scholarly journals Changes in global and thalamic brain connectivity in LSD-induced altered states of consciousness are attributable to the 5-HT2A receptor

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Katrin H Preller ◽  
Joshua B Burt ◽  
Jie Lisa Ji ◽  
Charles H Schleifer ◽  
Brendan D Adkinson ◽  
...  
Keyword(s):  
Gene Expression ◽  
Clinical Trial ◽  
Brain Connectivity ◽  
Critical Role ◽  
Resting State Functional Connectivity ◽  
Healthy Human ◽  
Double Blind ◽  
Trial Number ◽  
Rational Development ◽  
Human Participants

Background:Lysergic acid diethylamide (LSD) has agonist activity at various serotonin (5-HT) and dopamine receptors. Despite the therapeutic and scientific interest in LSD, specific receptor contributions to its neurobiological effects remain unknown.Methods:We therefore conducted a double-blind, randomized, counterbalanced, cross-over studyduring which 24 healthy human participants received either (i) placebo+placebo, (ii) placebo+LSD (100 µg po), or (iii) Ketanserin, a selective 5-HT2A receptor antagonist,+LSD. We quantified resting-state functional connectivity via a data-driven global brain connectivity method and compared it to cortical gene expression maps.Results:LSD reduced associative, but concurrently increased sensory-somatomotor brain-wide and thalamic connectivity. Ketanserin fully blocked the subjective and neural LSD effects. Whole-brain spatial patterns of LSD effects matched 5-HT2A receptor cortical gene expression in humans.Conclusions:Together, these results strongly implicate the 5-HT2A receptor in LSD’s neuropharmacology. This study therefore pinpoints the critical role of 5-HT2A in LSD’s mechanism, which informs its neurobiology and guides rational development of psychedelic-based therapeutics.Funding:Funded by the Swiss National Science Foundation, the Swiss Neuromatrix Foundation, the Usona Institute, the NIH, the NIAA, the NARSAD Independent Investigator Grant, the Yale CTSA grant, and the Slovenian Research Agency.Clinical trial number:NCT02451072.

scholarly journals Changes in global brain connectivity in LSD-induced altered states of consciousness are attributable to the 5-HT2A receptor

2017 ◽  
Author(s):  
Katrin H. Preller ◽  
Joshua B. Burt ◽  
Jie Lisa Ji ◽  
Charles Schleifer ◽  
Brendan Adkinson ◽  
...  
Keyword(s):  
Receptor Antagonist ◽  
Resting State ◽  
Brain Connectivity ◽  
Subjective Effects ◽  
Critical Role ◽  
Resting State Fmri ◽  
Data Driven ◽  
Resting State Functional Connectivity ◽  
Double Blind ◽  
Global Brain

ABSTRACTLysergic acid diethylamide (LSD) is a psychedelic drug with predominantly agonist activity at various serotonin (5-HT) and dopamine receptors. Despite the therapeutic and scientific interest in LSD, the specific receptor contributions to its neurobiological effects remain largely unknown. To address this knowledge gap, we conducted a double-blind, randomized, counterbalanced, cross-over study during which 24 healthy participants received either i) placebo+placebo, ii) placebo+LSD (100 μg po), or iii) ketanserin – a selective 5-HT2A receptor antagonist. Here we focus on resting-state fMRI, a measure of spontaneous neural fluctuations that can map functional brain connectivity. We collected resting-state data 75 and 300 minutes after LSD/placebo administration. We quantified resting-state functional connectivity via a fully data-driven global brain connectivity (GBC) method to comprehensively map LSD neuropharmacological effects. LSD administration caused widespread GBC alterations that followed a specific topography: LSD reduced connectivity in associative areas, but concurrently increased connectivity across sensory and somatomotor areas. The 5-HT2A receptor antagonist, ketanserin, fully blocked the subjective and neural LSD effects. We show that whole-brain data-driven spatial patterns of LSD effects matched 5-HT2A receptor cortical gene expression in humans, which along with ketanserin effects, strongly implicates the 5-HT2A receptor in LSD’s neuropharmacology. Critically, the LSD-induced subjective effects were associated with somatomotor networks GBC changes. These data-driven neuropharmacological results pinpoint the critical role of 5-HT2A in LSD’s mechanism, which informs its neurobiology and guides rational development of psychedelic-based therapeutics

