A Multicenter Examination and Strategic Revisions of the Yale Global Tic Severity Scale

Objective To examine the internal consistency and distribution of the Yale Global Tic Severity Scale (YGTSS) scores to inform modification of the measure. Methods This cross-sectional study included 617 participants with a tic disorder (516 children and 101 adults), who completed an age-appropriate diagnostic interview and the YGTSS to evaluate tic symptom severity. The distributions of scores on YGTSS dimensions were evaluated for normality and skewness. For dimensions that were skewed across motor and phonic tics, a modified Delphi consensus process was used to revise selected anchor points. Results Children and adults had similar clinical characteristics, including tic symptom severity. All participants were examined together. Strong internal consistency was identified for the YGTSS Motor Tic score (α = 0.80), YGTSS Phonic Tic score (α = 0.87), and YGTSS Total Tic score (α = 0.82). The YGTSS Total Tic and Impairment scores exhibited relatively normal distributions. Several subscales and individual item scales departed from a normal distribution. Higher scores were more often used on the Motor Tic Number, Frequency, and Intensity dimensions and the Phonic Tic Frequency dimension. By contrast, lower scores were more often used on Motor Tic Complexity and Interference, and Phonic Tic Number, Intensity, Complexity, and Interference. Conclusions The YGTSS exhibits good internal consistency across children and adults. The parallel findings across Motor and Phonic Frequency, Complexity, and Interference dimensions prompted minor revisions to the anchor point description to promote use of the full range of scores in each dimension. Specific minor revisions to the YGTSS Phonic Tic Symptom Checklist were also proposed

A Flicker Change Detection Task Reveals Object-in-Scene Memory Across Species

Tests of recognition memory in macaques typically assay memory for objects or isolated images, over time spans of seconds to hours from stimulus presentation, and/or require extensive training. Here, we propose a new application of the flicker change detection task that could measure object-in-scene memory days after single-trial exposures. In three experiments, participants searched for a changing object – or “target” – embedded within a scene as their eye movements were tracked. For new targets-in-scenes, the change is difficult to detect and requires extensive search. Once the target is found, however, the change becomes obvious. We reasoned that the decreased times required to find a target in a repeated scene would indicate memory for the target. In humans, targets were found faster when the targets-and-scenes were explicitly remembered than when they were forgotten, or had never been seen before. This led to faster repeated-trial compared to novel-trial search times. Based solely on repeated-trial search times, we were able to select distributions comprised of predominantly remembered or predominantly forgotten trials. Macaques exhibited the same repetition effects as humans, suggesting that remembered trials could be dissociated from novel or forgotten trials using the same procedures we established in humans. Finally, an anterograde amnesic patient with damage that included the medial temporal lobe (MTL) showed no search time differences, suggesting that memory revealed through search times on this task requires MTL integrity. Together, these findings indicate that the time required to locate a changing object reveals object-in-scene memory over long retention intervals in humans and macaques

Searching for Exoplanets Using a Microresonator Astrocomb

Detection of weak radial velocity shifts of host stars induced by orbiting planets is an important technique for discovering and characterizing planets beyond our solar system. Optical frequency combs enable calibration of stellar radial velocity shifts at levels required for detection of Earth analogs. A new chip-based device, the Kerr soliton microcomb, has properties ideal for ubiquitous application outside the lab and even in future space-borne instruments. Moreover, microcomb spectra are ideally suited for astronomical spectrograph calibration and eliminate filtering steps required by conventional mode-locked-laser frequency combs. Here, for the calibration of astronomical spectrographs, we demonstrate an atomic/molecular line-referenced, near-infrared soliton microcomb. Efforts to search for the known exoplanet HD 187123b were conducted at the Keck-II telescope as a first in-the-field demonstration of microcombs

