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| Open AccessRecruitment of upper-limb motoneurons with epidural electrical stimulation of the cervical spinal cord
The efficacy of epidural electrical stimulation (EES) to engage arm muscles and improve movement after spinal cord injury is still unclear. Here, the authors investigated how EES can recruit upper-limb motor neurons by combining computational modelling with experiments in non-human primates.
- Nathan Greiner
- , Beatrice Barra
- & Marco Capogrosso
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Article
| Open AccessNon-invasive suppression of essential tremor via phase-locked disruption of its temporal coherence
Aberrant synchronous oscillations have been associated with numerous brain disorders, including essential tremor. The authors show that synchronous cerebellar activity can casually affect essential tremor and that its underlying mechanism may be related to the temporal coherence of the tremulous movement.
- Sebastian R. Schreglmann
- , David Wang
- & Nir Grossman
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Article
| Open AccessAge-related and disease locus-specific mechanisms contribute to early remodelling of chromatin structure in Huntington’s disease mice
The dynamics of chromatin and transcriptional changes underlying Huntington’s disease remain poorly understood. Here the authors use a Huntington’s mouse model to profile the striatal chromatin landscape, finding that the Huntington’s mutation accelerates age-dependent epigenetic and transcriptional changes, and locally affects 3D chromatin organization.
- Rafael Alcalá-Vida
- , Jonathan Seguin
- & Karine Merienne
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Article
| Open AccessCerebral small vessel disease genomics and its implications across the lifespan
White matter hyperintensities (WMH) are a common brain-imaging feature of cerebral small vessel disease. Here, the authors carry out a GWAS and followup analyses for WMH-volume, implicating several variants with potential for risk stratification and drug targeting.
- Muralidharan Sargurupremraj
- , Hideaki Suzuki
- & Stéphanie Debette
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Perspective
| Open AccessIncreasing the reproducibility of fluid biomarker studies in neurodegenerative studies
Many fluid biomarker findings have had low reproducibility despite initially promising results. Here, the authors review possible sources for low reproducibility of studies on fluid biomarkers for neurodegenerative diseases and suggest guidelines for the biomarker community to agree on and implement.
- Niklas Mattsson-Carlgren
- , Sebastian Palmqvist
- & Oskar Hansson
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Article
| Open AccessAstrocyte deletion of α2-Na/K ATPase triggers episodic motor paralysis in mice via a metabolic pathway
Mutations of α2-Na/K ATPase can cause familial hemiplegic migraine via unclear mechanisms. Here, the authors show that deletion of α2-Na/K ATPase in astrocytes results in gene expression and metabolic changes leading to cortical spreading depression and episodic transient motor paralysis in mice.
- Sarah E. Smith
- , Xiaoying Chen
- & Azad Bonni
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Article
| Open AccessBETs inhibition attenuates oxidative stress and preserves muscle integrity in Duchenne muscular dystrophy
Duchenne muscular dystrophy (DMD) is characterised by progressive muscle degeneration. Here, the authors show that the BET protein BRD4 is increased in the muscle of DMD mouse models, and that pharmacological inhibition of BRD4 leads to reduced muscle pathology in mice, by modulating NADPH oxidase expression.
- Marco Segatto
- , Roberta Szokoll
- & Giuseppina Caretti
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Article
| Open AccessEssential omega-3 fatty acids tune microglial phagocytosis of synaptic elements in the mouse developing brain
Altered fatty acid intake during pregnancy is associated with neurodevelopmental disorders. Here, the authors show that maternal omega-3 fatty acids deficiency results in altered microglia-mediated phagocytosis of synaptic elements leading to impaired cognitive functions in the offspring in mice.
- C. Madore
- , Q. Leyrolle
- & S. Layé
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Article
| Open AccessA clinically applicable deep-learning model for detecting intracranial aneurysm in computed tomography angiography images
Interpretation of Computed Tomography Angiography for intracranial aneurysm diagnosis can be time-consuming and challenging. Here, the authors present a deep-learning-based framework achieving improved performance compared to that of radiologists and expert neurosurgeons.
- Zhao Shi
- , Chongchang Miao
- & Long Jiang Zhang
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Article
| Open AccessEpigenome-wide meta-analysis of DNA methylation differences in prefrontal cortex implicates the immune processes in Alzheimer’s disease
Previous studies have identified DNA methylation changes in Alzheimer’s disease. Here the authors perform a meta-analysis of DNA methylation datasets to identify epigenetic correlates of Alzheimer’s disease in the prefrontal cortex.
