Discussion
mood deterioration, fatigue, anxiety, mood disorders, depressed mood, depressive, depressive symptoms
The main goal of the current manuscript was to characterize the changes in directed connectivity during COC treatment related to concurrent mood symptoms. Our results showed how effective connectivity changes noted during COC treatment related to mood deterioration. Mood lability was the most prominent COC-induced symptom [Overall, we found the expected pattern of enhanced connectivity within the DMN and decreased connectivity within the ECN during COC use [However, and contrary to our hypothesis, only the connectivity from rAG to PCC was positively related to depressive symptoms. In that respect, different sub-items in depressive scales have been shown to be associated with abnormal activity of various brain areas [Alongside the decreased ECN within-network connectivity, which is line with previous findings [Remarkably, an important role seems to emerge for the dACC. Better emotional regulation and lower anxiety levels have been related to stronger dACC activity [The above-described changes and related experienced side effects could be a consequence of the synthetic hormones, the abolishment of cyclic endogenous hormonal fluctuations, or both. Although animal research shows a differential binding affinity of synthetic compared to endogenous hormones (levonorgestrel has a 5-fold affinity vs. progesterone for progesterone receptors) [Some potential limitations need to be noted. First, an exclusion criterion was the use of hormonal contraceptives within the previous two months. While it could be argued that this represents a short wash-out period, it should be noted that prior to randomization, every participant had regular menstrual cycles. Second, the pre-treatment mood assessment was obtained during the luteal phase, while the pre-treatment MRI session was performed during menses. Correspondingly, differences in mood lability, fatigue and depressed mood were operationalized as the difference between the third week of treatment and the luteal pre-treatment phase, in order to avoid potential confounding effects of menstrual-cycle related variations. Last, although five minutes of resting state scanner sequence may seem short, and statistical significance is higher with increased sequence length, longer scans have been associated with similar or even diminished reliability [In summary, the present randomized placebo-controlled trial showed effective connectivity changes during COC treatment related to worsened mood in women with a history of mood COC side effects. The most confident effects corresponded to connections that changed during COC treatment compared to placebo and were related to an increased in mood lability. These differences during COC treatment in the triple network model may affect cognitive processes important for mood stability and mental health and similar disruptions have been reported across mood disorders [