Examining the Role of Narrative Performance Appraisal Comments on Performance

Despite their prevalence in performance appraisal systems and purported importance in theory, narrative performance appraisal comments have been rarely examined. This study aimed to contribute to the literature by developing and testing a theory of quality narrative feedback. The author argues that managerial feedback that is both directive (i.e., lengthy, specific, and includes goals) and motivational (i.e., positive and high in interactional justice) would be related to year-lagged performance. Negative and positive emotions are also proposed as mediators of this relationship. Performance appraisal comments were coded for a sample of 1,019 clinical nurses. The structural equations modeling results provided preliminary evidence that feedback favorability and interactional justice demonstrated significant direct and indirect (through positive and negative emotion) effects on year-lagged employee performance. © 2013 Copyright Taylor and Francis Group, LLC

From mechanisms to markers: novel noninvasive EEG proxy markers of the neural excitation and inhibition system in humans.

Brain function is a product of the balance between excitatory and inhibitory (E/I) brain activity. Variation in the regulation of this activity is thought to give rise to normal variation in human traits, and disruptions are thought to potentially underlie a spectrum of neuropsychiatric conditions (e.g., Autism, Schizophrenia, Downs' Syndrome, intellectual disability). Hypotheses related to E/I dysfunction have the potential to provide cross-diagnostic explanations and to combine genetic and neurological evidence that exists within and between psychiatric conditions. However, the hypothesis has been difficult to test because: (1) it lacks specificity-an E/I dysfunction could pertain to any level in the neural system- neurotransmitters, single neurons/receptors, local networks of neurons, or global brain balance - most researchers do not define the level at which they are examining E/I function; (2) We lack validated methods for assessing E/I function at any of these neural levels in humans. As a result, it has not been possible to reliably or robustly test the E/I hypothesis of psychiatric disorders in a large cohort or longitudinal patient studies. Currently available, in vivo markers of E/I in humans either carry significant risks (e.g., deep brain electrode recordings or using Positron Emission Tomography (PET) with radioactive tracers) and/or are highly restrictive (e.g., limited spatial extent for Transcranial Magnetic Stimulation (TMS) and Magnetic Resonance Spectroscopy (MRS). More recently, a range of novel Electroencephalography (EEG) features has been described, which could serve as proxy markers for E/I at a given level of inference. Thus, in this perspective review, we survey the theories and experimental evidence underlying 6 novel EEG markers and their biological underpinnings at a specific neural level. These cheap-to-record and scalable proxy markers may offer clinical utility for identifying subgroups within and between diagnostic categories, thus directing more tailored sub-grouping and, therefore, treatment strategies. However, we argue that studies in clinical populations are premature. To maximize the potential of prospective EEG markers, we first need to understand the link between underlying E/I mechanisms and measurement techniques

Identification and functional modelling of plausibly causative cis-regulatory variants in a highly-selected cohort with X-linked intellectual disability.

Identifying causative variants in cis-regulatory elements (CRE) in neurodevelopmental disorders has proven challenging. We have used in vivo functional analyses to categorize rigorously filtered CRE variants in a clinical cohort that is plausibly enriched for causative CRE mutations: 48 unrelated males with a family history consistent with X-linked intellectual disability (XLID) in whom no detectable cause could be identified in the coding regions of the X chromosome (chrX). Targeted sequencing of all chrX CRE identified six rare variants in five affected individuals that altered conserved bases in CRE targeting known XLID genes and segregated appropriately in families. Two of these variants, FMR1CRE and TENM1CRE, showed consistent site- and stage-specific differences of enhancer function in the developing zebrafish brain using dual-color fluorescent reporter assay. Mouse models were created for both variants. In male mice Fmr1CRE induced alterations in neurodevelopmental Fmr1 expression, olfactory behavior and neurophysiological indicators of FMRP function. The absence of another likely causative variant on whole genome sequencing further supported FMR1CRE as the likely basis of the XLID in this family. Tenm1CRE mice showed no phenotypic anomalies. Following the release of gnomAD 2.1, reanalysis showed that TENM1CRE exceeded the maximum plausible population frequency of a XLID causative allele. Assigning causative status to any ultra-rare CRE variant remains problematic and requires disease-relevant in vivo functional data from multiple sources. The sequential and bespoke nature of such analyses renders them time-consuming and challenging to scale for routine clinical use

