Cross‐sectional and longitudinal abnormalities in brain structure in children with severe mood dysregulation or bipolar disorder

It remains unclear whether BD presents in youth, as in adults, with only episodic mood symptoms or if chronic, severe non-episodic irritability is a developmental phenotype of BD. To study this question, Leibenluft et al. defined a new syndrome, severe mood dysregulation (SMD), to codify youth with chronic, non-episodic irritability. Although outcome and family history data (Brotman et al., 2007; Stringaris et al., 2010) differentiate SMD from `classic,' episodic BD, the underlying pathophysiology of these disorders is unclear. Functional magnetic resonance imaging (fMRI) studies comparing children with SMD and BD suggest that these two groups have both overlapping and distinct neural dysfunction (Adleman et al., 2011; Brotman et al., 2010; Deveney et al., 2012). However, no study compares neuroanatomy in children with SMD to those with BD and healthy volunteers (HV). In pediatric BD, research demonstrates structural abnormalities in many brain regions. Most studies report decreased cortical gray matter (GM) in BD vs. HV in a range of association cortex areas (Dickstein et al., 2005; Frazier et al., 2005; James et al., 2011; Wilke, Kowatch, DelBello, Mills, & Holland, 2004), and increased basal ganglia volumes in pediatric BD (DelBello, Zimmerman, Mills, Getz, & Strakowski, 2004; Liu et al., 2011; Wilke, et al., 2004). A recent meta-analysis in children and adults with BD reported that decreased prefrontal cortex and increased globus pallidus volumes were two of the most consistent findings (Arnone et al., 2009). Although there have been no structural MRI (sMRI) studies of SMD, the syndrome combines hyperarousal symptoms seen in attention-deficit/hyperactivity disorder (ADHD) with severe irritability (Leibenluft, 2011). In the ADHD neuroanatomical literature, the most replicated abnormality is decreased basal ganglia GM (Nakao, Radua, Rubia, & Mataix-Cols, 2011). However, since data suggest that SMD and non-irritable ADHD differ in neural activity (Brotman, et al., 2010), ADHD may differ from SMD neuroanatomically, and a study of children with SMD is warranted. While an emerging cross-sectional literature demonstrates structural brain abnormalities in adult and pediatric BD (Arnone, et al., 2009), the developmental trajectory of these abnormalities is unclear, and the trajectory is completely unstudied in SMD. Most previous longitudinal sMRI studies in pediatric BD include small samples, averaging around 10 patients (Blumberg et al., 2005; Gogtay et al., 2007; Kalmar et al., 2009). The most recent, and largest, study combined 58 late-adolescent and adult patients and reported greater GM volume increases over time in BD vs. HV in several regions, including superior temporal gyrus, basal ganglia, and medial temporal structures (Lisy et al., 2011). Given the limited literature in pediatric BD and the absence of research in SMD, we conducted a study comparing brain volume both cross-sectionally and longitudinally over two years in SMD, BD and HV. As previous fMRI and behavioral findings suggest that BD and SMD have both overlapping and distinct dysfunction, we hypothesized that we would find regions in which both SMD and BD differed from HV, and regions where the two patient groups differed from each other as well as HV. We expected group differences in association cortices and in basal ganglia, as such abnormalities have been reported in both BD and ADHD. However, given the lack of structural studies in SMD, we did not have specific hypotheses about the directionality of these findings. To explore both whole-brain and regional effects, as well as between- and within-group effects, we employed optimized voxel-based morphometry (VBM), a semi-automated method used to measure volume differences.