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Pain is a naturally occurring phenomenon that consistently inhibits exercise performance by imposing unconscious, neurophysiological alterations (e.g., corticospinal changes) as well as conscious, psychophysiological pressures (e.g., shared effort demands). Although several studies indicate that pain would elicit lower task outputs for a set intensity of perceived effort, no study has tested this. Therefore, this study investigated the impact of elevated muscle pain through a hypertonic saline injection on the power output, psychophysiological, cerebral oxygenation, and perceptual changes during fixed perceived effort exercise. Ten participants completed three visits (1 familiarization + 2 fixed perceived effort trials). Fixed perceived effort cycling corresponded to 15% above gas exchange threshold (GET) [mean rating of perceived effort (RPE) = 15 "hard"]. Before the 30-min fixed perceived effort exercise, participants received a randomized bilateral hypertonic or isotonic saline injection in the vastus lateralis. Power output, cardiorespiratory, cerebral oxygenation, and perceptual markers (e.g., affective valence) were recorded during exercise. Linear mixed-model regression assessed the condition and time effects and condition × time interactions. Significant condition effects showed that power output was significantly lower during hypertonic conditions [ t 107 = 208, P = 0.040, β = 4.77 W, 95% confidence interval (95% CI) [0.27 to 9.26 W]]. Meanwhile, all physiological variables (e.g., heart rate, oxygen uptake, minute ventilation) demonstrated no significant condition effects. Condition effects were observed for deoxyhemoglobin changes from baseline ( t 107 = -3.29, P = 0.001, β = -1.50 ΔμM, 95% CI [-2.40 to -0.61 ΔμM]) and affective valence ( t 127 = 6.12, P = 0.001, β = 0.93, 95% CI [0.63 to 1.23]). Results infer that pain impacts the self-regulation of fixed perceived effort exercise, as differences in power output mainly occurred when pain ratings were higher after hypertonic versus isotonic saline administration. NEW & NOTEWORTHY This study identifies that elevated muscle pain through a hypertonic saline injection causes significantly lower power output when pain is experienced but does not seem to affect exercise behavior in a residual manner. Results provide some evidence that pain operates on a psychophysiological level to alter the self-regulation of exercise behavior due to differences between conditions in cerebral deoxyhemoglobin and other perceptual parameters.

Background: Altered sensory processing is a pervasive symptom in individuals with Autism Spectrum Disorders (ASD); people with Phelan McDermid syndrome (PMS), in particular, show reduced responses to sensory stimuli. PMS is caused by deletions of the terminal end of chromosome 22 or point mutations in Shank3. People with PMS can present with an array of symptoms including ASD, epilepsy, gastrointestinal distress, and reduced responses to sensory stimuli. People with PMS are often medicated to manage behaviors like aggression and/or self-harm and/or epilepsy, and it remains unclear how these medications might impact perception/sensory processing. Here we test this using zebrafish mutant shank3ab PMS models that likewise show reduced sensory responses in a visual motor response (VMR) assay, in which increased locomotion is triggered by light to dark transitions. Methods: We screened three medications, risperidone, lithium chloride (LiCl), and carbamazepine (CBZ), prescribed to people with PMS and one drug, 2-methyl-6-(phenylethynyl) pyridine (MPEP) tested in rodent models of PMS, for their effects on a sensory-induced behavior in two zebrafish PMS models with frameshift mutations in either the N- or C- termini. To test how pharmacological treatments affect the VMR, we exposed larvae to selected drugs for 24 hours and then quantified their locomotion during four ten-minute cycles of lights on-to-off stimuli. Results: We found that risperidone normalized the VMR in shank3 models. LiCl and CBZ had no effect on the VMR in any of the three genotypes. MPEP reduced the VMR in wildtype (WT) to levels seen in shank3 models but caused no changes in either shank3 model. Finally, shank3 mutants showed resistance to the seizure-inducing drug pentylenetetrazol (PTZ), at a dosage that results in hyperactive swimming in WT zebrafish. Conclusions: Our work shows that the effects of drugs on sensory processing are varied in ways that can be highly genotype- and drug-dependent., Competing Interests: No competing interests were disclosed., (Copyright: © 2023 Kozol RA and Dallman JE.)

Throughout evolution, the need for single-celled organisms to associate and form a single cluster of cells has had several evolutionary advantages. In complex, multicellular organisms, each tissue or organ has a specialty and function that make life together possible, and the organism as a whole needs to act in balance and adapt to changes in the environment. Sensory organs are essential for connecting external stimuli into a biological response, through the senses: sight, smell, taste, hearing, and touch. The G-protein-coupled receptors (GPCRs) are responsible for many of these senses and therefore play a key role in the perception of the cells' external environment, enabling interaction and coordinated development between each cell of a multicellular organism. The malaria-causing protozoan parasite, Plasmodium falciparum , has a complex life cycle that is extremely dependent on a finely regulated cellular signaling machinery. In this review, we summarize strong evidence and the main candidates of GPCRs in protozoan parasites. Interestingly, one of these GPCRs is a sensor for K + shift in Plasmodium falciparum , PfSR25. Studying this family of proteins in P. falciparum could have a significant impact, both on understanding the history of the evolution of GPCRs and on finding new targets for antimalarials.

Prolonged exercise in the heat elicits a number of physiological changes as glycogen stores are low and water and electrolytes are lost through sweat. However, it is unclear whether these changes provoke an increase in liking of saltiness and, therefore, palatability of an oral rehydration solution (ORS). Twenty-seven recreationally active participants ( n = 13 males; n = 14 females) completed sensory analysis of an ORS, a traditional sports drink (TS), and a flavored water placebo (PL) at rest and during 60 min (3 × 20-min bouts) of cycling exercise at 70% age-predicted maximum heart rate (HR max ) at 35.3 ± 1.4 °C and 41 ± 6% relative humidity. Before and after every 20 min of exercise, drinks were rated (using 20-mL beverage samples) based on liking of sweetness, liking of saltiness, thirst-quenching ability, and overall liking on a nine-point hedonic scale. Hydration status was assessed by changes in semi-nude body mass, saliva osmolality (S Osm ), and saliva total protein concentration (S PC ). After 60 min of exercise, participants lost 1.36 ± 0.39% (mean ± SD) of body mass and there were increases in S Osm and S PC. At all time points, liking of sweetness, saltiness, thirst-quenching ability, and overall liking was higher for the TS and PL compared to the ORS ( p < 0.05). However, the saltiness liking and thirst-quenching ability of the ORS increased after 60 min of exercise compared to before exercise ( p < 0.05). There was also a change in predictors of overall liking with pre-exercise ratings mostly determined by liking of sweetness, saltiness, and thirst-quenching ability ( p < 0.001), whereas only liking of saltiness predicted overall liking post-exercise (R 2 = 0.751; p < 0.001). There appears to be a hedonic shift during exercise in which the perception of saltiness becomes the most important predictor of overall liking. This finding supports the potential use of an ORS as a valuable means of hydration during the latter stages of prolonged and/or intense exercise in the heat.

Background: Perceiving accurately that others are looking away from us (averted gaze) is as important, for social interactions, as perceiving that others are looking at us (direct gaze). However, previous studies have revealed that when the deflection angle of averted gaze is small, individuals tend to falsely perceive it as direct gaze. Oxytocin (OXT) has been shown to increase orientation to the eye region. Therefore, a critical question is whether and how OXT would facilitate the perception of ambiguous averted gaze., Objectives: The present study aimed to measure the effects of OXT on the performance of males and females in distinguishing ambiguous averted gaze from direct gaze of different emotional faces., Methods: In a double-blind placebo-controlled crossover experiment, 48 participants were presented successively two emotional faces with direct gaze (defined as 0, indicating the center of the eye) or averted gaze (defined as ±4, indicating the corner of the eye; +4 means that the iris moves 4 steps to the right; and -4 means that the iris moves 4 steps to the left) following intranasal oxytocin or placebo treatment and asked to make judgments on whether or not the two faces were the same in terms of identity. The interference effect of gaze direction was calculated by subtracting the mean accuracy and reaction time in the congruent gaze condition from those in the incongruent gaze condition. The logic of the measurement was if intranasal OXT would facilitate the detection of ambiguous averted gaze, we would observe a larger interference effect in the gaze incongruent condition compared with the gaze congruent condition, leading to longer RT or/and lower accuracy for identification judgment in the gaze incongruent condition., Results: While there were no OXT effects in accuracy, we found a significant interaction between treatment, sex, and gaze congruency in reaction times. That is, following OXT as compared to placebo, women displayed stronger interference of gaze direction, whereas in men no significant difference was observed. Besides, this interaction did not vary across different emotional expressions., Conclusions: Our findings provide the first evidence for sex-dependent effects of OXT on the perception of ambiguous averted gaze. Given potential therapeutic applications of OXT to patients with developmental and psychiatric disorders, who are characterized as atypical in encoding gaze features, the findings suggest that rather different treatment outcomes could be anticipated in males and females.

