Neural Correlates of Adolescent Irritability and Its Comorbidity With Psychiatric Disorders

Chaarani, Bader; Kan, Kees-Jan; Mackey, Scott; Spechler, Philip A.; Potter, Alexandra; Banaschewski, Tobias; Millenet, Sabina; Bokde, Arun L.W.; Bromberg, Uli; Büchel, Christian; Cattrell, Anna; Desrivières, Sylvane; Flor, Herta; Frouin, Vincent; Gallinat, Jürgen; Gowland, Penny; Heinz, Andreas; Ittermann, Bernd; Martinot, Jean‐Luc; Nees, Frauke; Paus, Tomáš; Poustka, Luise; Smolka, Michael N.; Walter, Henrik; Whelan, Robert; Stringaris, Argyris; Higgins, Stephen T.; Schumann, Günter; Garavan, Hugh; Althoff, Robert R.; Rapp, Michael A.; Artiges, Éric; Schneider, Sophia; Bach, C.; Barbot, Alexis; Barker, Gareth; Vetter, Nora C.; Constant, Patrick; Crombag, Hans S.; Czech, Katharina; Dalley, Jeffrey W.; Decideur, Benjamin; Spranger, Tade Matthias; Ripley, Tamzin; Heym, Nadja; Sommer, Wolfgang H.; Fuchs, Birgit; Spanagel, Rainer; Kaviani, Mehri; Heinrichs, Bert; Subramaniam, Naresh; Jia, Tianye; Ihlenfeld, Albrecht; Ireland, James; Conrod, Patricia J.; Jones, Jennifer; Klaassen, Arno; Lalanne, Christophe; Lanzerath, Dirk; Lawrence, Claire; Lemaître, Hervé; Mallik, Catherine; Mann, Karl; Mar, Adam; Martinez-Medina, Lourdes; Mennigen, Eva; Carvahlo, Fabiana Mesquita de; Schwartz, Yannick; Bruehl, Ruediger; Müller, Kathrin; Nymberg, Charlotte; Lathrop, Mark; Robbins, Trevor W.; Pausová, Zdenka; Pentilla, Jani; Biondo, Francesca; Poline, Jean‐Baptiste; Fröhner, Juliane H.; Struve, Maren; Williams, Steve; Hübner, Thomas; Aydın, Semiha; Rogers, John; Romanowski, Alexander; Schmäl, Christine; Schmidt, Dirk; Ripke, Stephan; Arroyo, Mercedes; Schubert, Florian; Peña-Oliver, Yolanda; Fauth‐Bühler, Mira; Mignon, Xavier; Speiser, Claudia; Fadai, Tahmine; Stephens, D.N.; Ströhle, Andreas; Paillère, Marie-Laure; Strache, Nicole; Theobald, David E.; Jurk, Sarah; Vulser, Hélène; Miranda, Rubén; Yacubilin, Juliana; Genauck, Alexander; Parchetka, Caroline; Gemmeke, Isabel; Kruschwitz, Johann; Weiß, Katharina; Feng, Jianfeng; Papadopoulos, Dimitri; Filippi, Irina; Ing, Alex; Ruggeri, Barbara; Xu, Bing; Macare, Christine; Chu, Congying; Hanratty, Éanna; Quinlan, Erin Burke; Robert, Guillaume; Yu, Tao; Ziesch, Veronika; Stedman, Alicia

doi:10.1016/j.jaac.2019.11.028

Cited by 23 publications

(36 citation statements)

References 29 publications

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“…A recent fMRI study of irritability in youth used a stop-signal task [ 39 ], which is similar to our “change-signal” task except that only ours requires the execution of an alternate response after inhibiting the prepotent response. This study found that irritability in youth is associated with decreased activation in the primary motor and somatosensory cortex [ 39 ]. Research on the irritability-related construct of aggression also finds links between aggression and dysfunction in the primary motor cortex [ 40 , 41 ].…”

Section: Discussionmentioning

confidence: 99%

“…Research on the irritability-related construct of aggression also finds links between aggression and dysfunction in the primary motor cortex [ 40 , 41 ]. Moreover, structural connectivity and voxel-based studies suggest that irritability in youth is associated with abnormal white matter microstructure in the corticospinal tract, a major motor pathway [ 42 ], and lower gray matter volume in the primary motor and somatosensory cortex [ 39 ] and presupplementary motor area [ 43 ]. Behaviorally, research in animals and human suggest that following frustration, animals and human showed increased motor activity, aggression, and approach behavior [ 9 , 10 ].…”

Section: Discussionmentioning

confidence: 99%

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Functional connectivity during frustration: a preliminary study of predictive modeling of irritability in youth

Scheinost

Dadashkarimi

Finn

et al. 2021

Neuropsychopharmacol.

