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

Abstract

The Journal’s 175^th anniversary combined with recent advances in research provides 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. We 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, we 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.

Introduction

Mental disorders are increasingly recognized as neurodevelopmental phenomena evolving from preclinical signs, to symptoms, and chronic illness (1-4). However, relevant science is evolving more rapidly than clinical application (3, 4). The Journal’s upcoming 175^th anniversary provides an opportunity to present a neurodevelopmental roadmap toward clinical integration. Because early childhood conditions markedly influence health trajectories, illuminating their neurodevelopmental substrates is key. To do so we look back – via a historical lens focused on The Journal — and ahead, drawing on advances in many areas, particularly neuroscience, and the clinical and developmental sciences, to explicate the neurodevelopmental basis of early childhood disruptive behavior.

Disruptive behavior is one of the earliest-onset psychopathologies, whose serious form is nearly always expressed in some manner before age five (5, 6). It is also common and predictive of diverse problems across the lifespan (7-9). Yet, it is not currently counted within the lexicon of neurodevelopmental disorders in DSM 5, despite inclusion of similar conditions such as ADHD. Neurodevelopmental disorders such as autism are characterized by abnormal behaviors (e.g., stereotypies) that do not occur in typical development. In contrast, disruptive behavior and ADHD both exhibit waxing and waning expressions over time, and require developmentally-sensitive differentiation of clinical forms from normative variation in early childhood (10, 11). This commentary reviews a nomological net of evidence on the neurodevelopmental nature of early disruptive behavior, emphasizing two of its prominent dimensional phenotypes: irritability and callous behavior. Burgeoning science demonstrates that: (1) narrow-band phenotypes illuminate brain-based mechanisms (12); (2) abnormalities in salient behavior and physiology manifest early, portending developmental impairments in multiple systems (13-18); and (3) neurodevelopmental syndromes have perinatal roots, multi-factorial origins, and clear genetic components (19-22).

Defining the Neurodevelopmental in Early Childhood Syndromes

In broad strokes, “neurodevelopmental” connotes developmental unfolding of behavior underpinned by brain maturation, through interactions among brain systems (4). “Neurodevelopmental mental disorders” connote delays or deviations in behavioral and psychological function due to delays or deviations in brain development (3, 4). Thus, neurodevelopmental disorders require both disrupted physiology and impaired functioning. Although psychiatric disorders unfold in complex and heterogeneous ways, for heuristic purposes, we define two primary ways in which atypical neurodevelopment impacts behavior and functioning. One class of disorders manifests as neurodevelopmental predisposing features that probabilistically increase risk for later symptoms. Most mental disorders possess such features, which should be more strongly emphasized in DSM and the NIMH Research Domain Criteria (RDoC) (3). In the current review, our focus is on a second class of disorders that manifest as early childhood-onset neurodevelopmental conditions. These are clinically expressed in early life and associated with impaired developmental capacities and an atypical neurodevelopmental course. Our emphasis on this latter set of conditions reflects the potential for early identification and treatment to reduce the public health burden of psychiatric illness, since experience-dependent neuroplasticity is at its peak during early childhood (18).

Historical Perspectives on Disruptive Behavior in Psychiatric Research

Disruptive behavior reflects a pattern of irritability and disregard for social norms (23). Its pediatric form, classified as DSM 5 oppositional defiant- and conduct disorders, represents a widely-validated, early-onsetting developmental psychopathology, with prevalence similar to ADHD (2-17%) (24). Early disruptive behavior frequently co-occurs with other neurodevelopmental disorders and is a marker for chronic mental disorder risk (9, 14, 25-27). However, its exclusion from the DSM 5 neurodevelopmental lexicon (28), highlights continuing controversy about its phenomenology and mechanisms (29-31). Uncertainty about the neurodevelopmental nature of disruptive behavior partly reflects its heterogeneous developmental expressions, as currently reflected in typologies based on age-of-onset and persistence seminally introduced by Moffitt (32). Historically, this has led to emphasis of sociological features of disruptive behavior only indirectly related to brain development (33), despite the fact that Moffitt’s theory emphasizes the prominence of neurodevelopment in early emergence (34). Other early work, including Patterson’s social learning “coercive cycle” model, also prominently emphasized sociological and family environmental factors in early disruptive behavior (35). Over time, this framework has failed to explain heterogeneity of early-onset pathways, however. In particular, it underemphasizes prominent neurodevelopmental atypicality evident very early in life for childhood disruptive behavior, and the fact that young children receiving competent parenting also manifest disruptive behavior (5, 21, 36, 37). Further, this framework fails to adopt current perspectives on gene-environment interplay, which now recognize how social experience impacts outcomes in neurodevelopmental disorders with very high genetic burden (38, 39).