Attention to the relations between visual features modulates hippocampal representations. Moreover, hippocampal damage impairs discrimination of spatial relations. We explore a mechanism by which this might occur: modulation by the acetylcholine system. Acetylcholine enhances afferent input to the hippocampus and suppresses recurrent connections within it. This biases hippocampal processing toward environmental input, and should improve externally oriented, hippocampally mediated attention and perception. We examined cholinergic modulation on an attention task that recruits the hippocampus. On each trial, participants viewed two images (rooms with paintings). On "similar room" trials, they judged whether the rooms had the same spatial layout from a different perspective. On "similar art" trials, they judged whether the paintings could have been painted by the same artist. On "identical" trials, participants simply had to detect identical paintings or rooms. We hypothesized that cholinergic modulation would improve performance on the similar room task, given past findings that hippocampal representations predicted, and hippocampal damage impaired, behavior on this task. To test this, nicotine cigarette smokers took part in two sessions: one before which they abstained from nicotine for 12 hours, and one before which they ingested nicotine in the past hour. Individual differences in expired breath carbon monoxide levels-a measure of how recently or how much someone smoked-predicted performance improvements on the similar room task. This finding provides novel support for computational models that propose that acetylcholine enhances externally oriented attentional states in the hippocampus. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Clinical and pre-clinical evidence demonstrates divergent psychotropic effects of THC vs. CBD. While THC can induce perceptual distortions and anxiogenic effects, CBD displays antipsychotic and anxiolytic properties. A key brain region responsible for regulation of cognition and affect, the medial prefrontal cortex (PFC), is strongly modulated by cannabinoids, suggesting that these dissociable THC/CBD-dependent effects may involve functional and molecular interplay within the PFC. The primary aim of this study was to investigate potential interactions and molecular substrates involved in PFC-mediated effects of THC and CBD on differential cognitive and affective behavioural processing. Male Sprague Dawley rats received intra-PFC microinfusions of THC, CBD or their combination, and tested in the latent inhibition paradigm, spontaneous oddity discrimination test, elevated T-maze and open field. To identify local, drug-induced molecular modulation in the PFC, PFC samples were collected and processed with Western Blotting. Intra-PFC THC induced strong panic-like responses that were counteracted with CBD. In contrast, CBD did not affect panic-like behaviours but blocked formation of associative fear memories and impaired latent inhibition and oddity discrimination performance. Interestingly, these CBD effects were dependent upon 5-HT 1A receptor transmission but not influenced by THC co-administration. Moreover, THC induced robust phosphorylation of ERK1/2 that was prevented by CBD, while CBD decreased phosphorylation of p70S6K, independently of THC. These results suggest that intra-PFC infusion of THC promotes panic-like behaviour associated with increased ERK1/2 phosphorylation. In contrast, CBD impairs perceptive functions and latent inhibition via activation of 5-HT 1A receptors and reduced phosphorylation of p70S6K., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Inc. All rights reserved.)

The rating of perceived exertion (RPE) indicates the feeling of fatigue. However, hypoxia worsens the condition and can worsen RPE. We evaluated whether carbohydrate and glutamine supplementation alters RPE and physiological markers in running at 70% peak oxygen uptake until exhaustion in a simulated altitude of 4500 m. Nine volunteers underwent three running tests at 70% peak oxygen uptake until exhaustion: (1) hypoxia and placebo, (2) hypoxia and 8% maltodextrin, and (3) hypoxia after six days of glutamine supplementation (20 g/day) and 8% maltodextrin. The exercise and supplementation were randomized and double-blinded. Lactate, heart rate, haemoglobin O 2 saturation (SpO 2 %), and RPE (6-20 scale) were analyzed at the 15th and 30th min. The level of significance was set at p ≤ 0.05. SpO 2 % decreased at the 15th and 30th minutes compared to resting in placebo, carbohydrate, and glutamine supplementation. RPE increased at the 30th minute compared to the 15th minute in placebo and carbohydrate supplementation; however, there was no difference in the glutamine supplementation condition. Heart rate and lactate increased after the 15th and 30th minutes compared to resting, similar to the three conditions studied. We conclude that previous supplementation with glutamine and carbohydrate during intense exercise in hypoxia similar to 4500 m can attenuate the increase in RPE by the increase in glycemia and can be a useful strategy for people who exercise in these conditions.

Psychedelic drugs, including the serotonin 2a (5-HT 2A ) receptor partial agonist psilocybin, are receiving renewed attention for their possible efficacy in treating a variety of neuropsychiatric disorders. Psilocybin induces widespread dysregulation of cortical activity, but circuit-level mechanisms underlying this effect are unclear. The claustrum is a subcortical nucleus that highly expresses 5-HT 2A receptors and provides glutamatergic inputs to arguably all areas of the cerebral cortex. We therefore tested the hypothesis that psilocybin modulates claustrum function in humans. Fifteen healthy participants (10M, 5F) completed this within-subjects study in which whole-brain resting-state blood-oxygenation level-dependent (BOLD) signal was measured 100 ​min after blinded oral administration of placebo and 10 mg/70 ​kg psilocybin. Left and right claustrum signal was isolated using small region confound correction. Psilocybin significantly decreased both the amplitude of low frequency fluctuations as well as the variance of BOLD signal in the left and right claustrum. Psilocybin also significantly decreased functional connectivity of the right claustrum with auditory and default mode networks (DMN), increased right claustrum connectivity with the fronto-parietal task control network (FPTC), and decreased left claustrum connectivity with the FPTC. DMN integrity was associated with right-claustrum connectivity with the DMN, while FPTC integrity and modularity were associated with right claustrum and left claustrum connectivity with the FPTC, respectively. Subjective effects of psilocybin predicted changes in the amplitude of low frequency fluctuations and the variance of BOLD signal in the left and right claustrum. Observed effects were specific to claustrum, compared to flanking regions of interest (the left and right insula and putamen). This study used a pharmacological intervention to provide the first empirical evidence in any species for a significant role of 5-HT 2A receptor signaling in claustrum functioning, and supports a possible role of the claustrum in the subjective and therapeutic effects of psilocybin., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

It is well established that acute stress produces negative effects on high level cognitive functions. However, these effects could be due to the physiological components of the stress response (among which cortisol secretion is prominent), to its psychological concomitants (the thoughts generated by the stressor) or to any combination of those. Our study shows for the first time that the typical cortisol response to stress is sufficient to impair metacognition, that is the ability to monitor one's own performance in a task. In a pharmacological protocol, we administered either 20 mg hydrocortisone or placebo to 46 male participants, and measured their subjective perception of stress, their performance in a perceptual task, and their metacognitive ability. We found that hydrocortisone selectively impaired metacognitive ability, without affecting task performance or creating a subjective state of stress. In other words, the single physiological response of stress produces a net effect on metacognition. These results inform our basic understanding of the physiological bases of metacognition. They are also relevant for applied or clinical research about situations involving stress, anxiety, depression, or simply cortisol use.

