Relationship between cardiac cycle and the timing of actions during action execution and observation.

Previous research suggests that there may be a relationship between the timing of motor events and phases of the cardiac cycle. This relationship has thus far only been researched using simple isolated movements such as key-presses in reaction-time tasks and only in a single subject acting alone. Other research has shown both movement and cardiac coordination among interacting individuals. Here, we investigated how the cardiac cycle relates to ongoing self-paced movements in both action execution and observation using a novel dyadic paradigm. We recorded electrocardiography (ECG) in 26 subjects who formed 19 dyads containing an action executioner and observer as they performed a self-paced sequence of movements. We demonstrated that heartbeats are timed to movements during both action execution and observation. Specifically, movements were less likely to culminate synchronously with the heartbeat around the time of the R-peak of the ECG. The same pattern was observed for action observation, with the observer's heartbeats occurring off-phase with movement culmination. These findings demonstrate that there is coordination between an action executioner's cardiac cycle and the timing of their movements, and that the same relationship is mirrored in an observer. This suggests that previous findings of interpersonal coordination may be caused by the mirroring of a phasic relationship between movement and the heart.

Assessment of differentially methylated loci in individuals with end-stage kidney disease attributed to diabetic kidney disease: an exploratory study.

BACKGROUND: A subset of individuals with type 1 diabetes mellitus (T1DM) are predisposed to developing diabetic kidney disease (DKD), the most common cause globally of end-stage kidney disease (ESKD). Emerging evidence suggests epigenetic changes in DNA methylation may have a causal role in both T1DM and DKD. The aim of this exploratory investigation was to assess differences in blood-derived DNA methylation patterns between individuals with T1DM-ESKD and individuals with long-duration T1DM but no evidence of kidney disease upon repeated testing to identify potential blood-based biomarkers. Blood-derived DNA from individuals (107 cases, 253 controls and 14 experimental controls) were bisulphite treated before DNA methylation patterns from both groups were generated and analysed using Illumina's Infinium MethylationEPIC BeadChip arrays (n = 862,927 sites). Differentially methylated CpG sites (dmCpGs) were identified (false discovery rate adjusted p ≤ × 10-8 and fold change ± 2) by comparing methylation levels between ESKD cases and T1DM controls at single site resolution. Gene annotation and functionality was investigated to enrich and rank methylated regions associated with ESKD in T1DM. RESULTS: Top-ranked genes within which several dmCpGs were located and supported by functional data with methylation look-ups in other cohorts include: AFF3, ARID5B, CUX1, ELMO1, FKBP5, HDAC4, ITGAL, LY9, PIM1, RUNX3, SEPTIN9 and UPF3A. Top-ranked enrichment pathways included pathways in cancer, TGF-ß signalling and Th17 cell differentiation. CONCLUSIONS: Epigenetic alterations provide a dynamic link between an individual's genetic background and their environmental exposures. This robust evaluation of DNA methylation in carefully phenotyped individuals has identified biomarkers associated with ESKD, revealing several genes and implicated key pathways associated with ESKD in individuals with T1DM.

Dissociation in How Core Autism Features Relate to Interoceptive Dimensions: Evidence from Cardiac Awareness in Children.

Interoception in autism is receiving increasing research attention. Previously, differences were identified in autism on both objective and subjective measures of interoception, and an association with anxiety. Yet, it is currently unknown how interoception relates to core autism features. Here, in 49 autistic children, we consider how interoceptive accuracy (measured with heartbeat detection tasks) and sensibility (subjective judgements of awareness) relate to overall severity on the Autism Diagnostic Observation Schedule, and symptom domains of social-affective and repetitive, restricted behaviors. Socio-affective features were related to interoceptive sensibility, while repetitive restricted behaviors were related to interoceptive accuracy. This dissociation suggests disparate interoceptive mechanisms for the formation and/or maintenance of autistic features.

