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Brain Sci., Volume 9, Issue 1 (January 2019)

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Cover Story (view full-size image) Like humans, some rodents will drink to excess, and a tendency to binge drink is in part inherited. [...] Read more.
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Open AccessReview CRISPR to the Rescue: Advances in Gene Editing for the FMR1 Gene
Brain Sci. 2019, 9(1), 17; https://doi.org/10.3390/brainsci9010017
Received: 28 November 2018 / Revised: 13 January 2019 / Accepted: 15 January 2019 / Published: 21 January 2019
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Abstract
Gene-editing using Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) is promising as a potential therapeutic strategy for many genetic disorders. CRISPR-based therapies are already being assessed in clinical trials, and evaluation of this technology in Fragile X syndrome has been performed by a [...] Read more.
Gene-editing using Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) is promising as a potential therapeutic strategy for many genetic disorders. CRISPR-based therapies are already being assessed in clinical trials, and evaluation of this technology in Fragile X syndrome has been performed by a number of groups. The findings from these studies and the advancement of CRISPR-based technologies are insightful as the field continues towards treatments and cures of Fragile X-Associated Disorders (FXADs). In this review, we summarize reports using CRISPR-editing strategies to target Fragile X syndrome (FXS) molecular dysregulation, and highlight how differences in FXS and Fragile X-associated Tremor/Ataxia Syndrome (FXTAS) might alter treatment strategies for each syndrome. We discuss the various modifications and evolutions of the CRISPR toolkit that expand its therapeutic potential, and other considerations for moving these strategies from bench to bedside. The rapidly growing field of CRISPR therapeutics is providing a myriad of approaches to target a gene, pathway, or transcript for modification. As cures for FXADs have remained elusive, CRISPR opens new avenues to pursue. Full article
(This article belongs to the Special Issue Towards Mechanism-based Treatments for Fragile X Syndrome)
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Open AccessCase Report Sustained Opening of the Blood-Brain Barrier with Progressive Accumulation of White Matter Hyperintensities Following Ischemic Stroke
Brain Sci. 2019, 9(1), 16; https://doi.org/10.3390/brainsci9010016
Received: 30 November 2018 / Revised: 7 January 2019 / Accepted: 17 January 2019 / Published: 21 January 2019
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Abstract
Objective: To report a patient in whom an acute ischemic stroke precipitated chronic blood-brain barrier (BBB) disruption and expansion of vascular white matter hyperintensities (WMH) into regions of normal appearing white matter (NAWM) during the following year. Background: WMH are a common finding [...] Read more.
Objective: To report a patient in whom an acute ischemic stroke precipitated chronic blood-brain barrier (BBB) disruption and expansion of vascular white matter hyperintensities (WMH) into regions of normal appearing white matter (NAWM) during the following year. Background: WMH are a common finding in patients with vascular risk factors such as a history of stroke. The pathophysiology of WMH is not fully understood; however, there is growing evidence to suggest that the development of WMH may be preceded by the BBB disruption in the NAWM. Methods: We studied a patient enrolled in the National Institutes of Health Natural History of Stroke Study who was scanned with magnetic resonance imaging (MRI) after presenting to the emergency room with an acute stroke. After a treatment with IV tPA, she underwent further MRI scanning at 2 h, 24 h, 5 days, 30 days, 90 days, 6 months, and 1-year post stroke. BBB permeability images were generated from the perfusion weighted imaging (PWI) source images. MRIs from each time point were co-registered to track changes in BBB disruption and WMH over time. Results: An 84-year-old woman presented after acute onset right hemiparesis, right-sided numbness and aphasia with an initial NIHSS of 13. MRI showed diffusion restriction in the left frontal lobe and decreased blood flow on perfusion imaging. Fluid attenuated inversion recovery (FLAIR) imaging showed bilateral confluent WMH involving the deep white matter and periventricular regions. She was treated with IV tPA without complication and her NIHSS improved initially to 3 and ultimately to 0. Permeability maps identified multiple regions of chronic BBB disruption remote from the acute stroke, predominantly spanning the junction of WMH and NAWM. The severity of BBB disruption was greatest at 24 h after the stroke but persisted on subsequent MRI scans. Progression of WMH into NAWM over the year of observation was detected bilaterally but was most dramatic in the regions adjacent to the initial stroke. Conclusions: WMH-associated BBB disruption may be exacerbated by an acute stroke, even in the contralateral hemisphere, and can persist for months after the initial event. Transformation of NAWM to WMH may be evident in areas of BBB disruption within a year after the stroke. Further studies are needed to investigate the relationship between chronic BBB disruption and progressive WMH in patients with a history of cerebrovascular disease and the potential for acute stroke to trigger or exacerbate the process leading to the development of WMH. Full article
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Open AccessReview Executive Function in Fragile X Syndrome: A Systematic Review
Brain Sci. 2019, 9(1), 15; https://doi.org/10.3390/brainsci9010015
Received: 15 December 2018 / Revised: 9 January 2019 / Accepted: 11 January 2019 / Published: 16 January 2019
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Abstract
Executive function (EF) supports goal-directed behavior and includes key aspects such as working memory, inhibitory control, cognitive flexibility, attention, processing speed, and planning. Fragile X syndrome (FXS) is the leading inherited monogenic cause of intellectual disability and is phenotypically characterized by EF deficits [...] Read more.