Introduction: This study assessed the influence of High (H, 4.13%), Medium (M, 2.0%) and Low (L, 0.1%) doses of menthol on temperature perception and regulation, compared to a Placebo Condition (P)., Method: Sixteen participants underwent the aforementioned conditions on four separate days. During each test participants rested supine (Environmental conditions: 30 °C, 50% rh) for 30-min before 40 mL of L, M, H or P gel was applied to the anterior upper body, then rested 30-min thereafter. Primary measures included thermal sensation (TS), thermal comfort (TC), irritation (IRR), rectal temperature (Tre), and skin temperature (chest, forearm, thigh, calf), and EMG (trapezius, pectoralis major, sternocleidomastoid). The area under the curve (AUC) from minute 30 to 60 was compared between conditions using relevant non/parametric tests (alpha level = 0.05)., Results: A cooling trend in Tre was observed following Placebo gel application, but this significantly (p < 0.05) reversed into a heat storage response in M and H. Both TS and TC significantly differed by condition (p < 0.001) in a dose-dependent manner, with L, M, and H doses eliciting significantly cooler sensations and more discomfort than P (p < 0.05). Irritation significantly differed by condition (p < 0.01) in a dose-dependent manner, with L and M eliciting significantly greater irritation than P (p < 0.01). No other differences were observed., Conclusions: Menthol exerts perceptual and thermoregulatory effects independent of skin temperature. A menthol dose-dependent perceptual cooling effect was evident with possible saturation at the moderate dose. A dose-dependent alteration in deep body temperature was also evident., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Rationale: The regular consumption of very small doses of psychedelic drugs (known as microdosing) has been a source of growing media and community attention in recent years. However, there is currently limited clinical and social research evidence on the potential role of microdosing as therapies for mental and substance use disorders., Objectives: This paper examined subjective experiences of microdosing psychedelics to improve mental health or to cease or reduce substance use, and examined sociodemographic and other covariates of perceived improvements in mental health that individuals attributed to microdosing., Methods: An international online survey was conducted in 2018 and examined people's experiences of using psychedelics for self-reported therapeutic or enhancement purposes. This paper focuses on 1102 respondents who reported current or past experience of psychedelic microdosing., Results: Twenty-one percent of respondents reported primarily microdosing as a therapy for depression, 7% for anxiety, 9% for other mental disorders and 2% for substance use cessation or reduction. Forty-four percent of respondents perceived that their mental health was "much better" as a consequence of microdosing. In a multivariate analysis, perceived improvements in mental health from microdosing were associated with a range of variables including gender, education, microdosing duration and motivations, and recent use of larger psychedelic doses., Conclusions: Given the promising findings of clinical trials of standard psychedelic doses as mental health therapies, clinical microdosing research is needed to determine its potential role in psychiatric treatment, and ongoing social research to better understand the use of microdosing as self-managed mental health and substance use therapies.

Introduction: Sensory properties have a great importance for cosmetics and personal care products. If literature permits to consult articles comparing different formulations on their sensory attributes, there are only a few articles concerning ingredients., Objective: The overall objective of this study was to carry out an original study combining the sensory evaluation of different natures of ingredients, in order to initiate a sensory data set that could help researchers to identify differentiating sensory characteristics, as well as initiating a comparison between sensory data and texturometer instrumental measurements., Methods: Oils, glycolic extracts, butter and starch were evaluated according to descriptive sensory analysis methodology with the help of panel of 25 experts. In order to compare responses obtained from the panel to instrumental measurements, texture analyzes were performed in compression traction model., Results: Significant differences were detected in ten of the eleven evaluated sensory attributes, indicating that ingredients have distinct sensory profiles. The mainly discriminative attributes for the analyzed ingredients were: gloss, opacity, fluidity, freshness, whitening and oily residue. The oils are mostly related to oily residue and slipperiness while extracts are mostly related to gloss, fluidity and freshness attributes. Both Tapioca Starch and Shea Butter were related to non-fluidity, opacity, and Tapioca Starch was related to freshness too. This study was completed by a texturometer analysis which lead to show the opposite correlation between the sensory attribute fluidity and the consistent index., (© 2020 Society of Cosmetic Scientists and the Société Française de Cosmétologie.)

Objective: The purpose of the present study was to compare psychological distress between patients with epilepsy and healthy controls and to evaluate potentially related factors to psychological distress in patients with epilepsy. Furthermore, we assessed how psychological distress and other potential factors mediate illness perception in patients with epilepsy in an urban area of Northwest Greece., Materials and Methods: A case-control study was conducted in adult patients with epilepsy followed up at the University Hospital of Ioannina and in healthy controls. The Symptom Checklist-90 Revised (SCL-90R) for symptoms of psychological distress and the overall psychological distress Global Severity Index (GSI) evaluation, the brief illness perception questionnaire (B-IPQ), and the Adverse Event Profile (AEP) questionnaire for the antiepileptic drugs (AEDs) were used., Results: Seventy patients with epilepsy and 70 controls were recruited in the study. Somatic, depression, and anxiety symptoms and the GSI were higher in patients than in controls. In patients with epilepsy, the AEP score was significantly associated with psychological distress. Illness perception was associated with the number and the total number of administered AEDs; the AEP score; somatic, obsessive, depressive, and anxiety symptoms; and the GSI. After regression analysis, epilepsy characteristics, AEDs, and psychological distress accounted for 11.7%, 28.7%, and 5.5% of variance in BIP-Q score, respectively., Conclusion: Screening for psychological distress in patients with epilepsy is of high importance in clinical practice as somatic, depression, and anxiety symptoms and overall psychological distress are more severe in patients with epilepsy than in healthy controls. The symptoms of psychological distress are strongly associated with the adverse effects of AEDs. The epilepsy characteristics, the AEDs, and the psychological distress could determine a large part of illness perception in epilepsy, with the adverse effects of AEDs being the strongest predictor., (Copyright © 2019 Elsevier Inc. All rights reserved.)

The purpose of the study was to investigate the effect of inhaling 1600 μg of salbutamol (SAL) on 30 m sprint before and after the Yo-Yo Intermittent Recovery test. In a randomised cross over single blind study 13 male non-asthmatic, football players volunteered (mean ± SD; age 18.1 ± 0.9 years; weight 69.5 ± 8.3 kg; height 1.78 ± 0.07 m). Participants completed two visits and were randomly assigned to either (SAL) or (PLA) treatment and performed a set of three sprints of 30 m before and after the Yo-Yo Intermittent Recovery Test (Yo-Yo IRT). Best sprint and mean sprint were analysed in addition to the distance covered during the Yo-Yo IRT; rating of perceived exertion and heart rate were collected at the end of each level completed. Repeated measures ANOVA were performed to investigate changes in performance between groups. Following the inhalation of supra-therapeutic salbutamol dose (1600 μg) neither 30 m sprint time (PLA 4.43 ± 0.14 s; SAL 4.44 ± 0.15 s, p = 0.76) nor distance covered in the Yo-Yo IRT test reported significant variation between PLA conditions (1660 ± 217 m) and SAL (1610 ± 229 m, p = 0.16). Moreover, lactate values, heart rate and RPE did not differ significantly between groups. The inhalation of 1600 μg salbutamol does not enhance 30 m sprint performance in non-fatigued and fatigue conditions. Our findings suggest when football players acutely inhale double the permitted dose of salbutamol, as indicated in the World Anti-Doping Agency List of Prohibited Substances and Methods, they will not experience improvements in sprint or endurance performance., (© Journal of Sports Science and Medicine.)

The involvement of fronto-striatal circuits in item and associative memory retrieval as well as in the stabilization of memories by retrieval practice suggests that both retrieval and re-encoding of stored memories might rely on dopaminergic mechanisms in humans. We tested these hypotheses in a placebo-controlled pharmacological fMRI study using 2 mg of the D2 antagonist haloperidol administered acutely before a cued associative recall task of previously encoded picture-word pairs in 53 healthy humans of both sexes. The cued associative recall was moreover repeated 3 d later outside the scanner without pharmacological intervention. Dopaminergic modulation significantly improved associative recall performance and recognition accuracy of verbal items. Moreover, we observed a significant dopamine effect on re-encoding in terms of increased specificity of associative memories from the first to the second cued associative recall. Better association memory under haloperidol was linked with higher activity in the left lateral prefrontal cortex and right parietal cortex, suggesting that dopamine facilitates associative retrieval through increased recruitment of frontoparietal monitoring processes. In contrast, improved recognition of verbal items under haloperidol was reflected by enhanced novelty detection in the hippocampus and increased activity in saliency networks. Together, these results show distinct but concomitant positive effects of dopamine on associative recall and item recognition and suggest that the specificity of associative recall through re-encoding mechanisms is likewise augmented by dopamine. SIGNIFICANCE STATEMENT Although the neurotransmitter dopamine has been linked with learning and memory for a long time, dopaminergic effects on item recognition in humans were demonstrated only recently. The involvement of fronto-striatal monitoring processes in association retrieval suggests that associative memory might be particularly affected by dopamine. Moreover, fronto-striatal dopaminergic signals have been hypothesized to determine the updating and re-encoding of previously retrieved memories. We here demonstrate clear facilitative effects of dopamine on associative recall and item recognition mediated by prefrontal and hippocampal mechanisms respectively. Additionally, effects on re-encoding were reflected by increased specificity of associative memories. These results augment our understanding of dopaminergic processes in episodic memory retrieval and offer new perspectives on memory impairments in dopamine-related disorders and their treatment., (Copyright © 2019 the authors.)

