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Visual hallucinations in Parkinson's disease can be viewed from a systems-level perspective, whereby dysfunctional 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 functional MRI data, in order to characterize 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 control subjects. 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, suggesting an additional layer of complexity in the functional brain network abnormalities implicated in hallucinations, which was not apparent in traditional functional connectivity analyses. Together, the results confirm abnormal brain organization 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. [ABSTRACT FROM AUTHOR]

The neuromodulatory arousal system imbues the nervous system with the flexibility and robustness required to facilitate adaptive behaviour. While there are well understood mechanisms linking dopamine, noradrenaline and acetylcholine to distinct behavioural states, similar conclusions have not been as readily available for serotonin. Fascinatingly, despite clear links between serotonergic function and cognitive capacities as diverse as reward processing, exploration, and the psychedelic experience, over 95% of the serotonin in the body is released in the gastrointestinal tract, where it controls digestive muscle contractions (peristalsis). Here, we argue that framing neural serotonin as a rostral extension of the gastrointestinal serotonergic system dissolves much of the mystery associated with the central serotonergic system. Specifically, we outline that central serotonin activity mimics the effects of a digestion/satiety circuit mediated by hypothalamic control over descending serotonergic nuclei in the brainstem. We review commonalities and differences between these two circuits, with a focus on the heterogeneous expression of different classes of serotonin receptors in the brain. Much in the way that serotonin-induced peristalsis facilitates the work of digestion, serotonergic influences over cognition can be reframed as performing the work of cognition. Extending this analogy, we argue that the central serotonergic system allows the brain to arbitrate between different cognitive modes as a function of serotonergic tone: low activity facilitates cognitive automaticity, whereas higher activity helps to identify flexible solutions to problems, particularly if and when the initial responses fail. This perspective sheds light on otherwise disparate capacities mediated by serotonin, and also helps to understand why there are such pervasive links between serotonergic pathology and the symptoms of psychiatric disorders. [ABSTRACT FROM AUTHOR]