Cognitive control training with domain-general response inhibition does not change children's brains or behavior.

Cognitive control is required to organize thoughts and actions and is critical for the pursuit of long-term goals. Childhood cognitive control relates to other domains of cognitive functioning and predicts later-life success and well-being. In this study, we used a randomized controlled trial to test whether cognitive control can be improved through a pre-registered 8-week intervention in 235 children aged 6-13 years targeting response inhibition and whether this leads to changes in multiple behavioral and neural outcomes compared to a response speed training. We show long-lasting improvements of closely related measures of cognitive control at the 1-year follow-up; however, training had no impact on any behavioral outcomes (decision-making, academic achievement, mental health, fluid reasoning and creativity) or neural outcomes (task-dependent and intrinsic brain function and gray and white matter structure). Bayesian analyses provide strong evidence of absent training effects. We conclude that targeted training of response inhibition does little to change children's brains or their behavior.

EXAMINING MECHANISMS OF CHILDHOOD COGNITIVE CONTROL.

Childhood cognitive control is an important predictor for positive development, yet interventions seeking to improve it have provided mixed results. This is partly due to lack of clarity surrounding mechanisms of cognitive control, notably the role of inhibition and context monitoring. Here we use a randomized controlled trial to causally test the contributions of inhibition and context monitoring to cognitive control in childhood. Sixty children aged 6 to 9-years were assigned to three groups training either inhibition, context monitoring group or response speed using a gamified, highly variable and maximally adaptive training protocol. Whereas all children improved in the targeted cognitive functions over the course of training, pre-post data show that only the inhibition group improved on cognitive control. These findings serve as a first step in demonstrating the promise inhibition-based cognitive control interventions may hold.

Intra-individual variability adaptively increases following inhibition training during middle childhood.

There is ongoing debate on the relationship between intra-individual variability (IIV) of cognitive processes and task performance. While psychological research has traditionally assumed that lower intra-individual variability (IIV) aids consistent task performance, some studies suggest that greater IIV can also be adaptive, especially when flexible responding is required. Here we selectively manipulate inhibitory control (Stopping) and response speed (Going) by means of a training paradigm to 1) assess how this manipulation impacts Stopping IIV and its relationship to task performance, and 2) replicate previous findings showing that reductions in Going IIV are adaptive. A group of 208 6-13-year-old children were randomly allocated to an 8-week training targeting Stopping (experimental group) or Going (control group). The stop signal task was administered before and after training. Training Stopping led to adaptive increases in Stopping IIV, where greater flexibility in cognitive processing may be required to meet higher task demands. In line with previous studies, training Going led to adaptive reductions in Going IIV, which allows more consistent and efficient Going performance. These findings provide systematic and causal evidence of the process-dependent relationship of IIV and task performance in the context of Stopping and Going, suggesting a more nuanced perspective on IIV with implications for developmental, ageing and intervention studies.

Promoting mental health and well-being in schools: examining mindfulness, relaxation and strategies for safety and well-being in English primary and secondary schools-study protocol for a multi-school, cluster randomised controlled trial (INSPIRE).

There are increasing rates of internalising difficulties, particularly anxiety and depression, being reported in children and young people in England. School-based universal prevention programmes are thought to be one way of helping tackle such difficulties. This paper describes an update to a four-arm cluster randomised controlled trial ( http://www.isrctn.com/ISRCTN16386254 ), investigating the effectiveness of three different interventions when compared to usual provision, in English primary and secondary pupils. Due to the COVID-19 pandemic, the trial was put on hold and subsequently prolonged. Data collection will now run until 2024. The key changes to the trial outlined here include clarification of the inclusion and exclusion criteria, an amended timeline reflecting changes to the recruitment period of the trial due to the COVID-19 pandemic and clarification of the data that will be included in the statistical analysis, since the second wave of the trial was disrupted due to COVID-19.Trial registration ISRCTN Registry ISRCTN16386254. Registered on 30 August 2018.

Characteristics of Early Interventions for Pain and Function Following Lower Extremity Joint Replacement: Systematic Review.

