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

Abstract

Neural representation can extend beyond localised activity to encompass global patterns, where information is distributed across brain networks in a hierarchical manner. Recent research suggests that the hierarchy of causal influences shaping these patterns can serve as a signature of distinct brain states, with implications for neuropsychiatric disorders. Here, we first delve into how whole-brain models, guided by the Thermodynamics of Mind framework, can estimate the brain hierarchy of specific brain states, and how perturbations of such models can study the in-silico transitions to other states represented by static functional connectivity. We then show an application for major depressive disorder, where different brain hierarchical reconfigurations have been found following psilocybin and escitalopram treatments. We build whole-brain models of depressed patients before and after psilocybin and escitalopram interventions, and we carry a dynamic sensitivity analysis to explore the susceptibility of brain states and their drivability to healthier states. We show that susceptibility is on average reduced by escitalopram and increased by psilocybin, and that both treatments succeed in promoting healthier transitions. These results align with the post-treatment window of plasticity opened by serotonergic psychedelics, as well as with the similar clinical efficacy of both drugs observed in clinical trials. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=193 HEIGHT=200 SRC="FIGDIR/small/631011v1_ufig1.gif" ALT="Figure 1"> View larger version (56K): org.highwire.dtl.DTLVardef@7f1b46org.highwire.dtl.DTLVardef@d7a883org.highwire.dtl.DTLVardef@783e39org.highwire.dtl.DTLVardef@3d334d_HPS_FORMAT_FIGEXP M_FIG C_FIG We apply whole-brain models of brain hierarchy based on the Thermodynamics of Mind framework to investigate state transitions in depression. Dynamic sensitivity analysis explores how psilocybin and escitalopram affect susceptibility and drivability to healthier states. Results show that psilocybin increases susceptibility, while escitalopram reduces it, with both enabling optimal transitions. This pipeline demonstrates the promise of in-silico approaches to inform neurostimulation protocols, potentially enhancing or complementing antidepressant therapies.