Mechanisms of burst release from pH-responsive polymeric microparticles.

Microencapsulation of drugs into preformed polymers is commonly achieved through solvent evaporation techniques or spray drying. We compared these encapsulation methods in terms of controlled drug release properties of the prepared microparticles and investigated the underlying mechanisms responsible for the “burst release” effect. Using two different pH-responsive polymers with a dissolution threshold of pH 6 (Eudragit L100 and AQOAT AS-MG), hydrocortisone, a model hydrophobic drug, was incorporated into microparticles below and above its solubility within the polymer matrix. Although, spray drying is an attractive approach due to rapid particle production and relatively low solvent waste, the oil-in-oil microencapsulation method is superior in terms of controlled drug release properties from the microparticles. Slow solvent evaporation during the oil-in-oil emulsification process allows adequate time for drug and polymer redistribution in the microparticles and reduces uncontrolled drug burst release. Electron microscopy showed that this slower manufacturing procedure generated non-porous particles whereas thermal analysis and X-ray diffractometry showed that drug loading above the solubility limit of the drug in the polymer generated excess crystalline drug on the surface of the particles. Raman spectral mapping illustrated that drug was homogeneously distributed as a solid solution in the particles when loaded below saturation in the polymer with consequently minimal burst release.

ERP correlates of shared control mechanisms involved in saccade preparation and in covert attention

We investigated whether attention shifts and eye movement preparation are mediated by shared control mechanisms, as claimed by the premotor theory of attention. ERPs were recorded in three tasks where directional cues presented at the beginning of each trial instructed participants to direct their attention to the cued side without eye movements (Covert task), to prepare an eye movement in the cued direction without attention shifts (Saccade task) or both (Combined task). A peripheral visual Go/Nogo stimulus that was presented 800 ms after cue onset signalled whether responses had to be executed or withheld. Lateralised ERP components triggered during the cue–target interval, which are assumed to reflect preparatory control mechanisms that mediate attentional orienting, were very similar across tasks. They were also present in the Saccade task, which was designed to discourage any concomitant covert attention shifts. These results support the hypothesis that saccade preparation and attentional orienting are implemented by common control structures. There were however systematic differences in the impact of eye movement programming and covert attention on ERPs triggered in response to visual stimuli at cued versus uncued locations. It is concluded that, although the preparatory processes underlying saccade programming and covert attentional orienting may be based on common mechanisms, they nevertheless differ in their spatially specific effects on visual information processing.

Turning on the alarm: the neural mechanisms of the transition from innocuous to painful sensation

The experience of pain occurs when the level of a stimulus is sufficient to elicit a marked affective response, putatively to warn the organism of potential danger and motivate appropriate behavioral responses. Understanding the biological mechanisms of the transition from innocuous to painful levels of sensation is essential to understanding pain perception as well as clinical conditions characterized by abnormal relationships between stimulation and pain response. Thus, the primary objective of this study was to characterize the neural response associated with this transition and the correspondence between that response and subjective reports of pain. Towards this goal, this study examined BOLD response profiles across a range of temperatures spanning the pain threshold. 14 healthy adults underwent functional magnetic resonance imaging (fMRI) while a range of thermal stimuli (44-49oC) were applied. BOLD responses showed a sigmoidal profile along the range of temperatures in a network of brain regions including insula and mid- cingulate, as well as a number of regions associated with motor responses including ventral lateral nuclei of the thalamus, globus pallidus and premotor cortex. A sigmoid function fit to the BOLD responses in these regions explained up to 85% of the variance in individual pain ratings, and yielded an estimate of the temperature of steepest transition from non-painful to painful heat that was nearly identical to that generated by subjective ratings. These results demonstrate a precise characterization of the relationship between objective levels of stimulation, resulting neural activation, and subjective experience of pain and provide direct evidence for a neural mechanism supporting the nonlinear transition from innocuous to painful levels along the sensory continuum.