Research led by two BBRF grantees has shed important new light on the relationship between multiple sclerosis (MS) and major depression.

In MS, the fatty myelin coating that protects nerve fibers in the brain and central nervous system deteriorates, causing muscle weakness, vision changes, numbness, and memory issues. The illness often progresses over time, with the damage to nerve fibers becoming increasingly disabling in its effects.

As many as 50% of MS patients experience depression, a rate that is consistent in patients from around the world. Major depression in MS is associated with suicide rates twice that of persons without MS. Depression comorbidity in MS is higher than in other chronic autoimmune illnesses—illnesses in which the body’s immune system attacks the body’s own cells, being unable to distinguish them from legitimate threats like toxins or foreign invaders like viruses. The frequency of depression’s comorbidity with MS leads researchers to ask whether there is some unique relation between the disease process in MS and that in depression.

“Despite the overlap between MS and depression, their association is not well understood,” writes a team led by Erica B. Baller, M.D., a 2023 BBRF Young Investigator at the University of Pennsylvania.

The team explored the relationship of MS and depression through the lens of white matter lesions in the brain—injuries to nerve fibers connecting neurons that are characteristic of MS and reflect the demyelination that impairs neurotransmission. Specifically, the researchers studied white matter lesions in MS patients with and without depression, and how they might be related to circuitry implicated in a previously mapped brain “depression network.”

The team reported its results in Biological Psychiatry. The paper’s senior author was Theodore D. Satterthwaite, M.D., 2014 winner of the BBRF Klerman Prize for Exceptional Clinical Research and a 2010 BBRF Young Investigator.

In the new study, the team used electronic health records to assemble a study cohort of 380 individuals with MS, all of whom had functional MRI scans. Of these, 232 had experienced or were currently experiencing depression; 148 had no history of depression. A method called lesion network mapping (LNM) was used to assess the actual locations of white matter lesions in the study participants—regardless of whether they did or did not have a depression history. LNM employs data on the human connectome—a view of structural connections across the brain that represents a consensus, or average, of connections seen in a wide diversity of human subjects. In this study, this “normative” view of structural brain connectivity was viewed against a map of each MS patient’s white matter lesions. The researchers then compared circuitry between patients with and without depression.

They were looking for overlaps between lesions and the white matter backbone of the previously established “depression network” in the cohort of 380 MS patients. The depression network was assembled on the basis of data from 14 unrelated cohorts of individuals. This work was performed by a team led by Shan Siddiqi, M.D., of Harvard, winner of the 2022 BBRF Klerman Prize and a 2019 BBRF Young Investigator. Their results were published in 2022. Siddiqi and colleagues, in a subsequent paper, also established that individuals with MS whose lesions were more robustly connected to the common depression circuit had higher depression scores. 

Dr. Baller and colleagues in the new study asked: where do MS white matter lesions overlap with the structural connections that support the depression network? Overlaps forming a putative “white matter depression network” included areas known to be commonly affected in MS, including the brain’s corpus callosum and projections from the thalamus.

The results were striking. Lesions in MS patients—regardless of whether they had a history of depression or not—preferentially affected nerve tracts within the depression network, compared with those outside of it. Patients in the study cohort who had both MS and depression history had a greater burden of white matter lesions, and this result was driven by lesions occurring within the depression network.

The fact that MS patients had more pathology within the white matter depression network led the team to propose that “this anatomical predilection may create a vulnerability to depression comorbidity in MS.”

MS patients with depression “had higher disease burden across the whole brain” than those without depression. They also had “greater burden specifically within the white matter depression network.” Those with depression history “had greater injury in [white matter tracts] with more overlap with the depression network.” They also had “greater functional impairment” than patients with no depression history.

One thing the results indicate is that white matter lesions across the entire depression network, i.e., not just located in one or two specific brain areas, likely contribute to depression in MS patients.

The team also made this observation: the depression network identified by Dr. Siddiqi and colleagues includes the frontoparietal and dorsal attention network of the brain. These are involved in executive function and attention. Planning and concentration difficulties, the team notes, are core deficits in depression. Additionally, they noted, the dorsolateral prefrontal cortex, a central brain region in the frontoparietal network, is a target for transcranial magnetic stimulation (TMS) and electroconvulsive therapies for severe major depressive disorder. White matter lesions in these areas “may therefore impact treatment outcomes and warrant further study” the team wrote.

Follow-up research, the team said, needs to relate lesions with currently occurring depression. More research is also needed to explain why MS patients with depression have more functional impairment than patients without depression. The researchers also noted that since MS is also associated with grey matter atrophy, it will be important to incorporate measures of grey matter disease into future studies of MS and depression.