Background: Among the neurological consequences of alcoholism is peripheral neuropathy. Relative to human immunodeficiency virus (HIV) or diabetes-related neuropathies, neuropathy associated with alcohol use disorders (AUD) is understudied. In both the diabetes and HIV literature, emerging evidence supports a central nervous system (CNS) component to peripheral neuropathy., Methods: In seeking a central substrate for AUD-related neuropathy, the current study was conducted in 154 individuals with AUD (43 women, age 21 to 74 years) and 99 healthy controls (41 women, age 21 to 77 years) and explored subjective symptoms (self-report) and objective signs (perception of vibration, deep tendon ankle reflex, position sense, 2-point discrimination) of neuropathy separately. In addition to regional brain volumes, risk factors for AUD-related neuropathy, including age, sex, total lifetime ethanol consumed, nutritional indices (i.e., thiamine, folate), and measures of liver integrity (i.e., γ-glutamyltransferase), were evaluated., Results: The AUD group described more subjective symptoms of neuropathy and was more frequently impaired on bilateral perception of vibration. From 5 correlates, the number of AUD-related seizures was most significantly associated with subjective symptoms of neuropathy. There were 15 correlates of impaired perception of vibration among the AUD participants: Of these, age and volume of frontal precentral cortex were the most robust predictors., Conclusions: This study supports CNS involvement in objective signs of neuropathy in AUD., (© 2019 by the Research Society on Alcoholism.)

Sensory responses of the neocortex are strongly influenced by brain state changes. However, it remains unclear whether and how the sensory responses of the midbrain are affected. Here we addressed this issue by using in vivo two-photon calcium imaging to monitor the spontaneous and sound-evoked activities in the mouse inferior colliculus (IC). We developed a method enabling us to image the first layer of non-lemniscal IC (IC shell L1) in awake behaving mice. Compared with the awake state, spectral tuning selectivity of excitatory neurons was decreased during isoflurane anesthesia. Calcium imaging in behaving animals revealed that activities of inhibitory neurons were highly correlated with locomotion. Compared with stationary periods, spectral tuning selectivity of excitatory neurons was increased during locomotion. Taken together, our studies reveal that neuronal activities in the IC shell L1 are brain state dependent, whereas the brain state modulates the excitatory and inhibitory neurons differentially., Competing Interests: Competing interestsThe authors declare no competing interests., (© The Author(s) 2019.)

Rationale: Δ-9-Tetrahydrocannabinol (Δ-9-THC) produces psychotomimetic effects in humans. However, the role of dopamine signaling in producing such effects is unclear. We hypothesized that dopaminergic antagonism would reduce the psychotomimetic effect of Δ-9-THC., Objective: The objective of this study was to evaluate whether pre-treatment with haloperidol would alter the psychotomimetic and perceptual-altering effects of Δ-9-THC, measured by the Positive and Negative Syndrome Scale for Schizophrenia (PANSS) and the Clinician-Administered Dissociative Symptom Scale (CADSS) in humans., Methods: In a two-test-day double-blind study, 28 healthy individuals were administered with active (0.057 mg/kg) or placebo oral haloperidol, followed 90 and 215 min later by intravenous administration of active (0.0286 mg/kg) Δ-9-THC and placebo, respectively. This secondary analysis was conducted because of the observation in other studies and in our data that a significant proportion of individuals may not have an adequate response to THC (floor effect), thus limiting the ability to test an interaction. Therefore, this analysis was performed including only responders to THC (n = 10), defined as individuals who had an increase of at least one point on the PANSS positive scale, consistent with prior human laboratory studies., Results: In the 10 responders, Δ-9-THC-induced increases in PANSS positive scores were significantly lower in the haloperidol condition (1.1 + 0.35) compared with the placebo condition (2.9 + 0.92)., Conclusion: This responder analysis showed that haloperidol did reduce the psychotomimetic effect of Δ-9-THC, supporting the hypothesis that dopaminergic signaling may participate in the psychosis-like effects of cannabinoids.

Introduction and Aims: While the perceived risks of driving under the influence of cannabis (DUIC) have been a focus of recent drug-driving research, relevant concepts from the social cognition literature have rarely been applied to inform understanding of DUIC. This study aims to expand knowledge of perceived collision risk and social influences associated with DUIC and driving after other substance use., Design and Methods: Semi-structured interviews were conducted with 20 participants of a remedial program for impaired drivers. Thematic analysis began with two independent coders. Early discussion of emergent themes resulted in the identification of applicable social cognition concepts, resulting in selective coding and interpretation., Results: Many participants identified DUIC as less risky than driving under the influence of alcohol or other drugs. Mixed perceptions regarding the dangerousness of DUIC were expressed, with some participants denying increased collision risk except among novice cannabis users. Comparative optimism bias was also expressed by participants who perceived themselves as less likely than others to be involved in a collision when DUIC. In view of normative influence, friends were generally seen as more accepting of DUIC than family, and there were indications that the opinions of others who use cannabis were regarded as more credible than the opinions of those who do not use the drug., Discussion and Conclusions: Comparative optimism bias and normative influence may contribute to perceived risks associated with DUIC and may, therefore, be useful concepts to employ to increase the effectiveness of public health and road safety initiatives., (© 2019 Australasian Professional Society on Alcohol and other Drugs.)

Prescription stimulants are used to treat attention deficit hyperactivity disorder (ADHD). Psychostimulants are also used off-label by non-ADHD patients as performance-enhancing agents across academic, occupational, athletic, and social settings. Extensive work has focused on the reinforcing effects and abuse liability of psychostimulants, but understanding the mechanisms through which these agents regulate neural circuit functions that govern cognitive and sensorimotor processes to result in their performance-enhancing effects has received less attention. Optimal detection of sensory information within complex, dynamic environments is critical for appropriate decision making and executive actions. As such, overall performance enhancement may significantly rely on improvements in the processing of incoming sensory stimuli. Psychostimulants enhance catecholamine neurotransmission through the blockade of dopamine and norepinephrine (NE) reuptake transporters. The ascending locus coeruleus (LC)-NE system regulates behavioral state and modulates state dependent transmission of sensory signals. LC stimulation and local administration of NE to sensory processing areas of the brain can change the dynamics of both cellular and circuit activity in response to incoming sensory information. Here we explore the LC-NE system's neuromodulatory role in altering sensory signal processing as a plausible mechanism through which psychostimulant agents amplify physiological responses to important sensory stimuli as a component of their performance-enhancing effects in both ADHD patients and otherwise healthy individuals. We further consider sensory enhancement as a desirable outcome that has not previously been explored as an element of therapeutic efficacy, as well as added motivation for otherwise healthy individuals to engage in off-label self-administration of psychostimulant drugs., (Copyright © 2018. Published by Elsevier B.V.)

Purpose: This study investigated the effect of β-blockade on physiological and perceived exertion (RPE) responses during incremental treadmill exercise., Methods: Sixteen healthy participants (n = 8 men; age, 25.3 ± 4.6 yr) performed a maximal treadmill exercise test after ingestion of 100 mg metoprolol or placebo, with a double-blind, randomized, and counterbalanced design. Heart rate (HR), ventilatory, and gas exchange variables were measured continuously, and participants reported RPE at the end of each minute. Physiological and RPE responses during each condition were compared at the ventilatory threshold (VT), respiratory compensation point, and at maximal exercise using repeated-measures ANOVA. Linear regression modeled relationships between perceived exertion and physiological variables., Results: The HR and V˙O2 at the VT, respiratory compensation point, and maximal exercise were all significantly lower after β-blockade (P < 0.05). However, when standardized to within condition peak values, differences were no longer significant. The RPE associated with VT was higher after β-blockade (12.9 ± 1.0 vs 12.3 ± 1.2, P < 0.05) but lower at maximal exercise (19.1 ± 0.6 vs 19.4 ± 0.5, P < 0.05). Increases in RPE relative to HR were greater after β-blockade and remained significant when expressed relative to peak HR. There was no difference in the growth of the relationship between RPE and V˙O2 across conditions, although the origin of the relationship was higher with β-blockade., Conclusions: Although β-blockade resulted in a significant reduction in exercising HR and V˙O2, the RPE for a given relative intensity remained unchanged. The relationship between RPE and V˙O2 was not affected by β-blockade. The results provide evidence that RPE is a useful and reliable measure for exercise testing and prescription in patients prescribed β-blockade therapy.

