Resting-state functional connectivity of the amygdala and longitudinal changes in depression severity in adolescent depression

Abstract

Background The incidence of major depressive disorder (MDD) rises during adolescence, yet the neural mechanisms of MDD during this key developmental period are unclear. Altered amygdala resting-state functional connectivity (RSFC) has been associated with both adolescent and adult MDD, as well as symptom improvement in response to treatment in adults. However, no study to date has examined whether amygdala RSFC is associated with changes in depressive symptom severity in adolescents. Method We examined group differences in amygdala RSFC between medication-naïve depressed adolescents (N=48) and well-matched healthy controls (N=53) cross-sectionally. We then longitudinally examined whether baseline amygdala RSFC was associated with change in depression symptoms three months later in a subset of the MDD group (N=24). Results Compared to healthy controls, depressed adolescents showed reduced amygdala-based RSFC with the dorsolateral prefrontal cortex (DLPFC) and the ventromedial prefrontal cortex (VMPFC). Within the depressed group, more positive baseline RSFC between the amygdala and insulae was associated with greater reduction in depression symptoms three months later. Limitations Only a subset of depressed participants was assessed at follow-up and treatment type and delivery were not standardized. Conclusions Adolescent depression may be characterized by dysfunction of frontolimbic circuits (amygdala-DLPFC, amygdala-VMPFC) underpinning emotional regulation, whereas those circuits (amygdala-insula) subserving affective integration may index changes in depression symptom severity and may therefore potentially serve as a candidate biomarker for treatment response. Furthermore, these results suggest that the biomarkers of MDD presence are distinct from those associated with change in depression symptoms over time.

Reduced fronto-amygdalar connectivity in adolescence is associated with increased depression symptoms over time

“…Based on previous research showing reduced RSFC between the amygdala and prefrontal regions in depressed adolescents compared with healthy controls (Connolly et al, 2017; Pannekoek et al, 2014), we hypothesized weaker connectivity between these brain regions in escalators compared to controls. To our knowledge, this is the first study to examine whether amygdala RSFC abnormalities precede depressive symptom expression.…”

“…Resting state functional connectivity (RSFC) magnetic resonance imaging allows the examination of functional connections in the brain, in the absence of external task demands, by correlating temporally synchronous spontaneous blood-oxygen-level dependent (BOLD) activity (Fox and Raichle, 2007; van den Heuvel and Hulshoff Pol, 2010). Though widespread differences in functional connectivity have been observed between depressed adolescents and controls using this technique (Bebko et al, 2015; Connolly et al, 2017; Pannekoek et al, 2014; Rzepa and McCabe, 2016; Sacchet et al, 2016), several studies have demonstrated fronto-amygdalar hypo-connectivity in adolescents with MDD compared to healthy controls, including reduced RSFC between the right amygdala and the left frontal pole and right anterior cingulate cortex (Pannekoek et al, 2014) and between the right amygdala and ventromedial and bilateral dorsolateral PFC (Connolly et al, 2017). Another study examining children with MDD, with and without maternal MDD, showed reduced RSFC between the amygdala and bilateral dorsolateral PFC in both groups compared to controls (Luking et al, 2011).…”

“…The present study addresses this gap by using RSFC to examine potential neurobiological connectivity markers of later escalating depression symptoms in an adolescent sample. Based on previous findings of abnormalities in functional connectivity of the limbic system in depressed adolescents (Bebko et al, 2015; Connolly et al, 2017; Pannekoek et al, 2014), we compared baseline whole-brain, seed-based amygdala RSFC of youth who showed a significant increase in depression symptoms over time to that of well-matched youth who showed a stable mood presentation. We hypothesized weaker premorbid fronto-amygdalar functional connectivity in those adolescents who later showed an increase in depressive symptoms.…”

Abnormal dynamic functional connectivity of amygdalar subregions in untreated patients with first-episode major depressive disorder

“…Consistent with our results, a recent study of medication-naive depressed adolescents showed reduced amygdala-based resting-state FC with the dorsolateral prefrontal cortex and ventromedial prefrontal cortex. 10 Animal studies have also revealed negative FC between the amygdala and mPFC. In rats, stimulation of the amygdala inhibits neuronal ensemble activity in the mPFC, and stimulation of the mPFC to the amygdala excites intraamygdaloid GABAergic cells that inhibit neuronal activity in the central amygdaloid nucleus.…”

“…9 Furthermore, reduced amygdalar connectivity with the dorsolateral prefrontal cortex, ventromedial prefrontal cortex and ventrolateral prefrontal cortex has been reported in depressed adolescents, and greater positive resting-state FC between the amygdala and insula is associated with a greater reduction in depression severity over time. 10 Notably, previous studies have focused on amygdalar FC, which usually estimates stationary synchronization between brain regions during the entire scan period but ignores its dynamic, time-varying characteristics. Researchers have recently applied newly developed dynamic FC (dFC) analysis strategies to investigate neuropsychiatric diseases such as Alzheimer disease 11 and schizophrenia, 12 and provided novel understandings of their pathology.…”