Grandfathers-to-Grandsons Transgenerational Transmission of Exercise Positive Effects on Cognitive Performance.

Physical exercise is a robust lifestyle intervention known for its enhancement of cognitive abilities. Nevertheless, the extent to which these benefits can be transmitted across generations (intergenerational inheritance to F1, and transgenerational to F2 and beyond) remains a topic of limited comprehension. We have already shown that cognitive improvements resulting from physical exercise can be inherited from parents to their offspring, proving intergenerational effects. So, we set out to explore whether these enhancements might extend transgenerationally, impacting the F2 generation. In this study, we initially examined the behavioral traits of second generation (F2) male mice, whose grandfathers (F0) had an exercise intervention. Our findings revealed that F2 mice with physically active grandpaternal F0 progenitors displayed significantly improved memory recall, encompassing both spatial and non-spatial information when compared to their counterparts from sedentary F0 progenitors, and proving for the first time the transgenerational inheritance of physical exercise induced cognitive enhancement. Surprisingly, while F2 memory improved (as was the case with F1), adult hippocampal neurogenesis remained unchanged between experimental and control groups (unlike in F1). Additionally, our analysis of small RNA sequences in the hippocampus identified 35 differentially expressed miRNAs linked to important brain function categories. Notably, two of these miRNAs, miRNA-144 and miRNA-298, displayed a robust negative correlation with cognitive performance. These findings highlight the enduring transgenerational transmission of cognitive benefits associated with exercise, even after two generations, suggesting that moderate exercise training can have lasting positive effects, possibly orchestrated by a specific set of miRNAs that exert their influence across multiple generations.

Response to chronic crowding stress in shy and bold behavioral groups of male and female zebrafish.

In recent years, there has been a burgeoning interest in exploring the nuances of animal stress physiology, particularly in relation to parameters such as sex and behavioral phenotype-dependent variations, which is crucial for understanding phenotypic variation and its role in evolutionary selection. However, a significant dearth remains in how chronic stressors affect organismal stress physiology concerning the aforesaid parameters. This void is even wider pertaining to the response of peripheral tissues, such as the skin, the organ with the highest surface contact area with the environment. Hence, we behaviorally grouped the zebrafishes based on their boldness and the body condition, whole body cortisol response, along with examining the transcriptional response, global DNA methylome, and oxidative DNA damage in the skin upon chronic crowding. Upon baseline conditions, clear distinction between bold and shy phenotypes was found, particularly in males. The boldness index score distribution exhibited greater uniformity in males than in females. Regarding the body condition response to chronic crowding, shy males showed a significant relative decline compared with their bold counterparts, while this trend did not hold true for females. qPCR data revealed distinctive expression patterns in key genes that play critical roles in cellular processes such as stress-mediated gene regulation, immune response, oxidative stress protection, and maintenance of genomic integrity through epigenetic modifications across behavioral phenotypes and sexes under both with and without chronic crowding stress. Global DNA methylation levels significantly declined only in chronically crowded shy males, and sex/behavioral phenotype-dependent trends in oxidative DNA damage were identified.NEW & NOTEWORTHY This paper analyzes the response of zebrafish to crowding stress through a new approach focused on the peripheral response dynamics of the skin, the main mucosal tissue, and involving sex and behavioral phenotype influences. Shy males showed significant distress as observed by body condition, physiological and transcriptional response, and global DNA methylation. Nuances in stress response across behavioral phenotypes and sex indicate a genetic and behavioral specificity and further inherent epigenetic regulatory dimension.

Severe behavior problems in SYNGAP1-related disorder: A summary of 11 consecutive patients in a tertiary care specialty clinic.

SYNGAP1-related disorder (SYNGAP1-RD) is a neurodevelopmental disorder that is commonly associated with epilepsy, autism spectrum disorder (ASD), and disruptive behaviors. In this study, behavior problems in 11 consecutive patients with SYNGAP1-RD are described and quantified based on a behavioral screening conducted within the context of a multi-disciplinary tertiary care specialty clinic visit. The behavioral phenotype was then compared to published samples of behavior problems in ASD and other genetic cause of epilepsy occurring in the context of neurodevelopmental disorders using results from the Aberrant Behavior Checklist-Community (ABC-C), an empirically derived outcome measure. We report common antecedent and consequent events surrounding problem behavior across individuals. Additionally, we report on the management approach of caregivers and the impact of problem behaviors on the family. Our results suggest a number of commonalities between behavioral profiles in SYNGAP1-RD with ASD and other genetic causes of developmental and epileptic encephalopathies, and also highlight severe behavior problems as a specific behavioral phenotype of SYNGAP1-RD.

