Triple network model of brain connectivity changes related to adverse mood effects in an oral contraceptive placebo-controlled trial

Abstract

Combined oral contraceptives (COC) are among the most commonly used contraceptive methods worldwide, and mood side effects are the major reason for discontinuation of treatment. We here investigate the directed connectivity patterns associated with the mood side effects of an androgenic COC in a double-blind randomized, placebo-controlled trial in women with a history of affective COC side effects (n=34). We used spectral dynamic causal modeling on a triple network model consisting of the default mode network (DMN), salience network (SN), and executive central network (ECN). Within this framework, we assessed the treatment-related changes in directed connectivity associated with adverse mood side effects. Overall, during COC use, we found a pattern of enhanced connectivity within the DMN and decreased connectivity within the ECN. The dorsal anterior cingulate cortex mediates an increased recruitment of the DMN by the ECN during treatment. Mood lability was the most prominent COC-induced symptom and also arose as the side effect most consistently related to connectivity changes. Connections that were related to increased mood lability showed increased connectivity during COC treatment, while connections that were related to decreased mood lability showed decreased connectivity during COC treatment. Among these, the connections with the highest effect size could also predict the participants' treatment group above chance. Significance Statement Mood side effects are the major reason for discontinuation of oral contraceptive (OC) use. However, the neural substrate underlying these adverse mood effects is still unknown. Here, we investigate the connectivity changes during OC use in women with a history of OC-related mood side effects. We show that mood lability experienced during OC use relates to connectivity patterns previously reported across different mood disorders. The dorsal anterior cingulate cortex, crucial for emotional and cognitive regulation, arose as a mediator area between networks. These neural dynamics during OC treatment may affect cognitive processes underlying mood stability. These findings have important implications for women's mental health and well-being.

Menstrual cycle phase modulates causal connectivity in the resting-state brain of healthy females

“…Similar to our findings, Haraguchi et al (63) found the first phase of the menstrual cycle to have greater activity in the frontal brain areas. Our findings are also consistent with work by Hidalgo-Lopez et al (48,49), who reported increased recruitment from the right side during the mid-luteal phase. However, Hidalgo-lopez et al (48) found a right-lateralized pattern during the early follicular phase, which we did not observe.…”

“…In the mid-luteal phase, there were right-lateralized connections from the SN, and increased connectivity from the right insula to the frontal regions, from the frontal-ECN to the SN, and from the posterior-ECN to the posterior-DMN. More recent work by the same group (49) corroborated these findings, showing that compared to the follicular phase, the luteal phase had increased connectivity within the DMN and SN, from the DMN to the SN, and from the ECN to the DMN. There was also a decrease in connectivity from the parietal-ECN to the DMN and from the parietal-ECN to the SN.…”

“…Second, we only included females who were not using hormonal contraceptives, a common exclusion in menstrual cycle research. Hidalgo-Lopez (49) is, to our knowledge, the only group to consider menstrual cycle causal connectivity without excluding those on birth control. As of 2019, almost half of all women of reproductive age (15 to 49 years) worldwide (>300 million) were using hormonal contraceptives (69).…”