Study Identifies Myelinated Axonal Bends as Primary Neural Target of Transcranial Magnetic Stimulation
A new computational modeling study published on bioRxiv proposes that myelinated axons bending from the cortex into superficial white matter are the primary neural structures activated by transcranial magnetic stimulation (TMS). Researchers used high-resolution electron microscopy data, including the petavoxel H01 human cortex dataset, to build biologically realistic neuron models and simulate TMS-induced activation thresholds. The findings help resolve a longstanding uncertainty about where in the brain TMS actually triggers action potentials, with implications for how the technique is understood and applied clinically.
Transcranial magnetic stimulation (TMS) is widely used in neuroscience and clinical medicine, yet the specific neural structures it activates have remained poorly understood. To address this, researchers developed a novel computational pipeline that extracts morphologically realistic, multi-compartment neuron models directly from serial-section electron microscopy segmentations, including the high-resolution H01 human cortex dataset. They systematically compared multiple candidate excitation sites — including axon terminations, bifurcations, bends, and a simplified 'ball-and-two-sticks' model — under both uniform and anatomically realistic electric field conditions. Axon terminations were found to be excitable only when fully myelinated, a condition the histological evidence suggests is rare; even partial demyelination just 10 micrometers from the terminal raised activation thresholds by more than 100%. Most other candidate structures showed low activation thresholds only under histologically unrealistic parameter assumptions. By contrast, myelinated axonal bends at the cortex-to-white-matter transition consistently showed low, physiologically plausible activation thresholds, with larger-diameter fibers approaching experimentally measured motor thresholds. The study concludes that these bending fibers are the most biophysically credible targets of TMS, and underscores the importance of integrating detailed histological data into computational neuroscience models.
What's missing
As a preprint, this study has not yet undergone formal peer review, and its conclusions rest on computational simulations rather than direct experimental validation in living tissue. The model's generalizability across different cortical regions, individual anatomical variability, and TMS coil configurations is not fully addressed. It also remains unclear how these findings translate to clinical TMS protocols targeting non-motor areas.
What different sources said
- bioRxivCenter
Histologically Informed Multiscale Modeling of the Neuronal Elements Activated by TMS
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