The developmental trajectories of the behavioral phenotype and neuropsychiatric functioning in Cornelia de Lange and Rubinstein Taybi syndromes: A longitudinal study.

Several changes in the behavioral phenotype arise with the growth of children affected by Cornelia de Lange Syndrome (CdLS) and Rubinstein-Taybi Syndrome (RSTS). However, previous research relied on a cross-sectional study design turning into age-related comparisons of different syndromic cohorts to explore age-dependent changes. We aim to outline the variating pathways of the neuropsychiatric functioning across the lifespan in CdLS and RSTS, through the setting up of a longitudinal study design. The sample included 14 patients with CdLS and 15 with RSTS. The assessments were carried out in two different timepoints. Our findings highlight that the cognitive profile of CdLS is subjected to a worsening trend with decreasing Intellectual Quotient (IQ) scores from T0 to T1, whereas RSTS shows a stable IQ over time. Patients affected by RSTS show greater improvements compared to CdLS in communication, daily living skills, social abilities, and motor skills across the lifespan. Both syndromes report an upward trend in behavioral and emotional difficulties even if CdLS exhibit a significant and major deterioration compared to individuals with RSTS. Being aware of the early dysfunctional patterns which might pave the way for later neuropsychiatric impairments is the first step for planning preventive interventions.

Developmental environment has lasting effects on amphibian post-metamorphic behavior and thermal physiology.

Environmental challenges early in development can result in complex phenotypic trade-offs and long-term effects on individual physiology, performance and behavior, with implications for disease and predation risk. We examined the effects of simulated pond drying and elevated water temperatures on development, growth, thermal physiology and behavior in a North American amphibian, Rana sphenocephala. Tadpoles were raised in outdoor mesocosms under warming and drying regimes based on projected climatic conditions in 2070. We predicted that amphibians experiencing the rapid pond drying and elevated pond temperatures associated with climate change would accelerate development, be smaller at metamorphosis and demonstrate long-term differences in physiology and exploratory behavior post-metamorphosis. Although both drying and warming accelerated development and reduced survival to metamorphosis, only drying resulted in smaller animals at metamorphosis. Around 1 month post-metamorphosis, animals from the control treatment jumped relatively farther at high temperatures in jumping trials. In addition, across all treatments, frogs with shorter larval periods had lower critical thermal minima and maxima. We also found that developing under warming and drying resulted in a less exploratory behavioral phenotype, and that drying resulted in higher selected temperatures in a thermal gradient. Furthermore, behavior predicted thermal preference, with less exploratory animals selecting higher temperatures. Our results underscore the multi-faceted effects of early developmental environments on behavioral and physiological phenotypes later in life. Thermal preference can influence disease risk through behavioral thermoregulation, and exploratory behavior may increase risk of predation or pathogen encounter. Thus, climatic stressors during development may mediate amphibian exposure and susceptibility to predators and pathogens into later life stages.

Exploring the Effect of the Dynamics of Behavioral Phenotypes on Health Outcomes in an mHealth Intervention for Childhood Obesity: Longitudinal Observational Study.

