Elucidating Neural Network Functional Connectivity Abnormalities in Bipolar Disorder: Toward a Harmonized Methodological Approach

Abstract

Bipolar disorder (BD), a mood disorder characterized by emotional lability and dysregulation, is associated with alterations in functional connectivity, particularly as assessed using functional MRI. Here, we provide an overview of the extant literature, and themes that have emerged within it. We identified published research describing functional connectivity in BD using PubMed and follow-up searches. The most consistent evidence favors abnormally heightened functional connectivity between the amygdala and the lateral regions of the ventral prefrontal cortex (PFC), both during rest or emotional processing. Altered interactions between the amygdala and more medial PFC regions have been implicated in BD, but are less consistently related to core symptoms and are sometimes associated with mood state or psychosis. Interactions between medial and lateral ventral PFC have also been reported to be altered in BD, and may mediate estimates of amygdala/vlPFC connectivity. We also describe other themes, including an emerging literature examining reward circuitry, which has highlighted abnormal functional interactions between the ventral striatum and medial prefrontal cortex, as well as the advent of examining global network abnormalities in BD. Functional connectivity studies in BD have established altered interactions between PFC and the amygdala. To address the inconsistencies in the literature, we suggest avenues for the adoption of large scale, and network-based analysis of connectivity, the integration of structural connectivity and the acknowledgement of dynamic and context-related shifts in functional connectivity as a means of clarifying the abnormal neural circuitry in the disorder.

Neural connectivity in youth at-risk for bipolar disorder: a review of functional magnetic resonance imaging studies

“…In summary, the findings of this qualitative systematic review in youth at-risk for BD are compatible with the consensus model of the functional neuroanatomy of BD [36] and are also consistent with reviews of functional connectivity neuroimaging research in patients with BD [20,21] which suggests that alterations of functional connectivity are putative risk biomarkers for the disorder. Ventrolateral PFC emerged as an important node of the frontolimbic networks showing functional connectivity alterations in adolescents and young adults at-risk for BD.…”

“…Collectively, the literature provides evidence for a role of frontolimbic network anomalous connection patterns in the development of BD. The findings are consistent with reviews of functional connectivity neuroimaging research in patients with BD [20,21] which suggests that alterations of functional connectivity are putative risk biomarkers for the disorder.…”

“…Altered connectivity between the ventrolateral PFC and the amygdala, with individuals atrisk for BD showing more functional connectivity between these regions during emotion processing tasks [23,26] and less functional connectivity during affective cognitive tasks [25], partially overlaps with findings of abnormally heightened functional connectivity between the amygdala and ventrolateral PFC during rest or emotional processing in BD patients [21]. Abnormally high connectivity between the amygdala and ventrolateral PFC may represent a lack of flexibility to incorporate feedback from other neocortical areas, such as the dorsolateral PFC and ACC, that may predispose youths to the development of mood dysregulation and eventually BD [37].…”

“…Functional connectivity studies have focused predominantly on the amygdala and striatal-prefrontal cortical networks during emotional processing, emotional regulation, reward-processing and cognitive control tasks [21]. Several of these studies have shown, in individuals with BD, both abnormally increased positive functional connectivity between the amygdala and ventrolateral prefrontal cortex (PFC) or abnormally decreased inverse functional connectivity between these regions.…”

“…Connectivity between the amygdala and medial prefrontal regions and between medial and lateral regions within the PFC has also been implicated in BD, but the direction of findings is less consistent. Recent studies have also demonstrated altered connectivity in reward-related networks, particularly the ventral striatum (VS) and its interactions with medial PFC [21].…”