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Neuroscience
Local striatal reward signals can be predicted from corticostriatal connectivity
Jul 24, 2017   NeuroImage
Smittenaar P, Kurth-Nelson Z, Mohammadi S, Weiskopf N, Dolan RJ
Local striatal reward signals can be predicted from corticostriatal connectivity
Jul 24, 2017
NeuroImage
A defining feature of the basal ganglia is their anatomical organization into multiple cortico-striatal loops. A central tenet of this architecture is the idea that local striatal function is determined by its precise connectivity with cortex, creating a functional topography that is mirrored within cortex and striatum. Here we formally test this idea using both human anatomical and functional imaging, specifically asking whether within striatal subregions one can predict between-voxel differences in functional signals based on between-voxel differences in corticostriatal connectivity. We show that corticostriatal connectivity profiles predict local variation in reward signals in bilateral caudate nucleus and putamen, expected value signals in bilateral caudate nucleus, and response effector activity in bilateral putamen. These data reveal that, even within individual striatal regions, local variability in corticostriatal anatomical connectivity predicts functional differentiation. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.
Task-dependent recurrent dynamics in visual cortex
Jul 24, 2017   ELife
Tajima S, Koida K, Tajima CI, Suzuki H, Aihara K, Komatsu H
Task-dependent recurrent dynamics in visual cortex
Jul 24, 2017
ELife
The capacity for flexible sensory-action association in animals has been related to context-dependent attractor dynamics outside the sensory cortices. Here we report a line of evidence that flexibly modulated attractor dynamics during task switching are already present in the higher visual cortex in macaque monkeys. With a nonlinear decoding approach, we can extract the particular aspect of the neural population response that reflects the task-induced emergence of bistable attractor dynamics in a neural population, which could be obscured by standard unsupervised dimensionality reductions such as PCA. The dynamical modulation selectively increases the information relevant to task demands, indicating that such modulation is beneficial for perceptual decisions. A computational model that features nonlinear recurrent interaction among neurons with a task-dependent background input replicates the key properties observed in the experimental data. These results suggest that the context-dependent attractor dynamics involving the sensory cortex can underlie flexible perceptual abilities.
ADHD symptoms impact smoking outcomes and withdrawal in response to Varenicline treatment for smoking cessation
Jul 24, 2017   Drug And Alcohol Dependence
Bidwell LC, Karoly HC, Hutchison KE, Bryan AD
ADHD symptoms impact smoking outcomes and withdrawal in response to Varenicline treatment for smoking cessation
Jul 24, 2017
Drug And Alcohol Dependence
Attention-Deficit/Hyperactivity Disorder (ADHD) is associated with nicotine dependence and difficulty quitting smoking. Few cessation trials specifically consider the impact of ADHD on treatment outcomes, including those testing established pharmacological therapies, such as varenicline. The current study focused on the impact of pretreatment ADHD inattention (IN) and hyperactivity-impulsivity (HI) symptoms on treatment outcome in a randomized controlled trial of varenicline [N=205, average age=34.13(10.07), average baseline cigarettes per day=14.71(7.06)]. Given that varenicline's putative therapeutic mechanism is attenuation of withdrawal severity during abstinence, we also tested changes in withdrawal as a mediator of treatment effects in high and low ADHD groups. ADHD symptom severity in this sample was in the subclinical range. Cessation was associated with HI, but not IN, such that high HI individuals on varenicline reported the lowest smoking levels at the end of treatment across all groups (3.06cig/day for high HI vs 4.02cig/day for low HI). Individuals with high HI who received placebo had the highest smoking at the end of treatment (7.69cigs/day for high HI vs 5.56cig/day for low HI). Patterns continued at follow-up. Varenicline significantly reduced withdrawal for those with high HI, but not low HI. However, path models did not support an indirect effect of medication on reducing smoking via withdrawal in either group, suggesting that unmeasured variables are involved in varenicline's effect on reducing smoking. These data add to a gap in the smoking cessation literature regarding the impact of ADHD symptoms on the efficacy and mechanisms of frontline pharmacological treatments. Copyright © 2017. Published by Elsevier B.V.
Computational training for the next generation of neuroscientists
Jul 24, 2017   Current Opinion In Neurobiology
Goldman MS, Fee MS
Computational training for the next generation of neuroscientists
Jul 24, 2017
Current Opinion In Neurobiology
Neuroscience research has become increasingly reliant upon quantitative and computational data analysis and modeling techniques. However, the vast majority of neuroscientists are still trained within the traditional biology curriculum, in which computational and quantitative approaches beyond elementary statistics may be given little emphasis. Here we provide the results of an informal poll of computational and other neuroscientists that sought to identify critical needs, areas for improvement, and educational resources for computational neuroscience training. Motivated by this survey, we suggest steps to facilitate quantitative and computational training for future neuroscientists. Copyright © 2017 Elsevier Ltd. All rights reserved.
