Mapping the relationship of white matter lesions to depression in multiple sclerosis
Authors: Baller Erica B. , Sweeney Elizabeth M. , Cieslak Matthew C. , Robert-Fitzgerald Timothy , Covitz Sydney C. , Martin Melissa L. , Schindler Matthew K. , Bar-Or Amit , Elahi Ameena , Larsen Bart S. , Manning Abigail R. , Markowitz Clyde E. , Perrone Christopher M. , Rautman Victoria , Seitz Madeleine M. , Detre John A. , Fox Michael D. , Shinohara Russell T. , Satterthwaite Theodore D. 
Published: June 2023

ABSTRACTImportanceMultiple 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.ObjectiveTo investigate how white matter network disruption is related to depression in MS.DesignRetrospective 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.SettingSingle-center academic medical specialty MS clinic.ParticipantsParticipants 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.ExposureDepression diagnosis.Main Outcome(s) and Measure(s)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.ResultsThree 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 RelevanceWe 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.KEY POINTSQuestionAre white matter lesions that impact fascicles connecting a previously-described depression network associated with depression in patients with multiple sclerosis (MS)?FindingsIn this retrospective, case-control study of patients with MS including 232 patients with depression and 148 nondepressed MS comparators, patients with MS had more disease within the depression network, irrespective of depression diagnosis. Patients with depression had more disease than those without depression, which was driven by disease within the depression network specifically.MeaningLesion location and burden may contribute to depression comorbidity in MS.