Individuals being high in their sensitivity to the environment: Are sensitive period changes in play?

All individuals on planet earth are sensitive to the environment, but some more than others. These individual differences in sensitivity to environments are seen across many animal species including humans, and can influence personalities as well as vulnerability and resilience to mental disorders. Yet, little is known about the underlying brain mechanisms. Key genes that contribute to individual differences in environmental sensitivity are the serotonin transporter, dopamine D4 receptor and brain-derived neurotrophic factor genes. By synthesizing neurodevelopmental findings of these genetic factors, and discussing them through the lens of mechanisms related to sensitive periods, which are phases of heightened neuronal plasticity during which a certain network is being finetuned by experiences, we propose that these genetic factors delay but extend postnatal sensitive periods. This may explain why sensitive individuals show behavioral features that are characteristic of a young brain state at the level of sensory information processing, such as reduced filtering or blockade of irrelevant information, resulting in a sensory processing system that 'keeps all options open'.

Genetic Overlap Between Midfrontal Theta Signals and Attention-Deficit/Hyperactivity Disorder and Autism Spectrum Disorder in a Longitudinal Twin Cohort.

BACKGROUND: Cognitive control has been strongly linked to midfrontal theta (4-8 Hz) brain activity. Such control processes are known to be impaired in individuals with psychiatric conditions and neurodevelopmental diagnoses, including attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD). Temporal variability in theta, in particular, has been associated with ADHD, with shared genetic variance underlying the relationship. Here, we investigated the phenotypic and genetic relationships between theta phase variability, theta-related signals (the N2, error-related negativity, and error positivity), reaction time, and ADHD and ASD longitudinally in a large twin study of young adults to investigate the stability of the genetic relationships between these measures over time. METHODS: Genetic multivariate liability threshold models were run on a longitudinal sample of 566 participants (283 twin pairs). Characteristics of ADHD and ASD were measured in childhood and young adulthood, while an electroencephalogram was recorded in young adulthood during an arrow flanker task. RESULTS: Cross-trial theta phase variability in adulthood showed large positive phenotypic and genetic relationships with reaction time variability and both childhood and adult ADHD characteristics. Error positivity amplitude was negatively related phenotypically and genetically to ADHD and ASD at both time points. CONCLUSIONS: We showed significant genetic associations between variability in theta signaling and ADHD. A novel finding from the current study is that these relationships were stable across time, indicating a core dysregulation of the temporal coordination of control processes in ADHD that persists in individuals with childhood symptoms. Error processing, indexed by the error positivity, was altered in both ADHD and ASD, with a strong genetic contribution.

A qualitative and quantitative study of self-reported positive characteristics of individuals with ADHD.

Research in Attention-deficit/hyperactivity disorder (ADHD) has had a clear focus on treatment and the dysfunction in specific situation associated with the condition. However, self-report, observational and anecdotal evidence indicates that there are also positive aspects associated with ADHD. Research on the potential positive features in individuals with an ADHD diagnosis is still limited, especially studies with larger representative samples. Here we performed qualitative research to identify positive aspects and strengths associated with ADHD in a large convenience sample from the Dutch organization for people with ADHD, dyslexia and dyscalculia. We sent out open-ended questionnaires to the members of the organization, asking what they consider to be positive aspects of their ADHD. From the responses of individuals with ADHD (n = 206), we extracted 116 codes, which were assigned to thirteen subthemes, which in turn led to five themes. These themes were: Creativity, Being dynamic, Flexibility, Socio-affective skills, and Higher-order cognitive skills. Core symptoms of ADHD such as impulsivity and hyperactivity were also considered positive aspects of ADHD by a minority of participants. After showing our results to a group of additional individuals with ADHD (focus group) they confirmed the identified positive aspects of ADHD. They also helped us with the interpretation of our findings and mentioned certain positive aspects to be a consequence of living with ADHD (being open minded and being honest). In conclusion, experiencing positive aspects seems to be common in ADHD as almost all participants reported positive aspect of ADHD, these aspects cover many different domains. Awareness about ADHD's strengths might help individuals with ADHD and their environment to better cope with, accept or embrace their diagnosis and for example make educational or occupational choices that fit them well. To incorporate these positive aspects in the understanding of ADHD, future research should focus on quantifying strengths in ADHD, and on investigating the link between these aspects and clinical characteristics and how this new knowledge can be implemented in psychoeducation and find its way to education and occupational settings.