BACKGROUND: Advancements in mobile health technologies and machine learning approaches have expanded the framework of behavioral phenotypes in obesity treatment to explore the dynamics of temporal changes. OBJECTIVE: This study aimed to investigate the dynamics of behavioral changes during obesity intervention and identify behavioral phenotypes associated with weight change using a hybrid machine learning approach. METHODS: In total, 88 children and adolescents (ages 8-16 years; 62/88, 71% male) with age- and sex-specific BMI ≥85th percentile participated in the study. Behavioral phenotypes were identified using a hybrid 2-stage procedure based on the temporal dynamics of adherence to the 5 behavioral goals during the intervention. Functional principal component analysis was used to determine behavioral phenotypes by extracting principal component factors from the functional data of each participant. Elastic net regression was used to investigate the association between behavioral phenotypes and weight change. RESULTS: Functional principal component analysis identified 2 distinctive behavioral phenotypes, which were named the high or low adherence level and late or early behavior change. The first phenotype explained 47% to 69% of each factor, whereas the second phenotype explained 11% to 17% of the total behavioral dynamics. High or low adherence level was associated with weight change for adherence to screen time (ß=-.0766, 95% CI -.1245 to -.0312), fruit and vegetable intake (ß=.1770, 95% CI .0642-.2561), exercise (ß=-.0711, 95% CI -.0892 to -.0363), drinking water (ß=-.0203, 95% CI -.0218 to -.0123), and sleep duration. Late or early behavioral changes were significantly associated with weight loss for changes in screen time (ß=.0440, 95% CI .0186-.0550), fruit and vegetable intake (ß=-.1177, 95% CI -.1441 to -.0680), and sleep duration (ß=-.0991, 95% CI -.1254 to -.0597). CONCLUSIONS: Overall level of adherence, or the high or low adherence level, and a gradual improvement or deterioration in health-related behaviors, or the late or early behavior change, were differently associated with weight loss for distinctive obesity-related lifestyle behaviors. A large proportion of health-related behaviors remained stable throughout the intervention, which indicates that health care professionals should closely monitor changes made during the early stages of the intervention. TRIAL REGISTRATION: Clinical Research Information Science KCT0004137; https://tinyurl.com/ytxr83ay.

The Role of Smad2 in Adult Neuroplasticity as Seen through Hippocampal-Dependent Spatial Learning/Memory and Neurogenesis.

Adult neural plasticity is an important and intriguing phenomenon in the brain, and adult hippocampal neurogenesis is directly involved in modulating neural plasticity by mechanisms that are only partially understood. We have performed gain-of-function and loss-of-function experiments to study Smad2, a transcription factor selected from genes that are demethylated after exercise through the analysis of an array of physical activity-induced factors, and their corresponding gene expression, and an efficient inducer of plasticity. In these studies, changes in cell number and morphology were analyzed in the hippocampal dentate gyrus (cell proliferation and survival, including regional distribution, and structural maturation/differentiation, including arborization, dendritic spines, and neurotransmitter-specific vesicles) of sedentary male mice, after evaluation in a battery of behavioral tests. As a result, we reveal a role for Smad2 in the balance of proliferation versus maturation of differentiating immature cells (Smad2 silencing increases both the proliferation and survival of cycling cells in the dentate granule cell layer), and in the plasticity of both newborn and mature neurons in mice (by decreasing dendritic arborization and dendritic spine number). Moreover, Smad2 silencing specifically compromises spatial learning in mice (through impairments of spatial tasks acquisition both in long-term learning and working memory). These data suggest that Smad2 participates in adult neural plasticity by influencing the proliferation and maturation of dentate gyrus neurons.SIGNIFICANCE STATEMENT Smad2 is one of the main components of the transforming growth factor-ß (TGF-ß) pathway. The commitment of cell fate in the nervous system is tightly coordinated by SMAD2 signaling, as are further differentiation steps (e.g., dendrite and axon growth, myelination, and synapse formation). However, there are no studies that have directly evaluated the role of Smad2 gene in hippocampus of adult animals. Modulation of these parameters in the adult hippocampus can affect hippocampal-dependent behaviors, which may shed light on the mechanisms that regulate adult neurogenesis and behavior. We demonstrate here a role for Smad2 in the maturation of differentiating immature cells and in the plasticity of mature neurons. Moreover, Smad2 silencing specifically compromises the spatial learning abilities of adult male mice.

Neurocognitive and neurobehavioral characterization of two frequent forms of neurodevelopmental disorders: the DYRK1A and the Wiedemann-Steiner syndromes.

DYRK1A and Wiedemann-Steiner syndromes (WSS) are two genetic conditions associated with neurodevelopmental disorders (NDDs). Although their clinical phenotype has been described, their behavioral phenotype has not systematically been studied using standardized assessment tools. To characterize the latter, we conducted a retrospective study, collecting data on developmental history, autism spectrum disorder (ASD), adaptive functioning, behavioral assessments, and sensory processing of individuals with these syndromes (n = 14;21). In addition, we analyzed information collected from families (n = 20;20) using the GenIDA database, an international patient-driven data collection aiming to better characterize natural history of genetic forms of NDDs. In the retrospective study, individuals with DYRK1A syndrome showed lower adaptive behavior scores compared to those with WSS, whose scores showed greater heterogeneity. An ASD diagnosis was established for 57% (8/14) of individuals with DYRK1A syndrome and 24% (5/21) of those with WSS. Language and communication were severely impaired in individuals with DYRK1A syndrome, which was also evident from GenIDA data, whereas in WSS patients, exploration of behavioral phenotypes revealed the importance of anxiety symptomatology and ADHD signs, also flagged in GenIDA. This study, describing the behavioral and sensorial profiles of individuals with WSS and DYRK1A syndrome, highlighted some specificities important to be considered for patients' management.

