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Brain Sci., Volume 8, Issue 12 (December 2018)

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Cover Story (view full-size image) Targeted treatment development in fragile X syndrome (FXS) has experienced significant interest and [...] Read more.
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Open AccessReview A Homeostatic Model of Subjective Cognitive Decline
Brain Sci. 2018, 8(12), 228; https://doi.org/10.3390/brainsci8120228
Received: 31 October 2018 / Revised: 3 December 2018 / Accepted: 17 December 2018 / Published: 19 December 2018
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Abstract
Subjective Cognitive Decline (SCD) is possibly one of the earliest detectable signs of dementia, but we do not know which mental processes lead to elevated concern. In this narrative review, we will summarize the previous literature on the biomarkers and functional neuroanatomy of [...] Read more.
Subjective Cognitive Decline (SCD) is possibly one of the earliest detectable signs of dementia, but we do not know which mental processes lead to elevated concern. In this narrative review, we will summarize the previous literature on the biomarkers and functional neuroanatomy of SCD. In order to extend upon the prevailing theory of SCD, compensatory hyperactivation, we will introduce a new model: the breakdown of homeostasis in the prediction error minimization system. A cognitive prediction error is a discrepancy between an implicit cognitive prediction and the corresponding outcome. Experiencing frequent prediction errors may be a primary source of elevated subjective concern. Our homeostasis breakdown model provides an explanation for the progression from both normal cognition to SCD and from SCD to advanced dementia stages. Full article
(This article belongs to the Special Issue Cognitive Aging)
Open AccessArticle Integrative Analysis of Global Gene Expression Identifies Opposite Patterns of Reactive Astrogliosis in Aged Human Prefrontal Cortex
Brain Sci. 2018, 8(12), 227; https://doi.org/10.3390/brainsci8120227
Received: 30 October 2018 / Revised: 28 November 2018 / Accepted: 4 December 2018 / Published: 19 December 2018
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Abstract
The prefrontal cortex (PFC) is one of the brain regions with more prominent changes in human aging. The molecular processes related to the cognitive decline and mood changes during aging are not completely understood. To improve our knowledge, we integrated transcriptomic data of [...] Read more.
The prefrontal cortex (PFC) is one of the brain regions with more prominent changes in human aging. The molecular processes related to the cognitive decline and mood changes during aging are not completely understood. To improve our knowledge, we integrated transcriptomic data of four studies of human PFC from elderly people (58–80 years old) compared with younger people (20–40 years old) using a meta-analytic approximation combined with molecular signature analysis. We identified 1817 differentially expressed genes, 561 up-regulated and 1256 down-regulated. Pathway analysis revealed down-regulation of synaptic genes with conservation of gene expression of other neuronal regions. Additionally, we identified up-regulation of markers of astrogliosis with transcriptomic signature compatible with A1 neurotoxic astrocytes and A2 neuroprotective astrocytes. Response to interferon is related to A1 astrocytes and the A2 phenotype is mediated in aging by activation of sonic hedgehog (SHH) pathway and up-regulation of metallothioneins I and genes of the family ERM (ezrin, radixin, and moesin). The main conclusions of our study are the confirmation of a global dysfunction of the synapses in the aged PFC and the evidence of opposite phenotypes of astrogliosis in the aging brain, which we report for the first time in the present article. Full article
(This article belongs to the Section Molecular and Cellular Neuroscience)
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Open AccessReview NRSF and Its Epigenetic Effectors: New Treatments for Neurological Disease
Brain Sci. 2018, 8(12), 226; https://doi.org/10.3390/brainsci8120226
Received: 26 November 2018 / Revised: 13 December 2018 / Accepted: 14 December 2018 / Published: 19 December 2018
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Abstract
The Neuron Restrictive Silencer Factor (NRSF) is the well-known master transcriptional repressor of the neuronal phenotype. Research to date has shown that it is an important player in the growth and development of the nervous system. Its role in the maturation of neural [...] Read more.
The Neuron Restrictive Silencer Factor (NRSF) is the well-known master transcriptional repressor of the neuronal phenotype. Research to date has shown that it is an important player in the growth and development of the nervous system. Its role in the maturation of neural precursor cells to adult neurons has been well characterized in stem cell models. While much has been characterized from a developmental perspective, research is revealing that NRSF plays a role in various neurological diseases, ranging from neurodegenerative, neuropsychiatric, to cancer. Dysregulation of NRSF activity disrupts downstream gene expression that is responsible for neuronal cell homeostasis in several models that contribute to pathologic states. Interestingly, it is now becoming apparent that the dysregulation of NRSF contributes to neurological disease through epigenetic mechanisms. Although NRSF itself is a transcription factor, its major effectors are chromatin modifiers. At the level of epigenetics, changes in NRSF activity have been well characterized in models of neuropathic pain and epilepsy. Better understanding of the epigenetic basis of brain diseases has led to design and use of small molecules that can prevent NRSF from repressing gene expression by neutralizing its interactions with its chromatin remodelers. This review will address the basic function of NRSF and its cofactors, investigate their mechanisms, then explore how their dysfunction can cause disease states. This review will also address research on NRSF as a therapeutic target and delve into new therapeutic strategies that focus on disrupting NRSF’s ability to recruit chromatin remodelers. Full article
(This article belongs to the Special Issue Novel Mechanisms and Strategies for Neural Repair)
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Open AccessArticle Alterations in Motor Cortical Representation of Muscles Following Incomplete Spinal Cord Injury in Humans
Brain Sci. 2018, 8(12), 225; https://doi.org/10.3390/brainsci8120225
Received: 15 November 2018 / Revised: 7 December 2018 / Accepted: 14 December 2018 / Published: 16 December 2018
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Abstract
(1) Background: The primary motor cortex (M1) experiences reorganization following spinal cord injury (SCI). However, there is a paucity of research comparing bilateral M1 organization in SCI and questions remain to be answered. We explored the presence of somatotopy within the M1 representation [...] Read more.