Executive function (EF) supports goal-directed behavior and includes key aspects such as working memory, inhibitory control, cognitive flexibility, attention, processing speed, and planning. Fragile X syndrome (FXS) is the leading inherited monogenic cause of intellectual disability and is phenotypically characterized by EF deficits beyond what is expected given general cognitive impairments. Yet, a systematic review of behavioral studies using performance-based measures is needed to provide a summary of EF deficits across domains in males and females with FXS, discuss clinical and biological correlates of these EF deficits, identify critical limitations in available research, and offer suggestions for future studies in this area. Ultimately, this review aims to advance our understanding of the underlying pathophysiological mechanisms contributing to EF in FXS and to inform the development of outcome measures of EF and identification of new treatment targets in FXS. Full article
(This article belongs to the Special Issue Towards Mechanism-based Treatments for Fragile X Syndrome)
Open AccessReview Potential Mechanisms Underlying the Deleterious Effects of Synthetic Cannabinoids Found in Spice/K2 Products
Brain Sci. 2019, 9(1), 14; https://doi.org/10.3390/brainsci9010014
Received: 27 December 2018 / Revised: 11 January 2019 / Accepted: 13 January 2019 / Published: 16 January 2019
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Abstract
The chief psychoactive constituent of many bioactive phytocannabinoids (Δ9-tetrahydrocannabinol, Δ9-THC) found in hemp, cannabis or marijuana plants are scientifically denoted by the Latin term, Cannabis sativa, acts on cell surface receptors. These receptors are ubiquitously expressed. To date, [...] Read more.
The chief psychoactive constituent of many bioactive phytocannabinoids (Δ9-tetrahydrocannabinol, Δ9-THC) found in hemp, cannabis or marijuana plants are scientifically denoted by the Latin term, Cannabis sativa, acts on cell surface receptors. These receptors are ubiquitously expressed. To date, two cannabinoid receptors have been cloned and characterized. Cannabinoid receptor type 1 (CB1R) is found to serve as the archetype for cannabinoid action in the brain. They have attracted wide interest as the mediator of all psychoactive properties of exogenous and endogenous cannabinoids and they are abundantly expressed on most inhibitory and excitatory neurons. Recent evidence established that cannabinoid receptor type 2 (CB2R) is also expressed in the neurons at both presynaptic and postsynaptic terminals and are involved in neuropsychiatric effects. Distinct types of cells in many regions in the brain express CB2Rs and the cellular origin of CB2Rs that induce specific behavioral effects are emerging. To mimic the bliss effects of marijuana, synthetic cannabinoids (SCBs) have been sprayed onto plant material, and this plant material has been consequently packaged and sold under brand name “Spice” or “K2”. These SCBs have been shown to maintain their affinity and functional activity for CB1R and CB2R and have been shown to cause severe harmful effects when compared to the effects of Δ9-THC. The present review discusses the potential brain mechanisms that are involved in the deleterious effects of SCBs. Full article
(This article belongs to the Section Molecular and Cellular Neuroscience)
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Open AccessArticle Comparative Behavioral Phenotypes of Fmr1 KO, Fxr2 Het, and Fmr1 KO/Fxr2 Het Mice
Brain Sci. 2019, 9(1), 13; https://doi.org/10.3390/brainsci9010013
Received: 6 November 2018 / Revised: 8 January 2019 / Accepted: 10 January 2019 / Published: 16 January 2019
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Abstract
Fragile X syndrome (FXS) is caused by silencing of the FMR1 gene leading to loss of the protein product fragile X mental retardation protein (FMRP). FXS is the most common monogenic cause of intellectual disability. There are two known mammalian paralogs of FMRP, [...] Read more.
