Multimodal Comprehension in Left Hemisphere Stroke Patients

Hand gestures, imagistically related to the content of speech, are ubiquitous in face-to-face communication. Here we investigated people with aphasia’s (PWA) processing of speech accompanied by gestures using lesion-symptom mapping. Twenty-nine PWA and 15 matched controls were shown a picture of an object/action and then a video-clip of a speaker producing speech and/or gestures in one of the following combinations: speech-only, gesture-only, congruent speech-gesture, and incongruent speech-gesture. Participants’ task was to indicate, in different blocks, whether the picture and the word matched (speech task), or whether the picture and the gesture matched (gesture task). Multivariate lesion analysis with Support Vector Regression Lesion-Symptom Mapping (SVR-LSM) showed that benefit for congruent speech-gesture was associated with 1) lesioned voxels in anterior fronto-temporal regions including inferior frontal gyrus (IFG), and sparing of posterior temporal cortex and lateral temporal-occipital regions (pTC/LTO) for the speech task, and 2) conversely, lesions to pTC/LTO and sparing of anterior regions for the gesture task. The two tasks did not share overlapping voxels. Costs from incongruent speech-gesture pairings were associated with lesioned voxels in these same anterior (for the speech task) and posterior (for the gesture task) regions, but crucially, also shared voxels in superior temporal gyri (STG) and middle temporal gyri (MTG), including the anterior temporal lobe. These results suggest that IFG and pTC/LTO contribute to extracting semantic information from speech and gesture, respectively; however, they are not causally involved in integrating information from the two modalities. In contrast, regions in anterior STG/MTG are associated with performance in both tasks and may thus be critical to speech-gesture integration. These conclusions are further supported by associations between performance in the experimental tasks and performance in tests assessing lexical-semantic processing and gesture recognition

Galileo mission planning for Low Gain Antenna based operations

The Galileo mission operations concept is undergoing substantial redesign, necessitated by the deployment failure of the High Gain Antenna, while the spacecraft is on its way to Jupiter. The new design applies state-of-the-art technology and processes to increase the telemetry rate available through the Low Gain Antenna and to increase the information density of the telemetry. This paper describes the mission planning process being developed as part of this redesign. Principal topics include a brief description of the new mission concept and anticipated science return (these have been covered more extensively in earlier papers), identification of key drivers on the mission planning process, a description of the process and its implementation schedule, a discussion of the application of automated mission planning tool to the process, and a status report on mission planning work to date. Galileo enhancements include extensive reprogramming of on-board computers and substantial hard ware and software upgrades for the Deep Space Network (DSN). The principal mode of operation will be onboard recording of science data followed by extended playback periods. A variety of techniques will be used to compress and edit the data both before recording and during playback. A highly-compressed real-time science data stream will also be important. The telemetry rate will be increased using advanced coding techniques and advanced receivers. Galileo mission planning for orbital operations now involves partitioning of several scarce resources. Particularly difficult are division of the telemetry among the many users (eleven instruments, radio science, engineering monitoring, and navigation) and allocation of space on the tape recorder at each of the ten satellite encounters. The planning process is complicated by uncertainty in forecast performance of the DSN modifications and the non-deterministic nature of the new data compression schemes. Key mission planning steps include quantifying resource or capabilities to be allocated, prioritizing science observations and estimating resource needs for each, working inter-and intra-orbit trades of these resources among the Project elements, and planning real-time science activity. The first major mission planning activity, a high level, orbit-by-orbit allocation of resources among science objectives, has already been completed; and results are illustrated in the paper. To make efficient use of limited resources, Galileo mission planning will rely on automated mission planning tools capable of dealing with interactions among time-varying downlink capability, real-time science and engineering data transmission, and playback of recorded data. A new generic mission planning tool is being adapted for this purpose

Advancing Paternal Age Is Associated with Deficits in Social and Exploratory Behaviors in the Offspring: A Mouse Model

Background: Accumulating evidence from epidemiological research has demonstrated an association between advanced paternal age and risk for several psychiatric disorders including autism, schizophrenia and early-onset bipolar disorder. In order to establish causality, this study used an animal model to investigate the effects of advanced paternal age on behavioural deficits in the offspring. Methods: C57BL/6J offspring (n = 12 per group) were bred from fathers of two different ages, 2 months (young) and 10 months (old), and mothers aged 2 months (n = 6 breeding pairs per group). Social and exploratory behaviors were examined in the offspring. Principal Findings: The offspring of older fathers were found to engage in significantly less social (p = 0.02) and exploratory (p = 0.02) behaviors than the offspring of younger fathers. There were no significant differences in measures of motor activity. Conclusions: Given the well-controlled nature of this study, this provides the strongest evidence for deleterious effects of advancing paternal age on social and exploratory behavior. De-novo chromosomal changes and/or inherited epigeneti