(1) Background: The primary motor cortex (M1) experiences reorganization following spinal cord injury (SCI). However, there is a paucity of research comparing bilateral M1 organization in SCI and questions remain to be answered. We explored the presence of somatotopy within the M1 representation of arm muscles, and determined whether anatomical shifts in these representations occur, and investigated the symmetry in organization between the two hemispheres.; (2) Methods: Transcranial magnetic stimulation (TMS) was used to map the representation of the biceps, flexor carpi radialis and abductor pollicis brevis (APB) bilaterally in nine individuals with chronic incomplete cervical spinal cord injury and nine aged- and handed-matched uninjured controls. TMS was delivered over a 6 × 5 point grid that encompassed M1 using an intensity specific to the resting motor threshold for each muscle tested.; (3) Results: Results indicate that, compared to controls, muscle representations in SCI are shifted medially but preserve a general somatotopic arrangement, and that territory dedicated to the APB muscle is greater.; (4) Conclusions: These findings demonstrate differences in the organization of M1 between able-bodied controls and those with incomplete cervical SCI. This altered organization may have future implications in understanding the functional deficits observed in SCI and rehabilitation techniques aimed at restoring function. Full article
(This article belongs to the collection Collection on Clinical Neuroscience)
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Open AccessCommentary Best Practices in Fragile X Syndrome Treatment Development
Brain Sci. 2018, 8(12), 224; https://doi.org/10.3390/brainsci8120224
Received: 21 November 2018 / Revised: 10 December 2018 / Accepted: 12 December 2018 / Published: 15 December 2018
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Abstract
Preclinical studies using animal models of fragile X syndrome have yielded several agents that rescue a wide variety of phenotypes. However, translation of these treatments to humans with the disorder has not yet been successful, shedding light on a variety of limitations with [...] Read more.
Preclinical studies using animal models of fragile X syndrome have yielded several agents that rescue a wide variety of phenotypes. However, translation of these treatments to humans with the disorder has not yet been successful, shedding light on a variety of limitations with both animal models and human trial design. As members of the Clinical Trials Committee of the National Fragile X Foundation, we have discussed a variety of recommendations at the level of preclinical development, transition from preclinical to human projects, family involvement, and multi-site trial planning. Our recommendations are made with the vision that effective new treatment will lie at the intersection of innovation, rigorous and reproducible research, and stakeholder involvement. Full article
(This article belongs to the Special Issue Towards Mechanism-based Treatments for Fragile X Syndrome)
Open AccessReview Update on Insomnia after Mild Traumatic Brain Injury
Brain Sci. 2018, 8(12), 223; https://doi.org/10.3390/brainsci8120223
Received: 18 November 2018 / Revised: 8 December 2018 / Accepted: 11 December 2018 / Published: 13 December 2018
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Abstract
Sleep disturbance after traumatic brain injury (TBI) has received growing interest in recent years, garnering many publications. Insomnia is highly prevalent within the mild traumatic brain injury (mTBI) population and is a subtle, frequently persistent complaint that often goes undiagnosed. For individuals with [...] Read more.
Sleep disturbance after traumatic brain injury (TBI) has received growing interest in recent years, garnering many publications. Insomnia is highly prevalent within the mild traumatic brain injury (mTBI) population and is a subtle, frequently persistent complaint that often goes undiagnosed. For individuals with mTBI, problems with sleep can compromise the recovery process and impede social reintegration. This article updates the evidence on etiology, epidemiology, prognosis, consequences, differential diagnosis, and treatment of insomnia in the context of mild TBI. This article aims to increase awareness about insomnia following mTBI in the hopes that it may improve diagnosis, evaluation, and treatment of sleeping disturbance in this population while revealing areas for future research. Full article
(This article belongs to the Special Issue Insomnia: Beyond Hyperarousal)
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Open AccessReview The Genetic Diagnosis of Neurodegenerative Diseases and Therapeutic Perspectives
Brain Sci. 2018, 8(12), 222; https://doi.org/10.3390/brainsci8120222
Received: 11 October 2018 / Revised: 26 November 2018 / Accepted: 7 December 2018 / Published: 13 December 2018
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Abstract
Genetics has led to a new focus regarding approaches to the most prevalent diseases today. Ascertaining the molecular secrets of neurodegenerative diseases will lead to developing drugs that will change natural history, thereby affecting the quality of life and mortality of patients. The [...] Read more.
