Persistent Frustration-Induced Reconfigurations of Brain Networks Predict Individual Differences in Irritability

Linke, Julia; Haller, Simone P.; Xu, Ellie; Nguyen, Lynn; Chue, Amanda; Botz-Zapp, Christian; Revzina, Olga; Perlstein, Samantha; Ross, Andrew; Tseng, Wan‐Ling; Shaw, Philip; Brotman, Melissa A.; Pine, Daniel S.; Gotts, Stephen J.; Leibenluft, Ellen; Kircanski, Katharina

doi:10.1016/j.jaac.2022.11.009

Cited by 8 publications

(11 citation statements)

References 48 publications

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“…Mechanistic understanding of irritability is needed to guide development of new treatments. Youths with severe irritability have elevated responses to FNR; the latter is a cross-species, translational construct (9, 35, 36). Therefore, translational research elucidating the neurobiology of FNR can facilitate research on the pathophysiology of irritability.…”

Section: Discussionmentioning

confidence: 99%

“…Studies suggest that youth with severe irritability have elevated responses to frustrative non-reward (FNR) i.e., the emotional and behavioral response to the omission of an expected reward (9). FNR is a translational, cross-species construct that can be leveraged to uncover pathophysiological mechanisms of irritability.…”

Section: Introductionmentioning

confidence: 99%

“…Human studies of brain-based mechanisms of irritability are limited and have yielded mixed results (18). Preliminary studies find that high levels of irritability following frustration in patients with DMDD correspond with increased frontal-striatal activation in the anterior cingulate cortex, dorsolateral prefrontal cortex, caudate, amygdala, and parietal cortex (9, 19, 20). Recent network-based pilot studies using both task-based and resting-state fMRI found predictive associations between irritability and post-frustration connectivity in limbic, reward, and sensorimotor networks (9, 21).…”

Section: Introductionmentioning

confidence: 99%

“…Preliminary studies find that high levels of irritability following frustration in patients with DMDD correspond with increased frontal-striatal activation in the anterior cingulate cortex, dorsolateral prefrontal cortex, caudate, amygdala, and parietal cortex (9, 19, 20). Recent network-based pilot studies using both task-based and resting-state fMRI found predictive associations between irritability and post-frustration connectivity in limbic, reward, and sensorimotor networks (9, 21). However, human fMRI studies with inadequate spatial and temporal resolution cannot identify the impact of frustration at the level of neuronal ensembles.…”

Section: Introductionmentioning

confidence: 99%

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A New Behavioral Paradigm for Frustrative Non-reward Reveals a Global Change in Brain Networks by Frustration

Naik

Munyeshyaka

et al. 2023

Preprint

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BackgroundIrritability, which can be defined as proneness to anger that can reach a pathological extent, is one of the most common reasons youth present for psychiatric evaluation and care. Aberrant responses to frustrative non-reward (FNR, the response to omission of an expected reward) are central to the pathophysiology of irritability. FNR is a cross-species RDoC construct. The development of preclinical FNR models could advance mechanistic studies of the important, and relatively understudied, clinical phenomenon of irritability.MethodsWe used FNR, a translational construct across species, as a conceptual framework for a novel behavioral paradigm (Alternate Poking Reward Omission, APRO) in mice. After APRO, mice were examined with a battery of behavioral tests to determine the effects of frustration. Also, whole brain imaging of c-Fos expression was used to identify brain regions activated by FNR.ResultsMice, regardless of sex, increased locomotion, and aggression towards conspecifics after APRO. There was no change in anxiety-like, depression-like, or non-aggressive social behaviors. APRO causes activation of 13 regions in the prelimbic, ACC, hippocampus, dorsal thalamus, cuneiform nucleus, pons, and pallidum areas, and shifts the brain network towards a more global processing mode.ConclusionOur novel FNR paradigm produces a frustration effect and alters brain processing in ways resembling the symptoms and brain network reconfiguration observed in youth with severe irritability. The novel behavioral paradigm and brain regions identified to be selectively activated by it lay the groundwork for further mechanistic studies of frustration and irritability in rodents.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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A New Behavioral Paradigm for Frustrative Non-reward Reveals a Global Change in Brain Networks by Frustration