Common variation in the autism risk gene CNTNAP2, brain structural connectivity and multisensory speech integration
Jul 24, 2017   Brain And Language
Ross LA, Del Bene VA, Molholm S, Jae Woo Y, Andrade GN, Abrahams BS, Foxe JJ
Common variation in the autism risk gene CNTNAP2, brain structural connectivity and multisensory speech integration
Jul 24, 2017
Brain And Language
Three lines of evidence motivated this study. 1) CNTNAP2 variation is associated with autism risk and speech-language development. 2) CNTNAP2 variations are associated with differences in white matter (WM) tracts comprising the speech-language circuitry. 3) Children with autism show impairment in multisensory speech perception. Here, we asked whether an autism risk-associated CNTNAP2 single nucleotide polymorphism in neurotypical adults was associated with multisensory speech perception performance, and whether such a genotype-phenotype association was mediated through white matter tract integrity in speech-language circuitry. Risk genotype at rs7794745 was associated with decreased benefit from visual speech and lower fractional anisotropy (FA) in several WM tracts (right precentral gyrus, left anterior corona radiata, right retrolenticular internal capsule). These structural connectivity differences were found to mediate the effect of genotype on audiovisual speech perception, shedding light on possible pathogenic pathways in autism and biological sources of inter-individual variation in audiovisual speech processing in neurotypicals. Copyright © 2017 Elsevier Inc. All rights reserved.
Presymptomatic atrophy in autosomal dominant Alzheimer's disease: A serial MRI study
Jul 24, 2017   Alzheimer's & Dementia : The Journal Of The Alzheimer's Association
Kinnunen KM, Cash DM, Poole T, Frost C, Benzinger TLS,   . . . . . .   , Rowe CC, Rossor MN, Ourselin S, Fox NC, Dominantly Inherited Alzheimer Network (DIAN)
Presymptomatic atrophy in autosomal dominant Alzheimer's disease: A serial MRI study
Jul 24, 2017
Alzheimer's & Dementia : The Journal Of The Alzheimer's Association
Identifying at what point atrophy rates first change in Alzheimer's disease is important for informing design of presymptomatic trials. Serial T1-weighed magnetic resonance imaging scans of 94 participants (28 noncarriers, 66 carriers) from the Dominantly Inherited Alzheimer Network were used to measure brain, ventricular, and hippocampal atrophy rates. For each structure, nonlinear mixed-effects models estimated the change-points when atrophy rates deviate from normal and the rates of change before and after this point. Atrophy increased after the change-point, which occurred 1-1.5 years (assuming a single step change in atrophy rate) or 3-8 years (assuming gradual acceleration of atrophy) before expected symptom onset. At expected symptom onset, estimated atrophy rates were at least 3.6 times than those before the change-point. Atrophy rates are pathologically increased up to seven years before "expected onset". During this period, atrophy rates may be useful for inclusion and tracking of disease progression. Copyright © 2017 the Alzheimer's Association. Published by Elsevier Inc. All rights reserved.
The placebo effect and its clinical associations in gambling disorder
Jul 24, 2017   Annals Of Clinical Psychiatry : Official Journal Of The American Academy Of Clinical Psychiatrists
Grant JE, Chamberlain SR
The placebo effect and its clinical associations in gambling disorder
Jul 24, 2017
Annals Of Clinical Psychiatry : Official Journal Of The American Academy Of Clinical Psychiatrists
Although gambling disorder is prevalent and functionally impairing, no FDA-approved medications exist for its treatment. The ability of clinical trials to detect the benefits of active treatment has been hindered by an unusually high placebo response. Virtually nothing is known about baseline clinical characteristics that might predict placebo response in those with gambling disorder. Participants (N = 152) assigned to placebo were pooled from multiple double-blind trials of gambling disorder. Participants were classified as placebo responders or non-responders based on a cut-off of 35% reduction in symptom severity on the Gambling Symptom Assessment Scale. Baseline group differences were characterized using t tests and equivalent non-parametric tests as appropriate. Fifty-one percent of individuals assigned to placebo showed a significant clinical response. Compared with non-responders, placebo responders remained in treatment for significantly longer, were more likely to report "enjoyment" as a trigger for gambling, and were less likely to state that "boredom" or "loneliness" triggered their gambling. Placebo responders and non-responders did not differ significantly in age, sex, age at symptom onset, baseline symptom severity, comorbidities, or likelihood of having received a previous treatment. Predictors of placebo response for gambling disorder appear markedly different from those reported for other mental illnesses.
Short-term sleep deprivation leads to decreased systemic redox metabolites and altered epigenetic status
Jul 24, 2017   PloS One
Trivedi MS, Holger D, Bui AT, Craddock TJA, Tartar JL
Short-term sleep deprivation leads to decreased systemic redox metabolites and altered epigenetic status
Jul 24, 2017
PloS One
Sleep is critical for repair as well as the rejuvenation processes in the body and many of these functions are regulated via underlying cellular metabolic homeostasis. Changes in sleep pattern are reported to alter such metabolic function resulting in altered disease susceptibility or behavior. Here, we measured the extent to which overnight total sleep deprivation (SD) in young adult humans can influence systemic (plasma-derived) redox-metabolism including the major antioxidant, glutathione as well as DNA methylation levels. Nineteen participants (n = 19, μ age = 21, SD = 3.09) underwent morning testing before and after overnight total SD. Biochemical measures before and after SD revealed that glutathione, ATP, cysteine, and homocysteine levels were significantly reduced following one night of sleep deprivation (all p's < 0.01). Parallel to the well-recognized fact that sleep deprivation (maintaining wakefulness) uses up metabolic reserves, we observed that morning cortisol levels were blunted after sleep deprivation. There were no significant correlations between self-reported or actigraphy-measured sleep and the biochemical measurements, strongly indicating that prior sleep behavior did not have any direct influence on the biochemical measures taken at baseline or after sleep deprivation. Results from the current investigation supports the previous literature implicating the induction of oxidative stress and ATP depletion with sleep deprivation. Furthermore, such altered antioxidant status can also induce downstream epigenetic changes. Although we did not measure the specific genes that were altered under the influence of such sleep deprivation, such epigenetic changes could potentially contribute towards disease predisposition.