Genetics has led to a new focus regarding approaches to the most prevalent diseases today. Ascertaining the molecular secrets of neurodegenerative diseases will lead to developing drugs that will change natural history, thereby affecting the quality of life and mortality of patients. The sequencing of candidate genes in patients suffering neurodegenerative pathologies is faster, more accurate, and has a lower cost, thereby enabling algorithms to be proposed regarding the risk of neurodegeneration onset in healthy persons including the year of onset and neurodegeneration severity. Next generation sequencing has resulted in an explosion of articles regarding the diagnosis of neurodegenerative diseases involving exome sequencing or sequencing a whole gene for correlating phenotypical expression with genetic mutations in proteins having key functions. Many of them occur in neuronal glia, which can trigger a proinflammatory effect leading to defective proteins causing sporadic or familial mutations. This article reviews the genetic diagnosis techniques and the importance of bioinformatics in interpreting results from neurodegenerative diseases. Risk scores must be established in the near future regarding diseases with a high incidence in healthy people for defining prevention strategies or an early start for giving drugs in the absence of symptoms. Full article
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Open AccessEditorial Recent Changes in Drug Abuse Scenarios: The New/Novel Psychoactive Substances (NPS) Phenomenon
Brain Sci. 2018, 8(12), 221; https://doi.org/10.3390/brainsci8120221
Received: 7 December 2018 / Accepted: 9 December 2018 / Published: 13 December 2018
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Abstract
Over the last decade, the emergence of a vast range of new/novel/emerging psychoactive substances (NPS) has progressively changed drug market scenarios, which have shifted from the ‘street’ to a ‘virtual’/online environment. [...] Full article
Open AccessArticle The Cultural Cognitive Development of Personal Beliefs and Classroom Behaviours of Adult Language Instructors: A Qualitative Inquiry
Brain Sci. 2018, 8(12), 220; https://doi.org/10.3390/brainsci8120220
Received: 22 October 2018 / Revised: 25 November 2018 / Accepted: 9 December 2018 / Published: 11 December 2018
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Abstract
The researcher employed personal belief system (PBS) theory as the theoretical foundation for this study because it holds that teachers’ PBSs may influence their teaching behaviours, teaching styles, and pedagogies in classroom practice due to cultural influences. The purpose of this qualitative study [...] Read more.
The researcher employed personal belief system (PBS) theory as the theoretical foundation for this study because it holds that teachers’ PBSs may influence their teaching behaviours, teaching styles, and pedagogies in classroom practice due to cultural influences. The purpose of this qualitative study was to explore how teachers’ personal beliefs influence how they teach and how their approach may align with or diverge from cultural expectations in a private adult learning facility for English learning in Macau Special Administrative Region, China. The participants in this study were classroom teachers in a learning community who believe in collaborating to create environments for best practices. Two main research questions guided this study: (1) What is the relationship between teachers’ personal belief systems and their classroom practice; and (2) How does a teacher’s educational experience as a K-12 student affect their pedagogy in an adult English language learning program? Three types of data collection methods were employed: interview, classroom observation, and field note taking. The findings showed that teachers utilize their personal belief systems to engage their students through interactive teaching strategies, which was counter-intuitive for both teachers and students who had been taught with Eastern teaching styles. This study contributed to personal belief system theory and broadens the understanding of the perspectives and concepts of English teaching and supervision. The beliefs of teachers influenced their understanding of teaching and their classroom practices. Full article
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Open AccessArticle Facial Sadness Recognition is Modulated by Estrogen Receptor Gene Polymorphisms in Healthy Females
Brain Sci. 2018, 8(12), 219; https://doi.org/10.3390/brainsci8120219
Received: 1 November 2018 / Revised: 26 November 2018 / Accepted: 4 December 2018 / Published: 7 December 2018
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Abstract
Polymorphisms of the estrogen receptor ESR1 and ESR2 genes have been linked with cognitive deficits and affective disorders. The effects of these genetic variants on emotional processing in females with low estrogen levels are not well known. The aim was to explore the [...] Read more.
Polymorphisms of the estrogen receptor ESR1 and ESR2 genes have been linked with cognitive deficits and affective disorders. The effects of these genetic variants on emotional processing in females with low estrogen levels are not well known. The aim was to explore the impact of the ESR1 and ESR2 genes on the responses to the facial emotion recognition task in females. Postmenopausal healthy female volunteers were genotyped for the polymorphisms Xbal and PvuII of ESR1 and the polymorphism rs1256030 of ESR2. The effect of these polymorphisms on the response to the facial emotion recognition of the emotions happiness, sadness, disgust, anger, surprise, and fear was analyzed. Females carrying the P allele of the PvuII polymorphism or the X allele of the Xbal polymorphism of ESR1 easily recognized facial expressions of sadness that were more difficult for the women carrying the p allele or the x allele. They displayed higher accuracy, fast response time, more correct responses, and fewer omissions to complete the task, with a large effect size. Women carrying the ESR2 C allele of ESR2 showed a faster response time for recognizing facial expressions of anger. These findings link ESR1 and ESR2 polymorphisms in facial emotion recognition of negative emotions. Full article
(This article belongs to the Special Issue Neurobiology Research of Depression)
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Open AccessFeature PaperReview Nutrition, Energy Expenditure, Dysphagia, and Self-Efficacy in Stroke Rehabilitation: A Review of the Literature
Brain Sci. 2018, 8(12), 218; https://doi.org/10.3390/brainsci8120218
Received: 30 October 2018 / Revised: 3 December 2018 / Accepted: 5 December 2018 / Published: 7 December 2018
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Abstract
While significant research has been performed regarding the use of thrombolytic agents and thrombectomy in the setting of acute stroke, other factors, such as nutritional status of stroke patients, is a less explored topic. The topic of nutrition is critical to the discussion [...] Read more.
