Prior work has distinguished regions in the intraparietal sulcus (IPs) and frontal eye field (FEF) involved in the voluntary control of attention, from more ventral regions in the temporoparietal junction (TPJ) involved in target detection. The present results show that when subjects search for and detect a visual target stimulus among nontargets, these regions show sensory-, search-, and detection-related signals that both confirm and refine these functional distinctions. The different signals were isolated by an additive model that accounted for a large fraction of BOLD (blood oxygenation level-dependent) signal modulation over the brain. Both IPs and FEF were activated during search through nontargets, consistent with a role in maintaining attention-related signals during search. However, unlike FEF, IPs also showed stimulus-related activations, and may combine signals related to sensory and task-dependent components of salience. Although IPs-FEF showed search-related activations, the TPJ was deactivated during search. TPJ activations were confined to detection-related signals. These results provide a much stronger dissociation between the TPJ and IPs-FEF than previous work, while indicating functional differences between frontal and parietal regions that are often coactivated in studies of attention. Finally, continuous flow models of information processing predict that during search, signals from missed targets should be fed from sensory to associative regions rather than being gated by the decision criterion. Correspondingly, missed targets significantly activated parietal (e.g., right TPJ) and frontal (e.g., anterior insula, anterior cingulate) regions, although with a smaller magnitude than detected targets. Surprisingly, many cortical regions showed equivalent signals from detected targets and the completion of target-absent trials, reflecting a widespread signal unrelated to motor execution.

Previous studies have suggested that recovery or compensation of language function after a lesion in the left hemisphere may depend on mechanisms in the right hemisphere. However, a direct relationship between performance and right hemisphere activity has not been established. Here, we show that patients with left frontal lesions and partially recovered aphasia learn, at a normal rate, a novel word retrieval task that requires the damaged cortex. Verbal learning is accompanied by specific response decrements in right frontal and right occipital cortex, strongly supporting the compensatory role of the right hemisphere. Furthermore, responses in left occipital cortex are abnormal and not modulated by practice. These findings indicate that frontal cortex is a source of top-down signals during learning.

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Objective:To evaluate efficacy, safety, and tolerability of laquinimod in patients with primary progressive multiple sclerosis (PPMS).Methods:In the randomized, double-blind, placebo-controlled, phase 2 study ARPEGGIO (A Randomized Placebo-controlled trial Evaluating laquinimod in PPMS, Gauging Gradations In MRI and clinical Outcomes), eligible PPMS patients were randomized 1:1:1 to receive once-daily oral laquinimod 0.6 mg or 1.5 mg or matching placebo. Percentage brain volume change (PBVC; primary endpoint) from baseline to week 48 was assessed by MRI. Secondary and exploratory endpoints included clinical and MRI measures. Efficacy endpoints were evaluated using a predefined, hierarchical statistical testing procedure. Safety was monitored throughout the study. The laquinimod 1.5 mg dose arm was discontinued on January 1, 2016 due to findings of cardiovascular events.Results:374 patients were randomized to laquinimod 0.6 mg (n = 139) or 1.5 mg (n = 95) or placebo (n = 140). ARPEGGIO did not meet the primary endpoint of significant treatment effect with laquinimod 0.6 mg versus placebo on PBVC from baseline to week 48 (adjusted mean difference = 0.016%, p = 0.903). Laquinimod 0.6 mg reduced the number of new T2 brain lesions at week 48 (risk ratio = 0.4; 95% confidence interval, 0.26–0.69; p = 0.001). Incidence of adverse events was higher among patients treated with laquinimod 0.6 mg (83%) versus laquinimod 1.5 mg (66%) and placebo (78%).Conclusions:Laquinimod 0.6 mg did not demonstrate a statistically significant effect on brain volume loss in PPMS at week 48.