Pubertal maturation and timing effects on resting state electroencephalography in autistic and comparison youth.

Autistic and comparison individuals differ in resting-state electroencephalography (EEG), such that sex and age explain variability within and between groups. Pubertal maturation and timing may further explain variation, as previous work has suggested alterations in pubertal timing in autistic youth. In a sample from two studies of 181 autistic and 94 comparison youth (8 years to 17 years and 11 months), mixed-effects linear regressions were conducted to assess differences in EEG (midline power for theta, alpha, and beta frequency bands). Alpha power was analyzed as a mediator in the relation between pubertal maturation and timing with autistic traits in the autistic groups to understand the role of puberty in brain-based changes that contribute to functional outcomes. Individuals advanced in puberty exhibited decreased power in all bands. Those who experienced puberty relatively early showed decreased power in theta and beta bands, controlling for age, sex, and diagnosis. Autistic individuals further along in pubertal development exhibited lower social skills. Alpha mediated the relation between puberty and repetitive behaviors. Pubertal maturation and timing appear to play unique roles in the development of cognitive processes for autistic and comparison youth and should be considered in research on developmental variation in resting-state EEG.

Linking social motivation with social skill: The role of emotion dysregulation in autism spectrum disorder.

Autism spectrum disorder (ASD) is associated with pervasive social deficits as well as marked emotion dysregulation across the life span. Decreased social motivation accounts in part for social difficulties, but factors moderating its influence are not fully understood. In this paper, we (a) characterize social and emotional functioning among children and adolescents with ASD, (b) explore contributions of social motivation and emotion dysregulation to social skill, and (c) consider biological sex and intellectual functioning as moderators of these associations. In a sample of 2,079 children and adolescents with ASD from the Simons Simplex Collection, we document direct effects of social motivation, internalizing symptoms, aggression, attention problems, irritability, and self-injurious behavior on children's social skills. Furthermore, dysregulation in several domains moderated the association between social motivation and social skill, suggesting a blunting effect on social motivation in the context of emotional difficulties. Moreover, when considering only individuals with intellectual skills in the average range or higher, biological sex further moderated these associations. Findings add to our understanding of social-emotional processes in ASD, suggest emotion dysregulation as a target of intervention in the service of social skill improvements, and build on efforts to understand sources of individual difference that contribute to heterogeneity among individuals with ASD.

Social motivation by self- and caregiver-report: Reporter concordance and social correlates among autistic and neurotypical youth.

Differences in social motivation underlie the core social-communication features of autism according to several theoretical models, with decreased social motivation among autistic youth relative to neurotypical peers. However, research on social motivation often relies on caregiver reports and rarely includes firsthand perspectives of children and adolescents with autism. Furthermore, social motivation is typically assumed to be constant across social settings when it may actually vary by social context. Among a sample of 58 verbally fluent youth (8-13 years old; 22 with autism, 36 neurotypical), we examined correspondence between youth and caregiver reports of social motivation with peers and with adults, as well as diagnostic group differences and associations with social outcomes. Results suggest youth and caregivers provide overlapping but distinct information. Autistic youth had lower levels of social motivation relative to neurotypical youth, and reported relatively consistent motivation toward peers and adults. Youth self- and caregiver-report were correlated for motivation toward adults, but not toward peers. Despite low correspondence between self- and caregiver-reported motivation toward peers, autistic youths' self-report corresponded to caregiver-reported social skills and difficulties whereas caregiver-report of peer motivation did not. For neurotypical youth, self- and caregiver-reported motivation toward adults was correlated, but motivation by both reporters was largely independent of broader social outcomes. Findings highlight the unique value of self-report among autistic children and adolescents, and warrant additional work exploring the development, structure, and correlates of social motivation among autistic and neurotypical youth.

Predicting Intervention Use in Youth with Rare Variants in Autism-Associated Genes.

