Baseline markers of cortical excitation and inhibition predict response to theta burst stimulation treatment for youth depression

Abstract

Theta burst stimulation (TBS), a specific form of repetitive transcranial magnetic stimulation (TMS), is a promising treatment for youth with Major Depressive Disorder (MDD) who do not respond to conventional therapies. However, given the variable response to TBS, a greater understanding of how baseline features relate to clinical response is needed to identify which patients are most likely to benefit from this treatment. In the current study, we sought to determine if baseline neurophysiology, specifically cortical excitation and/or inhibition, is associated with antidepressant response to TBS. In two independent open-label clinical trials, youth (aged 16-24 years old) with MDD underwent bilateral dorsolateral prefrontal cortex (DLPFC) TBS treatment. Clinical trial one and two consisted of 10 and 20 daily sessions of bilateral DLPFC TBS, respectively. At baseline, single-pulse TMS combined with electroencephalography was used to assess the neurophysiology of 4 cortical sites: bilateral DLPFC and inferior parietal lobule. Measures of cortical excitation and inhibition were indexed by TMS-evoked potentials (i.e., P30, N45, P60, N100, and P200). Depression severity was measured before, during and after treatment completion using the Hamilton Rating Scale for Depression-17. In both clinical trials, the baseline left DLPFC N45 and P60, which are believed to reflect inhibitory and excitatory mechanisms respectively, were predictors of clinical response. Specifically, greater (i.e., more negative) N45 and smaller P60 baseline values were associated with greater treatment response to TBS. Accordingly, cortical excitation and inhibition circuitry of the left DLPFC may have value as a TBS treatment response biomarker for youth with MDD.Clinical trial 1 registration number: NCT02472470 (June 15, 2015).Clinical trial 2 registration number: NCT03708172 (October 17, 2018).

Figure 1

TEPs from Stimulation of the Left DLPFC and Their Association with Treatment Response to TBS in Clinical Trial One. Each row illustrates the relationship between the left DLPFC N45 (top row) and P60 (bottom row) and treatment response to TBS. The left topoplot shows the mean amplitude values. The right topoplot shows the p-value of the interaction term of interest (i.e., TEP × time) as obtained from the linear mixed effects model. Electrodes illustrated with a white asterisk are those that were significant at a FDR-corrected p-value of less than 0.05. Boxplots illustrate the distribution of the amplitude values across all participants for an exemplar electrode. Line plots depict the significant interaction from the exemplar electrode by splitting participants into groups of three based on their TEP amplitude and illustrating their predicted treatment response over time. Error bars represent one standard error of the mean.

Figure 2

TEPs from Stimulation of the Left DLPFC and Their Association with Treatment Response to TBS in Clinical Trial Two. Each row illustrates the relationship between the left DLPFC N45 (top row) and P60 (bottom row) and treatment response to TBS. The left topoplot shows the mean amplitude values. The right topoplot shows the p-value of the interaction term of interest (i.e., TEP × time) as obtained from the linear mixed effects model. Electrodes illustrated with a white asterisk are those that were significant at a FDR-corrected p-value of less than 0.05. Boxplots illustrate the distribution of the amplitude values across all participants for an exemplar electrode. Line plots depict the significant interaction from the exemplar electrode by splitting participants into groups of three based on their TEP amplitude and illustrating their predicted treatment response over time. Error bars represent one standard error of the mean.