Error-related Persistence of Motor Activity in Resting-state Networks

2018 ◽  
Vol 30 (12) ◽  
pp. 1883-1901 ◽  
Author(s):  
Nicolò F. Bernardi ◽  
Floris T. Van Vugt ◽  
Ricardo Ruy Valle-Mena ◽  
Shahabeddin Vahdat ◽  
David J. Ostry
Keyword(s):  
Motor Learning ◽  
Resting State ◽  
Brain Connectivity ◽  
Brain Activity ◽  
Brain Networks ◽  
Neural Activation ◽  
Resting State Functional Connectivity ◽  
Movement Training ◽  
Movement Error ◽  
Human Participants

The relationship between neural activation during movement training and the plastic changes that survive beyond movement execution is not well understood. Here we ask whether the changes in resting-state functional connectivity observed following motor learning overlap with the brain networks that track movement error during training. Human participants learned to trace an arched trajectory using a computer mouse in an MRI scanner. Motor performance was quantified on each trial as the maximum distance from the prescribed arc. During learning, two brain networks were observed, one showing increased activations for larger movement error, comprising the cerebellum, parietal, visual, somatosensory, and cortical motor areas, and the other being more activated for movements with lower error, comprising the ventral putamen and the OFC. After learning, changes in brain connectivity at rest were found predominantly in areas that had shown increased activation for larger error during task, specifically the cerebellum and its connections with motor, visual, and somatosensory cortex. The findings indicate that, although both errors and accurate movements are important during the active stage of motor learning, the changes in brain activity observed at rest primarily reflect networks that process errors. This suggests that error-related networks are represented in the initial stages of motor memory formation.

scholarly journals An Oral SARS-CoV-2 Mpro Inhibitor Clinical Candidate for the Treatment of COVID-19

2021 ◽  
Author(s):  
Dafydd R Owen ◽  
Charlotte M N Allerton ◽  
Annaliesa S Anderson ◽  
Lisa Aschenbrenner ◽  
Melissa Avery ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Plasma Concentrations ◽  
Healthy Human ◽  
Clinical Trial Registration ◽  
Global Pandemic ◽  
Main Protease ◽  
Orally Bioavailable ◽  
Human Participants

The worldwide outbreak of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become an established global pandemic. Alongside vaccines, antiviral therapeutics are an important part of the healthcare response to counter the ongoing threat presented by COVID-19. Here, we report the discovery and characterization of PF-07321332, an orally bioavailable SARS-CoV-2 main protease inhibitor with in vitro pan-human coronavirus antiviral activity, and excellent off-target selectivity and in vivo safety profiles. PF-07321332 has demonstrated oral activity in a mouse-adapted SARS-CoV-2 model and has achieved oral plasma concentrations exceeding the in vitro antiviral cell potency, in a phase I clinical trial in healthy human participants. Clinical Trial Registration ID #: NCT04756531

scholarly journals (Lack of) Effects of noradrenergic stimulation on human working memory performance

2020 ◽  
Vol 237 (10) ◽  
pp. 3033-3046
Author(s):  
Nadine Wanke ◽  
Jana Christina Müller ◽  
Klaus Wiedemann ◽  
Lars Schwabe
Keyword(s):  
Working Memory ◽  
Spatial Working Memory ◽  
Memory Performance ◽  
Interactive Effect ◽  
Control Group ◽  
Healthy Human ◽  
Double Blind ◽  
Healthy Humans ◽  
Before And After ◽  
Human Participants

Abstract Rationale Working memory depends on prefrontal cortex functioning, which is particularly sensitive to levels of noradrenaline. Studies in non-human primates have shown that modest levels of noradrenaline improve working memory, and that higher levels of noradrenaline impair working memory performance. However, research in humans provided inconsistent findings concerning noradrenergic effects on working memory. Objective The present study aimed at assessing dose-dependent effects of yohimbine, an alpha-2 adrenoceptor antagonist, on working memory performance in healthy humans. We further aimed to explore a potential interactive effect between noradrenergic arousal and lack of control over aversive events on working memory performance. Methods We used a double-blind, fully crossed, placebo-controlled, between-subject design. Participants (N = 121) performed an adaptive n-back task before and after oral administration of either a placebo, 20 mg, or 40 mg yohimbine and a manipulation of controllability, during which participants could either learn to avoid electric shocks (controllability groups), had no instrumental control over shock administration (uncontrollability groups), or did not receive any shocks (no-shock control group). Results While no significant results of noradrenergic stimulation through yohimbine were obtained using conventional frequentist analyses, additional Bayesian analyses provided strong evidence for the absence of an association between pharmacological treatment and working memory performance. We further observed no effect of controllability and no interaction between noradrenergic stimulation and the manipulation of controllability. Conclusions Our results suggest that noradrenergic stimulation through yohimbine does not affect (non-spatial) working memory in healthy human participants.