Specialized multidisciplinary supports are important for long-term outcomes for autistic youth. Although family and child factors predict service utilization in autism, little is known with respect to youth with rare, autism-associated genetic variants, who frequently have increased psychiatric, developmental, and behavioral needs. We investigate the impact of family factors on service utilization to determine whether caregiver (autistic features, education, income) and child (autistic features, sex, age, IQ, co-occurring conditions) factors predicted service type (e.g., speech, occupational, behavioral) and intensity (hours/year) among children with autism-associated variants (N = 125), some of whom also had a confirmed ASD diagnosis. Analyses revealed variability in the types of services used across a range of child demographic, behavioral, and mental health characteristics. Speech therapy was the most received service (87.2%). Importantly, behavior therapy was the least received service and post-hoc analyses revealed that use of this therapy was uniquely predicted by ASD diagnosis. However, once children received a particular service, there was largely comparable intensity of services, independent of caregiver and child factors. Findings suggest that demographic and clinical factors impact families' ability to obtain services, with less impact on the intensity of services received. The low receipt of therapies that specifically address core support needs in autism (i.e., behavior therapy) indicates more research is needed on the availability of these services for youth with autism-associated variants, particularly for those who do not meet criteria for an ASD diagnosis but do demonstrate elevated and impactful child autistic features as compared to the general population.

Visual and auditory attention in individuals with DYRK1A and SCN2A disruptive variants.

This preliminary study sought to assess biomarkers of attention using electroencephalography (EEG) and eye tracking in two ultra-rare monogenic populations associated with autism spectrum disorder (ASD). Relative to idiopathic ASD (n = 12) and neurotypical comparison (n = 49) groups, divergent attention profiles were observed for the monogenic groups, such that individuals with DYRK1A (n = 9) exhibited diminished auditory attention condition differences during an oddball EEG paradigm whereas individuals with SCN2A (n = 5) exhibited diminished visual attention condition differences noted by eye gaze tracking when viewing social interactions. Findings provide initial support for alignment of auditory and visual attention markers in idiopathic ASD and neurotypical development but not monogenic groups. These results support ongoing efforts to develop translational ASD biomarkers within the attention domain.

A common genetic variant in the Neurexin family member CNTNAP2 is related to language but not communication skills in youth with Autism Spectrum Disorder.

One of the candidate genes related to language variability in individuals with Autism Spectrum Disorder (ASD) is the contactin-associated protein-like 2 gene (CNTNAP2), a member of the Neurexin family. However, due to the different assessment tools used, it is unknown whether the polymorphisms of the CNTNAP2 gene are linked to structural language skills or more general communication abilities. A total of 302 youth aged 7 to 18 years participated in the present study: 131 verbal youth with ASD (62 female), 130 typically developing (TD) youth (64 female), and 41 unaffected siblings (US) of youth with ASD (25 female). Blood samples were collected to obtain genomic DNA and processed by the Rutgers University Cell and Data Repository or using standard protocols (Gentra Puregene Blood DNA extraction kit; Qiagen). Language and verbal communication skills were screened with the Clinical Evaluation of Language Fundamental-4 (CELF-4) and Vineland-II Communication domain, subsequently. The results showed that the polymorphism of CNTNAP2 (SNP rs2710102) was related to structural language abilities, such that participants carrying the A-allele had lower language skills in comparison to the G-allele homozygotes. No relationship was found between the polymorphism of CNTNAP2 and more general communication abilities. Although the study revealed genetic mechanisms that are associated with CELF-4 measures but not Vineland-II in youth with ASD, follow-up studies are needed that will include measures of language and communication that are less correlated to each other as well as will include a group of minimally and/or non-verbal individuals with ASD.

Time is of the essence: Age at autism diagnosis, sex assigned at birth, and psychopathology.

LAY ABSTRACT: Previous research has shown that girls/women are diagnosed later than boys/men with autism. Individuals who are diagnosed later in life, especially girls/women, have greater anxious and depressive symptoms. Previous research has been limited due to narrow inclusionary criteria for enrollment in studies. The present study uses two samples-one clinic-based, large "real-world" sample and another research-based sample with strict criteria for autism diagnosis-to understand the relationships between diagnostic age, sex assigned at birth, and symptoms of anxiety/depression. In both samples, those who were diagnosed later had greater anxious/depressive symptoms, and anxiety was not predicted by sex. In the clinic-based but not research-based sample, those assigned female at birth were diagnosed later than those assigned male at birth. In the clinic-based sample only, individuals assigned female at birth and who were later diagnosed experienced greater symptoms of anxiety/depression compared to those assigned male who benefited from earlier diagnostic timing. Within the research-based sample, those assigned female at birth had greater depressive symptoms than those assigned male. These findings highlight the importance of timely identification of autism, especially for girls/women who are often diagnosed later. Community-based samples are needed to better understand real-world sex-based and diagnostic age-based disparities in mental health.

