Intranasal oxytocin is attracting attention as a potential treatment for several brain disorders ... more 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.
Preservation of neuronal tissue is crucial for recovery after stroke, but studies suggest that pr... more 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 co...
Glucocorticoid receptor (GR) antagonism is a promising new treatment for cognitive dysfunction in... more 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.
Drugs that are clinically effective against anxiety disorders modulate the innate defensive behav... more 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 ...
Background There is growing concern about possible cognitive consequences of COVID-19, with repor... more 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
Human Psychopharmacology: Clinical and Experimental
The most typical expression of cystic fibrosis (CF)-related liver disease is a cholangiopathy tha... more The most typical expression of cystic fibrosis (CF)-related liver disease is a cholangiopathy that can progress to cirrhosis. We aimed to determine the potential impact of environmental and genetic factors on the development of CF-related cholangiopathy in mice. Cystic fibrosis transmembrane conductance regulator (Cftr)-/mice and Cftr +/+ littermates in a congenic C57BL/6J background were fed a high medium-chain triglyceride (MCT) diet. Liver histopathology, fecal microbiota, intestinal inflammation and barrier function, bile acid homeostasis, and liver transcriptome were analyzed in 3-month-old males. Subsequently, MCT diet was changed for chow with polyethylene glycol (PEG) and the genetic background for a mixed C57BL/6J;129/Ola background (resulting from three backcrosses), to test their effect on phenotype. C57BL/6J Cftr-/mice on an MCT diet developed cholangiopathy features that were associated with dysbiosis, primarily Escherichia coli enrichment, and low-grade intestinal inflammation. Compared with Cftr +/+ littermates, they displayed increased intestinal permeability and a lack of secondary bile acids together with a low expression of ileal bile acid transporters. Dietary-induced (chow with PEG) changes in gut microbiota composition largely prevented the development of cholangiopathy in Cftr-/mice. Regardless of Cftr status, mice in a mixed C57BL/6J;129/Ola background developed fatty liver under an MCT diet. The Cftr-/mice in the mixed background showed no cholangiopathy, which was not explained by a difference in gut microbiota or intestinal permeability, compared with congenic mice. Transcriptomic analysis of the liver revealed differential expression, notably of immune-related genes, in mice of the congenic versus mixed background. In conclusion, our findings suggest that CFTR deficiency causes abnormal intestinal permeability, which, combined with diet-induced dysbiosis and immunerelated genetic susceptibility, promotes CF-related cholangiopathy. (Hepatology Communications 2018;2:1533-1549). C ystic fibrosis (CF) is a disease caused by genetic defects in cystic fibrosis transmembrane conductance regulator (CFTR), a chloride channel driving ion and fluid secretion in various epithelia, including the lungs, intestine, pancreas, and bile ducts. Liver disease is increasingly frequent and severe in patients with CF, which has been attributed, at least partly, to an increase in median survival. (1,2) Yet, the phenotypic expression and severity of CF liver disease is extremely variable, ranging from simple steatosis to cirrhosis. (3,4) A cholangiopathy in patients with CF, referred to as focal biliary cirrhosis, has been described
Case studies have revealed neurological problems in severely affected COVID-19 patients. However,... more Case studies have revealed neurological problems in severely affected COVID-19 patients. However, there is little information regarding the nature and broader prevalence of cognitive problems post-infection or across the full spread of severity. We analysed cognitive test data from 84,285 Great British Intelligence Test participants who completed a questionnaire regarding suspected and biologically confirmed COVID-19 infection. People who had recovered, including those no longer reporting symptoms, exhibited significant cognitive deficits when controlling for age, gender, education level, income, racial-ethnic group and pre-existing medical disorders. They were of substantial effect size for people who had been hospitalised, but also for mild but biologically confirmed cases who reported no breathing difficulty. Finer grained analyses of performance support the hypothesis that COVID-19 has a multi-system impact on human cognition.Significance statementThere is evidence that COVID-19...
326 Background: DARO is an oral androgen receptor antagonist with a unique structure and a low bl... more 326 Background: DARO is an oral androgen receptor antagonist with a unique structure and a low blood–brain barrier penetrance noted in rodents. Here we compare CBF following administration of DARO, ENZA, and PBO using arterial spin labelled magnetic resonance imaging (ASL-MRI) in humans. Methods: This phase I, randomized, PBO-controlled, 3-period crossover study investigated drug-induced changes in CBF for brain grey matter and for specific regions related to cognitive function in healthy males (age 19–44). Twenty-three participants received a single oral dose of DARO, ENZA, or PBO at 6-week intervals at similar unbound concentrations . An ASL-MRI scan was performed ~4 hours after each dose. Blood samples for drug analysis and physiological measures were collected prior to drug administration and immediately post-scan. ASL data were preprocessed and statistical parametric modelling was used for treatment comparisons (paired t-tests). Whole-brain results were considered significant a...
BACKGROUND: Generalized anxiety disorder is associated with hyperactivity in the amygdala-prefron... more 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 anxietyrelated networks in humans have not been investigated. METHODS: We administered a novel a7 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.
