Susceptibility to visual hallucinations in the amyotrophic lateral sclerosis-frontotemporal dementia spectrum: The role of dysfunctional attentional networks

Abstract

Psychotic symptoms are well established across the amyotrophic lateral sclerosis-frontotemporal dementia (ALS-FTD) spectrum and contribute to patient and carer distress and poorer prognosis. However, there are no objective tools to probe these symptoms and the underlying functional neurobiology has been unexplored to date. Leveraging clinical interview, neuropsychological testing, and a validated behavioural paradigm of visual misperception combined with connectome-wide fMRI analysis, we directly probed visual hallucinatory tendencies and the associated cognitive and functional connectivity signatures in ALS-FTD. In 82 participants across the ALS-FTD spectrum (24 ALS patients, 7 ALS-FTD, 31 behavioural-variant FTD [19 C9orf72 expansion carriers and 43 non-carriers] and 20 healthy controls), we showed that an ecologically valid behavioural task was sensitive to hallucinatory tendencies. We observed selective involvement of attentional deficits in visual misperception beyond the influence of executive function and psychomotor speed (r ranging from .344-.603; FDR-corrected at p < .05). Following quality control, data-driven whole-brain fMRI analysis in a subset of 26 patients converged to implicate the attentional systems, wherein abnormally heightened connectivity anchored in the attentional, default mode and executive control networks worsened as a function of visual misperception severity (FWE-corrected p = .042 with 10,000 permutations). Our findings underscore the critical role of attentional disruptions, characterised by altered interactions between top-down and bottom-up attentional, introspective, and salience detection processes, in ALS-FTD visual hallucinatory predisposition. Aligning with current models of hallucination generation postulated in schizophrenia, Parkinson's disease, and dementia with Lewy bodies, our findings point towards common neural underpinnings of psychosis vulnerability shared by ALS-FTD.