Development of the Ontogenetic Self-Regulation Clock.

To date, there is no overarching proposition for the ontogenetic-neurobiological basis of self-regulation. This paper suggests that the balanced self-regulatory reaction of the fetus, newborn and infant is based on a complex mechanism starting from early brainstem development and continuing to progressive control of the cortex over the brainstem. It is suggested that this balance occurs through the synchronous reactivity between the sympathetic and parasympathetic systems, both which originate from the brainstem. The paper presents an evidence-based approach in which molecular excitation-inhibition balance, interchanges between excitatory and inhibitory roles of neurotransmitters as well as cardiovascular and white matter development across gestational ages, are shown to create sympathetic-parasympathetic synchrony, including the postnatal development of electroencephalogram waves and vagal tone. These occur in developmental milestones detectable in the same time windows (sensitive periods of development) within a convergent systematic progress. This ontogenetic stepwise process is termed "the self-regulation clock" and suggest that this clock is located in the largest connection between the brainstem and the cortex, the corticospinal tract. This novel evidence-based new theory paves the way towards more accurate hypotheses and complex studies of self-regulation and its biological basis, as well as pointing to time windows for interventions in preterm infants. The paper also describes the developing indirect signaling between the suprachiasmatic nucleus and the corticospinal tract. Finally, the paper proposes novel hypotheses for molecular, structural and functional investigation of the "clock" circuitry, including its associations with other biological clocks. This complex circuitry is suggested to be responsible for the developing self-regulatory functions and their neurobehavioral correlates.

Cheating behavior in children: Integrating gaze allocation and social awareness.

Children's cheating and factors supporting honesty are not well understood. The current work explored variables involved in children's cheating through eye-tracking and an implicit manipulation in which extrinsic awareness of the effects of one's behaviors on others was primed. Participants played a computer game with the option for a monetary gain in which they could earn more if they selectively erred in response to more profitable stimuli. Results show that children cheat by making selective effort toward more profitable errors; however, extrinsic awareness inhibits these cheating behaviors. Importantly, gaze toward children's earnings mediates this relationship, suggesting that extrinsic awareness mitigates an impulsive looking pattern, which in turn results in less cheating. Findings suggest that an implicit manipulation, highlighting the potential implications of one's actions for others, seems to effectively suppress cheating among children. Furthermore, attention toward earnings offers a cognitive process that acts to mediate the effect of this manipulation on cheating. Taken together, this framework suggests psychoneurocognitive and social processes that influence cheating in children, offering a direction for future implicit intervention techniques to support honest performance.

Feeding Imprinting: The Extreme Test Case of Premature Infants Born With Very Low Birth Weight.

Feeding imprinting, considered a survival-enabling process, is not well understood. Infants born very preterm, who first feed passively, are an effective model for studying feeding imprinting. Retrospective analysis of neonatal intensive care unit (NICU) records of 255 infants (Mgestational age  = 29.98 ± 1.64) enabled exploring the notion that direct breastfeeding (DBF) during NICU stay leads to consumption of more mother's milk and earlier NICU discharge. Results showed that DBF before the first bottle feeding is related to shorter transition into oral feeding, a younger age of full oral feeding accomplishment and earlier discharge. Furthermore, the number of DBF meals before first bottle feeding predicts more maternal milk consumption and improved NICU outcomes. Improved performance in response to initial exposure to DBF at the age of budding feeding abilities supports a feeding imprinting hypothesis.

Brainstem as a developmental gateway to social attention.

