Neural effects of TMS trains on the human prefrontal cortex

Abstract

How does a train of TMS pulses modify neural activity in humans? Despite adoption of repetitive TMS (rTMS) for the treatment of neuropsychiatric disorders, we still do not understand how rTMS changes the human brain. This limited understanding stems in part from a lack of methods for noninvasively measuring the neural effects of a single TMS train—a fundamental building block of treatment—as well as the cumulative effects of consecutive TMS trains. Gaining this understanding would provide foundational knowledge to guide the next generation of treatments. Here, to overcome this limitation, we developed methods to noninvasively measure causal and acute changes in cortical excitability and evaluated this neural response to single and sequential TMS trains. In 16 healthy adults, standard 10 Hz trains were applied to the dorsolateral prefrontal cortex in a randomized, sham-controlled, event-related design and changes were assessed based on the TMS-evoked potential (TEP), a measure of cortical excitability. We hypothesized that single TMS trains would induce changes in the local TEP amplitude and that those changes would accumulate across sequential trains, but primary analyses did not indicate evidence in support of either of these hypotheses. Exploratory analyses demonstrated non-local neural changes in sensor and source space and local neural changes in phase and source space. Together these results suggest that single and sequential TMS trains may not be sufficient to modulate local cortical excitability indexed by typical TEP amplitude metrics but may cause neural changes that can be detected outside the stimulation area or using phase or source space metrics. This work should be contextualized as methods development for the monitoring of transient noninvasive neural changes during rTMS and contributes to a growing understanding of the neural effects of rTMS.

Real-time optimization to enhance noninvasive cortical excitability assessment in the human dorsolateral prefrontal cortex

“…This real-time optimization approach introduced here could have broad applications in understanding physiology and pathophysiology in neurological and psychiatric disorders. The early local response to single pulses of TMS (here and in our former work (Gogulski et al, 2023b(Gogulski et al, , 2023bRoss et al, 2023) referred to as EL-TEPs) are thought to at least in part index cortical excitability (Belardinelli et al, 2021).…”

“…This real-time optimization approach introduced here could have broad applications in understanding physiology and pathophysiology in neurological and psychiatric disorders. The early local response to single pulses of TMS (here and in our former work (Gogulski et al, 2023b, 2023b; Ross et al, 2023) referred to as EL-TEPs) are thought to at least in part index cortical excitability (Belardinelli et al, 2021). Since the dlPFC is a commonly used therapeutic target for TMS treatment and a core region putatively involved in psychiatric disorders such as depression (Ferrarelli and Phillips, 2021; Lefaucheur et al, 2020), our focus has been to evaluate local cortical changes via EL-TEPs in and around the dlPFC.…”

“…The TEP is derived from EEG after averaging the response to multiple single TMS pulses (Ahn and Fröhlich, 2021). The early local TEP, or EL-TEP, is a short-latency (20-60 ms) multi-phasic response recorded over the stimulation target (i.e., directly underneath the TMS coil) that occurs prior to large amplitude sensory EEG (Ahn and Fröhlich, 2021;Gogulski et al, 2023bGogulski et al, , 2023cParmigiani et al, 2023;Ross et al, 2023). Also known as the 'P20' and 'N40' complex, EL-TEPs may reflect a combination of GABAergic inhibition and NMDA receptor-mediated glutamatergic excitation (Ahn and Fröhlich, 2021;Belardinelli et al, 2021;Hill et al, 2016), and their size has been shown to correlate with depression severity (Voineskos et al, 2019) and predict the clinical response to TMS treatment of depression (Eshel et al, 2020).…”