TMS Targeting Method and Autonomic Regulation: A Matched Comparison of BEAM and MRI-Guided Approaches
DOI: Pending DOI
Synopsis
TMS targeting precision varies across studies. BEAM-based approaches (Beam, 2009) identify stimulation sites behaviorally, while MRI-guided methods use individualized neuroimaging and e-field modeling. Whether targeting method influences autonomic regulation outcomes is unknown. We compared two complementary indices of autonomic regulation, heart rate variability (HRV) during active regulation and time to return to baseline (RTB) following each stressor, in matched samples receiving left-sided and right-sided prefrontal TMS via BEAM (n=15) or MRI-guided targeting (n=15). Mixed models examined HRV across five two-minute regulation bins and three stressor cycles (covarying pre-task baseline HRV), and RTB across the three stressor cycles (covarying post-habituation vanilla baseline HRV). MRI-guided targeting was associated with higher HRV during early-to-mid regulation (bins 2–3; ps=.046–.065), with effects attenuating by late regulation. RTB increased progressively across stressor cycles (occasion 3 vs. 1: β=0.41, p=.012), independent of targeting method. Together, findings suggest targeting precision may influence autonomic regulatory capacity during active emotion regulation, while cumulative autonomic loading accrues regardless of approach, warranting adequately powered replication.
Background
Transcranial magnetic stimulation (TMS) of the left dorsolateral prefrontal cortex (dlPFC) is an established intervention for depression and is increasingly studied as a mechanism for enhancing emotion regulation. A critical but underexamined source of variability in TMS outcomes is targeting method. Conventional approaches such as the beam F3 method (BEAM; Beam, 2009) localize stimulation sites using scalp-based measurements without individualized neuroimaging. In contrast, MRI-guided targeting uses structural or functional neuroimaging combined with electric field (e-field) modeling to identify subject-specific stimulation coordinates and optimize cortical dose delivery. These methods differ substantially in their precision and in the degree to which stimulation reaches intended cortical targets. Despite growing use of both approaches, no study has directly compared their effects on psychophysiological outcomes during emotion regulation. The present study examined two complementary indices of autonomic regulation following TMS: heart rate variability (HRV) during active emotion regulation, reflecting prefrontal inhibitory control over autonomic arousal in real time, and time to return to autonomic baseline (RTB) following each stressor, reflecting regulatory persistence or sustained recovery. Both outcomes are sensitive to prefrontal TMS effects and together capture distinct temporal phases of the regulation cycle. We compared these indices across repeated stress-regulation cycles in matched samples who received prefrontal TMS via BEAM or MRI-guided targeting.
Methods
Participants were drawn from two studies using identical psychophysiological protocols: a BEAM-targeted TMS study (NARSAD; n=15) and an MRI-guided TMS study (KL R01; n=15), matched on age and sex. All participants completed a repeated stress-regulation task following TMS administration, consisting of three stressor-regulation cycles. Each regulation period lasted 10 minutes and was divided into five consecutive two-minute bins. Two complementary autonomic outcomes were examined. HRV was computed for each regulation bin and log-transformed to correct for positive skew. A linear mixed model examined log-HRV across the regulation window as a function of targeting method (BEAM vs. MRI-guided), regulation bin (1–5), and stressor cycle (1–3), with pre-task vanilla baseline HRV (most proximal pre-stressor bin) as a covariate and TMS laterality as a nuisance variable. Time to return to autonomic baseline (RTB) was operationalized as the duration (in seconds) from stressor offset until the participant’s HRV returned to pre-stressor baseline levels, log-transformed to correct for positive skew. A separate linear mixed model examined log-RTB across the three stressor cycles as a function of targeting method, stressor cycle, and TMS laterality, covarying post-habituation vanilla baseline HRV as an index of individual differences in tonic autonomic capacity. For both models, random intercepts were specified at the subject level; random slopes were not estimable given the limited number of observations per person. Estimated marginal means were computed using Kenward-Roger degrees of freedom. All analyses were conducted in R using lme4 and emmeans.
Results
Thirty participants contributed 447 observations to the HRV analysis. The intraclass correlation was .62, indicating substantial between-person clustering and underscoring the appropriateness of the mixed-effects approach. Pre-task baseline HRV was a strong predictor of regulation-phase HRV (β=.92, SE=.10, p<.001), and did not differ between groups (p=.75), ruling out baseline differences as a confound. TMS laterality and stressor cycle were not significant predictors.
The main effect of targeting method on HRV did not reach significance (β=.16, SE=.10, p=.105), with MRI-guided targeting associated with numerically higher HRV across the full regulation window. Targeting method × bin contrasts revealed a consistent pattern of higher HRV in the MRI-guided group, peaking during bins 2 and 3 (early-to-mid regulation): bin 2, Δ=0.20, p=.046; bin 3, Δ=0.19, p=.065. Effects attenuated across later bins (bin 4, Δ=0.16, p=.116; bin 5, Δ=0.16, p=.122). No significant targeting method × bin interaction was detected, consistent with a small, consistent directional effect insufficiently powered for detection at n=15 per group.
In the RTB analysis (n=27; 65 observations; three participants excluded due to complete missingness on the RTB outcome), post-habituation vanilla baseline HRV was not a significant predictor of log-RTB (b=0.15, SE=0.49, p=.760). Stressor cycle was a significant predictor: autonomic recovery took progressively longer across the session, with occasion 3 significantly slower than occasion 1 (b=0.41, SE=0.16, p=.012). The occasion 2 vs. 1 contrast was not significant (b=0.16, p=.355), nor was occasion 3 vs. 2 (b=0.26, p=.106), suggesting the increment accumulated primarily between the first and third cycles. Targeting method did not significantly predict RTB (b=-0.34, SE=0.42, p=.424), and the targeting method x occasion interaction was not significant (all terms ps>.13).
Discussion
These preliminary findings suggest that MRI-guided TMS targeting may support greater autonomic regulatory capacity during active emotion regulation relative to BEAM-based targeting, with the most pronounced differences in HRV emerging during early-to-mid regulation, the phase most associated with effortful prefrontal engagement. The attenuation of group differences across later regulation bins is consistent with regulatory fatigue or ceiling effects in both groups over time. The RTB findings complement the HRV results by capturing a distinct temporal dimension of the regulation cycle: not the quality of active regulation, but the persistence of recovery once the stressor ends. Progressive slowing of RTB across stressor cycles, independent of targeting method, is consistent with cumulative autonomic loading across a demanding repeated-stress protocol. The absence of a targeting method effect on RTB may reflect limited power in this subsample (n=27), or may suggest that targeting precision specifically influences the active regulatory window captured by HRV without altering downstream recovery speed. The absence of baseline HRV differences between groups strengthens the interpretation that HRV effects reflect targeting-related differences rather than pre-existing autonomic variability. The present sample was intentionally matched but underpowered for both outcomes. With ICC=.62 for HRV, between-person variance substantially limits sensitivity to between-group effects at this sample size. Effect sizes from the present data can inform power analyses for adequately powered trials. Together, these findings support the hypothesis that targeting precision is a meaningful moderator of TMS effects on autonomic outcomes during active regulation, and motivate prospective examination of e-field dose metrics as predictors of psychophysiological response across both the active regulation and post-stressor recovery phases.
Disclosures
This work was supported by the Misophonia Research Fund. Nothing to disclose by any authors.