- Email: [email protected]
38. How Much of individual Differences in Childhood Irritability can be Explained by Macroscopic Brain Morphology?
Biological Psychiatry
Thursday Abstracts
side-effects (Frequency, Intensity, and Burden of Side-Effects Rating Scale) were assessed with mixed model analyses. Results: Overall treatment outcomes did not differ among treatment arms. The treatment-arm-by-baseline biomarker level interaction was significant for depression severity wit IL-17 (p50.04) and CRP (p50.04) and only with CRP for sideeffects (p50.005). Interactions for serum amyloid component P and alpha-2-macroglobulin were insignificant. When treated with bupropion-plus-escitalopram but not with escitalopramplus-placebo or venlafaxine-plus-mirtazapine, one standard deviation higher IL-17 level at baseline led to 1.6 points greater reduction in QIDS-SR over 3 months. Similarly, higher baseline CRP levels resulted in smaller reductions in QIDS-SR scores with escitalopram-plus-placebo and venlafaxine-plus-mirtazapine but higher reductions with bupropion-plus-escitalopram. Higher CRP levels were associated with higher side-effects only with venlafaxineplus-mirtazapine. Conclusions: Higher pre-treatment levels of pro-inflammatory cytokine IL-17 predict better outcomes with bupropion whereas lower CRP levels predict better outcomes with escitalopram. These findings support clinical use of inflammatory biomarkers to personalize antidepressant treatment selection. Supported By: NIMH, Hersh Foundation Keywords: Depression, Antidepressant response, Biomarkers, Inflammation, C-reactive protein
SYMPOSIUM Childhood Irritability: Insights from Multiple Brain-Based Modalities Thursday, May 18, 2017, 12:30 PM – 2:30 PM Sapphire 400 AB Chair: Ellen Leibenluft 37. Neural Mechanisms of Frustration and Irritability across Diagnoses Wan-Ling Tseng1, Christen Deveney2, Melissa Brotman3, Joel Stoddard4, Elizabeth Moroney3, Laura Machlin3, Laura Donahue5, Jennifer Yi6, Kenneth Towbin3, Daniel Pine1, and Ellen Leibenluft3 National Institute of Mental Health, 2Wellesley College, NIMH, 4University of Colorado Anschutz Medical Campus, Children’s Hospital, 5University of Michigan, 6 University of North Carolina at Chapel Hill 1
3
Background: Although irritability is a common presenting complaint in child psychiatry, its neural mechanisms are poorly understood. Irritability is a core feature of disruptive mood dysregulation disorder (DMDD) but is present in other disorders. Thus, it is important to do trans-diagnostic studies of the pathophysiology of irritability. We used a frustrating fMRI task to model the frustrative non-reward construct in the RDoC matrix and examined associations between brain activation and irritability across three psychiatric diagnoses and healthy subjects. Methods: Participants are 197 youth (Mean age512.9 years; 49.7% girls) from groups with varying degrees of irritability: 52 DMDD, 40 attention-deficit/hyperactivity disorder (ADHD), 44
S16
anxiety disorder, and 61 healthy volunteers. During fMRI, participants completed an attentional task in which frustration was elicited by rigged feedback. We contrasted neural activity during trials of the attentional task that followed rigged vs. positive feedback to assess how attention was impacted by preceding frustrating vs. non-frustrating events. Irritability was measured dimensionally as the mean of parent- and child-report on the Affective Reactivity Index. Results: Multivariate analyses revealed that across diagnoses, higher irritability was related to greater activation in the cingulate gyrus, superior frontal gyrus, dorsolateral prefrontal cortex, and precentral gyrus, after receiving rigged vs. positive feedback (rs5.33-.37, ps,.001). These effects are independent of cooccurring anxiety and ADHD symptoms. Conclusions: In highly irritable children, frustration disrupts neural function in frontal circuits mediating attention and response selection. These data have important clinical implications in identifying brain mechanisms mediating the adverse impact of frustration on cognitive function in irritable youth. Supported By: This research was supported by the Intramural Research Program of the National Institute of Mental Health (NIMH). Keywords: fMRI, Irritability, children and adolescence, frustration, RDoC
38. How Much of individual Differences in Childhood Irritability can be Explained by Macroscopic Brain Morphology? Giovanni Salum1, André Zugman2, Andrea Jackowski2, Luis Rohde1, Eurípedes Miguel3, Rodrigo Bressa2, Tian Ge4, and Mert Sabuncu4 Federal University of Rio Grande do Sul, 2Federal University of São Paulo, 3University of São Paulo, 4 Massachusetts Institute of Technology
1
Background: Irritability refers to inter-individual differences in proneness to anger. It is a trait that is dimensionally distributed in the population and may reach a pathological extent. The objective of this study is to quantify the extent to which individual differences in levels of irritability can be explained by differences in macroscopic brain morphology. Methods: A total of 6-14 years of age children (n5633) participated in the study. Irritability was defined using a previously validated measure from the Child Behavior Checklist (CBCL) that assessed temper tantrums and hot temper. T1 weighted images were used to estimate volumetric and thickness measures using FreeSurfer software, used as input to calculate the morphometricity measure. Morphometricity is grounded in linear mixed effects (LME) modeling, similar to what is used in population genetics to quantify SNP-based heritability. Results: Irritability was not found to be significantly morphometric in our sample, with only 0.0001% (SE514%) of the trait variability in irritability being explained by morphological differences in the brain. No other psychiatric trait as measured by the CBCL had significant morphometricity estimates; contrasting with cognitive traits such as intelligence which showed significant morphometricity estimates above 50%.
