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The Neurodevelopmental Basis of Early Childhood Disruptive Behavior: Irritable and Callous Phenotypes as Exemplars.

ABSTRACT: The arrival of the Journal's 175th anniversary occurs at a time of recent advances in research, providing an ideal opportunity to present a neurodevelopmental roadmap for understanding, preventing, and treating psychiatric disorders. Such a roadmap is particularly relevant for early-childhood-onset neurodevelopmental conditions, which emerge when experience-dependent neuroplasticity is at its peak. Employing a novel developmental specification approach, this review places recent neurodevelopmental research on early childhood disruptive behavior within the historical context of the Journal. The authors highlight irritability and callous behavior as two core exemplars of early disruptive behavior. Both phenotypes can be reliably differentiated from normative variation as early as the first years of life. Both link to discrete pathophysiology: irritability with disruptions in prefrontal regulation of emotion, and callous behavior with abnormal fear processing. Each phenotype also possesses clinical and predictive utility. Based on a nomologic net of evidence, the authors conclude that early disruptive behavior is neurodevelopmental in nature and should be reclassified as an early-childhood-onset neurodevelopmental condition in DSM-5. Rapid translation from neurodevelopmental discovery to clinical application has transformative potential for psychiatric approaches of the millennium. [AJP at 175: Remembering Our Past As We Envision Our Future November 1938: Electroencephalographic Analyses of Behavior Problem Children Herbert Jasper and colleagues found that brain abnormalities revealed by EEG are a potential causal factor in childhood behavioral disorders. (Am J Psychiatry 1938; 95:641-658 )].

SUBMITTER: Wakschlag LS

PROVIDER: S-EPMC6075952 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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The Neurodevelopmental Basis of Early Childhood Disruptive Behavior: Irritable and Callous Phenotypes as Exemplars.

Wakschlag Lauren S LS Perlman Susan B SB Blair R James RJ Leibenluft Ellen E Briggs-Gowan Margaret J MJ Pine Daniel S DS

The American journal of psychiatry 20171117 2

The arrival of the Journal's 175th anniversary occurs at a time of recent advances in research, providing an ideal opportunity to present a neurodevelopmental roadmap for understanding, preventing, and treating psychiatric disorders. Such a roadmap is particularly relevant for early-childhood-onset neurodevelopmental conditions, which emerge when experience-dependent neuroplasticity is at its peak. Employing a novel developmental specification approach, this review places recent neurodevelopment ...[more]

PMID: 29145753

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Project description:IntroductionIrritability has both mood and behavioral manifestations. These frequently co-occur, and it is unclear to what extent they are dissociable domains. We used confirmatory factor analysis and external validators to investigate the independence of mood and behavioral components of irritability.MethodsThe sample comprised 246 patients (mean age 45 years; 63% female) from four outpatient programs (depression, anxiety, bipolar, and schizophrenia) at a tertiary hospital. A clinical instrument rated by trained clinicians was specifically designed to capture irritable mood and disruptive behavior dimensionally, as well as current categorical diagnoses i.e., intermittent explosive disorder (IED); oppositional defiant disorder (ODD); and an adaptation to diagnose disruptive mood dysregulation disorder (DMDD) in adults. Confirmatory factor analysis (CFA) was used to test the best fitting irritability models and regression analyses were used to investigate associations with external validators.ResultsIrritable mood and disruptive behavior were both frequent, but diagnoses of disruptive syndromes were rare (IED, 8%; ODD, 2%; DMDD, 2%). A correlated model with two dimensions, and a bifactor model with one general dimension and two specific dimensions (mood and behavior) both had good fit indices. The correlated model had root mean square error of approximation (RMSEA) = 0.077, with 90% confidence interval (90%CI) = 0.071-0.083; comparative fit index (CFI) = 0.99; and Tucker-Lewis index (TLI) = 0.99, while the bifactor model had RMSEA = 0.041; CFI = 0.99; and TLI = 0.99 respectively). In the bifactor model, external validity for differentiation of the mood and behavioral components of irritability was also supported by associations between irritable mood and impairment and clinical measures of depression and mania, which were not associated with disruptive behavior.ConclusionsPsychometric and external validity data suggest both overlapping and specific features of the mood vs. disruptive behavior dimensions of irritability.

