Mapping brain structural differences and neuroreceptor correlates in Parkinson’s disease visual hallucinations: a mega-analysis

Abstract

Parkinson's psychosis (PDP) describes a spectrum of symptoms that may arise in Parkinson's disease (PD) including visual hallucinations (VH). Imaging studies investigating the neural correlates of PDP have been inconsistent in their findings, due to differences in study design and limitations of scale. Here we use empirical Bayes harmonisation to pool together structural imaging data from multiple research groups into a large-scale mega-analysis, allowing us to apply new methodological approaches to identify cortical regions and networks involved in VH and their relation to receptor binding. Differences of cortical thickness and surface area show a wider cortical involvement underlying VH than previously recognised, including primary visual cortex and its surrounds, and the hippocampus, independent of its role in cognitive decline. Structural covariance analyses point to a strong involvement of the attentional control networks in PD-VH, while associations with receptor density maps suggest neurotransmitter loss may drive the cortical changes.

Neuroanatomical substrates in Parkinson’s Disease psychosis and their association with serotonergic receptor gene expression: A coordinate-based meta-regression analysis

“…Presumably, the development of psychosis in PD patients could then be due to dysfunction in networks involved in attention control and visual information processing (Lenka et al, 2015;Muller et al, 2014;Shine et al, 2011;Shine, O'Callaghan, et al, 2014) that become pathological due to grey matter reduction in their nodes, as shown in the meta-analysis results, which consequently leads to abnormal functionality at a network level. Our results are to some extent different from those of the mega-analysis (Vignando et al, 2021) and may be due to the diverse methodologies used (mega-analysis vs.…”

“…This is in contrast with Vignando et al (2021) who found associations with dopaminergic receptor density with cortical thickness in regions where PDP and PDnP had significant differences, and with surface area for significant regions of difference as well as across the cortex. However, we were only able to extract data on D1/D2 receptors unlike Vignando et al (2021) who investigated the relationship with D2/D3 joint receptor density distribution. This discrepancy may also be due to methodological differences: they used mean thickness differences as the outcome variable, whilst we employed Hedges' g effect-size estimates extracted from SDM-PSI used as a measure of grey matter loss in PDP patients, lastly they examined in-vivo PET data from an independent healthy cohort whilst we relied on gene expression data extracted from six healthy donors of the Allen Human Brain Atlas (Arnatkevic̆iūtė et al, 2019;Desikan et al, 2006).…”

“…Complementing this, a recent mega-analysis (Vignando et al, 2021) has reported extensive reduction of whole-brain cortical thickness and surface areas in visual cortex, left insula and hippocampus in PD patients with visual hallucinations compared to those without, as well as a relationship between cortical thickness loss and higher regional availability serotonergic (5-HT2a and 5-HT1a) and dopaminergic receptors (D2/D3). Collectively, these reviews focused on related different metrics of brain structure (volume, cortical thickness and surface).…”

“…This is consistent with a recent meta-analytic synthesis reporting fronto-temporo-parieto-occipital brain grey matter reduction in a mixed group of participants with PD and Lewy body dementia (DLB) with visual hallucinations (Pezzoli et al, 2021), although they did not consider the effect of potential confounders such as PD medication or concomitant symptoms, e.g., cognitive decline. Complementing this, a recent mega-analysis (Vignando et al, 2021) has reported extensive reduction of whole-brain cortical thickness and surface areas in visual cortex, left insula and hippocampus in PD patients with visual hallucinations compared to those without, as well as a relationship between cortical thickness loss and higher regional availability serotonergic (5-HT2a and 5-HT1a) and dopaminergic receptors (D2/D3). Collectively, these reviews focused on related different metrics of brain structure (volume, cortical thickness and surface).…”

“…Further, we examined whether the spatial distribution of brain structure alteration was associated with the spatial architecture of brain expression of the genes for dopaminergic (D1 and D2) and serotonergic receptors (namely 5-HT2a and 5-HT1a), the key candidate pathways implicated in PD psychosis (Hacksell et al, 2014). Unlike the approach adopted by Vignando et al (2021) where they examined the relationship between the structural neuroimaging correlate and the density distribution data for each receptor of interest separately, we included the key candidate receptors of interest in a multiple regression model to allow investigation of their relationship with neuroimaging correlates after taking into account the effect of receptors belonging to other candidate pathways of interest.…”