Biological Psychiatry May 15, 2017; 81:S1–S139 www.sobp.org/journal
Biological Psychiatry
Thursday Abstracts
Conclusions: Brain morphology estimated from T1 weighted volume and thickness measures were not able to significantly explain variation in trait irritability. This study poses questions on whether volumetric and thickness differences among subjects can help in explaining the pathophysiology of irritability in children. It also reinforces the importance of other imaging modalities as a way to advance the understanding the pathophysiology of irritability. Supported By: Brazilian government institutions (FAPERGS, FAPESP, CNPq, CAPES, FIPE) Keywords: Irritability, Brain Imaging, Structural MRI, Developmental Psychopathology, Morphometrics
39. Temporally Sensitive Neural Measures of Inhibition in Preschool Children with Varying Irritability Symptoms Christen Deveney1, David Pagliaccio2, Ryne Estabrook3, James Burns3, Joel Voss3, Elvira Zobel3, Melissa Brotman2, Margaret Briggs-Gowan4, and Lauren Wakschlag3 1 4
Wellesley College, 2NIMH, University of Connecticut
3
Northwestern University,
Background: Identifying problematic irritability in preschool children may facilitate early intervention and prevention efforts. However, the frequency of angry moods and temper outbursts among preschoolers impedes the field’s ability to distinguish between typical and atypical behaviors. Research into the brain mechanisms mediating problematic irritability in preschoolers may aid this process. Some research links irritability with abnormal medial and lateral prefrontal cortex recruitment during cognitive control tasks under non-emotional and frustrating conditions, however, studying brain functioning in young children is challenging and data are limited. Methods: Sixty two preschool children oversampled for disruptive behaviors completed a developmentally appropriate go/no go task under three conditions (non-frustration, frustration, and recovery). N2 and P300 event-related brain potentials to go and no go stimuli were compared across conditions. Irritability was identified from a recent bifactor model of the PAPA. Mixed linear models tested whether irritability predicts changes in N2 and P300 amplitudes across the three task conditions. Results: Across youth, N2 and P300 amplitudes were larger during trials requiring motor inhibition (no go) versus trials without inhibition (go trials; p,.05). Greater irritability scores were associated with reduced N200 amplitudes during no go trials (β52.0, t(276)52.37, p5.019) and reduced P300 amplitudes during go trials (β522.0, t(281)522.73, p5.007) over the course of the task. Conclusions: Investigations of emotional, behavioral, and neural measures of irritability in preschoolers are challenging. The present study linked higher irritability in preschoolers with reduced neural markers of inhibition over time and is consistent with prior studies linking irritability with aberrant cognitive control processes. Supported By: NIMH R01 MH082830 (PI Lauren Wakschlag) Keywords: Irritability, ERP
40. Neural Correlates of Adolescent Irritability and Its Comorbidity Robert Althoff1, Bader Chaarani1, Kees-Jan Kan2, Scott Mackey1, Phil Spechler1, Catherine Orr1, Kelsey Hudson1, Argyris Stringaris3, and Hugh Garavan1 University of Vermont, 2VU University Amsterdam, 3Kings College London 1