Occupational therapy is beneficial among adults with chronic pain; however, occupational therapy interventions addressing earlier phases of pain have not been clearly explicated. This systematic review characterized acute and subacute interventions billable by occupational therapy after hip or knee replacement to improve pain and function. Seven articles met inclusion criteria. Six articles had a low risk of bias. Three intervention types were found: task-oriented exercise, water-based, and modalities. Only task-oriented interventions improved both pain and function one-year after surgery. There are long-term benefits to early task-oriented exercise. Further research is needed to contextualize occupational therapy's role in early pain interventions.

Changes in BOLD variability are linked to the development of variable response inhibition.

Research on the development of response inhibition in humans has focused almost exclusively on average stopping performance. The development of intra-individual variability in stopping performance and its underlying neural circuitry has remained largely unstudied, even though understanding variability is of core importance for understanding development. In a total sample of 45 participants (19 children aged 10-12 years and 26 adults aged 18-26 years) of either sex we aimed to identify age-related changes in intra-individual response inhibition performance and its underlying brain signal variability. While there was no difference in average stopping performance between children and adults, stop signal latencies for the children were more variable. Further, brain signal variability during successful stopping was significantly higher in adults compared to children, especially in bilateral thalamus, but also across regions of the inhibition network. Finally, brain signal variability was significantly associated with stopping performance behavioral variability in adults. Together these results indicate that variability in stopping performance decreases, whereas neural variability in the inhibition network increases, from childhood to adulthood. Future work will need to assess whether developmental changes in neural variability drive those in behavioral variability. In sum, both, neural and behavioral variability indices might be a more sensitive measure of developmental differences in response inhibition compared to the standard average-based measurements.

Computational modelling of attentional bias towards threat in paediatric anxiety.

Computational modelling can be used to precisely characterize the cognitive processes involved in attentional biases towards threat, yet so far has only been applied in the context of adult anxiety. Furthermore, studies investigating attentional biases in childhood anxiety have largely used tasks that conflate automatic and controlled attentional processes. By using a perceptual load paradigm, we separately investigate contributions from automatic and controlled processes to attentional biases towards negative stimuli and their association with paediatric anxiety. We also use computational modelling to investigate these mechanisms in children for the first time. In a sample of 60 children (aged 5-11 years) we used a perceptual load task specifically adapted for children, in order to investigate attentional biases towards fearful (compared with happy and neutral) faces. Outcome measures were reaction time and percentage accuracy. We applied a drift diffusion model to investigate the precise cognitive mechanisms involved. The load effect was associated with significant differences in response time, accuracy and the diffusion modelling parameters drift rate and extra-decisional time. Greater anxiety was associated with greater accuracy and the diffusion modelling parameter 'drift rate' on the fearful face trials. This was specific to the high load condition. These findings suggest that attentional biases towards fearful faces in childhood anxiety are driven by increased perceptual sensitivity towards fear in automatic attentional systems. Our findings from computational modelling suggest that current attention bias modification treatments should target perceptual encoding directly rather than processes occurring afterwards.

Age-related differences in white matter diffusion measures in autism spectrum condition.

BACKGROUND: Autism spectrum condition (ASC) is accompanied by developmental differences in brain anatomy and connectivity. White matter differences in ASC have been widely studied with diffusion imaging but results are heterogeneous and vary across the age range of study participants and varying methodological approaches. To characterize the neurodevelopmental trajectory of white matter maturation, it is necessary to examine a broad age range of individuals on the autism spectrum and typically developing controls, and investigate age × group interactions. METHODS: Here, we employed a spatially unbiased tract-based spatial statistics (TBSS) approach to examine age-related differences in white matter connectivity in a sample of 41 individuals with ASC, and 41 matched controls between 7-17 years of age. RESULTS: We found significant age-related differences between the ASC and control group in widespread brain regions. This included age-related differences in the uncinate fasciculus, corticospinal tract, inferior longitudinal fasciculus, inferior fronto-occipital fasciculus, anterior thalamic radiation, superior longitudinal fasciculus and forceps major. Measures of fractional anisotropy (FA) were significantly positively associated with age in both groups. However, this relationship was significantly stronger in the ASC group relative to controls. Measures of radial diffusivity (RD) were significantly negatively associated with age in both groups, but this relationship was significantly stronger in the ASC group relative to controls. LIMITATIONS: The generalisability of our findings is limited by the restriction of the sample to right-handed males with an IQ > 70. Furthermore, a longitudinal design would be required to fully investigate maturational processes across this age group. CONCLUSIONS: Taken together, our findings suggest that autistic males have an altered trajectory of white matter maturation relative to controls. Future longitudinal analyses are required to further characterize the extent and time course of these differences.

