Acute effects of mifepristone on emotional processing related brain activity: A functional MRI study.

The Hypothalamic-pituitary-adrenal (HPA) axis plays an important role in the pathophysiology of mood disorders, and preliminary data suggests that glucocorticoid receptor (GR) antagonism may be an important therapeutic mechanism. The effects of modulating HPA axis function on emotional processing related brain activity, which may be abnormal in depressed mood, is poorly understood. This study used a pharmacological functional magnetic resonance imaging (fMRI) design to determine the effects of the GR and progesterone receptor antagonist mifepristone on emotional faces processing task related brain activations in 19 right-handed healthy male participants. Each participant received 600 mg mifepristone or placebo on two separate imaging days and then performed an emotional processing fMRI task four hours later. The effect of mifepristone on task related brain activations was determined using Region-of-Interest (ROI) analyses and an exploratory whole brain voxel-wise analyses. No significant changes were observed in the defined ROIs (amygdala, anterior cingulate cortex, insula) or in the exploratory whole brain analyses that was associated with mifepristone administration in either the angry vs happy faces or angry and happy faces vs implicit baseline contrasts. Task reaction times and accuracy were similar in both mifepristone and placebo conditions (all p > 0.05). Our study failed to show significant evidence of modulation of emotional processing related brain activity associated with acute mifepristone administration. Future research should use fMRI to investigate the longer-term administration effects of mifepristone on mood in healthy participants and people with mood disorders to provide a deeper understanding of the potential effects on depressive symptoms.

Comparison of Cerebral Blood Flow in Regions Relevant to Cognition After Enzalutamide, Darolutamide, and Placebo in Healthy Volunteers: A Randomized Crossover Trial.

BACKGROUND: Off-target central nervous system (CNS) effects are associated with androgen receptor (AR)-targeting treatments for prostate cancer. Darolutamide is a structurally distinct AR inhibitor with low blood-brain barrier penetration. OBJECTIVE: We compared cerebral blood flow (CBF) in grey matter and specific regions related to cognition after darolutamide, enzalutamide, or placebo administration, using arterial spin-label magnetic resonance imaging (ASL-MRI). METHODS: This phase I, randomized, placebo-controlled, three-period crossover study administered single doses of darolutamide, enzalutamide, or placebo to 23 healthy males (aged 18-45 years) at 6-week intervals. ASL-MRI mapped CBF 4 h post-treatment. Treatments were compared using paired t-tests. RESULTS: Drug concentrations during scans confirmed similar unbound exposure of darolutamide and enzalutamide, with complete washout between treatments. A significant localized 5.2% (p = 0.01) and 5.9% (p < 0.001) CBF reduction in the temporo-occipital cortices was observed for enzalutamide versus placebo and versus darolutamide, respectively, with no significant differences for darolutamide versus placebo. Enzalutamide reduced CBF in all prespecified regions, with significant reductions versus placebo (3.9%, p = 0.045) and versus darolutamide (4.4%, p = 0.037) in the left and right dorsolateral prefrontal cortices, respectively. Darolutamide showed minimal changes in CBF versus placebo in cognition-relevant regions. CONCLUSIONS: Darolutamide did not significantly alter CBF, consistent with its low blood-brain barrier penetration and low risk of CNS-related adverse events. A significant reduction in CBF was observed with enzalutamide. These results may be relevant to cognitive function with early and extended use of second-generation AR inhibitors, and warrant further investigation in patients with prostate cancer. TRIAL REGISTRATION NUMBER: NCT03704519; date of registration: October 2018.

Androgens, or male sex hormones, bind to androgen receptors within prostate cells and can cause growth of prostate cancer. The treatment of prostate cancer often includes drugs that bind to androgen receptors, called androgen receptor inhibitors, keeping androgens from binding to the receptors and preventing prostate cancer growth. In clinical studies, these drugs may have adverse effects on the central nervous system, or brain, including dizziness, falls, and impaired thinking and problem solving. This study compared the effects of two androgen receptor inhibitors, darolutamide and enzalutamide, and placebo on blood flow in the brain. Blood flow was measured by a type of magnetic resonance imaging in healthy men after receiving a single dose of treatment. Blood flow in the brain was reduced by enzalutamide compared with both placebo and darolutamide. Darolutamide did not decrease brain blood flow. This lack of effect on brain blood flow is in line with preclinical studies that showed darolutamide's limited ability to cross the blood­brain barrier, which is the naturally occurring barrier that protects the brain from harmful substances. In clinical studies of patients with prostate cancer treated with darolutamide, adverse effects on the brain have occurred in similar proportions of patients receiving darolutamide and placebo. In contrast, enzalutamide treatment has an increased risk of adverse effects on the brain versus placebo. The results of this study provide information on the effects of these androgen receptor inhibitors on brain blood flow that may be related to their adverse effects on the brain and its functioning.