Atypical speech versus non-speech detection and discrimination in 4- to 6- yr old children with autism spectrum disorder: An ERP study
Jul 24, 2017   PloS One
Galilee A, Stefanidou C, McCleery JP
Atypical speech versus non-speech detection and discrimination in 4- to 6- yr old children with autism spectrum disorder: An ERP study
Jul 24, 2017
PloS One
Previous event-related potential (ERP) research utilizing oddball stimulus paradigms suggests diminished processing of speech versus non-speech sounds in children with an Autism Spectrum Disorder (ASD). However, brain mechanisms underlying these speech processing abnormalities, and to what extent they are related to poor language abilities in this population remain unknown. In the current study, we utilized a novel paired repetition paradigm in order to investigate ERP responses associated with the detection and discrimination of speech and non-speech sounds in 4- to 6-year old children with ASD, compared with gender and verbal age matched controls. ERPs were recorded while children passively listened to pairs of stimuli that were either both speech sounds, both non-speech sounds, speech followed by non-speech, or non-speech followed by speech. Control participants exhibited N330 match/mismatch responses measured from temporal electrodes, reflecting speech versus non-speech detection, bilaterally, whereas children with ASD exhibited this effect only over temporal electrodes in the left hemisphere. Furthermore, while the control groups exhibited match/mismatch effects at approximately 600 ms (central N600, temporal P600) when a non-speech sound was followed by a speech sound, these effects were absent in the ASD group. These findings suggest that children with ASD fail to activate right hemisphere mechanisms, likely associated with social or emotional aspects of speech detection, when distinguishing non-speech from speech stimuli. Together, these results demonstrate the presence of atypical speech versus non-speech processing in children with ASD when compared with typically developing children matched on verbal age.
Magnetic resonance imaging and tensor-based morphometry in the MPTP non-human primate model of Parkinson's disease
Jul 24, 2017   PloS One
Modo M, Crum WR, Gerwig M, Vernon AC, Patel P, Jackson MJ, Rose S, Jenner P, Iravani MM
Magnetic resonance imaging and tensor-based morphometry in the MPTP non-human primate model of Parkinson's disease
Jul 24, 2017
PloS One
Parkinson's disease (PD) is the second most common neurodegenerative disorder producing a variety of motor and cognitive deficits with the causes remaining largely unknown. The gradual loss of the nigrostriatal pathway is currently considered the pivotal pathological event. To better understand the progression of PD and improve treatment management, defining the disease on a structural basis and expanding brain analysis to extra-nigral structures is indispensable. The anatomical complexity and the presence of neuromelanin, make the use of non-human primates an essential element in developing putative imaging biomarkers of PD. To this end, ex vivo T2-weighted magnetic resonance images were acquired from control and 1-methyl-4 phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated marmosets. Volume measurements of the caudate, putamen, and substantia nigra indicated significant atrophy and cortical thinning. Tensor-based morphometry provided a more extensive and hypothesis free assessment of widespread changes caused by the toxin insult to the brain, especially highlighting regional cortical atrophy. The results highlight the importance of developing imaging biomarkers of PD in non-human primate models considering their distinct neuroanatomy. It is essential to further develop these biomarkers in vivo to provide non-invasive tools to detect pre-symptomatic PD and to monitor potential disease altering therapeutics.
Loss-of-function mutations in co-chaperone BAG3 destabilize small HSPs and cause cardiomyopathy
Jul 24, 2017   The Journal Of Clinical Investigation
Fang X, Bogomolovas J, Wu T, Zhang W, Liu C,   . . . . . .   , Lange S, Ouyang K, Peterson KL, Evans SM, Chen J
Loss-of-function mutations in co-chaperone BAG3 destabilize small HSPs and cause cardiomyopathy
Jul 24, 2017
The Journal Of Clinical Investigation
Defective protein quality control (PQC) systems are implicated in multiple diseases. Molecular chaperones and co-chaperones play a central role in functioning PQC. Constant mechanical and metabolic stress in cardiomyocytes places great demand on the PQC system. Mutation and downregulation of the co-chaperone protein BCL-2-associated athanogene 3 (BAG3) are associated with cardiac myopathy and heart failure, and a BAG3 E455K mutation leads to dilated cardiomyopathy (DCM). However, the role of BAG3 in the heart and the mechanisms by which the E455K mutation leads to DCM remain obscure. Here, we found that cardiac-specific Bag3-KO and E455K-knockin mice developed DCM. Comparable phenotypes in the 2 mutants demonstrated that the E455K mutation resulted in loss of function. Further experiments revealed that the E455K mutation disrupted the interaction between BAG3 and HSP70. In both mutants, decreased levels of small heat shock proteins (sHSPs) were observed, and a subset of proteins required for cardiomyocyte function was enriched in the insoluble fraction. Together, these observations suggest that interaction between BAG3 and HSP70 is essential for BAG3 to stabilize sHSPs and maintain cardiomyocyte protein homeostasis. Our results provide insight into heart failure caused by defects in BAG3 pathways and suggest that increasing BAG3 protein levels may be of therapeutic benefit in heart failure.