Do nose-to-brain pathways provide a privileged route of direct entry to the brain for peptides su... more Do nose-to-brain pathways provide a privileged route of direct entry to the brain for peptides such as oxytocin (OT)? We addressed this question by contrasting two methods of intranasal administration (a standard nasal spray, and a nebulizer expected to improve OT deposition in nasal areas putatively involved in direct nose-to-brain transport) to intravenous administration in terms of effects on regional cerebral blood flow during two hours post-dosing. We demonstrate that OT-induced decreases in amygdala perfusion, a key hub of the OT central circuitry, are explained entirely by OT increases in systemic circulation following both intranasal and intravenous OT administration. Yet we also provide robust evidence confirming the validity of the intranasal route to target specific brain regions. Our work has important translational implications and demonstrates the need to carefully consider the method of administration in our efforts to engage specific central oxytocinergic targets for...
Disruptions in social decision-making are becoming evident in many psychiatric conditions. These ... more 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 (R = 0.26, p = 0.025). In the MDMA study, we investigated third-party decision-m...
Intranasal oxytocin is receiving increasing research attention as a potential treatment for sever... more Intranasal oxytocin is receiving increasing research attention as a potential treatment for several brain disorders due to promising preclinical results. However, translating these 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) and a novel administration device, we demonstrate that oxytocin-induced physiological changes in the amygdala at rest, a key-hub of the brain oxytocin system, follow a dose-response curve with maximal effects for lower doses. Yet, the effects of oxytocin 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...
Background: The adult brain has the capacity to reorganize after acute stroke and the ability to ... more Background: The adult brain has the capacity to reorganize after acute stroke and the ability to follow neuroplastic processes can be useful in predicting and monitoring recovery after stroke. This study investigates the ability of 1H-MRS to measure metabolic events in the structurally intact peri-infarct region between 2-12 weeks after stroke and their relationship to motor recovery. Method: The study included 15 first-ever stroke patients aged 18-75 years and age/sex matched controls. Structural, perfusion and 1H-MRS imaging was undertaken to measure regional cerebral blood flow (rCBF), N-acetylaspartate (NAA), choline (Cho), myoinositol (mI), creatine (cr) and lactate in the ipsilesional and contralesional hemisphere of stroke patients at 2 weeks, 6±1 and 12±3 weeks after stroke onset. Simultaneous clinical assessments were undertaken to measure motor impairments using the Fugl-Meyer [F-M]) scale. Patients were compared with controls at all time-points and the relationships betwe...
Intranasal oxytocin is attracting attention as a potential treatment for several brain disorders ... more 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.
Preservation of neuronal tissue is crucial for recovery after stroke, but studies suggest that pr... more 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 co...
Glucocorticoid receptor (GR) antagonism is a promising new treatment for cognitive dysfunction in... more 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.
Drugs that are clinically effective against anxiety disorders modulate the innate defensive behav... more 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 ...
Background There is growing concern about possible cognitive consequences of COVID-19, with repor... more 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
Human Psychopharmacology: Clinical and Experimental
The most typical expression of cystic fibrosis (CF)-related liver disease is a cholangiopathy tha... more The most typical expression of cystic fibrosis (CF)-related liver disease is a cholangiopathy that can progress to cirrhosis. We aimed to determine the potential impact of environmental and genetic factors on the development of CF-related cholangiopathy in mice. Cystic fibrosis transmembrane conductance regulator (Cftr)-/mice and Cftr +/+ littermates in a congenic C57BL/6J background were fed a high medium-chain triglyceride (MCT) diet. Liver histopathology, fecal microbiota, intestinal inflammation and barrier function, bile acid homeostasis, and liver transcriptome were analyzed in 3-month-old males. Subsequently, MCT diet was changed for chow with polyethylene glycol (PEG) and the genetic background for a mixed C57BL/6J;129/Ola background (resulting from three backcrosses), to test their effect on phenotype. C57BL/6J Cftr-/mice on an MCT diet developed cholangiopathy features that were associated with dysbiosis, primarily Escherichia coli enrichment, and low-grade intestinal inflammation. Compared with Cftr +/+ littermates, they displayed increased intestinal permeability and a lack of secondary bile acids together with a low expression of ileal bile acid transporters. Dietary-induced (chow with PEG) changes in gut microbiota composition largely prevented the development of cholangiopathy in Cftr-/mice. Regardless of Cftr status, mice in a mixed C57BL/6J;129/Ola background developed fatty liver under an MCT diet. The Cftr-/mice in the mixed background showed no cholangiopathy, which was not explained by a difference in gut microbiota or intestinal permeability, compared with congenic mice. Transcriptomic analysis of the liver revealed differential expression, notably of immune-related genes, in mice of the congenic versus mixed background. In conclusion, our findings suggest that CFTR deficiency causes abnormal intestinal permeability, which, combined with diet-induced dysbiosis and immunerelated genetic susceptibility, promotes CF-related cholangiopathy. (Hepatology Communications 2018;2:1533-1549). C ystic fibrosis (CF) is a disease caused by genetic defects in cystic fibrosis transmembrane conductance regulator (CFTR), a chloride channel driving ion and fluid secretion in various epithelia, including the lungs, intestine, pancreas, and bile ducts. Liver disease is increasingly frequent and severe in patients with CF, which has been attributed, at least partly, to an increase in median survival. (1,2) Yet, the phenotypic expression and severity of CF liver disease is extremely variable, ranging from simple steatosis to cirrhosis. (3,4) A cholangiopathy in patients with CF, referred to as focal biliary cirrhosis, has been described
Case studies have revealed neurological problems in severely affected COVID-19 patients. However,... more Case studies have revealed neurological problems in severely affected COVID-19 patients. However, there is little information regarding the nature and broader prevalence of cognitive problems post-infection or across the full spread of severity. We analysed cognitive test data from 84,285 Great British Intelligence Test participants who completed a questionnaire regarding suspected and biologically confirmed COVID-19 infection. People who had recovered, including those no longer reporting symptoms, exhibited significant cognitive deficits when controlling for age, gender, education level, income, racial-ethnic group and pre-existing medical disorders. They were of substantial effect size for people who had been hospitalised, but also for mild but biologically confirmed cases who reported no breathing difficulty. Finer grained analyses of performance support the hypothesis that COVID-19 has a multi-system impact on human cognition.Significance statementThere is evidence that COVID-19...