Shared and divergent mental health characteristics of ADNP-, CHD8- and DYRK1A-related neurodevelopmental conditions.

BACKGROUND: Neurodevelopmental conditions such as intellectual disability (ID) and autism spectrum disorder (ASD) can stem from a broad array of inherited and de novo genetic differences, with marked physiological and behavioral impacts. We currently know little about the psychiatric phenotypes of rare genetic variants associated with ASD, despite heightened risk of psychiatric concerns in ASD more broadly. Understanding behavioral features of these variants can identify shared versus specific phenotypes across gene groups, facilitate mechanistic models, and provide prognostic insights to inform clinical practice. In this paper, we evaluate behavioral features within three gene groups associated with ID and ASD - ADNP, CHD8, and DYRK1A - with two aims: (1) characterize phenotypes across behavioral domains of anxiety, depression, ADHD, and challenging behavior; and (2) understand whether age and early developmental milestones are associated with later mental health outcomes. METHODS: Phenotypic data were obtained for youth with disruptive variants in ADNP, CHD8, or DYRK1A (N = 65, mean age = 8.7 years, 40% female) within a long-running, genetics-first study. Standardized caregiver-report measures of mental health features (anxiety, depression, attention-deficit/hyperactivity, oppositional behavior) and developmental history were extracted and analyzed for effects of gene group, age, and early developmental milestones on mental health features. RESULTS: Patterns of mental health features varied by group, with anxiety most prominent for CHD8, oppositional features overrepresented among ADNP, and attentional and depressive features most prominent for DYRK1A. For the full sample, age was positively associated with anxiety features, such that elevations in anxiety relative to same-age and same-sex peers may worsen with increasing age. Predictive utility of early developmental milestones was limited, with evidence of early language delays predicting greater difficulties across behavioral domains only for the CHD8 group. CONCLUSIONS: Despite shared associations with autism and intellectual disability, disruptive variants in ADNP, CHD8, and DYRK1A may yield variable psychiatric phenotypes among children and adolescents. With replication in larger samples over time, efforts such as these may contribute to improved clinical care for affected children and adolescents, allow for earlier identification of emerging mental health difficulties, and promote early intervention to alleviate concerns and improve quality of life.

The relationship between gamma-band neural oscillations and language skills in youth with Autism Spectrum Disorder and their first-degree relatives.

BACKGROUND: Most children with Autism Spectrum Disorder (ASD) have co-occurring language impairments and some of these autism-specific language difficulties are also present in their non-autistic first-degree relatives. One of the possible neural mechanisms associated with variability in language functioning is alterations in cortical gamma-band oscillations, hypothesized to be related to neural excitation and inhibition balance. METHODS: We used a high-density 128-channel electroencephalography (EEG) to register brain response to speech stimuli in a large sex-balanced sample of participants: 125 youth with ASD, 121 typically developing (TD) youth, and 40 unaffected siblings (US) of youth with ASD. Language skills were assessed with Clinical Evaluation of Language Fundamentals. RESULTS: First, during speech processing, we identified significantly elevated gamma power in ASD participants compared to TD controls. Second, across all youth, higher gamma power was associated with lower language skills. Finally, the US group demonstrated an intermediate profile in both language and gamma power, with nonverbal IQ mediating the relationship between gamma power and language skills. LIMITATIONS: We only focused on one of the possible neural contributors to variability in language functioning. Also, the US group consisted of a smaller number of participants in comparison to the ASD or TD groups. Finally, due to the timing issue in EEG system we have provided only non-phase-locked analysis. CONCLUSIONS: Autistic youth showed elevated gamma power, suggesting higher excitation in the brain in response to speech stimuli and elevated gamma power was related to lower language skills. The US group showed an intermediate pattern of gamma activity, suggesting that the broader autism phenotype extends to neural profiles.

Characterizing Sleep Problems in 16p11.2 Deletion and Duplication.

Studies of 16p11.2 copy number variants (CNVs) provide an avenue to identify mechanisms of impairment and develop targeted treatments for individuals with neurodevelopmental disorders. 16p11.2 deletion and duplication phenotypes are currently being ascertained; however, sleep disturbances are minimally described. In this study, we examine sleep disturbance in a well-characterized national sample of 16p11.2 CNVs, the Simons Foundation Autism Research Initiative (SFARI) database of youth and adults (n = 692). Factor analyses and multilevel models of derived sleep questionnaires for youth (n = 345) and adults (n = 347) indicate that 16p11.2 carriers show elevated sleep disturbance relative to community controls. Non-carrier family members also show elevated sleep disturbance. However, sleep duration does not differ between carriers and controls. Further studies of sleep in 16p11.2 are needed.