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Irritability cuts across many pediatric disorders and is a common presenting complaint in child psychiatry; however, its neural mechanisms remain unclear. One core pathophysiological deficit of irritability is aberrant responses to frustrative nonreward. Here, we conducted a preliminary fMRI study to examine the ability of functional connectivity during frustrative nonreward to predict irritability in a transdiagnostic sample. This study included 69 youths (mean age = 14.55 years) with varying levels of irritability across diagnostic groups: disruptive mood dysregulation disorder (n = 20), attention-deficit/hyperactivity disorder (n = 14), anxiety disorder (n = 12), and controls (n = 23). During fMRI, participants completed a frustrating cognitive flexibility task. Frustration was evoked by manipulating task difficulty such that, on trials requiring cognitive flexibility, “frustration” blocks had a 50% error rate and some rigged feedback, while “nonfrustration” blocks had a 10% error rate. Frustration and nonfrustration blocks were randomly interspersed. Child and parent reports of the affective reactivity index were used as dimensional measures of irritability. Connectome-based predictive modeling, a machine learning approach, with tenfold cross-validation was conducted to identify networks predicting irritability. Connectivity during frustration (but not nonfrustration) blocks predicted child-reported irritability (ρ = 0.24, root mean square error = 2.02, p = 0.03, permutation testing, 1000 iterations, one-tailed). Results were adjusted for age, sex, medications, motion, ADHD, and anxiety symptoms. The predictive networks of irritability were primarily within motor-sensory networks; among motor-sensory, subcortical, and salience networks; and between these networks and frontoparietal and medial frontal networks. This study provides preliminary evidence that individual differences in irritability may be associated with functional connectivity during frustration, a phenotype-relevant state.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Functional connectivity during frustration: a preliminary study of predictive modeling of irritability in youth

Scheinost

Dadashkarimi

Finn

et al. 2021

Neuropsychopharmacol.

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show abstract

“…In both clinical groups, authors found a decrease in gray matter volume in the pre-supplementary motor area, the insula and the dlPFC, with additional changes in other brain regions for the BD group. On the other hand, a study from the IMAGEN consortium found a correlation between irritability and decreased gray matter volumes in the rostral inferior frontal gyrus in 14-year-old adolescents ( 20 ). A study with a similar design ran a multivariate analysis of non-negative matrix factorization and found decreases in cortical thickness in the orbitofrontal cortex and temporal lobe regions ( 18 ).…”

Section: Discussionmentioning

confidence: 99%

Irritability Is Associated With Decreased Cortical Surface Area and Anxiety With Decreased Gyrification During Brain Development

Piguet

Mihailov²,

Grigis³

et al. 2021

Front. Psychiatry

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Background: Brain development is of utmost importance for the emergence of psychiatric disorders, as the most severe of them arise before 25 years old. However, little is known regarding how early transdiagnostic symptoms, in a dimensional framework, are associated with cortical development. Anxiety and irritability are central vulnerability traits for subsequent mood and anxiety disorders. In this study, we investigate how these dimensions are related to structural changes in the brain to understand how they may increase the transition risk to full-blown disorders.Methods: We used the opportunity of an open access developmental cohort, the Healthy Brain Network, to investigate associations between cortical surface markers and irritability and anxiety scores as measured by parents and self-reports.Results: We found that in 658 young people (with a mean age of 11.6) the parental report of irritability is associated with decreased surface area in the bilateral rostral prefrontal cortex and the precuneus. Furthermore, parental reports of anxiety were associated with decreased local gyrification index in the anterior cingulate cortex and dorsomedial prefrontal cortex.Conclusions: These results are consistent with current models of emotion regulation network maturation, showing decreased surface area or gyrification index in regions associated with impaired affective control in mood and anxiety disorders. Our results highlight how dimensional traits may increase vulnerability for these disorders.

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“…Others have used a similar symptom threshold to identify youth with behavioral problems as having elevated irritability or not ( 33 , 34 , 36 ). These 3 items also map directly on the DSM-5 ODD “angry/irritable mood” category ( 2 ) and the items in the Development and Well-Being Assessment, which has been used by others to assess irritability in pediatric populations ( 37 , 38 ). Parent report on structured rating scales has been found to be as valid for measuring irritability in youth as clinician-administered interviews ( 39 ).…”

Section: Methodsmentioning

confidence: 99%

The Impact of Persistent Irritability on the Medication Treatment of Paediatric Attention Deficit Hyperactivity Disorder

et al. 2021

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This study compares the efficacy and tolerability of central nervous system (CNS) stimulants in children with attention deficit hyperactivity disorder (ADHD) with and without prominent irritability (IRR) over the course of 30 months. This is a secondary analysis of a study examining growth patterns in medication naïve children with ADHD subsequently treated with CNS stimulants (predominantly OROS-Methylphenidate, up to 54 mg per day) for 30 months. Participants had to meet full diagnostic criteria for ADHD and been treated with CNS stimulants for under 30 days. Children were classified as IRR if they were rated as pretty much or very much on either of the “often angry” or easily annoyed” items plus “lose temper,” items of the Disruptive Behavior Disorders Rating Scale (DBDRS). Structured ratings of ADHD symptoms, impairment, side effects, and symptoms of oppositional defiant disorder (ODD) were collected every 2–12 weeks for the duration of the study. Medication use was measured by pill count and parent report. The IRR group comprised 28% of all participants. The IRR group had significantly higher levels of ADHD and ODD symptoms, impairment, and side effects ratings at baseline. In the IRR group, ODD symptoms, emotional lability, and impairment significantly decreased for participants with higher medication use. Total side effects increased for non-IRR participants with higher medication use. Emotional side effects decreased for IRR participants with higher medication use. Central nervous system stimulants were a tolerable and efficacious treatment in treatment naïve youth with ADHD with irritability.Clinical Trials Registration: NCT01109849

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Neural Correlates of Adolescent Irritability and Its Comorbidity With Psychiatric Disorders

Cited by 23 publications

References 29 publications

Functional connectivity during frustration: a preliminary study of predictive modeling of irritability in youth

Functional connectivity during frustration: a preliminary study of predictive modeling of irritability in youth

Irritability Is Associated With Decreased Cortical Surface Area and Anxiety With Decreased Gyrification During Brain Development

The Impact of Persistent Irritability on the Medication Treatment of Paediatric Attention Deficit Hyperactivity Disorder

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