- Lanyu Zhang
- , Tiago C. Silva
- & Lily Wang
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Article
| Open AccessPlasma N-terminal tau fragment levels predict future cognitive decline and neurodegeneration in healthy elderly individuals
Previously it was shown that an N-terminal tau fragment (NT1) measured in plasma can differentiate individuals with Alzheimer’s disease from healthy controls. Here the authors show that plasma levels of NT1 can associate with future cognitive decline in cognitively normal elderly individuals.
- Jasmeer P. Chhatwal
- , Aaron P. Schultz
- & Dennis J. Selkoe
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Article
| Open AccessConcordant peripheral lipidome signatures in two large clinical studies of Alzheimer’s disease
The onset and pathology of Alzheimer’s disease (AD) is associated with changes to lipid metabolism. Here, the authors analysed 569 lipids from 32 classes and subclasses in two independent patient cohorts to identify key lipid pathways to link the plasma lipidome with AD and the future onset of AD.
- Kevin Huynh
- , Wei Ling Florence Lim
- & Peter J. Meikle
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Article
| Open AccessIncreased RNA editing in maternal immune activation model of neurodevelopmental disease
Interferon can be induced by the viral mimic PolyI:C, which can in turn activate RNA editing enzymes. Here the authors identify transient changes in A-to-I RNA editing following maternal immune activation in mice.
- Hadas Tsivion-Visbord
- , Eli Kopel
- & Erez Y. Levanon
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Article
| Open AccessCardio-centric hemodynamic management improves spinal cord oxygenation and mitigates hemorrhage in acute spinal cord injury
Clinical neuroprotective strategies for acute spinal cord injury (SCI) have largely overlooked the heart. Here the authors show cardiac contractility is immediately impaired in a porcine model of T2 SCI, and cardio-centric treatment with dobutamine optimizes cord oxygenation and mitigates haemorrhage.
- Alexandra M. Williams
- , Neda Manouchehri
- & Christopher R. West
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Article
| Open AccessIntegrative genomics identifies a convergent molecular subtype that links epigenomic with transcriptomic differences in autism
Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by impaired social interactions with repetitive and restrictive behaviours. Here the authors integrate mRNA expression, miRNA expression, DNA methylation, and histone acetylation datasets from a collection of post mortem brain tissues and identify a convergent molecular subtype of ASD.
- Gokul Ramaswami
- , Hyejung Won
- & Daniel H. Geschwind
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Article
| Open AccessRisk prediction of late-onset Alzheimer’s disease implies an oligogenic architecture
Despite the identification of genetic risk loci for late-onset Alzheimer’s disease (LOAD), the genetic architecture and prediction remains unclear. Here, the authors use genetic risk scores for prediction of LOAD across three datasets and show evidence suggesting oligogenic variant architecture for this disease.
- Qian Zhang
- , Julia Sidorenko
- & Peter M. Visscher
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Article
| Open AccessGlioma-initiating cells at tumor edge gain signals from tumor core cells to promote their malignancy
Intratumoural spatial heterogeneity is crucial to enhance therapeutic resistance in glioblastoma. Here, the authors show a paracrine signaling mechanism where glioblastoma-initiating cells located in the tumour edge elevate their malignancy by interaction with core-located tumour cells.
- Soniya Bastola
- , Marat S. Pavlyukov
- & Ichiro Nakano
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Article
| Open AccessNEMF mutations that impair ribosome-associated quality control are associated with neuromuscular disease
Defective protein quality control is a key feature of neurodegeneration. Here, the authors show that mutations in Nemf/NEMF, a component of the Ribosome-associated Quality Control complex, have a neurodegenerative effect in mice and may underlie neuromuscular disease in seven unrelated families.
- Paige B. Martin
- , Yu Kigoshi-Tansho
- & Gregory A. Cox
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Article
| Open AccessDNA methylation study of Huntington’s disease and motor progression in patients and in animal models
Although Huntington’s disease (HD) is a well-studied genetic disorder, less is known about the epigenetic changes underlying it. Here, the authors characterize DNA methylation levels in tissues from patients, a mouse huntingtin (Htt) gene knock-in model, and a transgenic HTT sheep model, and provide evidence that HD is accompanied by DNA methylation changes in these three species.
- Ake T. Lu
- , Pritika Narayan
- & Steve Horvath
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Article
| Open AccessABHD4-dependent developmental anoikis safeguards the embryonic brain
During embryonic development, neural progenitor cells undergo numerous cell divisions. Here, the authors show that ABHD4-mediated developmental anoikis distinguishes the physiological delamination and the pathological detachment of progenitor cells with relevance to fetal alcohol-induced apoptosis.
