Neuromodulation of excitation-inhibition balance in dementia with lewy bodies: a translational framework.

Dementia with Lewy bodies (DLB) is a complex neurodegenerative disorder characterized by cognitive fluctuations, visual hallucinations, parkinsonism, mood disturbances and REM sleep behavioural disorder. Despite extensive research into its neuropathology, most notably the deposition of Lewy pathology and widespread neural loss, the mechanistic link between cellular pathology and clinical manifestations remains elusive. In this review, we propose a translational framework that focuses on the disruption of the excitation-inhibition (E/I) balance in large-scale networks, governed by the dysfunction of neuromodulatory systems. The dopaminergic, cholinergic, serotonergic, and noradrenergic systems, each affected in DLB, modulate excitatory and inhibitory signalling, synaptic plasticity, and large-scale neural dynamics. We synthesize evidence from molecular, neuroimaging, and clinical studies to support the notion that neuromodulatory impairment leads to E/I imbalance, contributing to altered brain connectivity and dysfunctional network states. These disruptions underlie key neuropsychiatric symptoms including cognitive deficits, hallucinations, and mood disturbances. Moreover, we discuss current and emerging pharmacologic strategies, targeting neurotransmitter receptors and synaptic excitability, that may restore E/I balance and improve symptom management. Finally, we highlight the role of neuromodulation in regulating brain states and propose that DLB symptoms emerge from dysfunction of network states, reflecting a failure of the neuromodulatory control. We also explore how risk factors, cognitive reserve, and disease progression affect compensatory capacity and the integrity of E/I homeostasis. This integrative model provides a mechanistic basis for understanding symptom emergence in DLB and offers a translational roadmap for novel therapeutic interventions.