Rationale: Microdosing psychedelics-the regular consumption of small amounts of psychedelic substances such as LSD or psilocybin-is a growing trend in popular culture. Recent studies on full-dose psychedelic psychotherapy reveal promising benefits for mental well-being, especially for depression and end-of-life anxiety. While full-dose therapies include perception-distorting properties, microdosing mayprovide complementary clinical benefits using lower-risk, non-hallucinogenic doses., Objectives: This pre-registered study aimed to investigate whether microdosing psychedelics is related to differences in personality, mental health, and creativity., Methods: In this observational study, respondents recruited from online forums self-reported their microdosing behaviors and completed questionnaires concerning dysfunctional attitudes, wisdom, negative emotionality, open-mindedness, and mood. Respondents also performed the Unusual Uses Task to assess their creativity., Results: Current and former microdosers scored lower on measures of dysfunctional attitudes (p < 0.001, r = - 0.92) and negative emotionality (p = 0.009, r = - 0.85) and higher on wisdom (p < 0.001, r = 0.88), openmindedness(p = 0.027, r = 0.67), and creativity (p < 0.001, r = 0.15) when compared to non-microdosing controls., Conclusions: These findings provide promising initial evidence that warrants controlled experimental research to directly test safety and clinical efficacy. As microdoses are easier to administer than full-doses, this new paradigm has the exciting potential to shape future psychedelic research.

Androsta-4,16,-dien-3-one and estra-1,3,5(10),16-tetraen-3-ol have previously been shown to communicate opposite sex information that is differently effective to the two sex groups. The current study critically examines if the two human steroids could facilitate interactions with potential mates rather than competitors by acting on the recipients' emotional perception in a sex-appropriate manner. Using dynamic point-light displays that portray the gaits of walkers whose emotional states are digitally morphed along the valence and the arousal axes, we show that smelling androstadienone subconsciously biases heterosexual women, but not men, towards perceiving the male, but not female, walkers as happier and more relaxed. By contrast, smelling estratetraenol subconsciously biases heterosexual men, but not women, towards perceiving the female, but not male, walkers as happier and more relaxed. These findings indicate that androstadienone and estratetraenol prime the identification of emotionally receptive states for the potential mates with whom they are associated, in manners contingent upon not only the recipients' own sex but also their sex perception of other individuals that ensure sex-appropriate behavior., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Vulnerability to obesity includes eating in response to food cues, which acquire incentive value through conditioning. The conditioning process is largely subserved by dopamine, theorized to encode the discrepancy between expected and actual rewards known as the reward prediction error (RPE). Ghrelin is a gut-derived homeostatic hormone that triggers hunger and eating. Despite extensive evidence that ghrelin stimulates dopamine, it remains unknown in humans whether ghrelin modulates food cue learning. Here, we show using fMRI that intravenously administered ghrelin increased RPE-related activity in dopamine-responsive areas during food odor conditioning in healthy volunteers. Participants responded faster to food odor-associated cues and perceived them to be more pleasant following ghrelin injection. Ghrelin also increased functional connectivity between the hippocampus and the ventral striatum. Our work demonstrates that ghrelin promotes the ability of food cues to acquire incentive salience and has implications for the development of vulnerability to obesity., (Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objective: To correlate the perceptions related to dietary intake with the domains and subscales of health-related quality of life (HRQL) in women with breast neoplasms receiving chemotherapy., Methods: In this prospective study, 55 women with breast cancer were followed up during chemotherapy at three different times (T0, T1, T2). Before chemotherapy, perceptions related to food consumption were evaluated. HRQL was analyzed with the EORTC QLQ-C30 and Br23 instruments 21 days after each investigated cycle. The differences (T2-T0) in the subscales and HRQL domains were correlated with the differences (T2-T0) in the appetite scores. Spearman's correlation was used to verify a possible correlation between differences in functional and overall HRQL domains (T2-T0) and differences in appetite scores for certain foods and between the differences in some subscales of EORTC QLQ-C30 and Br23 (T2-T0) and differences in appetite scores for certain food groups (T2-T0)., Results: Correlations between pain and appetite for bitter taste and between an increased appetite for juices and pain intensification or fatigue were identified, and pain was correlated with an appetite for starchy foods. An appetite for vegetables, legumes and meat/eggs was correlated with physical function. The only significant correlation with social functions occurred between the appetite for sweet foods and these functions. We found a correlation between overall health, emotional function, social function and physical function and the appetite for juices., Conclusion: Chemotherapy alters the individual's relationship with food and, consequently, the individual's HRQL.

Increasing evidence suggests that humans can communicate both trait-dominance and state-dominance via body odor. Androstadienone (androsta-4,16,-dien-3-one), a chemosignal found in human sweat, seems to be a likely candidate for signaling dominance in humans. The aim of the current study was to investigate the effects of androstadienone on the perception of social dominance. Moreover, we examined whether high levels of social anxiety, a psychopathology involving concerns that specifically pertain to social dominance, are associated with increased sensitivity to androstadienone as a chemical cue of dominance. In a double-blind, placebo-controlled, within-subject design, 64 heterosexual male participants (32 with high social anxiety and 32 with low social anxiety) viewed facial images of males depicting dominant, neutral and submissive postures, and were asked to recognize and rate the dominance expressed in those images. Participants completed the task twice, once under exposure to androstadienone and once under exposure to a control solution. The results indicate that androstadienone increased the perceived dominance of men's faces, specifically among participants with high social anxiety. These findings suggest a direct influence of androstadienone on dominance perception and further highlight the preferential processing of dominance and social threat signals evident in social anxiety., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Cannabis is commonly used to alleviate symptoms of negative affect. However, a paucity of research has examined the acute effects of cannabis on negative affect in everyday life. The current study provides a naturalistic account of perceived changes in symptoms of depression, anxiety, and stress as a function of dose and concentration of Δ 9 tetrahydrocannabinol (THC) and cannabidiol (CBD)., Method: Data from the app Strainprint TM (which provides medical cannabis users a means of tracking changes in symptoms as a function of different doses and chemotypes of cannabis) were analyzed using multilevel modeling. In total, 11,953 tracked sessions were analyzed (3,151 for depression, 5,085 for anxiety, and 3,717 for stress)., Results: Medical cannabis users perceived a 50% reduction in depression and a 58% reduction in anxiety and stress following cannabis use. Two puffs were sufficient to reduce ratings of depression and anxiety, while 10+ puffs produced the greatest perceived reductions in stress. High CBD (>9.5%)/low THC (<5.5%) cannabis was associated with the largest changes in depression ratings, while high CBD (>11%)/high THC (>26.5%) cannabis produced the largest perceived changes in stress. No changes in the perceived efficacy of cannabis were detected across time. However, baseline symptoms of depression (but not anxiety or stress) appeared to be exacerbated across time/tracked sessions., Limitations: The primary limitations are the self-selected nature of the sample and the inability to control for expectancy effects., Conclusions: Cannabis reduces perceived symptoms of negative affect in the short-term, but continued use may exacerbate baseline symptoms of depression over time., (Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Studying the effects of anaesthetic drugs on the processing of semantic stimuli could yield insights into how brain functions change in the transition from wakefulness to unresponsiveness. Here, we explored the N400 event-related potential during dexmedetomidine- and propofol-induced unresponsiveness., Methods: Forty-seven healthy subjects were randomised to receive either dexmedetomidine (n=23) or propofol (n=24) in this open-label parallel-group study. Loss of responsiveness was achieved by stepwise increments of pseudo-steady-state plasma concentrations, and presumed loss of consciousness was induced using 1.5 times the concentration required for loss of responsiveness. Pre-recorded spoken sentences ending either with an expected (congruous) or an unexpected (incongruous) word were presented during unresponsiveness. The resulting electroencephalogram data were analysed for the presence of the N400 component, and for the N400 effect defined as the difference between the N400 components elicited by congruous and incongruous stimuli, in the time window 300-600 ms post-stimulus. Recognition of the presented stimuli was tested after recovery of responsiveness., Results: The N400 effect was not observed during dexmedetomidine- or propofol-induced unresponsiveness. The N400 component, however, persisted during dexmedetomidine administration. The N400 component elicited by congruous stimuli during unresponsiveness in the dexmedetomidine group resembled the large component evoked by incongruous stimuli at the awake baseline. After recovery, no recognition of the stimuli heard during unresponsiveness occurred., Conclusions: Dexmedetomidine and propofol disrupt the discrimination of congruous and incongruous spoken sentences, and recognition memory at loss of responsiveness. However, the processing of words is partially preserved during dexmedetomidine-induced unresponsiveness., Clinical Trial Registration: NCT01889004., (Copyright © 2018 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