Comparison of methylation patterns generated from genomic and cell-line derived DNA using the Illumina Infinium MethylationEPIC BeadChip array.

OBJECTIVES: Genomic DNA (gDNA) is the optimal source of DNA for methylation analysis. This study compared methylation patterns in gDNA derived from blood with cell-line derived DNA (clDNA) from the same individuals. The clDNA had been generated via an Epstein-Barr virus transformation of the participant's lymphocytes. This analysis sought to determine whether clDNA has the potential to be utilised in lieu of finite/unavailable gDNA in methylation analyses using Illumina Infinium MethylationEPIC BeadChip arrays that assess 862,927 CpG sites. RESULTS: DNA samples were divided into two groups with eight gDNA and eight matched clDNA samples compared in each group (n = 16 individuals with 32 samples in total). Methylation patterns for gDNA samples generated for both groups were compared to the clDNA equivalent samples using Partek® Genomics Suite® to assess whether the significantly different CpG sites were consistent between both groups. In total, 28,632 CpG sites with significantly different levels of methylation (p < ×10-8) were common to both groups while 828,072 CpG sites assessed by the MethylationEPIC array were not significantly different in either group. This indicates that there is potential for clDNA to be used as a replacement for finite gDNA samples when absolutely necessary in DNA methylation studies.

The link between interoceptive processing and anxiety in children diagnosed with autism spectrum disorder: Extending adult findings into a developmental sample.

Anxiety is a major associated feature of autism spectrum disorders. The incidence of anxiety symptoms in this population has been associated with altered interoceptive processing. Here, we investigated whether recent findings of impaired interoceptive accuracy (quantified using heartbeat detection tasks) and exaggerated interoceptive sensibility (subjective sensitivity to internal sensations on self-report questionnaires) in autistic adults, can be extended into a school-age sample of children and adolescents (n = 75). Half the sample had a verified diagnosis of an Autism Spectrum Disorder (ASD) and half were IQ- and age-matched children and adolescents without ASD. The discrepancy between an individual's score on these two facets of interoception (interoceptive accuracy and interoceptive sensibility), conceptualized as an interoceptive trait prediction error, was previously found to predict anxiety symptoms in autistic adults. We replicated the finding of reduced interoceptive accuracy in autistic participants, but did not find exaggerated interoceptive sensibility relative to non-autistic participants. Nonetheless, the positive association between anxiety and interoceptive trait prediction error was replicated. However, in this sample, the best predictor of anxiety symptoms was interoceptive sensibility. Finally, we observed lower metacognitive accuracy for interoception in autistic children and adolescents, relative to their non-autistic counterparts. Despite their reduced interoceptive accuracy on the heartbeat tracking task and comparable accuracy on the heartbeat discrimination task, the autistic group reported higher confidence than the typical group in the discrimination task. Findings are consistent with theories of ASD as a disorder of interoceptive processing, but highlight the importance of validating cognitive models of developmental conditions within developmental populations.

Altering movement parameters disrupts metacognitive accuracy.

Correctly estimating the confidence we should have in our decisions has traditionally been viewed as a perceptual judgement based solely on the strength or quality of sensory information. However, accumulating evidence has demonstrated that the motor system contributes to judgements of perceptual confidence. Here, we manipulated the speed at which participants' moved using a behavioural priming task and showed that increasing movement speed above participants' baseline measures disrupts their ability to form accurate confidence judgements about their performance. Specifically, after being primed to move faster than they would naturally, participants reported higher confidence in their incorrect decisions than when they moved at their natural pace. We refer to this finding as the adamantly wrong effect. The results are consistent with the hypothesis that veridical feedback from the effector used to indicate a decision is employed to form accurate metacognitive judgements of performance.

Event related desynchronisation predicts functional propriospinal myoclonus.

