Networks and genes modulated by posterior hypothalamic stimulation in patients with aggressive behaviours: Analysis of probabilistic mapping, normative connectomics, and atlas-derived transcriptomics of the largest international multi-centre dataset
Abstract
Deep brain stimulation targeting the posterior hypothalamus (pHyp-DBS) is being investigated as 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 volume of activated tissue modeling, probabilistic mapping, normative connectomics, and atlas-derived transcriptomics. 91% 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 posterior hypothalamic area and normative connectomic analyses identified fiber tracts and interconnected brain areas associated with sensorimotor function, emotional regulation, and monoamine production. Functional connectivity between the target, periaqueductal gray and the amygdala – together with patient age – was highly predictive of treatment outcome. Finally, transcriptomic analysis showed that genes involved in mechanisms of aggressive behaviour, neuronal communication, plasticity and neuroinflammation may underlie this functional network.
SIGNIFICANCE STATEMENT
This study investigated the brain mechanisms associated with symptom improvement following deep brain stimulation of the posterior hypothalamus for severe and refractory aggressive behavior. Conducting an integrated imaging analysis of a large international multi-center dataset of patients treated with hypothalamic deep brain stimulation, we were able to show for the first time that treatment is highly efficacious across various patients with an average improvement greater than 70%. Leveraging this unique dataset allowed us to demonstrate that some patient characteristics are important for treatment success, describe the optimal target zone for maximal benefit, that engagement of distinct fiber tracts and networks within the emotional neurocircuitry are key for positive outcome, and - using imaging transcriptomics - elucidate some potential molecular underpinnings. The provided optimal stimulation site allows for direct clinical application.
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