Toward Precision Medicine in ADHD.

Attention-Deficit Hyperactivity Disorder (ADHD) is a complex and heterogeneous neurodevelopmental condition for which curative treatments are lacking. Whilst pharmacological treatments are generally effective and safe, there is considerable inter-individual variability among patients regarding treatment response, required dose, and tolerability. Many of the non-pharmacological treatments, which are preferred to drug-treatment by some patients, either lack efficacy for core symptoms or are associated with small effect sizes. No evidence-based decision tools are currently available to allocate pharmacological or psychosocial treatments based on the patient's clinical, environmental, cognitive, genetic, or biological characteristics. We systematically reviewed potential biomarkers that may help in diagnosing ADHD and/or stratifying ADHD into more homogeneous subgroups and/or predict clinical course, treatment response, and long-term outcome across the lifespan. Most work involved exploratory studies with cognitive, actigraphic and EEG diagnostic markers to predict ADHD, along with relatively few studies exploring markers to subtype ADHD and predict response to treatment. There is a critical need for multisite prospective carefully designed experimentally controlled or observational studies to identify biomarkers that index inter-individual variability and/or predict treatment response.

Correction: Protocol of the Healthy Brain Study: An accessible resource for understanding the human brain and how it dynamically and individually operates in its bio-social context.

[This corrects the article DOI: 10.1371/journal.pone.0260952.].

The P-factor and its genomic and neural equivalents: an integrated perspective.

Different psychiatric disorders and symptoms are highly correlated in the general population. A general psychopathology factor (or "P-factor") has been proposed to efficiently describe this covariance of psychopathology. Recently, genetic and neuroimaging studies also derived general dimensions that reflect densely correlated genomic and neural effects on behaviour and psychopathology. While these three types of general dimensions show striking parallels, it is unknown how they are conceptually related. Here, we provide an overview of these three general dimensions, and suggest a unified interpretation of their nature and underlying mechanisms. We propose that the general dimensions reflect, in part, a combination of heritable 'environmental' factors, driven by a dense web of gene-environment correlations. This perspective calls for an update of the traditional endophenotype framework, and encourages methodological innovations to improve models of gene-brain-environment relationships in all their complexity. We propose concrete approaches, which by taking advantage of the richness of current large databases will help to better disentangle the complex nature of causal factors underlying psychopathology.

A randomised controlled trial (MindChamp) of a mindfulness-based intervention for children with ADHD and their parents.

BACKGROUND: Family mindfulness-based intervention (MBI) for child attention-deficit/hyperactivity disorder (ADHD) targets child self-control, parenting and parental mental health, but its effectiveness is still unclear. METHODS: MindChamp is a pre-registered randomised controlled trial comparing an 8-week family MBI (called 'MYmind') in addition to care-as-usual (CAU) (n = 55) with CAU-only (n = 48). Children aged 8-16 years with remaining ADHD symptoms after CAU were enrolled together with a parent. Primary outcome was post-treatment parent-rated child self-control deficits (BRIEF); post hoc, Reliable Change Indexes were explored. Secondary child outcomes included ADHD symptoms (parent/teacher-rated Conners' and SWAN; teacher-rated BRIEF), other psychological symptoms (parent/teacher-rated), well-being (parent-rated) and mindfulness (self-rated). Secondary parent outcomes included self-ratings of ADHD symptoms, other psychological symptoms, well-being, self-compassion and mindful parenting. Assessments were conducted at post-treatment, 2- and 6-month follow-up. RESULTS: Relative to CAU-only, MBI+CAU resulted in a small, statistically non-significant post-treatment improvement on the BRIEF (intention-to-treat: d = 0.27, p = .18; per protocol: d = 0.33, p = .11). Significantly more children showed reliable post-treatment improvement following MBI+CAU versus CAU-only (32% versus 11%, p < .05, Number-Needed-to-Treat = 4.7). ADHD symptoms significantly reduced post-treatment according to parent (Conners' and SWAN) and teacher ratings (BRIEF) per protocol. Only parent-rated hyperactivity impulsivity (SWAN) remained significantly reduced at 6-month follow-up. Post-treatment group differences on other secondary child outcomes were consistently favour of MBI+CAU, but mostly non-significant; no significant differences were found at follow-ups. Regarding parent outcomes, significant post-treatment improvements were found for their own ADHD symptoms, well-being and mindful parenting. At follow-ups, some significant effects remained (ADHD symptoms, mindful parenting), some additional significant effects appeared (other psychological symptoms, self-compassion) and others disappeared/remained non-significant. CONCLUSIONS: Family MBI+CAU did not outperform CAU-only in reducing child self-control deficits on a group level but more children reliably improved. Effects on parents were larger and more durable. When CAU for ADHD is insufficient, family MBI could be a valuable addition.