Background: We examined irritability (IRR) in IMAGEN, a sample of 2024 14-year-youth from five European countries. Irritable mood is a very common and often impairing symptom of psychopathology and is defined by temper outbursts and proneness to anger. It has been associated with a host of psychiatric and nonpsychiatric conditions including suicide, violence, and cardiovascular disease. Relatively little is known about the neural mechanisms of irritability in childhood and adolescence. Methods: The Development and Well-Being Assessment (DAWBA) was used to assess ADHD, MDD, ODD, and GAD. Three items from the DAWBA, selected as close matches to the Affective Reactivity Index, were used to assess irritability. Structural MRI (sMRI) was examined using whole brain Voxel Based Morphometry analysis and functional MRI (fMRI) was examined during a stop signal task of inhibitory control. sMRI and fMRI data for these regions were included in structural equation models to examine the direct and indirect associations between IRR and comorbid DSM diagnoses. Results: A voxelwise regression analysis between GMV and irritability showed, after correcting for multiple comparisons (p,0.05), a significant negative correlation in two bilateral clusters and included the bilateral frontal gyrus and the left insula. The seven regions showing GMV reductions revealed significantly decreased activity in irritable subjects vs controls, in the bilateral superior temporal gyrus (STG), the right insula, and the right ventral pre- and postcentral gyrus (VPPG) (p,0.05), after controlling for other diagnoses. Conclusions: Decreased GMV and less response inhibition activity was observed within the right VPPG and the bilateral STG for individuals with high IRR. Supported By: NIGMS Keywords: Brain Imaging, Irritability, Comorbidity, ADHD, Anxiety
SYMPOSIUM Translational Neuroscience of CompulsiveImpulsive Disorders: Common Mechanisms in Binge Eating Disorder and Related Conditions Thursday, May 18, 2017, 12:30 PM – 2:30 PM Sapphire 410 AB Chair: Eric Hollander 41. Neurocognition of Compulsive-Impulsive Disorders Naomi Fineberg1, Claire Gillan2, Mathilde Vaghi3, Annemieke Apergis-Schoute3, Samuel Chamberlain3, Paula Banca3, Eduardo Cinosi4, Barbara Sahakian3, Trevor Robbins3, and Jemma Reid5
Biological Psychiatry May 15, 2017; 81:S1–S139 www.sobp.org/journal
S17
Thursday Abstracts
side-effects (Frequency, Intensity, and Burden of Side-Effects Rating Scale) were assessed with mixed model analyses. Results: Overall treatment outcomes did not differ among treatment arms. The treatment-arm-by-baseline biomarker level interaction was significant for depression severity wit IL-17 (p50.04) and CRP (p50.04) and only with CRP for sideeffects (p50.005). Interactions for serum amyloid component P and alpha-2-macroglobulin were insignificant. When treated with bupropion-plus-escitalopram but not with escitalopramplus-placebo or venlafaxine-plus-mirtazapine, one standard deviation higher IL-17 level at baseline led to 1.6 points greater reduction in QIDS-SR over 3 months. Similarly, higher baseline CRP levels resulted in smaller reductions in QIDS-SR scores with escitalopram-plus-placebo and venlafaxine-plus-mirtazapine but higher reductions with bupropion-plus-escitalopram. Higher CRP levels were associated with higher side-effects only with venlafaxineplus-mirtazapine. Conclusions: Higher pre-treatment levels of pro-inflammatory cytokine IL-17 predict better outcomes with bupropion whereas lower CRP levels predict better outcomes with escitalopram. These findings support clinical use of inflammatory biomarkers to personalize antidepressant treatment selection. Supported By: NIMH, Hersh Foundation Keywords: Depression, Antidepressant response, Biomarkers, Inflammation, C-reactive protein
SYMPOSIUM Childhood Irritability: Insights from Multiple Brain-Based Modalities Thursday, May 18, 2017, 12:30 PM – 2:30 PM Sapphire 400 AB Chair: Ellen Leibenluft 37. Neural Mechanisms of Frustration and Irritability across Diagnoses Wan-Ling Tseng1, Christen Deveney2, Melissa Brotman3, Joel Stoddard4, Elizabeth Moroney3, Laura Machlin3, Laura Donahue5, Jennifer Yi6, Kenneth Towbin3, Daniel Pine1, and Ellen Leibenluft3 National Institute of Mental Health, 2Wellesley College, NIMH, 4University of Colorado Anschutz Medical Campus, Children’s Hospital, 5University of Michigan, 6 University of North Carolina at Chapel Hill 1
