1c
Chi C. Chan, Daniel H. Vaccaro, Nina L. J. Rose, Laura E. Kessler, and Erin A. Hazlett
Commentaries from Chang and Baskin-Sommers (this volume) as well as Beeney (this volume) cogently highlight limitations of current methods in neuroimaging research on personality disorders and suggest approaches that would further specify neural mechanisms and increase clinical relevance. Both commentaries noted the need to incorporate multiple sources of evidence from neuroimaging, genetics, and behavioral data and the need to examine patterns of brain activation in addition to individual regions of interest (ROIs). Here, we use examples from the study of affect regulation to illustrate how these methods combined with a transdiagnostic approach could advance neurobiological understanding of personality pathology.
A large body of research implicates serotonin in affect regulation (Hariri & Holmes, 2006), and a common polymorphism in the serotonin transporter gene (5-HTTLPR) has downstream effects that modulate serotoninergic activity at the synapse. However, studies and meta-analyses have reported conflicting findings on whether the 5-HTTLPR short allelic variant is associated with affect regulation traits such as neuroticism or harm avoidance (Munafò, Clark, & Flint, 2005; Sen, Burmeister, & Ghosh, 2004), or whether there is any significant genetic effect at all on either trait (Munafò et al., 2009). One challenge is the difficulty in detecting the modest effect of a single common polymorphism on a highly complex phenotype.
Neuroimaging data can serve as an endophenotype to bridge the gap between genes and behavior, as endophenotypes are thought to be more closely related to genotype than distant behavioral phenotype. The 5-HTTLPR polymorphism may account for up to 10 percent of the variance in responsivity of the amygdala, a brain region highly involved in emotion processing (Munafò, Brown, & Hariri, 2008), but a more recent meta-analysis revealed no such effect (Bastiaansen et al., 2014). Going beyond individual ROIs and examining brain connectivity patterns provide important insight into potential mechanisms. Studies report that 5-HTTLPR short allele variant carriers have reduced amygdala–anterior cingulate cortex coupling (Pezawas et al., 2005), increased amygdala–insula coupling (Klucken et al., 2015), and increased amygdala–prefrontal cortex coupling (Madsen et al., 2016). Importantly, while structure and function of individual regions were unrelated to self-reported harm avoidance, amygdala–anterior cingulate cortex functional connectivity accounted for about 30 percent of the variance in the trait (Pezawas et al., 2005). Additionally, increased neuroticism was associated with decreased functional connectivity of the amygdala with other brain regions (Madsen et al., 2016).
Applying these methods to the study of emotion regulation in personality disorders requires further consideration of within-disorder heterogeneity and cross-disorder overlap. For example, 5-HTTLPR appears related to the number of BPD symptoms (Hankin et al., 2011) and individual affective symptoms (Maurex, Zaboli, Ohman, Asberg, & Leopardi, 2010), but not the diagnosis of borderline personality disorder as a whole (BPD; Calati, Gressier, Balestri, & Serretti, 2013). On the other hand, neurobiological studies on affective instability across clinical disorders including BPD converge on the role of the amygdala and its functional connectivity with other brain regions (Broome, He, Iftikhar, Eyden, & Marwaha, 2015).
Research on the neurobiology of affect regulation demonstrates the utility of combining multiple units of analysis with a dimensional approach, consistent with the Research Domain Criteria framework as suggested by Beeney. Together with neural network analyses that appreciate the complexity of the brain, these methods hold promise for illuminating the neurobiology of personality pathology. The alternative DSM-5 model for personality disorders can guide investigation of clinically relevant constructs that directly inform treatment development.
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