Naik

Munyeshyaka

et al. 2023

Preprint

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“…We extracted functional connectivity as Pearson correlations transformed for normality using Fisher's z ′ -transformation from 216 regions: 200 cortical parcels previously assigned to known intrinsic functional networks (Schaefer et al, 2018) and 16 subcortical regions from the FreeSurfer segmentation. This parcellation approach was selected because the parcels are particularly homogenous with regard to functions and connections and have been used in youth samples with comparable features (Linke et al, 2021(Linke et al, , 2023. From these time series, we regressed white-matter signal, cerebrospinal fluid signal, and components classified as head motion.…”

Section: Resting-state Functional Connectivitymentioning

confidence: 99%

Multivariate Assessment of Inhibitory Control in Youth: Links With Psychopathology and Brain Function

Cardinale,

Bezek,

Siegal

et al. 2024

Psychol Sci

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Inhibitory control is central to many theories of cognitive and brain development, and impairments in inhibitory control are posited to underlie developmental psychopathology. In this study, we tested the possibility of shared versus unique associations between inhibitory control and three common symptom dimensions in youth psychopathology: attention-deficit/hyperactivity disorder (ADHD), anxiety, and irritability. We quantified inhibitory control using four different experimental tasks to estimate a latent variable in 246 youth (8–18 years old) with varying symptom types and levels. Participants were recruited from the Washington, D.C., metro region. Results of structural equation modeling integrating a bifactor model of psychopathology revealed that inhibitory control predicted a shared or general psychopathology dimension, but not ADHD-specific, anxiety-specific, or irritability-specific dimensions. Inhibitory control also showed a significant, selective association with global efficiency in a frontoparietal control network delineated during resting-state functional magnetic resonance imaging. These results support performance-based inhibitory control linked to resting-state brain function as an important predictor of comorbidity in youth psychopathology.

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Understanding irritability through the lens of self-regulatory control processes in children and adolescents: a systematic review

Urben,

Ochoa Williams,

Ben Jemia

et al. 2024

Eur Child Adolesc Psychiatry

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Among youths, pathological irritability is highly prevalent and severely disabling. As a frequent symptom, it often leads to referrals to child and adolescent mental health services. Self-regulatory control (SRC) processes are a set of socio-psycho-physiological processes that allow individuals to adapt to their ever-changing environments. This conceptual framework may enhance the current understanding of the cognitive, emotional, behavioural and social dysregulations underlying irritability. The present systematic review (PROSPERO registration: #CRD42022370390) aims to synthesize existing studies that examine irritability through the lens of SRC processes among youths (< 18 years of age). We conducted a comprehensive literature search among six bibliographic databases: Embase.com, Medline ALL Ovid, APA PsycInfo Ovid, Web of Science Core Collection, the Cochrane Database of Systematic Reviews Wiley and ProQuest Dissertations & Theses A&I. Additional searches were performed using citation tracing strategies. The retrieved reports totalled 2612, of which we included 82 (i.e., articles) from 74 studies. More than 85% of reports were published during the last 6 years, highlighting the topicality of this work. The studies sampled n = 26,764 participants (n = 12,384 girls and n = 12,905 boys, n = 1475 no information) with an average age of 8.08 years (SD = 5.26). The included reports suggest that irritability has an association with lower effortful control, lower cognitive control and delay intolerance. Further, evidence indicates both cross-sectional and longitudinal associations between irritability and a lack of regulation skills for positive and negative emotions, particularly anger. Physiological regulation seems to moderate the association between irritability and psychopathology. Finally, the mutual influence between a child’s irritability and parenting practice has been established in several studies. This review uses the lens of SRC to illustrate the current understanding of irritability in psychopathology, discusses important gaps in the literature, and highlights new avenues for further research.

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Persistent Frustration-Induced Reconfigurations of Brain Networks Predict Individual Differences in Irritability

Cited by 8 publications

References 48 publications

A New Behavioral Paradigm for Frustrative Non-reward Reveals a Global Change in Brain Networks by Frustration

A New Behavioral Paradigm for Frustrative Non-reward Reveals a Global Change in Brain Networks by Frustration

Multivariate Assessment of Inhibitory Control in Youth: Links With Psychopathology and Brain Function

Understanding irritability through the lens of self-regulatory control processes in children and adolescents: a systematic review

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