Shedding Light on Interaction Between Neurological Symptoms and Psychiatric Episodes in Multiple Sclerosis: Novel Hypothesis and Therapeutic Avenues.

Multiple sclerosis is a chronic neuroinflammatory disorder, with different central nervous system lesions being induced at distinct time points. Anxiety disorders and major depressive disorder are common comorbidities of multiple sclerosis. In such cases, a correlation between psychiatric episode severity and neurological symptom progression is evident; however, the detailed cause-effect relationship is unclear. Data suggest that dysregulated and/or myelin antigen-reactive lymphocytes penetrate the brain tissue, promoting inflammatory macrophages/microglia and astrocytes, which induce axonal damage, demyelination, remyelination failure, neuroinflammation, and atrophy of the thalamus, insula, cingulate cortex, hippocampus, amygdala, and dorsolateral prefrontal cortex, accompanied by impaired dorsolateral prefrontal cortex regulation of the related brain regions, at the early as well as late stage. The pathological alterations are likely involved in neurological symptoms, including pain, physical disability, fatigue, and neurocognitive deficits. The neurological signs can be linked with emotions, such as relapse-associated anticipatory anxiety along with depressed mood, while neurological symptom-related cognitive-perceptual bias presumably mediates cognitive distortion with catastrophizing about sensory, proprioceptive, interoceptive, and emotional signals. These psychiatric episodes may cooperatively result in uncontrollable sensory perception, proprioception, interoception, and neurocognition, which are likely implicated in the progression of pain, physical disability, fatigue, and neurocognitive deficits. Collectively, in multiple sclerosis comorbid with psychiatric disorders, autoimmune responses initiate neurological symptoms, which may be associated with psychiatric episodes, with these clinical signs potentially influencing each other. This view identifies novel agents possibly capable of improving the effectiveness of currently approved disease-modifying medications in combination therapy by attenuating imbalance between proinflammatory and anti-inflammatory/prorepair microglia.