Astrocytic tight junctions control inflammatory CNS lesion pathogenesis
Jul 24, 2017   The Journal Of Clinical Investigation
Horng S, Therattil A, Moyon S, Gordon A, Kim K,   . . . . . .   , Crandall ED, Borok Z, Sofroniew MV, Chapouly C, John GR
Astrocytic tight junctions control inflammatory CNS lesion pathogenesis
Jul 24, 2017
The Journal Of Clinical Investigation
Lesions and neurologic disability in inflammatory CNS diseases such as multiple sclerosis (MS) result from the translocation of leukocytes and humoral factors from the vasculature, first across the endothelial blood-brain barrier (BBB) and then across the astrocytic glia limitans (GL). Factors secreted by reactive astrocytes open the BBB by disrupting endothelial tight junctions (TJs), but the mechanisms that control access across the GL are unknown. Here, we report that in inflammatory lesions, a second barrier composed of reactive astrocyte TJs of claudin 1 (CLDN1), CLDN4, and junctional adhesion molecule A (JAM-A) subunits is induced at the GL. In a human coculture model, CLDN4-deficient astrocytes were unable to control lymphocyte segregation. In models of CNS inflammation and MS, mice with astrocyte-specific Cldn4 deletion displayed exacerbated leukocyte and humoral infiltration, neuropathology, motor disability, and mortality. These findings identify a second inducible barrier to CNS entry at the GL. This barrier may be therapeutically targetable in inflammatory CNS disease.
Dynamic coupling between fMRI local connectivity and interictal EEG in focal epilepsy: A wavelet analysis approach
Jul 24, 2017   Human Brain Mapping
Omidvarnia A, Pedersen M, Vaughan DN, Walz JM, Abbott DF, Zalesky A, Jackson GD
Dynamic coupling between fMRI local connectivity and interictal EEG in focal epilepsy: A wavelet analysis approach
Jul 24, 2017
Human Brain Mapping
Simultaneous scalp EEG-fMRI recording is a noninvasive neuroimaging technique for combining electrophysiological and hemodynamic aspects of brain function. Despite the time-varying nature of both measurements, their relationship is usually considered as time-invariant. The aim of this study was to detect direct associations between scalp-recorded EEG and regional changes of hemodynamic brain connectivity in focal epilepsy through a time-frequency paradigm. To do so, we developed a voxel-wise framework that analyses wavelet coherence between dynamic regional phase synchrony (DRePS, calculated from fMRI) and band amplitude fluctuation (BAF) of a target EEG electrode with dominant interictal epileptiform discharges (IEDs). As a proof of concept, we applied this framework to seven patients with focal epilepsy. The analysis produced patient-specific spatial maps of DRePS-BAF coupling, which highlight regions with a strong link between EEG power and local fMRI connectivity. Although we observed DRePS-BAF coupling proximate to the suspected seizure onset zone in some patients, our results suggest that DRePS-BAF is more likely to identify wider 'epileptic networks'. We also compared DRePS-BAF with standard EEG-fMRI analysis based on general linear modelling (GLM). There was, in general, little overlap between the DRePS-BAF maps and GLM maps. However, in some subjects the spatial clusters revealed by these two analyses appeared to be adjacent, particularly in medial posterior cortices. Our findings suggest that (1) there is a strong time-varying relationship between local fMRI connectivity and interictal EEG power in focal epilepsy, and (2) that DRePS-BAF reflect different aspects of epileptic network activity than standard EEG-fMRI analysis. These two techniques, therefore, appear to be complementary. Hum Brain Mapp, 2017. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.