Fragile X syndrome (FXS) is caused by silencing of the FMR1 gene leading to loss of the protein product fragile X mental retardation protein (FMRP). FXS is the most common monogenic cause of intellectual disability. There are two known mammalian paralogs of FMRP, FXR1P, and FXR2P. The functions of FXR1P and FXR2P and their possible roles in producing or modulating the phenotype observed in FXS are yet to be identified. Previous studies have revealed that mice lacking Fxr2 display similar behavioral abnormalities as Fmr1 knockout (KO) mice. In this study, we expand upon the behavioral phenotypes of Fmr1 KO and Fxr2+/− (Het) mice and compare them with Fmr1 KO/Fxr2 Het mice. We find that Fmr1 KO and Fmr1 KO/Fxr2 Het mice are similarly hyperactive compared to WT and Fxr2 Het mice. Fmr1 KO/Fxr2 Het mice have more severe learning and memory impairments than Fmr1 KO mice. Fmr1 KO mice display significantly impaired social behaviors compared to WT mice, which are paradoxically reversed in Fmr1 KO/Fxr2 Het mice. These results highlight the important functional consequences of loss or reduction of FMRP and FXR2P. Full article
(This article belongs to the Special Issue Towards Mechanism-based Treatments for Fragile X Syndrome)
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Open AccessArticle Self-Esteem Group: Useful Intervention for Inpatients with Anorexia Nervosa?
Brain Sci. 2019, 9(1), 12; https://doi.org/10.3390/brainsci9010012
Received: 12 December 2018 / Revised: 7 January 2019 / Accepted: 9 January 2019 / Published: 13 January 2019
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Abstract
Low self-esteem is a common feature in Anorexia Nervosa (AN) and has been hypothesised to act as a predisposing, precipitating, and perpetuating factor. The aim of this study was to assess the effectiveness of a Cognitive Behavioural Therapy (CBT)-based self-esteem group in a [...] Read more.
Low self-esteem is a common feature in Anorexia Nervosa (AN) and has been hypothesised to act as a predisposing, precipitating, and perpetuating factor. The aim of this study was to assess the effectiveness of a Cognitive Behavioural Therapy (CBT)-based self-esteem group in a naturalistic setting of patients with AN in an inpatient treatment programme. Included in this study were 119 female patients diagnosed with AN, with all participants completing self-report questionnaires before and after the intervention. The group consisted of five to six weekly sessions. The self-esteem group led to a statistically significant improvement in self-esteem, which could not be explained by an increase in BMI alone, suggesting that the group is facilitating positive changes within an AN group. The group also had a small effect on improving patients self-perceived ability to change. These findings suggest that the brief self-esteem group has some benefits in improving patients’ self-esteem/self-efficacy and should be replicated in the future with a control condition to confirm findings. Full article
(This article belongs to the Special Issue Psychotherapeutic Treatment for Anorexia Nervosa)
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Open AccessReview Closing the Gender Gap in Fragile X Syndrome: Review of Females with Fragile X Syndrome and Preliminary Research Findings
Brain Sci. 2019, 9(1), 11; https://doi.org/10.3390/brainsci9010011
Received: 1 December 2018 / Revised: 21 December 2018 / Accepted: 10 January 2019 / Published: 12 January 2019
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Abstract
Fragile X syndrome (FXS) is a genetic condition known to increase the risk of cognitive impairment and socio-emotional challenges in affected males and females. To date, the vast majority of research on FXS has predominantly targeted males, who usually exhibit greater cognitive impairment [...] Read more.