The μ-opioid system modulates responses to pain and psychosocial stress and mediates non-social and social reward. In humans, the μ-opioid agonist morphine can increase overt attention to the eye-region and visual exploration of faces with neutral expressions. However, little is known about how the human μ-opioid system influences sensitivity to and appraisal of subtle and explicit cues of social threats and reward. Here, we examined the effects of selective μ-opioid stimulation on perception of anger and happiness in faces with explicit, neutral or implicit emotion expressions. Sixty-three healthy adults (32 females) attended two sessions where they received either placebo or 10 mg per oral morphine in randomised order under double-blind conditions. Based on the known μ-opioid reduction of pain and discomfort, as well as reports suggesting that the non-specific partial agonist buprenorphine or the non-specific antagonist naltrexone affect appraisal of social emotional stimuli, we hypothesised that morphine would reduce threat sensitivity and enhance perception of happy facial expressions. While overall perception of others' happiness was unaffected by morphine treatment, morphine reduced perception of anger in stimuli with neutral and implicit expressions without affecting perception of explicit anger. This effect was statistically unrelated to gender, subjective drug effects, mood and autism trait measures. The finding that a low dose of μ-agonist reduced the propensity to perceive anger in photos with subtle facial expressions is consistent with the notion that μ-opioids mediate social confidence and reduce sensitivity to threat cues., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Itch is an unpleasant sensation that evokes behavioral responses such as scratching the skin. Interestingly, it is conceived that the perception of itch sensation is influenced by age. Indeed, accumulating evidence supports the idea that even children or younger adults show distinctive itch sensation depending on age. This evidence implies the presence of a mechanism that regulates the perception of itch sensation in an age-dependent fashion. Therefore, the purpose of the present study was to investigate a putative mechanism for the age-dependent perception of itch sensation by comparing histamine-induced scratching behaviors in 45-day old (D45) and 75-day old male "young adult" mice. The results indicated that, following histamine administration, the D75 mice spent a longer time scratching than D45 mice. However, the intensity of the calcium influx induced by histamine in primary culture of dorsal root ganglia (DRG) neurons was not different between D45 and D75 mice. Moreover, no apparent difference was observed in mRNA levels of a characteristic His-related receptor and ion channel. In contrast, the mRNA levels of Toll-Like Receptor 4 (TLR4) were increased approximately by two-fold in D75 DRG compared with D45 DRG. Additionally, D75-derived DRG neurons exhibited enhanced intracellular calcium increase by lipopolysaccharide (LPS, a TLR4 agonist) than those of D45 mice. Furthermore, intensities of calcium influx induced by histamine were significantly potentiated when co-treated with LPS in D75 DRG neurons, but not in those of D45 mice. Thus, it appears that D75 mice showed enhanced histamine-induced scratching behaviors not by increased expression levels of histamine-related genes, but probably due to augmented TLR4 expression in DRG neurons. Consequently, the current study found that different perception levels of histamine-induced itch sensation are present in different age groups of young adult mice., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Virtual Reality (VR) is used for a variety of applications ranging from entertainment to psychological medicine. VR has been demonstrated to influence higher order cognitive functions and cortical plasticity, with implications on phobia and stroke treatment. An integral part for successful VR is a high sense of presence - a feeling of 'being there' in the virtual scenario. The underlying cognitive and perceptive functions causing presence in VR scenarios are however not completely known. It is evident that the brain function is influenced by drugs, such as ethanol, potentially confounding cortical plasticity, also in VR. As ethanol is ubiquitous and forms part of daily life, understanding the effects of ethanol on presence and user experience, the attitudes and emotions about using VR applications, is important. This exploratory study aims at contributing towards an understanding of how low-dose ethanol intake influences presence, user experience and their relationship in a validated VR context. It was found that low-level ethanol consumption did influence presence and user experience, but on a minimal level. In contrast, correlations between presence and user experience were strongly influenced by low-dose ethanol. Ethanol consumption may consequently alter cognitive and perceptive functions related to the connections between presence and user experience.

Aims: Little is known about features of e-cigarettes (EC) that facilitate or hinder the switch from smoking to vaping. We tested eight brands of EC to determine how nicotine delivery and other product characteristics influence user's initial reactions., Methods: Fifteen vapers tested each product after overnight abstinence from both smoking and vaping. At each session, participant's vaped ad lib for 5 min. Blood samples were taken at baseline and at 2, 4, 6, 8, 10 and 30 min after starting vaping. Participants rated the products on a range of characteristics. The products tested included six 'cig-a-like' and two refillable products, one with variable voltage. We also tested participants' own EC., Results: All products significantly reduced urges to smoke. Refillable products delivered more nicotine and received generally superior ratings in terms of craving relief, subjective nicotine delivery, throat hit and vapour production but in overall ratings, they were joined by a cig-a-like, Blu. Participants puffed more on low nicotine delivery products. Participants' estimates of nicotine delivery from different EC were closely linked to 'throat hit'. Nicotine delivery was less important in the initial product ratings than draw resistance, mouthpiece comfort and effects on reducing urge to smoke., Conclusions: All EC products reduced urges to smoke. Refillable products received generally more favourable ratings than 'cig-a-likes' with similar nicotine content. Perception of nicotine delivery was guided by throat sensations. Lower nicotine delivery was associated with more frequent puffing. The first impressions of EC products are guided less by nicotine delivery than by sensory signals.

Introduction: It is well established that some individuals self-medicate their anxiety with alcohol. Though much evidence exists that alcohol consumption can be negatively reinforcing, there remains uncertainty regarding what mediates the relationship between alcohol and anxiety. An unexplored possibility is that, for some, alcohol impairs interoceptive sensitivity (the ability to accurately perceive one's physiological state), thereby decreasing state anxiety. Consistent with this, highly accurate heartbeat perception is a risk factor both for elevated trait anxiety and anxiety disorders. However, the direct impact of alcohol on cardioceptive accuracy has not to our knowledge been previously examined., Methods: Sixty-one social drinkers came to the lab in groups of 4-6 on two days spaced a week apart. Each participant was randomly assigned to receive alcoholic drinks targeting a BAC of 0.05% on one testing day and placebo drinks on the other, with the order counter-balanced. On both testing days, participants engaged in a Schandry heartbeat perception task on three occasions: at baseline, after an alcohol absorption period, and after physiological arousal was raised via exercise., Results: For men only, alcohol significantly impaired cardioceptive accuracy relative to a placebo at both low and high levels of arousal, with medium to large effect sizes., Conclusions: Though preliminary, this finding is consistent with the proposed hypothesis linking alcohol consumption and anxiety, at least for men. Future studies should directly examine whether, among individuals with anxiety disorders, cardioceptive sensitivity mediates the relationship between alcohol consumption and state anxiety., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Subjective perceptions and self-administration of cigarettes are each influenced by nicotine. Yet, differences specifically due to menthol in perceptions and choice of cigarettes varying in nicotine, and the association between these responses, have not been directly tested. Using a mixed between- and within-subjects design, acute responses to each of two menthol or non-menthol Spectrum research cigarettes, moderate (16-17 mg/g) versus very low (0.4 mg/g) in nicotine contents, were compared following brief abstinence in adult smokers preferring menthol ( n=44) or non-menthol ( n=29) brands. To ensure reliable perceptions, they experienced five exposures to each cigarette, then chose between them. All perceptions and choices were greater for moderate vs very low nicotine, as expected, and the magnitude of difference in four of six perceptions was associated with subsequently greater choice of the moderate nicotine cigarette. Importantly, virtually no differences were found between menthol and non-menthol, as nearly all perceptions, cigarette choices, and the association between perceptions and choice were not moderated by menthol or the interaction of nicotine by menthol. Our results indicate perceptions and reinforcement from cigarettes do not differ due to menthol when nicotine content and smoking topography are carefully controlled. Thus, regardless of menthol, smoking perceptions directly predict self-administration behavior.