The behavioral phenotype of Rubinstein-Taybi syndrome: A scoping review of the literature.

Rubinstein-Taybi syndrome (RTS) is a rare genetic syndrome associated with growth delay, phenotypic facial characteristics, microcephaly, developmental delay, broad thumbs, and big toes. Most research on RTS has focused on the genotype and physical phenotype; however, several studies have described behavioral, cognitive, social, and emotional characteristics, elucidating the behavioral phenotype of RTS. The reporting of this review was informed by PRISMA guidelines. A systematic search of CINAHL, Medline, and PsychINFO was carried out in March 2021 to identify group studies describing behavioral, cognitive, emotional, psychiatric, and social characteristics in RTS. The studies were quality appraised. Characteristics reported include repetitive behavior, behaviors that challenge, intellectual disability, mental health difficulties, autism characteristics, and heightened sociability. Findings were largely consistent across studies, indicating that many characteristics are likely to form part of the behavioral phenotype of RTS. However, methodological limitations, such as a lack of appropriate comparison groups and inconsistency in measurement weaken these conclusions. There is a need for multi-disciplinary studies, combining genetic and psychological measurement expertise within single research studies. Recommendations are made for future research studies in RTS.

Hormones do not maketh the mole-rat: No steroid hormone signatures of subordinate behavioral phenotypes.

In some cooperatively breeding groups, individuals have distinct behavioral characteristics that are often stable and predictable across time. However, in others, as in the eusocial naked mole-rat, evidence for behavioral phenotypes is ambiguous. Here, we study whether the naked mole-rat can be divided into discrete phenotypes and if circulating hormone concentrations underpin these differences. Naked mole-rat colonies consist of a single breeding female and large numbers of non-reproductive subordinates that in some cases can exceed several hundred in a colony. The subordinates can potentially be divided into soldiers, who defend the colony; workers, who maintain it; and dispersers, who want to leave it. We established six colonies de novo, tracked them over three years, and assessed the behavior and hormone concentrations of the subordinates. We found that soldiers tended to be from earlier litters and were higher ranked compared to workers, whereas dispersers were distributed throughout litters and rankings. There was no difference in estradiol, testosterone, or dehydroepiandrosterone (DHEA) concentrations among phenotypes. Progesterone concentrations were higher in soldiers, but this difference appeared to be driven by a few individuals. Principal component analysis demonstrated that soldiers separated into a discrete category relative to workers/dispersers, with the highest ranked loadings being age, body mass, and testosterone concentrations. However, the higher testosterone in soldiers was correlated with large body size instead of strictly behavioral phenotype. Workers and dispersers have more overlap with each other and no hormonal differences. Thus the behavioral variation in subordinate naked mole-rats is likely not driven by circulating steroid hormone concentrations, but rather it may stem from alternative neural and/or neuroendocrine mechanisms.

Assessment of intellectual impairment, health-related quality of life, and behavioral phenotype in patients with neurotransmitter related disorders: Data from the iNTD registry.

Inherited disorders of neurotransmitter metabolism are a group of rare diseases, which are caused by impaired synthesis, transport, or degradation of neurotransmitters or cofactors and result in various degrees of delayed or impaired psychomotor development. To assess the effect of neurotransmitter deficiencies on intelligence, quality of life, and behavior, the data of 148 patients in the registry of the International Working Group on Neurotransmitter Related Disorders (iNTD) was evaluated using results from standardized age-adjusted tests and questionnaires. Patients with a primary disorder of monoamine metabolism had lower IQ scores (mean IQ 58, range 40-100) within the range of cognitive impairment (<70) compared to patients with a BH4 deficiency (mean IQ 84, range 40-129). Short attention span and distractibility were most frequently mentioned by parents, while patients reported most frequently anxiety and distractibility when asked for behavioral traits. In individuals with succinic semialdehyde dehydrogenase deficiency, self-stimulatory behaviors were commonly reported by parents, whereas in patients with dopamine transporter deficiency, DNAJC12 deficiency, and monoamine oxidase A deficiency, self-injurious or mutilating behaviors have commonly been observed. Phobic fears were increased in patients with 6-pyruvoyltetrahydropterin synthase deficiency, while individuals with sepiapterin reductase deficiency frequently experienced communication and sleep difficulties. Patients with BH4 deficiencies achieved significantly higher quality of life as compared to other groups. This analysis of the iNTD registry data highlights: (a) difference in IQ and subdomains of quality of life between BH4 deficiencies and primary neurotransmitter-related disorders and (b) previously underreported behavioral traits.