Determining Physical Therapists' Readiness for Integrating Yoga Therapeutics into Rehabilitation.

The positive health effects of yoga have led physical therapists (PTs) to integrate elements of the discipline into their treatments in some settings. Formal PT education includes limited, if any, training in yoga, and there is no system in place to provide education on safely implementing therapeutic yoga (TY) as an adjunctive treatment approach. The purposes of this study were to: (1) assess the readiness of PTs (those who do not currently prescribe TY to patients) to integrate TY into treatment, and (2) determine the feasibility of a 5-week online TY training to improve the readiness of PTs to utilize TY in their practices. Licensed PTs (n = 103) were recruited nationally through social media and email. Eligible and consented PTs registered for a 5-week online TY training course. PTs' perceptions of TY and the role of safety and confidence in prescribing TY to patients were measured at baseline and postintervention. Feasibility outcomes were measured after completion of the course. Benchmarks included: (1) > 70% of PTs would find the course acceptable; (2) > 60% would finish the course; and (3) there would be significant improvements in PTs' perceptions of TY. A total of 95 eligible PTs consented and registered for the course, with 60 (63.1%) completing the intervention. Prior to the training, most PTs felt they were not ready (n = 19/60, 31.7%) or somewhat ready (n = 25/60, 41.7%) to integrate TY. More than half thought the online training was acceptable (n = 50/60, 83.3%) and finished the course (n = 60/95, 63.1%). There were significant improvements in personal readiness and confidence to safely prescribe TY, current understanding/knowledge of TY, and feeling adequately trained to use some form of TY with patients. A 5-week online TY training course is feasible to deliver for improving PTs' readiness to prescribe TY. Future studies are proposed to test the effectiveness of TY training and education with PTs.

Sensitive periods in executive function development.

Executive functions (EFs) are cognitive processes that support flexible goal pursuit. Healthy development of EFs during childhood is critical for later life outcomes including health, wealth and educational attainment. As such it is crucial to understand how EFs can be supported and protected against insult. Here we examine whether there are sensitive periods in the development of EFs, by drawing on deprivation and enrichment studies in humans. While there is suggestive evidence that pre-6 months of age constitutes a sensitive period for EF development, given the higher-order nature of EF, we argue for the possibility of multiple sensitive periods of constituent processes. We identify relevant future questions and outline a research agenda to systematically test for sensitive period in EF development.

A new invariant of 4-manifolds.

We define an integer invariant [Formula: see text] of a smooth, compact, closed 4-manifold X by minimizing a certain complexity of a trisection of X over all trisections. The good feature of [Formula: see text] is that when [Formula: see text] and X is a homology 4-sphere, then X is diffeomorphic to the 4-sphere. Naturally, L is hard to compute.

Palatable Food Affects HPA Axis Responsivity and Forebrain Neurocircuitry in an Estrous Cycle-specific Manner in Female Rats.

