Sustained Extracellular Electrical Stimulation Modulates the Permeability of Gap Junctions in rd1 Mouse Retina with Photoreceptor Degeneration.

Neurons build vast gap junction-coupled networks (GJ-nets) that are permeable to ions or small molecules, enabling lateral signaling. Herein, we investigate (1) the effect of blinding diseases on GJ-nets in mouse retinas and (2) the impact of electrical stimulation on GJ permeability. GJ permeability was traced in the acute retinal explants of blind retinal degeneration 1 (rd1) mice using the GJ tracer neurobiotin. The tracer was introduced via the edge cut method into the GJ-net, and its spread was visualized in histological preparations (fluorescent tagged) using microscopy. Sustained stimulation was applied to modulate GJ permeability using a single large electrode. Our findings are: (1) The blind rd1 retinas displayed extensive intercellular coupling via open GJs. Three GJ-nets were identified: horizontal, amacrine, and ganglion cell networks. (2) Sustained stimulation significantly diminished the tracer spread through the GJs in all the cell layers, as occurs with pharmaceutical inhibition with carbenoxolone. We concluded that the GJ-nets of rd1 retinas remain coupled and functional after blinding disease and that their permeability is regulatable by sustained stimulation. These findings are essential for understanding molecular signaling in diseases over coupled networks and therapeutic approaches using electrical implants, such as eliciting visual sensations or suppressing cortical seizures.

Effects of DRD2/ANKK1 and COMT Val158Met polymorphisms on stabilization against and adaptation to unexpected events.

Genetic variations affecting dopaminergic neuromodulation such as the DRD2/ANKK1 and the COMT Val158Met polymorphisms contribute to goal-directed behavior that requires a balance between stabilization and updating of current states and behaviors. Dopamine is also thought to be relevant for encoding of surprise signals to sensory input and adaptive learning. A link between goal-directed behavior and learning from surprise is therefore plausible. In the present fMRI study, we investigated whether DRD2 and COMT polymorphisms are related to behavioral responses and neural signals in the caudate nucleus and dlPFC during updating or stabilizing internal models of predictable digit sequences. To-be-detected switches between sequences and to-be-ignored digit omissions within a sequence varied by information-theoretic quantities of surprise and entropy. We found that A1 noncarriers and Val-carriers showed a lower response threshold along with increased caudate and dlPFC activation to surprising switches compared with A1-carriers and Met-homozygotes, whose dlPFC activity increased with decreasing switch surprise. In contrast, there were overall smaller differences in behavioral and neural modulation by drift surprise. Our results suggest that the impact of dopamine-relevant polymorphisms in the flexibility-stability trade-off may result in part from the role of dopamine in encoding the weight afforded to events requiring updating or stabilization.

Network degeneration in Parkinson's disease: multimodal imaging of nigro-striato-cortical dysfunction.