Transcriptional profiling of C57 and DBA strains of mice in the absence and presence of morphine

BACKGROUND: The mouse C57BL/6 (C57) and DBA/2J (DBA) inbred strains differ substantially in many aspects of their response to drugs of abuse. The development of microarray analyses represents a genome-wide method for measuring differences across strains, focusing on expression differences. In the current study, we carried out microarray analysis in C57 and DBA mice in the nucleus accumbens of drug-naïve and morphine-treated animals. RESULTS: We identified mRNAs with altered expression between the two strains. We validated the mRNA expression changes of several such mRNAs, including Gnb1, which has been observed to be regulated by several drugs of abuse. In addition, we validated alterations in the enzyme activity of one mRNA product, catechol-O-methyltransferase (Comt). Data mining of expression and behavioral data indicates that both Gnb1 and Comt expression correlate with aspects of drug response in C57/DBA recombinant inbred strains. Pathway analysis was carried out to identify pathways showing significant alterations as a result of treatment and/or due to strain differences. These analyses identified axon guidance genes, particularly the semaphorins, as showing altered expression in the presence of morphine, and plasticity genes as showing altered expression across strains. Pathway analysis of genes showing strain by treatment interaction suggest that the phosphatidylinositol signaling pathway may represent an important difference between the strains as related to morphine exposure. CONCLUSION: mRNAs with differing expression between the two strains could potentially contribute to strain-specific responses to drugs of abuse. One such mRNA is Comt and we hypothesize that altered expression of Comt may represent a potential mechanism for regulating the effect of, and response to, multiple substances of abuse. Similarly, a role for Gnb1 in responses to multiple drugs of abuse is supported by expression data from our study and from other studies. Finally, the data support a role for semaphorin signaling in morphine effects, and indicate that altered expression of genes involved in phosphatidylinositol signaling and plasticity might also affect the altered drug responses in the two strains

A kinematic examination of dual-route processing for action imitation

The dual-route model of imitation suggests that meaningful and meaningless actions are processed through either an indirect or direct route, respectively. Evidence indicates that the direct route is more cognitively demanding, since it relies on mapping visuospatial properties of the observed action on to a performed one. These cognitive demands might negatively influence reaction time and accuracy for actions performed following a meaningless action under time constraints. However, how meaningful and meaningless action imitation processing is reflected in movement kinematics is not yet clear. We wanted to confirm whether meaningless action performance incurs a reaction time cost, whether the cost is reflected in kinematics, and, more generally, to examine kinematic markers of emblematic meaningful and meaningless action imitation. We examined participants’ reaction time and wrist movements when they imitated emblematic meaningful or matched meaningless gestures in either blocks of the same action type, or mixed blocks. Meaningless actions were associated with a greater correction period at the end of the movement, possibly reflecting a strategy designed to ensure accurate completion for less familiar actions under time constraints. Furthermore, in mixed blocks, trials following meaningless actions had a significantly increased reaction time, supporting previous claims that route selection for action imitation may be stimulus-driven. However, there was only convincing evidence for this effect with an interval of ~2948ms, but not ~3573ms or ~2553ms, between movements. Future work motion-tracking the entire hand to assess imitation accuracy, and more closely examining the influence of duration between movements, may help to explain these effects

De novo SCN2A splice site mutation in a boy with autism spectrum disorder

BACKGROUND: SCN2A is a gene that codes for the alpha subunit of voltage-gated, type II sodium channels, and is highly expressed in the brain. Sodium channel disruptions, such as mutations in SCN2A, may play an important role in psychiatric disorders. Recently, de novo SCN2A mutations in autism spectrum disorder (ASD) have been identified. The current study characterizes a de novo splice site mutation in SCN2A that alters mRNA and protein products. CASE PRESENTATION: We describe results from clinical and genetic characterizations of a seven-year-old boy with ASD. Psychiatric interview and gold standard autism diagnostic instruments (ADOS and ADI-R) were used to confirm ASD diagnosis, in addition to performing standardized cognitive and adaptive functioning assessments (Leiter-R and Vineland Adaptive Behavior Scale), and sensory reactivity assessments (Sensory Profile and Sensory Processing Scales). Genetic testing by whole exome sequencing revealed four de novo events, including a splice site mutation c.476 + 1G > A in SCN2A, a missense mutation (c.2263G > A) causing a p.V755I change in the TLE1 gene, and two synonymous mutations (c.2943A > G in the BUB1 gene, and c.1254 T > A in C10orf68 gene). The de novo SCN2A splice site mutation produced a stop codon 10 amino acids downstream, possibly resulting in a truncated protein and/or a nonsense-mediated mRNA decay. The participant met new DSM-5 criteria for ASD, presenting with social and communication impairment, repetitive behaviors, and sensory reactivity issues. The participant's adaptive and cognitive skills fell in the low range of functioning. CONCLUSION: This report indicates that a splice site mutation in SCN2A might be contributing to the risk of ASD. Describing the specific phenotype associated with SCN2A mutations might help to reduce heterogeneity seen in ASD