Project description:BACKGROUND:Neurodevelopmental disorders (NDDs) such as autism spectrum disorder, intellectual disability, developmental disability, and epilepsy are characterized by abnormal brain development that may affect cognition, learning, behavior, and motor skills. High co-occurrence (comorbidity) of NDDs indicates a shared, underlying biological mechanism. The genetic heterogeneity and overlap observed in NDDs make it difficult to identify the genetic causes of specific clinical symptoms, such as seizures. METHODS:We present a computational method, MAGI-S, to discover modules or groups of highly connected genes that together potentially perform a similar biological function. MAGI-S integrates protein-protein interaction and co-expression networks to form modules centered around the selection of a single "seed" gene, yielding modules consisting of genes that are highly co-expressed with the seed gene. We aim to dissect the epilepsy phenotype from a general NDD phenotype by providing MAGI-S with high confidence NDD seed genes with varying degrees of association with epilepsy, and we assess the enrichment of de novo mutation, NDD-associated genes, and relevant biological function of constructed modules. RESULTS:The newly identified modules account for the increased rate of de novo non-synonymous mutations in autism, intellectual disability, developmental disability, and epilepsy, and enrichment of copy number variations (CNVs) in developmental disability. We also observed that modules seeded with genes strongly associated with epilepsy tend to have a higher association with epilepsy phenotypes than modules seeded at other neurodevelopmental disorder genes. Modules seeded with genes strongly associated with epilepsy (e.g., SCN1A, GABRA1, and KCNB1) are significantly associated with synaptic transmission, long-term potentiation, and calcium signaling pathways. On the other hand, modules found with seed genes that are not associated or weakly associated with epilepsy are mostly involved with RNA regulation and chromatin remodeling. CONCLUSIONS:In summary, our method identifies modules enriched with de novo non-synonymous mutations and can capture specific networks that underlie the epilepsy phenotype and display distinct enrichment in relevant biological processes. MAGI-S is available at https://github.com/jchow32/magi-s .

Project description:ObjectiveDisruptive mood dysregulation disorder (DMDD) in DSM, characterized by severe, chronic irritability, currently excludes children <6 years of age. However, capitalizing on a burgeoning developmental science base to differentiate clinically salient irritability in young children may enable earlier identification. The objective of this study was to advance an empirically derived framework for early childhood DMDD (EC-DMDD) by modeling and validating DMDD patterns in early childhood and generating clinically informative, optimized behaviors with thresholds.MethodData (N = 425) were from 3 longitudinal assessments of the MAPS Study, spanning preschool (means = 4.7 and 5.5 years) to early school age (mean = 6.8 years). The Multidimensional Assessment Profile of Disruptive Behavior (MAP-DB) Temper Loss scale captured irritability, the Family Life Impairment Scale (FLIS) assessed cross-domain impairment at the preschool time points and the Schedule for Affective Disorders and Schizophrenia for School-Age Children (K-SADS) was used to assess clinical status at early school age. Latent transition analyses differentiated children with EC-DMDD from children with low, transient, or nonimpairing irritability.ResultsDevelopmental patterning of irritability proved important for normal:abnormal differentiation. Of children, 27% had initially high irritability, but only two-thirds of these were persistently highly irritable. Thus, "false positives" based on a single screen would be substantial. Yet, "false negatives" are low, as <1% of children with baseline low irritability demonstrated later high irritability. Based on the sequential preschool-age time points, 6.7% of children were identified with EC-DMDD, characterized by persistent irritability with pervasive impairment, similar to prevalence at older ages. Specific behaviors included low frustration tolerance; dysregulated, developmentally unexpectable tantrums; and sustained irritable mood, all of which sensitively (0.85-0.96) and specifically (0.80-0.91) identified EC-DMDD. EC-DMDD predicted irritability-related syndromes (DMDD, oppositional defiant disorder) at early school age better than downward extension of DSM DMDD criteria to preschool age.ConclusionThese findings provide empirical thresholds for preschool-age clinical identification of DMDD patterns. The results lay the foundation for validation of DMDD in early childhood and inform revision of DSM criteria.

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The Neurodevelopmental Basis of Early Childhood Disruptive Behavior: Irritable and Callous Phenotypes as Exemplars.

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The Neurodevelopmental Basis of Early Childhood Disruptive Behavior: Irritable and Callous Phenotypes as Exemplars.

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