Pharmacological Fingerprints of Contextual Uncertainty

Successful interaction with the environment requires flexible updating of our beliefs about the world. By estimating the likelihood of future events, it is possible to prepare appropriate actions in advance and execute fast, accurate motor responses. According to theoretical proposals, agents track the variability arising from changing environments by computing various forms of uncertainty. Several neuromodulators have been linked to uncertainty signalling, but comprehensive empirical characterisation of their relative contributions to perceptual belief updating, and to the selection of motor responses, is lacking. Here we assess the roles of noradrenaline, acetylcholine, and dopamine within a single, unified computational framework of uncertainty. Using pharmacological interventions in a sample of 128 healthy human volunteers and a hierarchical Bayesian learning model, we characterise the influences of noradrenergic, cholinergic, and dopaminergic receptor antagonism on individual computations of uncertainty during a probabilistic serial reaction time task. We propose that noradrenaline influences learning of uncertain events arising from unexpected changes in the environment. In contrast, acetylcholine balances attribution of uncertainty to chance fluctuations within an environmental context, defined by a stable set of probabilistic associations, or to gross environmental violations following a contextual switch. Dopamine supports the use of uncertainty representations to engender fast, adaptive responses. \ua9 2016 Marshall et al

ABR and auditory P300 findings inchildren with ADHD Achados em ABR e P300 auditivo em crianças com TDAH

Auditory processing disorders (APD), also referred as central auditory processing disorders (CAPD) and attention deficit hyperactivity disorders (ADHD) have become popular diagnostic entities for school age children. It has been demonstrated a high incidence of comorbid ADHD with communication disorders and auditory processing disorder. The aim of this study was to investigate ABR and P300 auditory evoked potentials in children with ADHD, in a double-blind study. Twenty-one children, ages between 7 and 10 years, with a primary diagnosis of ADHD, participated in this experiment. Results showed that all children had normal ABR with normal latency for wave V. Results also showed that among 42 ears combined 52.38% did not have P300. For the medicated subjects we observed that among 28 ears, 42.85% did not have P300 and for the non-medicated 71.43% (N = 14 ears) did not have P300. Our results suggest that the medicated subjects had more presence of P300 (57.15%) than the non-medicated group (28.57%), though the absence of these potentials were high among the group - 52.38%.<br>Alterações do processamento auditivo, também chamadas alterações no processamento auditivo central e o transtorno do deficit de atenção/ hiperatividade (TDAH), tornaram-se entidades populares nos diagnósticos de crianças escolares. Uma grande incidência de TDAH em comorbidade com alterações na comunicação e com o processamento auditivo central tem sido demonstrada. O objetivo deste estudo foi investigar potenciais evocados auditivos, ABR e P300, em crianças com TDAH, em um estudo duplo cego. Vinte e uma crianças, idades entre 7 e 10 anos, com diagnostico primário de TDAH, participaram deste experimento. Os resultados mostraram que todas as crianças tinham ABR com latência normal para a onda V e que, entre 42 orelhas, 52,38% não tinham P300. Para os sujeitos medicados observou-se que entre 28 orelhas, 42,85% não tinham P300 e para os não medicados 71,43% (N = 14 orelhas) não tinham P300. Nossos resultados sugerem que os sujeitos medicados tinham maior presença de P300 (57,15%) do que o grupo não medicado (28,57%), apesar da ausência desses potenciais serem altos entre o grupo (52,38%)

In Vitro and In Vivo Characterization of Two C-11-Labeled PET Tracers for Vesicular Acetylcholine Transporter

PURPOSE: The vesicular acetylcholine transporter (VAChT) is a specific biomarker for imaging presynaptic cholinergic neurons. Herein, two potent and selective (11)C-labeled VAChT inhibitors were evaluated in rodents and nonhuman primates for imaging VAChT in vivo. PROCEDURES: For both (−)-[(11)C]2 and (−)-[(11)C]6, biodistribution, autoradiography, and metabolism studies were performed in male Sprague Dawley rats. Positron emission tomography (PET) brain studies with (−)-[(11)C]2 were performed in adult male cynomolgus macaques; 2 h dynamic data was acquired, and the regions of interest were drawn by co-registration of the PET images with the MRI. RESULTS: The resolved enantiomers (−)-2 and (−)-6 were very potent and selective for VAChT in vitro (K(i)<5 nM for VAChT with >35-fold selectivity for VAChT vs. σ receptors); both radioligands, (−)-[(11)C]2 and (−)-[(11)C]6, demonstrated high accumulation in the VAChT-enriched striatum of rats. (−)-[(11)C]2 had a higher striatum to cerebellum ratio of 2.4-fold at 60 min; at 30 min, striatal uptake reached 0.550±0.086 %ID/g. Uptake was also specific and selective; following pretreatment with (±)-2, striatal uptake of (−)-[(11)C]2 in rats at 30 min decreased by 50 %, while pretreatment with a potent sigma ligand had no significant effect on striatal uptake in rats. In addition, (−)-[(11)C]2 displayed favorable in vivo stability in rat blood and brain. PET studies of (−)-[(11)C]2 in nonhuman primates indicate that it readily crosses the blood-brain barrier (BBB) and provides clear visualization of the striatum; striatal uptake reaches the maximum at 60 min, at which time the target to nontarget ratio reached ~2-fold. CONCLUSIONS: The radioligand (−)-[(11)C]2 has high potential to be a suitable PET radioligand for imaging VAChT in the brain of living subjects

Nicotine modulates reorienting of visuospatial attention and neural activity in human parietal cortex

Prior studies in animals and humans indicate that reorienting of visuospatial attention is modulated by the cholinergic agonist nicotine. We have previously identified neural correlates of alerting and reorienting attention in humans and found that the parietal cortex is specifically involved in reorienting. This study investigates whether the alerting and reorienting systems, especially in the parietal cortex, are modulated by nicotine. We used event-related functional magnetic resonance imaging (fMRI) and studied 15 nonsmoking volunteers under placebo and nicotine (NICORETTE) polacrilex gum 1 and 2 mg). Subjects performed a cued target detection task with four different types of randomly intermixed trials (no, neutral, valid, and invalid cue trials). Alerting was captured by comparing BOLD activity and reaction times (RTs) in neutrally cued trials with no cue trials. Reorienting was isolated by comparing invalidly with validly cued trials. On the behavioral level, nicotine affected reorienting of attention by speeding RTs in invalidly cued trials; alerting was not affected by nicotine. Neurally, however, nicotine modulated both attentional systems. Pharmacologic effects on alerting-related brain activity were mainly evident as modulation of BOLD responses in the right angular gyrus and right middle frontal gyrus due to a reduction of neural activity in no cue trials. In the reorienting system, effects of nicotine were mainly evident in the left intraparietal sulcus and precuneus and due to a reduction of neural activity in invalidly cued trials. We conclude that nicotine enhances reorienting of attention in visuospatial tasks and that one behavioral correlate of speeded RTs is reduced parietal activity