While significant research has been performed regarding the use of thrombolytic agents and thrombectomy in the setting of acute stroke, other factors, such as nutritional status of stroke patients, is a less explored topic. The topic of nutrition is critical to the discussion of stroke, as up to half of stroke survivors may be considered malnourished at discharge. Dysphagia, old age, restricted upper limb movement, visuospatial impairment, and depression are all important risk factors for malnutrition in this cohort. The purpose of this review is to analyze current literature discussing neuroprotective diets, nutritional, vitamin, and mineral supplementation, dysphagia, and post-stroke coaching in stroke patients. Full article
(This article belongs to the collection Collection on Clinical Neuroscience)
Open AccessArticle Striatal Neurodegeneration that Mimics Huntington’s Disease Modifies GABA-induced Currents
Brain Sci. 2018, 8(12), 217; https://doi.org/10.3390/brainsci8120217
Received: 23 October 2018 / Revised: 20 November 2018 / Accepted: 4 December 2018 / Published: 6 December 2018
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Abstract
Huntington’s Disease (HD) is a degenerative disease which produces cognitive and motor disturbances. Treatment with GABAergic agonists improves the behavior and activity of mitochondrial complexes in rodents treated with 3-nitropropionic acid to mimic HD symptomatology. Apparently, GABA receptors activity may protect striatal medium [...] Read more.
Huntington’s Disease (HD) is a degenerative disease which produces cognitive and motor disturbances. Treatment with GABAergic agonists improves the behavior and activity of mitochondrial complexes in rodents treated with 3-nitropropionic acid to mimic HD symptomatology. Apparently, GABA receptors activity may protect striatal medium spiny neurons (MSNs) from excitotoxic damage. This study evaluates whether mitochondrial inhibition with 3-NP that mimics the early stages of HD, modifies the kinetics and pharmacology of GABA receptors in patch clamp recorded dissociated MSNs cells. The results show that MSNs from mice treated with 3-NP exhibited differences in GABA-induced dose-response currents and pharmacological responses that suggests the presence of GABAC receptors in MSNs. Furthermore, there was a reduction in the effect of the GABAC antagonist that demonstrates a lessening of this GABA receptor subtype activity as a result of mitochondria inhibition. Full article
(This article belongs to the Special Issue New Insights in Huntington's Disease)
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Open AccessArticle Peripheral Anti-Angiogenic Imbalance during Pregnancy Impairs Myogenic Tone and Increases Cerebral Edema in a Rodent Model of HELLP Syndrome
Brain Sci. 2018, 8(12), 216; https://doi.org/10.3390/brainsci8120216
Received: 1 October 2018 / Revised: 4 December 2018 / Accepted: 4 December 2018 / Published: 6 December 2018
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Abstract
Using an animal model of hemolysis elevated liver enzymes low platelets (HELLP) that has systemic inflammation and neuroinflammation we wanted to determine if blood brain barrier (BBB) permeability, cerebral edema, vascular tone, and occludin expression were altered in pregnant rats. Anti-angiogenic proteins sFlt-1 [...] Read more.
Using an animal model of hemolysis elevated liver enzymes low platelets (HELLP) that has systemic inflammation and neuroinflammation we wanted to determine if blood brain barrier (BBB) permeability, cerebral edema, vascular tone, and occludin expression were altered in pregnant rats. Anti-angiogenic proteins sFlt-1 and sEng (4.7 and 7 µg/kg/day, respectively) were chronically infused into normal pregnant (NP) rats beginning on gestational day 12 via a mini-osmotic pump. On gestational day 19, blood pressure was measured via a carotid catheter and brains were collected. BBB permeability was assessed in select brain regions from rats infused with 0.5 mg/mL Texas Red Dextran and phenylephrine. Occludin, sFlt-1, and sEng were analyzed via western blot or ELISA. Infusion of sFlt-1 and sEng into NP rats increased hemolysis and liver enzymes, and decreased platelets and led to hypertension. HELLP rats had significant impairment in the myogenic response and increased BBB permeability in the posterior cortex and brainstem. Brain water content in the posterior cortex was increased and sEng protein expression in the brainstem was significantly increased in HELLP rats. The results from this study suggest that a peripheral anti-angiogenic imbalance during pregnancy is associated with decreased myogenic tone, vasogenic edema, and an increase in BBB permeability, but not anti-angiogenic imbalance in the brain. Full article
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Open AccessArticle Retrieval-Induced Forgetting in a Pentylenetetrazole-Induced Epilepsy Model in the Rat
Brain Sci. 2018, 8(12), 215; https://doi.org/10.3390/brainsci8120215
Received: 28 October 2018 / Revised: 2 December 2018 / Accepted: 4 December 2018 / Published: 5 December 2018
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Abstract
The selective retrieval of some information may lead to the forgetting of related, but non-retrieved information. This memory phenomenon is termed retrieval-induced forgetting (RIF). Active inhibition is thought to function to resolve interference from competing information during retrieval, which results in forgetting. Epilepsy [...] Read more.
The selective retrieval of some information may lead to the forgetting of related, but non-retrieved information. This memory phenomenon is termed retrieval-induced forgetting (RIF). Active inhibition is thought to function to resolve interference from competing information during retrieval, which results in forgetting. Epilepsy is associated with impaired inhibitory control that contributes to executive dysfunction. The purpose of this study is to investigate whether rats in a kindling model of epilepsy demonstrate normal levels of RIF. Rats were divided into two groups: saline and kindling. Pentylenetetrazole was injected intraperitoneally until the rats kindled. RIF was tested using a modified version of the spontaneous object recognition test, consisting of a sample phase, retrieval or interference phase, and a test phase. Exploration time for each object was analyzed. RIF was demonstrated in the saline group when rats subjected to the retrieval phase failed to discriminate between the familiar object and the novel object later in the test phase. Kindled rats, on the other hand, did not suffer forgetting even when they were subjected to the retrieval phase, as they spent significantly longer times exploring the novel rather than the familiar object in the test phase. Therefore, RIF was not observed in the kindling group. These findings indicate impaired retrieval-induced forgetting in kindled rats, which may be suggestive of a deficit in the inhibitory control of memory. Full article
(This article belongs to the collection Collection on Cognitive Neuroscience)
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Open AccessReview Clinical Development of Targeted Fragile X Syndrome Treatments: An Industry Perspective
Brain Sci. 2018, 8(12), 214; https://doi.org/10.3390/brainsci8120214
Received: 14 November 2018 / Revised: 28 November 2018 / Accepted: 30 November 2018 / Published: 5 December 2018
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Abstract
Fragile X syndrome (FXS) is the leading known cause of inherited intellectual disability and autism spectrum disorder. It is caused by a mutation of the fragile X mental retardation 1 (FMR1) gene, resulting in a deficit of fragile X mental retardation [...] Read more.
