Linking Synaptic Pathology to Network-Level Reorganization in Neurological Disease

Abstract

Neurological diseases are increasingly recognized as disorders of distributed brain networks rather than consequences of isolated focal lesions, yet large-scale dysfunction originates in microscopic alterations of synaptic structure and function that propagate across hierarchical levels of neural organization. This paper develops a multilevel theoretical framework linking synaptic pathology to network-level reorganization by tracing how structural synaptic loss, functional transmission abnormalities, and disrupted plasticity reshape microcircuit dynamics through altered excitation–inhibition balance, impaired interneuron timing, and disturbed oscillatory coordination. These microcircuit changes propagate via long-range projections, leading to modifications in functional connectivity, modular architecture, and large-scale network dynamics. The model incorporates threshold effects and nonlinear amplification to explain abrupt transitions into pathological states such as hypersynchrony, network slowing, and instability. Cross-disease comparison across epilepsy, Alzheimer’s disease, and Parkinson’s disease demonstrates how distinct synaptic perturbations produce characteristic network phenotypes while following a common hierarchical cascade. By conceptualizing disease progression as a dynamic transformation from synaptic disturbance to consolidated network reconfiguration, this framework positions network remodeling as the core systems-level expression of neurological pathology and underscores the necessity of analyzing brain disorders across synaptic, circuit, and distributed network scales.