Emotional Picture and Word Processing: An fMRI Study on Effects of Stimulus Complexity

Neuroscientific investigations regarding aspects of emotional experiences usually focus on one stimulus modality (e.g., pictorial or verbal). Similarities and differences in the processing between the different modalities have rarely been studied directly. The comparison of verbal and pictorial emotional stimuli often reveals a processing advantage of emotional pictures in terms of larger or more pronounced emotion effects evoked by pictorial stimuli. In this study, we examined whether this picture advantage refers to general processing differences or whether it might partly be attributed to differences in visual complexity between pictures and words. We first developed a new stimulus database comprising valence and arousal ratings for more than 200 concrete objects representable in different modalities including different levels of complexity: words, phrases, pictograms, and photographs. Using fMRI we then studied the neural correlates of the processing of these emotional stimuli in a valence judgment task, in which the stimulus material was controlled for differences in emotional arousal. No superiority for the pictorial stimuli was found in terms of emotional information processing with differences between modalities being revealed mainly in perceptual processing regions. While visual complexity might partly account for previously found differences in emotional stimulus processing, the main existing processing differences are probably due to enhanced processing in modality specific perceptual regions. We would suggest that both pictures and words elicit emotional responses with no general superiority for either stimulus modality, while emotional responses to pictures are modulated by perceptual stimulus features, such as picture complexity.     

Murine Efficacy and Pharmacokinetic Evaluation of the Flaviviral NS5 Capping Enzyme 2-Thioxothiazolidin-4-One Inhibitor BG-323

Arthropod-borne flavivirus infection continues to cause significant morbidity and mortality worldwide. Identification of drug targets and novel antiflaviviral compounds to treat these diseases has become a global health imperative. A previous screen of 235,456 commercially available small molecules identified the 2-thioxothiazolidin-4-one family of compounds as inhibitors of the flaviviral NS5 capping enzyme, a promising target for antiviral drug development. Rational drug design methodologies enabled identification of lead compound BG-323 from this series. We have shown previously that BG-323 potently inhibits NS5 capping enzyme activity, displays antiviral effects in dengue virus replicon assays and inhibits growth of West Nile and yellow fever viruses with low cytotoxicity in vitro. In this study we further characterized BG-323’s antiviral activity in vitro and in vivo. We found that BG-323 was able to reduce replication of WNV (NY99) and Powassan viruses in culture, and we were unable to force resistance into WNV (Kunjin) in long-term culture experiments. We then evaluated the antiviral activity of BG-323 in a murine model. Mice were challenged with WNV NY99 and administered BG-323 or mock by IP inoculation immediately post challenge and twice daily thereafter. Mice were bled and viremia was quantified on day three. No significant differences in viremia were observed between BG-323-treated and control groups and clinical scores indicated both BG-323-treated and control mice developed signs of illness on approximately the same day post challenge. To determine whether differences in in vitro and in vivo efficacy were due to unfavorable pharmacokinetic properties of BG-323, we conducted a pharmacokinetic evaluation of this small molecule. Insights from pharmacokinetic studies indicate that BG-323 is cell permeable, has a low efflux ratio and does not significantly inhibit two common cytochrome P450 (CYP P450) isoforms thus suggesting this molecule may be less likely to cause adverse drug interactions. However, the T_1/2 of BG-323 was suboptimal and the percent of drug bound to plasma binding proteins was high. Future studies with BG-323 will be aimed at increasing the T_1/2 and determining strategies for mitigating the effects of high plasma protein binding, which likely contribute to low in vivo efficacy.