A Transdiagnostic Symptom Requires a Transdiagnostic Approach: Neural Mechanisms of Pediatric Irritability

Irritability, a hallmark feature of the new DSM-5 category of disruptive mood dysregulation disorder (DMDD), is present in many pediatric disorders including attention-deficit/hyperactivity disorder (ADHD), oppositional defiant disorder (ODD), depressive and anxiety disorders, and autism spectrum disorders. Indeed, irritability is among the most common presenting complaints in child psychiatry¹ and predicts long-term impairments including high suicidality and decreased education and income attainment.²

Despite the significant clinical toll and adverse outcomes of childhood irritability, our understanding of its neural mechanisms remains unclear. Studies designed a priori to measure irritability explicitly are particularly lacking. In pediatric psychopathology, irritability is ubiquitous and transdiagnostic. Given this, two fundamental questions are central to pathophysiological research on irritability – What neural mechanisms are unique to irritability vs. shared with other co-occurring symptoms (e.g., anxiety, ADHD, etc.)? Are the neural mechanisms underlying dimensionally-assessed irritability similar or different across diagnostic categories (i.e., is there an irritability by diagnosis interaction for neural mechanisms)? Two studies in this issue, Kryza-Lacombe et al.³ and Chaarani et al.,⁴ address these important questions by using Magnetic Resonance Imaging (MRI) to examine the neural mechanisms of dimensionally-assessed irritability transdiagnostically in two large samples.

Kryza-Lacombe et al. conducted the first study to investigate the neural underpinnings of irritability in a sample that included youths with autism. The authors examined associations between irritability and neural activation and amygdala connectivity in 120 youths (47 with high-functioning autism and 73 without autism; ages = 8–19 years) using an implicit face emotion task during which participants identified the gender (not the emotion) of faces expressing fear, anger, or happiness. Irritability was assessed using three items from the Child Behavior Checklist (CBCL). Higher levels of irritability were associated with less activation to fearful and happy faces in the left middle frontal gyrus and to happy faces in the left inferior frontal gyrus. Moreover, higher levels of irritability were associated with altered connectivity between the right amygdala and the left superior frontal gyrus during viewing of fearful and sad faces.

Chaarani et al. leveraged the large community-based IMAGEN dataset to examine structural and functional neural correlates of irritability in 14-year-old adolescents. Irritability was assessed using three items from the Development and Well-Being Assessment (DAWBA). Comparing 160 adolescents with moderate or high irritability to 160 controls without irritability, the irritable group showed lower grey matter volumes in the inferior frontal gyrus, ventral pre- and post-central gyrus, superior temporal gyrus, and insula. When participants with generalized anxiety symptoms were removed (leaving n=76 and 121 for the irritable and control groups, respectively), the results were similar. The findings with inferior frontal gyrus and insula were confirmed in a regression analysis in 851 adolescents across the full irritability spectrum. However, in this instance, the associations with irritability became non-significant after adjusting for generalized anxiety symptoms.

Finally, the authors used the regions identified in the structural analysis as regions of interest to examine associations between irritability and neural activation during a Stop Signal Task. During successful inhibition, youths with high irritability vs. those without showed less activation in the ventral pre- and post-central gyrus and superior temporal gyrus; no association with irritability was found during inhibition failures. In addition to being the largest MRI study to date examining neural correlates of irritability, another strength of this study is the use of a task probing inhibitory control — a central, highly-relevant yet relatively understudied process for irritability and temper outbursts.¹

In both clinically-referred and community-based samples, irritability commonly co-occurs with depressive and anxiety disorders, ODD, and ADHD.^1,5 One important goal of irritability research is to disentangle unique vs. shared neural mechanisms of irritability and commonly co-occurring symptoms. To tackle this, investigators often covary dimensional measures of the co-occurring symptoms to identify the “unique” effect of irritability. This quantifies the estimated effects of irritability above and beyond comorbid symptoms and the contribution of covariates to the identified neural correlates. However, doing so may reduce the variances and thus the power of analyses. That is, the individual differences and variability in the neural mechanisms explained by irritability may be reduced, and as a result, it is less likely to find “significant” neural correlates of irritability. Further, results may only apply to a small subset of irritable youths (i.e., those with “irritability only”), given that most irritable youths have comorbid symptoms. Thus, reporting results both with and without covariates is informative. Fortunately, both studies here had sufficiently large samples to adjust for comorbid symptoms/diagnoses by including them as covariates in the analyses. Both studies identified structural and functional neural correlates of irritability that were not attributable to comorbid symptoms/diagnoses, at least across the disorders and symptom dimensions sampled (i.e., high-functioning autism, ADHD, ODD, depression, and generalized anxiety disorder).

Another important goal of irritability research is to determine whether the neural correlates of dimensionally-assessed irritability are similar or different across diagnostic categories. This question has significant clinical implications. If the neural mechanisms of irritability are shared across diagnoses, treatments and intervention for irritability can be broadly applied across disorders. Conversely, if the neural mechanisms of irritability differ across disorders, then tailored, disorder-specific treatments would be required. To address this question, investigators can integrate dimensional and categorical approaches by testing whether the mechanisms of dimensionally-assessed irritability vary with categorical diagnoses (i.e., an irritability by diagnosis interaction). This requires large, well-powered study designs and sampling that includes a wide range of irritability levels within and across diagnostic categories.

Using this strategy, Kryza-Lacombe et al. attempted to test the moderating effect of diagnosis (high-functioning autism vs. non-autism) on the neural mechanisms of irritability, but their analysis was limited by the low prevalence of irritability in the non-autism group and the absence of an additional diagnostic group. However, given the large datasets now available through collaborative efforts and consortia such as the Adolescent Brain Cognitive Development study and IMAGEN, such analyses can be empirically conducted with adequate power. Preliminary evidence suggests that the neural mechanisms of irritability may be similar across DMDD, ODD, ADHD, anxiety disorders, and typically-developing youths⁶ but different in bipolar disorder.⁷ Kryza-Lacombe et al. provides preliminary evidence that the neural mechanisms of irritability may also be similar across autism and typically-developing youths, while Chaarani et al. did not test for the moderating effect of comorbid symptoms/diagnoses.

The two studies highlighted here used large, existing datasets as the source of important data about the neural mechanisms of irritability. Despite the large data, one limitation of many existing datasets is the post-hoc selection of measurements to capture irritability. Kryza-Lacombe et al. used three items from the CBCL, while Chaarani et al. used three items from the DAWBA to assess irritability. The CBCL irritability is, at best, moderately correlated with the Affective Reactivity Index⁸ (ARI) (r’s = .26–.64),⁹ one of the most widely used irritability scales; the correlation between DAWBA irritability and ARI is unknown. Although the measurement of irritability has improved, it is critical to establish common, standard measurements of childhood irritability to increase generalizability and comparisons across studies, thus facilitating biomarker discovery.

In sum, the two articles here advance empirical efforts to understand the pathophysiology of pediatric irritability. More research targeting irritability a priori is crucial to guide the development of evidence-based treatments for irritability that presents either alone or with other symptoms and disorders. The result will bring much-need relief to the children and families affected by irritability.