No abstract

Unconscious neural activity has been repeatedly shown to precede and potentially even influence subsequent free decisions. However, to date, such findings have been mostly restricted to simple motor choices, and despite considerable debate, there is no evidence that the outcome of more complex free decisions can be predicted from prior brain signals. Here, we show that the outcome of a free decision to either add or subtract numbers can already be decoded from neural activity in medial prefrontal and parietal cortex 4 s before the participant reports they are consciously making their choice. These choice-predictive signals co-occurred with the so-called default mode brain activity pattern that was still dominant at the time when the choice-predictive signals occurred. Our results suggest that unconscious preparation of free choices is not restricted to motor preparation. Instead, decisions at multiple scales of abstraction evolve from the dynamics of preceding brain activity.T he subjective experience that our voluntary actions are initiated in the conscious mind has been challenged by the finding that the human brain may already start shaping spontaneous decisions even before they enter into conscious awareness (1, 2). Specifically, the human brain can start preparing spontaneous movements up to several seconds before a person believes themselves to be consciously making a decision to move (1-3).To date, such early choice-predictive signals have only been investigated for simple movement decisions (1-6). However, there are several reasons to assess whether preparatory processes also occur for higher-level, more abstract types of decisions. First, the relevance of motor decisions for understanding the neural formation and preparation of intentions has been heavily debated (7,8), mainly because of their reduced complexity (9, 10) and the limited levels of awareness in motor control (11,12). Second, previous studies on predictive signals for motor choices have revealed early information in prefrontal and parietal brain regions. These regions are not generally considered "motor," but they have been sporadically observed in motor preparation (13,14). This invites the question of whether these regions provide only unconscious preparation of motor intentions or a common, task-independent network for preparing multiple types of decisions before awareness. Given the fundamentally different neural processes involved in performing motor acts and mental calculations, identifying overlap between the early choice-predictive signals would be of high relevance because it would point toward a common cerebral starting point for different types of choices.We also aimed to address another question regarding the prediction of free choices. Previous studies (2, 4) have found early choice-predictive information in areas that overlap with the so-called "default mode" network (DMN) (15)(16)(17). For this reason, we also directly investigated the link between our choice-predictive signals and these "off-task" brain signals. Interestingl...

Recently, we demonstrated using functional magnetic resonance imaging (fMRI) that the outcome of free decisions can be decoded from brain activity several seconds before reaching conscious awareness. Activity patterns in anterior frontopolar cortex (BA 10) were temporally the first to carry intention-related information and thus a candidate region for the unconscious generation of free decisions. In the present study, the original paradigm was replicated and multivariate pattern classification was applied to functional images of frontopolar cortex, acquired using ultra-high field fMRI at 7 Tesla. Here, we show that predictive activity patterns recorded before a decision was made became increasingly stable with increasing temporal proximity to the time point of the conscious decision. Furthermore, detailed questionnaires exploring subjects' thoughts before and during the decision confirmed that decisions were made spontaneously and subjects were unaware of the evolution of their decision outcomes. These results give further evidence that FPC stands at the top of the prefrontal executive hierarchy in the unconscious generation of free decisions.

for the MSBase Study Group IMPORTANCE After multiple sclerosis (MS) relapse while a patient is receiving an injectable disease-modifying drug, many physicians advocate therapy switch, but the relative effectiveness of different switch decisions is often uncertain.OBJECTIVE To compare the effect of the oral immunomodulator fingolimod with that of all injectable immunomodulators (interferons or glatiramer acetate) on relapse rate, disability, and treatment persistence in patients with active MS. DESIGN, SETTING, AND PARTICIPANTSMatched retrospective analysis of data collected prospectively from MSBase, an international, observational cohort study. The MSBase cohort represents a population of patients with MS monitored at large MS centers. The analyzed data were collected between July 1996 and April 2014. Participants included patients with relapsing-remitting MS who were switching therapy to fingolimod or injectable immunomodulators up to 12 months after on-treatment clinical disease activity (relapse or progression of disability), matched on demographic and clinical variables. Median follow-up duration was 13.1 months (range, 3-80). Indication and attrition bias were controlled with propensity score matching and pairwise censoring, respectively. Head-to-head analyses of relapse and disability outcomes used paired, weighted, negative binomial models or frailty proportional hazards models adjusted for magnetic resonance imaging variables. Sensitivity analyses were conducted.EXPOSURES Patients had received fingolimod, interferon beta, or glatiramer acetate for a minimum of 3 months following a switch of immunomodulatory therapy. MAIN OUTCOMES AND MEASURESAnnualized relapse rate and proportion of relapse-free patients, as well as the proportion of patients without sustained disability progression. RESULTSOverall, 379 patients in the injectable group were matched to 148 patients in the fingolimod group. The fingolimod group had a lower mean annualized relapse rate (0.31 vs 0.42; 95% CI, 0.02-0.19; P = .009), lower hazard of first on-treatment relapse (hazard ratio [HR], 0.74; 95% CI, 0.56-0.98; P = .04), lower hazard of disability progression (HR, 0.53; 95% CI, 0.31-0.91; P = .02), higher rate of disability regression (HR, 2.0; 95% CI, 1.2-3.3; P = .005), and lower hazard of treatment discontinuation (HR, 0.55; P = .04) compared with the injectable group. CONCLUSIONS AND RELEVANCESwitching from injectable immunomodulators to fingolimod is associated with fewer relapses, more favorable disability outcomes, and greater treatment persistence compared with switching to another injectable preparation following on-treatment activity of MS.