Impaired Communication Between the Dorsal and Ventral Stream: Indications from Apraxia

Patients with apraxia perform poorly when demonstrating how an object is used, particularly when pantomiming the action. However, these patients are able to accurately identify, and to pick up and move objects, demonstrating intact ventral and dorsal stream visuomotor processing. Appropriate object manipulation for skilled use is thought to rely on integration of known and visible object properties associated with “ventro-dorsal” stream neural processes. In apraxia, it has been suggested that stored object knowledge from the ventral stream may be less readily available to incorporate into the action plan, leading to an over-reliance on the objects’ visual affordances in object-directed motor behavior. The current study examined grasping performance in left hemisphere stroke patients with (N = 3) and without (N = 9) apraxia, and in age-matched healthy control participants (N = 14), where participants repeatedly grasped novel cylindrical objects of varying weight distribution. Across two conditions, object weight distribution was indicated by either a memory-associated cue (object color) or visual-spatial cue (visible dot over the weighted end). Participants were required to incorporate object-weight associations to effectively grasp and balance each object. Control groups appropriately adjusted their grasp according to each object’s weight distribution across each condition, whereas throughout the task two of the three apraxic patients performed poorly on both the memory-associated and visual-spatial cue conditions. A third apraxic patient seemed to compensate for these difficulties but still performed differently to control groups. Patients with apraxia performed normally on the neutral control condition when grasping the evenly weighted version. The pattern of behavior in apraxic patients suggests impaired integration of visible and known object properties attributed to the ventro-dorsal stream: in learning to grasp the weighted object accurately, apraxic patients applied neither pure knowledge-based information (the memory-associated condition) nor higher-level information given in the visual-spatial cue condition. Disruption to ventro-dorsal stream predicts that apraxic patients will have difficulty learning to manipulate new objects on the basis of information other than low-level visual cues such as shape and size

Temporal proteomic profiling of postnatal human cortical development.

Healthy cortical development depends on precise regulation of transcription and translation. However, the dynamics of how proteins are expressed, function and interact across postnatal human cortical development remain poorly understood. We surveyed the proteomic landscape of 69 dorsolateral prefrontal cortex samples across seven stages of postnatal life and integrated these data with paired transcriptome data. We detected 911 proteins by liquid chromatography-mass spectrometry, and 83 were significantly associated with postnatal age (FDR < 5%). Network analysis identified three modules of co-regulated proteins correlated with age, including two modules with increasing expression involved in gliogenesis and NADH metabolism and one neurogenesis-related module with decreasing expression throughout development. Integration with paired transcriptome data revealed that these age-related protein modules overlapped with RNA modules and displayed collinear developmental trajectories. Importantly, RNA expression profiles that are dynamically regulated throughout cortical development display tighter correlations with their respective translated protein expression compared to those RNA profiles that are not. Moreover, the correspondence between RNA and protein expression significantly decreases as a function of cortical aging, especially for genes involved in myelination and cytoskeleton organization. Finally, we used this data resource to elucidate the functional impact of genetic risk loci for intellectual disability, converging on gliogenesis, myelination and ATP-metabolism modules in the proteome and transcriptome. We share all data in an interactive, searchable companion website. Collectively, our findings reveal dynamic aspects of protein regulation and provide new insights into brain development, maturation, and disease

The prognosis of allocentric and egocentric neglect : evidence from clinical scans

