By Dave DeFusco
People living with Multiple Sclerosis, often called MS, frequently describe fatigue as one of the most difficult parts of the disease. It is not simply feeling tired after a long day. For many patients, the exhaustion can affect thinking, movement, language, memory and emotional well-being. Depression is also common among people with MS, but doctors have long struggled to understand how the symptoms connect and influence one another.
A recent study published in the journal Multiple Sclerosis and Related Disorders offers new insight into that relationship. The research found that when different fatigue questionnaires produce conflicting results, patients may actually be showing signs of deeper depression that could otherwise go unnoticed.
The study, “,” examined 712 people with MS over a 14-year period at a comprehensive MS center. Researchers analyzed how patients answered two widely used fatigue surveys—the Fatigue Severity Scale, known as FSS, and the Modified Fatigue Impact Scale, or MFIS—alongside a standard depression screening tool called the Beck Depression Inventory.
Joining Marissa Barrera, assistant dean of health sciences at the Katz School of Science and Health, on the study was an international team of interdisciplinary researchers from leading institutions around the world, including Johns Hopkins University, Northwestern University, N鶹ýӳ Langone, Georgetown University School of Medicine, Cleveland Clinic, Bern University Hospital, Technion–Israel Institute of Technology, Western University, Monash University, Sunnybrook Research Institute, University at Buffalo and University of Chicago.
MS is a disease in which the immune system mistakenly attacks the protective covering around nerves in the brain and spinal cord. Symptoms vary widely, but many patients experience problems with movement, numbness, memory, concentration and severe fatigue. More than 80% of people with MS report fatigue, while depression affects as many as 60%.
The researchers wanted to better understand why some patients score differently on fatigue tests that are supposed to measure the same symptom.
The FSS questionnaire mainly focuses on physical exhaustion. The MFIS, however, looks at fatigue more broadly, including its impact on thinking, emotions and social functioning. Researchers discovered that about 21 percent of patients showed “discordant” fatigue scores, meaning one survey suggested severe fatigue while the other did not.
Most of those patients had high MFIS scores but low FSS scores. As important, that group also had much higher depression scores. Patients with discordant fatigue scores had an average depression score of 23 on the Beck Depression Inventory, compared with 9.8 among patients whose fatigue scores aligned on both questionnaires. They also showed higher suicidality scores despite having similar physical disability levels.
Barrera said the findings suggest that differences between fatigue questionnaires may reveal important emotional or cognitive struggles that standard physical fatigue measures miss.
“Fatigue in multiple sclerosis is far more complex than simply feeling physically tired,” she said. “What we found is that when patients report fatigue differently across these questionnaires, it may be signaling underlying depression, particularly cognitive and psychosocial distress that clinicians might otherwise overlook.”
The research builds on , also published in Multiple Sclerosis and Related Disorders, examining word-finding difficulties in people with MS. That study analyzed 586 patients and found a strong link between trouble finding words and broader cognitive impairment. Researchers discovered that 43% of patients with cognitive impairment also experienced significant word-finding difficulties, compared with just 14% of patients who had word-finding problems without overall cognitive impairment.
“Importantly, the study found that word-finding difficulties were tied more closely to cognitive changes than to physical disability, fatigue or depression,” said Barbara O’Connor Wells, an associate professor in the Katz School’s medical speech-pathology program. “The findings suggest that communication struggles in MS may often be part of a broader pattern of cognitive impairment rather than an isolated symptom.”
Barrera said the combined findings from both studies underscore how invisible symptoms of MS, including depression, fatigue, memory problems and communication challenges, can overlap in ways that are easy to miss during routine medical visits.
“This research reinforces the need for comprehensive neuropsychiatric assessment in MS care,” she said. “If clinicians see mismatched fatigue scores, cognitive complaints or communication difficulties, that should prompt deeper conversations about mood, sleep, cognition and emotional well-being. Identifying these issues earlier could improve quality of life and help patients better manage daily activities.”
That focus on the cognitive and emotional effects of MS extends beyond the research lab. In a recent episode of the MS Living Well Podcast titled “Handling MS: Word-Finding and Memory Strategies,” Barrera discussed practical ways people with MS can manage everyday communication and memory challenges. The episode shares easy-to-use strategies for making information easier to remember, talking around a missing word during conversation and creating routines that reduce mental overload—all issues that often accompany the fatigue and depression explored in the new study.
The researchers noted that depression and fatigue are deeply intertwined in MS. Biological factors linked to inflammation, sleep disruption, brain changes and hormone activity may all contribute to both symptoms. At the same time, depression itself can worsen how fatigue is experienced, especially in areas involving concentration, motivation and emotional resilience.
“Although the research cannot prove cause and effect, the findings may help doctors identify patients who need additional psychological support,” said Barrera. “We hope future long-term studies will determine whether treating depression can also ease fatigue and improve daily functioning for people living with MS.”