Protocol of the Healthy Brain Study: An accessible resource for understanding the human brain and how it dynamically and individually operates in its bio-social context.

The endeavor to understand the human brain has seen more progress in the last few decades than in the previous two millennia. Still, our understanding of how the human brain relates to behavior in the real world and how this link is modulated by biological, social, and environmental factors is limited. To address this, we designed the Healthy Brain Study (HBS), an interdisciplinary, longitudinal, cohort study based on multidimensional, dynamic assessments in both the laboratory and the real world. Here, we describe the rationale and design of the currently ongoing HBS. The HBS is examining a population-based sample of 1,000 healthy participants (age 30-39) who are thoroughly studied across an entire year. Data are collected through cognitive, affective, behavioral, and physiological testing, neuroimaging, bio-sampling, questionnaires, ecological momentary assessment, and real-world assessments using wearable devices. These data will become an accessible resource for the scientific community enabling the next step in understanding the human brain and how it dynamically and individually operates in its bio-social context. An access procedure to the collected data and bio-samples is in place and published on https://www.healthybrainstudy.nl/en/data-and-methods/access. Trail registration: https://www.trialregister.nl/trial/7955.

Experiences of Adults High in the Personality Trait Sensory Processing Sensitivity: A Qualitative Study.

Sensory processing sensitivity (SPS) is a personality trait reflecting inter-individual differences in sensitivity to negative and positive environmental information. Being high in SPS is associated with increased stress-related problems if environments are unfavourable but also appears to enhance one's ability to benefit from health-promoting environments. In understanding SPS, therefore, lies the potential for innovating the ways we use to promote mental health. However, as a young research field, the core characteristics of SPS are yet debated. Qualitative research interviewing highly sensitive adults is important to conduct ecologically valid research connected with the complex realities of people. This study was the first to systematically report the perceptions and experiences of SPS characteristics in adults high in this trait. Semi-structured interviews (n = 26) were analysed thematically and described following consolidated criteria for reporting qualitative research. Six themes emerged: (1) emotional responding; (2) relatedness to others; (3) thinking; (4) overstimulation; (5) perceiving details; and (6) global SPS characteristics. With regards to coping with negative consequences of high SPS, the main themes were: (1) reducing sensory input and (2) psychological strategies. We gained fine-grained information on experiences of adults high in SPS and derived new hypotheses regarding the fostering of well-being related to high SPS.

Early Predictors of De Novo and Subthreshold Late-Onset ADHD in a Child and Adolescent Cohort.

Objective: The study aimed to identify early childhood risk factors for de novo and subthreshold late-onset ADHD. Method: ADHD symptoms were assessed in 9,875 participants from the Twins Early Development Study (TEDS) using the Conners' Parent Rating Scale at ages 8, 12, 14, and 16 years, along with other childhood characteristics and adolescent outcomes. Multinomial logistic regressions were implemented to identify early childhood predictors of late-onset ADHD and childhood-onset persistent ADHD, with non-ADHD controls as the reference category. Results: Male sex, increased childhood conduct problems, and low socioeconomic status predicted de novo late-onset ADHD. Additional risk factors predicted subthreshold late-onset ADHD and childhood-onset persistent ADHD. Late-onset ADHD symptoms were also accompanied by increased co-occurring behavioral and emotional problems. Conclusion: Findings of different childhood predictors between subthreshold and de novo late-onset ADHD suggest further investigation into time-varying environmental and biological factors driving psychopathological changes is warranted to fully characterize late-onset ADHD.

Mindfulness for Children With ADHD and Mindful Parenting (MindChamp): A Qualitative Study on Feasibility and Effects.

