Perturbing whole-brain models of brain hierarchy: an application for depression following pharmacological treatment

Abstract

Determining the scale of neural representations is a central challenge in neuroscience. While localized representations have traditionally dominated, evidence suggests information is also encoded in distributed, hierarchical networks. Recent research indicates that the hierarchy of causal influences shaping functional patterns serves as a signature of distinct brain states, with implications for neuropsychiatric disorders. Here, we first explore how whole-brain models, guided by the thermodynamics of mind framework, estimate brain hierarchy and how perturbing such models enables the study of in-silico transitions represented by static functional connectivity. We then apply this to major depressive disorder, where different brain hierarchical reconfigurations emerge following psilocybin and escitalopram treatments. We build resting-state whole-brain models of depressed patients before and after interventions and conduct a dynamic sensitivity analysis to explore brain states' susceptibility-measuring their capacity to change-and their drivability to healthier states. We show that susceptibility is on average reduced by escitalopram and increased by psilocybin, and that both treatments promote healthier transitions. These results align with the post-treatment window of plasticity opened by serotonergic psychedelics and the similar clinical efficacy of both drugs in trials. Overall, this work demonstrates how whole-brain models of brain hierarchy can inform in-silico neurostimulation protocols for neuropsychiatric disorders.

Jakub Vohryzek is supported by EU H2020 FET Proactive project Neurotwin grant agreement no. 101017716, Yonatan Sanz-Perl is supported by 'ERDF A way of making Europe,' ERDF, EU, Project NEurological MEchanismS of Injury, and Sleep-like cellular dynamics (NEMESIS; ref. 101071900) funded by the EU ERC Synergy Horizon Europe, Morten L. Kringelbach is supported by the European Research Council Consolidator Grant: CAREGIVING (615539), Pettit Foundation, Carlsberg Foundation, and Center for Music in the Brain, funded by the Danish National Research Foundation (DNRF117). Gustavo Deco is supported by the Spanish Research Project PSI2016-75688-P (Agencia Estatal de Investigación/Fondo Europeo de Desarrollo Regional, European Union); by the European Union's Horizon 2020 Research and Innovation Programme under Grant Agreements 720270 (Human Brain Project [HBP] SGA1) and 785907 (HBP SGA2); and by the Catalan Agency for Management of University and Research Grants Programme 2017 SGR 1545. The neuroimaging analysis and whole-brain modeling is based on clinical research carried out at the National Institute for Health Research/Wellcome Trust Imperial Clinical Research Facility. The open-label trial was funded by a Medical Research Council clinical development scheme grant (MR/J00460X/1). The double-blind randomized controlled trial was funded by a private donation from the Alexander Mosley Charitable Trust, supplemented by Founders of Imperial College London's Centre for Psychedelic Research. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the paper.