Mapping the Relationship of White Matter Lesions to Depression in Multiple Sclerosis

Importance:Multiple sclerosis (MS) is an immune-mediated neurological disorder that affects nearly one million people in the United States. Up to 50% of patients with MS experience depression. Objective:To investigate how white matter network disruption is related to depression in MS. Design:Retrospective case-control study of participants who received research-quality 3-tesla neuroimaging as part of MS clinical care from 2010-2018. Analyses were performed from May 1 to September 30, 2022. Setting:Single-center academic medical specialty MS clinic. Participants:Participants with MS were identified via the electronic health record (EHR). All participants were diagnosed by an MS specialist and completed research-quality MRI at 3T. After excluding participants with poor image quality, 783 were included. Inclusion in the depression group (MS+Depression) required either: 1) ICD-10 depression diagnosis (F32-F34.*); 2) prescription of antidepressant medication; or 3) screening positive via Patient Health Questionnaire-2 (PHQ-2) or -9 (PHQ-9). Age- and sex-matched nondepressed comparators (MS-Depression) included persons with no depression diagnosis, no psychiatric medications, and were asymptomatic on PHQ-2/9. Exposure:Depression diagnosis. Main Outcomes and Measures:We first evaluated if lesions were preferentially located within the depression network compared to other brain regions. Next, we examined if MS+Depression patients had greater lesion burden, and if this was driven by lesions specifically in the depression network. Outcome measures were the burden of lesions (e.g., impacted fascicles) within a network and across the brain. Secondary measures included between-diagnosis lesion burden, stratified by brain network. Linear mixed-effects models were employed. Results:Three hundred-eighty participants met inclusion criteria, (232 MS+Depression: age[SD]=49[12], %females=86; 148 MS-Depression: age[SD]=47[13], %females=79). MS lesions preferentially affected fascicles within versus outside the depression network (β=0.09, 95% CI=0.08-0.10, P<0.001). MS+Depression had more white matter lesion burden (β=0.06, 95% CI=0.01-0.10, P=0.015); this was driven by lesions within the depression network (β=0.02, 95% CI 0.003-0.040, P=0.020). Conclusions and Relevance:We provide new evidence supporting a relationship between white matter lesions and depression in MS. MS lesions disproportionately impacted fascicles in the depression network. MS+Depression had more disease than MS-Depression, which was driven by disease within the depression network. Future studies relating lesion location to personalized depression interventions are warranted.