Non-BOLD contrast for laminar fMRI in humans: CBF, CBV, and CMR02
Jul 24, 2017   NeuroImage
Huber L, Uludağ K, Möller HE
Non-BOLD contrast for laminar fMRI in humans: CBF, CBV, and CMR02
Jul 24, 2017
NeuroImage
Functional magnetic resonance imaging (fMRI) using the blood oxygenation level-dependent (BOLD) contrast indirectly probes neuronal activity changes via evoked cerebral blood flow (CBF), cerebral blood volume (CBV) and cerebral metabolic rate of oxygen (CMR02) changes. The gradient-echo BOLD signal is mostly sensitive to ascending veins in the tissue and to pial veins. Thereby, the achievable spatial specificity to neuronal activation is limited. Furthermore, the non-linear interaction of CBF, CBV and CMR02 can hamper quantitative interpretations of the BOLD signal across cortical depths with different baseline physiology. Measuring CBF, CBV or CMR02 directly on a depth-dependent level has the potential to overcome these limitations. Here, we review these candidates of physiologically well-defined contrasts with the particular focus on arterial spin labeling (ASL), vascular space occupancy (VASO) and calibrated fMRI. These methods are reviewed with respect to their fMRI sequence parameter space and the applicability for neuroscientific studies in humans. We show representative results of depth-dependent 'non-BOLD-fMRI' in humans and their spatiotemporal characteristics. We conclude that non-BOLD methods are promising alternatives compared to conventional fMRI as they can provide improved spatial specificity, quantifiability and, hence, physiological interpretability as a function of cortical depth. At submillimeter resolution with inherently low signal-to-noise ratio (SNR), however, their use is still challenging. Nevertheless, we believe that 'non-BOLD-fMRI' is a useful alternative for depth-dependent investigations, by providing valuable insights into neurovascular coupling models that facilitate the interpretability of fMRI for neuroscientific applications. Copyright © 2017. Published by Elsevier Inc.
Does developmental regression in autism spectrum disorder have biological origins?
Jul 24, 2017   Developmental Medicine And Child Neurology
Parr JR
MicroRNAs: Roles in Regulating Neuroinflammation
Jul 24, 2017   The Neuroscientist : A Review Journal Bringing Neurobiology, Neurology And Psychiatry
Gaudet AD, Fonken LK, Watkins LR, Nelson RJ, Popovich PG
MicroRNAs: Roles in Regulating Neuroinflammation
Jul 24, 2017
The Neuroscientist : A Review Journal Bringing Neurobiology, Neurology And Psychiatry
MicroRNAs (miRNAs) are small noncoding RNAs that broadly affect cellular and physiological function in all multicellular organisms. Here, the role of miRNAs in neuroinflammation is considered. miRNAs are 21- to 23-oligonucleotide RNAs that regulate translation of specific RNAs by binding to complementary regulatory RNA sequences, thereby causing mRNA degradation or sequestration. More than 5000 miRNAs likely exist in humans, and each miRNA binds an average of 200 RNAs. Specific immunomodulatory miRNAs can regulate a set of RNAs in a coordinated manner, suggesting that effective miRNA-based therapeutic manipulations for neuroinflammatory conditions may be revealed. For instance, miRNAs that preferentially inhibit translation of many cellular anti-inflammatory proteins could drive a pro-inflammatory response. Key pro-inflammatory ( miR-155, miR-27b, miR-326), anti-inflammatory ( miR-124, miR-146a, miR-21, miR-223), and mixed immunomodulatory ( let-7 family) miRNAs regulate neuroinflammation in various pathologies, including spinal cord injury, multiple sclerosis, ischemic stroke, and Alzheimer's disease. miRNAs represent a newly revealed layer of physiological complexity, the therapeutic benefits of which remain to be fully explored and exploited. In this review, we discuss the role of miRNAs in neuroinflammatory regulation and discuss how controlling miRNAs could alter cellular machinery to improve neuroinflammatory dynamics.
Evaluation of spiral acquisition variants for functional imaging of human superior colliculus at 3T field strength
Jul 24, 2017   Magnetic Resonance In Medicine
Singh V, Pfeuffer J, Zhao T, Ress D
Evaluation of spiral acquisition variants for functional imaging of human superior colliculus at 3T field strength
Jul 24, 2017
Magnetic Resonance In Medicine
High-resolution functional magnetic resonance imaging of human subcortical brain structures is challenging because of their deep location in the cranium, and their comparatively weak blood oxygen level dependent responses to strong stimuli. Magnetic resonance imaging data for subcortical brain regions exhibit both low signal-to-noise ratio and low functional contrast-to-noise ratio. To overcome these challenges, this work evaluates the use of dual-echo spiral variants that combine outward and inward trajectories. Specifically, in-in, in-out, and out-out combinations are evaluated. For completeness, single-echo spiral-in and parallel-receive-accelerated echo-planar-imaging sequences are also evaluated. Sequence evaluation was based on comparison of functional contrast-to-noise ratio within retinotopically predefined regions of interest. Superior colliculus was chosen as sample subcortical brain region because it exhibits a strong visual response. All sequences were compared relative to a single-echo spiral-out trajectory to establish a within-session reference. In superior colliculus, the dual-echo out-out outperformed the reference trajectory by 55% in contrast-to-noise ratio, while all other trajectories had performance similar to the reference. The sequences were also compared in early visual cortex. Here, both dual-echo spiral out-out and in-out outperformed the reference by ∼25%. Dual-echo spiral variants offer improved contrast-to-noise ratio performance for high-resolution imaging for both superior colliculus and cortex. Magn Reson Med, 2017. © 2017 International Society for Magnetic Resonance in Medicine. © 2017 International Society for Magnetic Resonance in Medicine.
