Role of Human Premotor Dorsal Region in Learning a Conditional Visuo-Motor Task

Conditional learning is an important component of our everyday activities, e.g. handling a phone or sorting work files and requires identification of the arbitrary stimulus, accurate selection of the motor response, monitoring of the response, and storing in memory the stimulus-response association for future recall. Learning this type of conditional visuo-motor task appears to engage the premotor dorsal region (PMd). However, the extent to which PMd might be involved in specific or all processes of conditional learning is not well understood. Using transcranial magnetic stimulation (TMS), we demonstrate the role of human PMd in specific stages of learning of a novel conditional visuo-motor task that required subjects to identify object center of mass using a color cue, and apply appropriate torque on the object at lift onset to minimize tilt. TMS over PMd, but not vertex, increased error in torque exerted on the object during the learning trials. Analyses of digit position and forces further revealed that the slowing in conditional visuo-motor learning resulted from impaired monitoring of the object orientation during lift, rather than stimulus identification, thus compromising the ability to accurately reduce performance error across trials. Importantly, TMS over PMd did not alter production of torque based on the recall of learned color-torque associations. We conclude that the role of PMd for conditional learning is highly sensitive to the stage of learning visuo-motor associations.

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Calcium dynamics and regulation in horizontal cells of the vertebrate retina: lessons from teleosts

Horizontal cells (HCs) are inhibitory interneurons of the vertebrate retina. Unlike typical neurons, HCs are chronically depolarized in the dark, leading to a constant influx of Ca²⁺. Therefore, mechanisms of Ca²⁺ homeostasis in HCs must differ from neurons elsewhere in the central nervous system, which undergo excitotoxicity when they are chronically depolarized or stressed with Ca²⁺. Horizontal cells are especially well characterized in teleost fish, and have been used to unlock mysteries of the vertebrate retina for over a century. More recently, mammalian models of the retina have been increasingly informative for HC physiology. We draw from both teleost and mammalian models in this review, using a comparative approach to examine what is known about Ca²⁺ pathways in vertebrate HCs. We begin with a survey of Ca²⁺-permeable ion channels, exchangers, and pumps, and summarize Ca²⁺ influx and efflux pathways, buffering, and intracellular stores. This includes evidence for Ca²⁺-permeable α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) and N-methyl-D-aspartate receptors (NMDARs), and for voltage-gated Ca²⁺ channels. Special attention is given to interactions between ion channels, to differences between species, and in which subtypes of HCs these channels have been found. We then discuss a number of unresolved issues pertaining to Ca²⁺ dynamics in HCs, including: a potential role for Ca²⁺ in feedback to photoreceptors, the role for Ca²⁺-induced Ca²⁺ release, and the properties and functions of Ca²⁺-based action potentials. This review aims to highlight the unique Ca²⁺ dynamics in HCs, as these are inextricably tied to retinal function.

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Neuromuscular responses differ between slip-induced falls and recoveries in older adults

How does the robust control of walking and balance break down during a fall? As a first step in identifying the neuromuscular determinants of falls, we tested the hypothesis that falls and recoveries are characterized by differences in neuromuscular responses. Using muscle synergy analysis, conventional onset latencies, and peak activity, we identified differences in muscle coordination between older adults who fell and those who recovered from a laboratory-induced slip. We found that subjects who fell recruited fewer muscle synergies than those who recovered, suggesting a smaller motor repertoire. During slip trials subjects who fell had delayed knee flexor and extensor onset times in the leading/slip leg, as well as different muscle synergy structure involving those muscles. Therefore, the ability to coordinate muscle activity around the knee in a timely manner may be critical to avoiding falls from slips. Unique to subjects who fell during slip trials were greater bilateral muscle activation, and the recruitment of a muscle synergy with excessive co-activation. These differences in muscle coordination between subjects who fell and those who recovered could not be explained by differences in gait-related variables at slip onset (i.e. initial motion state) nor variations in slip difficulty. This suggests that differences in muscle coordination likely reflected differences in the neural control of movement rather than biomechanical constraints imposed by perturbation or walking mechanics. These results are the first step in determining the causation of falls from the perspective of muscle coordination. They suggest that there may be a neuromuscular basis for falls.