Characterizing the autism spectrum phenotype in DYRK1A-related syndrome.

Likely gene-disrupting (LGD) variants in DYRK1A are causative of DYRK1A syndrome and associated with autism spectrum disorder (ASD) and intellectual disability (ID). While many individuals with DYRK1A syndrome are diagnosed with ASD, they may present with a unique profile of ASD traits. We present a comprehensive characterization of the ASD profile in children and young adults with LGDs in DYRK1A. Individuals with LGD variants in DYRK1A (n = 29) were compared to children who had ASD with no known genetic cause, either with low nonverbal IQ (n = 14) or average or above nonverbal IQ (n = 41). ASD was assessed using the ADOS-2, ADI-R, SRS-2, SCQ, and RBS-R. Quantitative score comparisons were conducted, as were qualitative analyses of clinicians' behavioral observations. Diagnosis of ASD was confirmed in 85% and ID was confirmed in 89% of participants with DYRK1A syndrome. Individuals with DYRK1A syndrome showed broadly similar social communication behaviors to children with idiopathic ASD and below-average nonverbal IQ, with specific challenges noted in social reciprocity and nonverbal communication. Children with DYRK1A syndrome also showed high rates of sensory-seeking behaviors. Phenotypic characterization of individuals with DYRK1A syndrome may provide additional information on mechanisms contributing to co-occurring ASD and ID and contribute to the identification of genetic predictors of specific ASD traits.

Characterizing Sensory Phenotypes of Subgroups with a Known Genetic Etiology Pertaining to Diagnoses of Autism Spectrum Disorder and Intellectual Disability.

We aimed to identify unique constellations of sensory phenotypes for genetic etiologies associated with diagnoses of autism spectrum disorder (ASD) and intellectual disability (ID). Caregivers reported on sensory behaviors via the Sensory Profile for 290 participants (younger than 25 years of age) with ASD and/or ID diagnoses, of which ~ 70% have a known pathogenic genetic etiology. Caregivers endorsed poor registration (i.e., high sensory threshold, passive behaviors) for all genetic subgroups relative to an "idiopathic" comparison group with an ASD diagnosis and without a known genetic etiology. Genetic profiles indicated prominent sensory seeking in ADNP, CHD8, and DYRK1A, prominent sensory sensitivities in SCN2A, and fewer sensation avoidance behaviors in GRIN2B (relative to the idiopathic ASD comparison group).

Frontal EEG alpha asymmetry in youth with autism: Sex differences and social-emotional correlates.

In youth broadly, EEG frontal alpha asymmetry (FAA) associates with affective style and vulnerability to psychopathology, with relatively stronger right activity predicting risk for internalizing and externalizing behaviors. In autistic youth, FAA has been related to ASD diagnostic features and to internalizing symptoms. Among our large, rigorously characterized, sex-balanced participant group, we attempted to replicate findings suggestive of altered FAA in youth with an ASD diagnosis, examining group differences and impact of sex assigned at birth. Second, we examined relations between FAA and behavioral variables (ASD features, internalizing, and externalizing) within autistic youth, examining effects by sex. Third, we explored whether the relation between FAA, autism features, and mental health was informed by maternal depression history. In our sample, FAA did not differ by diagnosis, age, or sex. However, youth with ASD had lower total frontal alpha power than youth without ASD. For autistic females, FAA and bilateral frontal alpha power correlated with social communication features, but not with internalizing or externalizing symptoms. For autistic males, EEG markers correlated with social communication features, and with externalizing behaviors. Exploratory analyses by sex revealed further associations between youth FAA, behavioral indices, and maternal depression history. In summary, findings suggest that individual differences in FAA may correspond to social-emotional and mental health behaviors, with different patterns of association for females and males with ASD. Longitudinal consideration of individual differences across levels of analysis (e.g., biomarkers, family factors, and environmental influences) will be essential to parsing out models of risk and resilience among autistic youth.

Clinical Characteristics of Youth with Autism or Developmental Disability during Inpatient Psychiatric Admission.