Objective: We describe qualitative results on facilitators and barriers to participating in a family mindfulness-based intervention (MBI) for youth with ADHD and their parents and perceived effects on child and parent. Method: Sixty-nine families started the 8-week protocolized group-based MBI called "MYmind." After the MBI, individual semi-structured interviews were conducted with a purposive sample of parents (n = 20), children (n = 17, ages 9-16 years), and mindfulness teachers (n = 3). Interviews were analyzed using Grounded Theory. Results: Facilitators and barriers regarding contextual factors (e.g., time investment), MBI characteristics (e.g., parallel parent-child training), and participant characteristics (e.g., ADHD-symptoms) are described. Perceived effects were heterogeneous: no/adverse effects, awareness/insight, acceptance, emotion regulation/reactivity, cognitive functioning, calmness/relaxation, relational changes, generalization. Conclusion: MYmind can lead to a variety of transferable positively perceived effects beyond child ADHD-symptom decrease. Recommendations on MYmind participant inclusion, program characteristics, mindfulness teachers, and evaluating treatment efficacy are provided.

Added value of Mindfulness-Based Cognitive Therapy for Depression: A Tree-based Qualitative Interaction Analysis.

AIM: To identify moderators of treatment effect for Mindfulness-Based Cognitive Therapy (MBCT) versus Treatment As Usual (TAU) in depressed patients. METHODS: An individual patient data-analysis was performed on three randomized-controlled trials, investigating the effect of MBCT + TAU versus TAU alone (N = 292). Patients were either in (partial) remission, currently depressed or had chronic, treatment-resistant depression. Outcomes were depressive symptoms and quality of life. The QUalitative INteraction Trees (QUINT) method was used to identify subgroups that benefited more from either condition. RESULTS: MBCT + TAU outperformed TAU in reducing depressive symptoms. For both conditions, the effect of baseline depressive symptoms on post-treatment depressive symptoms was curvilinear. QUINT analyses revealed that MBCT + TAU was more beneficial than TAU for patients with an earlier onset and higher rumination levels in terms of depressive symptom reduction and for patients with a lower quality of life in terms of improving quality of life. CONCLUSIONS: The results suggest that MBCT might be more beneficial for those with earlier onset and higher levels of rumination and for patients with a lower quality of life. Sophisticated analytical techniques such as QUINT can be used in future research to improve personalized assignment of MBCT to patients. Long-term outcome could also be integrated in this.

Social-communicative and attention problems in infancy and toddlerhood as precursors of preschool autistic traits.

This longitudinal study focused on early behavioural problems and autistic traits. In a stratified, population-derived sample of 119 children, mothers reported through questionnaires on externalizing, internalizing, and social-communicative characteristics of their child in infancy (14 months) and toddlerhood (37 months), and on autistic traits at preschool age (4-5 years). Children with consistently normal behaviour from infancy to toddlerhood showed lower autistic traits at preschool age than children with deviant behaviour on one or both time points. High autistic traits at preschool age were predominantly preceded by problems in interaction, communication, language, play, and affect in infancy and/or toddlerhood, but also by inattention in toddlerhood. Adequate support and specific interventions in these domains are needed in an attempt to diminish further derailment of the child's behaviour and development, and to prevent the full manifestation of ASD or related disorders such as ADHD.

Genetic and environmental aetiologies of associations between dispositional mindfulness and ADHD traits: a population-based twin study.

To get additional insight into the phenotype of attentional problems, we examined to what extent genetic and environmental factors explain covariation between lack of dispositional mindfulness and attention-deficit/hyperactivity disorder (ADHD) traits in youth, and explored the incremental validity of these constructs in predicting life satisfaction. We used data from a UK population-representative sample of adolescent twins (N = 1092 pairs) on lack of dispositional mindfulness [Mindful Attention Awareness Scale (MAAS)], ADHD traits [Conners' Parent Rating Scale-Revised (CPRS-R): inattentive (INATT) and hyperactivity/impulsivity (HYP/IMP) symptom dimensions] and life satisfaction (Students' Life Satisfaction Scale). Twin model fitting analyses were conducted. Phenotypic correlations (rp) between MAAS and CPRS-R (INATT: rp = 0.18, HYP/IMP: rp = 0.13) were small, but significant and largely explained by shared genes for INATT (% rp INATT-MAAS due to genes: 93%, genetic correlation rA = 0.37) and HYP/IMP (% rp HYP/IMP-MAAS due to genes: 81%; genetic correlation rA = 0.21) with no significant contribution of environmental factors. MAAS, INATT and HYP/IMP significantly and independently predicted life satisfaction. Lack of dispositional mindfulness, assessed as self-reported perceived lapses of attention (MAAS), taps into an aspect of attentional functioning that is phenotypically and genetically distinct from parent-rated ADHD traits. The clinically relevant incremental validity of both scales implicates that MAAS could be used to explore the underlying mechanisms of an aspect of attentional functioning that uniquely affects life satisfaction and is not captured by DSM-based ADHD scales. Further future research could identify if lack of dispositional mindfulness and high ADHD traits can be targeted by different therapeutic approaches resulting in different effects on life satisfaction.