Important papers in The Journal provide a useful historical context for illuminating evolving conceptualizations of disruptive behavior. During the 20^th century, most papers on disruptive behavior focused on adolescent delinquency. As early as the 1920s, The Journal published studies emphasizing the role of socio-environmental factors in childhood disruptive behavior (40), an emphasis notable well into the latter part of the century (41, 42). A focus on pathophysiologic underpinnings of disruptive behavior also emerged in the early 20^th Century, as reflected in emphasis on epilepsy-related neurophysiologic abnormalities (43). Papers in the mid-20^th century and beyond placed greater emphasis on developmental origins of antisocial behavior, highlighting the predictive utility of childhood disruptive behavior for adult psychiatric disease, and its physiologic underpinnings, including the interaction of perinatal risk and early harsh environments in antisocial pathways (44-50). Consistent with broader, evolving trends at the turn of the century (51-53), more recent papers began to conceptualize early childhood psychopathology within a mental disorder framework (54-58). During this same period, emergent evidence began to uncover the clinical utility of parsing heterogeneous clinical phenomena into component features, with particular emphasis on irritability and its incremental predictive utility for later mood disorders (59-65). Building on this foundation, leading voices have called for qualitative shifts in approach –away from avoidance of early identification for fear of stigmatizing children with psychiatric labels as connoting a “fateful and unchangeable condition” (66), towards a view of early-childhood psychopathology as a critical public health opportunity (18).

The Developmental Phenotype of Early Disruptive Behavior

Core features of disruptive behavior include deficient ability to control irritable affect and conform with social rules (23, 29, 67). In DSM, these behaviors have traditionally been conceptualized along a developmental sequence, beginning with ODD, followed by adolescent CD, and culminating in adult antisocial personality (68). However, we have suggested that rather than an ordered emergence of increasingly severe phenomenology, this sequence actually reflects the adolescence-driven emphasis in traditional disruptive behavior phenotyping, where symptoms such as truancy cannot occur in young children (53). Research at younger ages fails to support this traditional developmental sequence, as noncompliance, aggression, and tantrums commonly co-occur as the presenting features of early childhood disruptive behavior (53, 69). Finally, a number of studies now support parsing the heterogeneity of childhood disruptive behavior via narrow-band dimensional phenotypes. In particular, these studies differentiate childhood dimensions of ODD, with irritable vs. noncompliant symptoms differentially predicting mood vs. conduct problems respectively. This pattern is evident from early childhood and has utility for specification of mechanisms (64, 70-75).

Dimensional focus.

Our own work generates a model of disruptive behavior with four dimensions: 1) aggression, 2) noncompliance, 3) irritability, and 4) callous behavior (75). The current review focuses on irritability and callous behavior for two key reasons: First, these two dimensions possess a strong neurodevelopmental science base (76, 77). Second, a comparison of their phenomenology highlights heterogeneous developmental expressions. For example, expression of irritability is exemplified by behaviors such as temper tantrums, which occur normatively in most young children and are only pathognomonic when very frequent and dysregulated (65, 78). In contrast, callous traits, as reflected in diminished response to the distress of others, do not normatively occur in development. When they do, however, they are a developmental risk marker for severe antisocial syndromes (79-81). Concern for others’ feelings manifests in rudimentary form as early as infancy, making identification of callous tendencies from very early in life plausible (82- 84). Together, these two dimensions predict many common childhood- and adult-onset mental disorders (5, 9, 11, 85). Thus, characterizing their neurodevelopment within a mental disorder framework could impact potentially chronic problems at a much earlier phase of the clinical sequence, which is of great import for prevention (4).

Our in-depth focus on these two phenotypes is intended as an exemplar of the neurodevelopment of disruptive behavior, leveraging the specificity and rich science base of irritability and callous behaviors. Aggression, another core disruptive behavior dimension, also emerges early and predicts later antisocial pathways (5, 6). However, it lacks clinical specificity as its varied forms are associated with both irritability (reactive aggression) and callous behaviors (proactive aggression) (76, 77). Further, relative to these first three dimensions, noncompliance has received far less attention in neuroscience.

Developmental Specification Framework

We employ a novel developmental specification framework to synthesize neurodevelopmental data, with implications for nosology and early identification. Defining the neurodevelopmental nature of mental disorder is complex, because it requires characterizing expectable age-related changes, individual differences in these patterns, and their intersection within a rapidly changing field of development (4, 23). This can be accomplished within a developmental specification framework (see heuristic, Figure 1). The initial stage identifies normative neurodevelopmental processes supporting functions within clinically-relevant domains (1a) (23). The second stage statistically differentiates behavioral abnormalities and their co-occurrence in relation to normative patterns. At the behavioral level, determination of abnormality is based on frequency (i.e., rare occurrence such as < 10% of the population) (51, 75), and severity that maps behaviors across a normal-abnormal spectrum based on qualitative features such as impairment in function (1b). We concretely illustrate this approach through psychometric work on the MAPS Study via the Multidimensional Assessment Profile of Disruptive Behavior (MAP-DB), with dimensional irritability (“Temper Loss”) and callous behavior (“Low Concern for Others”) scales (75). The MAP-DB was created to quantify the full normal:abnormal spectrum of disruptive behavior in early childhood, using item response theory (IRT) methods (65, 75).

Figure 1.

