Multi-centre analysis of networks and genes modulated by hypothalamic stimulation in patients with aggressive behaviours

  1. Flavia Venetucci Gouveia  Is a corresponding author
  2. Jurgen Germann
  3. Gavin JB Elias
  4. Alexandre Boutet
  5. Aaron Loh
  6. Adriana Lucia Lopez Rios
  7. Cristina Torres Diaz
  8. William Omar Contreras Lopez
  9. Raquel Chacon Ruiz Martinez
  10. Erich Talamoni Fonoff
  11. Juan Carlos Benedetti-Isaac
  12. Peter Giacobbe
  13. Pablo M Arango Pava
  14. Han Yan
  15. George M Ibrahim
  16. Nir Lipsman
  17. Andres Lozano
  18. Clement Hamani  Is a corresponding author
  1. Hospital for Sick Children, Canada
  2. University Health Network, Canada
  3. University Hospital San Vicente Fundación, Colombia
  4. University Hospital La Princesa, Spain
  5. Universidad Autonoma de Bucaramanga, Colombia
  6. Sírio-Libanês Hospital, Brazil
  7. University of São Paulo, Brazil
  8. International Misericordia Clinic, Colombia
  9. Sunnybrook Research Institute, Canada
  10. Clinica Comuneros Bucaramanga, Colombia
  11. University of Toronto, Canada

Abstract

Deep brain stimulation targeting the posterior hypothalamus (pHyp-DBS) is being investigated as a treatment for refractory aggressive behaviour, but its mechanisms of action remain elusive. We conducted an integrated imaging analysis of a large multi-centre dataset, incorporating the volume of activated tissue modelling, probabilistic mapping, normative connectomics, and atlas-derived transcriptomics. Ninety-one percent of the patients responded positively to treatment, with a more striking improvement recorded in the pediatric population. Probabilistic mapping revealed an optimized surgical target within the posterior-inferior-lateral region of the posterior hypothalamic area. Normative connectomic analyses identified fibre tracts and interconnected brain areas associated with sensorimotor function, emotional regulation, and monoamine production. Functional connectivity between the target, periaqueductal gray and key limbic areas - together with patient age - were highly predictive of treatment outcome. Transcriptomic analysis showed that genes involved in mechanisms of aggressive behaviour, neuronal communication, plasticity and neuroinflammation might underlie this functional network.

Data availability

The codes for electrode localization, modelling of the volume of activated tissue, and imaging connectomics (i.e. functional and structural connectivity) are freely available in Lead-DBS (https://www.lead-dbs.org/). The codes, along with the Allen Human Brain Atlas (AHBA) microarray dataset, for the analysis of spatial transcriptomics are freely available in abagen (https://abagen.readthedocs.io/en/stable/). Along with the codes, the websites for these two toolboxes provide manuals describing the step-by-step procedure for successful analysis. The dataset accompanying this study is freely available at Zenodo (doi: 10.5281/zenodo.7344268).

The following previously published data sets were used

Article and author information

Author details

  1. Flavia Venetucci Gouveia

    Neuroscience and Mental Health, Hospital for Sick Children, Toronto, Canada
    For correspondence
    fvenetucci@gmail.com
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0029-1269
  2. Jurgen Germann

    Department of Surgery, University Health Network, Toronto, Canada
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0995-8226
  3. Gavin JB Elias

    Department of Surgery, University Health Network, Toronto, Canada
    Competing interests
    The authors declare that no competing interests exist.
  4. Alexandre Boutet

    Department of Surgery, University Health Network, Toronto, Canada
    Competing interests
    The authors declare that no competing interests exist.
  5. Aaron Loh

    Department of Surgery, University Health Network, Toronto, Canada
    Competing interests
    The authors declare that no competing interests exist.
  6. Adriana Lucia Lopez Rios

    Department of Functional and Stereotactic Neurosurgery, University Hospital San Vicente Fundación, Medellin, Colombia
    Competing interests
    The authors declare that no competing interests exist.
  7. Cristina Torres Diaz

    Department of Neurosurgery, University Hospital La Princesa, Madrid, Spain
    Competing interests
    The authors declare that no competing interests exist.
  8. William Omar Contreras Lopez

