From increased activity and aggression in animals to changes in brain responses in humans, this review shows how irritability research can shed light on why irritability is clinically impaired.
Review: Frustrated non-rewards: A heterogeneous exploration to study the brain mechanisms of irritation. Image credit: Roman Samborskyi / Shutterstock
In a recent study published in the journal translational psychiatryresearchers reviewed research on frustration in humans and animals and discussed opportunities for cross-species research.
Recently, there has been an increase in clinical research on irritability, especially among young people. Irritability is a tendency toward anger that is normal at low levels but can be disabling at high levels. Irritability-related behaviors are a common driver of mental health care in young people, but treatment advances have lagged behind clinical need. Research shows that maladaptive or abnormal responses to frustration may be a central mechanism contributing to irritability.
Such reactions may include extreme or prolonged behavioral and emotional reactions to frustration, or a low threshold for frustration. Clinical observations suggest a link between abnormal frustration reactions and irritability. Clinically significant irritability may manifest as frequent, developmentally inappropriate outbursts of anger that are disproportionate to the precipitating event. One model of irritability suggests that these outbursts represent a maladaptive irritable nonreward (FNR) response.
FNR is a behavioral and emotional response to the reduction, delay, or omission of an anticipated reward. This is a normative, evolutionarily conserved response that helps organisms adapt when expected outcomes change. However, if these reactions are unusually intense, prolonged, frequent, or easily triggered, they can contribute to irritable behavior. Additionally, longitudinal and cross-sectional studies have revealed an association between frustration and nonnormative responses to irritation, supporting clinical observations. In this study, the researchers argued that cross-species research on irritability provides a promising approach to elucidate the underlying mechanisms of irritability and identify potential therapeutic targets.
FNR studies in animals
Although FNR research has primarily been conducted in animals, there has been a recent surge in human research. FNR in vertebrates has been studied using multiple behavioral paradigms, including non-instrumental and instrumental tasks, depending on whether the animal performs the behavior to obtain a reward. Across species, increased aggression and motor activity are common in both non-instrumental and instrumental tasks, with increased motor activity being the most consistently observed.
Research shows that the magnitude of the FNR response increases with the number of non-reward trials and the strength of reward expectations. For example, in chimpanzees and rats, preferential reward and long-term dietary restriction produce stronger behavioral effects. Additionally, the lack of rewards increases frustration. Animal FNR studies have mainly focused on behavior, with limited neurobiological studies.
Lesions in the anterior cingulate cortex (ACC) and nucleus accumbens (NAC) increase aggression in monkeys frustrated by not being able to reach food in front of them. Furthermore, studies have shown that the paraventricular thalamus (PVT), NAC, and prefrontal cortex (PFC) are involved in FNR responses. FNR at the molecular level has not yet been studied. Although some studies suggest that increased GABAergic effects may reduce aggression in cows and increase resistance to extinction in rats, the findings in rats may reflect the effects of amobarbital on running rather than a frustration-specific process.
FNR studies in humans
The FNR paradigm in humans is similar to that in animal studies and can be non-instrumental or instrumental. However, most human studies have used an instrumental paradigm in which individuals perform behaviors to obtain rewards. Although some instrumental paradigms are well suited for cross-species research, many require higher cognitive functions such as arithmetic, which impede cross-species reasoning.
There was only one direct cross-species study of FNR in rats and humans. Although both species demonstrated increased responding following the absence of an unexpected reward, the effects in humans were more pronounced among participants high than low in negative urgency and mood-related impulsivity. Similar to animals, FNR in humans is associated with increased resistance to extinction, the continued pursuit of rewards after they are no longer available, and activated behavior. Additionally, after FNR, children and adults experience decreased cognitive performance and increased reaction speed and vitality.
Instrumental paradigms involving loss or absence of reward are associated with changes in activation and connectivity in brain regions involved in motor activity and aggression, reward processing, emotional and sensory processing in healthy individuals. These regions include the ACC, PFC, amygdala, ventral striatum, and anterior insula. Increased dorsolateral PFC activation was observed during irritability in preschoolers, and the magnitude of activation was associated with parent reports of child anger/frustration. However, many neuroimaging studies involve small to moderate samples, limiting confidence in the reproducibility of individual findings.
treatment research
Only a few hypersensitivity treatment trials have investigated FNR as a mediating mechanism for symptom relief. During 14 weeks of parent management training combined with cognitive behavioral therapy (PMT-CBT) in children aged 8 to 12 years with internalizing and externalizing problems, improvers showed decreased N2 amplitude, a neural marker associated with inhibitory control in the ventral PFC, during an FNR task, a loss of unexpected reward compared to pretreatment, and responses closer to those of healthy controls.
In another study of children with externalizing problems, N2 amplitudes in the anterior medial temporal lobe and dorsomedial and ventral PFC were normalized from pre- to post-treatment. P3 amplitude remained unchanged, 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.
conclusion
Taken together, the literature suggests that abnormal responses to frustration may be an important mechanism contributing to clinically significant irritability. Studies in animals have provided detailed behavioral evidence and are beginning to delineate the underlying neural circuits. Meanwhile, human research has identified links between neural circuits and altered neural responses to frustration and irritability, but much of this evidence remains correlational. Future research should focus on developing cross-species paradigms for translational studies of neural circuits and behavior, including individual differences and recovery after setbacks.
