Entropy and Neural Manifolds: The Primacy of Regulation in Brain Function and Clinical Implications

Contemporary neuroscience and psychiatry frequently organize brain function around cognitive domains, behavioral outputs, or symptom clusters. However, converging evidence from thermodynamics, cybernetics, nonlinear dynamics, and predictive processing suggests that neural systems are fundamentally organized around the regulation of internal states. In this review, we synthesize theoretical and empirical work supporting the primacy of regulation in brain function. Drawing on principles of far-from-equilibrium biology, self-organization, and active inference, we argue that cognition, emotion, and behavior emerge from — and remain constrained by — underlying regulatory architectures that maintain biological viability. We examine evolutionary perspectives indicating that early neural systems evolved to stabilize internal milieu prior to the development of complex representational capacities, and we integrate findings from physiological complexity research, systems neuroscience, and computational psychiatry. This framework reframes psychopathology and neurological disorder as disruptions in regulatory integrity rather than isolated deficits in discrete cognitive modules. Furthermore, aging and clinical decompensation may be understood as threshold transitions in regulatory robustness within dynamic biological systems. By situating brain function within a broader regulatory and thermodynamic context, this synthesis offers a unifying perspective across levels of analysis, from cellular metabolism to behavior. We propose that recognizing the primacy of regulation clarifies the organization of neural systems and provides a coherent framework for understanding resilience, instability, and recovery in health and disease.