"Less is more": A dose-response account of intranasal oxytocin pharmacodynamics in the human brain.

Intranasal oxytocin is attracting attention as a potential treatment for several brain disorders due to promising preclinical results. However, translating findings to humans has been hampered by remaining uncertainties about its pharmacodynamics and the methods used to probe its effects in the human brain. Using a dose-response design (9, 18 and 36 IU), we demonstrate that intranasal oxytocin-induced changes in local regional cerebral blood flow (rCBF) in the amygdala at rest, and in the covariance between rCBF in the amygdala and other key hubs of the brain oxytocin system, follow a dose-response curve with maximal effects for lower doses. Yet, the effects on local rCBF might vary by amygdala subdivision, highlighting the need to qualify dose-response curves within subregion. We further link physiological changes with the density of the oxytocin receptor gene mRNA across brain regions, strengthening our confidence in intranasal oxytocin as a valid approach to engage central targets. Finally, we demonstrate that intranasal oxytocin does not disrupt cerebrovascular reactivity, which corroborates the validity of haemodynamic neuroimaging to probe the effects of intranasal oxytocin in the human brain. DATA AVAILABILITY: Participants did not consent for open sharing of the data. Therefore, data can only be accessed from the corresponding author upon reasonable request.

Cognitive deficits in people who have recovered from COVID-19.

BACKGROUND: There is growing concern about possible cognitive consequences of COVID-19, with reports of 'Long COVID' symptoms persisting into the chronic phase and case studies revealing neurological problems in severely affected patients. However, there is little information regarding the nature and broader prevalence of cognitive problems post-infection or across the full spread of disease severity. METHODS: We sought to confirm whether there was an association between cross-sectional cognitive performance data from 81,337 participants who between January and December 2020 undertook a clinically validated web-optimized assessment as part of the Great British Intelligence Test, and questionnaire items capturing self-report of suspected and confirmed COVID-19 infection and respiratory symptoms. FINDINGS: People who had recovered from COVID-19, including those no longer reporting symptoms, exhibited significant cognitive deficits versus controls when controlling for age, gender, education level, income, racial-ethnic group, pre-existing medical disorders, tiredness, depression and anxiety. The deficits were of substantial effect size for people who had been hospitalised (N = 192), but also for non-hospitalised cases who had biological confirmation of COVID-19 infection (N = 326). Analysing markers of premorbid intelligence did not support these differences being present prior to infection. Finer grained analysis of performance across sub-tests supported the hypothesis that COVID-19 has a multi-domain impact on human cognition. INTERPRETATION: Interpretation. These results accord with reports of 'Long Covid' cognitive symptoms that persist into the early-chronic phase. They should act as a clarion call for further research with longitudinal and neuroimaging cohorts to plot recovery trajectories and identify the biological basis of cognitive deficits in SARS-COV-2 survivors. FUNDING: Funding. AH is supported by the UK Dementia Research Institute Care Research and Technology Centre and Biomedical Research Centre at Imperial College London. WT is supported by the EPSRC Centre for Doctoral Training in Neurotechnology. SRC is funded by a Wellcome Trust Clinical Fellowship 110,049/Z/15/Z. JMB is supported by Medical Research Council (MR/N013700/1). MAM, SCRW and PJH are, in part, supported by the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King's College London.

Cholinergic modulation of disorder-relevant human defensive behaviour in generalised anxiety disorder.

Drugs that are clinically effective against anxiety disorders modulate the innate defensive behaviour of rodents, suggesting these illnesses reflect altered functioning in brain systems that process threat. This hypothesis is supported in humans by the discovery that the intensity of threat-avoidance behaviour is altered by the benzodiazepine anxiolytic lorazepam. However, these studies used healthy human participants, raising questions as to their validity in anxiety disorder patients, as well as their generalisability beyond GABAergic benzodiazepine drugs. BNC210 is a novel negative allosteric modulator of the alpha 7 nicotinic acetylcholine receptor and we recently used functional Magnetic Resonance Imaging to show it reduced amygdala responses to fearful faces in generalised anxiety disorder patients. Here we report the effect of BNC210 on the intensity of threat-avoidance behaviour in 21 female GAD patients from the same cohort. We used the Joystick Operated Runway Task as our behavioural measure, which is a computerised human translation of the Mouse Defense Test Battery, and the Spielberger state anxiety inventory as our measure of state affect. Using a repeated-measures, within-subjects design we assessed the effect of BNC210 at two dose levels versus placebo (300 mg and 2000 mg) upon two types of threat-avoidance behaviour (Flight Intensity and Risk Assessment Intensity). We also tested the effects of 1.5 mg of the benzodiazepine lorazepam as an active control. BNC210 significantly reduced Flight Intensity relative to placebo and the low dose of BNC210 also significantly reduced self-reported state anxiety. Risk Assessment Intensity was not significantly affected. Results show both human defensive behaviour and state anxiety are influenced by cholinergic neurotransmission and there provide converging evidence that this system has potential as a novel target for anxiolytic pharmacotherapy.