Anxiety symptoms and children's eye gaze during fear learning
Jul 24, 2017   Journal Of Child Psychology And Psychiatry, And Allied Disciplines
Michalska KJ, Machlin L, Moroney E, Lowet DS, Hettema JM, Roberson-Nay R, Averbeck BB, Brotman MA, Nelson EE, Leibenluft E, Pine DS
Anxiety symptoms and children's eye gaze during fear learning
Jul 24, 2017
Journal Of Child Psychology And Psychiatry, And Allied Disciplines
The eye region of the face is particularly relevant for decoding threat-related signals, such as fear. However, it is unclear if gaze patterns to the eyes can be influenced by fear learning. Previous studies examining gaze patterns in adults find an association between anxiety and eye gaze avoidance, although no studies to date examine how associations between anxiety symptoms and eye-viewing patterns manifest in children. The current study examined the effects of learning and trait anxiety on eye gaze using a face-based fear conditioning task developed for use in children. Participants were 82 youth from a general population sample of twins (aged 9-13 years), exhibiting a range of anxiety symptoms. Participants underwent a fear conditioning paradigm where the conditioned stimuli (CS+) were two neutral faces, one of which was randomly selected to be paired with an aversive scream. Eye tracking, physiological, and subjective data were acquired. Children and parents reported their child's anxiety using the Screen for Child Anxiety Related Emotional Disorders. Conditioning influenced eye gaze patterns in that children looked longer and more frequently to the eye region of the CS+ than CS- face; this effect was present only during fear acquisition, not at baseline or extinction. Furthermore, consistent with past work in adults, anxiety symptoms were associated with eye gaze avoidance. Finally, gaze duration to the eye region mediated the effect of anxious traits on self-reported fear during acquisition. Anxiety symptoms in children relate to face-viewing strategies deployed in the context of a fear learning experiment. This relationship may inform attempts to understand the relationship between pediatric anxiety symptoms and learning. © 2017 Association for Child and Adolescent Mental Health.
Risky Decision Making in Neurofibromatosis Type 1: An Exploratory Study
Jul 24, 2017   Biological Psychiatry. Cognitive Neuroscience And Neuroimaging
Jonas RK, Roh E, Montojo CA, Pacheco LA, Rosser T, Silva AJ, Bearden CE
Risky Decision Making in Neurofibromatosis Type 1: An Exploratory Study
Jul 24, 2017
Biological Psychiatry. Cognitive Neuroscience And Neuroimaging
Neurofibromatosis type 1 (NF1) is a monogenic disorder affecting cognitive function. About one third of children with NF1 have attentional disorders, and the cognitive phenotype is characterized by impairment in prefrontally-mediated functions. Mouse models of NF1 show irregularities in GABA release and striatal dopamine metabolism. We hypothesized that youth with NF1 would show abnormal behavior and neural activity on a task of risk-taking reliant on prefrontal-striatal circuits. Youth with NF1 (N=29) and demographically comparable healthy controls (N=22), ages 8-19, were administered a developmentally sensitive gambling task, in which they chose between low-risk gambles with a high probability of obtaining a small reward, and high-risk gambles with a low probability of obtaining a large reward. We used functional magnetic resonance imaging (fMRI) to investigate neural activity associated with risky decision making, as well as age-associated changes in these behavioral and neural processes. Behaviorally, youth with NF1 tended to make fewer risky decisions than controls. Neuroimaging analyses revealed significantly reduced neural activity across multiple brain regions involved in higher-order semantic processing and motivation (i.e., anterior cingulate, paracingulate, supramarginal, and angular gyri) in patients with NF1 relative to controls during the task. We also observed atypical age-associated changes in neural activity in patients with NF1, such that during risk taking, neural activity tended to decrease with age in controls, whereas it tended to increase with age in patients with NF1. Findings suggest that developmental trajectories of neural activity during risky decision-making may be disrupted in youth with NF1.
High-dynamic-range fluorescence laminar optical tomography (HDR-FLOT)
Jul 24, 2017   Biomedical Optics Express
Tang Q, Liu Y, Tsytsarev V, Lin J, Wang B, Kanniyappan U, Li Z, Chen Y
High-dynamic-range fluorescence laminar optical tomography (HDR-FLOT)
Jul 24, 2017
Biomedical Optics Express
Three-dimensional fluorescence laminar optical tomography (FLOT) can achieve resolutions of 100-200 µm and penetration depths of 2-3 mm. FLOT has been used in tissue engineering, neuroscience, as well as oncology. The limited dynamic range of the charge-coupled device-based system makes it difficult to image fluorescent samples with a large concentration difference, limits its penetration depth, and diminishes the quantitative accuracy of 3D reconstruction data. Here, incorporating the high-dynamic-range (HDR) method widely used in digital cameras, we present HDR-FLOT, increasing penetration depth and improving the ability to image fluorescent samples with a large concentration difference. The method was tested using an agar phantom and a B6 mouse for brain imaging in vivo.
