnormalities were determined from three ASL-fMRI sessions. I-rTMS multi-target interventions targeted all reachable bi-frontal abnormalities, upregulating hypoperfusions and downregulating hyperperfusions. S-rTMS and tDCS were placed on F3. rTMS interventions used neuronavigation and a robotic targeting device. Each arm included 20 sessions over two weeks.

Results: Twenty-two patients with TRD were included and analyzed. While at the group level they presented subgenual cingulate hyperperfusion, they presented heterogeneous prefrontal perfusion abnormalities individually. I-rTMS was the only intervention to have specific effects on brain perfusion, showing perfusion reductions compatible with the disengagement of negative emotional systems, e.g. subgenual cingulate, anterior insula.

Conclusions: Paradoxically, I-rTMS induced more reproducible remote effects on cerebral perfusion than S-rTMS, while the I-rTMS protocol differed considerably between participants. These results suggest that the heterogeneities observed in ASL-MRI at the individual level are significant and may have the potential to inform individualized treatment.

Clinicaltrials: gov no NCT02863380, registered on 2016-08-05.