Impaired automatic but intact volitional inhibition in primary tic disorders.

The defining character of tics is that they can be transiently suppressed by volitional effort of will, and at a behavioural level this has led to the concept that tics result from a failure of inhibition. However, this logic conflates the mechanism responsible for the production of tics with that used in suppressing them. Volitional inhibition of motor output could be increased to prevent the tic from reaching the threshold for expression, although this has been extensively investigated with conflicting results. Alternatively, automatic inhibition could prevent the initial excitation of the striatal tic focus-a hypothesis we have previously introduced. To reconcile these competing hypotheses, we examined different types of motor inhibition in a group of 19 patients with primary tic disorders and 15 healthy volunteers. We probed proactive and reactive inhibition using the conditional stop-signal task, and applied transcranial magnetic stimulation to the motor cortex, to assess movement preparation and execution. We assessed automatic motor inhibition with the masked priming task. We found that volitional movement preparation, execution and inhibition (proactive and reactive) were not impaired in tic disorders. We speculate that these mechanisms are recruited during volitional tic suppression, and that they prevent expression of the tic by inhibiting the nascent excitation released by the tic generator. In contrast, automatic inhibition was abnormal/impaired in patients with tic disorders. In the masked priming task, positive and negative compatibility effects were found for healthy controls, whereas patients with tics exhibited strong positive compatibility effects, but no negative compatibility effect indicative of impaired automatic inhibition. Patients also made more errors on the masked priming task than healthy control subjects and the types of errors were consistent with impaired automatic inhibition. Errors associated with impaired automatic inhibition were positively correlated with tic severity. We conclude that voluntary movement preparation/generation and volitional inhibition are normal in tic disorders, whereas automatic inhibition is impaired-a deficit that correlated with tic severity and thus may constitute a potential mechanism by which tics are generated.

Motor cortical excitability during voluntary inhibition of involuntary tic movements.

BACKGROUND: Tics can be voluntarily inhibited. However, the neurophysiology of voluntary tic inhibition remains underexplored. The objective of this study was to explore state-dependent effects of voluntary tic inhibition on M1 excitability. METHODS: Neurophysiological assessments (single motor-evoked potentials, corticospinal recruitment curves, short-interval intracortical inhibition, H-reflex) were performed in 14 adults with Tourette syndrome during voluntary tic inhibition and free ticcing. Regressions between behavioral performance and neurophysiological measures were also performed. RESULTS: Voluntary tic inhibition reduced corticospinal excitability: the greater the ability to inhibit tics, the greater was the reduction in excitability. Voluntary tic inhibition was not associated with changes in the excitability of short-interval intracortical inhibition or the H-reflex. CONCLUSIONS: Voluntary inhibition of tics reduces the excitability of corticospinal output. The pattern of neurophysiological findings is consistent with a withdrawal of excitation, but not with modulation of the inhibitory interneuronal mechanisms involved in short-interval intracortical inhibition. © 2018 International Parkinson and Movement Disorder Society.

Dysregulation of lysosomal morphology by pathogenic LRRK2 is corrected by TPC2 inhibition.

Two-pore channels (TPCs) are endolysosomal ion channels implicated in Ca(2+) signalling from acidic organelles. The relevance of these ubiquitous proteins for human disease, however, is unclear. Here, we report that lysosomes are enlarged and aggregated in fibroblasts from Parkinson disease patients with the common G2019S mutation in LRRK2. Defects were corrected by molecular silencing of TPC2, pharmacological inhibition of TPC regulators [Rab7, NAADP and PtdIns(3,5)P2] and buffering local Ca(2+) increases. NAADP-evoked Ca(2+) signals were exaggerated in diseased cells. TPC2 is thus a potential drug target within a pathogenic LRRK2 cascade that disrupts Ca(2+)-dependent trafficking in Parkinson disease.

Protocol for the COG-UK hospital-onset COVID-19 infection (HOCI) multicentre interventional clinical study: evaluating the efficacy of rapid genome sequencing of SARS-CoV-2 in limiting the spread of COVID-19 in UK NHS hospitals.