BACKGROUND: Evolution preserves social attention due to its key role in supporting survival. Humans are attracted to social cues from infancy, but the neurobiological mechanisms for the development of social attention are unknown. An evolutionary-based, vertical-hierarchical theoretical model of self-regulation suggests that neonatal brainstem inputs are key for the development of well-regulated social attention. METHODS: Neonates born preterm (N = 44, GA 34 w.) were recruited and diagnosed at birth as a function of their auditory brainstem evoked responses (ABR). Participants enrolled in a prospective 8-year-long, double-blind, follow-up study comparing participants with brainstem dysfunctions and well-matched controls. Groups had comparable fetal, neonatal, and familial characteristics. Methods incorporated EEG power analysis and gaze tracking during the Attention Network Test (ANT, four cue types, and two targets) and a Triadic Gaze Engagement task (TGE, three social cue levels). RESULTS: Results showed that neonatal brainstem compromise is related to long-term changes in Alpha- and Theta-band power asymmetries (p < .034, p < .016, respectively), suggesting suppressed bottom-up input needed to alert social attention. Gaze tracking indicated dysregulated arousal-modulated attention (p < .004) and difficulty in gaze engagement to socially neutral compared to nonsocial cues (p < .012). CONCLUSIONS: Integrating models of Autism and cross-species data with current long-term follow-up of infants with discrete neonatal brainstem dysfunction suggests neonatal brainstem input as a gateway for bottom-up regulation of social attention.

Hot executive control and response to a stimulant in a double-blind randomized trial in children with ADHD.

Attention deficit hyperactivity disorder (ADHD) is thought to involve an executive inhibitory control (IC) deficit, yet it is not clear if this is a general deficit affecting both cold and hot EC, and if methylphenidate (MPH) affects both systems in treated children. We explored this by using a Stroop-like task in children with ADHD as compared to controls, containing different types of emotional stimuli (six levels), and we investigated the role of intervention with MPH on IC as compared to placebo. Children with ADHD and controls (N = 40; 7-13 years old) were tested with a hot and cold Stroop-like task. This was followed by a double-blind placebo-controlled crossover trial of the effect of MPH on these skills. Children with ADHD showed a specific difficulty inhibiting their responses, particularly to hot, angry and frustration-inducing stimuli. Further, treatment with MPH was effective in reducing errors toward frustration-inducing stimuli as compared to placebo (p < .05, η 2 = .347), particularly with repeated exposure to the stimuli. Results indicate that children with ADHD experience executive control difficulties, particularly in hot negative emotional contexts. These emotion regulation difficulties are amenable to stimulant intervention.

Reward Dependence and Harm Avoidance among Patients with Binge-Purge Type Eating Disorders.

INTRODUCTION: The Cloninger's Psychobiological Model of Temperament and Character includes temperamental dimensions such as reward dependence (RD) and harm avoidance (HA). Studies of RD differentiate between sensitivity to reward (SR) versus to punishment (SP). We investigated the interrelationship between HA and RD in acutely ill patients with binge/purge (B/P) type eating disorders (EDs) and following symptomatic stabilization. METHODS: Fifty patients with B/P EDs were assessed at admission to inpatient treatment, 36 of whom were reassessed at discharge. Thirty-six controls were similarly assessed. Participants completed Tridimensional Personality Questionnaire (TPQ), Sensitivity to Punishment and Sensitivity to Reward Questionnaire (SPSRQ), and took the Gambling Task. RESULTS: Patients with B/P EDs had higher TPQ-RD and lower TPQ-HA accompanied by lower SPSRQ-SR and SPSRQ-SP. SPSRQ-SP correlated positively and negatively with TPQ-HA and TPQ-RD, respectively. CONCLUSIONS: Combination of lower TPQ-HA, lower SPSRQ-SP, and greater risk-taking inclination may maintain disordered eating in patients with B/P EDs. Copyright © 2017 John Wiley & Sons, Ltd and Eating Disorders Association.

Memory outcomes following cognitive interventions in children with neurological deficits: A review with a focus on under-studied populations.

Given the primary role of memory in children's learning and well-being, the aim of this review was to examine the outcomes of memory remediation interventions in children with neurological deficits as a function of the affected memory system and intervention method. Fifty-seven studies that evaluated the outcome of memory interventions in children were identified. Thirty-four studies met the inclusion criteria, and were included in a systematic review. Diverse rehabilitation methods for improving explicit and implicit memory in children were reviewed. The analysis indicates that teaching restoration strategies may improve, and result in the generalisation of, semantic memory and working memory performance in children older than 7 years with mild to moderate memory deficits. Factors such as longer protocols, emotional support, and personal feedback contribute to intervention efficacy. In addition, the use of compensation aids seems to be highly effective in prospective memory tasks. Finally, the review unveiled a lack of studies with young children and the absence of group interventions. These findings point to the importance of future evidence-based intervention protocols in these areas.