- Zsófia I. László
- , Zsolt Lele
- & István Katona
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Article
| Open AccessRNA-binding proteins Musashi and tau soluble aggregates initiate nuclear dysfunction
The Musashi family of RNA binding proteins are found in an oligomeric state in the brains of patients with Alzheimer’s disease. Here the authors show that Mushashi1 and Musashi2 interact with tau protein in patient tissue and in models of tauopathy.
- Mauro Montalbano
- , Salome McAllen
- & Rakez Kayed
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Article
| Open AccessBlood substitution therapy rescues the brain of mice from ischemic damage
Acute stroke causes complex, pathological, and systemic responses which remain challenging to treat. Here, the authors show that substituting the blood of stroke model mice with whole-blood from naive healthy donor mice reduces infarct volume and improves neurological deficits.
- Xuefang Ren
- , Heng Hu
- & James W. Simpkins
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Article
| Open AccessDeep neural networks enable quantitative movement analysis using single-camera videos
In the context of diseases impairing movement, quantitative assessment of motion is critical to medical decision-making but is currently possible only with expensive motion capture systems and trained personnel. Here, the authors present a method for predicting clinically relevant motion parameters from an ordinary video of a patient.
- Łukasz Kidziński
- , Bryan Yang
- & Michael H. Schwartz
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Article
| Open AccessLoss of NARS1 impairs progenitor proliferation in cortical brain organoids and leads to microcephaly
Asparaginyl-tRNA synthetase1 (NARS1) is required for protein synthesis. Here, the authors identify biallelic NARS1 mutations in individuals with microcephaly and neurodevelopmental delay. Cortical brain organoid modeling recapitulates microcephaly characteristics and scRNA-seq reveals a role for NARS1 in radial glial cell proliferation.
- Lu Wang
- , Zhen Li
- & Joseph G. Gleeson
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Article
| Open AccessA neurovascular high-frequency optical coherence tomography system enables in situ cerebrovascular volumetric microscopy
High resolution intravascular imaging in the brain is limited by the high tortuosity of the vasculature. Here the authors present a fiber optic imaging technology using high-frequency optical coherence tomography (HF-OCT) to provide volumetric high resolution images in the highly tortuous cerebral vasculature.
- Giovanni J. Ughi
- , Miklos G. Marosfoi
- & Ajit S. Puri
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Article
| Open AccessThe circadian phase of antenatal glucocorticoid treatment affects the risk of behavioral disorders
Antenatal glucocorticoid therapy is indicated for mothers at risk of preterm delivery. Here, the authors show that the circadian phase of antenatal glucocorticoid treatment affects the risk of behavioral disorders later in life in mice and in a retrospective observational study in human infants.
- Mariana Astiz
- , Isabel Heyde
- & Henrik Oster
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Article
| Open AccessA genome-wide cross-phenotype meta-analysis of the association of blood pressure with migraine
The association between blood pressure (BP) and migraine is poorly understood. Here, the authors explore this relationship using summary-level GWAS data for BP and migraine. Cross-trait meta-analysis reveals shared loci between BP and migraine, while Mendelian randomization suggests that diastolic BP specifically plays a key role in migraine susceptibility.
- Yanjun Guo
- , Pamela M. Rist
- & Daniel I. Chasman
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Article
| Open AccessStructural characterization of a novel human adeno-associated virus capsid with neurotropic properties
Adeno-associated viruses (AAVs) are vehicles for gene therapy in humans, but currently only a limited amount of AAV serotypes is available. Here, the authors identify a novel AAV, AAVv66, and demonstrate enhanced production yields, virion stability, and CNS transduction compared to the clinically approved serotype AAV2.
- Hung-Lun Hsu
- , Alexander Brown
- & Guangping Gao
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Article
| Open AccessAlterations of gut microbiota contribute to the progression of unruptured intracranial aneurysms
Unruptured intracranial aneurysm (UIA) is a life-threatening cerebrovascular condition. Here the authors report altered gut microbiota including low abundance of Hungatella hathewayi in patients with UIAs, and show that supplementation with Hungatella hathewayi or the metabolite taurine prevents UIAs in mice.
- Hao Li
- , Haochen Xu
- & Jingzhou Chen
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Article
| Open AccessTranscriptomics and proteomics reveal a cooperation between interferon and T-helper 17 cells in neuromyelitis optica
Type I IFN has apposing effects in neuromyelitis optica spectrum disorder (NMOSD) and multiple sclerosis (MS). Here the authors perform molecular profiling of NMOSD patients and mouse mechanistic experiments of neuro-inflammation to show that IFN-I stimulates pathogenic Th17 via IL-6 production by B cells.