OBJECTIVE: Recent diagnostic criteria for functional movement disorders have proposed a "laboratory supported" level of diagnostic certainty where the clinical diagnosis is supported by a positive test. For functional myoclonus the Bereitschaftspotential (BP) is generally accepted as a positive laboratory test. We hypothesised that a different EEG measure, event-related desynchronisation (ERD), might be more effective. METHODS: We analysed 20 patients with functional propriospinal myoclonus (fPSM) and 9 controls with organic myoclonus and performed back-averaging for BPs plus time-frequency decomposition to assess ERD and calculated sensitivity and specificity for both techniques. RESULTS: The BP was present in only 25% of patients with fPSM while the majority showed a significant ERD (mean 38 Hz; sensitivity 65%). ERD was significant at the group level (p < 0.001), but not the BP (p > 0.05). Both BP and ERD were absent in our control group. CONCLUSION: ERD in high-beta may be a useful new test for positive diagnosis of functional myoclonus.

Abnormal movement-related suppression of sensory evoked potentials in upper limb dystonia.

BACKGROUND: Gating of sensory evoked potentials (SEPs) around the onset of a voluntary movement is a physiological phenomenon with centripetal and central components, and may reflect sensorimotor integration required for normal movement control. OBJECTIVE: Our objective was the investigation of SEP suppression at the onset of movement and the interaction between SEP suppression and vibration of the limb. METHODS: Fourteen patients with primary focal/segmental dystonia and 17 age-matched healthy volunteers were studied. SEPs were elicited after electrical stimulation of the median nerve at the wrist. Electroencephalograms (EEGs) were recorded over the scalp at three sites according to the International 10-20 System (F3, C3 and P3). SEPs were recorded in four conditions: at rest, at the onset of movement (a self-paced abduction movement of the right thumb), both in the absence and in the presence of vibration of the limb. RESULTS: Repeated measures anova revealed that there was a significant main effect of group [F(1, 11.1) = 0.471, P = 0.002]. Post hoc exploration of this effect revealed it to be due to an absence of SEP suppression at movement onset in patients (mean ratio SEP movement onset/rest 1.15 at F3, 1.13 at C3, 1.01 at P3) compared to controls, who had SEP suppression at movement onset (mean ratio SEP movement onset/rest 0.79 at F3, 0.78 at C3, 0.77 at P3). With vibration, SEP suppression reduced in both patients and controls to a similar extent. CONCLUSION: These results demonstrate abnormal SEP suppression at the onset of movement in patients with primary dystonia, and in addition that vibration of the limb reduces SEP suppression in patients and controls.

Linking differences in action perception with differences in action execution.

Successful human social interactions depend upon the transmission of verbal and non-verbal signals from one individual to another. Non-verbal social communication is realized through our ability to read and understand information present in other people's actions. It has been proposed that employing the same motor programs, we use to execute an action when observing the same action underlies this action understanding. The main prediction of this framework is that action perception should be strongly correlated with parameters of action execution. Here, we demonstrate that subjects' sensitivity to observed movement speeds is dependent upon how quickly they themselves executed the observed action. This result is consistent with the motor theory of social cognition and suggests that failures in non-verbal social interactions between individuals may in part result from differences in how those individuals move.

Genetics of superionic conductivity in lithium lanthanum titanates.

The self-diffusion of ions is a fundamental mass transport process in solids and has a profound impact on the performance of electrochemical devices such as the solid oxide fuel cell, batteries and electrolysers. The perovskite system lithium lanthanum titanate, La2/3-xLi3xTiO3 (LLTO) has been the subject of much academic interest as it displays very high lattice conductivity for a solid state Li conductor; making it a material of great technological interest for deployment in safe durable mobile power applications. However, so far, a clear picture of the structural features that lead to efficient ion diffusion pathways in LLTO, has not been fully developed. In this work we show that a genetic algorithm in conjunction with molecular dynamics can be employed to elucidate diffusion mechanisms in systems such as LLTO. Based on our simulations we provide evidence that there is a three-dimensional percolated network of Li diffusion pathways. The present approach not only reproduces experimental ionic conductivity results but the method also promises straightforward investigation and optimisation of the properties relating to superionic conductivity in materials such as LLTO. Furthermore, this method could be used to provide insights into related materials with structural disorder.