326 Background: DARO is an oral androgen receptor antagonist with a unique structure and a low bl... more 326 Background: DARO is an oral androgen receptor antagonist with a unique structure and a low blood–brain barrier penetrance noted in rodents. Here we compare CBF following administration of DARO, ENZA, and PBO using arterial spin labelled magnetic resonance imaging (ASL-MRI) in humans. Methods: This phase I, randomized, PBO-controlled, 3-period crossover study investigated drug-induced changes in CBF for brain grey matter and for specific regions related to cognitive function in healthy males (age 19–44). Twenty-three participants received a single oral dose of DARO, ENZA, or PBO at 6-week intervals at similar unbound concentrations . An ASL-MRI scan was performed ~4 hours after each dose. Blood samples for drug analysis and physiological measures were collected prior to drug administration and immediately post-scan. ASL data were preprocessed and statistical parametric modelling was used for treatment comparisons (paired t-tests). Whole-brain results were considered significant a...
BACKGROUND: Generalized anxiety disorder is associated with hyperactivity in the amygdala-prefron... more 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 anxietyrelated networks in humans have not been investigated. METHODS: We administered a novel a7 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.
Do nose-to-brain pathways provide a privileged route of direct entry to the brain for peptides su... more Do nose-to-brain pathways provide a privileged route of direct entry to the brain for peptides such as oxytocin (OT)? We addressed this question by contrasting two methods of intranasal administration (a standard nasal spray, and a nebulizer expected to improve OT deposition in nasal areas putatively involved in direct nose-to-brain transport) to intravenous administration in terms of effects on regional cerebral blood flow during two hours post-dosing. We demonstrate that OT-induced decreases in amygdala perfusion, a key hub of the OT central circuitry, are explained entirely by OT increases in systemic circulation following both intranasal and intravenous OT administration. Yet we also provide robust evidence confirming the validity of the intranasal route to target specific brain regions. Our work has important translational implications and demonstrates the need to carefully consider the method of administration in our efforts to engage specific central oxytocinergic targets for...
Disruptions in social decision-making are becoming evident in many psychiatric conditions. These ... more 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 (R = 0.26, p = 0.025). In the MDMA study, we investigated third-party decision-m...
Intranasal oxytocin is receiving increasing research attention as a potential treatment for sever... more Intranasal oxytocin is receiving increasing research attention as a potential treatment for several brain disorders due to promising preclinical results. However, translating these 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) and a novel administration device, we demonstrate that oxytocin-induced physiological changes in the amygdala at rest, a key-hub of the brain oxytocin system, follow a dose-response curve with maximal effects for lower doses. Yet, the effects of oxytocin 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...
Background: The adult brain has the capacity to reorganize after acute stroke and the ability to ... more Background: The adult brain has the capacity to reorganize after acute stroke and the ability to follow neuroplastic processes can be useful in predicting and monitoring recovery after stroke. This study investigates the ability of 1H-MRS to measure metabolic events in the structurally intact peri-infarct region between 2-12 weeks after stroke and their relationship to motor recovery. Method: The study included 15 first-ever stroke patients aged 18-75 years and age/sex matched controls. Structural, perfusion and 1H-MRS imaging was undertaken to measure regional cerebral blood flow (rCBF), N-acetylaspartate (NAA), choline (Cho), myoinositol (mI), creatine (cr) and lactate in the ipsilesional and contralesional hemisphere of stroke patients at 2 weeks, 6±1 and 12±3 weeks after stroke onset. Simultaneous clinical assessments were undertaken to measure motor impairments using the Fugl-Meyer [F-M]) scale. Patients were compared with controls at all time-points and the relationships betwe...
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