Loss of interplay: Frontoparietal dynamics underlie working memory deficits in multiple sclerosis

Abstract Multiple sclerosis is a chronic demyelinating disease of the central nervous system that provokes motor, cognitive and neuropsychiatric symptoms. Cognitive symptoms are a core feature of the disease, affecting everyday life functioning in 40 to 70% of patients. Working Memory impairment is one of the most common cognitive deficits, crucially affecting goal-directed behavior. However, evidence of the neurobiological mechanisms underlying these impairments is scarce. To address this issue, we investigated a working memory task concomitantly with electroencephalographic records in twenty patients with relapsing-remitting multiple sclerosis who had minimal clinical cognitive alteration, and in twenty healthy control subjects. Participants first watched a memory set of two, four, or six consonants that had to be memorized and, after a black screen that was shown for two seconds, a target stimulus was displayed. We correlated both time-frequency and functional brain connectivity with memory load and behavioral performance. We found that patients and healthy controls presented similar accuracy rates. For high memory loads, patients demonstrated longer reaction times for incorrect responses when the probe was part of the memory set, revealing an increase in cognitive effort. We then evaluated the single trial correlation between the power of the oscillatory activity and the memory load. The healthy control group showed an increase of left frontal and parietal theta activity, while the patient group did not show this increase. The analysis of the successful memory performances demonstrated that controls presented a greater medial theta activity during the maintenance stage; whereas, the patient group showed a decrease in this activity. Interestingly, cortical connectivity analyses using Granger Causality revealed that healthy controls presented a load-modulated progression of the frontal-to-parietal connectivity that indicated successful memory performance, while the patients did not show this pattern. Consistently, phase-amplitude coupling analyses showed that this connectivity was carried out by frontal delta/theta phase to parietal gamma amplitude modulation. Frontal-to-parietal connectivity correlated with working memory capacity in patients measure by Paced Auditory Serial Addition Test. These results indicate that patients with multiple sclerosis present alterations in their capacity to sustain oscillatory dynamics that maintain information in working memory. Thus, differences in brain oscillations and connectivity could be useful for early detection and to study working memory alterations in multiple sclerosis, as well as to implement new therapeutic interventions using non-invasive brain stimulation.