Acquisition of Paleolithic toolmaking abilities involves structural remodeling to inferior frontoparietal regions.

Human ancestors first modified stones into tools 2.6 million years ago, initiating a cascading increase in technological complexity that continues today. A parallel trend of brain expansion during the Paleolithic has motivated over 100 years of theorizing linking stone toolmaking and human brain evolution, but empirical support remains limited. Our study provides the first direct experimental evidence identifying likely neuroanatomical targets of natural selection acting on toolmaking ability. Subjects received MRI and DTI scans before, during, and after a 2-year Paleolithic toolmaking training program. White matter fractional anisotropy (FA) showed changes in branches of the superior longitudinal fasciculus leading into left supramarginal gyrus, bilateral ventral precentral gyri, and right inferior frontal gyrus pars triangularis. FA increased from Scan 1-2, a period of intense training, and decreased from Scan 2-3, a period of reduced training. Voxel-based morphometry found a similar trend toward gray matter expansion in the left supramarginal gyrus from Scan 1-2 and a reversal of this effect from Scan 2-3. FA changes correlated with training hours and with motor performance, and probabilistic tractography confirmed that white matter changes projected to gray matter changes and to regions that activate during Paleolithic toolmaking. These results show that acquisition of Paleolithic toolmaking skills elicits structural remodeling of recently evolved brain regions supporting human tool use, providing a mechanistic link between stone toolmaking and human brain evolution. These regions participate not only in toolmaking, but also in other complex functions including action planning and language, in keeping with the hypothesized co-evolution of these functions.

Chemistry and structure of homoepitaxial SrTiO3 films and their influence on oxide-heterostructure interfaces.

The properties of single-crystal SrTiO3 substrates and homoepitaxial SrTiO3 films grown by pulsed laser deposition have been compared, in order to understand the loss of interfacial conductivity when more than a critical thickness of nominally homoepitaxial SrTiO3 is inserted between a LaAlO3 film and a SrTiO3 substrate. In particular, the chemical composition and the structure of homoepitaxial SrTiO3 investigated by low-energy ion-scattering and surface X-ray diffraction show that for insulating heterointerfaces, a Sr-excess is present between the LaAlO3 and homoepitaxial SrTiO3. Furthermore, an increase in the out-of-plane lattice constant is observed in LaAlO3, indicating that the conductivity both with and without insertion of the SrTiO3 thin film originates from a Zener breakdown associated with the polar catastrophe. When more than a critical thickness of homoepitaxial SrTiO3 is inserted between LaAlO3 and SrTiO3, the electrons transferred by the electronic reconstruction are trapped by the formation of a Sr-rich secondary phase and Sr-vacancies. The migration of Sr towards the surface of homoepitaxial SrTiO3 and accompanying loss of interfacial conductivity can be delayed by reducing the Sr-content in the PLD target.

Do monkey F5 mirror neurons show changes in firing rate during repeated observation of natural actions?

Mirror neurons were first discovered in area F5 of macaque monkeys. In humans, noninvasive studies have demonstrated an increased blood oxygen level-dependent (BOLD) signal in homologous motor areas during action observation. One approach to demonstrating that this indicates the existence of mirror neurons in humans has been to employ functional (f)MRI adaptation to test whether the same population of neurons is active during both observation and execution conditions. Although a number of human studies have reported fMRI adaptation in these areas, a recent study has shown that macaque mirror neurons do not attenuate their firing rate with two repetitions. Here we investigated whether mirror neurons modulate their firing rate when monkeys observed the same repeated natural action multiple times. We recorded from 67 mirror neurons in area F5 of two macaque monkeys while they observed an experimenter perform a reach-to-grasp action on a small food reward using a precision grip. Although no changes were detectable for the first two repetitions, we show that both the firing rate and the latency at which mirror neurons discharged during observation were subtly modulated by the repetition of the observed action over 7-10 trials. Significant adaption was mostly found in the period immediately before the grasp was performed. We also found that the local field potential activity in F5 (beta-frequency range, 16-23 Hz), which is attenuated during action observation, also showed systematic changes with repeated observation. These LFP changes occurred well in advance of the mirror neuron adaptation. We conclude that macaque mirror neurons can show intra-modal adaptation, but whether this is related to fMRI adaptation of the BOLD signal requires further investigation.