Developmental Specification Model: Clinical Neurodevelopmental Differentiation Process in Early Childhood

The developmental specification process for neural abnormalities mirrors the statistical approach for behavior (1c). Specification of brain-behavior substrates underlying particular clinical syndromes is still evolving. Consistent with RDoC, we view behavioral abnormalities as reflecting underlying pathophysiology (86). Optimally, neural abnormalities also would be determined at the population level (87, 88), but pathophysiology data generally exist only for smaller, extreme-group comparisons. Thus, the studies described below are a first step toward rigorous establishment of neural disruptions underlying early irritability and callous behaviors. Accruing evidence supports the utility of this framework, by deploying developmentally-sensitive neuroscientific tools, including fNIRS, eye tracking, EEG/ERP, and developmentally-modified MRI and fMRI methods (87, 89-91). This work finds meaningful parallels between early life and later correlates of irritability and callousness, which informs developmental perspectives (1c) (92, 93). Based on characterization in the first three phases (1a-1c), clinical salience is then determined (1d) by empirically demonstrating the utility of these brain:behavior abnormalities for clinical prediction and treatment delivery (1d).

Developmental Specification of Neurodevelopmental Patterns of Early Irritability

Irritability and its clinical manifestations

Irritability reflects a relative dispositional tendency to respond with anger to blocked goal attainment (65, 94, 95). There are substantial individual differences in the intensity, ease of elicitation, and persistence of irritability and the extent to which irritability impairs functioning. These individual differences are shaped by developmental assets and vulnerabilities as well as bi-directional associations with experience (96-101). Long considered a complicating factor in other developmental psychopathologies, irritability is more recently considered a problem in its own right (93). Clinical levels of irritability occur in 3-20% of children, with higher estimates in early childhood, and developmentally varying heritability estimates (i.e., .3-.8) (61, 97, 102). Irritability has traditionally been classified as a feature of ODD. In DSM 5, it is also the defining feature of the new Disruptive Mood Dysregulation Disorder (DMDD). ODD and DMDD are overlapping in their characterization of irritability, with most children meeting criteria for both disorders (103). In young children, irritability is currently best captured as a disruptive syndrome, as being younger than age six is an exclusion criterion for DMDD in DSM 5. Further, given the arbitrary, a developmental threshold for irritability severity in DMDD, its stability and incremental utility remains in question (103, 104). Irritable mood may also be an indicator of depressed mood in young children. However, predominant features of young children’s depression are anhedonia and sad/withdrawn affect, and disruptive behavior is much more common than depression at preschool age (105). Irritability also commonly co-occurs in many other childhood-onset disorders (98-100, 106-108), and increases the risk of adult mental disorder, particularly depression and anxiety, net effect of concurrent irritability symptoms (62, 109). Pervasive infant irritability is also associated with nearly triple the risk of disruptive behavior through middle childhood (101). As clinical investigations of irritability have been largely disorder-specific, work on the transdiagnostic import of its early emergence is needed (73, 98, 99, 110, 111). Since the transdiagnostic approach to irritability is relatively new, it is not yet known whether there is an adolescent or adult-onset phenotype. However, clinically salient, persistent childhood irritability is typically presaged by an irritable disposition in the first years of life. (112).

Normative developmental substrates of irritability (2a).

Clinical patterns of early childhood irritability are exaggerations of normative patterns. Irritable mood and temper tantrums are normative misbehaviors that occur in most children (113, 114). For example, 83.7% of preschoolers have regular temper tantrums (78). As a result, ODD irritability-symptom thresholds derived from older children result in triple the prevalence compared to developmentally-specified thresholds for early childhood (51). Thus, delineating the boundaries between normal and abnormal irritability in early childhood is particularly complex. Figure 2 highlights the application of the developmental specification framework to irritability.

Figure 2.

Application of Developmental Specification Model: Clinical Neurodevelopmental Differentiation of Early Childhood Irritability

Irritable mood and behavior are normatively heightened during early childhood as increased capacity leads to enhanced frustration with environmental limits (95). Emotion regulation, which involves both top-down arousal processes and bottom-up control processes, is the key developmental capacity undergirding modulation of irritability (25, 115, 116). Early executive function capabilities support self-regulation of anger and modulation. These capabilities become increasingly sophisticated across the preschool period (117-119), most likely due to growth during early childhood of cortical structures mediating anger regulation, with most rapid growth from 0-2 years, and 90% of adult brain volume achieved by age six (87).

Statistical differentiation of early abnormal irritability (2b).

We have established the normal:abnormal spectrum of irritability using the MAP-DB Temper Loss scale in the two large MAPS community samples of preschoolers (see Supplementary Online Table S1) (65, 75). Relatively mild expressions are common (Table S1; Figure 3 delineates severity of individual behaviors). In contrast, abnormal expressions are captured in items that are above a psychometrically-derived clinical threshold, representing the severe end of a latent irritability trait. Thus, abnormality is defined in terms of frequency, dysregulation (e.g. destructive tantrums), persistence (e.g. longer than five minutes), and developmental expectability in context (e.g., frustrated vs. ‘out of the blue”) (78). Similar patterns in multiple community and clinical samples demonstrates replicability (Table S1) (65, 78, 120). Thus, while most preschoolers exhibit some irritable behavior, frequent, highly dysregulated, and long- lasting behaviors are not endorsed for most children; these patterns appear to be parallel in infancy with some variation in frequency thresholds (121).

Figure 3.

