br Materials and Methods br

Materials and Methods
Discussion This study investigates the effect of treatment on rsFC in neural regions indexing the ‘hot’ emotional, and ‘cold’ cognitive systems in adolescents with MDD. As hypothesized, depressed adolescents had increased rsFC of parts of the ‘hot’ limbic system relative to controls. However, no difference was found with connectivity to the ‘cold’ PFC. These results suggest a specific pathology to the limbic system following the onset of symptoms. Whether this represents an illness-related effect or a putative marker prior to illness emergence cannot be determined from these cross-sectional findings. Evidence of such abnormalities has been found in high-risk individuals. Hyper-connectivity in left temporal cortex, insula, ACC, medial orbitofrontal PFC, and ventromedial PFC was observed in 6-month-old infants born to mothers with prenatal maternal depressive symptoms, similar to patterns observed in depressed adolescents and adults (Qiu et al., 2015). Development of ‘hot’ emotional processing and ‘cold’ cognitive processing systems may occur at different rates during adolescence, and asynchronous trajectories may have adverse consequences for mental health and contribute to the emergence of MDD (Hagan et al., 2015). In this study, elevated rsFC of the ‘hot’ (limbic) system in the absence of differences in the ‘cold’ (pre-frontal) system implies that depressive symptoms may emerge from physiologically overactive bottom-up cortical regions with a loss of influence from their top-down counterparts. Our study is aligned with previous research on adults with depression showing altered rsFC in areas which may be critical for mood regulation (Anand et al., 2005). The right insula exhibited significantly greater connectivity with left amygdala and bilateral supragenual ACC cyproheptadine hcl manufacturer regions. Altered insular rsFC has been shown in depressed adolescents and adults (Connolly et al., 2013; Veer et al., 2010). The right anterior insula may play a role in adaptively switching from rumination to interoceptive awareness (Horn et al., 2010). Hyper-connectivity between the ACC and insula has proved to be more equivocal in adolescents; both elevated and reduced rsFC to the subgenual ACC and the insula have been reported (Connolly et al., 2013; Cullen et al., 2009). Such differences may reflect variation in experimental details, or in sample characteristics, such as medication use. Here, 30 of 82 patients were medicated. However, comparing only those on medication to controls (Fig. S5) or medication-naïve to controls (Fig. S4) led to similar patterns of increased rsFC to left amygdala and bilateral supragenual ACC compared to healthy controls. Length of time on medication may also be a factor, but was not available. Early life stress has been associated with markedly elevated rates of MDD in child, adolescent, and adult cohorts, and may therefore affect brain function, leading to observable differences in rsFC prior to onset of a first episode (Henje Blom et al., 2015). All patients had improved symptoms following CBT. Successful treatment was associated with normalisation of rsFC (Fig. 3). The sensitivity of this change in right insula was corroborated by a normalisation of rsFC along with a reduction in symptoms scores; larger alterations in rsFC led to reductions in symptoms (Fig. 3B). Changes in insula activity have been shown to take place following various treatments, including medication, deep brain stimulation, vagus nerve stimulation, and mindfulness training, indicating a role for this region in mediating treatment response (McGrath et al., 2013). This suggests that cognitive mechanisms involved in recovery involve the inhibition of pathological rumination and the re-instigation of interoceptive processing and monitoring of bottom-up physiological signals. Significant time effects were observed for all seed regions which did not overlap with treatment effects. These may reflect maturation changes with time or accommodation of participants to the MRI environment, or both.