Ed Zigler's developmental approach to intellectual disabilities: Past, present, and future contributions.

Comprising two parts, Ed Zigler's developmental approach has greatly influenced how one conceptualizes children with intellectual disabilities (ID). In part one, Zigler championed a "two-group approach" concerning the cause of children's ID. He distinguished persons with a clear, organic cause of their ID from those displaying no clear cause. Members of this "organic" group often displayed IQs below 50 and co-occurring physical-medical conditions. The second, "cultural-familial" group, mostly showed IQs of 50-70, did not possess co-occurring physical or health problems, and often came from families of lower IQs and lower socioeconomic status. While the presence of these two groups has been supported, recent advances have also further differentiated the organic group, mostly in relation to behavioral phenotypes of persons with several genetic etiologies. In part two, Zigler championed the child with ID as a "whole person." Originally focused on the child's reactions to social deprivation and failure, recent studies directly examine parent-child, within-family, and wider system interactions throughout the life span. For decades a force within the ID field, Zigler's developmental approach to children with ID continues to influence researchers, interventionists, and policymakers.

Variability in Behavioral Phenotypes after Forced Swimming-Induced Stress in Rats Is Associated with Expression of the Glucocorticoid Receptor, Nurr1, and IL-1ß in the Hippocampus.

Individual differences in coping with stress may determine either a vulnerable or resilient phenotype. Therefore, it is important to better understand the biology underlying the behavioral phenotype. We assessed whether individual behavioral phenotype to acute stress is related with the hippocampal expression of glucocorticoid receptor (GR), Nurr1, interleukin-1 beta (IL-1ß) or brain-derived neurotrophic factor (BDNF). Wistar male rats were exposed to forced swimming for 15 min and sacrificed at different times. Behavioral response was analyzed, and it was compared with the gene and protein expression of GR, Nurr1, IL-1ß and BDNF in the hippocampus for each time point. Behavioral phenotyping showed a group with high immobility (vulnerable) while another had low immobility (resilient). No significant differences were found in the Nurr1, IL-1ß and BDNF mRNA levels between resilient and vulnerable rats at different recovery times except for Nr3c1 (gene for GR). However, exposure to stress caused significantly higher levels of GR, Nurr1 and IL-1ß proteins of vulnerable compared to resilient rats. This variability of behavioral phenotypes is associated with a differential molecular response to stress that involves GR, Nurr1, and IL-1ß as mediators in coping with stress. This contributes to identifying biomarkers of susceptibility to stress.

Effect of Mild Traumatic Brain Injury on Behavioral Reactions and Neocortical Morphology in Rats.

The original weight-drop model was employed to examine the effect of mild traumatic brain injury (TBI) on behavioral phenotype and neocortical morphology in rats. The neurological examination of rats with moderate TBI revealed the focal symptoms corresponding to pronounced neurological disorders, whereas in rats after mild TBI, there were only minor coordination disorders. On day 7 after injury, the rats with mild TBI demonstrated enhanced anxiety assessed by conditioned passive avoidance response. The morphometric analysis of the brain tissues revealed narrowing of the capillaries and increased score of hyperchromic neocortical neurons, which attested to cerebral hypoxia. The manifestations of mild TBI in original rat model demonstrated a close similarity to the symptoms of TBI in humans.

Application of animal experimental models in the research of schizophrenia.

Schizophrenia is a relatively common but serious mental illness that results in a heavy burden to patients, their families, and society. The disease can be triggered by multiple factors, while the specific pathogenesis remains unclear. The development of effective therapeutic drugs for schizophrenia relies on a comprehensive understanding of the basic biology and pathophysiology of the disease. Therefore, effective animal experimental models play a vital role in the study of schizophrenia. Based on different molecular mechanisms and modeling methods, the currently used experimental animal experimental models of schizophrenia can be divided into four categories that can better simulate the clinical symptoms and the interplay between susceptible genes and the environment: neurodevelopmental, drug-induced, genetic-engineering, and genetic-environmental interaction of animal experimental models. Each of these categories contains multiple subtypes, which has its own advantages and disadvantages and therefore requires careful selection in a research application. The emergence and utilization of these models are promising in the prediction of the risk of schizophrenia at the molecular level, which will shed light on effective and targeted treatment at the genetic level.

