Cortico-amygdalar maturational coupling is associated with depressive symptom trajectories during adolescence
Introduction
Adolescence is characterized by a dramatic rise in the incidence of depression – the leading cause of disability during the second decade of life in developed countries (World Health Organization, 2014). Future mental health trajectories are often shaped during this time, with the experience of a depressive symptom during adolescence increasing the likelihood of future disorder onset (Costello and Maughan, 2015). Research has investigated the neurobiological underpinnings of depression, identifying structural abnormalities in the amygdala, subgenual anterior cingulate cortex (ACC), and various regions of the prefrontal cortex (Dohm et al., 2016, Kerestes et al., 2014, Miller et al., 2015, Singh and Gotlib, 2014). However, given documented maturation of both subcortical and prefrontal regions during adolescence (Dennis and Brotman, 2003, Goddings et al., 2014, Mutlu et al., 2013, Raznahan et al., 2011b, Tamnes et al., 2010, Vijayakumar et al., 2016), it can also be speculated that coordinated development of these regions may help support adaptive functioning, while aberrations to this pattern may result in poorer regulatory capacities that have enduring effects on mental health.
Indeed, it is widely theorized that depression emerges from the development of, and interaction between two broadly defined brain systems that work in concert – the subcortical system that supports affect generation and reactivity, and the prefrontal cortex that is involved in the cognitive regulation of affective states (Badcock et al., 2017, Carver et al., 2008, Heller, 2016, Pfeifer and Allen, 2012, Siegle et al., 2007). Within the subcortical system, the amygdala is the most consistently implicated region in depression, with its extensive functional and anatomical connectivity highlighting the central role this region plays in emotional processing, learning and motivation (Mears and Pollard, 2016). As such, it is important to characterize coordinated development of the amygdala and PFC regions and understand how this may relate to the emergence of depressive symptomatology.
In comparison to traditional focal approaches, analyses investigating associations between brain regions have the potential to reveal more about cognitive and affective processes characterized by distributed neural activity (Evans, 2013). Within the structural neuroimaging field, this has resulted in a surge of studies on structural covariance or coupling of gray matter (i.e., how structural properties, such as volume or thickness, of different regions correlate with each other; Alexander-Bloch et al., 2013b, Zielinski et al., 2010). This is frequently hypothesized to arise from coordinated neurobiological development through mutually trophic effects mediated by underlying axonal connections (i.e., Hebbian principals of “neurons that fire together wire together”; Hebb, 1949). Indeed, past investigations have also documented patterns of maturational coupling (i.e., patterns of correlated change) across the cortical mantle (Lerch et al., 2006, Raznahan et al., 2011a). However, coupling of subcortical and cortical structures may be particularly relevant to understanding associations between neurodevelopment and depression, as described above.
Only two studies have investigated normative structural coupling between subcortical and cortical structures. Albaugh and colleagues (2013) identified negative coupling between the amygdala and prefrontal structures. While they examined longitudinal data, no age-related effects were found (i.e., the relationship between amygdala volume and cortex thickness remained constant at any given time from 5-to-23 years of age). However, they did not investigate whether change in amygdala structure over time was related to change in cortical structures. To our knowledge, Walhovd and colleagues (2015) are the only authors to examine this question, showing that development of the hippocampus and basal ganglia were both positively related to cortical development, with greater subcortical reductions being related to greater cortical reductions. Each subcortical structure also exhibited unique coupling with largely non-overlapping cortical areas. Such an investigation is yet to be undertaken on cortico-amygdalar coupling.
In light of research supporting the importance of functional maturational coupling of the cortex and amygdala in affective processes (Gee et al., 2013), along with research implicating structural brain development in depression (Ducharme et al., 2014, Whittle et al., 2014), it can be hypothesized that similar associations may be present in relation to maturational coupling of structure. Initial research into the functional relevance of structural covariance networks focused on cognitive functions (Lee et al., 2013, Raznahan et al., 2014), but one recent study investigated associations with behavioral problems. Ameis et al. (2014) found amygdala-orbitofrontal cortex (OFC) coupling varied as a function of externalizing problems in adolescents, with a lack of coupling being associated with higher levels of problems. However there has been no research examining how maturational coupling may relate to internalizing symptoms and associated psychopathology.
Therefore, the current study characterized cortico-amygdalar maturational coupling during adolescence, and subsequently investigated whether this pattern of coupling was related to concurrent changes in depressive symptomatology. We focused on the amygdala given its prominent role in affective processing and prior research implicating functional and structural abnormalities in this region with depression (Kerestes et al., 2014, Singh and Gotlib, 2014). The research question was addressed in a community sample of adolescents examined longitudinally from 11-to-20 years of age, with up to three brain scans obtained per individual, as well as concurrent assessment of depressive symptoms. While structural correlates of depressive symptomatology have previously been examined in this sample (Whittle et al., 2014, Whittle et al., 2011), this is the initial investigation into structural coupling. We first examined maturational cortico-amygdalar coupling, and given prior findings by Walhovd et al. (2015), hypothesized positive associations between change in amygdala volume and change in cortical thickness, particularly within regions implicated in modulating amygdala function (i.e., dorsolateral, dorsomedial and ventromedial PFC (dlPFC, dmPFC, vmPFC), OFC, and inferior parietal cortices; Arnsten and Rubia, 2012, Burnett et al., 2011, Rempel-Clower, 2007). We subsequently examined whether these patterns of cortico-amygdalar maturational coupling were related to changes in depressive symptomatology. Although exploratory in nature, we hypothesized that adolescents with positive coupling (particularly greater correlated reductions in the size of the amygdala and associated cortical regions) would experience reductions in symptoms over time. In order to examine the specificity of findings to depression, particularly given the predominant role of the amygdala in anxiety (Blackford and Pine, 2012), we also investigated whether maturational coupling was related to changes in anxiety symptoms.
Section snippets
Participants
The current sample was derived from a larger longitudinal cohort enrolled in the Orygen Adolescent Development Study (OADS), conducted in Melbourne, Australia. Students (N=2453) in the final year of primary school were recruited from schools to participate in an initial screening phase, which involved completion of the Early Adolescent Temperament Questionnaire-Revised (EATQR; Capaldi and Rothbart, 1992). Based on scores, a smaller sample of 415 students were selected by over-sampling
Results
Descriptive statistics for CES-D and BAI scores, and amygdala volumes, at each time point are reported in Table 3.
Analysis 1: Best fitting models for the left and right amygdala included a significant main effect of age, characterized by increases in volume with age. The best fitting model for the right amygdala additionally included a significant main effect of sex, with females having smaller volumes than males (but no sex-moderated age effect), while the best fitting model for the left
Discussion
This study identified positive maturational coupling between the right amygdala and various frontal and temporal cortices. Maturational coupling between the right amygdala and left anterior PFC was also associated with development of depressive symptomatology during adolescence. Specifically, greater positive coupling between these two regions was associated with reductions in depressive symptoms. This finding was specific to depressive symptomatology, with no such relationship identified with
Acknowledgements and Financial Disclosures
The authors report no conflicts of interest. Neuroimaging analysis was facilitated by the Neuropsychiatry Imaging Laboratory at the Melbourne Neuropsychiatry Centre. The authors would like to thank the Brain Research Institute and Royal Children's Hospital for support in acquiring the neuroimaging data, and the families who participated in the study. This research was supported by grants from the Colonial Foundation, the National Health and Medical Research Council (NHMRC; Australia; Program
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