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Contrast sensitivity, V1 neural activity, and natural vision

Contrast sensitivity is fundamental to natural visual processing and an important tool for characterizing both visual function and clinical disorders. We simultaneously measured contrast sensitivity and neural contrast response functions and compared measurements in common laboratory conditions with naturalistic conditions. In typical experiments, a subject holds fixation and a stimulus is flashed on, whereas in natural vision saccades bring stimuli into view. Motivated by our previous V1 findings, we tested the hypothesis that perceptual contrast sensitivity is lower in natural vision and that this effect is associated with corresponding changes in V1 activity. We find that contrast sensitivity and V1 activity are correlated and that the relationship is similar in laboratory and naturalistic paradigms. However, in the more natural situation, contrast sensitivity is reduced up to 25% compared to a standard fixation paradigm, particularly at lower spatial frequencies, and this effect correlates with significant reductions in V1 responses. Our results suggest that these reductions in natural vision result from fast adaptation on one fixation that lowers the response on a subsequent fixation. This is the first demonstration of rapid, natural-image adaptation that carries across saccades, a process that appears to constantly influence visual sensitivity in natural vision.

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Psychosocial stress alters the strength of reticulospinal input to the human upper trapezius

Psychosocial stress has been shown to influence several aspects of human motor control associated with the fight-or-flight response, including augmentation of upper trapezius muscle activity. Given the established role of the reticular formation in arousal, this study investigated the contribution of reticulospinal activation to trapezius muscle activity during exposure to an acute psychosocial stressor. Twenty-five healthy adults were exposed to startling acoustic stimuli (SAS) while performing a motor task during periods of low and high psychosocial stress. Acoustic startle reflexes (ASRs) were recorded in the upper trapezius during low-intensity contractions using both surface and intramuscular electromyography. Exposure to the stressor increased subjective and physiologic measures of arousal (p<0.01). The majority of participants demonstrated inhibitory ASRs, whereas a small subgroup with significantly higher trait anxiety (N=5) demonstrated excitatory ASRs in the low stress condition. Changes in synaptic input for inhibitory ASRs were confirmed by decreases in the discharge rate of single motor units in response to the SAS. ASRs decreased in magnitude for all participants during exposure to the acute psychosocial stressor. These findings suggest that the reticular formation has predominately inhibitory effects on the human upper trapezius during an ongoing motor task, and that disinhibition caused by psychosocial stress may contribute to augmentation of trapezius muscle activity. Further research is required to investigate mechanisms underlying the complex ASRs characterized by this study, particularly the phase reversal to excitatory responses observed among more anxious individuals.

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Caveolin-1 Regulation of Disrupted-in-Schizophrenia-1 as a Potential Therapeutic Target for Schizophrenia

Background: Schizophrenia is a debilitating psychiatric disorder manifested in early adulthood. Disrupted-In-Schizophrenia-1 (DISC1) is a susceptible gene for schizophrenia (54, 76, 101) implicated in neuronal development, brain maturation and neuroplasticity (12, 20). Therefore, DISC1 is a promising candidate gene for schizophrenia, but the molecular mechanisms underlying its role in the pathogenesis of the disease are still poorly understood. Interestingly, Caveolin-1 (Cav-1), a cholesterol binding and scaffolding protein, regulates neuronal signal transduction and promotes neuroplasticity. Here we examined the role of Cav-1 in mediating DISC1 expression in neurons in vitro and the hippocampus in vivo. Methods and Results: Overexpressing Cav-1 specifically in neurons using a neuron specific synapsin promoter (SynCav1) increased expression of DISC1 and proteins involved in synaptic plasticity (PSD95, synaptobrevin, synaptophysin, neurexin, and syntaxin-1). Similarly, SynCav1-transfected differentiated human neurons derived from induced pluripotent stem cells (hiPSCs) exhibited increased expression of DISC1 and markers of synaptic plasticity. Conversely, hippocampi from Cav-1 knockout (KO) exhibited decreased expression of DISC1 and proteins involved in synaptic plasticity. Finally, SynCav1 delivery to the hippocampus of Cav-1 KO mice and Cav-1 KO neurons in culture restored expression of DISC1 and markers of synaptic plasticity. Furthermore, we found that Cav-1 co-immunoprecipitated with DISC1 in brain tissues. Conclusion: These findings suggest an important role by which neuronal Cav-1 regulates DISC1 neurobiology with implications for synaptic plasticity. Therefore, SynCav1 might be a potential therapeutic target for restoring neuronal function in schizophrenia.