What we know currently about mirror neurons.

Mirror neurons were discovered over twenty years ago in the ventral premotor region F5 of the macaque monkey. Since their discovery much has been written about these neurons, both in the scientific literature and in the popular press. They have been proposed to be the neuronal substrate underlying a vast array of different functions. Indeed so much has been written about mirror neurons that last year they were referred to, rightly or wrongly, as "The most hyped concept in neuroscience". Here we try to cut through some of this hyperbole and review what is currently known (and not known) about mirror neurons.

Inferring subjective states through the observation of actions.

Estimating another person's subjective confidence is crucial for social interaction, but how this inference is achieved is unknown. Previous research has demonstrated that the speed at which people make decisions is correlated with their confidence in their decision. Here, we show that (i) subjects are able to infer the subjective confidence of another person simply through the observation of their actions and (ii) this inference is dependent upon the performance of each subject when executing the action. Crucially, the latter result supports a model in which motor simulation of an observed action mediates the successful understanding of other minds. We conclude that kinematic understanding allows access to the higher-order cognitive processes of others, and that this access plays a central role in social interactions.

Role of the parietal cortex in predicting incoming actions.

Animal and human studies have shown that the parietal and the ventral premotor cortices constitute the neural substrate of the so-called mirror system. The word "mirror" originally referred to the discovery of neurons in non-human primates whose visual response echoes their motor response. This account proposes that action understanding and imitation depend on a mechanism which activates directly our own motor system as we observe the actions of other agents (Rizzolatti and Sinigaglia, 2010). Single unit recording experiments have also demonstrated that parietal neurons have predictive activity and discharge well ahead of a planned movement. Interestingly, patients with parietal damage can show impairments in their ability to imitate or understand an observed action, but they have also difficulties in monitoring early phases of their own movement planning, be it simple reaching movements or more complex object-directed actions. The fact that both deficits may co-occur after a parietal lesion raises the question whether this reflects the impairment of a common mechanism. To address this question we examined EEG activity in patients with selective lesions in the inferior parietal lobe (N=6) who were requested to watch passively a video showing an actor grasping a colored object. The object's color cued the subject that the actor was about to move. We recorded the Readiness Potential (RP), a marker of motor preparation which also arises when preparing to observe an action (Kilner et al., 2004). Parietal patients' performance was compared to that of neurologically normal subjects (n=9) and patients with a ventral premotor cortex lesion (N=4). We show that neurologically normal subjects and premotor patients exhibit a significant RP prior to the observed action, whereas no such RP is observed in parietal patients. Our results indicate that parietal cortex injury alters the ability to monitor the early planning phases not only of one's own actions but those of other agents as well. We speculate that parietal activity during action observation does not only or essentially reflect a mirroring process, as recently proposed by mirror neurons' account, but involve instead an anticipatory process which arises through prior learning and predictive mechanisms.

Defect processes in orthorhombic LnBaCo2O5.5 double perovskites.

