Dynamic functional connectivity changes in the triple networks in patients with mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes

Background: Mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) is a rare maternally inherited disease. Cognitive impairment is one of the main clinical manifestations in MELAS patients, however, the underlying brain network mechanism of cognitive impairment is not entirely clear. The "triple network model" provides a common framework for understanding cognitive impairment in core neurocognitive networks, yet little is known about the dynamic functional connectivity (dFC) of MELAS patients in the triple network. Therefore, this study aimed to investigate the characteristics of dFC within the triple network in MELAS patients to better understand the neural network mechanisms underlying their cognitive impairment. Methods: This cross-sectional study analyzed data from an ongoing prospective cohort study of genetically confirmed MELAS patients. Thirty patients at the acute stage (MELAS-acute group), 30 patients at the chronic stage (MELAS-chronic group), and 30 healthy control volunteers (HC group) were included in this study. The triple network was confirmed using a group spatial independent component analysis (ICA), and dFC was analyzed using a sliding window approach (SWA) and k-means clustering algorithm. In addition, we explored the correlations between temporal properties of dFC states and volumes of stroke-like lesions (SLLs). Results: The intrinsic brain functional connectivity (FC) within the triple network was clustered into four states. The results revealed distinct FC states, characterized by varying patterns of inter-network coupling. State 4, characterized by the weakest FC across all networks, was the most prevalent state in all participants. State 2 exhibited the strongest positive default mode network (DMN)-central executive network (CEN) coupling but negative salience network (SN)-DMN/CEN integration. State 3 was characterized by weaker positive DMN-left CEN (lCEN) coupling and weaker negative SN-DMN/CEN integration than state 2. State 1 demonstrated stronger positive DMN-CEN coupling and stronger positive SN-DMN/CEN integration than state 3. We found that MELAS patients spent more time in states with weaker FC. Specifically, the MELAS-acute group had a lower recurrence fraction (RF) in state 1 (P=0.0229) and shorter mean dwell time (MDT) (P=0.0414) but higher RF (P=0.008) and longer MDT (P=0.0162) in state 3 compared with MELAS-chronic group. And that MELAS-chronic group had lower RF (P=0.0141) and shorter MDT (P=0.0137) in state 3 but higher RF (P=0.0499) in state 4 compared with HC group. And MELAS-chronic group switched less frequently across states compared with HC group (P=0.0347, Dunn's correction). Conclusions: This study revealed abnormal temporal properties of dFC states within the triple network in MELAS patients, providing novel insights for understanding neural network mechanisms of their cognitive impairment.