Fronto-insular circuit mechanisms of accelerated intermittent theta burst stimulation

Shane B Johnson; Devin Rocks; Laura Chalençon; Kenneth Johnson; Umair Hassan; Anisul Arefin; Gülcan Akgül; Alexander Donatelle; Henry Asher; Immanuel Elbau; David Estrin; Rebecca Zhang; Alexandra Lenz; Rachel Mikofsky; Cory Knox; Rachael Han; Pooja Suganthan; Tahrima Chowdhury; Christine Kuang; Daniel Shaver; Parsa Nilchian; Puja Parekh; Jacob Roshgadol; Natalia DeMarco Garcia; Matthew Wright; Lindsay Victoria; Benjamin Zebley; Joshua Levitz; Corey J Keller; Aaron D Boes; Conor Liston

doi:10.1016/j.cell.2026.04.030

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Fronto-insular circuit mechanisms of accelerated intermittent theta burst stimulation

Journal article

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Fronto-insular circuit mechanisms of accelerated intermittent theta burst stimulation

Shane B Johnson, Devin Rocks, Laura Chalençon, Kenneth Johnson, Umair Hassan, Anisul Arefin, Gülcan Akgül, Alexander Donatelle, Henry Asher, Immanuel Elbau, …

Cell, Vol.189(10), pp.3071-3090.e27

05/07/2026

DOI: 10.1016/j.cell.2026.04.030

PMID: 42102818

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Abstract

Transcranial magnetic stimulation (TMS) is a widely used neuromodulation treatment for depression, but its mechanisms are poorly understood. Indirect clinical evidence suggests that TMS enhances plasticity within the prefrontal cortical target site and engages downstream networks. However, establishing causal mechanisms to help optimize the large stimulation parameter space has been challenging. Using an optogenetic model of accelerated intermittent theta burst stimulation (prelimbic [PL]-aiTBS) that drives rapid antidepressant-like effects, we examined cell type-specific effects on synapse-related gene expression, increased spine density, and increased excitatory currents in prefrontal intratelencephalic projection neurons. Whole-brain c-Fos immunolabeling, fiber photometry, chemogenetic, and projection-specific optogenetic manipulations revealed that PL-aiTBS activates a fronto-insular network that is necessary and sufficient for its antidepressant-like behavioral effects. Finally, we validate a key role for fronto-insular connectivity and TMS-evoked responses in the human insula using intracortical stereo-electroencephalogram (EEG) and resting-state fMRI. These results establish a fronto-insular circuit as a critical mediator of the antidepressant effects of aiTBS.

brain stimulation

prefrontal cortex

spatial transcriptomics

optogenetics

TMS

depression

insular cortex

transcranial magnetic stimulation

dendritic spines

intermittent theta burst stimulation

Details

Title: Subtitle: Fronto-insular circuit mechanisms of accelerated intermittent theta burst stimulation
Creators: Shane B Johnson - Cornell University
Devin Rocks - Cornell University
Laura Chalençon - Cornell University
Kenneth Johnson - Cornell University
Umair Hassan - Stanford University
Anisul Arefin - Cornell University
Gülcan Akgül - Cornell University
Alexander Donatelle - Cornell University
Henry Asher - Cornell University
Immanuel Elbau - Cornell University
David Estrin - Cornell University
Rebecca Zhang - Cornell University
Alexandra Lenz - Cornell University
Rachel Mikofsky - Cornell University
Cory Knox - Cornell University
Rachael Han - Cornell University
Pooja Suganthan - Cornell University
Tahrima Chowdhury - Cornell University
Christine Kuang - Cornell University
Daniel Shaver - Cornell University
Parsa Nilchian - Cornell University
Puja Parekh - Cornell University
Jacob Roshgadol - Cornell University
Natalia DeMarco Garcia - Weill Cornell Medicine
Matthew Wright - Cornell University
Lindsay Victoria - Cornell University
Benjamin Zebley - Cornell University
Joshua Levitz - Cornell University
Corey J Keller - Stanford University
Aaron D Boes - University of Iowa
Conor Liston - Cornell University
Resource Type: Journal article
Publication Details: Cell, Vol.189(10), pp.3071-3090.e27
DOI: 10.1016/j.cell.2026.04.030
PMID: 42102818
NLM abbreviation: Cell
ISSN: 0092-8674
eISSN: 1097-4172
Publisher: Elsevier
Grant note: Allen Brain Atlas NIMH: MH123154, MH118451, MH118388, NS136073, UG3 MH137656 Hope for Depression Research Foundation Foundation for OCD Research Wellcome Leap Foundation: MH132074, MH120441, DC004290, 5T32DA039080, MH126639, MH129018
The authors are grateful for the experimental and analytical support provided by Tasif Mahmoud, Gabriela Manzano Nieves, and Joseph Stujenske; Alicia Alonso and Yushan Li at the Weill Cornell Epigenomics Core; and Bertrand Yeung from Curio Bioscience. Behavioral experiment diagrams and coronal brain images were created using BioRender (https://biorender.com ) . Whole-brain c -Fos atlas images were derived from the Allen Brain Atlas. 88 This work was supported by grants to C.L. from the NIMH (MH123154, MH118451, MH118388, NS136073, and UG3 MH137656) , the Hope for Depression Research Foundation, the Foundation for OCD Research, and the Wellcome Leap Foundation, as well as grants to A.D.B. (MH132074, MH120441, and DC004290) , A.D. (5T32DA039080) , and C.J.K. (MH126639, MH129018, and Burroughs Wellcome Fund Career Award) .
Language: English
Date published: 05/07/2026
Academic Unit: Roy J. Carver Department of Biomedical Engineering; Neurology; Psychiatry; Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Neurology (Pediatrics)
Record Identifier: 9985163467302771

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