Abnormal connectivity between the default mode and the visual system underlies the manifestation of visual hallucinations in Parkinson’s disease:A task-based fMRI study

Background: The neural substrates of visual hallucinations remain an enigma, due primarily to the difficulties associated with directly interrogating the brain during hallucinatory episodes. Aims: To delineate the functional patterns of brain network activity and connectivity underlying visual hallucinations in Parkinson’s disease. Methods: In this study, we combined functional magnetic resonance imaging (MRI) with a behavioral task capable of eliciting visual misperceptions, a confirmed surrogate for visual hallucinations, in 35 patients with idiopathic Parkinson’s disease. We then applied an independent component analysis to extract time series information for large-scale neuronal networks that have been previously implicated in the pathophysiology of visual hallucinations. These data were subjected to a task-based functional connectivity analysis, thus providing the first objective description of the neural activity and connectivity during visual hallucinations in patients with Parkinson’s disease. Results: Correct performance of the task was associated with increased activity in primary visual regions; however, during visual misperceptions, this same visual network became actively coupled with the default mode network (DMN). Further, the frequency of misperception errors on the task was positively correlated with the strength of connectivity between these two systems, as well as with decreased activity in the dorsal attention network (DAN), and with impaired connectivity between the DAN and the DMNs, and ventral attention networks. Finally, each of the network abnormalities identified in our analysis were significantly correlated with two independent clinical measures of hallucination severity. Conclusions: Together, these results provide evidence that visual hallucinations are due to increased engagement of the DMN with the primary visual system, and emphasize the role of dysfunctional engagement of attentional networks in the pathophysiology of hallucinations

Changes in structural network topology correlate with severity of hallucinatory behavior in Parkinson's disease

Inefficient integration between bottom-up visual input and higher order visual processing regions is implicated in visual hallucinations in Parkinson's disease (PD). Here, we investigated white matter contributions to this perceptual imbalance hypothesis. Twenty-nine PD patients were assessed for hallucinatory behavior. Hallucination severity was correlated to connectivity strength of the network using the network-based statistic approach. The results showed that hallucination severity was associated with reduced connectivity within a subnetwork that included the majority of the diverse club. This network showed overall greater between-module scores compared with nodes not associated with hallucination severity. Reduced between-module connectivity in the lateral occipital cortex, insula, and pars orbitalis and decreased within-module connectivity in the prefrontal, somatosensory, and primary visual cortices were associated with hallucination severity. Conversely, hallucination severity was associated with increased between- and within-module connectivity in the orbitofrontal and temporal cortex, as well as regions comprising the dorsal attentional and default mode network. These results suggest that hallucination severity is associated with marked alterations in structural network topology with changes in participation along the perceptual hierarchy. This may result in the inefficient transfer of information that gives rise to hallucinations in PD. Author SummaryInefficient integration of information between external stimuli and internal perceptual predictions may lead to misperceptions or visual hallucinations in Parkinson's disease (PD). In this study, we show that hallucinatory behavior in PD patients is associated with marked alterations in structural network topology. Severity of hallucinatory behavior was associated with decreased connectivity in a large subnetwork that included the majority of the diverse club, nodes with a high number of between-module connections. Furthermore, changes in between-module connectivity were found across brain regions involved in visual processing, top-down prediction centers, and endogenous attention, including the occipital, orbitofrontal, and posterior cingulate cortex. Together, these findings suggest that impaired integration across different sides across different perceptual processing regions may result in inefficient transfer of information

Cognitive training for freezing of gait in Parkinson's disease: a randomized controlled trial.

The pathophysiological mechanism of freezing of gait (FoG) has been linked to executive dysfunction. Cognitive training (CT) is a non-pharmacological intervention which has been shown to improve executive functioning in Parkinson's disease (PD). This study aimed to explore whether targeted CT can reduce the severity of FoG in PD. Patients with PD who self-reported FoG and were free from dementia were randomly allocated to receive either a CT intervention or an active control. Both groups were clinician-facilitated and conducted twice-weekly for seven weeks. The primary outcome was percentage of time spent frozen during a Timed Up and Go task, assessed both on and off dopaminergic medications. Secondary outcomes included multiple neuropsychological and psychosocial measures. A full analysis was first conducted on all participants randomized, followed by a sample of interest including only those who had objective FoG at baseline, and completed the intervention. Sixty-five patients were randomized into the study. The sample of interest included 20 in the CT group and 18 in the active control group. The primary outcome of percentage time spent frozen during a gait task was significantly improved in the CT group compared to active controls in the on-state. There were no differences in the off-state. Patients who received CT also demonstrated improved processing speed and reduced daytime sleepiness compared to those in the active control. The findings suggest that CT can reduce the severity of FoG in the on-state, however replication in a larger sample is required

Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial.

