Hallucinations are a core feature of psychosis and common in Parkinson’s. Their transient, unexpected nature suggests a change in dynamic brain states, but underlying causes are unknown. Here, we examine temporal dynamics and underlying structural connectivity in Parkinson’s-hallucinations using a combination of functional and structural MRI, network control theory, neurotransmitter density and genetic analyses. We show that Parkinson’s-hallucinators spent more time in a predominantly Segregated functional state with fewer between-state transitions. The transition from integrated-to-segregated state had lower energy cost in Parkinson’s-hallucinators; and was therefore potentially preferable. The regional energy needed for this transition was correlated with regional neurotransmitter density and gene expression for serotoninergic, GABAergic, noradrenergic and cholinergic, but not dopaminergic, receptors. We show how the combination of neurochemistry and brain structure jointly shape functional brain dynamics leading to hallucinations and highlight potential therapeutic targets by linking these changes to neurotransmitter systems involved in early sensory and complex visual processing.
Background: Neuropsychiatric symptoms are common in Parkinsons disease (PD) and predict poorer outcomes. Reward processing dysfunction is a candidate mechanism for the development of psychiatric symptoms including depression and impulse control disorders (ICD). We aimed to determine whether reward processing is impaired in PD and its relationship with neuropsychiatric syndromes and dopamine replacement therapy. Methods: The Ovid MEDLINE/PubMed, Embase and PsycInfo databases were searched for articles published up to November 5th, 2020. Studies reporting reward processing task performance by PD patients and healthy controls were included. Summary statistics comparing reward processing between groups were converted to standardized mean difference (SMD) scores and meta-analysed using a random effects model. Results: We identified 55 studies containing 2578 participants (1,638 PD and 940 healthy controls). Studies assessing three subcomponent categories of reward processing tasks were included: Option Valuation (n=12), Reinforcement Learning (n=37) and Reward Response Vigour (n=6). Across all studies, PD patients on medication exhibited a small-to-medium impairment versus healthy controls (SMD=0.34; 95%CI 0.14-0.53), with greater impairments observed off dopaminergic medication in within-subjects designs (SMD=0.43, 95%CI 0.29-0.57). Within-subjects subcomponent analysis revealed impaired processing off medication on Option Valuation (SMD=0.57, 95%CI 0.39-0.75) and Reward Response Vigour (SMD=0.36, 95%CI 0.13-0.59) tasks. However, the opposite applied for Reinforcement Learning, which relative to healthy controls was impaired on-medication (SMD=0.45, 95%CI 0.25-0.65) but not off-medication (SMD=0.28, 95%CI -0.03-0.59). ICD was the only neuropsychiatric syndrome with sufficient studies (n=13) for meta-analysis, but no significant impairment was identified compared to non-ICD patients (SMD=-0.02, 95%CI -0.43-0.39). Conclusion: Reward processing disruption in PD differs according to subcomponent and dopamine medication state and warrants further study as a potential treatment target and mechanism underlying associated neuropsychiatric syndromes.
