Aberrant Recovery of Timescale-Aligned Amplitude Balance Links to Symptoms and Cognition in Schizophrenia

Abstract

Schizophrenia has long been linked to impaired coordination of brain activity, yet most frameworks overlook two key dimensions: the amplitude of brain signals and the differing timescales on which regions operate. These factors are critical in disorders where neural activity is exaggerated and slowed. In healthy adults, networks compensate for mismatched processing speeds to maintain proportionate activity, but this process is poorly understood in schizophrenia. We developed a timescale-aligned, time-resolved framework that separates temporal distortions from genuine amplitude differences, enabling measurement of amplitude balance between networks across timescales. This approach was applied to large-scale fMRI datasets, including the Human Connectome Project and a multi-site schizophrenia cohort. Patients with schizophrenia showed greater amplitude imbalance, especially during fast fluctuations, along with more frequent re-entry into unbalanced states and slower recovery to stable coordination. We further identified a flexible intermediate state that patients occupied more often, and that predicted better working-memory performance. Across cohorts, amplitude imbalance was associated with greater symptom severity and poorer reasoning ability. These findings provide a new mechanistic view of dyscoordination in schizophrenia grounded in timescale-normalized amplitude dynamics, highlight aberrant recovery of amplitude balance as a core feature of the illness, and suggest that timescale-aligned amplitude imbalance may serve as a promising target for biomarker development.