Neuroimaging Mechanisms of Therapeutic Transcranial Magnetic Stimulation for Major Depressive Disorder

Abstract

Research into therapeutic transcranial magnetic stimulation (TMS) for major depression has dramatically increased in the last decade. Understanding the mechanism of action of TMS is crucial to improve efficacy and develop the next generation of therapeutic stimulation. Early imaging research provided initial data supportive of widely held assumptions about hypothesized inhibitory or excitatory consequences of stimulation. Early work also indicated that while TMS modulated brain activity under the stimulation site, effects at deeper regions, in particular, the subgenual anterior cingulate cortex, were associated with clinical improvement. Concordant with earlier findings, functional connectivity studies also demonstrated that clinical improvements were related to changes distal, rather than proximal, to the site of stimulation. Moreover, recent work suggests that TMS modulates and potentially normalizes functional relationships between neural networks. An important observation that emerged from this review is that similar patterns of connectivity changes are observed across studies regardless of TMS parameters. Though promising, we stress that these imaging findings must be evaluated cautiously given the widespread reliance on modest sample sizes and little implementation of statistical validation. Additional limitations included use of imaging before and after a course of TMS, which provided little insight into changes that might occur during the weeks of stimulation. Furthermore, as studies to date have focused on depression, it is unclear whether our observations were related to mechanisms of action of TMS for depression or represented broader patterns of functional brain changes associated with clinical improvement.

Keywords: Default mode network; Functional magnetic resonance imaging; Major depressive disorder; Mechanisms of action; Repetitive transcranial magnetic stimulation; Resting-state functional connectivity; Theta burst stimulation.

Figure 1. Clinical Variables in TMS Neuroimaging Research

Several important variables in TMS neuroimaging research include site of stimulation, stimulation frequency and treatment schedule. Each of these may impact imaging findings, the use of differing approaches complicates interpretation of the current literature. Abbreviations: DMPFC, dorsomedial prefrontal cortex; DLFPC, dorsolateral prefrontal cortex; TMS, transcranial magnetic stimulation; TBS, theta burst stimulation

Figure 2. Current and Future Approaches to TMS Neuroimaging

The most common approach in TMS neuroimaging research is to scan participants prior to and following TMS procedures. While this approach captures change over time, it does not provide information on what happens during the stimulation itself. Future designs may include a) serial neuroimaging, where multiple scans or other imaging modalities are performed at multiple timepoints during a course of TMS, b) causal assessments of neural network function using interleaved MRI/TMS, and c) testing the durability of neuroimaging findings across the course of depressive illness (e.g., over time or in the context of clinical relapse, etc.). Abbreviations: TMS, transcranial magnetic stimulation; EEG, electroencephalography; MRI, magnetic resonance imaging