Mifepristone enhances the neural efficiency of human visuospatial memory encoding and recall.

Glucocorticoid receptor (GR) antagonism is a promising new treatment for cognitive dysfunction in psychiatric disorders but the effects of GR antagonism on cognition related brain activity is poorly understood. This study examines the effects of the GR and progesterone receptor antagonist mifepristone on the neural correlates of visuospatial learning and working memory in healthy male participants. The study used a pharmacological functional magnetic resonance imaging (fMRI) design to determine mifepristone effects on visuospatial paired associates learning (vPAL) and n-back working memory (WM) fMRI task related brain activations. 20 right-handed healthy male participants received 600 mg mifepristone or placebo on two separate imaging days and each participant performed fMRI tasks four hours later. The effect of mifepristone on task related brain activations was determined using Region of Interest (ROI) fMRI analyses and an exploratory whole brain voxel-wise fMRI task analyses was also conducted. The vPAL task ROI analysis found that mifepristone administration was significantly associated with decreased fusiform cortex activations in first and second encoding blocks (p = 0.007, p = 0.04) and decreased angular and precuneal cortices activations in the first recall block (p = 0.01, p = 0.02). There were no significant differences in fMRI brain activations associated with mifepristone administration in the n-back task ROI's (all p > 0.05). Mifepristone administration did not significantly affect fMRI brain activations in the whole brain voxel-wise analyses for both tasks. N-back and vPAL task reaction times and accuracy were similar in both mifepristone and placebo conditions (all p > 0.05). Our finding of decreased fusiform, angular and precuneal vPAL task related brain activity associated with mifepristone administration for the same behavioural performance as found in the placebo condition may represent improved efficiency of visuospatial memory encoding and recall. These findings provide evidence that mifepristone may enhance the efficiency of human visuospatial memory and calls for further studies in patient populations using an fMRI approach to provide proof of concept for new treatments.

Subacute Changes in N-Acetylaspartate (NAA) Following Ischemic Stroke: A Serial MR Spectroscopy Pilot Study.

Preservation of neuronal tissue is crucial for recovery after stroke, but studies suggest that prolonged neuronal loss occurs following acute ischaemia. This study assessed the temporal pattern of neuronal loss in subacute ischemic stroke patients using 1H magnetic resonance spectroscopy, in parallel with functional recovery at 2, 6 and 12 weeks after stroke. Specifically, we measured N-acetylaspartate (NAA), choline, myoinositol, creatine and lactate concentrations in the ipsilesional and contralesional thalamus of 15 first-ever acute ischaemic stroke patients and 15 control participants and correlated MRS concentrations with motor recovery, measured at 12 weeks using the Fugl-Meyer scale. NAA in the ipsilesional thalamus fell significantly between 2 and 12 weeks (10.0 to 7.97 mmol/L, p = 0.003), while choline, myoinositol and lactate concentrations increased (p = 0.025, p = 0.031, p = 0.001, respectively). Higher NAA concentrations in the ipsilesional thalamus at 2 and 12 weeks correlated with higher Fugl Meyer scores at 12 weeks (p = 0.004 and p = 0.006, respectively). While these results should be considered preliminary given the modest sample size, the progressive fall in NAA and late increases in choline, myoinositol and lactate may indicate progressive non-ischaemic neuronal loss, metabolically depressed neurons and/or diaschisis effects, which have a detrimental effect on motor recovery. Interventions that can potentially limit this ongoing subacute tissue damage may improve stroke recovery.

Cholinergic Modulation of Disorder-Relevant Neural Circuits in Generalized Anxiety Disorder.