The spreading hypothesis of neurodegeneration assumes an expansion of neural pathologies along existing neural pathways. Multimodal neuroimaging studies have demonstrated distinct topographic patterns of cerebral pathologies in neurodegeneration. For Parkinson's disease the hypothesis so far rests largely on histopathological evidence of α-synuclein spreading in a characteristic pattern and progressive nigrostriatal dopamine depletion. Functional consequences of nigrostriatal dysfunction on cortical activity remain to be elucidated. Our goal was to investigate multimodal imaging correlates of degenerative processes in Parkinson's disease by assessing dopamine depletion and its potential effect on striatocortical connectivity networks and cortical metabolism in relation to parkinsonian symptoms. We combined 18F-DOPA-PET, 18F-fluorodeoxyglucose (FDG)-PET and resting state functional MRI to multimodally characterize network alterations in Parkinson's disease. Forty-two patients with mild-to-moderate stage Parkinson's disease and 14 age-matched healthy control subjects underwent a multimodal imaging protocol and comprehensive clinical examination. A voxel-wise group comparison of 18F-DOPA uptake identified the exact location and extent of putaminal dopamine depletion in patients. Resulting clusters were defined as seeds for a seed-to-voxel functional connectivity analysis. 18F-FDG metabolism was compared between groups at a whole-brain level and uptake values were extracted from regions with reduced putaminal connectivity. To unravel associations between dopaminergic activity, striatocortical connectivity, glucose metabolism and symptom severity, correlations between normalized uptake values, seed-to-cluster ß-values and clinical parameters were tested while controlling for age and dopaminergic medication. Aside from cortical hypometabolism, 18F-FDG-PET data for the first time revealed a hypometabolic midbrain cluster in patients with Parkinson's disease that comprised caudal parts of the bilateral substantia nigra pars compacta. Putaminal dopamine synthesis capacity was significantly reduced in the bilateral posterior putamen and correlated with ipsilateral nigral 18F-FDG uptake. Resting state functional MRI data indicated significantly reduced functional connectivity between the dopamine depleted putaminal seed and cortical areas primarily belonging to the sensorimotor network in patients with Parkinson's disease. In the inferior parietal cortex, hypoconnectivity in patients was significantly correlated with lower metabolism (left P = 0.021, right P = 0.018). Of note, unilateral network alterations quantified with different modalities corresponded with contralateral motor impairments. In conclusion, our results support the hypothesis that degeneration of nigrostriatal fibres functionally impairs distinct striatocortical connections, disturbing the efficient interplay between motor processing areas and impairing motor control in patients with Parkinson's disease. The present study is the first to reveal trimodal evidence for network-dependent degeneration in Parkinson's disease by outlining the impact of functional nigrostriatal pathway impairment on striatocortical functional connectivity networks and cortical metabolism.

Multidomain cognitive impairment in non-hospitalized patients with the post-COVID-19 syndrome: results from a prospective monocentric cohort.

BACKGROUND: A fraction of patients with asymptomatic to mild/moderate acute COVID-19 disease report cognitive deficits as part of the post-COVID-19 syndrome. This study aimed to assess the neuropsychological profile of these patients. METHODS: Assessment at baseline (three months or more following acute COVID-19) of a monocentric prospective cohort of patients with post-COVID-19 syndrome. Multidomain neuropsychological tests were performed, and questionnaires on depression, anxiety, fatigue, sleep, and general health status were administered. RESULTS: Of the 58 patients screened, six were excluded due to possible alternative causes of cognitive impairment (major depression, neurodegenerative disease). Of the remaining 52 individuals, only one had a below-threshold screening result on Mini-Mental State Examination, and 13 scored below the cut-off on Montreal Cognitive Assessment. Extended neuropsychological testing revealed a neurocognitive disorder (NCD) in 31 (59.6%) participants with minor NCD in the majority of cases (n = 26). In patients with NCD, the cognitive domains learning/memory and executive functions were impaired in 60.7%, complex attention in 51.6%, language in 35.5%, and perceptual-motor function in 29.0%. Cognitive profiles were associated with daytime sleepiness but not with depression, anxiety, sleep quality, total general health status, or fatigue. CONCLUSION: Neurocognitive impairment can be confirmed in around 60% of individuals with self-reported deficits as part of post-COVID-19 syndrome following a mild acute COVID-19 disease course. Notably, screening tests cannot reliably detect this dysfunction. Standard psychiatric assessments showed no association with cognitive profiles. Longitudinal studies are needed to further evaluate the course of neurocognitive deficits and clarify pathophysiology.

Clustering of Parkinson subtypes reveals strong influence of DRD2 polymorphism and gender.

Most classification approaches for idiopathic Parkinson's disease subtypes primarily focus on motor and non-motor symptoms. Besides these characteristics, other features, including gender or genetic polymorphism of dopamine receptors are potential factors influencing the disease's phenotype. By utilizing a kmeans-clustering algorithm we were able to identify three subgroups mainly characterized by gender, DRD2 Taq1A (rs1800497) polymorphism-associated with changes in dopamine signaling in the brain-and disease progression. A subsequent regression analysis of these subgroups further suggests an influence of their characteristics on the daily levodopa dosage, an indicator for medication response. These findings could promote further enhancements in individualized therapies for idiopathic Parkinson's disease.