Exercise in Early MS May Ease Mood Disorders via Immune Alterations

Reducing inflammation with exercise linked to less depression, anxiety

Lindsey Shapiro, PhD avatar

by Lindsey Shapiro, PhD |

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Exercise prior to being diagnosed with multiple sclerosis (MS) was associated with less depression and anxiety among patients, likely due to a reduction in the levels of an inflammatory molecule called interleukin-2 (IL-2), a study revealed.

“This finding supports the notion that exercise in the early stages may act as a disease-modifying therapy in MS, although further longitudinal studies are needed to clarify this,” the researchers wrote.

“In exercising MS patients, depression and anxiety were reduced compared to sedentary patients,” the team also wrote, noting that, in concurrent mouse studies, “a causal role of IL-2 in mood disorders was shown.”

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The study, “Preventive exercise attenuates IL-2-driven mood disorders in multiple sclerosis,” was published in Neurobiology of Disease

Mood disorders, including depression and anxiety, are common and debilitating symptoms of MS. It is thought that inflammation is a core driver of these symptoms.

Exercise has been demonstrated to be beneficial for MS patients. It has been suggested that such physical activity can slow disability progression and ease nonmotor symptoms, including mood and cognition.

Moreover, data from animal studies have shown that exercise initiated before or at the time of disease onset has immunomodulatory properties that could underlie these beneficial effects.

“This raises the outstanding question as to whether in MS patients physical activity in the early phases of the disease can shape the brain inflammatory milieu and clinical expression of the disease at the time of diagnosis,” the researchers wrote.

Investigating the effects of exercise in early MS

To learn more, the team of researchers explored the effects of different levels of physical activity on mood symptoms in the six months before an MS diagnosis. Their analysis included 235 people newly diagnosed with relapsing-remitting MS.

All of the patients were admitted to the neurology unit of the Neuromed Research Institute, in Italy, between 2017 and 2020. The study also involved 80 healthy adults, who served as controls.

Among the patients, 68.9% were women, with a median age of 35.2, while the healthy controls were 66.3% female, with a median age of 41.8.

At the time of their diagnosis, the patients were interviewed about their activity levels in the previous six months. Based on their responses, they were categorized into three groups: sedentary, lifestyle physical activity, and exercise.

Those in the exercise group performed at least 150 minutes (2.5 hours) per week of repetitive exercises, such as swimming or running. Those in the lifestyle physical activity group performed at least 150 minutes of daily activities of moderate intensity. All of the others were deemed sedentary.

More than half of the patients (60%) were considered sedentary, while 22.1% were in the lifestyle physical activity group, and 17.9% were in the exercise group.

In the overall patient group, depression was present in 25.9% of individuals. State anxiety — defined as acute anxiety directly related to adverse situations — was present in 28.2%, whereas trait anxiety, referring to a general tendency to be anxious, was present in 13.2%.

Statistical analyses were adjusted for factors such as age, sex, disease duration, disability, clinical and MRI disease activity, signs of brain inflammation, and fatigue. The results showed that increased physical activity was associated with significantly lower depression, state, and trait anxiety.

Next, the team sought to determine if these exercise-related changes in mood disorders were linked to alterations in inflammatory molecules. Thus, the team examined the levels of such molecules in the cerebrospinal fluid, the liquid surrounding the brain and spinal cord.

Levels of the inflammatory markers IL-2 and interleukin-6 (IL-6) were significantly increased in MS patients compared with controls, the results showed.

Among MS patients, levels of IL-2 also were significantly lower among patients who exercised compared with those who were sedentary — a relationship that remained significant even when controlling for other clinical characteristics.

The researchers next aimed to determine whether exercise eased mood symptoms in an MS mouse model, and if this could be linked to reductions in IL-2.

Mice that exercised on a running wheel at the time of disease onset showed an improvement in depressive-like symptoms and a partial recovery of anxiety-like behaviors compared with mice not exposed to the running wheel. Notably, while mice in the MS model had elevated IL-2 levels in their brains, those that exercised showed a nonsignificant decrease in IL-2 levels.

“Although exact parallelism between exercise effects in mice and in humans cannot be drawn, these data corroborate the idea that preventive exercise can positively influence mood disorders and that IL-2 is among the target cytokines [inflammatory molecules] of exercise,” the researchers wrote.

In another experiment with the mouse model, the team administered IL-2 directly into the brains of healthy mice. They found that these animals developed signs of anxiety and depression, supporting a causal role for IL-2 in MS mood disorders.

Additional analyses revealed that IL-2 treatment appeared to interfere with the activity of a set of brain receptors called cannabinoid 1 receptors, reflecting similar brain signaling dysfunction seen in MS mouse models.

Overall, the findings show that “preventive exercise in both human and experimental MS attenuated mood disturbances and reduced IL-2 increased brain levels, suggesting a protective effect against inflammation-induced mood disturbances,” the researchers wrote.

“Further studies are required to explore whether preventive exercise may induce protective effects on mood, cognitive and clinical disability during the disease course,” the researchers noted, adding that a follow-up study of this group of patients may be beneficial.

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