Background Amisulpride is an atypical antipsychotic which antagonises dopamine (D2, D3) receptors in vitro and in vivo (Schoemaker et al., 1997). Older people, particularly those with dementia are more susceptible to antipsychotic side effects, including amisulpride (Reeves et al., 2017). Clinical and basic science research suggested that blood‐brain barrier (BBB) disruption underpins this heightened sensitivity by increasing central drug access (Sekhar et al., 2019; Harwood et al., 1994). The current study examines healthy and Alzheimer’s disease (AD) physiology to further understand this increased sensitivity. Method We investigated the BBB transport of amisulpride in 5xFamilial Alzheimer’s mouse model (5xFAD), and in age‐matched wild type mice (WT, C57/BL6) (12‐15 months old). 5xFAD mice express human amyloid precursor protein and presenilin 1 transgenes with five AD‐linked mutations, they develop Aβ plaques and cognitive impairments (Oakley et al., 2006). All experiments were performed according the Animal Scientific Procedures Act (1986) and Amendment Regulations 2012. Anaesthesia was applied via intraperitoneal injection of medetomidine hydrochloride and ketamine mixture. The mice were perfused with artificial plasma, containing [3H]amisulpride (6.5 nM) and [14C]sucrose (9.4 μM). Brain amyloid plaques were confirmed in 5xFAD mice by transmission electron microscopy. In silico molecular docking using AuDock Vina and GOLD software identified transporters of interest for our model substrate. Amisulpride was considered a substrate for a given transporter, if it had free energy binding lower than ‐5 kcal/mole and high chem score. Result Compared to WT (n=6), the 5xFAD (n=7) mice had increased striatal [3H]amisulpride uptake of 79% (t=1.975, df=11, p=0.0370). The [14C]sucrose (passive permeability measure) permeability was not significantly changed. Preliminary in silico analysis suggested that amisulpride is a substrate for glucose transporter 1 (GLUT1) and a very weak substrate for multidrug and toxin extrusion transporter (MATE2) (Table 1). Conclusion In silico studies suggested amisulpride interacts with BBB solute carrier (SLC) transporters: organic cation transporter (OCT1), plasma membrane monoamine transporter (PMAT), MATE1 (Sekhar et al., 2019), GLUT1 and MATE2, but not with the adenosine triphosphate binding cassette (ABC) transporter P‐glycoprotein. The increased brain permeability to amisulpride in 5xFAD mice suggests altered BBB transporter function, possibly due to SLC transporter expression changes associated with AD.
metacarpals throughout the two years of observation. The oestrogen-treated group lost none, and loss in the calciumtreated group was intermediate.The main effect of oestrogen on the metacarpals was inhibition of endosteal bone resorption, possibly with stimulation of subperiosteal bone apposition. The slight increase in total bone width transformed a very small, non-significant decline in cortical width into a small, non-significant increase in cortical area. Cortical area is the better estimator of bone quantity,'1 and when the results are expressed in this way full account is taken of the effects of the treatment at both cortical surfaces. The positive mean ACA/t value in the oestrogen-treated group was consistent with the densitometric observations of slight (although again non-significant) increases in the mineral contents of the ulna and radius.Our results confirm the outcome of the prospective trial of oestrogen (mestranol) treatment in oophorectomised women reported by Aitken et al.6 These authors, however, suggested that oestrogen treatment is effective only when instituted within three years of the menopause, since in a group six years from the menopause oestrogen did not significantly change the rate of bone loss. An explanation for this may be that in untreated women there is a phase of rapid bone loss immediately after the menopause,'1 in which a significant effect of oestrogen treatment would be easier to see. Although the mean time since the menopause in our patients was about six years, all the groups contained a high proportion of women within three years of the menopause. This explains why our control group lost bone at a rate considerably higher than controls in previous series.9 Thus in our trial, as in that of Aitken et al, the detection of a response was facilitated by studying groups of women relatively close to the menopause, but we do not conclude that oestrogen treatment at a later stage would be ineffective.The data on the calcium-treated group are slightly less consistent. A significant effect of calcium treatment was shown on the ulna, and the mean rate of loss of bone mineral from the radius was also reduced, although not significantly. The morphometric data on the metacarpals, when expressed as changes in cortical width, disclose only a small, non-significant effect of calcium. Because the effect of calcium treatment appeared to be confined to the periosteal surface, however, the effect on cortical area was more pronounced. The mean rate of decrease in mean cortical area in the calcium-treated group was less than half that in the control group, with the difference approaching significance; it was not significantly different from the mean rate in the oestrogen-treated group, however.We thank Professor M S F McLachlan, head of the University Department of Radiodiagnosis, Leeds, and H B Bentley, principal of the School of Radiography, Leeds General Infirmary, for help with the radiographic aspects of the trial. We are also indebted to P A Kirby and R M Milner for technical help.
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