Person:

Milberg, William

The default mode network (DMN) has been used to study disruptions of functional connectivity in a wide variety of psychiatric and neurological conditions, including posttraumatic stress disorder (PTSD). Studies indicate that the serotonin system exerts a modulatory influence on DMN connectivity; however, no prior study has examined associations between serotonin receptor gene variants and DMN connectivity in either clinical or healthy samples. We examined serotonin receptor single nucleotide polymorphisms (SNPs), PTSD, and their interactions for association with DMN connectivity in 134 White non-Hispanic veterans. We began by analyzing candidate SNPs identified in prior meta-analyses of relevant psychiatric traits and found that rs7997012 (an HTR2A SNP), implicated previously in anti-depressant medication response in the Sequenced Treatment Alternatives for Depression study (STAR*D; McMahon et al., 2006), interacted with PTSD to predict reduced connectivity between the posterior cingulate cortex (PCC) and the right medial prefrontal cortex and right middle temporal gyrus (MTG). rs130058 (HTR1B) was associated with connectivity between the PCC and right angular gyrus. We then expanded our analysis to 99 HTR1B and HTR2A SNPs and found two HTR2A SNPs (rs977003 and rs7322347) that significantly moderated the association between PTSD severity and the PCC-right MTG component of the DMN after correcting for multiple testing. Finally, to obtain a more precise localization of the most significant SNP × PTSD interaction, we performed a whole cortex vertex-wise analysis of the rs977003 effect. This analysis revealed the locus of the pre-frontal effect to be in portions of the superior frontal gyrus, while the temporal lobe effect was centered in the middle and inferior temporal gyri. These findings point to the influence of HTR2A variants on DMN connectivity and advance knowledge of the role of 5-HT2A receptors in the neurobiology of PTSD.

Abstract Introduction: Interpersonal early life trauma (I‐ELT) is associated with a myriad of functional impairments in adulthood, increased risk of drug addiction, and neuropsychiatric disorders. While deficits in emotional regulation and amygdala functioning are well characterized, deficits in general cognitive functioning have also been documented. However, the neural underpinnings of cognitive dysfunction in adults with a history of I‐ELT and the potential relationship between amygdala‐based functional connectivity and behavioral performance are currently poorly understood. This study examined how I‐ELT affects the cognitive and neural mechanisms supporting sustained attention. Methods: A total of 66 Veterans (18 with and 48 without a history of I‐ELT) completed a nonemotional sustained attention task during functional MRI. Results: The individuals with I‐ELT showed significant impairments in sustained attention (i.e., higher error rates, greater response variability). This cohort exhibited increased amygdala functional connectivity with the prefrontal cortex and decreased functional connectivity with the parahippocampal gyrus when compared to those without I‐ELT. These connections were significantly correlated with individual differences in sustained attention performance. Notably, classification analyses revealed that the pattern of amygdala connectivity across the whole brain was able to classify I‐ELT status with 70% accuracy. Conclusion: These results provide evidence of a lasting negative impact for those with a history of I‐ELT on sustained attention ability. They also highlight a critical role for amygdala functioning in cognitive control and sustained attention for those with a history of I‐ELT, which may underlie the observed attention deficits in clinical assessments and cognitive tests involving both emotional and nonemotional stimuli.