- Agnieshka M. Agasing
- , Qi Wu
- & Robert C. Axtell
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Article
| Open AccessExtent of N-terminus exposure of monomeric alpha-synuclein determines its aggregation propensity
In Parkinson’s disease (PD) the monomeric protein alpha-synuclein (aSyn) misfolds and aggregates into insoluble fibrils. Here the authors use NMR measurements and hydrogen–deuterium exchange mass spectrometry and find that the more solvent exposed the N-terminus of aSyn is, the more aggregation prone its conformation becomes, and further show how PD mutations and post translational modifications influence the extent of the N-terminus solvent exposure.
- Amberley D. Stephens
- , Maria Zacharopoulou
- & Gabriele S. Kaminski Schierle
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Article
| Open AccessFMRP(1–297)-tat restores ion channel and synaptic function in a model of Fragile X syndrome
Fragile X Mental Retardation Protein regulates synaptic plasticity and its loss results in Fragile X Syndrome. Here, the authors show that the FMRP(1-297)-tat peptide can permeate the BBB, restore protein translation and mossy fiber LTP, and reduce elevated levels of activity in Fmr1 KO mice.
- Xiaoqin Zhan
- , Hadhimulya Asmara
- & Ray W. Turner
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Article
| Open AccessTriggering typical nemaline myopathy with compound heterozygous nebulin mutations reveals myofilament structural changes as pathomechanism
Nebulin-based nemaline myopathy is a heterogenous disease with unclear pathological mechanisms. Here, the authors generate a mouse model that mimics the most common genetic cause of the disease and demonstrate that muscle weakness in this model is associated with twisted actin filaments and altered tropomyosin and troponin behaviour.
- Johan Lindqvist
- , Weikang Ma
- & Henk Granzier
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Article
| Open AccessTRPV4 disrupts mitochondrial transport and causes axonal degeneration via a CaMKII-dependent elevation of intracellular Ca2+
Mutations in the TRPV4 channel cause inherited neurodegeneration syndromes, but the molecular mechanisms are unknown. Here the authors reveal that TRPV4 activation causes dose-dependent, CaMKII-mediated neuronal dysfunction and axonal degeneration via disruption of mitochondrial axonal transport.
- Brian M. Woolums
- , Brett A. McCray
- & Thomas E. Lloyd
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Article
| Open AccessPermissive microbiome characterizes human subjects with a neurovascular disease cavernous angioma
Gut microbiome has been linked to cavernous angioma (CA), a common vascular disease, but the role in humans remains unclear. Here, the authors combine 16S rRNA sequencing and shotgun metagenomics to profile the microbiome in a large cohort of human subjects with and without CA, and among subjects with different CA clinical features.
- Sean P. Polster
- , Anukriti Sharma
- & Issam A. Awad
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Article
| Open AccessA unified neurocognitive model of semantics language social behaviour and face recognition in semantic dementia
Semantic dementia patients present with a core semantic impairment and variations of language, behavioural and face recognition abilities. Here, the authors build a unified multidimensional model to capture all these graded symptoms and map them to the variations in the patients’ frontotemporal atrophy.
- Junhua Ding
- , Keliang Chen
- & Matthew. A. Lambon Ralph
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Article
| Open AccessMutations in the KIF21B kinesin gene cause neurodevelopmental disorders through imbalanced canonical motor activity
Kinesins regulate intracellular transport and microtubule dynamics. Here, the authors show that KIF21B variants in humans associate with corpus callosum agenesis and microcephaly. Using mice and zebrafish, they showed the cellular mechanisms altered by the missense KIF21B variants.
- Laure Asselin
- , José Rivera Alvarez
- & Juliette D. Godin
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Article
| Open AccessIncreased mitochondrial calcium levels associated with neuronal death in a mouse model of Alzheimer’s disease
Calvo-Rodriguez et al. show elevated calcium levels in neuronal mitochondria in a mouse model of cerebral β-amyloidosis after plaque deposition, which precede rare neuron death events in this model. The mechanism involves toxic extracellular Aβ oligomers and the mitochondrial calcium uniporter.
- Maria Calvo-Rodriguez
- , Steven S. Hou
- & Brian J. Bacskai
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Article
| Open AccessGenome-wide association study of MRI markers of cerebral small vessel disease in 42,310 participants
Cerebral small vessel disease (CSVD) is a major cause of stroke and associated with structural changes of the brain. Here, Persyn et al. perform genome-wide association studies for magnetic resonance imaging (MRI) markers of CSVD, explore genetic correlations and prioritize candidate genes.
