Supplementary Material for: Rostral anterior cingulate cortex oscillatory power indexes treatment-resistance to multiple therapies in major depressive disorder

Introduction: High rostral anterior cingulate cortex (rACC) activity is proposed as a non-specific prognostic marker for treatment response in Major Depressive Disorder, independent of treatment modality. However, other studies report a negative association between baseline high rACC activation and treatment response. Interestingly, these contradictory findings were also found when focusing on oscillatory markers, specifically rACC-theta power. An explanation could be that rACC-theta activity dynamically changes according to number of previous treatment attempts and thus is mediated by level of treatment-resistance. Methods: Primarily, we analyzed differences in rACC- and frontal-theta activity in large national cross-sectional samples representing various levels of treatment-resistance and resistance to multimodal treatments in depressed patients (psychotherapy (n=175), antidepressant medication (AD; n=106), repetitive transcranial magnetic stimulation (rTMS; n=196), and electroconvulsive therapy (ECT; n=41)), and the respective difference between remitters and non-remitters. For exploratory purposes, we also investigated other frequency bands (delta, alpha, beta, gamma). Results: rACC-theta activity was higher (p<.001) in the more resistant rTMS and ECT patients relative to the less resistant psychotherapy and AD patients (psychotherapy-rTMS: d=.315; AD-rTMS: d=.320; psychotherapy-ECT: d=1.031; AD-ECT: d=1.034), with no difference between psychotherapy and AD patients. This association was even more pronounced after controlling for frontal-theta. Post hoc analyses also yielded effects for delta, beta, and gamma bands. Conclusion: Our findings suggests that by factoring in degree of treatment-resistance during interpretation of the rACC-theta biomarker, its usefulness in treatment selection and prognosis could potentially be improved substantially in future real-world practice. Future research should however also investigate specificity of the theta band.