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.

引言：有研究提出，高水平的喙前扣带回皮层（rostral anterior cingulate cortex, rACC）活动可作为重度抑郁症（Major Depressive Disorder）治疗反应的非特异性预后标志物，且不受治疗方式的影响。然而，另有研究报告称，基线高水平rACC激活与治疗反应呈负相关。有趣的是，在聚焦于振荡标志物（尤其是rACCθ波功率）时，也观察到了这些矛盾的研究结果。一种可能的解释是，rACCθ波活动会随既往治疗尝试次数发生动态变化，因此其受到治疗抵抗程度的介导。

方法：本研究首先针对代表不同治疗抵抗程度、以及抑郁症患者多模式治疗抵抗水平的大型全国性横断面样本，分析了rACC与额叶θ波活动的差异，涉及的患者群体包括心理治疗组（n=175）、抗抑郁药物（antidepressant medication, AD; n=106）组、重复经颅磁刺激（repetitive transcranial magnetic stimulation, rTMS; n=196）组以及电抽搐治疗（electroconvulsive therapy, ECT; n=41）组，同时分析了缓解者与非缓解者之间的相应差异。此外，出于探索性目的，本研究还对其他频带（δ、α、β、γ波）进行了调查。

结果：与治疗抵抗程度更低的心理治疗组和抗抑郁药物组患者相比，治疗抵抗程度更高的rTMS组与ECT组患者的rACCθ波活动水平更高（p<.001），各组间效应量d值分别为：心理治疗组与rTMS组d=0.315；抗抑郁药物组与rTMS组d=0.320；心理治疗组与ECT组d=1.031；抗抑郁药物组与ECT组d=1.034；而心理治疗组与抗抑郁药物组患者之间无显著差异。在控制额叶θ波活动这一变量后，上述关联更为显著。事后分析还显示δ、β和γ波频带也存在相应效应。

结论：本研究结果表明，在解读rACCθ波生物标志物时，若将治疗抵抗程度纳入考量因素，未来实际临床实践中该标志物在治疗选择与预后评估中的应用价值有望得到大幅提升。不过，未来的研究还应进一步探究θ波频带的特异性。