A Guide for Concurrent TMS-fMRI to Investigate Functional Brain Networks

SOURCE: Frontiers in Human Neuroscience. 16 (no pagination), 2022. Article Number: 1050605.


AUTHORS: Riddle J.; Scimeca J.M.; Pagnotta M.F.; Inglis B.; Sheltraw D.; Muse-Fisher C.; D’Esposito M.

ABSTRACT: Transcranial Magnetic Stimulation (TMS) allows for the direct activation of neurons in the human neocortex and has proven to be fundamental for causal hypothesis testing in cognitive neuroscience. By administering TMS concurrently with functional Magnetic Resonance Imaging (fMRI), the effect of cortical TMS on activity in distant cortical and subcortical structures can be quantified by varying the levels of TMS output intensity. However, TMS generates significant fluctuations in the fMRI time series, and their complex interaction warrants caution before interpreting findings. We present the methodological challenges of concurrent TMS-fMRI and a guide to minimize induced artifacts in experimental design and post-processing. Our study targeted two frontal-striatal circuits: primary motor cortex (M1) projections to the putamen and lateral prefrontal cortex (PFC) projections to the caudate in healthy human participants. We found that TMS parametrically increased the BOLD signal in the targeted region and subcortical projections as a function of stimulation intensity. Together, this work provides practical steps to overcome common challenges with concurrent TMS-fMRI and demonstrates how TMS-fMRI can be used to investigate functional brain networks.

MATERIALS AND METHODS: Concurrent TMS-MRI data were collected at the Henry H. Wheeler Jr. Brain Imaging Center at the University of California, Berkeley, using a Siemens 3T MAGNETOM Trio (Erlangen, Germany). TMS was delivered with the MR-compatible figure-8 Mri-B91 TMS coil produced by MagVenture (Farum, Denmark) with the MagPro X100 with MagOption running software version 7.1.1. 3D stereotaxic tracking, referred to as neuronavigation, was performed using Rogue Research?? BrainSight v2.2.11 (Montreal, Canada) with a Northern Digital Polaris Spectra infrared long-range camera (Waterloo, Ontario, Canada) and custom-made MR-compatible components. Here, we describe our experimental procedure in detail with consideration of alternatives (see Section ??.1 Equipment and procedures??, describe signal artifact sources inherent to concurrent TMS-fMRI (see Section ??.2 Signal artifacts in concurrent TMS-fMRI??, explain our artifact removal approach in post-processing (see Section ??.3 Preprocessing and artifact removal during analysis??, and present an experiment that illustrates these considerations (see Section ??.4 Experimental design??.

RESULTS: This section summarizes the findings from developing a novel procedure for concurrent TMS-fMRI. While collecting pilot data, we observed that the coil output of TMS was systematically greater within the MRI (see Section ??.1 TMS intensity at the isocenter of the MRI??. By timing the delivery of TMS with microsecond precision, the induced artifact from TMS at each epoch of slice acquisition can be estimated, and the optimal time of TMS can be determined (see Section ??.2 Temporally targeting the crusher gradients??. Our preprocessing approach removed signal artifacts reflecting slice distortion temporally locked to TMS delivery and reflecting artifacts from within the TMS coil itself. Our statistical analysis demonstrated that these artifacts could be removed (see Section ??.3 Independent component analysis removes TMS coil artifacts??. Finally, we present our findings from an experiment illustrating that our approach delivering TMS during continuous fMRI revealed local and distal effects of TMS on neural activity (see Section ??.4 Activation of frontostriatal loops from TMS was hierarchical??.

DISCUSSION: The methodological framework established in this paper builds on previous efforts by providing the additional groundwork for implementing concurrent TMS-fMRI experiments and replicating this environment across labs. Our results demonstrate that, given the proper considerations, carefully-tailored TMS during continuous fMRI and thorough preprocessing can produce artifact-free data that reliably demonstrates activation in the targeted region and regions connected to it. Most TMS-induced artifacts are reduced through judicious timing of TMS during scanning and thorough attention to removing known artifacts in the preprocessing of the fMRI data. When TMS is delivered concurrently with continuous fMRI, we recommend that TMS is delivered during the crusher gradient prior to RF excitation. In our approach, contaminated slices were interpolated with the prior and subsequent slices in time. We used ICA to remove residual TMS coil discharge artifacts in the volumes acquired during TMS and residual signal dropout around the TMS coil. Artifacts around the location of the TMS coil could be reliably identified using a multiple regression model of instantaneous signal change. We caution researchers that when TMS is delivered concurrent with a standard EPI timing scheme, TMS artifacts in brain regions under the coil can persist for up to 8 s after TMS. We posit that these artifacts are due to leakage current as the capacitor recharges. A FIR model can be used to verify whether any discovered activation follows the canonical HRF or whether it tracks with an expected signal dropout radiating from the location of the TMS coil at the time of discharge. Our results also provide causal evidence that TMS delivered to PFC activates both the region under the coil and anatomically connected regions in the dorsal striatum in line with previous subcortical-targeted TMS-fMRI studies (Hermiller et al., 2020; Sydnor et al., 2022). Furthermore, we found causal evidence supporting the rostrocaudal hierarchy in PFC, characterized by asymmetrical projections toward more posterior sites (Verstynen et al., 2012). TMS to PFC spread to caudal regions in the cortex (M1) and striatum (putamen), whereas TMS to M1 did not spread to rostral regions in the cortex (PFC) or striatum (caudate).

FULL ARTICLE LINK: https://www.frontiersin.org/articles/10.3389/fnhum.2022.1050605/full