Left Frontal Connectivity Moderates the Relationship between Inflammation and Cognitive Performance in Patients following Cardiac Surgery: A Longitudinal fMRI Study

<b>Background:</b> Cardiac surgery patients frequently experience perioperative neurocognitive disorder. Cognitive reserve (CR) is known to mitigate such deficits. Here, we investigate whether global left frontal cortex (gLFC) connectivity, a neural proxy of CR, modulates the relationship between postoperative inflammation and cognitive recovery. <b>Methods:</b> Twenty-five patients scheduled for heart valve replacement surgery were compared to healthy controls using neuropsychological assessments, magnetic resonance imaging, and cytokine levels measured at 3 intervals (before surgery and 7 and 30 days after surgery). Linear regression analysis was used to examine the relationship between the increase in inflammation markers on postoperative day 7 (ΔInflammatory factor_{[7d-baseline]}) and changes in cognition from postoperative day 7 to 30 (ΔNeuropsychological assessment_[30d-7d]). Moderation analysis combined with Johnson-Neyman threshold testing was performed to assess how gLFC connectivity across 3 time points moderated the relationship between ΔIL-6_{[7d-baseline]} and cognitive change. <b>Results:</b> Patients exhibited significant cognitive decline, particularly in executive and memory function, as well as decreased gLFC connectivity on postoperative day 7, compared to controls. This decline was followed by recovery on postoperative day 30. In patients, ΔIL-6_{[7d-baseline]} was negatively correlated with ΔCorsi block test_(30d-7d): <i>β</i> = -0.62, <i>P</i> < 0.001 and ΔDigit symbol test_(30d-7d): <i>β</i> = -0.47, <i>P</i> = 0.017. The interactions of gLFC connectivity at 3 time points × ΔIL-6_{[7d-baseline]} were separately significant on postoperative cognitive recovery. Johnson-Neyman analysis revealed that the effect of ΔIL-6_{[7d-baseline]} was significant when gLFC connectivity was within a specific range. <b>Conclusion:</b> These findings suggest that gLFC connectivity, reflecting CR, may serve as a target for interventions to enhance cognitive resilience in cardiac surgery patients.