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Diagnostic Performance of Cortical Lesions and the Central Vein Sign in Multiple Sclerosis.
IMPORTANCE: Multiple sclerosis (MS) misdiagnosis remains an important issue in clinical practice. OBJECTIVE: To quantify the performance of cortical lesions (CLs) and central vein sign (CVS) in distinguishing MS from other conditions showing brain lesions on magnetic resonance imaging (MRI). DESIGN, SETTING, AND PARTICIPANTS: This was a retrospective, cross-sectional multicenter study, with clinical and MRI data acquired between January 2010 and May 2020. Centralized MRI analysis was conducted between July 2020 and December 2022 by 2 raters blinded to participants' diagnosis. Participants were recruited from 14 European centers and from a multicenter pan-European cohort. Eligible participants had a diagnosis of MS, clinically isolated syndrome (CIS), or non-MS conditions; availability of a brain 3-T MRI scan with at least 1 sequence suitable for CL and CVS assessment; presence of T2-hyperintense white matter lesions (WMLs). A total of 1051 individuals were included with either MS/CIS (n = 599; 386 [64.4%] female; mean [SD] age, 41.5 [12.3] years) or non-MS conditions (including other neuroinflammatory disorders, cerebrovascular disease, migraine, and incidental WMLs in healthy control individuals; n = 452; 302 [66.8%] female; mean [SD] age, 49.2 [14.5] years). Five individuals were excluded due to missing clinical or demographic information (n = 3) or unclear diagnosis (n = 2). EXPOSURES: MS/CIS vs non-MS conditions. MAIN OUTCOMES AND MEASURES: Area under the receiver operating characteristic curves (AUCs) were used to explore the diagnostic performance of CLs and the CVS in isolation and in combination; sensitivity, specificity, and accuracy were calculated for various cutoffs. The diagnostic importance of CLs and CVS compared to conventional MRI features (ie, presence of infratentorial, periventricular, and juxtacortical WMLs) was ranked with a random forest model. RESULTS: The presence of CLs and the previously proposed 40% CVS rule had a sensitivity, specificity, and accuracy for MS of 59.0% (95% CI, 55.1-62.8), 93.6% (95% CI, 91.4-95.6), and 73.9% (95% CI, 71.6-76.3) and 78.7% (95% CI, 75.5-82.0), 86.0% (95% CI, 82.1-89.5), and 81.5% (95% CI, 78.9-83.7), respectively. The diagnostic performance of the CVS (AUC, 0.89 [95% CI, 0.86-0.91]) was superior to that of CLs (AUC, 0.77 [95% CI, 0.75-0.80]; P
Structural and non-coding variants increase the diagnostic yield of clinical whole genome sequencing for rare diseases.
BACKGROUND: Whole genome sequencing is increasingly being used for the diagnosis of patients with rare diseases. However, the diagnostic yields of many studies, particularly those conducted in a healthcare setting, are often disappointingly low, at 25-30%. This is in part because although entire genomes are sequenced, analysis is often confined to in silico gene panels or coding regions of the genome. METHODS: We undertook WGS on a cohort of 122 unrelated rare disease patients and their relatives (300 genomes) who had been pre-screened by gene panels or arrays. Patients were recruited from a broad spectrum of clinical specialties. We applied a bioinformatics pipeline that would allow comprehensive analysis of all variant types. We combined established bioinformatics tools for phenotypic and genomic analysis with our novel algorithms (SVRare, ALTSPLICE and GREEN-DB) to detect and annotate structural, splice site and non-coding variants. RESULTS: Our diagnostic yield was 43/122 cases (35%), although 47/122 cases (39%) were considered solved when considering novel candidate genes with supporting functional data into account. Structural, splice site and deep intronic variants contributed to 20/47 (43%) of our solved cases. Five genes that are novel, or were novel at the time of discovery, were identified, whilst a further three genes are putative novel disease genes with evidence of causality. We identified variants of uncertain significance in a further fourteen candidate genes. The phenotypic spectrum associated with RMND1 was expanded to include polymicrogyria. Two patients with secondary findings in FBN1 and KCNQ1 were confirmed to have previously unidentified Marfan and long QT syndromes, respectively, and were referred for further clinical interventions. Clinical diagnoses were changed in six patients and treatment adjustments made for eight individuals, which for five patients was considered life-saving. CONCLUSIONS: Genome sequencing is increasingly being considered as a first-line genetic test in routine clinical settings and can make a substantial contribution to rapidly identifying a causal aetiology for many patients, shortening their diagnostic odyssey. We have demonstrated that structural, splice site and intronic variants make a significant contribution to diagnostic yield and that comprehensive analysis of the entire genome is essential to maximise the value of clinical genome sequencing.