We contrasted the neuroanatomical substrates of sub-acute and chronic visuospatial deficits associated with different aspects of unilateral neglect using computed tomography scans acquired as part of routine clinical diagnosis. Voxel-wise statistical analyses were conducted on a group of 160 stroke patients scanned at a sub-acute stage. Lesion-deficit relationships were assessed across the whole brain, separately for grey and white matter. We assessed lesions that were associated with behavioural performance (i) at a sub-acute stage (within 3 months of the stroke) and (ii) at a chronic stage (after 9 months post stroke). Allocentric and egocentric neglect symptoms at the sub-acute stage were associated with lesions to dissociated regions within the frontal lobe, amongst other regions. However the frontal lesions were not associated with neglect at the chronic stage. On the other hand, lesions in the angular gyrus were associated with persistent allocentric neglect. In contrast, lesions within the superior temporal gyrus extending into the supramarginal gyrus, as well as lesions within the basal ganglia and insula, were associated with persistent egocentric neglect. Damage within the temporo-parietal junction was associated with both types of neglect at the sub-acute stage and 9 months later. Furthermore, white matter disconnections resulting from damage along the superior longitudinal fasciculus were associated with both types of neglect and critically related to both sub-acute and chronic deficits. Finally, there was a significant difference in the lesion volume between patients who recovered from neglect and patients with chronic deficits. The findings presented provide evidence that (i) the lesion location and lesion size can be used to successfully predict the outcome of neglect based on clinical CT scans, (ii) lesion location alone can serve as a critical predictor for persistent neglect symptoms, (iii) wide spread lesions are associated with neglect symptoms at the sub-acute stage but only some of these are critical for predicting whether neglect will become a chronic disorder and (iv) the severity of behavioural symptoms can be a useful predictor of recovery in the absence of neuroimaging findings on clinical scans. We discuss the implications for understanding the symptoms of the neglect syndrome, the recovery of function and the use of clinical scans to predict outcome

Multiplex ligation-dependent probe amplification for genetic screening in autism spectrum disorders: Efficient identification of known microduplications and identification of a novel microduplication in ASMT

<p>Abstract</p> <p>Background</p> <p>It has previously been shown that specific microdeletions and microduplications, many of which also associated with cognitive impairment (CI), can present with autism spectrum disorders (ASDs). Multiplex ligation-dependent probe amplification (MLPA) represents an efficient method to screen for such recurrent microdeletions and microduplications.</p> <p>Methods</p> <p>In the current study, a total of 279 unrelated subjects ascertained for ASDs were screened for genomic disorders associated with CI using MLPA. Fluorescence in situ hybridization (FISH), quantitative polymerase chain reaction (Q-PCR) and/or direct DNA sequencing were used to validate potential microdeletions and microduplications. Methylation-sensitive MLPA was used to characterize individuals with duplications in the Prader-Willi/Angelman (PWA) region.</p> <p>Results</p> <p>MLPA showed two subjects with typical ASD-associated interstitial duplications of the 15q11-q13 PWA region of maternal origin. Two additional subjects showed smaller, <it>de novo </it>duplications of the PWA region that had not been previously characterized. Genes in these two novel duplications include <it>GABRB3 </it>and <it>ATP10A </it>in one case, and <it>MKRN3</it>, <it>MAGEL2 </it>and <it>NDN </it>in the other. In addition, two subjects showed duplications of the 22q11/DiGeorge syndrome region. One individual was found to carry a 12 kb deletion in one copy of the <it>ASPA </it>gene on 17p13, which when mutated in both alleles leads to Canavan disease. Two subjects showed partial duplication of the <it>TM4SF2 </it>gene on Xp11.4, previously implicated in X-linked non-specific mental retardation, but in our subsequent analyses such variants were also found in controls. A partial duplication in the <it>ASMT </it>gene, located in the pseudoautosomal region 1 (PAR1) of the sex chromosomes and previously suggested to be involved in ASD susceptibility, was observed in 6–7% of the cases but in only 2% of controls (P = 0.003).</p> <p>Conclusion</p> <p>MLPA proves to be an efficient method to screen for chromosomal abnormalities. We identified duplications in 15q11-q13 and in 22q11, including new <it>de novo </it>small duplications, as likely contributing to ASD in the current sample by increasing liability and/or exacerbating symptoms. Our data indicate that duplications in <it>TM4SF2</it> are not associated with the phenotype given their presence in controls. The results in PAR1/PAR2 are the first large-scale studies of gene dosage in these regions, and the findings at the <it>ASMT </it>locus indicate that further studies of the duplication of the <it>ASMT </it>gene are needed in order to gain insight into its potential involvement in ASD. Our studies also identify some limitations of MLPA, where single base changes in probe binding sequences alter results. In summary, our studies indicate that MLPA, with a focus on accepted medical genetic conditions, may be an inexpensive method for detection of microdeletions and microduplications in ASD patients for purposes of genetic counselling if MLPA-identified deletions are validated by additional methods.</p