Children with autism spectrum disorder and developmental disabilities (ASD/DD) often experience severe co-occurring psychological and behavioral challenges, which can warrant inpatient psychiatric care. However, very little is known about the characteristics and clinical care of children with ASD/DD within the context of inpatient psychiatric settings. In this paper, we describe factors unique to inpatients with ASD or DD, by drawing on electronic health records from over 2300 children and adolescents ages 4-17 years admitted to a pediatric psychiatric inpatient unit over a 3-year period. Patients with ASD/DD accounted for approximately 16% of inpatients and 21% of admissions, were younger, more likely to be readmitted, more likely to be male, and more likely to have Medicaid insurance, as compared to patients without ASD/DD. Clinically, those with ASD/DD more frequently had externalizing concerns documented in their records, in contrast to more frequent internalizing concerns among other patients. Within the ASD/DD group, we identified effects of patient age, sex, and race/ethnicity on multiple dimensions of clinical care, including length of stay, use of physical restraint, and patterns of medication use. Results suggest the need for psychiatric screening tools that are appropriate for ASD/DD populations, and intentional integration of anti-racist practices into inpatient care, particularly with regard to use of physical restraint among youth.

Language and Aggressive Behaviors in Male and Female Youth with Autism Spectrum Disorder.

Aggressive behaviors are common among youth with autism spectrum disorder (ASD) and correlate with pervasive social-emotional difficulties. Communication skill is an important correlate of disruptive behavior in typical development, and clarification of links between communication and aggression in ASD may inform intervention methods. We investigate child/family factors and communication in relation to aggression among 145 individuals with ASD (65 female; ages 8-17 years). Overall, more severe aggression was associated with younger age, lower family income, and difficulties with communication skills. However, this pattern of results was driven by males, and aggression was unrelated to child or family characteristics for females. Future work should incorporate these predictors in conjunction with broader contextual factors to understand aggressive behavior in females with ASD.

The effects of allostatic load on neural systems subserving motivation, mood regulation, and social affiliation.

The term allostasis, which is defined as stability through change, has been invoked repeatedly by developmental psychopathologists to describe long-lasting and in some cases permanent functional alterations in limbic-hypothalamic-pituitary-adrenal axis responding following recurrent and/or prolonged exposure to stress. Increasingly, allostatic load models have also been invoked to describe psychological sequelae of abuse, neglect, and other forms of maltreatment. In contrast, neural adaptations to stress, including those incurred by monoamine systems implicated in (a) mood and emotion regulation, (b) behavioral approach, and (c) social affiliation and attachment, are usually not included in models of allostasis. Rather, structural and functional alterations in these systems, which are exquisitely sensitive to prolonged stress exposure, are usually explained as stress mediators, neural plasticity, and/or programming effects. Considering these mechanisms as distinct from allostasis is somewhat artificial given overlapping functions and intricate coregulation of monoamines and the limbic-hypothalamic-pituitary-adrenal axis. It also fractionates literatures that should be mutually informative. In this article, we describe structural and functional alterations in serotonergic, dopaminergic, and noradrenergic neural systems following both acute and prolonged exposure to stress. Through increases in behavioral impulsivity, trait anxiety, mood and emotion dysregulation, and asociality, alterations in monoamine functioning have profound effects on personality, attachment relationships, and the emergence of psychopathology.

Social Motivation Across Multiple Measures: Caregiver-Report of Children with Autism Spectrum Disorder.

Social motivation is a foundational construct with regard to the etiology, neurobiology, and phenotype of autism spectrum disorder (ASD). Multiple theories suggest that early emerging alterations to social motivation underlie a developmental cascade of social and communication deficits across the lifespan. Despite this significance, methods to measure social motivation vary widely, with little data to date as to how different measures might compare. In this study, we explore three existing caregiver-report measures that have been proposed to quantify social motivation among school-age children with ASD (n = 18; all male) and without ASD (n = 36; 50% female), with the broad goal of characterizing social motivation across measures and specific aims of investigating (a) diagnostic and sex differences in social motivation, (b) correspondence between measures, and (c) relationships between social motivation and broader social outcomes. Across all three measures, individuals with ASD had lower social motivation by caregiver-report. However, they did display individual differences in the degree of social motivation reported. There were no differences in social motivation between males and females without ASD on any of the three measures. For the full sample, measures of social motivation correlated with one another as anticipated, and stronger social motivation was associated with stronger social skills and fewer social difficulties. Our data suggest that social motivation among children with ASD may be best conceptualized as an individual difference that is diminished on average relative to peers but which varies among children and adolescents with ASD, rather than as an absolute absence or uniform deficit. LAY SUMMARY: Several theories suggest that children with autism spectrum disorder (ASD) experience less social motivation than their peers without ASD, contributing to difficulties in social skills. Based on multiple caregiver-report questionnaires, social motivation was reduced on average for school-age children with ASD but also varied among children with ASD. Stronger social motivation was related to stronger social skills and fewer social problems. Future work should include more girls with ASD, consider social motivation across age groups, and include first-hand perspectives from people with ASD.