Fragile X syndrome (FXS) is the leading known cause of inherited intellectual disability and autism spectrum disorder. It is caused by a mutation of the fragile X mental retardation 1 (FMR1) gene, resulting in a deficit of fragile X mental retardation protein (FMRP). The clinical presentation of FXS is variable, and is typically associated with developmental delays, intellectual disability, a wide range of behavioral issues, and certain identifying physical features. Over the past 25 years, researchers have worked to understand the complex relationship between FMRP deficiency and the symptoms of FXS and, in the process, have identified several potential targeted therapeutics, some of which have been tested in clinical trials. Whereas most of the basic research to date has been led by experts at academic institutions, the pharmaceutical industry is becoming increasingly involved with not only the scientific community, but also with patient advocacy organizations, as more promising pharmacological agents are moving into the clinical stages of development. The objective of this review is to provide an industry perspective on the ongoing development of mechanism-based treatments for FXS, including identification of challenges and recommendations for future clinical trials. Full article
(This article belongs to the Special Issue Towards Mechanism-based Treatments for Fragile X Syndrome)
Open AccessArticle Design of Linear and Cyclic Mutant Analogues of Dirucotide Peptide (MBP82–98) against Multiple Sclerosis: Conformational and Binding Studies to MHC Class II
Brain Sci. 2018, 8(12), 213; https://doi.org/10.3390/brainsci8120213
Received: 20 November 2018 / Accepted: 30 November 2018 / Published: 4 December 2018
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Abstract
Background: Multiple sclerosis (MS) is an autoimmune disorder of the central nervous system. MS is a T cell-mediated disease characterized by the proliferation, infiltration, and attack of the myelin sheath by immune cells. Previous studies have shown that cyclization provides molecules with strict [...] Read more.
Background: Multiple sclerosis (MS) is an autoimmune disorder of the central nervous system. MS is a T cell-mediated disease characterized by the proliferation, infiltration, and attack of the myelin sheath by immune cells. Previous studies have shown that cyclization provides molecules with strict conformation that could modulate the immune system. Methods: In this study, we synthesized peptide analogues derived from the myelin basic protein (MBP)82–98 encephalitogenic sequence (dirucotide), the linear altered peptide ligand MBP82–98 (Ala91), and their cyclic counterparts. Results: The synthesized peptides were evaluated for their binding to human leukocyte antigen (HLA)-DR2 and HLA-DR4 alleles, with cyclic MBP82–98 being a strong binder with the HLA-DR2 allele and having lower affinity binding to the HLA-DR4 allele. In a further step, conformational analyses were performed using NMR spectroscopy in solution to describe the conformational space occupied by the functional amino acids of both linear and cyclic peptide analogues. This structural data, in combination with crystallographic data, were used to study the molecular basis of their interaction with HLA-DR2 and HLA-DR4 alleles. Conclusion: The cyclic and APL analogues of dirucotide are promising leads that should be further evaluated for their ability to alter T cell responses for therapeutic benefit against MS. Full article
(This article belongs to the Special Issue Diagnosis and Treatment of Multiple Sclerosis: Past, Present, Future)
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Open AccessArticle Multi-Study Proteomic and Bioinformatic Identification of Molecular Overlap between Amyotrophic Lateral Sclerosis (ALS) and Spinal Muscular Atrophy (SMA)
Brain Sci. 2018, 8(12), 212; https://doi.org/10.3390/brainsci8120212
Received: 24 September 2018 / Revised: 28 November 2018 / Accepted: 30 November 2018 / Published: 4 December 2018
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Abstract
Unravelling the complex molecular pathways responsible for motor neuron degeneration in amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA) remains a persistent challenge. Interest is growing in the potential molecular similarities between these two diseases, with the hope of better understanding disease [...] Read more.
Unravelling the complex molecular pathways responsible for motor neuron degeneration in amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA) remains a persistent challenge. Interest is growing in the potential molecular similarities between these two diseases, with the hope of better understanding disease pathology for the guidance of therapeutic development. The aim of this study was to conduct a comparative analysis of published proteomic studies of ALS and SMA, seeking commonly dysregulated molecules to be prioritized as future therapeutic targets. Fifteen proteins were found to be differentially expressed in two or more proteomic studies of both ALS and SMA, and bioinformatics analysis identified over-representation of proteins known to associate in vesicles and molecular pathways, including metabolism of proteins and vesicle-mediated transport—both of which converge on endoplasmic reticulum (ER)-Golgi trafficking processes. Calreticulin, a calcium-binding chaperone found in the ER, was associated with both pathways and we independently confirm that its expression was decreased in spinal cords from SMA and increased in spinal cords from ALS mice. Together, these findings offer significant insights into potential common targets that may help to guide the development of new therapies for both diseases. Full article
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Open AccessArticle Age-Related Deficits in Memory Encoding and Retrieval in Word List Free Recall
Brain Sci. 2018, 8(12), 211; https://doi.org/10.3390/brainsci8120211
Received: 1 November 2018 / Revised: 25 November 2018 / Accepted: 29 November 2018 / Published: 30 November 2018
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Abstract
Although ageing is known to affect memory, the precise nature of its effect on retrieval and encoding processes is not well understood. Here, we examine the effect of ageing on the free recall of word lists, in which the semantic structure of word [...] Read more.