3
Background: Although irritability is a common presenting complaint in child psychiatry, its neural mechanisms are poorly understood. Irritability is a core feature of disruptive mood dysregulation disorder (DMDD) but is present in other disorders. Thus, it is important to do trans-diagnostic studies of the pathophysiology of irritability. We used a frustrating fMRI task to model the frustrative non-reward construct in the RDoC matrix and examined associations between brain activation and irritability across three psychiatric diagnoses and healthy subjects. Methods: Participants are 197 youth (Mean age512.9 years; 49.7% girls) from groups with varying degrees of irritability: 52 DMDD, 40 attention-deficit/hyperactivity disorder (ADHD), 44
S16
anxiety disorder, and 61 healthy volunteers. During fMRI, participants completed an attentional task in which frustration was elicited by rigged feedback. We contrasted neural activity during trials of the attentional task that followed rigged vs. positive feedback to assess how attention was impacted by preceding frustrating vs. non-frustrating events. Irritability was measured dimensionally as the mean of parent- and child-report on the Affective Reactivity Index. Results: Multivariate analyses revealed that across diagnoses, higher irritability was related to greater activation in the cingulate gyrus, superior frontal gyrus, dorsolateral prefrontal cortex, and precentral gyrus, after receiving rigged vs. positive feedback (rs5.33-.37, ps,.001). These effects are independent of cooccurring anxiety and ADHD symptoms. Conclusions: In highly irritable children, frustration disrupts neural function in frontal circuits mediating attention and response selection. These data have important clinical implications in identifying brain mechanisms mediating the adverse impact of frustration on cognitive function in irritable youth. Supported By: This research was supported by the Intramural Research Program of the National Institute of Mental Health (NIMH). Keywords: fMRI, Irritability, children and adolescence, frustration, RDoC
38. How Much of individual Differences in Childhood Irritability can be Explained by Macroscopic Brain Morphology? Giovanni Salum1, André Zugman2, Andrea Jackowski2, Luis Rohde1, Eurípedes Miguel3, Rodrigo Bressa2, Tian Ge4, and Mert Sabuncu4 Federal University of Rio Grande do Sul, 2Federal University of São Paulo, 3University of São Paulo, 4 Massachusetts Institute of Technology
1
Background: Irritability refers to inter-individual differences in proneness to anger. It is a trait that is dimensionally distributed in the population and may reach a pathological extent. The objective of this study is to quantify the extent to which individual differences in levels of irritability can be explained by differences in macroscopic brain morphology. Methods: A total of 6-14 years of age children (n5633) participated in the study. Irritability was defined using a previously validated measure from the Child Behavior Checklist (CBCL) that assessed temper tantrums and hot temper. T1 weighted images were used to estimate volumetric and thickness measures using FreeSurfer software, used as input to calculate the morphometricity measure. Morphometricity is grounded in linear mixed effects (LME) modeling, similar to what is used in population genetics to quantify SNP-based heritability. Results: Irritability was not found to be significantly morphometric in our sample, with only 0.0001% (SE514%) of the trait variability in irritability being explained by morphological differences in the brain. No other psychiatric trait as measured by the CBCL had significant morphometricity estimates; contrasting with cognitive traits such as intelligence which showed significant morphometricity estimates above 50%.
