Abstract
Connections between the amygdala and medial prefrontal cortex (mPFC) are considered critical for the expression and regulation of emotional behavior. Abnormalities in frontoamygdala circuitry are reported across several internalizing conditions and associated risk factors (for example, childhood trauma), which may underlie the strong phenotypic overlap and co-occurrence of internalizing conditions. However, it is unclear if these findings converge on the same localized areas of mPFC or adjacent anterior cingulate cortex (ACC). Examining 46 resting-state functional connectivity magnetic resonance imaging studies of internalizing conditions or risk factors (for example, early adversity and family history), we conducted an activation likelihood estimation meta-analysis of frontoamygdala circuitry. We included all reported amygdala to frontal coordinate locations that fell within a liberal anatomically defined frontal mask. Peak effects across studies were centered in two focal subareas of the ACC: pregenual (pgACC) and subgenual (sgACC). Using publicly available maps and databases of healthy individuals, we found that observed subareas have unique connectivity profiles, patterns of neural co-activation across a range of neuropsychological tasks, and distribution of tasks spanning various behavioral domains within peak regions, also known as ‘functional fingerprints'. These results suggest disruptions in unique amygdala–ACC subcircuits across internalizing, genetic and environmental risk studies. Based on functional characterizations and the studies contributing to each peak, observed amygdala–ACC subcircuits may reflect separate transdiagnostic neural signatures. In particular, they may reflect common neurobiological substrates involved in developmental risk (sgACC), or the broad expression of emotional psychopathology (pgACC) across disease boundaries.
Highlights
The past few years have witnessed a paradigm shift in the characterization of neuropsychiatric disorders, away from categorical descriptions towards a dimensional view.[1]
Abnormal resting-state functional connectivity (FC) between amygdala and medial prefrontal cortex (mPFC) is repeatedly reported across studies of internalizing conditions and associated risk factors, for example, family history[9] and exposure to childhood adversity,[10] suggesting that frontoamygdala FC may be a transdiagnostic marker of internalizing psychopathology
We found that studies contributing to the subgenual ACC (sgACC) cluster consisted predominantly of young people ages 20 and under, with varied environmental and temperamental risk factors. χ2 analysis suggests that studies on youth and risk factors were over-represented in the sgACC peak relative to all studies included in the meta-analysis, χ2(1) = 19.92, P o 0.001
Summary
The past few years have witnessed a paradigm shift in the characterization of neuropsychiatric disorders, away from categorical descriptions towards a dimensional view.[1] This shift is due, in part, to the observations of common behavioral, neurobiological and genetic substrates shared across phenotypically related diagnoses This is true among the internalizing disorders (for example, anxiety, depression and posttraumatic stress disorder (PTSD)), which are highly comorbid and have common heritable and environmental influences.[2,3] These observations have prompted the search for potential transdiagnostic neural markers (for example, Goodkind et al.4), which may provide better understanding of the etiopathogenesis of internalizing psychopathology. Central to the internalizing disorders is the altered expression and/or regulation of emotional behavior.[5] As such, a core emotion circuitry comprised of amygdala and medial prefrontal cortex (mPFC) has become a prime translational target for understanding the neural substrates of internalizing conditions. Abnormal resting-state functional connectivity (FC) between amygdala and mPFC is repeatedly reported across studies of internalizing conditions (for example, Brown et al.,[6] Roy et al.[7] and Etkin et al.8) and associated risk factors, for example, family history[9] and exposure to childhood adversity,[10] suggesting that frontoamygdala FC may be a transdiagnostic marker of internalizing psychopathology
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