Guidelines on the diagnosis, clinical assessments, treatment and management for CLN2 disease patients

Background: CLN2 disease (Neuronal Ceroid Lipofuscinosis Type 2) is an ultra-rare, neurodegenerative lysosomal storage disease, caused by an enzyme deficiency of tripeptidyl peptidase 1 (TPP1). Lack of disease awareness and the non-specificity of presenting symptoms often leads to delayed diagnosis. These guidelines provide robust evidence-based, expert-agreed recommendations on the risks/benefits of disease-modifying treatments and the medical interventions used to manage this condition. Methods: An expert mapping tool process was developed ranking multidisciplinary professionals, with knowledge of CLN2 disease, diagnostic or management experience of CLN2 disease, or family support professionals. Individuals were sequentially approached to identify two chairs, ensuring that the process was transparent and unbiased. A systematic literature review of published evidence using Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidance was independently and simultaneously conducted to develop key statements based upon the strength of the publications. Clinical care statements formed the basis of an international modified Delphi consensus determination process using the virtual meeting (Within3) online platform which requested experts to agree or disagree with any changes. Statements reaching the consensus mark became the guiding statements within this manuscript, which were subsequently assessed against the Appraisal of Guidelines for Research and Evaluation (AGREEII) criteria. Results: Twenty-one international experts from 7 different specialities, including a patient advocate, were identified. Fifty-three guideline statements were developed covering 13 domains: General Description and Statements, Diagnostics, Clinical Recommendations and Management, Assessments, Interventions and Treatment, Additional Care Considerations, Social Care Considerations, Pain Management, Epilepsy / Seizures, Nutritional Care Interventions, Respiratory Health, Sleep and Rest, and End of Life Care. Consensus was reached after a single round of voting, with one exception which was revised, and agreed by 100% of the SC and achieved 80% consensus in the second voting round. The overall AGREE II assessment score obtained for the development of the guidelines was 5.7 (where 1 represents the lowest quality, and 7 represents the highest quality). Conclusion: This program provides robust evidence- and consensus-driven guidelines that can be used by all healthcare professionals involved in the management of patients with CLN2 disease and other neurodegenerative disorders. This addresses the clinical need to complement other information available

Cross-sectional and longitudinal neuroanatomical profiles of distinct clinical (adaptive) outcomes in autism

Individuals with autism spectrum disorder (henceforth referred to as autism) display significant variation in clinical outcome. For instance, across age, some individuals’ adaptive skills naturally improve or remain stable, while others’ decrease. To pave the way for ‘precision-medicine’ approaches, it is crucial to identify the cross-sectional and, given the developmental nature of autism, longitudinal neurobiological (including neuroanatomical and linked genetic) correlates of this variation. We conducted a longitudinal follow-up study of 333 individuals (161 autistic and 172 neurotypical individuals, aged 6–30 years), with two assessment time points separated by ~12–24 months. We collected behavioural (Vineland Adaptive Behaviour Scale-II, VABS-II) and neuroanatomical (structural magnetic resonance imaging) data. Autistic participants were grouped into clinically meaningful “Increasers”, “No-changers”, and “Decreasers” in adaptive behaviour (based on VABS-II scores). We compared each clinical subgroup’s neuroanatomy (surface area and cortical thickness at T1, ∆T (intra-individual change) and T2) to that of the neurotypicals. Next, we explored the neuroanatomical differences’ potential genomic associates using the Allen Human Brain Atlas. Clinical subgroups had distinct neuroanatomical profiles in surface area and cortical thickness at baseline, neuroanatomical development, and follow-up. These profiles were enriched for genes previously associated with autism and for genes previously linked to neurobiological pathways implicated in autism (e.g. excitation-inhibition systems). Our findings suggest that distinct clinical outcomes (i.e. intra-individual change in clinical profiles) linked to autism core symptoms are associated with atypical cross-sectional and longitudinal, i.e. developmental, neurobiological profiles. If validated, our findings may advance the development of interventions, e.g. targeting mechanisms linked to relatively poorer outcomes