Perspectives of Implementation of Closed-Loop Deep Brain Stimulation: From Neurological to Psychiatric Disorders.
BACKGROUND: Deep brain stimulation (DBS) is a highly efficient, evidence-based therapy to alleviate symptoms and improve quality of life in movement disorders such as Parkinson's disease, essential tremor, and dystonia, which is also being applied in several psychiatric disorders, such as obsessive-compulsive disorder and depression, when they are otherwise resistant to therapy. SUMMARY: At present, DBS is clinically applied in the so-called open-loop approach, with fixed stimulation parameters, irrespective of the patients' clinical state(s). This approach ignores the brain states or feedback from the central nervous system or peripheral recordings, thus potentially limiting its efficacy and inducing side effects by stimulation of the targeted networks below or above the therapeutic level. KEY MESSAGES: The currently emerging closed-loop (CL) approaches are designed to adapt stimulation parameters to the electrophysiological surrogates of disease symptoms and states. CL-DBS paves the way for adaptive personalized DBS protocols. This review elaborates on the perspectives of the CL technology and discusses its opportunities as well as its potential pitfalls for both clinical and research use in neuropsychiatric disorders.
A mechanism for hippocampal memory recall based on excitatory-inhibitory fluctuations in neocortex
ABSTRACT The brain has a remarkable capacity to acquire and store memories that can later be selectively recalled. These processes are supported by the hippocampus which is thought to index memory recall by reinstating information stored across distributed neocortical circuits. However, the mechanism that supports this interaction remains unclear. Here, in humans, we show that recall of a visual cue from a paired associate is accompanied by a transient increase in the ratio between glutamate and GABA in visual cortex. Moreover, these excitatory-inhibitory fluctuations are predicted by activity in the hippocampus. These data suggest the hippocampus gates memory recall by indexing information stored across neocortical circuits using a disinhibitory mechanism.
Dentate Spike Waveforms
This dataset contains the waveforms of dentate spikes extracted from the local field potential (sampled at 1 kHz) of the dorsal hippocampal formation of 8 mice using linear probes. These animals were subjects of research across three different laboratories, and the raw data from these recordings have been previously analyzed in distinct original studies. For comprehensive information, consult the relevant publication linked below. Each file within this dataset corresponds to the data collected from a single animal and is structured as a 3D matrix of channels by dentate spikes by amplitude samples. Each dentate spike is composed of 401 amplitude samples centred at the peak, with each sample representing a one-millisecond time bin. I.e., being the DS peak at t=0, the time window ranges from −200 to 200 ms. The number of channels varies according to the linear probe used in each mouse. The index of the channel in hilus, which was chosen for the DS detection, is indicated below: Mouse A (reference 4) – channel index 8 Mouse B1 (reference 3) – channel index 31 Mouse B2 (reference 2)– channel index 25 Mouse B3 (reference 2)– channel index 30 Mouse C1 (reference 1)– channel index 15 Mouse C2 (reference 1)– channel index 27 Mouse C3 (reference 1)– channel index 26 Mouse C4 (reference 1)– channel index 31 For guidance on how to read the data, please visit the following link https://github.com/tortlab/dentate-spikes. Related pre-print Santiago RMM, Lopes-dos-Santos V, Aery Jones, EA, Huang Y, Dupret D, Tort, ABL Waveform-based classification of dentate spikes 2023. bioRxiv doi: 10.1101/2023.10.24.563826 References 1. Aery Jones EA, Rao A, Zilberter M, Djukic B, Bant JS, Gillespie AK, Koutsodendris N, Nelson M, Yoon SY, Huang K, Yuan H, Gill TM, Huang Y, Frank LM. Dentate gyrus and CA3 GABAergic interneurons bidirectionally modulate signatures of internal and external drive to CA1. 2021. Cell Rep. 37(13):110159. doi: 10.1016/j.celrep.2021.110159 2. Lopes-dos-Santos V, Brizee D, Dupret D. Spatio-temporal organization of network activity patterns in the hippocampus. 2023. bioRxiv doi: 10.1101/2023.10.17.562689. 3. Lopes-dos-Santos V, van de Ven GM, Morley A, Trouche S, Campo-Urriza N, Dupret D. Parsing Hippocampal Theta Oscillations by Nested Spectral Components during Spatial Exploration and Memory-Guided Behavior. 2018. Neuron. 100(4):940-952.e7. doi: 10.1016/j.neuron.2018.09.031. 4. Senzai Y, Buzsáki G. Physiological Properties and Behavioral Correlates of Hippocampal Granule Cells and Mossy Cells. 2017. Neuron. 93(3):691-704.e5. doi: 10.1016/j.neuron.2016.12.011.