Psychometric Severity Spectrum of Early Childhood Irritability (MAP-DB Temper Loss in Early Childhood)

Early irritability and neurodevelopmental abnormalities (2c).

The central emphasis of pathophysiologic investigations identifies atypical responses to frustrative non-reward, reflecting abnormalities in intensity, duration, and ease of elicitation (65, 77). This mirrors clinical features of irritability in young children (78, 113). Dysfunctions may involve atypical reward processing, aberrant subcortical activation, and perturbed prefrontal functions. More recently, research on adolescents also points to dysfunctional threat processing in the pathophysiology of irritability (77, 122). However, this work has not yet been systematically extended to younger children. In early explorations in the MAPS Study, perturbed threat processing is implicated in preschool anxiety (123), but not irritability.

Executive functioning.

Executive function involves top-down control of processes that guide behavior and undergird emotion, self-regulation, and goal-oriented achievement (115, 118). Deficits in executive function impede children’s ability to regulate negative emotions and execute adaptive responses (118). Developmental perturbations of the prefrontal cortex may impair the regulation of emotional arousal in irritable children (124-126). In the only investigation to date of the neural processes underlying executive function in early irritability, Perlman and colleagues found that children who are dispositionally, but not clinically, irritable display increased lateral PFC activation during a task requiring cognitive flexibility relative to non-irritable children (72). The relative capacity of irritable children to recruit this region may serve an adaptive regulatory function.

From a behavioral perspective, young children with deficits in response reversal are less effective at regulating mood and behavior across varied social contexts, while those who can shift attention flexibly during frustration/demand tasks are at reduced risk of externalizing problems (116, 127, 128). In terms of predicting clinical problems, irritable preschoolers with a blunted error-related negativity (ERN) response manifest signs of deficient conflict monitoring (73). Such children face risk for later disruptive behavior, unlike irritable preschoolers with an enhanced ERN who face risk for anxious/depressed symptoms (73). These findings reflect the context-sensitive deployment of executive function processes (39). For example, irritable infants with left frontal electroencephalographic (EEG) asymmetry exhibit poorer inhibitory control (129). Parallels at older ages include the presence of cognitive flexibility deficits along with underlying PFC and striatal functional deficits in irritable adolescents (130, 131). Of course, executive function is both a common and dissociable mechanism of a range of psychopathologies (132). For example, although executive dysfunction is not the hallmark of callousness, there is evidence that serves as a moderator of clinical escalation from childhood irritability and callous behavior (133, 134).

Reward processing.

Individual differences in irritability are associated with aberrant reward processing (93). Irritable young children have a relatively high reward orientation and approach tendencies, putting them at risk for frequent and intense frustration (111). These patterns may differentiate irritable young children with adaptive vs. maladaptive functioning (12, 135). Variation in severity across the irritability spectrum is associated with differential activation in the dorsolateral prefrontal cortex (DLPFC), a region that also serves executive function, manifesting as an inverted U association (12). Specifically, along the ascending arm of the curve, irritability and DLPFC activation are positively associated at frustration onset, i.e., higher irritability is correlated with greater DLPFC activation. In contrast, in the descending arm of the inverted U curve, irritability and DLPFC activation are negatively associated at frustration activation, i.e., higher irritability is associated with weaker DLPF activation (12). Children within the first sub-group (ascending arm of inverted U) had variable irritability levels but all fell within the normative range of irritability on the MAP-DB Temper Loss scale, whereas the latter sub-group (descending arm of inverted U) had sub-clinical to clinical level MAP-DB Temper Loss scores. This inverted U-pattern points to the possibility that developmentally typical vs. atypical reward processing may be a pathophysiologic mechanism associated with the transition from vulnerability to clinical disorder in children at risk for irritability related pathology. Of note, in this study the neural threshold marking the transition of the inverted-U (i.e., the point at which the association between DLPFC activation and irritability switched from positive to negative) closely approximates the psychometrically derived severity on the MAP-DB scale. Other salient work relies on event-related potentials. Here, clinically salient patterns of irritability at preschool age, as captured via symptoms of Disruptive Mood Dysregulation Disorder (DMDD), predicted pre-adolescent enhanced neural sensitivity to reward (ERP reward positivity), possibly contributing to exaggerated stimulus response learning and perseveration (136).

Clinical and predictive validity of early childhood irritability (2d).

At least 10 studies have demonstrated specific clinical and predictive utility of early childhood irritability. These studies support five major conclusions (Table 1);(1) Clinically-significant irritability differs from normative variation in terms of qualitative features, including in frequency, dysregulation, and context (78, 113, 144); (2) Developmental patterns of irritability manifest across a dimensional spectrum. Probabilistic risk for clinical disorder occurs along the irritability spectrum at levels typically defined as within the normal range. For example, more than 2/3 of preschoolers at 1 SD above the population mean for MAP-DB Temper Loss meet criteria for DSM mood and/or behavioral disorders (65). This is not surprising given that the Temper Loss dimension encompasses both the dysregulated outbursts that are core features of ODD, and irritable mood features associated with depression and anxiety (65, 94). (3) Dysregulated tantrums are a clinical marker. These include intense, prolonged and destructive tantrums, and difficulty recovering from tantrums. Dysregulated tantrums are significantly more likely in clinic vs. community-based samples of 3-6 year old children, virtually always associated with impairment in referred children and developmental atypicality beginning at very young ages (113, 120, 147). These clinical findings converge with psychometric thresholds of severity (Figure 3); (4) Early irritability manifests coherent developmental patterning. Early childhood irritability is moderately stable (mean r=.70) but also demonstrates expectable intra- and inter-individual variability (65, 71, 133, 140, 148). Because of rapid rates of developmental change in emotion regulation in early childhood, accounting for longitudinal variability in growth of irritability across early childhood enhances clinical prediction (65); and (5) Early irritability has clinical and predictive validity. Despite these developmental fluctuations, early irritability has specific and incremental utility for later mood and disruptive disorders and impairment, above and beyond DSM symptoms (65, 71, 140).