Although ageing is known to affect memory, the precise nature of its effect on retrieval and encoding processes is not well understood. Here, we examine the effect of ageing on the free recall of word lists, in which the semantic structure of word sequences was manipulated from unrelated words to pairs of associated words with various separations (between pair members) within the sequence. We find that ageing is associated with reduced total recall, especially for sequences with associated words. Furthermore, we find that the degree of semantic clustering (controlled for chance clustering) shows an age effect and that it interacts with the distance between the words within a pair. The results are consistent with the view that age effects in memory are mediated both by retrieval and by encoding processes associated with frontal control and working memory. Full article
(This article belongs to the Special Issue Cognitive Aging)
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Open AccessCommunication Cross-Modal Priming Effect of Rhythm on Visual Word Recognition and Its Relationships to Music Aptitude and Reading Achievement
Brain Sci. 2018, 8(12), 210; https://doi.org/10.3390/brainsci8120210
Received: 22 October 2018 / Revised: 26 November 2018 / Accepted: 28 November 2018 / Published: 29 November 2018
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Abstract
Recent evidence suggests the existence of shared neural resources for rhythm processing in language and music. Such overlaps could be the basis of the facilitating effect of regular musical rhythm on spoken word processing previously reported for typical children and adults, as well [...] Read more.
Recent evidence suggests the existence of shared neural resources for rhythm processing in language and music. Such overlaps could be the basis of the facilitating effect of regular musical rhythm on spoken word processing previously reported for typical children and adults, as well as adults with Parkinson’s disease and children with developmental language disorders. The present study builds upon these previous findings by examining whether non-linguistic rhythmic priming also influences visual word processing, and the extent to which such cross-modal priming effect of rhythm is related to individual differences in musical aptitude and reading skills. An electroencephalogram (EEG) was recorded while participants listened to a rhythmic tone prime, followed by a visual target word with a stress pattern that either matched or mismatched the rhythmic structure of the auditory prime. Participants were also administered standardized assessments of musical aptitude and reading achievement. Event-related potentials (ERPs) elicited by target words with a mismatching stress pattern showed an increased fronto-central negativity. Additionally, the size of the negative effect correlated with individual differences in musical rhythm aptitude and reading comprehension skills. Results support the existence of shared neurocognitive resources for linguistic and musical rhythm processing, and have important implications for the use of rhythm-based activities for reading interventions. Full article
(This article belongs to the Special Issue Advances in the Neurocognition of Music and Language)
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Open AccessArticle Decreased Neuron Density and Increased Glia Density in the Ventromedial Prefrontal Cortex (Brodmann Area 25) in Williams Syndrome
Brain Sci. 2018, 8(12), 209; https://doi.org/10.3390/brainsci8120209
Received: 25 September 2018 / Revised: 22 November 2018 / Accepted: 27 November 2018 / Published: 29 November 2018
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Abstract
Williams Syndrome (WS) is a neurodevelopmental disorder caused by a deletion of 25–28 genes on chromosome 7 and characterized by a specific behavioral phenotype, which includes hypersociability and anxiety. Here, we examined the density of neurons and glia in fourteen human brains in [...] Read more.
Williams Syndrome (WS) is a neurodevelopmental disorder caused by a deletion of 25–28 genes on chromosome 7 and characterized by a specific behavioral phenotype, which includes hypersociability and anxiety. Here, we examined the density of neurons and glia in fourteen human brains in Brodmann area 25 (BA 25), in the ventromedial prefrontal cortex (vmPFC), using a postmortem sample of five adult and two infant WS brains and seven age-, sex- and hemisphere-matched typically developing control (TD) brains. We found decreased neuron density, which reached statistical significance in the supragranular layers, and increased glia density and glia to neuron ratio, which reached statistical significance in both supra- and infragranular layers. Combined with our previous findings in the amygdala, caudate nucleus and frontal pole (BA 10), these results in the vmPFC suggest that abnormalities in frontostriatal and frontoamygdala circuitry may contribute to the anxiety and atypical social behavior observed in WS. Full article
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Open AccessArticle Sex Differences in Context-Driven Reinstatement of Methamphetamine Seeking is Associated with Distinct Neuroadaptations in the Dentate Gyrus
Brain Sci. 2018, 8(12), 208; https://doi.org/10.3390/brainsci8120208
Received: 28 October 2018 / Revised: 16 November 2018 / Accepted: 22 November 2018 / Published: 28 November 2018
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Abstract
The present study examined differences in operant responses in adult male and female rats during distinct phases of addiction. Males and females demonstrated escalation in methamphetamine (0.05 mg/kg, i.v.) intake with females showing enhanced latency to escalate, and bingeing. Following protracted abstinence, females [...] Read more.