Zfp36l1 establishes the high affinity CD8 T cell response by directly linking TCR affinity to cytokine sensing.
How individual T cells compete for and respond to IL-2 at the molecular level, and, as a consequence, how this shapes population dynamics and the selection of high affinity clones is still poorly understood. Here we describe how the RNA binding protein ZFP36L1, acts as a sensor of TCR affinity to promote clonal expansion of high affinity CD8 T cells. As part of an incoherent feed forward loop ZFP36L1 has a non-redundant role in suppressing multiple negative regulators of cytokine signalling and mediating a selection mechanism based on competition for IL-2. We suggest that ZFP36L1 acts as a sensor of antigen affinity and establishes dominance of high affinity T cells by installing a hierarchical response to IL-2. This article is protected by copyright. All rights reserved.
Outlier detection of vital sign trajectories from COVID-19 patients.
In this work, we present a novel trajectory comparison algorithm to identify abnormal vital sign trends, with the aim of improving recognition of deteriorating health.There is growing interest in continuous wearable vital sign sensors for monitoring patients remotely at home. These monitors are usually coupled to an alerting system, which is triggered when vital sign measurements fall outside a predefined normal range. Trends in vital signs, such as increasing heart rate, are often indicative of deteriorating health, but are rarely incorporated into alerting systems.We introduce a dynamic time warp distance-based measure to compare time series trajectories. We split each multi-variable sign time series into 180 minute, non-overlapping epochs. We then calculate the distance between all pairs of epochs. Each epoch is characterized by its mean pairwise distance (average link distance) to all other epochs, with clusters forming with nearby epochs.We demonstrate in synthetically generated data that this method can identify abnormal epochs and cluster epochs with similar trajectories. We then apply this method to a real-world data set of vital signs from 8 patients who had recently been discharged from hospital after contracting COVID-19. We show how outlier epochs correspond well with the abnormal vital signs and identify patients who were subsequently readmitted to hospital.
Left Vagus Stimulation Modulates Contralateral Subthalamic β Power Improving the Gait in Parkinson's Disease.
BACKGROUND: Transcutaneous vagus nerve stimulation (VNS) showed early evidence of efficacy for the gait treatment of Parkinson's disease (PD). OBJECTIVES: Providing data on neurophysiological and clinical effects of transauricular VNS (taVNS). METHODS: Ten patients with recording deep brain stimulation (DBS) have been enrolled in a within participant design pilot study, double-blind crossover sham-controlled trial of taVNS. Subthalamic local field potentials (β band power), Unified Parkinson's Disease Rating Scales (UPDRS), and a digital timed-up-and-go test (TUG) were measured and compared with real versus sham taVNS during medication-off/DBS-OFF condition. RESULTS: The left taVNS induced a reduction of the total β power in the contralateral (ie, right) subthalamic nucleus and an improvement of TUG time, speed, and variability. The taVNS-induced β reduction correlated with the improvement of gait speed. No major clinical changes were observed at UPDRS. CONCLUSIONS: taVNS is a promising strategy for the management of PD gait, deserving prospective trials of chronic neuromodulation. © 2023 International Parkinson and Movement Disorder Society.