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Go-activation endures following the presentation of a stop-signal: Evidence from startle

It has been proposed that in a stop-signal task (SST), independent go- and stop-processes "race" to control behaviour. If the go-process wins, an overt response is produced, while if the stop-process wins, the response is withheld. One prediction that follows from this proposal is that if the activation associated with one process is enhanced, it is more likely to win the race. We looked to determine whether these initiation and inhibition processes (and thus response outcome) could be manipulated by using a startling acoustic stimulus (SAS), which has been shown to provide additional response activation. In the present study participants were to respond to a visual go-stimulus; however, if a subsequent stop-signal appeared they were to inhibit the response. The stop-signal was presented at a delay corresponding to a probability of responding of 0.4 (determined from a baseline block of trials). On stop-trials a SAS was presented either simultaneous with the go-signal or stop-signal, or 100, 150, or 200 ms following the stop-signal. Results showed that presenting a SAS during stop-trials led to an increase in probability of responding when presented with or following the stop-signal. The latency of SAS responses at the stop-signal+150 ms and stop-signal+200 ms probe times suggests they would have been voluntarily inhibited but instead were involuntarily initiated by the SAS. Thus, results demonstrate that go-activation endures even 200 ms following a stop-signal and remains accessible well after the response has been inhibited, providing evidence against a winner take all race between independent go- and stop-processes.

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Individual differences in implicit motor learning: Task specificity in sensorimotor adaptation and sequence learning

In standard taxonomies, motor skills are typically treated as representative of implicit or procedural memory. We examined two emblematic tasks of implicit motor learning, sensorimotor adaptation and sequence learning, asking whether individual differences in learning are correlated between these tasks, as well as how individual differences within each task are related to different performance variables. As a prerequisite, it was essential to establish the reliability of learning measures for each task. Participants were tested twice on a visuomotor adaptation task and on one of two sequence learning tasks, the serial reaction time task or the alternating reaction time task. Learning was evident in all tasks at the group level, and reliable at the individual level in visuomotor adaptation and the alternating reaction time task, but not in the serial reaction time task. Performance variability was predictive of learning in both domains, yet the relationship was in the opposite direction for adaptation and sequence learning. For the former, faster learning was associated with lower variability, consistent with models of sensorimotor adaptation in which learning rates are sensitive to noise. For the latter, greater learning was associated with higher variability and slower reaction times, factors that may facilitate the spread of activation required to form predictive, sequential associations. Interestingly, learning measures on the different tasks were not correlated. Together, these results argue against a shared process for implicit learning in sensorimotor adaptation and sequence learning, and provide insight into factors that account for individual differences in learning within each task domain.