Classic serotonergic hallucinogens or psychedelics produce an altered states of consciousness (ASC) that is characterized by profound alterations in sensory perception, mood, thought including the perception of reality, and the sense of self. Over the past years, there has been considerable progress in the search for invariant and common features of psychedelic states. In the first part of this review, we outline contemporary approaches to characterize the structure of ASCs by means of three primary etiology-independent dimensions including oceanic boundlessness, anxious ego-dissolution, and visionary restructuralization as well as by 11 lower-order factors, all of which can be reliably measured by the altered state of consciousness questionnaire (APZ-OAV). The second part sheds light on the dynamic nature of psychedelic experiences. Frequently, psychedelic subjects progress through different stages over time and levels of changes along a perception-hallucination continuum of increasing arousal and ego-dissolution. We then review in detail the acute effects of psychedelics on sensory perception, emotion, cognition, creativity, and time perception along with possible neural mechanisms underlying them. The next part of this review outlines the influence of non-pharmacological factors (predictors) on the acute psychedelic experience, such as demographics, genetics, personality, mood, and setting, and also discusses some long-term effects succeeding the acute experience. The last part presents some recent concepts and models attempting to understand different facets of psychedelic states of consciousness from a neuroscientific perspective.

Purpose: Although existing evidence indicates that e-cigarette use is a risk factor for cigarette smoking initiation, mechanisms of this association are not yet known. E-cigarette users perceive e-cigarette use to be less harmful relative to conventional cigarettes, but their absolute perceptions of addictiveness of conventional cigarette smoking are unknown. This study examines how e-cigarette users compare with nonusers (non-e-cigarette users/nonconventional cigarette smokers), conventional cigarette smokers, and dual users on perceptions of harm and the addictiveness of conventional cigarette smoking and on other known predictors of cigarette smoking such as peer smoking, influence of antismoking ads, and risk-taking propensity., Methods: National samples of 8th- and 10th-grade students from 2014 and 2015 (N = 14,151) were obtained from the Monitoring the Future Study. Multivariate logistic regression models were used to examine relationships between adolescent smoking status and perceptions of harm and the addictiveness of conventional cigarette smoking while controlling for potential confounders., Results: E-cigarette users had lower perceptions of the addictiveness of conventional cigarette smoking compared with nonusers but higher than cigarette smokers and dual users. E-cigarette users reported lower influence by antismoking ads, more conventional cigarette-smoking peers, and greater risk-taking propensity than nonusers. E-cigarette users and cigarette smokers did not differ in their perceived harm of conventional cigarette smoking or in their risk-taking propensity., Conclusions: E-cigarette users' attitudes and perceptions regarding conventional cigarette smoking may leave them vulnerable to becoming conventional cigarette smokers. Future studies should explore the prospective relationship between smoking-related perceptions of conventional cigarette smoking among e-cigarette users and the onset of cigarette smoking., (Copyright © 2017 The Society for Adolescent Health and Medicine. Published by Elsevier Inc. All rights reserved.)

Background: Iron deficiency and iron deficiency anemia have been shown to have negative effects on aspects of perception, attention, and memory. Objective: The purpose of this investigation was to assess the extent to which increases in dietary iron consumption are related to improvements in behavioral measures of perceptual, attentional, and mnemonic function. Methods: Women were selected from a randomized, double-blind, controlled food-fortification trial involving ad libitum consumption of either a double-fortified salt (DFS) containing 47 mg potassium iodate/kg and 3.3 mg microencapsulated ferrous fumarate/g (1.1 mg elemental Fe/g) or a control iodized salt. Participants' blood iron status (primary outcomes) and cognitive functioning (secondary outcomes) were assessed at baseline and after 10 mo at endline. The study was performed on a tea plantation in the Darjeeling district of India. Participants ( n = 126; 66% iron deficient and 49% anemic at baseline) were otherwise healthy women of reproductive age, 18-55 y. Results: Significant improvements were documented for iron status and for perceptual, attentional, and mnemonic function in the DFS group (percentage of variance accounted for: 16.5%) compared with the control group. In addition, the amount of change in perceptual and cognitive performance was significantly ( P < 0.05) related to the amount of change in blood iron markers (mean percentage of variance accounted for: 16.0%) and baseline concentrations of blood iron markers (mean percentage of variance accounted for: 25.0%). Overall, there was evidence that the strongest effects of change in iron status were obtained for perceptual and low-level attentional function. Conclusion: DFS produced measurable and significant improvements in the perceptual, attentional, and mnemonic performance of Indian female tea pickers of reproductive age. This trial was registered at clinicaltrials.gov as NCT01032005., Competing Interests: Author disclosures: MJW, LEM-K, JEHN, SV, and JDH, no conflicts of interest. GAR was previously affiliated with the Mathile Institute, which provided funding for this work. AW is associated with Nutrition International (formerly Micronutrient Initiative), which provided support for the study., (© 2017 American Society for Nutrition.)

Drug addiction has been associated with lack of insight into one's own abilities. However, the scope of metacognition impairment among drug users in general and opiate dependent individuals in particular is not fully understood. Investigating the impairments of metacognitive ability in Substance Dependent Individuals (SDIs) in different cognitive tasks could contribute to the ongoing debate over whether metacognition has domain-general or domain-specific neural substrates. We compared metacognitive self-monitoring ability of a group of SDIs during methadone maintenance treatment (n = 23) with a control group (n = 24) in a memory and a visual perceptual task. Post decision self judgements of probability of correct choice were obtained through trial by trial confidence ratings and were used to compute metacognitive ability. Results showed that despite comparable first order performance in the perceptual task, SDIs had lower perceptual metacognition than the control group. However, although SDIs had poorer memory performance, their metacognitive judgements in the memory task were as accurate as the control group. While it is commonly believed that addiction causes pervasive impairment in cognitive functions, including metacognitive ability, we observed that the impairment was only significant in one specific task, the perceptual task, but not in the memory task.

The endocannabinoid system is thought to modulate nociceptive signaling making it a potential therapeutic target for treating pain. However, there is evidence that endocannabinoids have both pro- and anti-nociceptive effects. In previous studies using Hirudo verbana (the medicinal leech), endocannabinoids were found to depress nociceptive synapses, but enhance non-nociceptive synapses. Here we examined whether endocannabinoids have similar bidirectional effects on behavioral responses to nociceptive vs. non-nociceptive stimuli in vivo. Hirudo were injected with either the 2-arachidonoylglycerol (2-AG) or anandamide and tested for changes in response to nociceptive and non-nociceptive stimuli. Both endocannabinoids enhanced responses to non-nociceptive stimuli and reduced responses to nociceptive stimuli. These pro- and anti-nociceptive effects were blocked by co-injection of a TRPV channel inhibitor, which are thought to function as an endocannabinoid receptor. In experiments to determine the effects of endocannabinoids on animals that had undergone injury-induced sensitization, 2-AG and anandamide diminished sensitization to nociceptive stimuli although the effects of 2-AG were longer lasting. Sensitized responses to non-nociceptive stimuli were unaffected 2-AG or anandamide. These results provide evidence that endocannabinoids can have opposing effects on nociceptive vs. non-nociceptive pathways and suggest that cannabinoid-based therapies may be more appropriate for treating pain disorders in which hyperalgesia and not allodynia is the primary symptom.

Purpose: The study investigated the effect of a non-thermal cooling agent, L-menthol, on exercise at a fixed subjective rating of perceived exertion (RPE) in a hot environment., Method: Eight male participants completed two trials at an exercise intensity between 'hard' and 'very hard', equating to 16 on the RPE scale at ~35 °C. Participants were instructed to continually adjust their power output to maintain an RPE of 16 throughout the exercise trial, stopping once power output had fallen by 30%. In a randomized crossover design, either L-menthol or placebo mouthwash was administered prior to exercise and at 10 min intervals. Power output, [Formula: see text]O 2 , heart rate, core and skin temperature was monitored, alongside thermal sensation and thermal comfort. Isokinetic peak power sprints were conducted prior to and immediately after the fixed RPE trial., Results: Exercise time was greater (23:23 ± 3:36 vs. 21:44 ± 2:32 min; P = 0.049) and average power output increased (173 ± 24 vs. 167 ± 24 W; P = 0.044) in the L-menthol condition. Peak isokinetic sprint power declined from pre-post trial in the L-menthol l (9.0%; P = 0.015) but not in the placebo condition (3.4%; P = 0.275). Thermal sensation was lower in the L-menthol condition (P = 0.036), despite no changes in skin or core temperature (P > 0.05)., Conclusion: These results indicate that a non-thermal cooling mouth rinse lowered thermal sensation, resulting in an elevated work rate, which extended exercise time in the heat at a fixed RPE.