Table 1:

Overview of Studies Demonstrating Clinical Validity of Early Childhood Irritability

Sample	Sample Size	Measurement1	Age(s)	Psychometri Validity1	Clinical & Predictive Validity
1. Barcelona Sample (71, 137)	622	DICA8 ODD symptoms	3, 4,5 & 6 yrs.	Yes	Differentiates association to concurrent disorders
					Trajectories differentiate normal:abnormal patterns to age 6
2. Bipolar At Risk Sample (138)	44	DB-DOS6 Observed Anger Modulation	3-6 yrs.	Yes	Preschoolers with family history of BPD have greater observed irritability
3. Connecticut Early Development Project (64)	532	ITSEA2 Temper Loss	3 yrs.	Yes	Concurrent impairment
4. Chicago Preschool Project (64, 139)	336	K-DBDs Index9 & DB-DOS6 Observed Anger Modulation	3-5 yrs.	Yes	Concurrent/ longitudinal impairment to age 6
5. Fragile Families & Child Wellbeing Study (140)	4,898	CBCL3	3, 5 & 9 yrs.	Yes	Trajectories over time differentiates normal:abnormal patterns: Stably high irritable have >risk of externalizing problems at age 9
6. Multidimensional Assessment of Preschoolers Study (MAPS) (75, 141, 142)	3,347 (psychometric), 497 (validity)	MAP-DB4 Temper Loss	3-5 yrs. with 9 mo. f-up.	Yes	Quality & frequency psychometrically distinguishes normal:abnormal patterns
					Concurrent/ longitudinal impairment, incremental utility beyond DSM-IV symptoms, differentiates clinical prediction to disruptive & mood disorders to age 8
7. Pittsburgh Developmental Psychopathology Study (127)	310 (boys)	Observed Anger Regulation	3.5 yrs. - 6 yrs.	Yes	Poorer regulation of anger predicts later externalizing problems to age 6
8. St. Louis Study of Early Depression (120)	279	PAPA7Tantrum Features	3-6 yrs.	Yes	Tantrum quality, duration and frequency differentiates disruptive and depressed preschoolers from healthy controls
9. Stonybrook Temperament & Clinical Samples (113, 136, 143, 144)	601	PAPA7Chronic Irritability	3-4 yrs. 6 & 9 yrs.	Yes	Current/longitudinal impairment & DSM-IV disorders.
					Incremental utility for disruptive & mood disorders, functional impairment & service use beyond baseline symptoms to age 9
					Differentiating facets of irritability (irritable mood and tantrums) has clinical utility
					DMDD prevalence: 6=8.2% (6.9% with daily criteria)
10. Twins Early Development Study (TEDS) (145)	3,154 twin pairs.	Irritability: SDQ5	4, 7 & 9 yrs.	Yes	Preschool irritability >stable through age 9 than behavioral conduct problems
11. Duke Preschool Study (146)	928	Irritability: PAPA7 DMDD symptoms	2-6 yrs.	Yes	DMDD prevalence: 3.3% (1.7% with daily criterion)

¹Psychometric validity, includes internal reliability, test-retest reliability, and contribution of unique model variance dissociable from general DB;

²ITSEA-Infant Toddler Social Emotional Assessment;

³CBCL-Child Behavior Checklist;

⁴MAP-DB-Multidimensional Assessment Profile of Disruptive Behavior;

⁵SDQ-Strengths and Difficulties Questionnaire;

⁶DB-DOS-Disruptive Behavior Diagnostic Observation Schedule;

⁷PAPA-Preschool Age Psychiatric Assessment;

⁸DICA-Diagnostic Interview for Children and Adolescents;

⁹K-DBDS-Kiddie Disruptive Behavior Disorder Schedule.

Developmental Specification of Neurodevelopmental Patterns of Early Callous Behavior

Callous behavior and its clinical manifestations.

Callous/unemotional traits reflect diminished responsiveness to the distress of others (67, 79, 149). Their early emergence is a marker of antisocial behavior persistence and severity, and may serve as a developmental substrate of psychopathy (150, 151). Prevalence of CD with CU traits in youth is estimated at 2-4% (~ 25-35% of children with CD), with heritability of 40-78% (149, 152). In DSM-5, CU traits are the core element of the “limited prosocial emotions” specifier for CD (153). However, as CU symptoms are not delineated in a developmentally-meaningful manner for young children, this has precluded their clinical evaluation in young children (53). Callous/unemotional traits probabilistically increase the risk of severe antisocial behavior and psychopathy, but most youth with these traits do not develop psychopathic tendencies. Thus, early CU traits represent a pattern of insensitivity to others which predisposes to severe antisocial behavior, however whether or not severe psychopathology develops likely depends on genetic risk, environment, learning, and opportunity (150, 154-156). [Note: We focus on callous behaviors, which have received far more attention in early childhood research than unemotional features.]

