Deafferentation and Network Dysregulation Hypotheses in Charles Bonnet Syndrome (CBS) Mechanisms

Abstract

Charles Bonnet Syndrome (CBS) is a rare condition characterized by complex, persistent visual hallucinations (VH) in patients with normal cognitive function and vision impairment.At present, the cause of CBS remains unclear; there is evidence that deafferentation, hallucinations caused by a deprivation of visual stimuli, which propagates neural hyperactivity through cortical excitability, is considered a putative mechanism by which CBS arises.However, emerging research posits that the condition stems from changes in sensory and control neural networks.Studies have shown reorganization of functional connectivity among different systems, including the default mode network (DMN), salience network (SN), and visual network (VN) in CBS patients, modeling alterations in brain activity.By comparing various neural network models, this review evaluates the extent to which different hypotheses drive visual hallucinations in CBS patients.Therefore, we propose a multi-stage process which systematically combines the two hypotheses in order to clarify the underlying mechanisms behind CBS. Introduction:Charles Bonnet Syndrome (CBS) is a neurological condition in which patients with severe vision loss experience vivid, chronic visual hallucinations (VH), despite being otherwise mentally healthy (Russell 2014).VH can be symptomatologically categorized as simple or complex, ranging from flashes of light and geometric shapes to real-life figures and scenes (Martial 2019, Vacchiano 2019).Unlike hallucinations from psychiatric diseases such as Parkinson's, schizophrenia, and Alzheimer's, of whose patients undergo cerebral atrophy or physical injury in the brain, the ones present in CBS primarily occur in individuals with severe vision degeneration, not neural (Kinakool 2015).Therefore, CBS stands as a uniquely neurobiological case of VH, not associated with psychiatric illness or cognitive impairment.CBS appears in nearly 20% of those with a history of ocular pathology, including macular degeneration, cataracts, and glaucoma, and affects 47 million people worldwide (Kelson 2022, Christoph 2024).Even so, it goes unrecognized by more than half of clinicians who treat patients with this condition and the underlying pathophysiology of CBS is largely understudied (Kelson 2022).Currently, two major models are used to explain the basic mechanisms of CBS.The bottom-up visual network model attributes CBS to deafferentation, or the lack of sensory input to the brain.Without typical amounts of input, the cortex becomes hyperexcitable, resulting in excessive reactions to the small amounts of stimuli it receives from the optic nerve; these assumptions lead to the formation of hallucinations (Kumral 2015, Spitzber 2025).This hyperexcitability can be modeled by an imbalance between excitatory and inhibitory neurotransmitters, glutamate and γ-aminobutyric acid (GABA), respectively.Glutamatergic neurotransmitters increase the likelihood of neuronal firing, amplifying activity in neuronal pathways, whereas inhibitory neurotransmitters suppress signal firing to prevent overstimulation (Andersen 2023).When this balance shifts towards excitation, the visual cortex becomes more prone to releasing hallucinations.This phenomenon, termed "phantom vision", is analogous to the studied