Sensory salience processing moderates attenuated gazes on faces in autism spectrum disorder: a case–control study

Background: Attenuated social attention is a key marker of autism spectrum disorder (ASD). Recent neuroimaging findings also emphasize an altered processing of sensory salience in ASD. The locus coeruleus-norepinephrine system (LC-NE) has been established as a modulator of this sensory salience processing (SSP). We tested the hypothesis that altered LC-NE functioning contributes to different SSP and results in diverging social attention in ASD. Methods: We analyzed the baseline eye-tracking data of the EU-AIMS Longitudinal European Autism Project (LEAP) for subgroups of autistic participants (n = 166, age = 6-30 years, IQ = 61-138, gender [female/male] = 41/125) or neurotypical development (TD; n = 166, age = 6-30 years, IQ = 63-138, gender [female/male] = 49/117) that were matched for demographic variables and data quality. Participants watched brief movie scenes (k = 85) depicting humans in social situations (human) or without humans (non-human). SSP was estimated by gazes on physical and motion salience and a corresponding pupillary response that indexes phasic activity of the LC-NE. Social attention is estimated by gazes on faces via manual areas of interest definition. SSP is compared between groups and related to social attention by linear mixed models that consider temporal dynamics within scenes. Models are controlled for comorbid psychopathology, gaze behavior, and luminance. Results: We found no group differences in gazes on salience, whereas pupillary responses were associated with altered gazes on physical and motion salience. In ASD compared to TD, we observed pupillary responses that were higher for non-human scenes and lower for human scenes. In ASD, we observed lower gazes on faces across the duration of the scenes. Crucially, this different social attention was influenced by gazes on physical salience and moderated by pupillary responses. Limitations: The naturalistic study design precluded experimental manipulations and stimulus control, while effect sizes were small to moderate. Covariate effects of age and IQ indicate that the findings differ between age and developmental subgroups. Conclusions: Pupillary responses as a proxy of LC-NE phasic activity during visual attention are suggested to modulate sensory salience processing and contribute to attenuated social attention in ASD

Macrophage fumarate hydratase restrains mtRNA-mediated interferon production

Metabolic rewiring underlies the effector functions of macrophages1-3, but the mechanisms involved remain incompletely defined. Here, using unbiased metabolomics and stable isotope-assisted tracing, we show that an inflammatory aspartate-argininosuccinate shunt is induced following lipopolysaccharide stimulation. The shunt, supported by increased argininosuccinate synthase (ASS1) expression, also leads to increased cytosolic fumarate levels and fumarate-mediated protein succination. Pharmacological inhibition and genetic ablation of the tricarboxylic acid cycle enzyme fumarate hydratase (FH) further increases intracellular fumarate levels. Mitochondrial respiration is also suppressed and mitochondrial membrane potential increased. RNA sequencing and proteomics analyses demonstrate that there are strong inflammatory effects resulting from FH inhibition. Notably, acute FH inhibition suppresses interleukin-10 expression, which leads to increased tumour necrosis factor secretion, an effect recapitulated by fumarate esters. Moreover, FH inhibition, but not fumarate esters, increases interferon-β production through mechanisms that are driven by mitochondrial RNA (mtRNA) release and activation of the RNA sensors TLR7, RIG-I and MDA5. This effect is recapitulated endogenously when FH is suppressed following prolonged lipopolysaccharide stimulation. Furthermore, cells from patients with systemic lupus erythematosus also exhibit FH suppression, which indicates a potential pathogenic role for this process in human disease. We therefore identify a protective role for FH in maintaining appropriate macrophage cytokine and interferon responses