Development of White Matter Microstructure and Intrinsic Functional Connectivity Between the Amygdala and Ventromedial Prefrontal Cortex: Associations With Anxiety and Depression

Abstract

Background Connectivity between the amygdala and ventromedial prefrontal cortex (vmPFC) is compromised in multiple psychiatric disorders, many of which emerge during adolescence. To identify what extent the deviations in amygdala-vmPFC maturation contribute to the onset of psychiatric disorders, it is essential to characterize amygdala-vmPFC connectivity changes during typical development. Methods Using an accelerated cohort longitudinal design (1–3 time points, 10–25 years, N=246), we characterized developmental changes of amygdala-vmPFC subregion functional and structural connectivity using resting state fMRI and diffusion-weighted imaging. Results Functional connectivity between the centromedial amygdala and rostral anterior cingulate (rACC), anterior vmPFC, and subgenual cingulate significantly decreased from late childhood to early adulthood in males and females. Age associated decreases were also observed between the basolateral amygdala and rACC. Importantly, these findings were replicated in a separate cohort (10–22 years, N=327). Similarly, structural connectivity, as measured by quantitative anisotropy, significantly decreased with age in the same regions. Functional connectivity between the centromedial amygdala and rACC was associated with structural connectivity in these same regions during early adulthood (ages 22–25). Finally, a novel time-varying coefficient analysis showed that increased centromedial amygdala-rACC functional connectivity was associated with greater anxiety and depression symptoms during early adulthood, while increased structural connectivity in centromedial amygdala-anterior vmPFC white matter was associated with greater anxiety/depression during late childhood. Conclusions Specific developmental periods of functional and structural connectivity between amygdala-prefrontal systems may contribute to the emergence of anxiety and depressive symptoms, and may play a critical role in the emergence of psychiatric disorders in adolescence.

Examining the relationship between prenatal depression, amygdala-prefrontal structural connectivity and behaviour in preschool children

“…Medications and psychotherapy that treat depression increase functional coupling between the amygdala and the striatum, thalamus, right frontal and cingulate cortex [52], likely resulting in increased PFC inhibition and regulation of amygdala responsivity. With this in mind, it is important to note that although data consistently shows altered amygdala-prefrontal cortex connectivity associated with mood and anxiety disorders, it is unclear whether that dysfunction is hypo-or hyper-connectivity [46]. Our results support the theory of weaker top-down amygdala inhibition in children who experienced higher prenatal maternal depression and show subsequent behavioural alterations, and provide evidence of a structural basis for previouslyobserved deficits in functional connectivity.…”

“…Previous results from our lab, in an overlapping sample, suggested an accelerated pattern of development (lower diffusivity) in right frontal-temporal white matter in children exposed to greater second trimester depressive symptoms [24]. Indeed, other data has found that potentially accelerated development may predispose children to psychiatric conditions later in life [46][47][48]. This may be a product of timing and brain areas.…”

Biological Aging in Childhood and Adolescence Following Experiences of Threat and Deprivation: A Systematic Review and Meta-Analysis

“…We will evaluate studies of ELA with this normative developmental pattern in mind; if children who have experienced adversity demonstrate greater negative connectivity for their age than children who have not, this would reflect accelerated development and if children who have experienced adversity exhibit more positive or less negative connectivity than comparison children, this would reflect delayed development. In contrast, studies investigating developmental patterns of connectivity at rest have been more mixed, with some studies demonstrating an increase in connectivity with age (e.g., Gabard-Durnam et al, 2014) and others demonstrating a decrease (Jalbrzikowski et al, 2017). Because a consensus has not been reached on the normative developmental pattern of amygdala-mPFC connectivity during rest, we focus only on papers that explore the associations of ELA with amygdala-mPFC connectivity using task-related functional connectivity.…”

Early maturational emergence of adult-like emotional reactivity and anxiety after brief exposure to an obesogenic diet

“…The highly conserved neurocircuitry connecting the mPFC and the amygdala plays a critical role in anxiety, and in the extinction of fear memories (Adhikari et al, 2015;Janak and Tye, 2015;Milad and Quirk, 2002;Phelps et al, 2004) and is abnormal in PTSD patients (Gilboa et al, 2004;Koenigs and Grafman, 2009). The PFC and amygdala undergo striking structural changes during adolescence (Jalbrzikowski et al, 2017), providing a biological basis that may underlie their unique vulnerability to the disruptive effects of obesity and the consumption of diets rich in saturated fats and sugars. Paralleling clinical data in humans (Geha et al, 2017;Riederer et al, 2016), we showed that DIO rats exhibit significant and partly irreversible microstructural alterations in mPFC regions and amygdalar nuclei associated with fear learning and fear extinction (Vega-Torres et al, 2018).…”