Static atomistic simulations based on the Born model were used to investigate intrinsic defect processes in orthorhombic LnBaCo(2)O(5.5) (Ln = Y, La, Pr, Nd, Sm, Gd, Dy, Ho, Er, and Yb) double perovskites. It was found that Ln/Ba antisite disorder is the lowest energy defect reaction, with the large Ln cations giving rise to smaller antisite energies. On the oxygen sublattice the oxygen Frenkel disorder dominates and also decreases in energy with increasing Ln cation size. The lowest energy oxygen vacancy and interstitial positions are in the LnO(0.5) and CoO(2) layers respectively. Interestingly, the calculations indicate that oxygen vacancies cluster with Ba antisite defects (occupying Ln sites). This suggests that the transport of oxygen vacancies will be influenced not only by the oxygen Frenkel energy but also the antisite energy. We propose that PrBaCo(2)O(5.5) most efficiently balances these two competing effects as it has an oxygen Frenkel energy of just 0.24 eV per defect combined with a high antisite energy (0.94 eV), which ensures that the A cation sublattice will remain more ordered.

Genetic polymorphisms in nitric oxide synthase 3 gene and implications for kidney disease: a meta-analysis.

BACKGROUND/AIMS: The NOS3 gene is a biological and positional candidate for diabetic nephropathy. However, the relationship between NOS3 polymorphisms and renal disease is inconclusive. This study aimed to clarify the association of NOS3 variants with nephropathy in individuals with type 1 diabetes. METHODS: We conducted a case-control study examining all common SNPs in the NOS3 gene by a tag SNP approach. Individuals with type 1 diabetes and persistent proteinuria (cases, n = 718) were compared with individuals with type 1 diabetes but no evidence of renal disease (controls, n = 749). Our replication collection comprised 1,105 individuals with type 1 diabetes recruited to a nephropathy case group and 862 control individuals with normal urinary albumin excretion rates. Meta-analysis was conducted for SNPs where more than three genotype datasets were available. RESULTS: A novel association was identified in the discovery collection (rs1800783, p(genotype) = 0.006, p(allele) = 0.002, OR = 1.26, 95% CI: 1.08-1.47) and supported by independent replication using a tag SNP (rs4496877, pairwise r² = 0.96 with rs1800783) in the replication collection (p(genotype) = 0.002, p(allele) = 0.0006, OR = 1.27, 95% CI: 1.10-1.45). CONCLUSION: The A allele of rs1800783 is a significant risk factor for nephropathy in individuals with type 1 diabetes, and further comprehensive studies are warranted to confirm the definitive functional variant in the NOS3 gene.

Investigation of the association of BMP gene variants with nephropathy in Type 1 diabetes mellitus.

AIMS: Diabetic nephropathy is a leading cause of end-stage renal disease. The transforming growth factor beta-bone morphogenic protein (BMP) pathway is implicated in the pathogenesis of diabetic nephropathy. The BMP2, BMP4 and BMP7 genes are located near linkage peaks for renal dysfunction, and we hypothesize that genetic polymorphisms in these biological and positional candidate genes may be risk factors for diabetic kidney disease. METHODS: The BMP7 gene was screened, variants identified and allele frequencies determined by bidirectionally sequencing 46 individuals to facilitate selection of tag SNPs (n = 4). For BMP2 and BMP4 genes, data were downloaded for 19 single nucleotide polymorphisms (SNPs) from the International HapMap project and six tag SNPs selected. RESULTS: The BMP7 gene was screened for novel genetic polymorphisms, haplotypes were identified, an appropriate subset of variants selected for the investigation of common genetic risk factors, and BMP2, BMP4 and BMP7 genes assessed for association with diabetic nephropathy in 1808 individuals. Thirty-two SNPs were identified, of which 11 were novel, including an amino-acid changing SNP (+63639C>T). No significant differences (P > 0.2) were observed when comparing genotype or allele or haplotype frequencies between 864 individuals with Type 1 diabetes and nephropathy compared with 944 individuals with Type 1 diabetes without nephropathy, stratified by recruitment centre. CONCLUSIONS: Common polymorphisms in these BMP genes do not strongly influence genetic susceptibility to diabetic nephropathy in White individuals with Type 1 diabetes mellitus.