Premenstrual syndrome (PMS) is a disorder that substantially impairs normal life activities and interpersonal relationships and is associated with a woman's menstruation cycle (1, 2). Premenstrual dysphoric disorder (PMDD) is a severe form of PMS (3). Established research indicated that PMS prevalence was 35.3% among Sharjah university students (4), 62.7% among Puducherry college students (5), 64.9% among female medical students in Saudi Arabia (6), and even higher in some regions. PMS causes various symptoms in women, commonly including affective symptoms, behavioral symptoms, and difficulty concentrating, impairing their quality of normal life (7, 8). Among them, women with PMS had difficulty in regulating their emotions (9), such as prominent depression (10), making them at higher risk of suicidality (11).

Although PMS pathogenesis remains unclear, the application of brain imaging technology has facilitated its intrinsic neural mechanism of neuropsychiatric disorders (12). Among them, blood oxygenation level-dependent (BOLD) functional magnetic resonance imaging (fMRI) has had a tremendous influence on human neuroscience over the last two decades (13). Qing Liu demonstrated decreased connectivity in the middle frontal gyrus (MFG) and parahippocampal gyrus (PHG) in PMS patients, as well as increased connectivity in the left medial/superior temporal gyri (MTG/STG) and precentral gyrus within the default mode network (DMN) using fMRI (14). Hai Liao revealed elevated regional homogeneity (ReHo) mainly in the bilateral precuneus, left inferior temporal cortex (ITC), right inferior frontal cortex (IFC), and left middle frontal cortex (MFC), as well as decreased ReHo in the right anterior cingulate cortex (ACC) of PMS patients during the luteal phase (15). Besides, structural MRI revealed increased gray matter (GM) volumes in precuneus/posterior cingulate cortex (precuneus/PCC) and thalamus, as well as decreased GM volumes in the insula of PMS patients (16). Concurrently, Demao Deng's research indicated that PMS patients have greater bilateral amygdalae volumes, increased FC between amygdala and certain regions of frontal cortex, the right temporal pole, and the insula, as well as decreased FC between bilateral amygdalae and right orbitofrontal cortex and right hippocampus (17). In addition, Peng Liu discovered decreased prefrontal-thalamic connectivity and increased posterior parietal-thalamic connectivity in PMS patients using resting-state fMRI (18).

Until now, few studies have been reported on the processing mechanism of depression emotion in PMS (3). Accordingly, this study aims to investigate the neural substrates of depression emotion processing in PMS using BOLD-fMRI.

According to established research, women with PMS appear to experience emotional dysregulation throughout the menstrual cycle (23). Additionally, students experienced more emotional regulation deficits (24). Among premenstrual symptoms, depression was the most prominent feature of PMS diagnosis and should be properly evaluated and treated (10). Our findings indicated that the depression degree in PMS patients was significantly higher than in the HC group (Figure 1B), which is consistent with our findings in PMDD (19). Women with PMS/PMDD show significant depression, which is a response to abnormal changes in the brain. When PMS patients are exposed to emotional stimuli, the function of the spindle gyrus in occipital and temporal lobes, as well as activation of the right infratemporal gyrus and cerebellum, are enhanced, while sub lobar, sub gyral, extra nucleus, frontal, marginal, and basal nuclei are weakened (Table 2 and Figure 2). It demonstrates that the above-mentioned brain area function regulation is abnormal before menstruation, followed by emotional, cognitive, and attention distribution changes, all of which are associated with PMS pathogenesis.

Our findings corroborate other research conducted both domestically and internationally. The frontal lobe is involved in spiritual activities associated with an individual's emotions (25). The prefrontal cortex (PFC) plays a critical role in emotion generation and regulation (26). Furthermore, the prefrontal cortex edge, especially the orbitofrontal cortex, influenced decision-making and emotional regulation (27). When untreated depression patients viewed negative emotional stimuli, the right orbitofrontal cortex (28) (middle frontal gyrus) oxygen-dependent reaction weakened, which may be linked to depression emotion.

Besides, insular is involved in emotional processing and influences individual decisions (29). In the task state, insula and insular cortex activity of PMDD patients significantly increased during the luteal phase (29). Our findings revealed that right insula activation decreased in task state, which is a new discovery in PMS research that is not identical to PMDD (19). Additionally, there were changes in the hippocampus cortex of PMDD patients (30). Amygdala, hippocampus, and anterior cingulate belong to the limbic lobe, which is intimately connected to emotional, functional activities (31). Cerebellum was linked to cognitive function (32). PMDD subjects had greater cerebral gray-matter volume than controls in the posterior cerebellum (33). The cerebellar activity of PMDD patients increased from follicular phase to late luteal phase (34), especially cerebellar vermis, which was correlated with emotional deterioration, as confirmed by our study. Additionally, our findings indicated that culmen, cerebellum anterior lobe, tuber, and cerebellar tonsil were intimately associated with PMS.

In summary, PMS's abnormal brain regions were localized using BOLD-fMRI in college students, indicating pathological brain changes. However, these new findings must be confirmed and replicated in the future using larger sample size and animal models.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

The studies involving human participants were reviewed and approved by Medicine Ethics Committee of the First Affiliated Hospital of Shandong University of Traditional Chinese Medicine. The patients/participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.

DG and MG designed the study, wrote the draft, and revised it. MG and YH performed the experiment. MG, QX, and LR collected data. MG performed the statistical analyses and finally edited manuscript. YY, LA, and JW provided key assistance. All authors contributed to and have approved the final manuscript.

This study was sponsored by Key project of Natural Science Foundation of Shandong Province (ZR2020ZD17), National Natural Science Foundation of China (81001484; 81473558), Natural Science Foundation of Shandong Province (ZR202102270167), Shandong medical and health science and technology development plan project (202105010467) and 20 articles for colleges and universities funded project in Jinan (2020GXRC002).

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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