From heightened activity and aggression in animals to altered brain responses in humans, the review shows how frustration research could reveal why irritability becomes clinically impairing.
Review: Frustrative non-reward: A cross-species probe to study brain mechanisms of irritability. Image Credit: Roman Samborskyi / Shutterstock
In a recent study published in the journal Translational Psychiatry, researchers reviewed studies on frustration in humans and animals and discussed opportunities for cross-species research.
Clinical research on irritability has recently increased, especially in youth. Irritability is the proneness to anger, which is normative at lower levels but can be functionally impairing at higher levels. Irritability-related behaviors are common precipitants for mental healthcare in young individuals, yet treatment advances lag behind clinical need. Research suggests that maladaptive or aberrant responses to frustration may be a core mechanism contributing to irritability.
Such responses may include extreme or prolonged behavioral and emotional reactions to frustration or a low threshold for frustration. Clinical observations suggest an association between aberrant frustration responses and irritability. Clinically significant irritability may manifest as frequent, severe, developmentally inappropriate temper outbursts that are disproportionate to the precipitating event. One model of irritability suggests that these outbursts represent maladaptive frustrative non-reward (FNR) responses.
FNR is the behavioral and emotional response to the decrease, delay, or omission of an anticipated reward. It is a normative, evolutionarily conserved response that can help organisms adapt when expected outcomes change. However, when these responses become unusually intense, prolonged, frequent, or easily triggered, they may contribute to irritable behavior. Moreover, longitudinal and cross-sectional studies reveal associations between non-normative responses to frustration and irritability, corroborating clinical observations. In this study, researchers argued that cross-species research on frustration offers a promising approach to elucidating the mechanisms underlying irritability and identifying potential treatment targets.
FNR Research in Animals
FNR research has largely been conducted in animals, but there has been a recent surge in human studies. FNR in vertebrates has been studied using multiple behavioral paradigms, including non-instrumental and instrumental tasks, depending on whether animals perform an action to gain a reward. Across species, increased aggression and motor activity are common in both non-instrumental and instrumental tasks, with increased motor activity observed most consistently.
Studies indicate that the magnitude of the FNR response increases with the number of non-reward trials and the strength of reward expectancy. For instance, preferred rewards and longer food restriction produce stronger behavioral effects in chimpanzees and rats. Moreover, frustration increases with the difficulty of obtaining a reward. Animal FNR research has predominantly focused on behavior, with limited neurobiological investigations.
Lesions in the anterior cingulate cortex (ACC) and the nucleus accumbens (NAC) elevate aggression in monkeys frustrated by their inability to reach food in sight. Moreover, studies have implicated the paraventricular thalamus (PVT), NAC, and prefrontal cortex (PFC) in FNR responses. Molecular-level FNR remains understudied; a few studies suggest that increasing GABAergic action may decrease aggression in cows and increase resistance to extinction in rats, although the rat finding may have reflected amobarbital’s effects on running rather than a frustration-specific process.
FNR Research in Humans
FNR paradigms in humans have been similar to those in animal research and can be non-instrumental or instrumental. However, most human studies have used instrumental paradigms in which individuals perform a behavior to gain rewards. While some instrumental paradigms are suitable for cross-species research, many require greater cognitive function, such as arithmetic, which impedes cross-species inference.
Only one direct cross-species study of FNR involved rats and humans; both species demonstrated increased responding after unexpected reward omission, while the effect in humans was more pronounced among participants with high rather than low negative urgency, or mood-related impulsivity. As in animals, human FNR is associated with increased resistance to extinction, meaning continued pursuit of a reward after it is no longer available, and invigorated behaviors. Furthermore, children and adults show poor cognitive performance and increased response speed and vigor following FNR.
Instrumental paradigms with reward loss or omission are associated with activation and connectivity changes in brain regions involved in motor activity and aggression, reward processing, and emotional and sensory processing in healthy people. These regions include the ACC, PFC, amygdala, ventral striatum, and anterior insula. Elevated dorsolateral PFC activation has been observed during frustration in preschoolers, and the degree of activation was associated with parental reports of the child’s anger/frustration. However, many neuroimaging studies involved small to moderate samples, limiting confidence in the reproducibility of individual findings.
Treatment Studies
Only a few trials of irritability treatment have investigated FNR as a mediating mechanism for symptom reduction. In a 14-week parent management training combined with cognitive-behavioral therapy (PMT-CBT) in children aged 8–12 years with internalizing and externalizing problems, improvers showed reduced N2 amplitudes, a neural marker associated with inhibitory control, in the ventral PFC during an FNR task with unexpected loss of rewards compared with pre-treatment, with responses approaching those of healthy controls.
In a separate study of children with externalizing problems, N2 amplitudes in the anterior medial temporal lobe and the dorsomedial and ventral PFC were normalized from pre- to post-treatment. P3 amplitudes did not change, suggesting possible mechanistic specificity. Overall, preliminary studies indicate that treatments such as PMT-CBT may selectively normalize inhibitory control processes during FNR, supporting further investigation of frustration-related processes as potential intervention targets.
Concluding Remarks
Taken together, the literature suggests that aberrant responses to frustration may be an important mechanism contributing to clinically significant irritability. Studies in animals have provided detailed behavioral evidence and begun to delineate the underlying neural circuits. Meanwhile, human research has identified neural circuits and associations between altered neural responses to frustration and irritability, although much of this evidence remains correlational. Future work should focus on developing cross-species paradigms for translational studies of neural circuitry and behavior, including individual differences and recovery after frustration.
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