Aims: To study bladder sensation during a forced diuresis protocol and to assess differences in sensation perceived by different ethnic groups and after drinking artificially sweetened water., Methods: Female Caucasian and south Indian Asian volunteers performed the diuresis protocol drinking water, or water sweetened with saccharin (5 mg/kg body weight). Participants recorded filling sensation every 5 min while drinking 250-350 mL/15 min. They were asked to record the strongest sensation before voiding as maximum sensation, before voiding. The void was measured and sensation immediately recorded as minimum. The process was repeated. Voided volume and time required to achieve maximum sensation during cycle 2 were compared by water and sweetener, ethnic group, and age., Results: Twenty Asian and 20 Caucasian volunteers participated. No differences in maximum voided volume or diuresis rate was seen by ethnicity. Median diuresis with sweetener was 16.7 mL/min (8.6-35) compared to 13.2 (7.1-25) with water (P = 0.008), a difference accounted for by 16 women with >5 mL/min difference in diuresis rate. These were excluded to leave 24 women with similar diuresis rates with both sweetener and water (14.8 mL/min (8.6-28.0) and 13.2 mL/min (7.1-25.0). In these women, time to achieve maximum sensation was lower with sweetener than water: 37.5 min (20-85) versus 50.0 min (20-80), P = 0.002, with no difference in voided volume., Conclusions: Water sweetened with saccharin produced an increased diuresis rate in some women. After controlling for this, time to recording maximum sensation was decreased with sweetened water, suggesting saccharin has an effect upon perceived sensation., (© 2016 Wiley Periodicals, Inc.)

The Rorschach-based Perceptual Thinking Index (PTI) is used to identify and rate features of psychotic disorders, but effects of antipsychotic treatment on such ratings is not clear. Accordingly, we examined potential effects of antipsychotic drugs on PTI measures in 114 patients with a psychotic or bipolar-I disorder. Use and doses of antipsychotic drugs (as chlorpromazine-equivalent [CPZ-eq] mg/day) were unrelated to PTI total or subscale scores in any diagnostic group. PTI scores were independently and significantly associated with psychotic symptomatic severity (PANSS score) and less with female sex. These findings support the validity and value of the PTI in identifying features of psychosis even in the presence of antipsychotic treatment., (Copyright © 2017 Elsevier Ireland Ltd. All rights reserved.)

Lysergic acid diethylamide (LSD) induces profound changes in various mental domains, including perception, self-awareness and emotions. We used functional magnetic resonance imaging (fMRI) to investigate the acute effects of LSD on the neural substrate of emotional processing in humans. Using a double-blind, randomised, cross-over study design, placebo or 100 μg LSD were orally administered to 20 healthy subjects before the fMRI scan, taking into account the subjective and pharmacological peak effects of LSD. The plasma levels of LSD were determined immediately before and after the scan. The study (including the a priori-defined study end point) was registered at ClinicalTrials.gov before study start (NCT02308969). The administration of LSD reduced reactivity of the left amygdala and the right medial prefrontal cortex relative to placebo during the presentation of fearful faces (P<0.05, family-wise error). Notably, there was a significant negative correlation between LSD-induced amygdala response to fearful stimuli and the LSD-induced subjective drug effects (P<0.05). These data suggest that acute administration of LSD modulates the engagement of brain regions that mediate emotional processing.

Caldwell, AR, Tucker, MA, Butts, CL, McDermott, BP, Vingren, JL, Kunces, LJ, Lee, EC, Munoz, CX, Williamson, KH, Armstrong, LE, and Ganio, MS. Effect of caffeine on perceived soreness and functionality following an endurance cycling event. J Strength Cond Res 31(3): 638-643, 2017-Caffeine can reduce muscle pain during exercise; however, the efficacy of caffeine in improving muscle soreness and recovery from a demanding long-duration exercise bout has not been established. The purpose of this study was to investigate the effects of caffeine intake on ratings of perceived muscle soreness (RPMS) and perceived lower extremity functionality (LEF) following the completion of a 164-km endurance cycling event. Before and after cycling RPMS (1-to-6; 6 = severe soreness) and LEF (0-to-80; 80 = full functionality) were assessed by questionnaires. Subjects ingested 3 mg/kg body mass of caffeine or placebo pills in a randomized, double-blind fashion immediately after the ride and for the next 4 mornings (i.e., ∼800 hours) and 3 afternoons (i.e., ∼1200 hours). Before each ingestion, RPMS and LEF were assessed. Afternoon ratings of LEF were greater with caffeine ingestion the first day postride (65.0 ± 6.1 vs. 72.3 ± 6.7; for placebo and caffeine, respectively; p = 0.04), but at no other time points (p > 0.05). The caffeine group tended to have lower overall RPMS in the afternoon versus placebo (i.e., main effect of group; 1.1 ± 0.2 vs. 0.5 ± 0.2; p = 0.09). Afternoon RPMS for the legs was significantly lower in the caffeine group (main effect of caffeine; 1.3 ± 0.2 vs. 0.5 ± 0.3; p = 0.05). In conclusion, ingesting caffeine improved RPMS for the legs, but not LEF in the days following an endurance cycling event. Athletes may benefit from ingesting caffeine in the days following an arduous exercise bout to relieve feelings of soreness and reduced functionality.

Study Objectives: During abstinence, chronic cocaine users experience an objective worsening of sleep that is perceived as qualitatively improving. This phenomenon has been termed "occult insomnia." The objective of this study was to determine whether chronic cocaine users experience positive sleep state misperception during abstinence., Methods: Forty-three cocaine-dependent persons were admitted to an inpatient research facility for 12 days and 11 nights to participate in a treatment study of modafinil. Polysomnographic sleep recordings were performed on study nights 3, 4, 10, and 11, when participants were on average 1 and 2 weeks abstinent from cocaine. Participants also completed sleep diary questionnaires every evening before bed and every morning upon awakening. Polysomnographic and sleep diary measurements of total sleep time, sleep latency, time awake after sleep onset, and time in bed after final awakening were compared., Results: Chronic cocaine users accurately reported total sleep time after 1 week of abstinence but overreported total sleep time by an average of 40 min after 2 weeks of abstinence. Underestimating sleep latency and time spent awake after sleep onset were responsible for this difference., Conclusions: Positive sleep state misperception is revealed in chronic cocaine users after 2 weeks of abstinence and is consistent with the previously identified "occult insomnia" in this population., (© Sleep Research Society 2016. Published by Oxford University Press on behalf of the Sleep Research Society. All rights reserved. For permissions, please e-mail journals.permissions@oup.com.)

Despite the well-known neuropsychiatric side effects of dopaminergic medications, the possible subjective psychotomimetic effects of a single dose of L-DOPA in newly diagnosed, drug-naïve patients with Parkinson's disease (PD) are not known. To investigate this question, we used a visual search task for latent inhibition (LI), the Community Assessment of Psychic Experiences (CAPE) scale, and visual analog scales for psychotomimetic effects (perception, relaxation, and dysphoria) in 28 de novo PD patients before (off) and after (on) the adminstration of L-DOPA and in 25 matched healthy control individuals. Results revealed increased LI in PD-off and decreased LI in PD-on relative to the control subjects. After the administration of L-DOPA, we observed a significant decline in LI in PD. L-DOPA also enhanced perceptual experiences (changes in subjective feelings in thinking, time perception, and mental "highness"). Greater reduction in LI was associated with enhanced perceptual experiences. These results suggest that a single dose of L-DOPA has a significant psychotomimetic effect, which is associated with decreased LI, a behavioral marker of psychosis-like experiences.

4-Methyl-N-methylcathinone (mephedrone) is a popular new psychoactive substance (NPS) that is structurally related to the parent compound cathinone, the β-keto analogue of amphetamine. Mephedrone appeared on the street drug market as a substitute for 3,4-methylenedioxy-N-methylamphetamine (MDMA, ecstasy) and was subsequently banned due to the potential health risks associated with its use. Nevertheless, mephedrone continues to be widely consumed among specific populations, with unique patterns of misuse. To date, most information about the biological effects of mephedrone comes from user experiences, epidemiological data, clinical cases, toxicological findings, and animal studies, whilst there are very few data regarding its human pharmacodynamics and pharmacokinetics. This chapter reviews the available published data on patterns of mephedrone use, its acute and chronic effects, and its pharmacokinetic properties. More human research is needed to elucidate the safety, toxicity, and addiction potential of mephedrone and related NPS.