Pediatric Irritability: A Systems Neuroscience Approach

Abstract

Irritability, defined as an increased propensity to exhibit increased anger relative to one's peers, is a common clinical problem in youth. Irritability can be conceptualized as aberrant responses to frustration (where frustration is the emotional response to blocked goal attainment) and/or aberrant 'approach' responses to threat. Irritable youth show hyper-reactivity to threat mediated by dysfunction in amygdala, medial prefrontal cortex (mPFC), anterior cingulate cortex (ACC), insula, striatum, and association cortex. Irritable youth also show abnormalities in reward learning, cognitive control, and responses to frustration. These abnormalities are mediated by circuitry that includes the inferior frontal gyrus (iFG), striatum, ACC, and parietal cortex. Effective treatments for irritability are lacking, but pathophysiological research could lead to more precisely targeted interventions.

Keywords: aggression; anger; frustration; irritability; reward; threat.

Figure 1 (Key Figure). Irritability in rodents and humans is associated with aberrant responses to threat and/or frustrative non-reward

The figure shows parallel processes that can be observed in rodents and humans. Drawings on the left show associations between aberrant responses to threat and irritability in both species. Experimental manipulations that expose an organism to threat can be used to probe this pathway to irritability. Top left: When exposed to the threat of a conspecific in a resident intruder paradigm, frustrated mice show increased aggressive behavior. This aggression is greater than that exhibited by non-frustrated mice (not shown) [12]. Bottom left: Irritability in youth is associated with aberrant amygdala-prefrontal cortex connectivity when viewing threatening faces [37]; see Figure 2 for details. Drawings on the right show associations between aberrant responses to frustration and irritability in in both species. Experimental manipulations that expose an organism to threat can be used to study between-strain or between-subject differences in response to frustration, in the form of irritable behavior. Top right: Frustration is induced in a mouse by withholding food reward when the appearance of the conditioned stimulus (light cue) signals the opportunity to obtain reward through lever press [12]. Bottom right: Frustration is induced in a child by a game that is rigged so that the child does not receive an expected reward [74]; see also Figure 3.

Figure 2. Amygdala-prefrontal cortex connectivity is driven by an interaction between levels of anxiety and levels of irritability when youth view a threatening face

For details, see Stoddard et al. [37]. Briefly summarized, fMRI data were obtained while youth (ages 8–17 y, n=93 with anxiety, DMDD and/or ADHD, 22 healthy volunteers) performed an implicit face emotion processing task (i.e., gender identification) on angry, happy, and fearful faces at 50%, 100%, and 150% intensity. Functional connectivity was examined using a psychophysiological interaction analysis with an amygdala seed. When subjects viewed a 150% angry face, amygdala connectivity was related to levels of irritability, anxiety, and their interaction. As illustrated in the three dimensional plane, an interaction between irritability (measured on the ARI scale) and anxiety (measured on the Scared scale) was found for amygdala-medial prefrontal cortex connectivity. Specifically, decreasing connectivity was associated with increasing levels of both irritability and anxiety, while increasing connectivity was associated with increasing anxiety in the absence of increasing irritability.

Figure 3. Amygdala de-activation differs between chronically irritable youth and healthy volunteers while playing a frustrating game

Frustration is induced in children by first inducing reward expectation i.e., children play a game in which they can easily earn a reward (non-frustration condition). This non-frustration condition is then followed by a frustration condition, during which the game is rigged so that the child no longer receives the reward he has come to expect. Physiological measures such as skin conductance and BOLD fMRI signal can be measured while the child plays. The data here are from an fMRI study in which youth with severe mood dysregulation (SMD, the research precursor to DMDD) and healthy youth played a frustrating game. During the frustration condition, youth with SMD showed decreased amygdala activity when receiving frustrating, negative feedback (“you lose”). For details, see Deveney et al. [74].