Emotional valence detection in adolescents with oppositional defiant disorder/conduct disorder or autism spectrum disorder.

Oppositional defiant disorder, conduct disorder (ODD/CD), and autism spectrum disorder (ASD) share poor empathic functioning and have been associated with impaired emotional processing. However, no previous studies directly compared similarities and differences in these processes for the two disorders. A two-choice emotional valence detection task requiring differentiation between positive, negative, and neutral IAPS pictures was administered to 52 adolescents (12-19 years) with ODD/CD, 52 with ASD and 24 typically developing individuals (TDI). Callous-unemotional (CU) traits were assessed by self- and parent reports using the Inventory of callous-unemotional traits. Main findings were that adolescents with ODD/CD or ASD both performed poorer than TDI in terms of accuracy, yet only the TDI-not both clinical groups-had relatively most difficulty in discriminating between positive versus neutral pictures compared to neutral-negative or positive-negative contrasts. Poorer performance was related to a higher level of CU traits. The results of the current study suggest youth with ODD/CD or ASD have a diminished ability to detect emotional valence which is not limited to facial expressions and is related to a higher level of CU traits. More specifically, youth with ODD/CD or ASD seem to have a reduced processing of positive stimuli and/or lack a 'positive perception bias' present in TDI that could either contribute to the symptoms and/or be a result of having the disorder and may contribute to the comorbidity of both disorders.

Sensory Processing Sensitivity in the context of Environmental Sensitivity: A critical review and development of research agenda.

Sensory Processing Sensitivity (SPS) is a common, heritable and evolutionarily conserved trait describing inter-individual differences in sensitivity to both negative and positive environments. Despite societal interest in SPS, scientific knowledge is lagging behind. Here, we critically discuss how SPS relates to other theories, how to measure SPS, whether SPS is a continuous vs categorical trait, its relation to other temperament and personality traits, the underlying aetiology and neurobiological mechanisms, and relations to both typical and atypical development, including mental and sensory disorders. Drawing on the diverse expertise of the authors, we set an agenda for future research to stimulate the field. We conclude that SPS increases risk for stress-related problems in response to negative environments, but also provides greater benefit from positive and supportive experiences. The field requires more reliable and objective assessment of SPS, and deeper understanding of its mechanisms to differentiate it from other traits. Future research needs to target prevention of adverse effects associated with SPS, and exploitation of its positive potential to improve well-being and mental health.

Mindfulness for children with ADHD and Mindful Parenting (MindChamp): Protocol of a randomised controlled trial comparing a family Mindfulness-Based Intervention as an add-on to care-as-usual with care-as-usual only.