OBJECTIVES: Nosocomial transmission of SARS-CoV-2 has been a significant cause of mortality in National Health Service (NHS) hospitals during the COVID-19 pandemic. The COG-UK Consortium Hospital-Onset COVID-19 Infections (COG-UK HOCI) study aims to evaluate whether the use of rapid whole-genome sequencing of SARS-CoV-2, supported by a novel probabilistic reporting methodology, can inform infection prevention and control (IPC) practice within NHS hospital settings. DESIGN: Multicentre, prospective, interventional, superiority study. SETTING: 14 participating NHS hospitals over winter-spring 2020/2021 in the UK. PARTICIPANTS: Eligible patients must be admitted to hospital with first-confirmed SARS-CoV-2 PCR-positive test result >48 hour from time of admission, where COVID-19 diagnosis not suspected on admission. The projected sample size is 2380 patients. INTERVENTION: The intervention is the return of a sequence report, within 48 hours in one phase (rapid local lab processing) and within 5-10 days in a second phase (mimicking central lab), comparing the viral genome from an eligible study participant with others within and outside the hospital site. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary outcomes are incidence of Public Health England (PHE)/IPC-defined SARS-CoV-2 hospital-acquired infection during the baseline and two interventional phases, and proportion of hospital-onset cases with genomic evidence of transmission linkage following implementation of the intervention where such linkage was not suspected by initial IPC investigation. Secondary outcomes include incidence of hospital outbreaks, with and without sequencing data; actual and desirable changes to IPC actions; periods of healthcare worker (HCW) absence. Health economic analysis will be conducted to determine cost benefit of the intervention. A process evaluation using qualitative interviews with HCWs will be conducted alongside the study. TRIAL REGISTRATION NUMBER: ISRCTN50212645. Pre-results stage. This manuscript is based on protocol V.6.0. 2 September 2021.

An Endosomal NAADP-Sensitive Two-Pore Ca2+ Channel Regulates ER-Endosome Membrane Contact Sites to Control Growth Factor Signaling.

Membrane contact sites are regions of close apposition between organelles that facilitate information transfer. Here, we reveal an essential role for Ca2+ derived from the endo-lysosomal system in maintaining contact between endosomes and the endoplasmic reticulum (ER). Antagonizing action of the Ca2+-mobilizing messenger NAADP, inhibiting its target endo-lysosomal ion channel, TPC1, and buffering local Ca2+ fluxes all clustered and enlarged late endosomes/lysosomes. We show that TPC1 localizes to ER-endosome contact sites and is required for their formation. Reducing NAADP-dependent contacts delayed EGF receptor de-phosphorylation consistent with close apposition of endocytosed receptors with the ER-localized phosphatase PTP1B. In accord, downstream MAP kinase activation and mobilization of ER Ca2+ stores by EGF were exaggerated upon NAADP blockade. Membrane contact sites between endosomes and the ER thus emerge as Ca2+-dependent hubs for signaling.

Methods for monitoring lysosomal morphology.

Lysosomes are abundant organelles best known for their crucial role in macromolecule turnover. Lysosome dysfunction features in several diseases exemplified by the lysosomal storage disorders and is often associated with marked changes in lysosome structure. Lysosomal morphology may therefore serve as a sensitive readout of endocytic well-being. Here we describe methods for monitoring lysosome morphology in fixed and live cells using fluorescent probes and electron microscopy.

Jumping to conclusions and the persistence of delusional beliefs in first episode psychosis.

BACKGROUND: Cognitive biases may contribute to delusion persistence. We tested this in a longitudinal study of first episode psychosis (FEP). METHODS: 34 FEP patients completed assessments of delusions and Jumping to Conclusions (JTC) at baseline and 12-month follow-up. RESULTS: JTC was associated with baseline delusion severity (t(32)=2.7, p=0.01). Baseline delusions persisted at follow-up for 8/20 participants (40%), who all jumped to conclusions (8/8, 100%), compared to half of those with no or changeable delusions (14/26, 54%; χ(2) (df=1)=5.7, p=0.03; Phi=0.4). CONCLUSION: Findings implicate cognitive biases in delusion persistence, and support the potential to reduce delusions through reasoning-focused interventions.