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Right Prefrontal Cortex Transcranial Direct Current Stimulation Enhances Multi-Day Savings in Sensorimotor Adaptation

We have previously reported that visuospatial working memory performance and magnitude of activation in the right dorsolateral prefrontal cortex predict the rate of visuomotor adaptation. Recent behavioral studies suggest that sensorimotor savings-or faster relearning upon second exposure to a task-are due to recall of these early, strategic components of adaptation. Here we applied anodal transcranial direct current stimulation to right or left prefrontal cortex or left motor cortex. We found that all groups adapted dart throwing movements while wearing prism lenses at the same rate as subjects receiving sham stimulation on Day 1. On test Day 2, which was conducted a few days later, the right prefrontal and left motor cortex groups adapted faster than the sham group. Moreover, only the right prefrontal group exhibited greater savings-expressed as a greater difference between Day 1 and Day 2 errors-in comparison to sham. These findings support the hypothesis that the right prefrontal cortex contributes to sensorimotor adaptation and savings.

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Visual search for object categories is predicted by the representational architecture of high-level visual cortex

Visual search is a ubiquitous visual behavior, and efficient search is essential for survival. Different cognitive models have explained the speed and accuracy of search based either on the dynamics of attention or on similarity of item representations. Here, we examined the extent to which performance on a visual search task can be predicted from the stable representational architecture of the visual system, independent of attentional dynamics. Participants performed a visual search task with 28 conditions reflecting different pairs of categories (e.g., searching for a face amongst cars, body amongst hammers, etc.). The time it took participants to find the target item varied as a function of category combination. In a separate group of participants, we measured the neural responses to these object categories when items were presented in isolation. Using representational similarity analysis, we then examined whether the similarity of neural responses across different subdivisions of the visual system had the requisite structure needed to predict visual search performance. Overall, we found strong brain/behavior correlations across most of the higher-level visual system, including both the ventral and dorsal pathways when considering both macro-scale sectors as well as smaller meso-scale regions. These results suggest that visual search for real-world object categories is well predicted by the stable, task-independent architecture of the visual system.

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snpGeneSets: An R Package for Genome-Wide Study Annotation

Genome-wide studies (GWS) of SNP associations and differential gene expressions have generated abundant results; next-generation sequencing technology has further boosted the number of variants and genes identified. Effective interpretation requires massive annotation and downstream analysis of these genome-wide results, a computationally challenging task. We developed the snpGeneSets package to simplify annotation and analysis of GWS results. Our package integrates local copies of knowledge bases for SNPs, genes, and gene sets, and implements wrapper functions in the R language to enable transparent access to low-level databases for efficient annotation of large genomic data. The package contains functions that execute three types of annotations: 1) genomic mapping annotation for SNPs and genes and functional annotation for gene sets; 2) bidirectional mapping between SNPs and genes, and genes and gene sets; and 3) calculation of gene effect measures from SNP associations and performance of gene set enrichment analyses to identify functional pathways. We applied snpGeneSets to type 2 diabetes (T2D) results from the NHGRI genome-wide association study (GWAS) catalog, a Finnish GWAS, and a genome-wide expression study (GWES). These studies demonstrate the usefulness of snpGeneSets for annotating and performing enrichment analysis of GWS results. The package is open-source, free, and can be downloaded at: http://ift.tt/2fxy3R0.

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Candida albicans Is Resistant to Polyglutamine Aggregation and Toxicity

Disruption of protein quality control can be detrimental, having toxic effects on single cell organisms, contributing to neurodegenerative diseases such as Alzheimer's, Parkinson's and Huntington's in humans. Here we examined the effects of polyQ aggregation in a major fungal pathogen of humans, Candida albicans, with the goal of identifying new approaches to disable this fungus. However, we discovered that expression of poly-glutamine (polyQ) stretches up to 230Q had no effect on C. albicans ability to grow and withstand proteotoxic stress. Bioinformatics analysis demonstrates that C. albicans has a similarly glutamine rich proteome to the unicellular fungus Saccharomyces cerevisiae, which exhibits polyQ toxicity with as few as 72Q. Surprisingly, global transcriptional profiles indicated no significant change upon induction of up to 230Q. Proteomic analysis highlighted two key interactors of 230Q, Sis1 and Sgt2, however, loss of either protein had no additional effect on C. albicans toxicity. Our data suggest that C. albicans has evolved powerful mechanisms to overcome the toxicity associated with aggregation-prone proteins, providing a unique model for studying polyQ associated diseases.