Fragile X syndrome (FXS) is a genetic condition known to increase the risk of cognitive impairment and socio-emotional challenges in affected males and females. To date, the vast majority of research on FXS has predominantly targeted males, who usually exhibit greater cognitive impairment compared to females. Due to their typically milder phenotype, females may have more potential to attain a higher level of independence and quality of life than their male counterparts. However, the constellation of cognitive, behavioral, and, particularly, socio-emotional challenges present in many females with FXS often preclude them from achieving their full potential. It is, therefore, critical that more research specifically focuses on females with FXS to elucidate the role of genetic, environmental, and socio-emotional factors on outcome in this often-overlooked population. Full article
(This article belongs to the Special Issue Towards Mechanism-based Treatments for Fragile X Syndrome)
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Open AccessArticle Sleep Disorders Following Mild and Moderate Traumatic Brain Injury
Brain Sci. 2019, 9(1), 10; https://doi.org/10.3390/brainsci9010010
Received: 27 November 2018 / Revised: 4 January 2019 / Accepted: 10 January 2019 / Published: 11 January 2019
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Abstract
(1) Background: Sleeping disorders are frequently reported following traumatic brain injury (TBI). Different forms of sleeping disorders have been reported, such as sleepiness, insomnia, changes in sleeping latency, and others. (2) Methods: A case-control study with 62 patients who were victims of mild [...] Read more.
(1) Background: Sleeping disorders are frequently reported following traumatic brain injury (TBI). Different forms of sleeping disorders have been reported, such as sleepiness, insomnia, changes in sleeping latency, and others. (2) Methods: A case-control study with 62 patients who were victims of mild or moderate TBI with previous admissions to Iraqi tertiary neurosurgical centers were enrolled as the first group, and 158 patients with no history of trauma were considered as the control. All were 18 years of age or older, and the severity of the trauma and sleep disorders was assessed. The Pittsburgh sleep quality index was used to assess sleep disorders with average need for sleep per day and average sleep latency were assessed in both groups. Chi-square and t-test calculations were used to compare different variables. (3) Results: 39 patients (24.7%) of the controlled group experienced sleeping disorders compared to TBI group with 45 patients (72.6%), P-value < 0.00001. A total of 42 patients were diagnosed on admission as having a mild degree of TBI (mean GCS 13.22 ± 1.76) and 20 patients were diagnosed with moderate TBI (mean GCS11.05 ± 1.14. 27). A total of 27 (46.28%) patients with mild severity TBI and 18 patients (90%) of moderate severity were considered to experience sleeping disorders, P-value 0.0339. Each of the mild and moderate TBI subgroups show a P-value < 0.00001 compared to the control group. Average sleep hours needed per day for TBI and the control were 8.02 ± 1.04 h and 7.26 ± 0.58 h, respectively, P-value < 0.00001. Average sleep latency for the TBI and the control groups were 13.32 ± 3.16 min and 13.93 ± 3.07 min respectively, P-value 0.065. (4) Conclusion: Sleep disturbances are more common following mild and moderate TBI three months after the injury with more hours needed for sleep per day and no significant difference in sleep latency. Sleep disturbances increase in frequency with the increase in the severity of TBI. Full article
(This article belongs to the Special Issue Insomnia: Beyond Hyperarousal)
Open AccessReply Dyslexia: Still Not a Neurodevelopmental Disorder
Brain Sci. 2019, 9(1), 9; https://doi.org/10.3390/brainsci9010009
Received: 22 December 2018 / Accepted: 9 January 2019 / Published: 10 January 2019
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Abstract
We recently pointed out that there is no evidence to support the commonly held view that there is something wrong with the brains of children who have great difficulty learning to read. In response, it was argued that dyslexia should be considered to [...] Read more.
We recently pointed out that there is no evidence to support the commonly held view that there is something wrong with the brains of children who have great difficulty learning to read. In response, it was argued that dyslexia should be considered to be a neurodevelopmental disorder because of its potential to adversely affect quality of life, and because there are differences between the brains of people with different levels of reading skill. We agree with these two points, but they are irrelevant to the issue in question, because neither establishes the critical notion of disrupted neurodevelopment; that is, a brain fault. Differences between groups do not imply that any individuals are abnormal, and calling a brain improperly developed on the basis of cultural issues has absurd implications. Even calling brains atypical is unfounded because reference to typicality hinges on knowledge of the relevant distributions, which is currently lacking. Moreover, there is at present no obvious role for neurology- or neuroscience-based input for the critical issue of the assessment and remediation of the reading difficulties themselves. We reiterate our conclusion that there is, at the moment, no credible foundation to support the claim that dyslexia is a neurodevelopmental disorder. Full article
(This article belongs to the Special Issue Dyslexia, Dysgraphia and Related Developmental Disorders)
Open AccessArticle MyomiRNAs Dysregulation in ALS Rehabilitation
Brain Sci. 2019, 9(1), 8; https://doi.org/10.3390/brainsci9010008
Received: 26 October 2018 / Revised: 21 December 2018 / Accepted: 5 January 2019 / Published: 10 January 2019
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Abstract
Amyotrophic lateral sclerosis (ALS) is a rare, progressive, neurodegenerative disorder caused by degeneration of upper and lower motor neurons. The disease process leads, because of lower motor neuron involvement, to progressive muscle atrophy, weakness, and fasciculations and for the upper motor neuron involvement [...] Read more.