Biological Psychiatry May 15, 2017; 81:S1–S139 www.sobp.org/journal
Biological Psychiatry
Thursday Abstracts
Conclusions: Brain morphology estimated from T1 weighted volume and thickness measures were not able to significantly explain variation in trait irritability. This study poses questions on whether volumetric and thickness differences among subjects can help in explaining the pathophysiology of irritability in children. It also reinforces the importance of other imaging modalities as a way to advance the understanding the pathophysiology of irritability. Supported By: Brazilian government institutions (FAPERGS, FAPESP, CNPq, CAPES, FIPE) Keywords: Irritability, Brain Imaging, Structural MRI, Developmental Psychopathology, Morphometrics
39. Temporally Sensitive Neural Measures of Inhibition in Preschool Children with Varying Irritability Symptoms Christen Deveney1, David Pagliaccio2, Ryne Estabrook3, James Burns3, Joel Voss3, Elvira Zobel3, Melissa Brotman2, Margaret Briggs-Gowan4, and Lauren Wakschlag3 1 4
Wellesley College, 2NIMH, University of Connecticut
3
Northwestern University,
Background: Identifying problematic irritability in preschool children may facilitate early intervention and prevention efforts. However, the frequency of angry moods and temper outbursts among preschoolers impedes the field’s ability to distinguish between typical and atypical behaviors. Research into the brain mechanisms mediating problematic irritability in preschoolers may aid this process. Some research links irritability with abnormal medial and lateral prefrontal cortex recruitment during cognitive control tasks under non-emotional and frustrating conditions, however, studying brain functioning in young children is challenging and data are limited. Methods: Sixty two preschool children oversampled for disruptive behaviors completed a developmentally appropriate go/no go task under three conditions (non-frustration, frustration, and recovery). N2 and P300 event-related brain potentials to go and no go stimuli were compared across conditions. Irritability was identified from a recent bifactor model of the PAPA. Mixed linear models tested whether irritability predicts changes in N2 and P300 amplitudes across the three task conditions. Results: Across youth, N2 and P300 amplitudes were larger during trials requiring motor inhibition (no go) versus trials without inhibition (go trials; p,.05). Greater irritability scores were associated with reduced N200 amplitudes during no go trials (β52.0, t(276)52.37, p5.019) and reduced P300 amplitudes during go trials (β522.0, t(281)522.73, p5.007) over the course of the task. Conclusions: Investigations of emotional, behavioral, and neural measures of irritability in preschoolers are challenging. The present study linked higher irritability in preschoolers with reduced neural markers of inhibition over time and is consistent with prior studies linking irritability with aberrant cognitive control processes. Supported By: NIMH R01 MH082830 (PI Lauren Wakschlag) Keywords: Irritability, ERP
40. Neural Correlates of Adolescent Irritability and Its Comorbidity Robert Althoff1, Bader Chaarani1, Kees-Jan Kan2, Scott Mackey1, Phil Spechler1, Catherine Orr1, Kelsey Hudson1, Argyris Stringaris3, and Hugh Garavan1 University of Vermont, 2VU University Amsterdam, 3Kings College London 1
Background: We examined irritability (IRR) in IMAGEN, a sample of 2024 14-year-youth from five European countries. Irritable mood is a very common and often impairing symptom of psychopathology and is defined by temper outbursts and proneness to anger. It has been associated with a host of psychiatric and nonpsychiatric conditions including suicide, violence, and cardiovascular disease. Relatively little is known about the neural mechanisms of irritability in childhood and adolescence. Methods: The Development and Well-Being Assessment (DAWBA) was used to assess ADHD, MDD, ODD, and GAD. Three items from the DAWBA, selected as close matches to the Affective Reactivity Index, were used to assess irritability. Structural MRI (sMRI) was examined using whole brain Voxel Based Morphometry analysis and functional MRI (fMRI) was examined during a stop signal task of inhibitory control. sMRI and fMRI data for these regions were included in structural equation models to examine the direct and indirect associations between IRR and comorbid DSM diagnoses. Results: A voxelwise regression analysis between GMV and irritability showed, after correcting for multiple comparisons (p,0.05), a significant negative correlation in two bilateral clusters and included the bilateral frontal gyrus and the left insula. The seven regions showing GMV reductions revealed significantly decreased activity in irritable subjects vs controls, in the bilateral superior temporal gyrus (STG), the right insula, and the right ventral pre- and postcentral gyrus (VPPG) (p,0.05), after controlling for other diagnoses. Conclusions: Decreased GMV and less response inhibition activity was observed within the right VPPG and the bilateral STG for individuals with high IRR. Supported By: NIGMS Keywords: Brain Imaging, Irritability, Comorbidity, ADHD, Anxiety
SYMPOSIUM Translational Neuroscience of CompulsiveImpulsive Disorders: Common Mechanisms in Binge Eating Disorder and Related Conditions Thursday, May 18, 2017, 12:30 PM – 2:30 PM Sapphire 410 AB Chair: Eric Hollander 41. Neurocognition of Compulsive-Impulsive Disorders Naomi Fineberg1, Claire Gillan2, Mathilde Vaghi3, Annemieke Apergis-Schoute3, Samuel Chamberlain3, Paula Banca3, Eduardo Cinosi4, Barbara Sahakian3, Trevor Robbins3, and Jemma Reid5
Biological Psychiatry May 15, 2017; 81:S1–S139 www.sobp.org/journal
S17