BACKGROUND: Self-control in childhood has been linked to long-term and cascading effects on health, academic, criminality, wealth and parenting outcomes. Hence it is important to target self-control deficits early in life. Self-control deficits are a hallmark of Attention Deficit/Hyperactivity Disorder (ADHD). Even after receiving care-as-usual (CAU) for ADHD, impaired self-control often remains. Pharmacotherapy can be hampered by side-effects, low adherence and short-term effectiveness. Other limitations of CAU are decreased effectiveness when parents have ADHD and little effect on parental well-being. Mindfulness-Based Interventions (MBIs) are an emerging non-pharmacological approach with potential to improve self-control and well-being in both children and parents. However, there is a lack of sufficiently powered randomised controlled trials (RCTs) to establish their effects in families with ADHD. This study protocol describes an RCT to investigate the effectiveness of a family MBI as an add-on to CAU in treatment of youth with ADHD, and is described in accordance with Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT). METHODS/DESIGN: An RCT will be conducted in N = 100 children (aged 8-16 years) with ADHD and their parents. The experimental condition will consist of a family MBI (MYmind): 8-week group-based MBI for youth combined with parallel group-based Mindful Parenting for their parents, as an add-on to CAU. The control condition will consist of CAU-only. Assessments will take place at baseline, end of treatment (3 months later), 2 and 6 months' follow-up. Primary outcome measure will be an ecologically valid assessment of child self-control with the parent-rated Behaviour Rating Inventory of Executive Function (BRIEF). Secondary child outcome measures will be teacher-rated BRIEF, computerised self-control tasks and questionnaires on psychological symptoms (e.g. ADHD, symptoms of autism), well-being and mindfulness. For parental outcomes, secondary measures will be self-rated BRIEF, computerised self-control tasks and questionnaires on psychological symptoms, well-being and mindful parenting. DISCUSSION: The proposed RCT will take account of methodological limitations of previous studies on MBIs in child ADHD populations. The current study will provide valuable information on family MBI as a potential effective intervention in targeting self-control deficits for youth with ADHD and their parents. TRIAL REGISTRATION: ClinicalTrials.gov NCT03220308 . Retrospectively registered 18 July 2017.

The role of birth weight on the causal pathway to child and adolescent ADHD symptomatology: a population-based twin differences longitudinal design.

BACKGROUND: Available evidence points towards lower birth weight as a risk factor for the development of attention deficit/hyperactivity disorder (ADHD) symptoms. We probed the causal nature of this putative effect of birth weight on ADHD symptoms using the twin differences design, which accounts for genetic and shared environmental confounds. METHOD: In a large population-based twin sample - 3,499 monozygotic (MZ) and 6,698 dizygotic (DZ) pairs - parents, teachers or twins rated the twins' ADHD symptoms at nine assessment waves (2-16 years). We implemented the twin differences design, which completely accounts for shared environmental and genetic confounding in MZ twins. We tested whether: (a) the lighter-born twins had elevated ADHD symptoms compared to the heavier-born twins, by regressing within-pair differences of ADHD symptoms on within-pair differences of birth weight among MZ twins; (b) the effect of birth weight on ADHD was moderated by gender, gestational age and low birth weight; (c) this effect changed with age at ADHD assessment using adapted latent growth curve models; and (d) results differed for inattention and hyperactivity/impulsivity. RESULTS: Birth weight significantly predicted ADHD symptoms from early childhood to late adolescence. The lighter-born twin had more ADHD symptoms than the heavier-born cotwin among MZ twins across assessment waves and raters. No moderation effect was detected. The magnitude of the effect of birth weight decreased significantly across time for hyperactivity/impulsivity, but the decrease failed to reach significance for inattention. Estimates for inattention were significantly larger than for hyperactivity/impulsivity at each time point, implying stronger effect of birth weight on inattention symptoms. CONCLUSIONS: Our findings provide stringent evidence for environmental effect of lower birth weight on the causal pathway to elevated ADHD symptoms. Effect of birth weight persists across a 14-year period from childhood into late adolescence, in particular for inattention symptoms.

Do High and Low Extremes of ADHD and ASD Trait Continua Represent Maladaptive Behavioral and Cognitive Outcomes? A Population-Based Study.

OBJECTIVE: Attention deficit hyperactivity disorder (ADHD) and autism spectrum disorders (ASD) are thought to reflect the high, symptomatic extreme of quantitative trait continua. However, extreme deviations in either direction on disorder continua, high and low, may both represent maladaptive behavioral and cognitive outcomes. We aimed to test this hypothesis. METHOD: In a population sample of 378 children, ADHD and ASD traits were rated by parents on questionnaires that provide resolution at high and low extremes of the ADHD and ASD trait continua. ADHD and ASD traits were related to parent-ratings of internalizing and externalizing behavior problems and tests of cognitive functioning using polynomial regression. RESULTS: The low ends of the ADHD and ASD trait continua were related to fewer behavior problems and better cognitive functioning than symptomatic ends. CONCLUSION: Studying the correlates of the low continuum ends may deepen our understanding of the mechanisms underlying adaptive behavioral and cognitive outcomes.