Behavioral and neurochemical characterization of the spontaneous mutation tremor, a new mouse model of audiogenic seizures.

The tremor mutant phenotype results from an autosomal recessive spontaneous mutation arisen in a Swiss-Webster mouse colony. The mutant mice displayed normal development until three weeks of age when they began to present motor impairment comprised by whole body tremor, ataxia, and decreased exploratory behavior. These features increased in severity with aging suggesting a neurodegenerative profile. In parallel, they showed audiogenic generalized clonic seizures. Results from genetic mapping identified the mutation tremor on chromosome 14, in an interval of 5 cM between D14Mit37 (33.21 cM) and D14Mit115 (38.21 cM), making Early Growth Response 3 (Egr3) the main candidate gene. Comparing with wild type (WT) mice, the tremor mice showed higher hippocampal gene expression of Egr3 and Gabra1 and increased concentrations of noradrenalin (NOR; p = .0012), serotonin (5HT; p = .0083), 5-hydroxyindoleacetic acid (5-HIAA; p = .0032), γ-amino butyric acid (GABA; p = .0123), glutamate (p = .0217) and aspartate (p = .0124). In opposition, the content of glycine (p = .0168) and the vanillylmandelic acid (VMA)/NOR ratio (p = .032) were decreased. Regarding to dopaminergic system, neither dopamine (DA) and 3,4-dihydroxyphenylacetic acid (DOPAC) contents nor the turnover rate of DA showed statistically significant differences between WT and mutant mice. Data demonstrated that audiogenic seizures of tremor mice are associated with progressive motor impairment as well as to hippocampal alterations of the Egr3 and Gabra1 gene expression and amino acid and monoamine content. In addition, the tremor mice could be useful for study of neurotransmission pathways as modulators of epilepsy and the pathogenesis of epilepsies occurring with generalized clonic seizures.

Post-acquisition effects of viruses on vector behavior are important components of manipulation strategies.

A growing number of studies suggest that plant viruses manipulate host plant phenotypes to increase transmission-conducive behaviors by vectors. Studies on this phenomenon frequently omit examination of interactions that occur after vectors acquire virions, which provides an incomplete understanding of the ecology of plant virus manipulation. Here, by taking a full factorial approach that considered both the infection status of the host (Montia perfoliata) and viruliferous status of the aphid (Myzus persicae), we explored the effects of a circulative, non-propagative virus (Turnip yellows virus [TuYV]) on a suite of behavior and performance metrics that are relevant for virus transmission. Our results demonstrate that viruliferous aphids exhibited an increased velocity of movement and increased activity levels in locomotor and dispersal-retention assays. They also had increased fecundity and showed a capacity to more efficiently exploit resources by taking less time to reach the phloem and ingesting more sap, regardless of plant infection status. In contrast, non-viruliferous aphids only exhibited enhanced fecundity and biomass on TuYV-infected hosts, and had overall reduced dispersal and locomotor activity relative to viruliferous aphids. In this pathosystem, post-acquisition effects were stronger and more conducive to virus transmission than the purely pre-acquisition effects mediated by virus effects on the host plant. Our study provides additional support for the hypothesis that virus manipulation of vector behavior includes both pre- and post-acquisition effects and demonstrates the importance of considering both components when studying putative virus manipulation strategies.

Profile repeatability: A new method for evaluating repeatability of individual hormone response profiles.