The present study examined differences in operant responses in adult male and female rats during distinct phases of addiction. Males and females demonstrated escalation in methamphetamine (0.05 mg/kg, i.v.) intake with females showing enhanced latency to escalate, and bingeing. Following protracted abstinence, females show reduced responses during extinction, and have greater latency to extinguish compared with males, indicating reduced craving. Females demonstrated lower context-driven reinstatement compared to males, indicating that females have less motivational significance to the context associated with methamphetamine. Whole-cell patch-clamp recordings on dentate gyrus (DG) granule cell neurons (GCNs) were performed in acute brain slices from controls and methamphetamine experienced male and female rats, and neuronal excitability was evaluated from GCNs. Reinstatement of methamphetamine seeking reduced spiking in males, and increased spiking in females compared to controls, demonstrating distinct neuroadaptations in intrinsic excitability of GCNs in males and females. Reduced excitability of GCNs in males was associated with enhanced levels of neural progenitor cells, expression of plasticity-related proteins including CaMKII, and choline acetyltransferase in the DG. Enhanced excitability in females was associated with an increased GluN2A/2B ratio, indicating changes in postsynaptic GluN subunit composition in the DG. Altered intrinsic excitability of GCNs was associated with reduced mossy fiber terminals in the hilus and pyramidal projections, demonstrating compromised neuroplasticity in the DG in both sexes. The alterations in excitability, plasticity-related proteins, and mossy fiber density were correlated with enhanced activation of microglial cells in the hilus, indicating neuroimmune responses in both sexes. Together, the present results indicate sexually dimorphic adaptive biochemical changes in excitatory neurotransmitter systems in the DG and highlight the importance of including sex as a biological variable in exploring neuroplasticity and neuroimmune changes that predict enhanced relapse to methamphetamine-seeking behaviors. Full article
(This article belongs to the Special Issue Molecular Regulation of Learning-induced Neuronal Plasticity)
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Open AccessArticle Exploring Causes of Depression and Anxiety Health Disparities (HD) by Examining Differences between 1:1 Matched Individuals
Brain Sci. 2018, 8(12), 207; https://doi.org/10.3390/brainsci8120207
Received: 23 October 2018 / Revised: 13 November 2018 / Accepted: 21 November 2018 / Published: 28 November 2018
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Abstract
Poor comparability of social groups is one of the major methodological problems that threatens the validity of health disparities (HD) research findings. We illustrate a methodological solution that can additionally unpack the mechanisms behind differential effects on depression and anxiety. We describe racial/ethnic [...] Read more.
Poor comparability of social groups is one of the major methodological problems that threatens the validity of health disparities (HD) research findings. We illustrate a methodological solution that can additionally unpack the mechanisms behind differential effects on depression and anxiety. We describe racial/ethnic differences in the prevalence of depression and anxiety scores between Black and White women using classic methods, and then we illustrate a 1:1 matching procedure that allows for building of individual-level difference scores, i.e., actual HD difference score variables, for each pair of comparable participants. We compare the prevalence of depression disorder between Black and White young women after matching them 1:1 on common socio-economic characteristics (age, employment, education, and marital status). In essence, we follow matching or stratification methods, but make a step further and match cases 1:1 on propensity scores, i.e., we create Black–White ‘dyads’. Instead of concluding from plain comparisons that 11% more White young women (18–30 years old) report a depressive disorder than Black young women, the matched data confirms the trend, but provides more nuances. In 27% of the pairs of comparable pairs the White woman was depressed (and the comparable Black woman was not), while in 15% of the pairs the Black woman was depressed (and the comparable White woman was not). We find that Black-to-White disparities in neighborhood disorder do not predict depression differences (HDs), while such an effect is evident for anxiety HDs. The 1:1 matching approach allows us to examine more complex HD effects, like differential mediational or resilience mechanisms that appear to be protective of Black women’s mental health. Full article
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Open AccessArticle Audiovisual Lexical Retrieval Deficits Following Left Hemisphere Stroke
Brain Sci. 2018, 8(12), 206; https://doi.org/10.3390/brainsci8120206
Received: 19 October 2018 / Revised: 18 November 2018 / Accepted: 27 November 2018 / Published: 28 November 2018
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Abstract
Binding sensory features of multiple modalities of what we hear and see allows formation of a coherent percept to access semantics. Previous work on object naming has focused on visual confrontation naming with limited research in nonverbal auditory or multisensory processing. To investigate [...] Read more.
Binding sensory features of multiple modalities of what we hear and see allows formation of a coherent percept to access semantics. Previous work on object naming has focused on visual confrontation naming with limited research in nonverbal auditory or multisensory processing. To investigate neural substrates and sensory effects of lexical retrieval, we evaluated healthy adults (n = 118) and left hemisphere stroke patients (LHD, n = 42) in naming manipulable objects across auditory (sound), visual (picture), and multisensory (audiovisual) conditions. LHD patients were divided into cortical, cortical–subcortical, or subcortical lesions (CO, CO–SC, SC), and specific lesion location investigated in a predictive model. Subjects produced lower accuracy in auditory naming relative to other conditions. Controls demonstrated greater naming accuracy and faster reaction times across all conditions compared to LHD patients. Naming across conditions was most severely impaired in CO patients. Both auditory and visual naming accuracy were impacted by temporal lobe involvement, although auditory naming was sensitive to lesions extending subcortically. Only controls demonstrated significant improvement over visual naming with the addition of auditory cues (i.e., multisensory condition). Results support overlapping neural networks for visual and auditory modalities related to semantic integration in lexical retrieval and temporal lobe involvement, while multisensory integration was impacted by both occipital and temporal lobe lesion involvement. The findings support modality specificity in naming and suggest that auditory naming is mediated by a distributed cortical–subcortical network overlapping with networks mediating spatiotemporal aspects of skilled movements producing sound. Full article
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Open AccessReview On the Design of Broad-Based Neuropsychological Test Batteries to Assess the Cognitive Abilities of Individuals with Down Syndrome in the Context of Clinical Trials
Brain Sci. 2018, 8(12), 205; https://doi.org/10.3390/brainsci8120205
Received: 16 October 2018 / Revised: 14 November 2018 / Accepted: 21 November 2018 / Published: 26 November 2018
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Abstract
Down syndrome (DS) is the most common genetically-defined cause of intellectual disability. Neurodevelopmental deficits displayed by individuals with DS are generally global, however, disproportionate deficits in cognitive processes that depend heavily on the hippocampus and prefrontal cortex are also well documented. Additionally, DS [...] Read more.
