Genetic contributions to brain serotonin transporter levels in healthy adults.

The serotonin transporter (5-HTT) critically shapes serotonin neurotransmission by regulating extracellular brain serotonin levels; it remains unclear to what extent 5-HTT levels in the human brain are genetically determined. Here we applied [11C]DASB positron emission tomography to image brain 5-HTT levels and evaluated associations with five common serotonin-related genetic variants that might indirectly regulate 5-HTT levels (BDNF rs6265, SLC6A4 5-HTTLPR, HTR1A rs6295, HTR2A rs7333412, and MAOA rs1137070) in 140 healthy volunteers. In addition, we explored whether these variants could predict in vivo 5-HTT levels using a five-fold cross-validation random forest framework. MAOA rs1137070 T-carriers showed significantly higher brain 5-HTT levels compared to C-homozygotes (2-11% across caudate, putamen, midbrain, thalamus, hippocampus, amygdala and neocortex). We did not observe significant associations for the HTR1A rs6295 and HTR2A rs7333412 genotypes. Our previously observed lower subcortical 5-HTT availability for rs6265 met-carriers remained in the presence of these additional variants. Despite this significant association, our prediction models showed that genotype moderately improved prediction of 5-HTT in caudate, but effects were not statistically significant after adjustment for multiple comparisons. Our observations provide additional evidence that serotonin-related genetic variants modulate adult human brain serotonin neurotransmission.

Effects of an Oral Contraceptive on Dynamic Brain States and Network Modularity in a Serial Single-Subject Study.

Hormonal contraceptive drugs are used by adolescent and adult women worldwide. Increasing evidence from human neuroimaging research indicates that oral contraceptives can alter regional functional brain connectivity and brain chemistry. However, questions remain regarding static whole-brain and dynamic network-wise functional connectivity changes. A healthy woman (23 years old) was scanned every day over 30 consecutive days during a naturally occurring menstrual cycle and again a year later while using a combined hormonal contraceptive. Here we calculated graph theory-derived, whole-brain, network-level measures (modularity and system segregation) and global brain connectivity (characteristic path length) as well as dynamic functional brain connectivity using Leading Eigenvector Dynamic Analysis and diametrical clustering. These metrics were calculated for each scan session during the serial sampling periods to compare metrics between the subject's natural and contraceptive cycles. Modularity, system segregation, and characteristic path length were statistically significantly higher across the natural compared to contraceptive cycle scans. We also observed a shift in the prevalence of two discrete brain states when using the contraceptive. Our results suggest a more network-structured brain connectivity architecture during the natural cycle, whereas oral contraceptive use is associated with a generally increased connectivity structure evidenced by lower characteristic path length. The results of this repeated, single-subject analysis allude to the possible effects of oral contraceptives on brain-wide connectivity, which should be evaluated in a cohort to resolve the extent to which these effects generalize across the population and the possible impact of a year-long period between conditions.