Eating palatable foods can provide stress relief, but the mechanisms by which this occurs are unclear. We previously characterized a limited sucrose intake (LSI) paradigm in which twice-daily access to a small amount of 30% sucrose (vs. water as a control) reduces hypothalamic-pituitary-adrenocortical (HPA) axis responses to stress and alters neuronal activation in stress-regulatory brain regions in male rats. However, women may be more prone to 'comfort feeding' behaviors than men, and stress-related eating may vary across the menstrual cycle. This suggests that LSI effects may be sex- and estrous cycle-dependent. The present study therefore investigated the effects of LSI on HPA axis stress responsivity, as well as markers of neuronal activation/plasticity in stress- and reward-related neurocircuitry in female rats across the estrous cycle. We found that LSI reduced post-restraint stress plasma ACTH in female rats specifically during proestrus/estrus (P/E). LSI also increased basal (non-stress) FosB/deltaFosB- and pCREB-immunolabeling in the basolateral amygdala (BLA) and central amygdala specifically during P/E. Finally, Bayesian network modeling of the FosB/deltaFosB and pCREB expression data identified a neurocircuit that includes the BLA, nucleus accumbens, prefrontal cortex, and bed nucleus of the stria terminalis as likely being modified by LSI during P/E. When considered in the context of our prior results, the present findings suggest that palatable food reduces stress responses in female rats similar to males, but in an estrous cycle-dependent manner. Further, the BLA may contribute to the LSI effects in both sexes, whereas the involvement of other brain regions appears to be sex-dependent.

Dietary Manipulations That Induce Ketosis Activate the HPA Axis in Male Rats and Mice: A Potential Role for Fibroblast Growth Factor-21.

In response to an acute threat to homeostasis or well-being, the hypothalamic-pituitary-adrenocortical (HPA) axis is engaged. A major outcome of this HPA axis activation is the mobilization of stored energy, to fuel an appropriate behavioral and/or physiological response to the perceived threat. Importantly, the extent of HPA axis activity is thought to be modulated by an individual's nutritional environment. In this study, we report that nutritional manipulations signaling a relative depletion of dietary carbohydrates, thereby inducing nutritional ketosis, acutely and chronically activate the HPA axis. Male rats and mice maintained on a low-carbohydrate high-fat ketogenic diet (KD) exhibited canonical markers of chronic stress, including increased basal and stress-evoked plasma corticosterone, increased adrenal sensitivity to adrenocorticotropin hormone, increased stress-evoked c-Fos immunolabeling in the paraventricular nucleus of the hypothalamus, and thymic atrophy, an indicator of chronic glucocorticoid exposure. Moreover, acutely feeding medium-chain triglycerides (MCTs) to rapidly induce ketosis among chow-fed male rats and mice also acutely increased HPA axis activity. Lastly, and consistent with a growing literature that characterizes the hepatokine fibroblast growth factor-21 (FGF21) as both a marker of the ketotic state and as a key metabolic stress hormone, the HPA response to both KD and MCTs was significantly blunted among mice lacking FGF21. We conclude that dietary manipulations that induce ketosis lead to increased HPA axis tone, and that the hepatokine FGF21 may play an important role to facilitate this effect.

Impaired Communication Between the Motor and Somatosensory Homunculus Is Associated With Poor Manual Dexterity in Autism Spectrum Disorder.

BACKGROUND: Fine motor skill impairments are common in autism spectrum disorder (ASD), significantly affecting quality of life. Sensory inputs reaching the primary motor cortex (M1) from the somatosensory cortex (S1) are likely involved in fine motor skill and specifically motor learning. However, the role of these connections has not been directly investigated in humans. This study aimed to investigate, for the first time, the role of the S1-M1 connections in healthy subjects in vivo and whether microstructural alterations are associated with motor impairment in ASD. METHODS: Sixty right-handed neurotypical adult men aged 18 to 45 years, and 60 right-handed age- and sex-matched subjects diagnosed with ASD underwent fine motor skill assessment and scanning with diffusion tensor imaging (DTI). The streamlines of the hand region connecting S1-M1 of the motor-sensory homunculus were virtually dissected using TrackVis, and diffusion properties were extracted. The face/tongue region connections were used as control tracts. RESULTS: The ASD group displayed lower motor performances and altered DTI measurements of the hand-region connection. Behavioral performance correlated with hand-region DTI measures in both groups, but not with the face/tongue connections, indicating anatomical specificity. There was a left-hemisphere association of motor ability in the control group and an atypical rightward shift in the ASD group. CONCLUSIONS: These findings suggest that direct interaction between S1 and M1 may contribute to the human ability to precisely interact with and manipulate the environment. Because electrophysiological evidence indicates that these connections may underpin long-term potentiation in M1, our findings may lead to novel therapeutic treatments for motor skill disorders.