Importance: Evidence regarding corticosteroid use for severe coronavirus disease 2019 (COVID-19) is limited. Objective: To determine whether hydrocortisone improves outcome for patients with severe COVID-19. Design, Setting, and Participants: An ongoing adaptive platform trial testing multiple interventions within multiple therapeutic domains, for example, antiviral agents, corticosteroids, or immunoglobulin. Between March 9 and June 17, 2020, 614 adult patients with suspected or confirmed COVID-19 were enrolled and randomized within at least 1 domain following admission to an intensive care unit (ICU) for respiratory or cardiovascular organ support at 121 sites in 8 countries. Of these, 403 were randomized to open-label interventions within the corticosteroid domain. The domain was halted after results from another trial were released. Follow-up ended August 12, 2020. Interventions: The corticosteroid domain randomized participants to a fixed 7-day course of intravenous hydrocortisone (50 mg or 100 mg every 6 hours) (n = 143), a shock-dependent course (50 mg every 6 hours when shock was clinically evident) (n = 152), or no hydrocortisone (n = 108). Main Outcomes and Measures: The primary end point was organ support-free days (days alive and free of ICU-based respiratory or cardiovascular support) within 21 days, where patients who died were assigned -1 day. The primary analysis was a bayesian cumulative logistic model that included all patients enrolled with severe COVID-19, adjusting for age, sex, site, region, time, assignment to interventions within other domains, and domain and intervention eligibility. Superiority was defined as the posterior probability of an odds ratio greater than 1 (threshold for trial conclusion of superiority >99%). Results: After excluding 19 participants who withdrew consent, there were 384 patients (mean age, 60 years; 29% female) randomized to the fixed-dose (n = 137), shock-dependent (n = 146), and no (n = 101) hydrocortisone groups; 379 (99%) completed the study and were included in the analysis. The mean age for the 3 groups ranged between 59.5 and 60.4 years; most patients were male (range, 70.6%-71.5%); mean body mass index ranged between 29.7 and 30.9; and patients receiving mechanical ventilation ranged between 50.0% and 63.5%. For the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively, the median organ support-free days were 0 (IQR, -1 to 15), 0 (IQR, -1 to 13), and 0 (-1 to 11) days (composed of 30%, 26%, and 33% mortality rates and 11.5, 9.5, and 6 median organ support-free days among survivors). The median adjusted odds ratio and bayesian probability of superiority were 1.43 (95% credible interval, 0.91-2.27) and 93% for fixed-dose hydrocortisone, respectively, and were 1.22 (95% credible interval, 0.76-1.94) and 80% for shock-dependent hydrocortisone compared with no hydrocortisone. Serious adverse events were reported in 4 (3%), 5 (3%), and 1 (1%) patients in the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively. Conclusions and Relevance: Among patients with severe COVID-19, treatment with a 7-day fixed-dose course of hydrocortisone or shock-dependent dosing of hydrocortisone, compared with no hydrocortisone, resulted in 93% and 80% probabilities of superiority with regard to the odds of improvement in organ support-free days within 21 days. However, the trial was stopped early and no treatment strategy met prespecified criteria for statistical superiority, precluding definitive conclusions. Trial Registration: ClinicalTrials.gov Identifier: NCT02735707

Retrospective neuropsychological profile of patients with Parkinson disease prior to developing visual hallucinations

Visual hallucinations (VH) are a common feature of Parkinson disease (PD); however, the cognitive profile preceding the onset of VH has not yet been established. The present study investigated longitudinal neuropsychological performance of patients with PD who developed VH during follow-up compared to a group who did not develop VH. The patient groups were matched for demographic and disease severity variables at their baseline assessments. Patients who developed VH displayed impaired performance at baseline on measures of psychomotor speed, executive functioning, reaction time, and attention compared to patients who did not develop VH. These results demonstrate a profile of cognitive deficits specific to patients with PD at risk of developing VH and implicate attentional dysfunction in the early pathogenesis of VH

Visual hallucinations are characterized by impaired sensory evidence accumulation : insights from Hierarchical drift diffusion modeling in Parkinson’s disease

Background: Models of hallucinations emphasise an imbalance between sensory input and top-down influences over perception, as false perceptual inference can arise when top-down predictions are afforded too much precision (certainty) relative to sensory evidence. Visual hallucinations in Parkinson’s disease (PD) are associated with lower-level visual and attentional impairments, accompanied by over activity in higher-order association brain networks. PD therefore provides an attractive framework to explore the contributions of bottom-up versus top-down disturbances in hallucinations. Methods: We characterised sensory processing during perceptual decision-making in PD patients with (n=20) and without (n=25) visual hallucinations, and controls (n=12), by fitting a hierarchical drift diffusion model (hDDM) to an attentional task. The hDDM uses Bayesian estimates to decompose task performance into parameters reflecting drift rates of evidence accumulation, decision thresholds and non-decision time. Results: We observed slower drift rates in patients with hallucinations, which were less sensitive to changes in task demand. In contrast, wider decision boundaries and shorter non decision times relative to controls were found in PD regardless of hallucinator status. Inefficient and less flexible sensory evidence accumulation emerge as unique features of PD hallucinators. Conclusions: We integrate these results with evidence accumulation and predictive coding models of hallucinations, suggesting that in PD sensory evidence is less informative, and may therefore be down-weighted resulting in over reliance on top-down influences. Considering impaired drift rates as an approximation of reduced sensory precision, our findings provide a novel computational framework to specify the impairments in sensory processing that contribute to the development of visual hallucinations