A novel concurrent TMS‐fMRI method to reveal propagation patterns of prefrontal magnetic brain stimulation

Abstract

Major depressive disorder (MDD) is a severe mental disorder associated with high morbidity and mortality rates, which remains difficult to treat, as both resistance and recurrence rates are high. Repetitive transcranial magnetic stimulation (TMS) of the left dorsolateral prefrontal cortex (DLPFC) provides a safe and effective treatment for selected patients with treatment‐resistant MDD. Little is known about the mechanisms of action of TMS provided to the left DLPFC in MDD and we can currently not predict who will respond to this type of treatment, precluding effective patient selection. In order to shed some light on the mechanism of action, we applied single pulse TMS to the left DLPFC in 10 healthy participants using a unique TMS‐fMRI set‐up, in which we could record the direct effects of TMS. Stimulation of the DLPFC triggered activity in a number of connected brain regions, including the subgenual anterior cingulate cortex (sgACC) in four out of nine participants. The sgACC is of particular interest, because normalization of activity in this region has been associated with relief of depressive symptoms in MDD patients. This is the first direct evidence that TMS pulses delivered to the DLPFC can propagate to the sgACC. The propagation of TMS‐induced activity from the DLPFC to sgACC may be an accurate biomarker for rTMS efficacy. Further research is required to determine whether this method can contribute to the selection of patients with treatment resistant MDD who will respond to rTMS treatment.

Stanford Accelerated Intelligent Neuromodulation Therapy for Treatment-Resistant Depression (SAINT-TRD)

“…A recent interleaved TMS-fMRI study showed that stimulating the subregion of the L-DLPFC that displays the greatest degree of functional connectivity with the sgACC resulted in stimulation propagation to the sgACC in all participants 47 . In comparison, in a separate study when the L-DLPFC was defined anatomically (border of BA9/BA46), stimulation propagated to the sgACC in only 44% of participants 48 . In the aiTBS study by the Baeken group 27 and a blinded iTBS trial 49 the same anatomical target (border of BA9/BA46) was utilized, which may have contributed to the limited efficacy of these approaches.…”

TMS alters multivoxel patterns in the absence of overall activity changes

“…Our results add important new evidence regarding the local effects of TMS under the coil outside the motor and visual cortices in the absence of a task. Previous research on this topic found inconsistent results with some studies reporting an increase of activity under the coil (Nahas et al, 2001; Li et al, 2004a; Bestmann et al, 2005; Vink et al, 2018a), while many others reported no such increase (Baudewig et al, 2001; Kemna and Gembris, 2003; Li et al, 2004b; Sack et al, 2007; De Weijer et al, 2014; Hawco et al, 2017; Dowdle et al, 2018). Critically, none of the studies that reported increased activity “under the coil” in the absence of a task actually had a precise estimate of exactly where the coil was positioned or defined the area under the coil as a region of interest.…”

“…The data from the resting state scan were not analyzed for the purposes of the current paper. The finger tapping run was intended as a control task that can be used to evaluate the power of our setup to detect brain activations, as done in previous concurrent TMS-fMRI studies (Bestmann et al, 2003, 2005; Navarro de Lara et al, 2017a; Vink et al, 2018b). During that run subjects were asked to tap with their right index finger once every second for 10 seconds, followed by a 10-second break with no finger movement.…”

“…Several studies have targeted areas in the association cortex but were typically not designed specifically to investigate whether TMS produces activations under the coil. Consequently, the results of these studies were inconsistent: some studies reported that in the absence of an explicit task, TMS produces positive BOLD activations in the regions immediately under the coil (Nahas et al, 2001; Li et al, 2004a; Bestmann et al, 2005; Vink et al, 2018b) but many other studies failed to find such activations (Baudewig et al, 2001; Kemna and Gembris, 2003; Li et al, 2004b; Sack et al, 2007; De Weijer et al, 2014; Hawco et al, 2017; Dowdle et al, 2018). These inconsistent results are likely due to the limitations present in many of these studies.…”

“…The feasibility of combining TMS with fMRI was first shown more than 20 years ago (Bohning et al, 1997) and the technique of concurrent TMS-fMRI has further gained in popularity since then (Bestmann and Feredoes, 2013; Heinen et al, 2014a; Leitão et al, 2015; Hawco et al, 2018; Vink et al, 2018a). Most of the initial studies using concurrent TMS-fMRI examined the effects of TMS delivered to the primary motor cortex (M1).…”