Neural Constraints on Cognitive Experience and Mental Health

Abstract: Understanding how neural dynamics shape cognitive experiences remains a central challenge in neuroscience and psychiatry. Here, we present a novel framework leveraging state-to-output controllability from dynamical systems theory to model the interplay between cognitive perturbations, neural activity, and subjective experience. We demonstrate that large-scale fMRI signals are constrained to low-dimensional manifolds, where affective and cognitive states are naturally organized. Furthermore, we provide a theoretically robust method to estimate the controllability Gramian from steady-state neural responses, offering a direct measure of the energy required to steer cognitive outcomes. In five healthy participants viewing 2,185 emotionally evocative short videos, our analyses reveal a strong alignment between neural activations and affective ratings, with an average correlation of $r \approx 0.7$. In a clinical cohort of 255 patients with major depressive disorder, biweekly Hamilton Rating Scale trajectories over 11 weeks significantly mapped onto these manifolds, explaining approximately 20% more variance than chance ($p < 10^{-10}$, numerically better than chance in 93% reaching statistical significance in one-third of subjects). Our work bridges dynamical systems theory and clinical neuroscience, providing a principled approach to optimize mental health treatments by targeting the most efficient neural pathways for cognitive change.