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.
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 funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
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).
© 2023, Venetucci Gouveia et al.
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