Multi-centre analysis of networks and genes modulated by hypothalamic stimulation in patients with aggressive behaviours
- Hospital for Sick Children, Canada
- University Health Network, Canada
- University Hospital San Vicente Fundación, Colombia
- University Hospital La Princesa, Spain
- Universidad Autonoma de Bucaramanga, Colombia
- Sírio-Libanês Hospital, Brazil
- University of São Paulo, Brazil
- International Misericordia Clinic, Colombia
- Sunnybrook Research Institute, Canada
- Clinica Comuneros Bucaramanga, Colombia
- 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).
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Single-unit analysis of the human posterior hypothalamus and red nucleus during deep brain stimulation for aggressivity.J Neurosurg. 2017 Apr;126(4):1158-1164.
Article and author information
Author details
Flavia Venetucci Gouveia
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.
Reviewing Editor
- Birte U Forstmann, University of Amsterdam, Netherlands
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).
Version history
- Received: October 29, 2022
- Preprint posted: November 1, 2022 (view preprint)
- Accepted: May 14, 2023
- Accepted Manuscript published: May 22, 2023 (version 1)
- Version of Record published: June 7, 2023 (version 2)
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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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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