Frontal networks in adults with autism spectrum disorder.

It has been postulated that autism spectrum disorder is underpinned by an 'atypical connectivity' involving higher-order association brain regions. To test this hypothesis in a large cohort of adults with autism spectrum disorder we compared the white matter networks of 61 adult males with autism spectrum disorder and 61 neurotypical controls, using two complementary approaches to diffusion tensor magnetic resonance imaging. First, we applied tract-based spatial statistics, a 'whole brain' non-hypothesis driven method, to identify differences in white matter networks in adults with autism spectrum disorder. Following this we used a tract-specific analysis, based on tractography, to carry out a more detailed analysis of individual tracts identified by tract-based spatial statistics. Finally, within the autism spectrum disorder group, we studied the relationship between diffusion measures and autistic symptom severity. Tract-based spatial statistics revealed that autism spectrum disorder was associated with significantly reduced fractional anisotropy in regions that included frontal lobe pathways. Tractography analysis of these specific pathways showed increased mean and perpendicular diffusivity, and reduced number of streamlines in the anterior and long segments of the arcuate fasciculus, cingulum and uncinate--predominantly in the left hemisphere. Abnormalities were also evident in the anterior portions of the corpus callosum connecting left and right frontal lobes. The degree of microstructural alteration of the arcuate and uncinate fasciculi was associated with severity of symptoms in language and social reciprocity in childhood. Our results indicated that autism spectrum disorder is a developmental condition associated with abnormal connectivity of the frontal lobes. Furthermore our findings showed that male adults with autism spectrum disorder have regional differences in brain anatomy, which correlate with specific aspects of autistic symptoms. Overall these results suggest that autism spectrum disorder is a condition linked to aberrant developmental trajectories of the frontal networks that persist in adult life.

The obesity-associated transcription factor ETV5 modulates circulating glucocorticoids.

The transcription factor E-twenty-six version 5 (ETV5) has been linked with obesity in genome-wide association studies. Moreover, ETV5-deficient mice (knockout; KO) have reduced body weight, lower fat mass, and are resistant to diet-induced obesity, directly linking ETV5 to the regulation of energy balance and metabolism. ETV5 is expressed in hypothalamic brain regions that regulate both metabolism and HPA axis activity, suggesting that ETV5 may also modulate HPA axis function. In order to test this possibility, plasma corticosterone levels were measured in ETV5 KO and wildtype (WT) mice before (pre-stress) and after (post-stress) a mild stressor (intraperitoneal injection). ETV5 deficiency increased both pre- and post-stress plasma corticosterone, suggesting that loss of ETV5 elevated glucocorticoid tone. Consistent with this idea, ETV5 KO mice have reduced thymus weight, suggestive of increased glucocorticoid-induced thymic involution. ETV5 deficiency also decreased the mRNA expression of glucocorticoid receptor (GR), mineralocorticoid receptor (MR), and vasopressin receptor 1A in the hypothalamus, without altering vasopressin, corticotropin-releasing hormone, or oxytocin mRNA expression. In order to test whether reduced MR and GR expression affected glucocorticoid negative feedback, a dexamethasone suppression test was performed. Dexamethasone reduced plasma corticosterone in both ETV5 KO and WT mice, suggesting that glucocorticoid negative feedback was unaltered by ETV5 deficiency. In summary, these data suggest that the obesity-associated transcription factor ETV5 normally acts to diminish circulating glucocorticoids. This might occur directly via ETV5 actions on HPA-regulatory brain circuitry, and/or indirectly via ETV5-induced alterations in metabolic factors that then influence the HPA axis.