Decreased amygdala–insula resting state connectivity in behaviorally and emotionally dysregulated youth
Introduction
Psychiatric disorders in youth characterized by behavioral and emotional dysregulation (difficulty regulating the experience and expression of behaviors and emotions) include major depressive disorder (MDD), bipolar spectrum disorders (BPSD), attention deficit hyperactivity disorder (ADHD), anxiety disorders, and disruptive behavior disorders (DBD). These disorders pose diagnostic and treatment challenges due to high comorbidity and the lack of clear biological trait markers (Kowatch et al., 2005, Pavuluri et al., 2005, Arnold et al., 2011, Arnold et al., 2012). NIMH Research Domain Criteria (RDoC) offer an alternative approach to identifying transdiagnostic pathophysiologic processes (Cuthbert and Insel, 2013) and biological disease markers (Bebko et al., 2014) through dimensions of behavioral and emotional dysregulation.
Neuroimaging techniques examining brain–behavior relationships are ideal for applying RDoC to study pediatric psychiatric disorders. One such technique, resting state functional connectivity (RSC), provides information about intrinsic connectivity in neural networks independent of specific cognitive contexts requiring sophisticated, and often challenging, cognitive tasks which may not represent daily activities. RSC may additionally be more ecologically valid, allowing observation of mind wandering, a commonly occurring activity in the daily lives of youth. In addition, by focusing on neural regions shown to be important in fMRI task-related analyses [such as the amygdala (Altshuler et al., 2005, Foland et al., 2008), striatum (Deveney et al., 2013), prefrontal cortical (Pavuluri et al., 2008, Kalmar et al., 2009, Passarotti et al., 2010, Ladouceur et al., 2011) and anterior cingulate cortical (Gogtay et al., 2007, Kalmar et al., 2009) regions, and an insula-centered neural network supporting salience, interoception, and emotion perception (Rubia et al., 2009; Taylor et al., 2009; Kurth et al., 2010; Cauda et al., 2012; Cloutman et al., 2012)], RSC studies may increase our understanding of pathophysiologic processes in behaviorally and emotionally dysregulated youth.
The small number of RSC studies in youth with behavioral and emotional dysregulation across a variety of psychiatric disorders have used different methods and reported different patterns of abnormal RSC between the amygdala and key prefrontal cortical, anterior cingulate cortical, and insula regions supporting emotion regulation. Using Independent Component Analysis, increased RSC in a neural network comprising the amygdala, orbitofrontal cortex, anterior cingulate cortex, and insula (Wu et al., 2013) in unmedicated, manic, BPSD versus healthy control (HC) youth was reported. In contrast, when using an amygdala seed region, no RSC differences between BPSD and HC (Dickstein et al., 2010) were shown. For youth with MDD, decreases in both amygdala–prefrontal cortical, and amygdala–striatal connectivity were reported relative to HC (Luking et al., 2011). In addition, differences were observed for MDD versus HC youth in RSC between right and left amygdala seed regions with prefrontal gyri (Pannekoek et al., 2014). Additional studies reported both increased (Davey et al., 2012) and decreased (Cao et al., 2006, Cullen et al., 2009, Sun et al., 2012, Pannekoek et al., 2014) RSC between prefrontal and anterior cingulate regions, as well as increased (Gabbay et al., 2013) and decreased (Bluhm et al., 2009, Davey et al., 2012) RSC between striatal and anterior cingulate cortical regions in youth with depression or ADHD versus HC. Together, these findings suggest inconsistent patterns of abnormal RSC in pediatric psychiatric disorders characterized by behavioral and emotional dysregulation.
While the variable nature of these findings may reflect differences in mood state, different analytic techniques, or both, it remains unclear whether there are more consistent patterns of abnormal amygdala-centered RSC associated with specific symptom dimensions across different diagnostic categories. A few studies examined relationships between RSC and symptom dimensions in youth with BPSD or MDD (Luking et al., 2011, Ford et al., 2013, Gabbay et al., 2013, Xiao et al., 2013) but may not represent the wider range of pediatric psychiatric disorders. Furthermore, these studies provided mixed findings of both positive and inverse relationships between mania and depression severity and RSC in networks linking amygdala, striatum, prefrontal, anterior cingulate, and other cortical regions (Luking et al., 2011, Gabbay et al., 2013, Xiao et al., 2013).