Developmental substrates of callous behavior (Figure 4).

Figure 4.

Application of Developmental Specification Model: Clinical Neurodevelopmental Differentiation of Early Childhood Callous Behaviors

Processes that go awry in callous syndromes are the development of empathic concern for others and of the moral emotions (e.g. shame) that undergird rule internalization (e.g., guilt) (4a) (75, 83, 152, 157, 158). While empathic concern was originally thought to be a late-developing process, developmental science now suggests that rudimentary concern for others is present at birth (83). The implication is that top down control is required to directly express concern; however, the capacity to feel for others is more automatic (83). For example, neonates are negatively aroused by the distress of others, reflecting overlap in the neural circuitry underlying perception of own vs. other emotions (159). Infants in the first year of life also demonstrate prosocial vs. antisocial preferences and empathic concern (83, 160-163). Moreover, toddlers exhibit stable dispositional empathy, internalization of rules, and perform prosocial acts to ameliorate others’ distress (161). Thus, sensitivity to others’ feelings and capacity to follow social norms manifests in the first years of life (83, 162). Moral emotions (e.g., guilt) are also identifiable in nascent forms as exhibited via bodily tension and gaze aversion following transgression in toddlers, and via expressions of remorse and reparation at preschool age (163). Both concern for others and guilt inhibit antisocial behavior that will cause others distress (164, 165).

Statistical differentiation of early callous behavior (4b).

Applying the psychometric approach, we have established the severity spectrum of callous behavior via the MAP-DB Low Concern for Others scale (75). Items range from indifference (e.g. “not seem to care about others’ feelings) to goal-oriented distress evocation (e.g., enjoy making others mad). In contrast to the common display of early irritable behaviors described above (Table S1), the severity spectrum of early Low Concern for Others indicates that these are not normative misbehaviors. None of the callous behaviors are common at preschool age (i.e., less than 1/3 of children are reported to have engaged in any these behaviors over the past month; Supplementary Online Table S2). Of note, all these behaviors were identified as psychometrically severe across two community samples of preschoolers (i.e., above the 95^th percentile severity threshold; Figure 5), regardless of SES context. Despite the greater severity of these callous type behaviors in general, there is still dimensional variation. The least severe item reflects insensitivity to others’ feelings in developmentally expectable contexts (e.g., “not caring about others feelings when upset”) whereas the most severe item reflects intentional provocation of distress in others (e.g., “doing things to humiliate others”) (Figure 5). This severity spectrum is consistent with findings that toddlers’ active evocation of others’ distress predicts adolescent CD symptoms whereas lower levels of prosocial concern do not (15).

Figure 5.

Psychometric Severity Spectrum of Early Childhood Callous Behaviors (MAP-DB Low Concern for Others Scale)

Early callous behavior and neurodevelopmental abnormalities (4c).

In adolescents and adults, specific affective and cognitive atypicalities have been robustly established as neural substrates of callousness, particularly amygdala dysfunction (166-168s). At least 10 studies have demonstrated specific, rather than general deficits, in emotion processing in callous youth (80, 81, 169). In particular, deficits in distress processing, especially fear processing, have been identified (170, 171). A recent fMRI meta-analysis also suggests specificity in patterns of neural disruptions of disruptive youth with and without psychopathic traits (which roughly parallels our irritable vs. callous distinction) (67).

Neurodevelopmentally, such socio-emotional deficits impair responsiveness to socialization. This is because attunement to others’ distress and displeasure inhibits other-directed negative behavior via transgression- and empathy-related arousal, and undergirds the development of conscience (84, 169). In terms of emotion processing deficits, we have demonstrated a specific association between MAP-DB Low Concern for Others and decrements in fear processing, net effects of impulsivity, aggression, and irritability at preschool age (81). While this requires replication, the specificity of these findings parallel to patterns in older youth is striking. Other pathophysiologic indicators of early callousness include impaired eye contact (during performance based and social interaction paradigms) (172), reduced cardiac and behavioral arousal in response to distress-eliciting stimuli; and increased fearlessness in contrast to irritable infants (173). The progression of early childhood callous behaviors to later externalizing problems is moderated by theory of mind deficits, underscoring the role of social processing deficits in these pathways (174). Evidence of heritability of callous traits in an adoption sample is also consistent with biologic plausibility (175). To our knowledge, developmentally sensitive neuroimaging techniques have not yet been employed to examine neural underpinnings of callous behavior in very young children, an important area for future research.