Changes in Retinal Sensitivity Associated With Cotoretigene Toliparvovec in X-Linked Retinitis Pigmentosa With RPGR Gene Variations
ImportanceX-linked retinitis pigmentosa (XLRP) is a severe cause of early-onset RP in male individuals, characterized by degeneration of photoreceptors, an extinguished electroretinogram, and vision loss.ObjectiveTo assess the duration of improvements in retinal sensitivity associated with a single, subretinal injection of cotoretigene toliparvovec (BIIB112/AAV8-RPGR) gene therapy after vitrectomy surgery in the dosed eye over 12 months in part 1 of the Clinical Trial of Retinal Gene Therapy for X-linked Retinitis Pigmentosa Using BIIB112 (XIRIUS) study, compared with untreated fellow eyes and eyes from the untreated subgroup from the Natural History of the Progression of X-Linked Retinitis Pigmentosa (XOLARIS) study.Design, Setting, and ParticipantsThis was a post hoc analysis of the XIRIUS and XOLARIS studies. Part 1 of the XIRIUS study was a phase 1, dose-escalation study of 18 male participants 18 years or older enrolled between March 8, 2017, and October 16, 2018, with genetically confirmed RPGR-variant XLRP with active disease and best-corrected visual acuity better than or equal to light perception (cohort 1), 34 to 73 letters (20/40 to 20/200 Snellen equivalent; cohorts 2-3), or greater than or equal to 34 letters (better than or equal to 20/200 Snellen equivalent; cohorts 4-6). Participants from the noninterventional, multicenter, global, prospective XOLARIS clinical study who met the inclusion and exclusion criteria of part 1 of XIRIUS were included as a comparator group (n = 103). Safety assessments included all XIRIUS participants; post hoc associations of retinal sensitivity assessments in XIRIUS only included the 12 participants receiving the 4 highest doses of cotoretigene toliparvovec. Data were analyzed on June 30, 2021.Main Outcomes and MeasuresIncidence of dose-limiting toxicities (DLTs), treatment-emergent adverse events, changes from baseline in retinal sensitivity (as assessed by macular integrity assessment microperimetry), retinal sensitivity response (achievement of ≥7-dB improvement from baseline at ≥5 of 16 central loci), and low-luminance visual acuity were assessed over 24 months.ResultsA total of 18 participants (mean [SD] age, 31.9 [9.4] years; male, 100%) were enrolled and completed the XIRIUS study. A subgroup of 103 participants (mean [SD] age, 30.8 [11.4] years; male, 100%) from the XOLARIS study was included. Administration of the 4 highest doses of cotoretigene toliparvovec (n = 12) among the 18 XIRIUS participants was associated with early improvements in retinal sensitivity. One of 103 untreated participants (1%) in the XOLARIS subgroup achieved improved retinal sensitivity at month 12. No DLTs were noted at any dose, and serious adverse events of reduced visual acuity (n = 2) and noninfective retinitis (n = 1) occurred.Conclusions and RelevanceResults suggest that early and sustained improvements in retinal sensitivity and low-luminance visual acuity in some participants through 12 months support consideration of additional clinical trials.Trial RegistrationClinicalTrials.gov Identifier: XIRIUS: NCT03116113; XOLARIS: NCT04926129
Congenital myasthenic syndromes: a retrospective natural history study of respiratory outcomes in a single centre.