Contemplating the GANE model using an extreme case paradigm.

Early experiences play a crucial role in programming brain function, affecting selective attention, learning, and memory. Infancy literature suggests an extension of the GANE (glutamate amplifies noradrenergic effects) model to conditions with minimal priority-map inputs, yet suggests qualifications by noting that its efficacy is increased when tonic levels of arousal are maintained in an optimal range, in manners that are age and exposure dependent.

Auditory verbal memory and psychosocial symptoms are related in children with idiopathic epilepsy.

OBJECTIVE: Idiopathic epilepsies are considered to have relatively good prognoses and normal or near normal developmental outcomes. Nevertheless, accumulating studies demonstrate memory and psychosocial deficits in this population, and the prevalence, severity and relationships between these domains are still not well defined. We aimed to assess memory, psychosocial function, and the relationships between these two domains among children with idiopathic epilepsy syndromes using an extended neuropsychological battery and psychosocial questionnaires. METHODS: Cognitive abilities, neuropsychological performance, and socioemotional behavior of 33 early adolescent children, diagnosed with idiopathic epilepsy, ages 9-14years, were assessed and compared with 27 age- and education-matched healthy controls. RESULTS: Compared to controls, patients with stabilized idiopathic epilepsy exhibited higher risks for short-term memory deficits (auditory verbal and visual) (p<0.0001), working memory deficits (p<0.003), auditory verbal long-term memory deficits (p<0.0021), and more frequent psychosocial symptoms (p<0.0001). The severity of auditory verbal memory deficits was related to severity of psychosocial symptoms among the children with epilepsy but not in the healthy controls. SIGNIFICANCE: Results suggest that deficient auditory verbal memory may be compromising psychosocial functioning in children with idiopathic epilepsy, possibly underscoring that cognitive variables, such as auditory verbal memory, should be assessed and treated in this population to prevent secondary symptoms.

Brain Plasticity following Intensive Bimanual Therapy in Children with Hemiparesis: Preliminary Evidence.

Neuroplasticity studies examining children with hemiparesis (CH) have focused predominantly on unilateral interventions. CH also have bimanual coordination impairments with bimanual interventions showing benefits. We explored neuroplasticity following hand-arm bimanual intensive therapy (HABIT) of 60 hours in twelve CH (6 females, mean age 11 ± 3.6 y). Serial behavioral evaluations and MR imaging including diffusion tensor (DTI) and functional (fMRI) imaging were performed before, immediately after, and at 6-week follow-up. Manual skills were assessed repeatedly with the Assisting Hand Assessment, Children's Hand Experience Questionnaire, and Jebsen-Taylor Test of Hand Function. Beta values, indicating the level of activation, and lateralization index (LI), indicating the pattern of brain activation, were computed from fMRI. White matter integrity of major fibers was assessed using DTI. 11/12 children showed improvement after intervention in at least one measure, with 8/12 improving on two or more tests. Changes were retained in 6/8 children at follow-up. Beta activation in the affected hemisphere increased at follow-up, and LI increased both after intervention and at follow-up. Correlations between LI and motor function emerged after intervention. Increased white matter integrity was detected in the corpus callosum and corticospinal tract after intervention in about half of the participants. Results provide first evidence for neuroplasticity changes following bimanual intervention in CH.

Neonatal brainstem dysfunction after preterm birth predicts behavioral inhibition.