- Elodie Persyn
- , Ken B. Hanscombe
- & Hugh S. Markus
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Article
| Open AccessNon-Invasive MRI of Blood–Cerebrospinal Fluid Barrier Function
The blood–cerebrospinal fluid barrier (BCSFB) is an important interface for brain homeostasis. Here the authors describe a non-invasive MRI technique for the quantitative assessment of BCSFB function.
- P. G. Evans
- , M. Sokolska
- & J. A. Wells
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Article
| Open AccessIdentification of therapeutics that target eEF1A2 and upregulate utrophin A translation in dystrophic muscles
One potential approach for the treatment of Duchenne muscular dysrophy is to increase expression of the dystrophin homolog utrophin. Here, the authors show that eEF1A2 regulates utrophin expression, and show that 2 FDA-approved drugs upregulate eEIF1A2 and utrophin level in mice, leading to improvement of the dystrophic phenotype.
- Christine Péladeau
- , Nadine Adam
- & Bernard J. Jasmin
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Article
| Open AccessLoss of MBNL1 induces RNA misprocessing in the thymus and peripheral blood
The activity of the RNA splicing factor MBNL1 is altered in myotonic dystrophy (DM) patients. Here the authors characterize the thymic phenotype of Mbnl1 knockout mice, including developmental defects, transcriptome changes, and RNA mis-splicing of transcripts encoding thymic transcription factors.
- Łukasz J. Sznajder
- , Marina M. Scotti
- & Maurice S. Swanson
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Article
| Open AccessNoninvasive electromagnetic source imaging of spatiotemporally distributed epileptogenic brain sources
Noninvasive electromagnetic measurements are utilized effectively to estimate large scale dynamic brain networks. Sohrabpour et al. propose a novel electrophysiological source imaging approach to estimate the location and size of epileptogenic tissues in patients with epilepsy.
- Abbas Sohrabpour
- , Zhengxiang Cai
- & Bin He
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Article
| Open AccessCerebrospinal fluid p-tau217 performs better than p-tau181 as a biomarker of Alzheimer’s disease
Cerebrospinal fluid (CSF) p-tau181 (tau phosphorylated at threonine 181) is an established biomarker of Alzheimer’s disease (AD) reflecting abnormal tau metabolism in the AD brain. Here the authors demonstrate that CSF p-tau217 shows better performance as an AD biomarker than p-tau181.
- Shorena Janelidze
- , Erik Stomrud
- & Oskar Hansson
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Article
| Open AccessAnalysis of DNA methylation associates the cystine–glutamate antiporter SLC7A11 with risk of Parkinson’s disease
Parkinson’s disease (PD) is a common neurodegenerative disorder with a complex etiology involving genetics and the environment. Here, Vallerga et al. identify two CpG probes associated with PD in a blood cell type-corrected epigenome-wide meta-analysis, implicating the SLC7A11 gene as a plausible biological target.
- Costanza L. Vallerga
- , Futao Zhang
- & Jacob Gratten
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Article
| Open AccessA disinhibitory nigra-parafascicular pathway amplifies seizure in temporal lobe epilepsy
The neural circuits through which the substantia nigra pars reticulata (SNr) exerts its role in epilepsy control are not known. Here the authors reveal that a long-range SNr-parafascicular nucleus disinhibitory circuit participates in regulating seizures in temporal lobe epilepsy and inhibition of this circuit can alleviate severity of epileptic seizures.
- Bin Chen
- , Cenglin Xu
- & Zhong Chen
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Article
| Open AccessInsights into the aetiology of snoring from observational and genetic investigations in the UK Biobank
Snoring is common in the population and tends to be more prevalent in older and/or male individuals. Here, the authors perform GWAS for habitual snoring, identify 41 genomic loci and explore potential causal relationships with anthropometric and cardiometabolic disease traits.
- Adrián I. Campos
- , Luis M. García-Marín
- & Miguel E. Rentería
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Article
| Open AccessSerum neurofilament light levels in normal aging and their association with morphologic brain changes
Neurofilament (NfL) levels in CSF and blood have been established as a biomarker of neuronal damage in neurodegenerative diseases, and there is an age-dependent increase in NfL levels in CSF. Here the authors demonstrate that serum NfL levels increase in healthy aging people and predict and correlate with brain volume loss.
- Michael Khalil
- , Lukas Pirpamer
- & Jens Kuhle
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Article
| Open AccessNon-invasive recording from the human olfactory bulb
Measures of neural processing can be obtained non-invasively from all areas of the human brain but one, the olfactory bulb. Here, the authors show that signals obtained from EEG electrodes at the nasal bridge represent responses from the human olfactory bulb, the so-called Electrobulbogram.
- Behzad Iravani
- , Artin Arshamian
- & Johan N. Lundström
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