A transdiagnostic review of safety, efficacy, and parameter space in accelerated transcranial magnetic stimulation

Abstract

Background: Accelerated transcranial magnetic stimulation (aTMS) is an emerging delivery schedule of repetitive TMS (rTMS). TMS is "accelerated" by applying two or more stimulation sessions within a day. This three-part review comprehensively reports the safety/tolerability, efficacy, and stimulation parameters affecting response across disorders.

Methods: We used the PubMed database to identify studies administering aTMS, which we defined as applying at least two rTMS sessions within one day.

Results: Our targeted literature search identified 85 aTMS studies across 18 diagnostic and healthy control groups published from July 2001 to June 2022. Excluding overlapping populations, 63 studies delivered 43,873 aTMS sessions using low frequency, high frequency, and theta burst stimulation in 1543 participants. Regarding safety, aTMS studies had similar seizure and side effect incidence rates to those reported for once daily rTMS. One seizure was reported from aTMS (0.0023% of aTMS sessions, compared with 0.0075% in once daily rTMS). The most common side effects were acute headache (28.4%), fatigue (8.6%), and scalp discomfort (8.3%), with all others under 5%. We evaluated aTMS efficacy in 23 depression studies (the condition with the most studies), finding an average response rate of 42.4% and remission rate of 28.4% (range = 0-90.5% for both). Regarding parameters, aTMS studies ranged from 2 to 10 sessions per day over 2-30 treatment days, 10-640 min between sessions, and a total of 9-104 total accelerated TMS sessions per participant (including tapering sessions). Qualitatively, response rate tends to be higher with an increasing number of sessions per day, total sessions, and total pulses.

Discussion: The literature to date suggests that aTMS is safe and well-tolerated across conditions. Taken together, these early studies suggest potential effectiveness even in highly treatment refractory conditions with the added potential to reduce patient burden while also expediting response time. Future studies are warranted to systematically investigate how key aTMS parameters affect treatment outcome and durability.

Keywords: Accelerated TMS (aTMS); High dose rTMS; Intensive rTMS; Theta burst stimulation; Transcranial magnetic stimulation; Transdiagnostic review.

Fig. 1.

Conventional, Once daily rTMS vs. Accelerated rTMS. This figure illustrates the difference between conventional, once daily rTMS and accelerated rTMS. Whereas standard practice applies one session per day, accelerated rTMS applies two or more sessions per day.

Fig. 2.

Per-Session Rate of Seizure. The per session seizure rate from accelerated rTMS was 0.0023%, or 1 in 43,873. This rate was lower than that of once daily rTMS overall (0.0075%), and similar to that of once daily rTMS when following the Rossi et al. (2009) safety guidelines (0.0017%).

Fig. 3.

Side Effects by Accelerated rTMS Frequency. Accelerated rTMS had a lower incidence of (a) headache (28.4%), and similar rates of (b) fatigue (8.6%) and (c) scalp pain (8.3%) as prior once daily rTMS trials. Results are presented by stimulation frequency, where similar rates of side effects were experienced by participants receiving each type of stimulation.

Fig. 4.

Response and Remission Rates of Accelerated rTMS for Depression. In a subset of 23 studies using accelerated rTMS for the overall response rate was 42.4% and remission rate was 28.4% (both ranges = 0–90.5%). Response and remission rates were similar to those previously observed in the THREE-D once daily rTMS trials.

Fig. 5.

Accelerated rTMS Parameters Plotted Against Response Rate. Here we plotted the two variables unique to accelerated rTMS, the number of sessions per day (a) and intersession interval (b) against response rate in 23 accelerated rTMS studies in depression. While acknowledging that these variables are inherently interrelated and do not account for the influence of others, these variables might impact therapeutic outcome and should be further investigated. Note that two studies reported response rates for different sub-conditions of accelerated rTMS and were separated for 25 total datapoints.

Fig. 6.

Total Accelerated rTMS Treatment Quantity Plotted Against Response Rate. By increasing the number of sessions per day in accelerated rTMS, more total sessions and pulses can be delivered. Here we visualize the influence of the total number of sessions (a) and total number of pulses (b) on treatment outcome. Note that two studies reported response rates for different sub-conditions of accelerated rTMS and were separated for 25 total datapoints.

Fig. 7.

General rTMS Treatment Parameters Plotted Against Response Rate. While stimulation intensity (a) and targeting method (b) are not specific to accelerated rTMS, it is important to consider the contribution of these parameters to treatment response. For both the stimulation intensity and targeting method, the response rate widely varies within each bin, suggesting that these variables are not what most drives therapeutic response within the ranges that utilized in these prior studies. Note that the three studies stimulating at 90% rMT (Williams et al., 2018; Cole et al. 2020, 2021) were individually depth corrected based on scalp-to-cortex distances read from each patient’s anatomical MRI scan; thus, the actual stimulation intensity at the scalp level was likely closer to approximately 120% rMT. Furthermore, the same three studies also utilized functional MRI targeting and simultaneously delivered the highest number of sessions per day, total sessions, and total pulses. Given that stimulation intensity and targeting method parameters were not systematically isolated and other variables simultaneously changed between studies, it remains unclear how they contribute to treatment response. Further investigation of these and other parameters is necessary to fully understand how to optimize aTMS.

Fig. 8.

Conceptual Framework for Systematically Testing Accelerated rTMS Parameters. (a) Number of Sessions Per Day. By interleaving different numbers of active vs. sham stimulation sessions, researchers could isolate the effects of the number of sessions per day on treatment response. Here we demonstrate three possible conditions with varying proportions of 5 active and/or sham stimulation sessions per day. (b) Intersession Interval. To isolate the effects of intersession interval on behavioral response, researchers could keep the number of active sessions the same between two accelerated rTMS conditions while varying the time between sessions. In this example, we show how researchers might compare an intersession interval of 30 vs. 60 min in 5 active accelerated rTMS sessions on the same day. (c) Total Number of Sessions. A largely untested question is whether it is the timing of accelerated rTMS (i.e., the number of sessions per day), the total number of sessions, or an interaction between the two variables that might be most clinically impactful. There is a need for research that systematically matches the total number of sessions while varying the timeframe of delivery. Here we show an example comparison between 20 total sessions delivered over 4 days (i.e., accelerated rTMS at 5 sessions/day) vs. 20 total sessions delivered over 20 days (i.e., once daily rTMS). Using this study design, researchers can measure the effects of rTMS by protocol at pre- and post-treatment timepoints while matching the same number of total sessions.