BACKGROUND: Behavioral inhibition (BI), the tendency to withdraw or exhibit negative affect when experiencing stressful situations, is a major risk factor for the development of social anxiety. However, neonatal biologic origins of this progression are still unknown. Click here to enter text.This study aimed to extend frameworks of behavioral inhibition by exploring empirically the central role of neonatal brainstem electrophysiologic functions in the development of social disengagement and BI. METHODS: Sixty-six preterm neonates (means ±SD: gestation age = 33.1 ± 1.22 weeks, birth weight = 1775 + 346.7 g; 51% female) participated in a prospective longitudinal study. The infants were tested within the first 2 weeks of postnatal life using an auditory brainstem-evoked response test. Based on the typicality of the major ABR wave latencies, waves I, III and V, neonates were divided into two groups (compromised, CBSF- with at least one component ≥1.5 SDs from the mean for the respective gestation age; normal, NBSF, with all components within 1.5 SD around the mean), and were enrolled in a prospective longitudinal follow-up study. This report extends previous work from 4 m by testing responses to socioemotional challenges during the Separation-Reunion paradigm at 12 m. RESULTS: Results show that infants with neonatal CBSF were more susceptible to be classified as BI at 12 m (age corrected for prematurity) than infants with NBSF (66% vs. 40%, respectively). The most striking symptom in the CBSF group was a disability to initiate self-regulatory activities in response to a socioemotional challenge, resulting in frequent passivity/dependency (p < .001). Statistical regression analysis revealed that face-to-face gaze engagement at 4 m moderates the risk related to neonatal CBSF for the emergence of BI at 12 m, but did not overturn the emergence of BI. CONCLUSION: Results support the hypothesis that neonatal brainstem dysfunction canalizes behavioral inhibition. These findings highlight, for the first time, the role of the early developing brainstem in later development of BI and in abilities to initiate self-regulatory behavior.

Asymmetric attention networks: the case of children.

Visuospatial attention-networks are represented in both hemispheres, with right-hemisphere dominance in adults. Little is known about the lateralization of the attentional-networks in children. To assess the lateralization of attentional-networks in children aged 5 years, performance on a Lateralized-Attention-Network-Test specifically designed for children (LANT-C) was compared with performance on the Attention-Network-Test for children (ANT-C). Participants were 82 children, aged 5-6 years (55% boys, middle-class, mainstream schooling). They were examined with both the ANT-C and the LANT-C along with evaluation of intelligence and attention questionnaires. Multiple analysis of variance showed a main effect for network, with high efficiency for orienting and lower executive efficiency (accuracy; p < .001; η2 = .282). An effect for procedure, elucidated higher efficiency in the ANT-C relatively to the LANT-C (accuracy; p < .01; η2 = .097). A procedure × network interaction effect was also found, showing that this procedure difference is present in the alerting and executive networks (accuracy; p < .05; η2 = .096). LANT-C analysis showed a left visual-field advantage in alerting, (accuracy; p < .05; η2 = .066), while executing with the right hand benefitted executive performance (response-time; p < .05; η2 = .06). Results extend previous findings manifesting a right-hemisphere advantage in children's alerting-attention, pointing to the importance of lateralization of brain function to the understanding of the integrity of attention-networks in children.

Diffuse excessive high signal intensity in low-risk preterm infants at term-equivalent age does not predict outcome at 1 year: a prospective study.

INTRODUCTION: The outcome of premature infants with only diffuse excessive high signal intensity (DEHSI) is not clear. We explored the relationship between DEHSI, white matter (WM) diffusion characteristics, perinatal characteristics, and neurobehavioral outcome at 1 year in a homogenous group of preterm infants without major brain abnormalities. METHODS: Fifty-eight preterm infants, gestational age 29 ± 2.6 weeks, underwent an MRI at term-equivalent age (TEA). Griffiths Mental Developmental Scales, neurological assessment, and Parental Stress Index (PSI) were performed at 1 year corrected age. These measures were compared between preterm infants according to DEHSI classification (none, mild, moderate). Diffusion tensor imaging was used in major WM volumes of interest to objectively measure the degree of WM maturation. RESULTS: No significant differences were detected in the perinatal risk characteristics, neurobehavioral outcome, and PSI at 1 year between infants with different DEHSI classifications. In infants with DEHSI, increased axial and radial diffusivities were detected in the optic radiations, centrum semiovale, and posterior limb of the internal capsule, indicating less advanced maturation of the WM. Significant correlations were detected between the time interval from birth to MRI and the WM microstructure in infants without DEHSI. CONCLUSION: DEHSI in premature infants is neither a predictive measure for short-term adverse neurobehavioral outcome nor related to perinatal risk characteristics. Extrauterine exposure time had a differential effect on WM maturational trajectories in infants with DEHSI compared to those without. We suggest DEHSI may represent an alteration in WM maturational characteristics. Further follow-up studies may verify later consequences of DEHSI in premature infants.

Vulnerabilities in social anxiety: Integrating intra- and interpersonal perspectives.