There is broad interest in determining repeatability of individual responses. Current methods calculate repeatability of individual points (initial and/or peak), time to peak value, or a single measure of the integrated total response (area under the curve), rather than the shape of the response profile. Repeatability estimates of response profiles using linear mixed models (LMM) generate an average repeatability for an aggregate of individuals, rather than an estimate of individual repeatability. Here we use a novel ad hoc method to calculate repeatability of individual response profiles and demonstrate the need for a more rigorous assessment protocol. Response profile repeatability has not been defined at the individual level. We do this using a new metric, Profile Repeatability (PR), which incorporates components of variance and the degree to which response profiles cross each other in a time series. Values range from 0 (no repeatability) to 1 (complete repeatability). We created synthetic data to represent a range of apparent time series repeatability, and 20 independent observers visually ranked those data sets by degree of repeatability. We also applied the method to real data on stress responses of European starlings Sturnus vulgaris. We then computed PR scores for the synthetic data and for real data from European starling corticosterone responses over time, and contrast the results to those from LMM. Finally, we assessed the sensitivity of PR to reductions in the number of time points in the corticosterone response, as well as reductions in the number of replicates per individual. We found the average PR scores for a group of individuals to be somewhat robust to reductions in points in the time series; however, the ranks of individuals (PR values relative to one another) could change substantially with reduction in the number of values in a time series. PR showed threshold sensitivity to losing replicate time series between 6 and 4 replicates. Surprisingly, human observers fell into two disparate groups when ranking repeatability of the synthetic data, and the PR score indicated that human observers may underestimate repeatability of data where replicates cross each other. In contrast to the average profile repeatability estimated using LMMs, our approach calculates individual repeatability. From our perspective, LMM does not provide a definitive idea of repeatability at the individual level; in essence, it concludes that suites of time series with low within-individual variance has high repeatability, regardless of replicate trajectories. LMM and PR have non-linear relationships between 0 and 1, but PR has greater discrimination for mid-values of repeatability. Consistent average group repeatability can be associated with substantial differences in individual ranks suggests that estimating individual repeatability is critical. The PR score should be useful in comparing repeatability of any type of nonlinear, including non-monotonic, response profiles over time, which are common in both physiology and behavior, and it demonstrates the specific needs for future improvements of a profile repeatability metric.

A review of joint attention and social-cognitive brain systems in typical development and autism spectrum disorder.

This article provides a review of the increasingly detailed imaging literature on the neurodevelopment of joint attention. Many findings from this literature support and inform the hypothesis that the neurodevelopment of joint attention contributes to the functional development of neural systems for human social cognition. Joint attention begins to develop by 5 months of age and is tantamount to the ability to adopt a common perspective with another person. It involves a whole-brain system with nodes in the: (a) dorsal and medial frontal cortex, (b) orbital frontal/insula cortex, (c) anterior/posterior cingulate cortex, (d) superior temporal cortex, (e) precuneus/parietal cortex, and (f) amygdala and striatum. This system integrates triadic information processing about (a) self-attention/action, (b) information about others' attention/action during social interactions that involve, (c) coordinated attention as well as processing a common referent in space. The results of this new imaging literature have the potential to advance current models of social cognition and the social brain, which rarely consider the contribution of the cognitive neurodevelopment of joint attention. The new neuroscience of joint attention is also extremely valuable for clinical research on social-cognitive neurodevelopmental disorders. This is most clearly the case for autism spectrum disorder (ASD) because it is consistent with the hypothesis of substantial functional neurodevelopmental continuity between the preschool impairments of joint attention, and childhood theory of mind ability that characterizes the development of ASD.

Rubinstein-Taybi syndrome: New neuroradiological and neuropsychiatric insights from a multidisciplinary approach.

Rubinstein-Taybi syndrome is a rare, autosomal dominant, plurimalformative disorder that is clinically characterized by intellectual disability and a wide spectrum of congenital anomalies; facial dysmorphisms are typical, and broad thumbs and great toes are particularly distinctive. Its genetic basis is only partially known, with a detection rate of approximately 65-70%; specifically, microdeletions or mutations in the CREBBP or EP300 genes can be found. Much is known about its clinical features and health-care protocols, but some areas of clinical knowledge are currently unsolved. In particular, few efforts have been made until now to understand the variability in the neuropsychological and neurobehavioral profile and to deepen knowledge of the neuroradiological malformative pattern. Consequently, little is known about the possible genotype-phenotype correlations of these issues. Here, we report clinical and genetic data from a cohort of 23 RSTS Italian patients. The most common features in brain magnetic resonance imaging (MRI) were dysmorphic aspects of the corpus callosum (73.6%) with or without minor dysmorphisms of cerebellar vermis, periventricular posterior white matter hyperintensity, and other less common anomalies. The most interesting feature on the whole spine MRI scans was the tendency for a low-lying conus medullaris without terminal filum thickening. These data will help to improve neuropsychiatric and neuroradiological knowledge and highlight specific genotype-phenotype correlations.