Focal brain stimulation sites that modify autonomic arousal map to a convergent brain circuit and potential therapeutic target

Webler, R.; Neudorfer, C.; Dijkstra, E.; Frandsen, S.; Chiulli, N.; Miller, J.; Kong, R.; Khosravani, S.; Meyer, G.; Boutet, A.; Germann, J.; Elias, G.; Balderston, N. L.; Strohman, A.; Legon, W.; Grafman, J.; Arns, M.; Lozano, A.; Siddiqi, S. H.

doi:10.64898/2026.01.08.698446

bioRxiv · 10.64898/2026.01.08.698446

Focal brain stimulation sites that modify autonomic arousal map to a convergent brain circuit and potential therapeutic target

Webler, R.·Neudorfer, C.·Dijkstra, E.·Frandsen, S.·Chiulli, N.·Miller, J.·Kong, R.·Khosravani, S.·Meyer, G.·Boutet, A.·Germann, J.·Elias, G.·Balderston, N. L.·Strohman, A.·Legon, W.·Grafman, J.·Arns, M.·Lozano, A.·Siddiqi, S. H.

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Abstract

Causal modulation of autonomic outflow could yield new therapeutic targets for autonomic hyperactivation. We employed three natural experiments in which different brain regions were targeted using transcranial magnetic stimulation (TMS) (n=139 sites, n=14 individuals), deep brain stimulation (n=392 sites, n=58 individuals), or low-intensity focused ultrasound (n=46 sites, n=23 individuals) with subsequent autonomic measurements. Using a human connectome database (n=1000) as a wiring diagram, we identified a convergent brain circuit that, when focally modulated, transiently reduces autonomic arousal. This circuit significantly resembled previously reported causal circuits for posttraumatic stress disorder (PTSD) and anxiety. In independent datasets, TMS to the autonomic arousal circuit reduced laboratory startle in healthy volunteers (n=28), lesions to this circuit reduced exaggerated startle in PTSD (n=193), and TMS to this circuit reduced anxiety-related autonomic symptoms in patients with clinically significant anxiety (n=30). Thus, the convergent circuit may serve as a potential neuromodulation target for autonomic hyperactivation.

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Webler, R., Neudorfer, C., Dijkstra, E., Frandsen, S., Chiulli, N., Miller, J., Kong, R., Khosravani, S., Meyer, G., Boutet, A., Germann, J., Elias, G., Balderston, N. L., Strohman, A., Legon, W., Grafman, J., Arns, M., Lozano, A., Siddiqi, S. H.. 2026-01-09. Focal brain stimulation sites that modify autonomic arousal map to a convergent brain circuit and potential therapeutic target. https://doi.org/10.64898/2026.01.08.698446

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