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Purpose:  To investigate the relationships between white matter hyperintensities (WMH) and hippocampal volume and their influence on brain networks by using resting-state functional connectivity (rs-fc) magnetic resonance (MR) according to their localization.  Methods:  In this exploratory cross-sectional study, 38 subjects from the public "Leipzig Study for Mind/Body/Emotion Interactions" (LEMON) data set were selected. Morphometric analyses of both WMH burden and the total hippocampal relative volume (tHRV) were performed for each subject with two automated software. The WMH were then categorized as total (tWMH), periventricular (pvWMH), deep (dWMH), and juxtacortical (jcWMH). Spearman's correlation analyses were performed to evaluate the relationships between the following variables: age, tWMH, pvWMH, dWMH, jcWMH, and tHRV. Subsequently, three different rs-fc MR group analyses were performed using a multiple regression model that included age, pvWMH, dWMH, and jcWMH as second-level covariates. The graph theoretical analysis was applied to evaluate the effects of pvWMH (analysis 1), jcWMH (analysis 2), and dWMH (analysis 3).  Results:  Spearman's correlation analysis revealed several statistically significant ( p  &lt; 0.05) positive and negative correlations, in particular positive between age and tWMH, and negative between dWMH and tHRV. rs-fc MR analysis 1 and 2 did not reveal statistically significant results; analysis 3 revealed that dWMH influenced network properties of several cerebral regions, in particular global and local efficiency of both the hippocampi.  Conclusion:  The localization of WMH influences brain activity in healthy subjects. In particular, dWMH are inversely correlated with tHRV and influence several properties of different cerebral areas, included both the hippocampi. Impact statement In this exploratory research we evidenced how both the load and the localization of white matter hyperintensities influence brain activity; in particular, we evidenced an inverse correlation between the volume of the deep white matter hyperintensities and hippocampal volume, as well as a direct influence on the connectivity properties of this important cerebral region. This finding represent a new element for understanding the effects of white matter hyperintensities on brain networking, and a cue that could be taken into account for possible future studies investigating brain connectivity and cognitive functions in healthy and pathological conditions.

Effects of White Matter Hyperintensities on Brain Connectivity and Hippocampal Volume in Healthy Subjects According to Their Localization