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Ryanodine-induced vasoconstriction of the gerbil spiral modiolar artery depends on the Ca2+ sensitivity but not on Ca2+ sparks or BK channels

In many vascular smooth muscle cells (SMCs), ryanodine receptor-mediated Ca2+ sparks activate large-conductance Ca2+-activated K+ (BK) channels leading to lowered SMC [Ca2+]i and vasodilation. Here we investigate...

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Microcephaly, intractable seizures and developmental delay caused by biallelic variants in TBCD: Further delineation of a new chaperone-mediated tubulinopathy

Abstract

Microtubule dynamics play a crucial role in neuronal development and function, and several neurodevelopmental disorders have been linked to mutations in genes encoding tubulins and functionally related proteins. Most recently, variants in the tubulin cofactor D (TBCD) gene, which encodes one of the five co-chaperones required for assembly and disassembly of α/β-tubulin heterodimer, were reported to underlie a recessive neurodevelopmental/neurodegenerative disorder.

We report on five patients from three unrelated families, who presented with microcephaly, intellectual disability, intractable seizures, optic nerve pallor/atrophy, and cortical atrophy with delayed myelination and thinned corpus callosum on brain imaging. Exome sequencing allowed the identification of biallelic variants in TBCD segregating with the disease in the three families.

TBCD protein level was significantly reduced in cultured fibroblasts from one patient, supporting defective TBCD function as the event underlying the disorder. Such reduced expression was associated with accelerated microtubule re-polymerization. Morpholino-mediated TBCD knockdown in zebrafish recapitulated several key pathological features of the human disease, and TBCD overexpression in the same model confirmed previous studies documenting an obligate dependency on proper TBCD levels during development.

Our findings confirm the link between inactivating TBCD variants and this newly-described chaperone-associated tubulinopathy, and provide insights into the phenotype of this disorder.

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Fampridine treatment and walking distance in multiple sclerosis:A randomised controlled trial

Modified-release fampridine is a slow release form of 4-aminopyridine that has been approved worldwide for the treatment of multiple sclerosis-related walking disability. Recent phase II and phase III studies of fampridine have demonstrated sustained clinical benefits on walking speed over short distances of 25 feet in ∼40% of MS patients (Goodman et al., 2008; Goodman et al., 2009; Goodman et al., 2010). Unlike the short-release form of 4-aminopyridine which has significant adverse effects, including the development of seizures, fampridine has a more acceptable safety profile with a lower risk of serious adverse events in controlled trials (Goodman et al., 2009).

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Bidirectional Associations between Sport Involvement and Mental Health in Adolescence.

Purpose: To investigate potential bidirectional relationships between sport participation and mental health during early adolescence. Methods: Data were taken from wave 5 (2012) and wave 6 (2014) of the K-Cohort of the Longitudinal Study of Australian Children. In total, there were 4023 participants aged 12.41 (SD = 0.49) years at baseline, and this sample were followed up 24 months later. Cross lagged panel models were used to examine bidirectional relationships between sport participation (hours[middle dot]wk-1 for team, individual and total sport participation) and mental health (total psychological difficulties, internalising problems, and externalising problems) as measured by the parent-report version of the Strengths and Difficulties Questionnaire. Results: Bidirectional relationships were evident between time involved in sport and overall mental health (Sport12->SDQ14: [beta] = -.048; SDQ12->Sport14: [beta] = -.062). Bidirectional relationships were also evident between time involved in sport participation and internalising (social and emotional) problems (Sport12->SDQ14: [beta] = -.068; SDQ12->Sport14: [beta] = -.067). The relationship between time in organised sport and externalising problems (conduct problems and inattention/hyperactivity problems) was not bidirectional. Externalising problems predicted later sports participation ([beta] = -.039), but not vice versa. Conclusion: Findings demonstrate bidirectional relationships between sport participation and adolescent mental health. The design and implementation of youth sport programs should maximise mental health benefits, and programs should be designed, implemented, and marketed to be attractive to participants with poor psychosocial health. (C) 2016 American College of Sports Medicine

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Long-Term Effects of Habitual Barefoot Running and Walking: A Systematic Review.