scholarly journals Disassociation of Vitamin D’s Calcemic Activity and Non-calcemic Genomic Activity and Individual Responsiveness: A Randomized Controlled Double-Blind Clinical Trial

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Arash Shirvani ◽  
Tyler Arek Kalajian ◽  
Anjeli Song ◽  
Michael F. Holick
Keyword(s):  
Gene Expression ◽  
Clinical Trial ◽  
Vitamin D ◽  
Blood Cells ◽  
White Blood Cells ◽  
Double Blind ◽  
Randomized Controlled ◽  
Double Blind Clinical Trial ◽  
The Impact ◽  
Dose Dependent

AbstractThe aims of this randomized controlled double-blind clinical trial were to assess the impact of vitamin D supplementation on calcium metabolism and non-calcemic broad gene expression by relating them to the individual’s responsiveness to varying doses of vitamin D3. Thirty healthy adults were randomized to receive 600, 4,000 or 10,000 IU/d of vitamin D3 for 6 months. Circulating parathyroid hormone (PTH), 25(OH)D, calcium and peripheral white blood cells broad gene expression were evaluated. We observed a dose-dependent increase in 25(OH)D concentrations, decreased PTH and no change in serum calcium. A plateau in PTH levels was achieved at 16 weeks in the 4000 and 10,000 IU/d groups. There was a dose-dependent 25(OH)D alteration in broad gene expression with 162, 320 and 1289 genes up- or down-regulated in their white blood cells, respectively. Our results clearly indicated that there is an individual’s responsiveness on broad gene expression to varying doses of vitamin D3. Vitamin D3 supplementation at 10,000 IU/d produced genomic alterations several fold higher than 4,000 IU/d even without further changes in PTH levels. Our findings may help explain why there are some inconsistency in the results of different vitamin D’s clinical trials.

scholarly journals Effect of Pudilan Keyanning antibacterial mouthwash on dental plaque and gingival inflammation in patients during periodontal maintenance phase: study protocol for double-blind, randomised clinical trial

BMJ Open ◽  
2021 ◽  
Vol 11 (11) ◽  
pp. e048992
Author(s):  
Jianru Liu ◽  
Yan Huang ◽  
Xinzhe Lou ◽  
Bei Liu ◽  
Wenyi Liu ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Study Protocol ◽  
Dental Plaque ◽  
Critical Role ◽  
Maintenance Phase ◽  
Controlled Clinical Trial ◽  
Double Blind ◽  
Periodontal Inflammation ◽  
Plaque Control ◽  
Periodontal Maintenance

IntroductionPlaque control plays a critical role in the prevention and treatment of periodontitis. Antibacterial mouthwash is one of the most important tools for plaque control. Pudilan, including extracts of Scutellaria baicalensis root, Taraxacum mongolicum, Bunge corydalis herb and Isatis indigotica, was reported playing the role of anti-inflammatory and anti-bacterial. However, its effect on dental plaque and periodontal inflammation remains unknown. We aimed to assess the efficacy of Pudilan Keyanning antibacterial mouthwash which contains the active essence of Pudilan and 0.03%–0.06% cetylpyridinium chloride, as well as Pudilan active essence for plaque control and gingival anti-inflammation in patients during periodontal maintenance phase.Methods and analysisIn this double-blind, randomised, placebo-controlled clinical trial, a total of 120 participants during periodontal maintenance phase will be enrolled. After supragingival scaling, they will be randomly assigned into three groups in a 1:1:1 ratio: the Pudilan Keyanning antibacterial mouthwash group, a chlorhexidine acetate mouthwash (0.12%) group or a placebo group with mouthwash containing the same components as the Pudilan Keyanning mouthwash except for Pudilan active ingredients. They will rinse with mouthwash, respectively, two times per day for 6 weeks. Clinical parameters (such as plaque index, bleeding index) and the level of volatile sulfide in the breath will be measured and analysed. The subgingival plaque will be collected and analysed microbiologically. Questionnaire feedback will be analysed.Ethics and disseminationThe study protocol (V.4) was reviewed and approved by the Medical Ethical Committee of Peking University School and Hospital of Stomatology (Ethics Approval No. PKUSSIRB-201950153b). All participants signed a written consent form.Trial registration numberChiCTR2000041253.

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