Amyotrophic lateral sclerosis (ALS) is a rare, progressive, neurodegenerative disorder caused by degeneration of upper and lower motor neurons. The disease process leads, because of lower motor neuron involvement, to progressive muscle atrophy, weakness, and fasciculations and for the upper motor neuron involvement leads to spasticity. Muscle atrophy in ALS is caused by a neural dysregulation in the molecular network controlling fast and slow muscle fibers. Denervation and reinnervation processes in skeletal muscle occur in the course of ALS and are modulated by rehabilitation. MicroRNAs (miRNAs) are small, non-coding RNAs that are involved in different biological functions under various pathophysiological conditions. MiRNAs can be secreted by various cell types and they are markedly stable in body fluids. MiR-1, miR-133 a miR-133b, and miR-206 are called “myomiRs” and are considered markers of myogenesis during muscle regeneration and contribute to neuromuscular junction stabilization or sprouting. We observed a positive effect of a standard aerobic exercise rehabilitative protocol conducted for six weeks in 18 ALS patients during hospitalization in our center. This is a preliminary study, in which we correlated clinical scales with molecular data on myomiRs. After six weeks of moderate aerobic exercise, we found lower levels in serum of myomiRNAs. Our data suggest that circulating miRNAs changed during skeletal muscle recovery in response to physical rehabilitation in ALS. However, no firm conclusions can be made on the ALS-specific effect of exercise on miRNA levels. Full article
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Open AccessEditorial Acknowledgement to Reviewers of Brain Sciences in 2018
Brain Sci. 2019, 9(1), 7; https://doi.org/10.3390/brainsci9010007
Published: 8 January 2019
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Abstract
Rigorous peer-review is the corner-stone of high-quality academic publishing.[...] Full article
Open AccessArticle The Motivational Power of the Happy Face
Brain Sci. 2019, 9(1), 6; https://doi.org/10.3390/brainsci9010006
Received: 28 November 2018 / Revised: 21 December 2018 / Accepted: 31 December 2018 / Published: 7 January 2019
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Abstract
People who are cheerful have better social relationships. This might be the case because happy faces communicate an invitation to interact. Thus, happy faces might have a strong motivational effect on others. We tested this hypothesis in a set of four studies. Study [...] Read more.
People who are cheerful have better social relationships. This might be the case because happy faces communicate an invitation to interact. Thus, happy faces might have a strong motivational effect on others. We tested this hypothesis in a set of four studies. Study 1 (N = 94) showed that approach reactions to happy faces are faster than other reactions to happy or angry faces. Study 2 (N = 99) found the same effect when comparing reactions to happy faces with reactions to disgusted faces. Supporting the notion that this effect is related to motivation, habitual social approach motivation intensified the motivational effect of happy faces (Study 3, N = 82). Finally, Study 4 (N = 40) showed that the reaction-time asymmetry does not hold for categorization tasks without approach and avoidance movements. These studies demonstrate that happy faces have a strong motivational power. They seem to activate approach reactions more strongly than angry or disgusted faces activate avoidance reactions. Full article
(This article belongs to the Special Issue Perceptual and Affective Mechanisms in Facial Expression Recognition)
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Open AccessReview How Deep Brain Stimulation of the Nucleus Accumbens Affects the Cingulate Gyrus and Vice Versa
Brain Sci. 2019, 9(1), 5; https://doi.org/10.3390/brainsci9010005
Received: 8 December 2018 / Accepted: 30 December 2018 / Published: 4 January 2019
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Abstract
The nucleus accumbens (NA) and the cingulate gyrus (CG) are two vital limbic brain structures. They have attracted attention as deep brain stimulation (DBS) targets in the treatment of common refractory psychiatric illness. The primary purpose of this article was to review the [...] Read more.
