Reduced signal propagation elicited by frontal transcranial magnetic stimulation is associated with oligodendrocyte abnormalities in treatment-resistant depression

Schematic diagram showing how combined TMS-EEG and MRI data were used to assess signal propagation in this study. (A) Brain neural activities comprise 3 main categories: noncausal correlated activity in the resting state; neural activity elicited by a specific task, which is assessed with endogenous neural activity specific to the task modality, elicited in the specific neural module corresponding to the task; and causal neural activity with a clear input–output relationship using an external mechanical physical stimulus as a probe. The first 2 categories have a limitation: although they can be used to evaluate local activity as the sum of the interactions between regions in the entire brain, they cannot be used to evaluate activity in the local brain region itself. The third category (extrinsic neural stimulation targeting specific brain regions using TMS as a probe) is characterized by its ability to evaluate both neural activity at the stimulation site and neural activity originating from the stimulation site to other regions to determine causal relationships, independent of neural activity from regions other than the stimulation site. (B) Rationale for using TMS-EEG to assess signal propagation in the present study. TMS-evoked neural activities (within and between regions) that show significant signal propagation from the stimulation site to other specific brain regions or neural networks are propagated in a causal manner. (C) An overview of TMS-EEG data analysis. First, for reconstruction of the TEP signal source, we manually registered EEG channel locations on individual MRI spaces, along with anatomic landmarks. Then, we projected EEG source activations onto individual surface spaces using forward and inverse modelling of EEG sources. Finally, to compare signal propagation from the stimulation site to each brain network between the TRD and healthy control groups, we extracted dSPM current densities from the 7 networks defined by Yeo and colleagues.31 To investigate the cellular-level abnormalities that would be associated with the signal propagation abnormalities, we examined correlations between the interregional profiles of cell-specific gene expression using the Allen Human Brain Atlas data set and the interregional profiles of altered signal propagation from our TMS-EEG data. dlPFC = dorsolateral prefrontal cortex; dSPM = dynamic statistical parametric mapping; EEG = electroencephalography; HC = healthy control; ROI = region of interest; TEP = TMS-evoked potential; TMS = transcranial magnetic stimulation; TRD = treatment-resistant depression.