837 5-Httlpr Gene Polymorphism Modulates Activity and Connectivity Within An Emotional Arousal Network of Healthy Control Subjects During Visceral Pain

Abstract

Background and Aims: Variants of the function polymorphism in the promoter region of the serotonin transporter gene (5-HTTLPR) have been implicated in the vulnerability for affective disorders and in IBS pathophysiology. We hypothesized that 5-HTTLPR genotype would moderate: 1) a significant pattern of brain activity discriminating pain from non-pain conditions and 2) the effective connectivity in an emotional arousal network, previously shown to be involved in central pain amplification. Methods: Regional cerebral blood flow (rCBF) of 21 healthy controls (Ctrls; 5 females and 16 males) was assessed using PET (H15O) during an intense (40 mm Hg) colorectal balloon inflation (INF) or during no INF (0 mm Hg). Polymerase chain reaction was used to determine the genetic polymorphism of the 5-HTTLPR (10 short (s/s) and 11 long (l) (included 9 l/s, 2 l/l). Task partial least squares (PLS) tested for distributed patterns of brain activity discriminating the INF conditions and interacting with genotype. Structural equation modeling (SEM) tested for group differences in the effective connectivity of an emotional arousal network during INF. Results: PLS revealed a significant network of regions (p<.01, 59% cross-covariance matrix variance) differentiating INF from non-INF. Compared to s/s, l carriers showed greater engagement of this network, which comprised regions of activation (including thalamus, insula, sACC, pons) and deactivation (including medial orbital frontal cortex, amygdala, and infragenual ACC) during INF. SEM showed genotype differences in the effective connectivity within the emotional arousal network. That is, s/s showed strong positive connectivity from sACC to amygdala (lack of feedback inhibition of amygdala), while l carriers showed the expected negative connectivity (sACC to AMYG [.46, -.40, χ2∆=7.7]). Conclusions: In healthy Ctrls, s/s genotype is associated with altered connectivity within an emotional arousal network activated by visceral pain. The resultant disinhibition of the amygdala may play a role in central pain amplification, and represent a vulnerability factor for the development of IBS. Support Contributed By: K08 DK 071626 (JSL) NR04881, P50 DK64539, R24 AT002681, DK 64539