Abnormal higher-order network interactions in Parkinson's disease visual hallucinations

Abstract

Visual hallucinations in Parkinson's disease can be viewed from a systems-level perspective, whereby abnormal communication between brain networks responsible for perception predisposes a person to hallucinate. To this end, abnormal functional interactions between higher-order and primary sensory networks have been implicated in the pathophysiology of visual hallucinations in Parkinson's disease, however the precise signatures remain to be determined. Dimensionality reduction techniques offer a novel means for simplifying the interpretation of multidimensional brain imaging data, identifying hierarchical patterns in the data that are driven by both within- and between- functional network changes. Here, we applied two complementary non-linear dimensionality reduction techniques - diffusion-map embedding and t-distributed Stochastic Neighbour Embedding (t-SNE) - to resting state fMRI data, in order to characterise the altered functional hierarchy associated with susceptibility to visual hallucinations. Our study involved 77 people with Parkinson's disease (31 with hallucinations; 46 without hallucinations) and 19 age-matched healthy controls. In patients with visual hallucinations, we found compression of the unimodal-heteromodal gradient consistent with increased functional integration between sensory and higher order networks. This was mirrored in a traditional functional connectivity analysis, which showed increased connectivity between the visual and default-mode networks in the hallucinating group. Together, these results suggest a route by which higher-order regions may have excessive influence over earlier sensory processes, as proposed by theoretical models of hallucinations across disorders. By contrast, the t-SNE analysis identified distinct alterations in prefrontal regions that were not apparent in the functional connectivity analysis, suggesting complex reconfigurations in functional brain network architecture as a function of the disease process. Together, the results confirm abnormal brain organisation associated with the hallucinating phenotype in Parkinson's disease, and highlight the utility of applying convergent dimensionality reduction techniques to investigate complex clinical symptoms. In addition, the patterns we describe in Parkinson's disease converge with those seen in other conditions, suggesting that reduced hierarchical differentiation across sensory-perceptual systems may be a common transdiagnostic vulnerability in neuropsychiatric disorders with perceptual disturbances.