Lower TMS Intensity Correlates With Greater Depression Improvement

A new study found lower absolute electric-field (E-Field) strength at the left dorsolateral prefrontal cortex (DLPFC), rather than higher stimulation intensity, was significantly associated with greater depression symptom improvement following accelerated intermittent theta-burst transcranial magnetic stimulation (TMS) guided by real-time E-Field modeling.¹ The finding comes from a secondary analysis of a randomized, placebo-controlled trial conducted at McLean Hospital in 28 patients with major depressive disorder (MDD).

"The association of lower absolute DLPFC E-Field strength with greater symptom reduction challenges the assumption higher stimulation intensity produces better clinical outcomes and warrants systematic investigation in larger trials,” wrote investigators, led by Joshua C. Brown, MD, PhD, from the Brain Stimulation Mechanisms Laboratory in the division of depression and anxiety disorders at McLean Hospital and assistant professor of psychiatry at Harvard Medical School.

Current depression protocols dose TMS at a fixed 120% of resting motor threshold (rMT) established at the primary motor cortex (M1), an approach assuming a uniform coil-to-cortex and excitability relationship across individuals. Prior offline finite element modeling studies reported wide variability in the intensity needed to match M1-equivalent E-Field strength at the DLPFC, with mean estimates of 114% rMT in 1 cohort and 133.5% rMT in another.^2,3 The new analysis used prospective, real-time spherical head modeling to individualize dosing during a single-day accelerated intermittent theta-burst stimulation (iTBS) protocol.¹

TMS Dosing Variability and E-Field Precision in Depression

The analysis drew from a McLean Hospital institutional review board-approved, randomized, double-blind, placebo-controlled trial enrolling 30 patients with MDD (17 women; mean age, 38.5 ± 16.0 years) randomized to 250 mg d-cycloserine or placebo capsules.¹ All patients underwent MRI-based finite element method (FEM) modeling in SimNIBS and completed a single-day accelerated iTBS protocol consisting of 10 sessions of 1800 pulses targeting the left DLPFC, dosed using real-time E-Field estimation from the Nexstim NBR 1.0 neuronavigation system. Two patients were excluded for poor MRI quality, leaving 28 for the final E-Field analysis.

Investigators calculated the %rMT each patient would need to achieve M1-equivalent E-Field strength at the DLPFC. Required intensity ranged from 49.7% to 150.4% rMT (mean, 99.7% ± 18.9%).¹

In total, 53.6% of patients (n = 15) needed less than 100% rMT to match motor-equivalent stimulation, and 10.7% (n = 3) needed more than the conventional 120% rMT.¹ Real-time E-Field-guided dosing produced significantly smaller deviation from the target motor-equivalent E-Field than fixed 120% rMT dosing (mean absolute deviation, 0.170 vs 0.293; t(27) = 2.45, P =.021), a 48.1% improvement in precision over the conventional approach.¹

“The 3-fold variability in required intensities (49.7%–150.4% rMT) demonstrates that fixed-percentage approaches inadequately account for individual anatomical and physiological differences,” investigators wrote.¹

DLPFC E-Field Strength and Depression Outcomes

QIDS-SR16 scores fell by a mean of 2.43 ± 4.14 points from baseline to 1 week after treatment, with 17.9% of patients (n = 5) meeting response criteria and 17.9% achieving remission.¹ Delivered %rMT, the conventional dosing metric, was not significantly associated with symptom change (P =.436).¹

By contrast, the ratio of DLPFC to M1 E-Field strength was significantly and negatively correlated with improvement (P =.008), as was absolute DLPFC E-Field strength (P =.008; 95% CI, -0.20 to -0.69), meaning patients receiving lower cortical field strength tended to show greater symptom reduction. The inverse relationship persisted after adjusting for d-cycloserine versus placebo assignment (P =.003) and held across intensity quartiles, with the lowest-intensity quartile showing the greatest mean QIDS-SR16 reduction (5.4 ± 2.8 points) versus 1.4 ± 2.1 points in the highest-intensity quartile (P =.042).¹ Responders received a mean DLPFC E-Field of 53.0 ± 7.2 V/m compared with 64.0 ± 15.4 V/m among non-responders, though this difference did not reach significance (P =.121).¹

Investigators noted the findings diverge from the widely used 120% rMT convention, which was adopted empirically rather than through systematic dose-finding, and align with prior plasticity research showing robust theta-burst effects at subthreshold intensities.¹ They called for prospective, randomized trials directly comparing conventional 120% rMT dosing against individualized E-Field-guided dosing at multiple intensity levels, such as 80%, 100%, and 120% of motor-equivalent E-Field, before any change to clinical practice.

References

1. Ganesh P, Kim H, Kweon J, Halko MA, Caulfield KA, Brown JC. Depression improvement correlates with lower TMS intensity in a randomized trial with real-time E-Field modeling. Hum Brain Mapp. Published online August 4, 2026. doi:10.1002/hbm.70607

2. Nahas Z, et al. Safety and benefits of distance-adjusted prefrontal transcranial magnetic stimulation in depressed patients 55-75 years of age: a pilot study. Depress Anxiety. 2004;19(4):249-256. doi:10.1002/da.20015

3. Caulfield KA, Li X, George MS. A reexamination of motor and prefrontal TMS in tobacco use disorder: Time for personalized dosing based on electric field modeling?. Clin Neurophysiol. 2021;132(9):2199-2207. doi:10.1016/j.clinph.2021.06.015