What are the major vulnerabilities in people with social anxiety? What are the most promising directions for translational research pertaining to this condition? The present paper provides an integrative summary of basic and applied translational research on social anxiety, emphasizing vulnerability factors. It is divided into two subsections: intrapersonal and interpersonal. The intrapersonal section synthesizes research relating to (a) self-representations and self-referential processes; (b) emotions and their regulation; and (c) cognitive biases: attention, interpretation and judgment, and memory. The interpersonal section summarizes findings regarding the systems of (a) approach and avoidance, (b) affiliation and social rank, and their implications for interpersonal impairments. Our review suggests that the science of social anxiety and, more generally, psychopathology may be advanced by examining processes and their underlying content within broad psychological systems. Increased interaction between basic and applied researchers to diversify and elaborate different perspectives on social anxiety is necessary for progress.

When the Mind Comes to Live Inside the Body: The Ontogeny of the Perceptual Control Clock.

In this editorial, we discuss the neurobiological processes underlying the early emergence of awareness that we term the "when" and "how" the mind comes to live inside the body. We describe an accumulative developmental process starting during embryonic life and continuing to fetal and postnatal development, of coupling of heart rate, body movements, and sleep states on the behavioral level with underlying mechanisms on the structural, functional, cellular, and molecular levels. A developmental perspective is proposed based on Perceptual Control Theory (PCT). This includes a developing sequence of modules starting from early sensing of neural intensities to early manifestation of human mindful capacities. We also address pharmacological treatments administered to preterm infants, which may interfere with this development, and highlight the need to consider this potential "side effect" of current pharmaceuticals when developing novel pharmacogenomic treatments.

Parents regulate arousal while sharing experiences with their child: a study of pupil diameter change responses.

Introduction: Parents provide their children with their first exposures to reciprocal shared experiences, and parental modeling of socio-emotional behaviors and regulatory responses largely influences their child's behavioral and neurological development. Some parental reactions are conscious, while others are non-volitional. This project aimed to explore parent-child pupil dilation change responses during shared interactions, specifically, whether parents' neuro-regulatory responses when sharing experiences with their child are different than responses of children interacting with their parents or children and adult peers sharing with each other. Methods: To test this, four distinct interacting groups were recruited: (1) Parents sharing with their child; (2) Children sharing with their parent; (3) Children sharing with peers; and (4) Adults sharing with peers. All dyads engaged in a computerized shared imagery task, which facilitates communication and mental imagery during a shared experience. During the task, pupil diameter change was recorded as a measure of regulatory response. Results: Findings highlight that parents sharing with their child have lower pupil diameter change than children sharing with their parents (p < 0.01), children sharing with peers (p < 0.01), and adults sharing with peers (p < 0.05), While no differences were seen between children sharing with parents, children sharing with peers or adults sharing with peers. Discussion: Findings deepen the understanding of the neuroscience of parenting, by suggesting that parents, even of older children and adolescents, tend to regulate their arousal when interacting with their child, a response that proves to be unique compared to other dyad types for sharing experiences. Considering this dynamic, findings may direct future parent-led intervention methods to improve the child's socio-emotional development.

Missed meal boluses and poorer glycemic control impact on neurocognitive function may be associated with white matter integrity in adolescents with type 1 diabetes.