Typical versus delayed speech onset influences verbal reporting of autistic interests
Jul 24, 2017   Molecular Autism
Chiodo L, Majerus S, Mottron L
Typical versus delayed speech onset influences verbal reporting of autistic interests
Jul 24, 2017
Molecular Autism
The distinction between autism and Asperger syndrome has been abandoned in the DSM-5. However, this clinical categorization largely overlaps with the presence or absence of a speech onset delay which is associated with clinical, cognitive, and neural differences. It is unknown whether these different speech development pathways and associated cognitive differences are involved in the heterogeneity of the restricted interests that characterize autistic adults. This study tested the hypothesis that speech onset delay, or conversely, early mastery of speech, orients the nature and verbal reporting of adult autistic interests. The occurrence of a priori defined descriptors for perceptual and thematic dimensions were determined, as well as the perceived function and benefits, in the response of autistic people to a semi-structured interview on their intense interests. The number of words, grammatical categories, and proportion of perceptual/thematic descriptors were computed and compared between groups by variance analyses. The participants comprised 40 autistic adults grouped according to the presence (N = 20) or absence (N = 20) of speech onset delay, as well as 20 non-autistic adults, also with intense interests, matched for non-verbal intelligence using Raven's Progressive Matrices. The overall nature, function, and benefit of intense interests were similar across autistic subgroups, and between autistic and non-autistic groups. However, autistic participants with a history of speech onset delay used more perceptual than thematic descriptors when talking about their interests, whereas the opposite was true for autistic individuals without speech onset delay. This finding remained significant after controlling for linguistic differences observed between the two groups. Verbal reporting, but not the nature or positive function, of intense interests differed between adult autistic individuals depending on their speech acquisition history: oral reporting of intense interests was characterized by perceptual dominance for autistic individuals with delayed speech onset and thematic dominance for those without. This may contribute to the heterogeneous presentation observed among autistic adults of normal intelligence.
Late onset asymptomatic pancreatic neuroendocrine tumor - A case report on the phenotypic expansion for MEN1
Jul 24, 2017   Hereditary Cancer In Clinical Practice
Kaiwar C, Macklin SK, Gass JM, Jackson J, Klee EW, Hines SL, Stauffer JA, Atwal PS
Late onset asymptomatic pancreatic neuroendocrine tumor - A case report on the phenotypic expansion for MEN1
Jul 24, 2017
Hereditary Cancer In Clinical Practice
Multiple endocrine neoplasia type 1 (MEN1) is a hereditary cancer syndrome associated with several endocrine as well as non-endocrine tumors and is caused by mutations in the MEN1 gene. Primary hyperparathyroidism affects the majority of MEN1 individuals by age 50 years. Additionally, MEN1 mutations trigger familial isolated hyperparathyroidism. We describe a seemingly unaffected 76-year-old female who presented to our Genetics Clinic with a family history of primary hyperparathyroidism and the identification of a pathogenic MEN1 variant. The patient was a 76 year-old woman who appeared to be unaffected. She had a family history of a known MEN1 pathogenic variant. Molecular testing for the known MEN1 mutation c.1A > G, as well as, biochemical testing, MRI of the brain and abdomen were all performed using standard methods. Molecular testing revealed our patient possessed the MEN1 pathogenic variant previously identified in her two offspring. Physical exam revealed red facial papules with onset in her seventies, involving her cheeks, nose and upper lip. Formerly, she was diagnosed with rosacea by a dermatologist and noted no improvement with treatment. Clinically, these lesions appeared to be facial angiofibromas. Brain MRI was normal. However, an MRI of her abdomen revealed a 1.5 cm lesion at the tail of the pancreas with normal adrenal glands. Glucagon was mildly elevated and pancreatic polypeptide was nearly seven times the upper limit of the normal range. The patient underwent spleen sparing distal pancreatectomy and subsequent pathology was consistent with a well-differentiated pancreatic neuroendocrine tumor (pNET). Age-related penetrance and variable expressivity are well documented in families with MEN1. It is thought that nearly all individuals with MEN1 manifest disease by age 40. We present a case of late-onset MEN1 in the absence of the most common feature, primary hyperparathyroidism, but with the presence of a pNET and cutaneous findings. This family expands the phenotype associated with the c.1A > G pathogenic variant and highlights the importance of providing comprehensive assessment of MEN1 mutation carriers in families that at first blush may appear to have isolated hyperparathyroidism.
