Differences in High-Frequency Connectivity Among Large-Scale Functional Networks Linked to Major Depressive Disorder and Treatment-Resistant Depression

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Major depressive disorder (MDD) and treatment-resistant depression (TRD) have each been characterized by altered neural connectivity largely associated with the triple model of the default mode (DMN), frontoparietal (FPN), and salience (SN) networks. However, the direction (i.e., hyper- vs. hypoconnectivity) and the specificity (i.e., depression broadly vs. TRD) of these alterations remains unclear. Thus, in the current study, we compared high-frequency between- and within-network resting-state functional connectivity (rsFC) in healthy control (HC) individuals, individuals with MDD, and individuals with TRD. Ninety-six channel resting-state electroencephalogram data were collected from 34 participants with MDD (22 women, mean ± SD age: 29.92 ± 9.57 years), 24 participants with TRD (16 women, age: 44.35 ± 15.86 years), and 34 HC participants (25 women, age: 32.49 ± 14.07 years). Based on previous findings, exact low-resolution electromagnetic tomography was used to estimate theta and beta rsFC within and between the DMN, FPN, and SN. Participants with depression (i.e., pooled MDD and TRD participants) had enhanced within-DMN beta1 (12.5–18 Hz) connectivity compared with controls. Compared with MDD participants, participants with TRD showed increased within-DMN, DMN to FPN, and FPN to SN beta3 (21.5–30 Hz) connectivity. These effects persisted when controlling for current depressive symptoms. Differences in high-frequency rsFC, particularly in the beta bands, among the DMN, FPN, and SN may partially account for neural mechanisms of treatment resistance. However, future work probing the heterogeneity (e.g., medication status, age of onset, lifetime episode count) and time course (e.g., length and frequency of episodes) of depression is needed to increase our understanding of these changes in neural connectivity. Major depressive disorder (MDD) and treatment-resistant depression (TRD) have been shown to be characterized by alterations in default mode (DMN), frontoparietal (FPN), and salience network (SN) connectivity. However, the direction and specificity of these changes remain unclear. We combined electroencephalography with exact low-resolution electromagnetic tomography to evaluate depression-related alteration of connectivity within and between these networks and found that: 1) individuals with depression showed enhanced within-DMN connectivity compared to controls and 2) TRD was associated with increased within-DMN, DMN to FPN, and FPN to SN connectivity compared to MDD, even when accounting for current depressive symptoms. These differences may partially account for neural mechanisms of depression and treatment resistance.