Working Memory (WM) impairment is the most common cognitive deficit of patients with Multiple Sclerosis (MS). However, evidence of its neurobiological mechanisms is scarce. Here we recorded electroencephalographic activity of twenty patients with relapsing-remitting MS and minimal cognitive deficit, and 20 healthy control (HC) subjects while they solved a WM task. In spite of similar performance, the HC group demonstrated both a correlation between temporoparietal theta activity and memory load, and a correlation between medial frontal theta activity and successful memory performances. MS patients did not show theses correlations leading significant differences between groups. Moreover, cortical connectivity analyses using granger causality and phase-amplitude coupling between theta and gamma revealed that HC group, but not MS group, presented a load-modulated progression of the frontal-to-parietal connectivity. This connectivity correlated with working memory capacity in MS groups. This early alterations in the oscillatory dynamics underlaying working memory could be useful for plan therapeutic interventions.

Attention Deficit Hyperactivity Disorder (ADHD) is a common neuropsychiatric disorder in which children present prefrontal cortex (PFC) related functions deficit. Proactive cognitive control is a process that anticipates the requirement of cognitive control and crucially depends on the maturity of the PFC. Since this process is important to ADHD symptomatology, we here test the hypothesis that children with ADHD have proactive cognitive control impairments and that these impairments are reflected in the PFC oscillatory activity. We recorded EEG signals from 29 male children with ADHD and 25 typically developing (TD) male children while they performed a Go-Nogo task, where the likelihood of a Nogo stimulus increased while a sequence of consecutive Go stimuli elapsed. TD children showed proactive cognitive control by increasing their reaction time (RT) concerning the number of preceding Go stimuli, whereas children with ADHD did not. This adaptation was related to modulations in both P3a potential and lateral prefrontal theta oscillation for TD children. Children with ADHD as a group did not demonstrate either P3a or theta modulation. But, individual variation in theta activity was correlated with the ADHD symptomatology. The results depict a neurobiological mechanism of proactive cognitive control impairments in children with ADHD.

Humans must often estimate reward values in the presence of ambiguous information to determine the best course of action. The degree of ambiguity during decision-making has been related to levels of activity in the parietal cortex, however, its specific computations and causal role remain unknown. We tested the hypothesis that the parietal cortex is causally related in the computation of ambiguous probabilities during decision-making, studied via fMRI and concurrent TMS-EEG recordings. We found that the parietal cortex computes the degree of ambiguity assigned to subjective probability estimates. Disruption of these parietal signals selectively increased the assignment of unknown probabilities to choice outcomes, and these effects were accompanied by a modulation of frontal theta oscillations related to prediction error signals emerging from ambiguous choices. These results contribute to evidence supporting a fundamental causal role for the parietal cortex in the computations of ambiguous information during risky decisions and learning in humans.

Humans often face the challenge of making decisions between ambiguous options. The level of ambiguity in decision-making has been linked to activity in the parietal cortex, but its exact computational role remains elusive. To test the hypothesis that the parietal cortex plays a causal role in computing ambiguous probabilities, we conducted consecutive fMRI and TMS-EEG studies. We found that participants assigned unknown probabilities to objective probabilities, elevating the uncertainty of their decisions. Parietal cortex activity correlated with both the objective degree of ambiguity and a process that underestimates the uncertainty during decision-making. Conversely, the midcingulate cortex encodes prediction errors and increases its connectivity with the parietal cortex during outcome processing. Disruption of the parietal activity increased the uncertainty evaluation of the options, decreasing cingulate cortex oscillations during outcome evaluation. These results provide evidence for a causal role of the parietal cortex in computing uncertainty during ambiguous decisions made by humans.

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 goaldirected 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 relapsingremitting 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. Frontalto-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.