Resting-state Functional Connections with the Hippocampus and with the Caudate Nucleus Predict Working Memory Performance in Multiple Sclerosis

Episodic memory (EM) dysfunction is a common symptom of multiple sclerosis (MS). A related process, working memory (WM), supports long-term EM and is often also impaired. Functional connectivity (FC) between the hippocampus and caudate nucleus supports EM performance. However, this connectivity’s specific influences on WM performance in MS is relatively unknown. Resting-state FC (RSFC) possesses clinical utility, including predicting cognitive impairments before they are captured by assessment. The present study tested whether RSFC with the hippocampus and caudate could predict WM performance in people with MS and in healthy individuals (HC). In a secondary analysis of 78 participants (42 MS, 36 HC), RSFC between the hippocampus, caudate nucleus, and other regions was quantified. These connections’ predictive influence on WM performance was then examined using a global WM performance measure for a subset with available neuropsychological data (26 MS, 15 HC). Across the entire sample (N=78), MS participants displayed stronger coupling between the right hippocampus and left dorsomedial prefrontal cortex, compared to HC participants. Within MS participants, stronger coupling between the left hippocampus (LHipp) and left ventral anterior cingulate (LvACC), and between the left caudate (LCaud) and right insula, were observed. Stronger decoupling between the LHipp and left supramarginal gyrus (LSMG) also emerged. Stronger LHipp-LvACC connectivity predicted worse WM performance, whereas stronger LHipp-LSMG connectivity and LCaud-RInsula connectivity each predicted better performance. The hippocampal connections were also inversely correlated. Findings identify a caudate circuit and potential hippocampal network whose aberrant, intrinsic activity could serve as neural markers for WM dysfunction in MS.