The nucleus accumbens (NA) and the cingulate gyrus (CG) are two vital limbic brain structures. They have attracted attention as deep brain stimulation (DBS) targets in the treatment of common refractory psychiatric illness. The primary purpose of this article was to review the current knowledge regarding the way that NA DBS affects the CG and vice versa. Methodologically, a thorough literature review was performed. According to the current literature, NA DBS modulates the function of several brain areas including the CG cortex. It specifically causes activation in the ipsilateral CG cortex and voltage-dependent reduction of its blood oxygenation. It also reverses anterior mid-CG cortex dysfunction and decreases metabolism in the subgenual CG. Moreover, NA DBS that induces mirth inhibits the function of the anterior CG cortex and enhances effective connectivity from anterior CG to the ventral striatum. On the other hand, although it is highly probable that CG DBS affects the NA, the exact nature of its effects remains unclear. Despite the increasing interest in psychiatric DBS, the available data on how NA DBS affects the CG and vice versa are restricted. This conclusion probably reflects the high complexity of the limbic circuits and necessitates further research. Full article
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Open AccessReview Early Identification of Fragile X Syndrome through Expanded Newborn Screening
Brain Sci. 2019, 9(1), 4; https://doi.org/10.3390/brainsci9010004
Received: 14 November 2018 / Revised: 21 December 2018 / Accepted: 24 December 2018 / Published: 3 January 2019
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Abstract
Over the past 20 years, research on fragile X syndrome (FXS) has provided foundational understanding of the complex experiences of affected individuals and their families. Despite this intensive focus, there has been little progress on earlier identification, with the average age of diagnosis [...] Read more.
Over the past 20 years, research on fragile X syndrome (FXS) has provided foundational understanding of the complex experiences of affected individuals and their families. Despite this intensive focus, there has been little progress on earlier identification, with the average age of diagnosis being 3 years. For intervention and treatment approaches to have the greatest impact, they need to begin shortly after birth. To access this critical timespan, differential methods of earlier identification need to be considered, with an emerging focus on newborn screening practices. Currently, barriers exist that prevent the inclusion of FXS on standard newborn screening panels. To address these barriers, an innovative program is being implemented in North Carolina to offer voluntary screening for FXS under a research protocol, called Early Check. This program addresses the difficulties observed in prior pilot studies, such as recruitment, enrollment, lab testing, and follow-up. Early Check provides an opportunity for stakeholders and the research community to continue to gain valuable information about the feasibility and greater impact of newborn screening on the FXS population. Full article
(This article belongs to the Special Issue Towards Mechanism-based Treatments for Fragile X Syndrome)
Open AccessArticle Multimodal Object Classification Models Inspired by Multisensory Integration in the Brain
Brain Sci. 2019, 9(1), 3; https://doi.org/10.3390/brainsci9010003
Received: 14 November 2018 / Revised: 12 December 2018 / Accepted: 25 December 2018 / Published: 2 January 2019
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Abstract
Two multimodal classification models aimed at enhancing object classification through the integration of semantically congruent unimodal stimuli are introduced. The feature-integrating model, inspired by multisensory integration in the subcortical superior colliculus, combines unimodal features which are subsequently classified by a multimodal classifier. The [...] Read more.
Two multimodal classification models aimed at enhancing object classification through the integration of semantically congruent unimodal stimuli are introduced. The feature-integrating model, inspired by multisensory integration in the subcortical superior colliculus, combines unimodal features which are subsequently classified by a multimodal classifier. The decision-integrating model, inspired by integration in primary cortical areas, classifies unimodal stimuli independently using unimodal classifiers and classifies the combined decisions using a multimodal classifier. The multimodal classifier models are implemented using multilayer perceptrons and multivariate statistical classifiers. Experiments involving the classification of noisy and attenuated auditory and visual representations of ten digits are designed to demonstrate the properties of the multimodal classifiers and to compare the performances of multimodal and unimodal classifiers. The experimental results show that the multimodal classification systems exhibit an important aspect of the “inverse effectiveness principle” by yielding significantly higher classification accuracies when compared with those of the unimodal classifiers. Furthermore, the flexibility offered by the generalized models enables the simulations and evaluations of various combinations of multimodal stimuli and classifiers under varying uncertainty conditions. Full article
(This article belongs to the Section Systems Neuroscience)
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Open AccessArticle Ethanol Conditioned Taste Aversion in High Drinking in the Dark Mice
Brain Sci. 2019, 9(1), 2; https://doi.org/10.3390/brainsci9010002
Received: 13 November 2018 / Revised: 20 December 2018 / Accepted: 20 December 2018 / Published: 1 January 2019
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Two independent lines of High Drinking in the Dark (HDID-1, HDID-2) mice have been bred to reach high blood alcohol levels after a short period of binge-like ethanol drinking. Male mice of both lines were shown to have reduced sensitivity to develop a [...] Read more.
