In psychiatric nosology, pathophysiology is an important but as yet elusive validator. A major goal of current psychiatric research is to identify biomarkers to guide diagnosis and treatment. Extending this approach, emerging research aims to identify neural mechanisms differentiating not only patients of one phenotype from healthy individuals but also patients of two phenotypes from each other and from healthy individuals (53
). In that vein, the first pathophysiologic studies of severe mood dysregulation were designed to provide “proof of principle” that, using behavioral and biological measures obtained in the laboratory and with functional MRI (fMRI), severe mood dysregulation and bipolar disorder could be differentiated from each other and from healthy individuals. Much like the family studies, studies in this area need to contrast children with classically defined bipolar disorder and children with other phenotypes, such as chronic irritability. As described below, behavioral data from these studies indicate that both youths with severe mood dysregulation and those with bipolar disorder differ from healthy comparison subjects in face emotion labeling ability, degree of subjective distress reported while performing a frustrating task, and performance on response reversal paradigms. In the first two domains, data also indicate that despite similar behavioral deficits in the two patient groups, the mediating neural circuitry differs. These findings are consistent with other work suggesting that neuroimaging techniques may be more sensitive than behavioral paradigms in detecting between-group differences (53
From a systems neuroscience perspective, irritability may result from an inability to engage top-down mechanisms (i.e., selective attention or higher-order mental processes [55
]) in order to inhibit maladaptive responses occurring in the setting of frustration, where frustration is conceptualized as the emotional response that occurs when goal attainment is blocked. The face emotion labeling, response reversal, and attentional deficits observed in severe mood dysregulation, combined with recent research on emotion regulation in healthy volunteers and in patients with affective aggression, suggest a testable pathophysiologic model for irritability in youths ().
Figure 2 Psychological Processes and Neural Circuits Hypothesized to Contribute to Pathologic Irritabilitya
The ability to accurately process social cues, which is a core social-emotional function that facilitates both emotion regulation and social competence (55
), appears to be deficient in both severe mood dysregulation and pediatric bipolar disorder (56
). Deficits in face emotion labeling are not simply nonspecific correlates of childhood psychopathology; Guyer et al. (56
) found deficits relative to healthy comparison subjects in patients with bipolar disorder and severe mood dysregulation but not in youths with ADHD and/or conduct disorder, or in those with anxiety disorders and/or major depressive disorder (). The fact that only the severe mood dysregulation and bipolar disorder groups differed from the healthy comparison group in performance on a face emotion identifi cation task suggests that severe mood dysregulation and bipolar disorder might share some pathophysiologic mechanisms.
Figure 3 Face Emotion Labeling Errors, Adjusted for Sex, Age, IQ, and Ethnicity, in Youths With Mood and Behavior Disordersa
However, examinations of the neural circuitry engaged in each group during face emotion labeling highlight the fact that similar behavioral deficits can result from multiple forms of circuitry dysfunction. fMRI data suggest that despite similar face emotion labeling deficits in severe mood dysregulation and bipolar disorder, neural activity in the amygdala differs between these two groups. Youths with severe mood dysregulation exhibited lower amygdala activity while rating their subjective fear versus nose width of neutral faces, relative to patients with bipolar disorder, nonirritable youths with ADHD, and healthy comparison subjects (58
) (). The finding of decreased amygdala activity in severe mood dysregulation during face emotion processing is similar to one reported earlier in youths with major depressive disorder (53
); the similarity is notable given longitudinal associations between severe mood dysregulation or chronic irritability and depressive disorders (29
Figure 4 Left Amygdala Activation During Ratings of Subjective Fear Versus Nose Width While Viewing Neutral Facesa
Another of the core abilities for social-emotional behavior suggested by Ochsner (55
) is “context-sensitive regulation,” or the ability to adapt one’s behavior to changing environmental contingencies. Such regulation can be assessed using response reversal paradigms, in which participants must adapt their responses to changing stimulus-reward associations. As suggested by Blair (59
), an individual with deficiencies in response reversal would be at high risk of encountering frustrating situations and thus of exhibiting irritable or aggressive behavior. In this way, response reversal deficits may play a causal role in the irritability characteristic of severe mood dysregulation. Patients with bipolar disorder and those with severe mood dysregulation both differ from healthy comparison subjects in performance on response reversal paradigms (60
). Ongoing research will test whether the neural circuitry mediating such deficits in severe mood dysregulation and bipolar disorder differs between these patient groups, as it did in the case of face emotion labeling. This fMRI work will use a response reversal paradigm that has already been used in youths with ADHD or psychopathic traits, thus also allowing for comparisons with these patient groups (62
While response reversal deficits may increase an individual’s likelihood of encountering frustrating situations, a complementary hypothesis is that the response of irritable individuals to frustrating contexts differs from that of healthy comparison subjects. If the goal is to elucidate mechanisms mediating irritable outbursts in youths, one research strategy involves neuroimaging while participants complete frustrating tasks. A study using a rigged task to elicit frustration found that while youths with severe mood dysregulation and those with bipolar disorder both reported more frustration than did healthy comparison subjects, event-related-potential measures differentiated the two groups. Youths with bipolar disorder had deficient top-down executive attention (i.e., decreased parietal P3 waves) specifically during frustration, while youths with severe mood dysregulation had deficits in bottom-up early attentional processes (i.e., decreased parietal, temporal, and central N1 and P1 waves) during both frustrating and nonfrustrating blocks (63
). Ongoing studies are extending this work using magnetoencephalography and fMRI (64
The finding of early attentional deficits in severe mood dysregulation is similar to results reported in youths with ADHD (65
). Indeed, since the criteria for severe mood dysregulation require the presence of three symptoms that overlap between ADHD and the criterion B symptoms for mania, it is not surprising that 86.3% of our severe mood dysregulation sample met criteria for ADHD (). The neurobiology of emotional dysfunction in ADHD has received relatively little research attention, although interest is growing (66
). Data indicate differences in amygdala activity in nonirritable youths with ADHD relative to those with severe mood dysregulation, those with bipolar disorder, and healthy comparison subjects during face processing (58
), and considerable research has found high comorbidity between oppositional defiant disorder and ADHD (33
). Thus, emotional dysregulation in ADHD merits significantly more study.
Conversely, few data have been generated to characterize the nature of attentional dysregulation in severe mood dysregulation, particularly in emotional contexts, so that too is an important area for future research. Behavioral and event-related-potential data suggest that youths with severe mood dysregulation, compared to those with bipolar disorder and/or healthy comparison subjects, may have reduced attentional interference from emotional distracters (63
). However, contradicting these findings are data from youths with severe mood dysregulation who had increased amygdala activation relative to other groups when asked to focus on nose width rather than on the emotional expression of a face, suggesting that youths with severe mood dysregulation may have difficulty focusing away from face emotions (58
). The extent to which emotion-attention interactions are abnormal in youths with severe mood dysregulation, and the precise nature of that abnormality, is important because such interactions may play a central role in emotion regulation (69
Of course, irritability occurs in the context of many different clinical presentations (e.g., chronically in severe mood dysregulation; during episodes of mania or depression in bipolar disorder; and in specific contexts in anxious children and individuals with posttraumatic stress disorder), and data suggest that the pathophysiology of irritability, including the specific nature of the attentional control deficits, will vary across clinical presentations. In some clinical states, such as acute mania, bottom-up mechanisms may be particularly important, since increased arousal may be associated with increased irritability (71
). The extent to which the model described in applies in different clinical phenotypes is therefore an important area for future research. In addition, once the heritability of irritability is established, genetic imaging studies can explore associations between genotype and neural activity in the setting of frustration and other emotional contexts.