BACKGROUND: Generalized anxiety disorder is associated with hyperactivity in the amygdala-prefrontal networks, and normalization of this aberrant function is thought to be critical for successful treatment. Preclinical evidence implicates cholinergic neurotransmission in the function of these systems and suggests that cholinergic modulation may have anxiolytic effects. However, the effects of cholinergic modulators on the function of anxiety-related networks in humans have not been investigated. METHODS: We administered a novel α7 nicotinic acetylcholine receptor-negative allosteric modulator, BNC210, to 24 individuals (3 male subjects) with generalized anxiety disorder and assessed its effects on neural responses to fearful face stimuli. RESULTS: BNC210 reduced amygdala reactivity to fearful faces relative to placebo and similarly to lorazepam and also reduced connectivity between the amygdala and the anterior cingulate cortex, a network involved in regulating anxious responses to aversive stimuli. CONCLUSIONS: These results demonstrate for the first time that the function of disorder-relevant neural circuits in generalized anxiety disorder can be beneficially altered through modulation of cholinergic neurotransmission and suggest potential for this system as a novel target for anxiolytic pharmacotherapy.

A New Method for Ethical and Efficient Evidence Generation for Off-Label Medication Use in Oncology (A Case Study in Glioblastoma).

In oncology, preclinical and early clinical data increasingly support the use of a number of candidate "non-cancer" drugs in an off-label setting against multiple tumor types. In particular, metabolically targeted drugs show promise as adjuvant chemo and radiosensitizers, improving or restoring sensitivity to standard therapies. The time has come for large scale clinical studies of off-label drugs in this context. However, it is well recognized that high-cost randomized controlled trials may not be an economically viable option for studying patent-expired off-label drugs. In some cases, randomized trials could also be considered as ethically controversial. This perspective article presents a novel approach to generating additional clinical data of sufficient quality to support changes in clinical practice and relabeling of such drugs for use in oncology. Here, we suggest that a pluralistic evidence base and triangulation of evidence can support clinical trial data for off-label drug use in oncology. An example of an off-label drug protocol brought to the clinic for glioblastoma patients is presented, along with preliminary retrospective data from the METRICS study (NCT02201381). METRICS is a novel participant-funded, open-label, non-randomized, single-arm real-world study designed to gather high-quality evidence on the safety, tolerability, and effectiveness of four off-label metabolically targeted medicines as an adjunctive cancer treatment for glioblastoma patients.

The practice of experimental studies in psychopharmacology: Top 10 tips from one centre's experience.

OBJECTIVE: Recent efforts to optimise translation of basic research findings to successful clinical trials have led to a sharper focus on experimental medicine translational studies. This is coupled with a movement towards greater methodological integrity and openness. Although this can be achieved through preregistration and detailed reporting of study methodology, the reality of study application can often be lost. METHODS: In practice, challenges in study application can often lead to diminished scientific robustness, even in well-designed studies. A detailed description of experiences is essential for learning and subsequent improvement. To this end, the authors undertook a description of the experience of a specialised psychopharmacology experimental study centre. RESULTS: This centre's experiences reveal that even supposedly routine study elements, such as screening parameters, peri-drug administration, and peri-discharge procedures, can pose significant practical obstacles to the achievement of minimal protocol deviation. Ultimately, these factors impact on academic standards such as enhanced data reliability; but they have additional implications for participant clinical safety and well-being, for instance in relation to adverse event and incidental finding recording. CONCLUSIONS: The facilitation of a scientific culture that is more transparent even at the operational level will hopefully augment translational process and probability of success.

Psilocybin and MDMA reduce costly punishment in the Ultimatum Game.

Disruptions in social decision-making are becoming evident in many psychiatric conditions. These are studied using paradigms investigating the psychological mechanisms underlying interpersonal interactions, such as the Ultimatum Game (UG). Rejection behaviour in the UG represents altruistic punishment - the costly punishment of norm violators - but the mechanisms underlying it require clarification. To investigate the psychopharmacology of UG behaviour, we carried out two studies with healthy participants, employing serotonergic agonists: psilocybin (open-label, within-participant design, N = 19) and 3,4-methylenedioxymethamphetamine (MDMA; placebo-controlled, double-blind, crossover design, N = 20). We found that both MDMA and psilocybin reduced rejection of unfair offers (odds ratio: 0.57 and 0.42, respectively). The reduction in rejection rate following MDMA was associated with increased prosociality (R2 = 0.26, p = 0.025). In the MDMA study, we investigated third-party decision-making and proposer behaviour. MDMA did not reduce rejection in the third-party condition, but produced an increase in the amount offered to others (Cohen's d = 0.82). We argue that these compounds altered participants' conceptualisation of 'social reward', placing more emphasis on the direct relationship with interacting partners. With these compounds showing efficacy in drug-assisted psychotherapy, these studies are an important step in the further characterisation of their psychological effects.