Respiratory problems are a major cause of morbidity and mortality in patients with congenital myasthenic syndromes, a rare heterogeneous group of neuromuscular disorders caused by genetic defects impacting the structure and function of the neuromuscular junction. Recurrent, life-threatening episodic apnoea in early infancy and childhood and progressive respiratory failure requiring ventilation are features of certain genotypes of congenital myasthenic syndromes. Robb et al. published empirical guidance on respiratory management of the congenital myasthenic syndromes, but other than this workshop report, there are little published longitudinal natural history data on respiratory outcomes of these disorders. We report a retrospective, single-centre study on respiratory outcomes in a cohort of 40 well characterized genetically confirmed cases of congenital myasthenic syndromes, including 10 distinct subtypes (DOK7, COLQ, RAPSN, CHAT, CHRNA1, CHRNG, COL13A1, CHRNE, CHRNE fast channel syndrome and CHRNA1 slow channel syndrome), with many followed up over 20 years in our centre. A quantitative and longitudinal analysis of key spirometry and sleep study parameters, as well as a description of historical hospital admissions for respiratory decompensation, provides a snapshot of the respiratory trajectory of congenital myasthenic syndrome patients based on genotype.
Opportunities for Understanding MS Mechanisms and Progression With MRI Using Large-Scale Data Sharing and Artificial Intelligence.
Patients with multiple sclerosis (MS) have heterogeneous clinical presentations, symptoms, and progression over time, making MS difficult to assess and comprehend in vivo. The combination of large-scale data sharing and artificial intelligence creates new opportunities for monitoring and understanding MS using MRI. First, development of validated MS-specific image analysis methods can be boosted by verified reference, test, and benchmark imaging data. Using detailed expert annotations, artificial intelligence algorithms can be trained on such MS-specific data. Second, understanding disease processes could be greatly advanced through shared data of large MS cohorts with clinical, demographic, and treatment information. Relevant patterns in such data that may be imperceptible to a human observer could be detected through artificial intelligence techniques. This applies from image analysis (lesions, atrophy, or functional network changes) to large multidomain datasets (imaging, cognition, clinical disability, genetics). After reviewing data sharing and artificial intelligence, we highlight 3 areas that offer strong opportunities for making advances in the next few years: crowdsourcing, personal data protection, and organized analysis challenges. Difficulties as well as specific recommendations to overcome them are discussed, in order to best leverage data sharing and artificial intelligence to improve image analysis, imaging, and the understanding of MS.
Associations between changes in habitual sleep duration and lower self-rated health among COVID-19 survivors: findings from a survey across 16 countries/regions.
BACKGROUND: Self-rated health (SRH) is widely recognized as a clinically significant predictor of subsequent mortality risk. Although COVID-19 may impair SRH, this relationship has not been extensively examined. The present study aimed to examine the correlation between habitual sleep duration, changes in sleep duration after infection, and SRH in subjects who have experienced SARS-CoV-2 infection. METHODS: Participants from 16 countries participated in the International COVID Sleep Study-II (ICOSS-II) online survey in 2021. A total of 10,794 of these participants were included in the analysis, including 1,509 COVID-19 individuals (who reported that they had tested positive for COVID-19). SRH was evaluated using a 0-100 linear visual analog scale. Habitual sleep durations of < 6 h and > 9 h were defined as short and long habitual sleep duration, respectively. Changes in habitual sleep duration after infection of ≤ -2 h and ≥ 1 h were defined as decreased or increased, respectively. RESULTS: Participants with COVID-19 had lower SRH scores than non-infected participants, and those with more severe COVID-19 had a tendency towards even lower SRH scores. In a multivariate regression analysis of participants who had experienced COVID-19, both decreased and increased habitual sleep duration after infection were significantly associated with lower SRH after controlling for sleep quality (β = -0.056 and -0.058, respectively, both p < 0.05); however, associations between current short or long habitual sleep duration and SRH were negligible. Multinomial logistic regression analysis showed that decreased habitual sleep duration was significantly related to increased fatigue (odds ratio [OR] = 1.824, p < 0.01), shortness of breath (OR = 1.725, p < 0.05), diarrhea/nausea/vomiting (OR = 2.636, p < 0.01), and hallucinations (OR = 5.091, p < 0.05), while increased habitual sleep duration was significantly related to increased fatigue (OR = 1.900, p < 0.01). CONCLUSIONS: Changes in habitual sleep duration following SARS-CoV-2 infection were associated with lower SRH. Decreased or increased habitual sleep duration might have a bidirectional relation with post-COVID-19 symptoms. Further research is needed to better understand the mechanisms underlying these relationships for in order to improve SRH in individuals with COVID-19.