Ras Signaling Inhibitors Attenuate Disease in Adjuvant-Induced Arthritis via Targeting Pathogenic Antigen-Specific Th17-Type Cells
Jul 24, 2017   Frontiers In Immunology
Zayoud M, Marcu-Malina V, Vax E, Jacob-Hirsch J, Elad-Sfadia G, Barshack I, Kloog Y, Goldstein I
Ras Signaling Inhibitors Attenuate Disease in Adjuvant-Induced Arthritis via Targeting Pathogenic Antigen-Specific Th17-Type Cells
Jul 24, 2017
Frontiers In Immunology
The Ras family of GTPases plays an important role in signaling nodes downstream to T cell receptor and CD28 activation, potentially lowering the threshold for T-cell receptor activation by autoantigens. Somatic mutation in NRAS or KRAS may cause a rare autoimmune disorder coupled with abnormal expansion of lymphocytes. T cells from rheumatoid arthritis (RA) patients show excessive activation of Ras/MEK/ERK pathway. The small molecule farnesylthiosalicylic acid (FTS) interferes with the interaction between Ras GTPases and their prenyl-binding chaperones to inhibit proper plasma membrane localization. In the present study, we tested the therapeutic and immunomodulatory effects of FTS and its derivative 5-fluoro-FTS (F-FTS) in the rat adjuvant-induced arthritis model (AIA). We show that AIA severity was significantly reduced by oral FTS and F-FTS treatment compared to vehicle control treatment. FTS was as effective as the mainstay anti-rheumatic drug methotrexate, and combining the two drugs significantly increased efficacy compared to each drug alone. We also discovered that FTS therapy inhibited both the CFA-driven in vivo induction of Th17 and IL-17/IFN-γ producing "double positive" as well as the upregulation of serum levels of the Th17-associated cytokines IL-17A and IL-22. By gene microarray analysis of effector CD4+ T cells from CFA-immunized rats, re-stimulated in vitro with the mycobacterium tuberculosis heat-shock protein 65 (Bhsp65), we determined that FTS abrogated the Bhsp65-induced transcription of a large list of genes (e.g., Il17a/f, Il22, Ifng, Csf2, Lta, and Il1a). The functional enrichment bioinformatics analysis showed significant overlap with predefined gene sets related to inflammation, immune system processes and autoimmunity. In conclusion, FTS and F-FTS display broad immunomodulatory effects in AIA with inhibition of the Th17-type response to a dominant arthritogenic antigen. Hence, targeting Ras signal-transduction cascade is a potential novel therapeutic approach for RA.
Microbial regulation of hippocampal miRNA expression: Implications for transcription of kynurenine pathway enzymes
Jul 24, 2017   Behavioural Brain Research
Moloney GM, O'Leary OF, Salvo-Romero E, Desbonnet L, Shanahan F, Dinan TG, Clarke G, Cryan JF
Microbial regulation of hippocampal miRNA expression: Implications for transcription of kynurenine pathway enzymes
Jul 24, 2017
Behavioural Brain Research
Increasing evidence points to a functional role of the enteric microbiota in brain development, function and behaviour including the regulation of transcriptional activity in the hippocampus. No changes in CNS miRNA expression have yet been linked to the colonisation status of the gut. Given the pivotal impact of miRNAs on gene expression, our study was based on the hypothesis that this would also be altered in the germ-free state in the hippocampus. We measured miRNAs in the hippocampus of Germ free (GF), conventional (C) and Germ free colonised (GFC) Swiss Webster mice. miRNAs were selected for follow up based on significant differences in expression between groups based on sex and colonization status. The expression of miR-294-5p was increased in male germ free animals and was normalised following colonisation. Targets of the differentially expressed miRNAs were over-represented in the kynurenine pathway. We show that the microbiota modulates the expression of miRNAs associated with kynurenine pathway metabolism and, for the first time, demonstrate that the gut microbiota regulates the expression of kynurenine pathway genes in the hippocampus. We also show a sex-specific role for the microbiota in the regulation of miR-294-5p expression in the hippocampus. The gut microbiota plays an important role in modulating small RNAs that influence hippocampal gene expression, a process critical to hippocampal development. Copyright © 2017. Published by Elsevier B.V.
It doesn't matter what you say: FMRI correlates of voice learning and recognition independent of speech content
Jul 24, 2017   Cortex; A Journal Devoted To The Study Of The Nervous System And Behavior
Zäske R, Awwad Shiekh Hasan B, Belin P
It doesn't matter what you say: FMRI correlates of voice learning and recognition independent of speech content
Jul 24, 2017
Cortex; A Journal Devoted To The Study Of The Nervous System And Behavior
Listeners can recognize newly learned voices from previously unheard utterances, suggesting the acquisition of high-level speech-invariant voice representations during learning. Using functional magnetic resonance imaging (fMRI) we investigated the anatomical basis underlying the acquisition of voice representations for unfamiliar speakers independent of speech, and their subsequent recognition among novel voices. Specifically, listeners studied voices of unfamiliar speakers uttering short sentences and subsequently classified studied and novel voices as "old" or "new" in a recognition test. To investigate "pure" voice learning, i.e., independent of sentence meaning, we presented German sentence stimuli to non-German speaking listeners. To disentangle stimulus-invariant and stimulus-dependent learning, during the test phase we contrasted a "same sentence" condition in which listeners heard speakers repeating the sentences from the preceding study phase, with a "different sentence" condition. Voice recognition performance was above chance in both conditions although, as expected, performance was higher for same than for different sentences. During study phases activity in the left inferior frontal gyrus (IFG) was related to subsequent voice recognition performance and same versus different sentence condition, suggesting an involvement of the left IFG in the interactive processing of speaker and speech information during learning. Importantly, at test reduced activation for voices correctly classified as "old" compared to "new" emerged in a network of brain areas including temporal voice areas (TVAs) of the right posterior superior temporal gyrus (pSTG), as well as the right inferior/middle frontal gyrus (IFG/MFG), the right medial frontal gyrus, and the left caudate. This effect of voice novelty did not interact with sentence condition, suggesting a role of temporal voice-selective areas and extra-temporal areas in the explicit recognition of learned voice identity, independent of speech content. Copyright © 2017 Elsevier Ltd. All rights reserved.

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