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The future of brain circuit-targeted therapeutics

Neuropsychopharmacology volume 49, pages 179–188 (2024)Cite this article

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Abstract

The principle of targeting brain circuits has drawn increasing attention with the growth of brain stimulation treatments such as transcranial magnetic stimulation (TMS), deep brain stimulation (DBS), and focused ultrasound (FUS). Each of these techniques can effectively treat different neuropsychiatric disorders, but treating any given disorder depends on choosing the right treatment target. Here, we propose a three-phase framework for identifying and modulating these targets. There are multiple approaches to identifying a target, including correlative neuroimaging, retrospective optimization based on existing stimulation sites, and lesion localization. These techniques can then be optimized using personalized neuroimaging, physiological monitoring, and engagement of a specific brain state using pharmacological or psychological interventions. Finally, a specific stimulation modality or combination of modalities can be chosen after considering the advantages and tradeoffs of each. While there is preliminary literature to support different components of this framework, there are still many unanswered questions. This presents an opportunity for the future growth of research and clinical care in brain circuit therapeutics.

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Fig. 1: Stepwise development of a brain circuit therapeutic.

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Funding

The present analysis was supported by the Brain & Behavior Research Foundation (SHS), the Baszucki Family Foundation (SHS and MDF), the National Institute of Mental Health (grant no. K23MH121657 to SHS.; grant nos. R01MH113929 and R01MH115949 to MDF), and the National Institute of Neurological Disorders and Stroke (K23NS114178 to JDR). The funders were not directly involved in the conceptualization, design, analysis, decision to publish, or preparation of the manuscript.

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Authors and Affiliations

  1. Center for Brain Circuit Therapeutics, Brigham and Women’s Hospital, Boston, MA, USA

    Shan H. Siddiqi, Sanaz Khosravani, John D. Rolston & Michael D. Fox

  2. Department of Psychiatry, Harvard Medical School, Boston, MA, USA

    Shan H. Siddiqi

  3. Department of Neurology, Harvard Medical School, Boston, MA, USA

    Sanaz Khosravani & Michael D. Fox

  4. Department of Neurosurgery, Harvard Medical School, Boston, MA, USA

    John D. Rolston

Authors
  1. Shan H. Siddiqi
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  2. Sanaz Khosravani
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  3. John D. Rolston
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  4. Michael D. Fox
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Contributions

SHS and MDF wrote the manuscript with input from all authors. SK illustrated the framework in Fig. 1. JDR wrote the section on invasive neuromodulation and provided consultation on the neurosurgical components of the manuscript.

Corresponding author

Correspondence to Shan H. Siddiqi.

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Competing interests

SHS and MDF are scientific consultants for Magnus Medical. SHS is a clinical consultant for Acacia Mental Health, Kaizen Brain Center, and Boston Precision Neurotherapeutics. SHS and MDF have jointly received investigator-initiated research funding from Neuronetics. SHS has served as a speaker for Brainsway and PsychU.org (unbranded, sponsored by Otsuka). SHS and MDF independently own intellectual property involving the use of functional connectivity to target TMS. JDR has previously consulted for Medtronic, Neuropace, and Corlieve Therapeutics. SK has no competing interests.

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Siddiqi, S.H., Khosravani, S., Rolston, J.D. et al. The future of brain circuit-targeted therapeutics. Neuropsychopharmacol. 49, 179–188 (2024). https://doi.org/10.1038/s41386-023-01670-9

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  • DOI: https://doi.org/10.1038/s41386-023-01670-9

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