    Nemod Research Group, Universidad Autonoma de Bucaramanga, Bucaramanga, Colombia
    Competing interests
    The authors declare that no competing interests exist.
  9. Raquel Chacon Ruiz Martinez

    Division of Neuroscience, Sírio-Libanês Hospital, Sao Paulo, Brazil
    Competing interests
    The authors declare that no competing interests exist.
  10. Erich Talamoni Fonoff

    Department of Neurology, University of São Paulo, São Paulo, Brazil
    Competing interests
    The authors declare that no competing interests exist.
  11. Juan Carlos Benedetti-Isaac

    Stereotactic and Functional Neurosurgery Division, International Misericordia Clinic, Barranquilla, Colombia
    Competing interests
    The authors declare that no competing interests exist.
  12. Peter Giacobbe

    Sunnybrook Research Institute, Toronto, Canada
    Competing interests
    The authors declare that no competing interests exist.
  13. Pablo M Arango Pava

    Servicio de Neuocirugia Funcional y Esterotaxia, Clinica Comuneros Bucaramanga, Bucaramanga, Colombia
    Competing interests
    The authors declare that no competing interests exist.
  14. Han Yan

    Department of Surgery, University of Toronto, Toronto, Canada
    Competing interests
    The authors declare that no competing interests exist.
  15. George M Ibrahim

    Division of Neurosurgery, Hospital for Sick Children, Toronto, Canada
    Competing interests
    The authors declare that no competing interests exist.
  16. Nir Lipsman

    Sunnybrook Research Institute, Toronto, Canada
    Competing interests
    The authors declare that no competing interests exist.
  17. Andres Lozano

    Department of Surgery, University Health Network, Toronto, Canada
    Competing interests
    The authors declare that no competing interests exist.
  18. Clement Hamani

    Sunnybrook Research Institute, Toronto, Canada
    For correspondence
    clement.hamani@sunnybrook.ca
    Competing interests
    The authors declare that no competing interests exist.

Funding

Canadian Institutes for Health Research (72484)

  • Flavia Venetucci Gouveia

Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (13/20602-5)

  • Flavia Venetucci Gouveia

Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (17/10466-8)

  • Flavia Venetucci Gouveia

Canadian Institutes for Health Research (471913)

  • Jurgen Germann

Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (11/08575-7)

  • Raquel Chacon Ruiz Martinez

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Human subjects: Individual trials and cases were evaluated by the corresponding local ethics committees. Written informed consent was obtained. Five international centers shared clinical data for this study. 1. Comité de Ética de la Investigación of Hospital Universitario San Vicente Fundación (#08-2022). 2. Comité de Ética de la Investigación con Medicamentos of Hospital Universitario La Princesa. 3. Comité de Ética de los Estudios Clínicos of La Misericordia Clínica Internacional (2012). 4. Comité Institucional de Ética of Universidad Autónoma de Bucaramanga. 5. Comitê de Ética em Pesquisa of Sociedade Beneficente de Senhoras Hospital Sírio-Libanês (#27470619.8.0000.5461).

Reviewing Editor

  1. Birte U Forstmann, University of Amsterdam, Netherlands

Publication history

  1. Received: October 29, 2022
  2. Accepted: May 14, 2023
  3. Accepted Manuscript published: May 22, 2023 (version 1)

Copyright

© 2023, Venetucci Gouveia et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Flavia Venetucci Gouveia
  2. Jurgen Germann
  3. Gavin JB Elias
  4. Alexandre Boutet
  5. Aaron Loh
  6. Adriana Lucia Lopez Rios
  7. Cristina Torres Diaz
  8. William Omar Contreras Lopez
  9. Raquel Chacon Ruiz Martinez
  10. Erich Talamoni Fonoff
  11. Juan Carlos Benedetti-Isaac
  12. Peter Giacobbe
  13. Pablo M Arango Pava
  14. Han Yan
  15. George M Ibrahim
  16. Nir Lipsman
  17. Andres Lozano
  18. Clement Hamani
(2023)
Multi-centre analysis of networks and genes modulated by hypothalamic stimulation in patients with aggressive behaviours
eLife 12:e84566.
https://doi.org/10.7554/eLife.84566

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