Down syndrome (DS) is the most common genetically-defined cause of intellectual disability. Neurodevelopmental deficits displayed by individuals with DS are generally global, however, disproportionate deficits in cognitive processes that depend heavily on the hippocampus and prefrontal cortex are also well documented. Additionally, DS is associated with relative strengths in visual processing and visuospatial short-term memory, and weaknesses in the verbal domain. Although reports of pharmacological rescuing of learning and memory deficits in mouse models of DS abound in the literature, proving the principle that cognitive ability of persons with DS can be boosted through pharmacological means is still an elusive goal. The design of customized batteries of neuropsychological efficacy outcome measures is essential for the successful implementation of clinical trials of potential cognitive enhancing strategies. Here, we review the neurocognitive phenotype of individuals with DS and major broad-based test batteries designed to quantify specific cognitive domains in these individuals, including the one used in a pilot trial of the drug memantine. The main goal is to illustrate the essential considerations in planning trials to enhance cognitive functions in individuals with DS, which should also have implications for the design of similar studies in individuals with other forms of intellectual disability. Full article
(This article belongs to the Special Issue Research on Down Syndrome)
Open AccessArticle The Benefits of Closed-Loop Transcranial Alternating Current Stimulation on Subjective Sleep Quality
Brain Sci. 2018, 8(12), 204; https://doi.org/10.3390/brainsci8120204
Received: 30 September 2018 / Revised: 15 November 2018 / Accepted: 20 November 2018 / Published: 22 November 2018
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Abstract
Background: Poor sleep quality is a common complaint, affecting over one third of people in the United States. While sleep quality is thought to be related to slow-wave sleep (SWS), there has been little investigation to address whether modulating slow-wave oscillations (SWOs) that [...] Read more.
Background: Poor sleep quality is a common complaint, affecting over one third of people in the United States. While sleep quality is thought to be related to slow-wave sleep (SWS), there has been little investigation to address whether modulating slow-wave oscillations (SWOs) that characterize SWS could impact sleep quality. Here we examined whether closed-loop transcranial alternating current stimulation (CL-tACS) applied during sleep impacts sleep quality and efficiency. Methods: CL-tACS was used in 21 participants delivered at the same frequency and in phase with endogenous SWOs during sleep. Sleep quality was assessed in the morning following either verum or sham control stimulation during sleep, with order counterbalanced within participants. Results: Higher sleep quality and efficiency were found after verum stimulation nights compared to control. The largest effects on sleep quality were found immediately following an adaptation night in the laboratory for which sleep quality was reduced. Conclusions: Applying CL-tACS at the same frequency and phase as endogenous SWOs may offer a novel method to improve subjective sleep quality after a night with poor quality sleep. CL-tACS might be helpful for increasing sleep quality and efficiency in otherwise healthy people, and in patients with clinical disorders that involve sleep deficits. Full article
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Open AccessConcept Paper Augmentation of 5-Aminolevulinic Acid Treatment of Glioblastoma by Adding Ciprofloxacin, Deferiprone, 5-Fluorouracil and Febuxostat: The CAALA Regimen
Brain Sci. 2018, 8(12), 203; https://doi.org/10.3390/brainsci8120203
Received: 5 November 2018 / Revised: 15 November 2018 / Accepted: 20 November 2018 / Published: 22 November 2018
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Abstract
The CAALA (Complex Augmentation of ALA) regimen was developed with the goal of redressing some of the weaknesses of 5-aminolevulinic acid (5-ALA) use in glioblastoma treatment as it now stands. 5-ALA is approved for use prior to glioblastoma surgery to better demarcate tumor [...] Read more.
The CAALA (Complex Augmentation of ALA) regimen was developed with the goal of redressing some of the weaknesses of 5-aminolevulinic acid (5-ALA) use in glioblastoma treatment as it now stands. 5-ALA is approved for use prior to glioblastoma surgery to better demarcate tumor from brain tissue. 5-ALA is also used in intraoperative photodynamic treatment of glioblastoma by virtue of uptake of 5-ALA and its preferential conversion to protoporphyrin IX in glioblastoma cells. Protoporphyrin IX becomes cytotoxic after exposure to 410 nm or 635 nm light. CAALA uses four currently-marketed drugs—the antibiotic ciprofloxacin, the iron chelator deferiprone, the antimetabolite 5-FU, and the xanthine oxidase inhibitor febuxostat—that all have evidence of ability to both increase 5-ALA mediated intraoperative glioblastoma demarcation and photodynamic cytotoxicity of in situ glioblastoma cells. Data from testing the full CAALA on living minipigs xenotransplanted with human glioblastoma cells will determine safety and potential for benefit in advancing CAALA to a clinical trial. Full article
(This article belongs to the Section Clinical Neuroscience)
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