Introduction: Barefoot locomotion is widely believed to be beneficial for motor development and biomechanics but are implied to be responsible for foot pathologies and running-related injuries. While most of available studies focused on acute effects of barefoot running and walking little is known regarding the effects of long-term barefoot vs. shod locomotion. The purpose of this study was to systematically review the literature to evaluate current evidence of habitual barefoot (HB) vs. habitual shod locomotion on foot anthropometrics, biomechanics, motor performance and pathologies. Methods: Four electronic databases were searched using terms related to habitually barefoot locomotion. Relevant studies were identified based on title, abstract and full text and a forward (citation tracking) and backward (references) search was performed. Risk of bias was assessed, data pooling and meta-analysis (random effects model) performed and finally levels of evidence determined. Results: Fifteen studies with 8399 participants were included. Limited evidence was found for a reduced ankle dorsiflexion at footstrike (pooled effect size -3.47 (95% CI -5.18 to -1.76)) and a lower pedobarographically measured hallux angle (-1.16 (95% CI -1.64 to -0.68)). HB populations had wider (0.55 (95% CI 0.06 to 1.05) but no shorter (-0.22 (95% CI -0.51 to 0.08)) feet compared to habitual shod populations. No differences in relative injury rates were found, with limited evidence for a different body part distribution of musculoskeletal injuries and more foot pathologies and less foot deformities and defects in HB runners. Conclusions: Only limited or very limited evidence is found for long-term effects of HB locomotion regarding biomechanics or health-related outcomes. Moreover, no evidence exists on any beneficial effects for motor performance. Future research should include prospective study designs. This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially. (C) 2016 American College of Sports Medicine

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Phenotypes and cellular effects of GJB1 mutations causing CMT1X in a cohort of 226 Chinese CMT families

Abstract

The aim of this study is to explore the phenotypic and genotypic features of X-linked Charcot-Marie-Tooth disease in the mainland of China and to study the cellular effects of six novel Gap junction protein beta-1 variants. We identified 25 missense and 1 nonsense mutations of GJB1 in 31 unrelated families out of 226 CMT families. The frequency of GJB1 mutations was 13.7% of the total and 65% of intermediate CMT. Six novel GJB1 variants (c.5A>G, c.8G>A, c.242T>C, c.269T>C, c.317T>C and c.434T>G) were detected in six unrelated intermediate CMT families. Fluorescence revealed that HeLa cells transfected with EGFP-GJB1-V74M, EGFP-GJB1-L81P or EGFP-GJB1-L90P had diffuse endoplasmic reticulum staining, HeLa cells transfected with EGFP-GJB1-L106P had diffuse intracellular staining, and HeLa cells transfected with EGFP-GJB1-N2S had cytoplasmic and nuclear staining. The distribution of Cx32 in HeLa cells transfected with EGFP-GJB1-F145C was similar to that of those transfected with wild-type. These six variants resulted in a higher percentage of apoptosis than did wild-type as detected by flow cytometry and Hoechst staining. In conclusion, mutation screening should be first performed in intermediate CMT patients, especially those with additional features. The novel GJB1 variants c.5A>G, c.8G>A, c.242T>C and c.269T>C are considered pathogenic, and c.317T>C and c.434T>G are classified as likely pathogenic.

Graphical Abstract

Flow chart of our study. CMT1: Demyelinating Charcot-Marie-Tooth disease; CMT2: Axonal Charcot-Marie-Tooth disease; ICMT: Intermediate Charcot-Marie-Tooth disease; MLPA: Multiplex Ligation-Dependent Probe Amplification; ACMG: American College of Medical Genetics and Genomics.

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