Increased Glymphatic System Activity and Hypothalamic Connectivity in Patients With Premenstrual Dysphoric Disorder

Premenstrual dysphoric disorder (PMDD), which is an emotional disorder characterized by symptoms of irritability, depression, anxiety, and sleep disturbances during the luteal phase of the menstrual cycle. Advanced neuroimaging findings provided insights into the neurobiological underpinnings of PMDD. However, the role of the glymphatic system and hypothalamus-related functional connectivity (FC) remains unclear. We aimed to investigate the abnormalities of glymphatic system and hypothalamus-related FC in PMDD patients.

In this study, 23 PMDD patients and 27 healthy controls (HCs) underwent diffusion tensor imaging (DTI) and functional magnetic resonance imaging scan. The DTI along the perivascular space (DTI-ALPS) indices were used as an indirect evaluation of glymphatic function. Altered hypothalamus-related FC was detected between PMDD patients and HCs, and machine learning was performed to assess the classification performance of these FC abnormalities in distinguishing PMDD patients from HCs. Leave-one-out cross-validation was used for modal validation. Classification accuracy and area under the receiver operating characteristic (ROC) curve were evaluated. Furthermore, the associations between DTI-ALPS index, clinical features, and hypothalamus-seeded FC were explored.

Compared to HCs, PMDD patients exhibited: (1) significantly higher value of left DTI-ALPS index; (2) increased intrinsic connectivity between the hypothalamus and anterior/middle cingulate cortex (ACC/MCC), middle frontal cortex (MFC), orbitofrontal cortex (OFC), insula, inferior temporal cortex (ITC), inferior parietal lobe (IPL), caudate, lentiform nucleus, and thalamus. The right and mean DTI-ALPS indices were positively correlated with the hypothalamus-right ACC/MCC FC in PMDD patients. Significantly positive correlations were observed between the hypothalamus-right ITC FC and anxiety, depression scores, as well as between the hypothalamus-bilateral lentiform nucleus FC and severity of symptoms in PMDD patients. Hypothalamus-related FC showed superior discriminative ability in differentiating PMDD patients from HCs.

The increased glymphatic system activity and hypothalamus-related FC might be associated with the supersensitive reactivity of emotional processing in PMDD patients. Brain regions primarily involved in the emotional network showed potential group-discriminative features when comparing PMDD patients to HCs. Trial Registration: Chinese Clinical Trial Registry identification: ChiCTR2000040935.