Background: The notion that pediatric type 1 diabetes impacts brain function and structure early in life is of great concern. Neurological manifestations, including neurocognitive and behavioral symptoms, may be present from childhood, initially mild and undetectable in daily life. Despite intensive management and technological therapeutic interventions, most pediatric patients do not achieve glycemic control targets for HbA1c. One of the most common causes of such poor control and frequent transient hyperglycemic episodes may be lifestyle factors, including missed meal boluses. Objective: The aim of this study was to assess the association between specific neurocognitive accomplishments-learning and memory, inhibition ability learning, and verbal and semantic memory-during meals with and without bolusing, correlated to diffusion tensor imaging measurements of major related tracts, and glycemic control in adolescents with type 1 diabetes compared with their healthy siblings of similar age. Study design and methods: This is a case-control study of 12- to 18-year-old patients with type 1 diabetes (N = 17, 8 male patients, diabetes duration of 6.53 ± 4.1 years) and their healthy siblings (N = 13). All were hospitalized for 30 h for continuous glucose monitoring and repeated neurocognitive tests as a function of a missed or appropriate pre-meal bolus. This situation was mimicked by controlled, patient blinded manipulation of lunch pre-meal bolus administration to enable capillary glucose level of <180 mg/dl and to >240 mg/d 2 hours after similar meals, at a similar time. The diabetes team randomly and blindly manipulated post-lunch glucose levels by subcutaneous injection of either rapid-acting insulin or 0.9% NaCl solution before lunch. A specific neurocognitive test battery was performed twice, after each manipulation, and its results were compared, along with additional neurocognitive tasks administered during hospitalization without insulin manipulation. Participants underwent brain imaging, including diffusion tensor imaging and tractography. Results: A significant association was demonstrated between glycemic control and performance in the domains of executive functions, inhibition ability, learning and verbal memory, and semantic memory. Inhibition ability was specifically related to food management. Poorer glycemic control (>8.3%) was associated with a slower reaction time. Conclusion: These findings highlight the potential impairment of brain networks responsible for learning, memory, and controlled reactivity to food in adolescents with type 1 diabetes whose glycemic control is poor.

Hyper and hypo attention networks activations affect social development in children with autism spectrum disorder.

Children with autism spectrum disorder (ASD) experience a range of social and non-social attention deficits. To date, most studies assessed the neurological framework or discrete behavioral traits related to one attention network, leaving a gap in the understanding of the developmental cascade affecting the inter-relations among attention networks in ASD in a pervasive manner. We propose a theoretical framework that integrates the behavioral deficits and neurological manifestations through a cohesive developmental prism of attention networks' activations while assessing their impact on social deficits in children with ASD. Insights arising from the model suggest hyper-and-hypoactivation of posterior attention networks leads to an altered prefrontal anterior attention network weight in ways that conjointly impact social performance in ASD. This perspective on how attention networks develop and interact in ASD may inform future research directions regarding ASD and attention development.

Gaze Behaviors of Preterm and Full-Term Infants in Nonsocial and Social Contexts of Increasing Dynamics: Visual Recognition, Attention Regulation, and Gaze Synchrony.

Although research has demonstrated poor visual skills in premature infants, few studies assessed infants' gaze behaviors across several domains of functioning in a single study. Thirty premature and 30 full-term 3-month-old infants were tested in three social and nonsocial tasks of increasing complexity and their gaze behavior was micro-coded. In a one-trial version of the visual recognition paradigm, where novel stimuli were paired with familiar stimuli, preterm infants showed longer first looks to novel stimuli. In the behavior response paradigm, which presented infants with 17 stimuli of increasing complexity in a predetermined "on-off" sequence, premature infants tended to look away from toys more during presentation. Finally, during mother-infant face-to-face interaction, the most dynamic interpersonal context, preterm infants and their mothers displayed short, frequent episodes of gaze synchrony, and lag-sequential analysis indicated that both mother and infant broke moments of mutual gaze within 2 sec of its initiation. The propotion of look away during the behavior response paradigm was related to lower gaze synchrony and more gaze breaks during mother-infant interactions. Results are discussed in terms of the unique and adaptive gaze patterns typical of low-risk premature infants.

The Brainstem-Informed Autism Framework: Early Life Neurobehavioral Markers.

Autism spectrum disorders (ASD) have long-term implications on functioning at multiple levels. In this perspective, we offer a brainstem-informed autism framework (BIAF) that traces the protracted neurobehavioral manifestations of ASD to early life brainstem dysfunctions. Early life brainstem-mediated markers involving functions of autonomic/arousal regulation, sleep-wake homeostasis, and sensorimotor integration are delineated. Their possible contributions to the early identification of susceptible infants are discussed. We suggest that the BIAF expands our multidimensional understanding of ASD by focusing on the early involvement of brainstem systems. Importantly, we propose an integrated BIAF screener that brings about the prospect of a sensitive and reliable early life diagnostic scheme for weighing the risk for ASD. The BIAF screener could provide clinicians substantial gains in the future and may carve customized interventions long before the current DSM ASD phenotype is manifested using dyadic co-regulation of brainstem-informed autism markers.