In summary, prior studies provide inconsistent reports of RSC among amygdala (Dickstein et al., 2010, Luking et al., 2011), striatal (Bluhm et al., 2009, Davey et al., 2012, Gabbay et al., 2013, Xiao et al., 2013), prefrontal cortical (Cao et al., 2006, Cullen et al., 2009, Dickstein et al., 2010, Davey et al., 2012, Sun et al., 2012, Wu et al., 2013), anterior cingulate cortical (Bluhm et al., 2009, Cullen et al., 2009, Davey et al., 2012, Gaffrey et al., 2012, Gabbay et al., 2013, Wu et al., 2013, Xiao et al., 2013), and insula (Wu et al., 2013) regions in behaviorally and emotionally dysregulated youth. In the present study, we aimed to elucidate for the first time the nature and extent of relationships between pathological dimensions and RSC versus relationships between diagnostic categories and RSC in a clinical cohort of youth with behavioral and emotional dysregulation. Given the central role of the amygdala in emotion processing (Ochsner and Gross, 2005, Phillips et al., 2008) and the inconsistencies shown in the literature, we used an amygdala seed region. We recruited a subset of youth selected from the Longitudinal Assessment of Manic Symptoms (LAMS) study (Horwitz et al., 2010a), a longitudinal, multisite study of youth seeking treatment for behavioral and emotional dysregulation. The LAMS study was designed to assess relationships among the longitudinal course of symptoms, clinical, and functional outcomes in these youth (Section 2). In addition to using DSM-IV classifications of pediatric psychiatric disorders and commonly-used dimensional symptom measures of emotional dysregulation in youth (rating scales of mania, depression, and anxiety), LAMS also uses the Parent General Behavior Inventory-10 Item Mania Scale (PGBI-10M), a parental report of manic-like behaviors associated with difficulty regulating mood and energy (Section 2) (Youngstrom et al., 2005, Youngstrom et al., 2008).
Primary Hypothesis-Dimensional: As suggested by previous reports of altered RSC in behaviorally and emotionally dysregulated youth implementing dimensional approaches (Luking et al., 2011, Ford et al., 2013, Gabbay et al., 2013, Xiao et al., 2013), we hypothesized that, across all behaviorally and emotionally dysregulated LAMS youth, irrespective of diagnosis, RSC between amygdala, striatum, prefrontal cortices, anterior cingulate cortices, and insula would be significantly associated with dimensional measures of behavioral and emotional dysregulation (PGBI-10M score, mania, depression. and anxiety).
Secondary Hypothesis-Categorical: Based on previous findings of differential patterns of RSC among the above regions between youth with and without specific diagnoses (Dickstein et al., 2010, Luking et al., 2011, Wu et al., 2013), current diagnostic categories in LAMS youth would be differentiated by patterns of amygdala RSC.
In addition, we recruited a comparison group of HC to examine the extent to which significant relationships between RSC and symptom dimensions, or diagnostic categories, represented abnormal RSC in LAMS youth versus HC.
Section snippets
Description of the Longitudinal Assessment of Manic Symptoms (LAMS) study
LAMS is a longitudinal NIMH-supported study of children and adolescents seeking treatment for behavioral and emotional dysregulation diagnoses such as BPSD, other mood disorders, ADHD, anxiety disorders, and disruptive disorders. Because behavioral and/or emotional dysregulation symptoms similar to manic-like behaviors are common to these disorders, the study name includes reference to “manic symptoms”.
The Parent General Behavior Inventory-10 Item Mania Scale (PGBI-10M; Supplementary material)
Results
In LAMS youth, right putamen (901 voxels), left putamen extending into posterior insula (1060 voxels), right BA47 extending into posterior insula (2 clusters: 19 voxels, 45 voxels), bilateral OFC/dACC (Left: BA 11/24, 130 voxels; Right: BA 11/32,34 voxels), and right dACC (BA24, 116 voxels) showed significant RSC with the amygdala (P<0.005,corrected P<0.05; Fig. 1A; Table 2), controlling for scan site.
Discussion
This study aimed to identify relationships between intrinsic (resting state) connectivity in neural regions supporting emotion processing/regulation and measures of behavioral and emotional dysregulation in LAMS youth presenting with a variety of psychiatric diagnoses. Dimensional and categorical relationships were tested. Supporting our dimension-focused primary hypothesis, we found significant inverse relationships between 1) amygdala–left posterior insula and putamen RSC and PGBI-10M score,
Acknowledgments
This work is supported by the National Institute of Mental Health Grants 2R01 MH73953-09A1 (Birmaher and Phillips, University of Pittsburgh), 2R01 MH73816-09A1 (Holland, Children׳s Hospital Medical Center), 2R01 MH73967-09A1 (Findling, Case Western Reserve University), and 2R01 MH73801-09A1 (Fristad, Ohio State University).
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Both authors contributed equally as 1st authors.