Clinical and predictive validity of early callous behavior (4d)

There has been a veritable explosion of research on callous behavior in early childhood (Table 2). Drawing on both direct observation and maternal report, at least 20 independent studies (beginning as young as 14 months of age) lead to the following conclusions: (1) Callous behavior can be assessed in a reliable and developmentally meaningful manner in very young children. Evidence of developmental validity includes data suggesting a dimensional spectrum and associations with developmental impairments in guilt, moral regulation, and empathy (75, 181); (2) Early callous behaviors have incremental clinical utility for prediction, above and beyond more common forms of disruptive behavior. Early callous behaviors are associated with increased risk of childhood disruptive behavior and later CD. For example, toddler observed disregard for others explains unique variance in adolescent CD symptoms (15). Conversely, observed indicators of emergent conscience predict reduced risk of conduct problems (161); (3) Early callous behavior manifests coherent developmental patterning. As the study of callous behavior in early childhood is relatively recent, few studies have examined its developmental patterning. There is evidence of moderate stability (ranging from .41-.83) (75, 195). Despite the more severe and pathognomonic nature of callous traits relative to irritability, their developmental patterns of stability and change are very similar in the MAPS sample (longitudinal instability in about 1/3 of the preschoolers). This is not surprising given that the developmental processes that undergird these behaviors are rapidly developing across early childhood. This variability in combination with the buffering effects of early parental sensitivity speak to the importance of considering callous behaviors as malleable in early childhood (84, 155, 184); and (4) Early callous behaviors predict more severe, and more treatment-resistant, forms of disruptive behavior. Early callous behaviors predict high and rising aggression and externalizing problems through adolescence (174, 181). Meta-analysis also indicates a large effect size of early callous behaviors on severity of preschool age conduct problems (r=.39, p<.001) (196).

Table 2:

Overview of Studies Demonstrating Clinical Validity of Early Childhood Callous Behaviors

Sample	Sample Size	Measurement	Age(s)	Psychometric Validity1	Clinical & Predictive Validity
1. Barcelona Study (176, 177)	622	ICU7	3 & 4 yrs.	Yes	Predicts DBD & co- morbid symptoms, impairment and service use @5 yrs., net age 3 DBDs& temperament
2. Colorado Longitudinal Twin Study (178, 15)	956	Observed and Interview derived Concern- & Disregard for Others	14-36 mo. (4x)	Yes	Disregard predicts CD symptoms to age 17 yrs.
3. Connecticut Early Development Project (64)	532	ITSEA2 Low Concern for Others	3 yrs.	Yes	No
4. Cyprus Sample (179)	214	ICU7 & University of New South Wales CU scale	3-6 yrs.	Yes	Associated with overt aggression & overall problem intensity
5. Chicago Preschool Project (64)	336	K-DBDs Low Concern for Others Index12	3-5 yrs.	Yes	No
6. Early Growth & Development Adoption Study (EGDS) (175, 180, 181)	561	CBCL3	26 mo.	Yes	Predicts externalizing problems @10 yrs. Severe antisocial behavior of biologic parent (+) and adoptive mother positive reinforcement (−) predicts callous behavior at 27 mos.
7. Early Steps Study (182-184)	731	CBCL3 + ECBI4+ ACRS5 Deceitful/Callous Behavior Scale	2-4 yrs. (3x)	Yes	Predicts problem behavior to 4 yrs., does not moderate treatment effectiveness
8. Durham Child Health & Development Study (173)	178	CBCL3	3 yrs.	Yes	No
9. Finnish Internet Assisted Parent Training Study (185)	464	ICU7	4 yrs.	Not reported	Is responsive to parent training
10. Head Start Sample (186)	49	ASPD6	2-5 yrs.	Yes	Associated with concurrent aggression
11. Hitkashrut Intervention Study (187)	209	ASPD6 & ICU7	3-5yrs.	Yes	Treatment improves CU behaviors & control group CU behaviors worsen
12. Iowa Family Study (161, 188)	102	ICU7 Decrements in observed features of conscience (empathy and internalization of rules)	5.5yrs. 25-52 mo. (3x)	Yes	Prediction of externalizing problems to 8 yrs.by:
					--interaction of CU behaviors & mutual parent- child engagement
					--poorly developed conscience
13. NICHD Early Child Care Study (189)	1,176	CBCL3	3 yrs.	Yes	Predicts stably high aggression to age 11
14. Michigan Preschool Externalizing Study (174, 181)	240	CBCL3	3 yrs.	Yes	Predicts growth of externalizing problems to age 10 yrs.
15. Multidimensional Assessment of Preschoolers Study (MAPS) (75, 141, 142)	3,347 (Psycho metric) 497 (validity)	MAP-DB8 Low Concern for Others & Punishment Insensitivity	3-5yrs.	Yes	Associated with concurrent & short-term longitudinal impairment
16. Parent Child Interaction Therapy (PCIT) Samples (190)	63	CBCL3	46 mo.	Yes	Predicts reduced response to treatment
17. Project Support Intervention Study (191)	66	APSD6 + ICU7	4-9yrs.	Yes	Treatment improves CU behaviors
18. Southeastern US Study (192)	102	APSD6 + SDQ10	4-6yrs.	Yes	No
19. Summer Treatment Camp Sample (193)	86	Peer nominations	5 yrs.	Yes	Associated with impairment in academic & social functioning
20. Pace Study (194)	610	ASPD6	4 yrs.	Yes	No

