Neural patterns associated with mixed valence feelings differ in consistency and predictability throughout the brain.

Mixed feelings, the simultaneous presence of feelings with positive and negative valence, remain an understudied topic. They pose a specific set of challenges due to individual variation, and their investigation requires analtyic approaches focusing on individually self-reported states. We used functional magnetic resonance imaging (fMRI) to scan 27 subjects watching an animated short film chosen to induce bittersweet mixed feelings. The same subjects labeled when they had experienced positive, negative, and mixed feelings. Using hidden-Markov models, we found that various brain regions could predict the onsets of new feeling states as determined by self-report. The ability of the models to identify these transitions suggests that these states may exhibit unique and consistent neural signatures. We next used the subjects' self-reports to evaluate the spatiotemporal consistency of neural patterns for positive, negative, and mixed states. The insula had unique and consistent neural signatures for univalent states, but not for mixed valence states. The anterior cingulate and ventral medial prefrontal cortex had consistent neural signatures for both univalent and mixed states. This study is the first to demonstrate that subjectively reported changes in feelings induced by naturalistic stimuli can be predicted from fMRI and the first to show direct evidence for a neurally consistent representation of mixed feelings.

Sclerostin antibody improves phosphate metabolism hormones, bone formation rates, and bone mass in adult Hyp mice.

X-linked hypophosphatemia (XLH) is caused by a loss-of-function mutation in the phosphate regulating gene with homology to endopeptidase located on the X chromosome (PHEX). Loss of functional PHEX results in elevated fibroblast growth factor 23 (FGF23), impaired phosphate reabsorption, and inhibited skeletal mineralization. Sclerostin, a protein produced primarily by osteocytes, suppresses bone formation by antagonizing canonical Wnt-signaling and is reported to be elevated in XLH patients. Our previous study reported that a monoclonal antibody to sclerostin (Scl-Ab) decreases FGF23 and increases phosphate and bone mass in growing Hyp mice (XLH murine model). In the current study, we investigated the efficacy of Scl-Ab in treating XLH pathophysiology in adult Hyp mice that are past the period of rapid skeletal growth (12 and 20-weeks old). We hypothesized that Scl-Ab would not only increase bone formation, bone strength and bone mass, but would also normalize phosphate regulating hormones, FGF23, parathyroid hormone (PTH), and vitamin 1,25(OH)2D. Scl-Ab treatment increased cortical area, trabecular bone volume fraction, trabecular bone formation rate, and the bending moment in both sexes of both age groups. Scl-Ab treatment suppressed circulating levels of intact FGF23 and c-term FGF23 in treated male and female wild-type and Hyp mice of both age groups and improved both vitamin 1,25(OH)2D and PTH. Scl-Ab treated Hyp mice also showed evidence of increased renal expression of the sodium-phosphate co-transporter, NPT2a, specifically in the female Hyp mice. Our study suggests that Scl-Ab treatment can improve several skeletal and metabolic pathologies associated with XLH, further establishes the role of sclerostin in the regulation of FGF23 and provides evidence that Scl-Ab can improve phosphate regulation by targeting the bone-renal axis.