Two independent lines of High Drinking in the Dark (HDID-1, HDID-2) mice have been bred to reach high blood alcohol levels after a short period of binge-like ethanol drinking. Male mice of both lines were shown to have reduced sensitivity to develop a taste aversion to a novel flavor conditioned by ethanol injections as compared with their unselected HS/NPT founder stock. We have subsequently developed inbred variants of each line. The current experiments established that reduced ethanol-conditioned taste aversion is also seen in the inbred variants, in both males and females. In other experiments, we asked whether HDID mice would ingest sufficient doses of ethanol to lead to a conditioned taste aversion upon retest. Different manipulations were used to elevate consumption of ethanol on initial exposure. Access to increased ethanol concentrations, to multiple tubes of ethanol, and fluid restriction to increase thirst motivation all enhanced initial drinking of ethanol. Each condition led to reduced intake the next day, consistent with a mild conditioned taste aversion. These experiments support the conclusion that one reason contributing to the willingness of HDID mice to drink to the point of intoxication is a genetic insensitivity to the aversive effects of ethanol. Full article
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Open AccessArticle Differential Expression of Genes Related to Innate Immune Responses in Ex Vivo Spinal Cord and Cerebellar Slice Cultures Infected with West Nile Virus
Brain Sci. 2019, 9(1), 1; https://doi.org/10.3390/brainsci9010001
Received: 29 October 2018 / Revised: 14 December 2018 / Accepted: 18 December 2018 / Published: 24 December 2018
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Abstract
West Nile virus (WNV) infection results in a spectrum of neurological symptoms, ranging from a benign fever to severe WNV neuroinvasive disease with high mortality. Many who recover from WNV neuroinvasive infection present with long-term deficits, including weakness, fatigue, and cognitive problems. While [...] Read more.
West Nile virus (WNV) infection results in a spectrum of neurological symptoms, ranging from a benign fever to severe WNV neuroinvasive disease with high mortality. Many who recover from WNV neuroinvasive infection present with long-term deficits, including weakness, fatigue, and cognitive problems. While neurons are a main target of WNV, other cell types, especially astrocytes, play an important role in promoting WNV-mediated central nervous system (CNS) damage. Conversely, it has been shown that cultured primary astrocytes secrete high levels of interferons (IFNs) immediately after WNV exposure to protect neighboring astrocytes, as well as neurons. However, how intrinsic responses to WNV in specific cell types and different regions of the brain modify immune protection is not fully understood. Here, we used a mouse ex vivo spinal cord slice culture (SCSC) and cerebellar slice culture (CSC) models to determine the innate immune responses specific to the CNS during WNV infection. Slices were prepared from the spinal cord and cerebellar tissue of 7–9-day-old mouse pups. Four-day-old SCSC or CSC were infected with 1 × 103 or 1 × 105 PFU of WNV, respectively. After 12 h exposure to WNV and 3 days post-infection in normal growth media, the pooled slice cultures were processed for total RNA extraction and for gene expression patterns using mouse Affymetrix arrays. The expression patterns of a number of genes were significantly altered between the mock- and WNV-treated groups, both in the CSCs and SCSCs. However, distinct differences were observed when CSC data were compared with SCSC. CSCs showed robust induction of interferons (IFNs), IFN-stimulated genes (ISGs), and regulatory factors. Some of the antiviral genes related to IFN were upregulated more than 25-fold in CSCs as compared to mock or SCSC. Though SCSCs had twice the number of dysregulated genes, as compared CSCs, they exhibited a much subdued IFN response. In addition, SCSCs showed astrogliosis and upregulation of astrocytic marker genes. In sum, our results suggest that early anti-inflammatory response to WNV infection in CSCs may be due to large population of distinct astrocytic cell types, and lack of those specialized astrocytes in SCSC may make spinal cord cells more susceptible to WNV damage. Further, the understanding of early intrinsic immune response events in WNV-infected ex vivo culture models could help develop potential therapies against WNV. Full article
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