Brief Report: Can a Composite Heart Rate Variability Biomarker Shed New Insights About Autism Spectrum Disorder in School-Aged Children?

Several studies show altered heart rate variability (HRV) in autism spectrum disorder (ASD), but findings are neither universal nor specific to ASD. We apply a set of linear and nonlinear HRV measures-including phase rectified signal averaging-to segments of resting ECG data collected from school-age children with ASD, age-matched typically developing controls, and children with other psychiatric conditions characterized by altered HRV (conduct disorder, depression). We use machine learning to identify time, frequency, and geometric signal-analytical domains that are specific to ASD (receiver operating curve area = 0.89). This is the first study to differentiate children with ASD from other disorders characterized by altered HRV. Despite a small cohort and lack of external validation, results warrant larger prospective studies.

Resting state EEG in youth with ASD: age, sex, and relation to phenotype.

BACKGROUND: Identification of ASD biomarkers is a key priority for understanding etiology, facilitating early diagnosis, monitoring developmental trajectories, and targeting treatment efforts. Efforts have included exploration of resting state encephalography (EEG), which has a variety of relevant neurodevelopmental correlates and can be collected with minimal burden. However, EEG biomarkers may not be equally valid across the autism spectrum, as ASD is strikingly heterogeneous and individual differences may moderate EEG-behavior associations. Biological sex is a particularly important potential moderator, as females with ASD appear to differ from males with ASD in important ways that may influence biomarker accuracy. METHODS: We examined effects of biological sex, age, and ASD diagnosis on resting state EEG among a large, sex-balanced sample of youth with (N = 142, 43% female) and without (N = 138, 49% female) ASD collected across four research sites. Absolute power was extracted across five frequency bands and nine brain regions, and effects of sex, age, and diagnosis were analyzed using mixed-effects linear regression models. Exploratory partial correlations were computed to examine EEG-behavior associations in ASD, with emphasis on possible sex differences in associations. RESULTS: Decreased EEG power across multiple frequencies was associated with female sex and older age. Youth with ASD displayed decreased alpha power relative to peers without ASD, suggesting increased neural activation during rest. Associations between EEG and behavior varied by sex. Whereas power across various frequencies correlated with social skills, nonverbal IQ, and repetitive behavior for males with ASD, no such associations were observed for females with ASD. CONCLUSIONS: Research using EEG as a possible ASD biomarker must consider individual differences among participants, as these features influence baseline EEG measures and moderate associations between EEG and important behavioral outcomes. Failure to consider factors such as biological sex in such research risks defining biomarkers that misrepresent females with ASD, hindering understanding of the neurobiology, development, and intervention response of this important population.

Ten good reasons to consider biological processes in prevention and intervention research.

Most contemporary accounts of psychopathology acknowledge the importance of both biological and environmental influences on behavior. In developmental psychopathology, multiple etiological mechanisms for psychiatric disturbance are well recognized, including those operating at genetic, neurobiological, and environmental levels of analysis. However, neuroscientific principles are rarely considered in current approaches to prevention or intervention. In this article, we explain why a deeper understanding of the genetic and neural substrates of behavior is essential for the next generation of preventive interventions, and we outline 10 specific reasons why considering biological processes can improve treatment efficacy. Among these, we discuss (a) the role of biomarkers and endophenotypes in identifying those most in need of prevention; (b) implications for treatment of genetic and neural mechanisms of homotypic comorbidity, heterotypic comorbidity, and heterotypic continuity; (c) ways in which biological vulnerabilities moderate the effects of environmental experience; (d) situations in which Biology x Environment interactions account for more variance in key outcomes than main effects; and (e) sensitivity of neural systems, via epigenesis, programming, and neural plasticity, to environmental moderation across the life span. For each of the 10 reasons outlined we present an example from current literature and discuss critical implications for prevention.