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Stokes, S.

Publications and source records attributed to Stokes, S..

2 recordsLinked to original sources

Frontoparietal Hub Connectivity Integrates Information from Multiple Sources

Frontoparietal connector hubs are thought to support information integration across the brain, but this role has largely been inferred from static connectivity, leaving unclear how computational processes shape inter-regional connectivity during behavior. Here, we address this question using a model-based functional connectivity approach in human fMRI data. Thirty-Eight participants (males and females) performed a task requiring the integration of sensory evidence with an internally maintained state belief to guide behavior. We developed a computational model that combines these information sources into an integrated representation and generates distinct variables at successive stages of integration: uncertainty before choice (entropy), the inferred task representation guiding action (task belief), and feedback-driven updating (task inference error). We then tested how these variables modulate the connectivity of frontoparietal connector hubs. Entropy increased coupling between hubs and regions encoding task-relevant inputs and outputs during cue processing, suggesting enhanced communication under uncertainty. During task selection, task belief selectively modulated hub connectivity with motor regions according to the selected task. During feedback, task inference errors increased coupling with regions supporting task-relevant inputs and internal state, while reducing coupling with motor regions, consistent with updating internal representations. Together, our findings show that frontoparietal connector hubs implement integrative control by using an integrated representation to generate distinct computational signals that selectively and dynamically reconfigure inter-regional communication. SignificanceFlexible behavior depends on combining different kinds of information, but how the brain coordinates this integration remains unclear. The frontoparietal cortex is well positioned to support this process because it is broadly connected with many other systems. Here, we combined a computational model with functional MRI to test how integrating information changes patterns of functional connectivity. We find that a common set of signals is associated with dissociable changes in how frontoparietal regions couple with systems involved in perception, action, and internal updating. These findings reveal that integration generates multiple control signals that dynamically reconfigure brain-wide interactions to support goal-directed behavior.

neuroscience↗

In vitro activity and in vivo efficacy against non-tuberculous mycobacteria of SPR719, the active moiety of the novel oral benzimidazole prodrug SPR720

Nontuberculous mycobacterial pulmonary disease (NTM-PD) is increasing globally, with Mycobacterium avium complex (MAC) accounting for 80% of cases and Mycobacterium abscessus among the next most prevalent pathogens. Current treatment necessitates long-term administration of poorly tolerated and modestly effective antibiotic combinations, highlighting the need for new oral agents. SPR719, the active moiety of the benzimidazole phosphate prodrug SPR720, inhibits the ATPase subunits of DNA gyrase B, a target with no human homolog and not exploited by current antibiotics. We demonstrated SPR719 activity against MAC (MIC90, 2 {micro}g/mL) and M. abscessus clinical isolates (MIC90, 4 {micro}g/mL), including those resistant to current standard-of-care (SOC) agents. In vivo efficacy of SPR720 was demonstrated against M. avium ATCC 700898 in a chronic C3HeB/FeJ murine model of pulmonary infection, both as a monotherapy and in combination with clarithromycin, ethambutol and rifabutin. SPR720 monotherapy exhibited a dose-dependent reduction in bacterial burden, with the largest reduction observed when combined with clarithromycin and ethambutol. Efficacy of SPR720 was also demonstrated against M. abscessus subspecies abscessus 1513, a virulent multidrug-resistant strain in a prolonged acute model of pulmonary infection in mice. SPR720 monotherapy exhibited a dose-dependent reduction in bacterial burden with further reductions when combined with SOC agents, clarithromycin and amikacin {+/-} clofazimine. Taken together, the in vitro activity of SPR720 against common NTM pathogens in concert with the proof-of-concept efficacy in murine infection models warrants the continued clinical evaluation of SPR720 as a new oral option for the treatment of NTM-PD.

microbiology↗