¹Psychometric validity, includes internal reliability, test-retest reliability, and contribution of unique model variance dissociable from general DB;

²ITSEA-Infant Toddler Social Emotional Assessment;

³CBCL-Child Behavior Checklist;

⁴ECBI-Eyberg Child Behavior Inventory;

⁵ACRS-Adult Child Relationship Scale;

⁶APSD-Antisocial Process Screening Device;

⁷ICU-Inventory of Callous/Unemotional Traits;

⁸MAP-DB-Multidimensional Assessment Profile of Disruptive Behavior;

⁹SDQ-Strengths and Difficulties Questionnaire;

¹⁰DB-DOS-Disruptive Behavior Diagnostic Observation Schedule;

¹¹PAPA-Preschool Age Psychiatric Assessment;

¹²K-DBDS-Kiddie Disruptive Behavior Disorder Schedule;

¹³DICA-Diagnostic Interview for Children and Adolescents

Intersection of Neurodevelopmental Predispositions and Environment in Shaping Disruptive Behavior Pathways

Our discussion to date has highlighted the substantial nomologic science base indicating that the behavioral and pathophysiologic atypicalities of irritable and callous syndromes are identifiable in early life. The likelihood that such early clinical and/or prodromal patterns will persist or escalate is probabilistic. That is, these early phenotypic patterns shape, and are shaped by, environmental inputs and outputs (155, 197, 198). For example, young children with aberrant eye gaze elicit less positive maternal feelings, and irritable children evoke more negative parenting behavior, with evidence of evocative rGE in adopted-out children (172, 197, 199). Such studies indicate the salience of bidirectional influences in the neurodevelopmental unfolding and persistence of clinical pathways. Longitudinal examination of the amplifying and buffering effects of these bidirectional processes in prediction of lifespan clinical trajectories is a critical next step for identifying modifiable, modulating influences for early neurodevelopmental atypicalities.

Conclusions and Future Directions

As The Journal nears its 175^th anniversary, the field is poised for a transformational shift, which embraces the neurodevelopmental nature of early childhood disruptive behavior based on integration of a robust and burgeoning evidence base at the intersection of developmental, clinical, and neuroscience fields. By The Journal’s 200^th anniversary, we envision early childhood disruptive behavior being fully incorporated within nosologic systems, such as the DSM, as a neurodevelopmental condition. This will serve as the foundation for brain-based prevention efforts designed to prevent exacerbation during this period of heightened neuroplasticity, and prevent the lifespan burden of chronic mental disorder at the point of origin. We anticipate that over these next few decades increased sharpening of irritable and callous and related disruptive behavior neurodevelopmental phenotypes may heighten clinical distinction, and perhaps result in demarcation of all or some of these as distinct early onset syndromes. In particular, we anticipate that irritability will emerge as a cross-cutting neurodevelopmental phenotype with targeted preventions that improve outcomes for young children with a host of early onset conditions including autism, ADHD, anxiety, and depression (26, 27, 58). Evidence that callous features can be meaningfully distinguished as early as the first years of life also points to the potential of targeted prevention for reducing lifecourse impact of severe antisocial behavior. More precise developmental specification linking behavior to pathophysiology supports such neuroscience-oriented preventive approaches (10, 200, 201).

These conclusions arise from a nomological net of evidence delineating coherent “neuro” and “developmental” perturbations underlying irritable and callous phenotypes. Clear gaps remain in this evidence base including insufficient neuroimaging research to clarify similarities and differences among early- and later-onset childhood disruptive behavior patterns, an intriguing compilation of neurodevelopmental findings, some of which still require replication, and the need for more systematic charting of normal variations in neurodevelopmental processes from the first years of life through adolescence. Despite these gaps, it is clear that these irritable and callous phenotypes reflect fundamental disruptions in neurodevelopment manifesting in the first years of life in ways distinct from the normative misbehavior of early childhood. Importantly, each phenotype signals distinct developmental perturbations in its own right, with associated patterns of pathophysiology replicating patterns in older youth. While further investigation can systematically strengthen the evidence base, the available data clearly and strongly point to these early disruptive behavior phenotypes as clinically meaningful and distinct neurodevelopmental entities.

While we here focus on early disruptive behavior, we also foresee that the developmental specification paradigm has broad applicability to advancing a neurodevelopmental understanding of mental disorder, with transformative implications for how we think about, identify, and treat psychiatric phenomenology across the lifespan (3). To the extent that investigation at the intersection of neuroscience, clinical and developmental science forms the basis for systematic clinical research approaches for both core types of neurodevelopmental conditions (i.e. those with neurodevelopmental predisposing factors and those that onset in early childhood), this will enable a truly neurodevelopmental nosology to be fully realized.

In conclusion, developmental, clinical, and cognitive sciences research on early childhood irritability and callous behavior converges to underscore the neurodevelopmental nature of early childhood disruptive behavior and points to the imperative to relinquish entrenched notions belied by recent research. Developmentally-specified, clinically informative toolkits set the stage for translation of neurodevelopmental discovery to clinical application for disruptive behavior and to mental disorders more broadly. Our review supports the strong imperative to “do better” at the earliest phases of this neurodevelopmental clinical sequence.