Publications
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Saleem A, Shah SIA, Mangar SA, et al., 2023, Cognitive dysfunction in patients treated with androgen deprivation therapy: a multimodality functional imaging study to evaluate neuroinflammation, Prostate Cancer, Vol: 2023, ISSN: 2090-3111
BACKGROUND: Androgen deprivation therapy (ADT) for prostate cancer is implicated as a possible cause of cognitive impairment (CI). CI in dementia and Alzheimer's disease is associated with neuroinflammation. In this study, we investigated a potential role of neuroinflammation in ADT-related CI. METHODS: Patients with prostate cancer on ADT for ≥3 months were categorized as having ADT-emergent CI or normal cognition (NC) based on self-report at interview. Neuroinflammation was evaluated using positron emission tomography (PET) with the translocator protein (TSPO) radioligand [11C]-PBR28. [11C]-PBR28 uptake in various brain regions was quantified as standardized uptake value (SUVR, normalized to cerebellum) and related to blood oxygen level-dependent functional magnetic resonance imaging (BOLD-fMRI) choice-reaction time task (CRT) activation maps. RESULTS: Eleven patients underwent PET: four with reported CI (rCI), six with reported NC (rNC), and one status unrecorded. PET did not reveal any between-group differences in SUVR regionally or globally. There was no difference between groups on brain activation to the CRT. Regardless of the reported cognitive status, there was strong correlation between PET-TSPO signal and CRT activation in the hippocampus, amygdala, and medial cortex. CONCLUSIONS: We found no difference in neuroinflammation measured by PET-TSPO between patients with rCI and rNC. However, we speculate that the strong correlation between TSPO uptake and BOLD-fMRI activation in brain regions involved in memory and known to have high androgen-receptor expression mediating plasticity (hippocampus and amygdala) might reflect inflammatory effects of ADT with compensatory upregulated/increased synaptic functions. Further studies of this imaging readout are warranted to investigate ADT-related CI.
Pelgrim TAD, Ramaekers JG, Wall MB, et al., 2023, Acute effects of?9-tetrahydrocannabinol (THC) on resting state connectivity networks and impact of COMT genotype: A multi-site pharmacological fMRI study, DRUG AND ALCOHOL DEPENDENCE, Vol: 251, ISSN: 0376-8716
Wall MB, Harding R, Zafar R, et al., 2023, Neuroimaging in psychedelic drug development: past, present, and future, MOLECULAR PSYCHIATRY, ISSN: 1359-4184
Ertl N, Lawn W, Mokrysz C, et al., 2023, Associations between regular cannabis use and brain resting-state functional connectivity in adolescents and adults, JOURNAL OF PSYCHOPHARMACOLOGY, Vol: 37, Pages: 904-919, ISSN: 0269-8811
Wall MB, Lam C, Ertl N, et al., 2023, Increased low-frequency brain responses to music after psilocybin therapy for depression, JOURNAL OF AFFECTIVE DISORDERS, Vol: 333, Pages: 321-330, ISSN: 0165-0327
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- Citations: 2
Lawn W, Trinci K, Mokrysz C, et al., 2023, The acute effects of cannabis with and without cannabidiol in adults and adolescents: A randomised, double-blind, placebo-controlled, crossover experiment., Addiction, Vol: 118, Pages: 1282-1294
BACKGROUND AND AIMS: Long-term harms of cannabis may be exacerbated in adolescence, but little is known about the acute effects of cannabis in adolescents. We aimed to (i) compare the acute effects of cannabis in adolescent and adult cannabis users and (ii) determine if cannabidiol (CBD) acutely modulates the effects of delta-9-tetrahydocannabinol (THC). DESIGN: Randomised, double-blind, placebo-controlled, crossover experiment. The experiment was registered on ClinicalTrials.gov (NCT04851392). SETTING: Laboratory in London, United Kingdom. PARTICIPANTS: Twenty-four adolescents (12 women, 16- to 17-year-olds) and 24 adults (12 women, 26- to 29-year-olds) who used cannabis 0.5-3 days/week and were matched on cannabis use frequency (mean = 1.5 days/week). INTERVENTION: We administered three weight-adjusted vaporised cannabis flower preparations: 'THC' (8 mg THC for 75 kg person); 'THC + CBD' (8 mg THC and 24 mg CBD for 75 kg person); and 'PLA' (matched placebo). MEASUREMENTS: Primary outcomes were (i) subjective 'feel drug effect'; (ii) verbal episodic memory (delayed prose recall); and (iii) psychotomimetic effect (Psychotomimetic States Inventory). FINDINGS: Compared with 'PLA', 'THC' and 'THC + CBD' significantly (P < 0.001) increased 'feel drug effect' (mean difference [MD] = 6.3, 95% CI = 5.3-7.2; MD = 6.8, 95% CI = 6.0-7.7), impaired verbal episodic memory (MD = -2.7, 95% CI = -4.1 to -1.4; MD = -2.9, 95% CI = -4.1 to -1.7) and increased psychotomimetic effects (MD = 7.8, 95% CI = 2.8-12.7; MD = 10.8, 95% CI = 6.2-15.4). There was no evidence that adolescents differed from adults in their responses to cannabis (interaction P ≥ 0.4). Bayesian analyses supported equivalent effects of cannabis in adolescents and adults (Bayes factor [BF01 ] >3
Zafar R, 2023, Psychedelic therapy in the treatment of addiction: the past, present and future, Frontiers in Psychiatry, Vol: 14, Pages: 1-24, ISSN: 1664-0640
Psychedelic therapy has witnessed a resurgence in interest in the last decade from the scientific and medical communities with evidence now building for its safety and efficacy in treating a range of psychiatric disorders including addiction (Nutt, Spriggs and Erritzoe, 2023). In this review we will chart the research investigating the role of these interventions in individuals with addiction beginning with an overview of the current socioeconomic impact of addiction, treatment options, and outcomes. We will start by examining historical studies from the first psychedelic research era of the mid-late 1900s, followed by an overview of the available real-world evidence gathered from naturalistic, observational, and survey-based studies. We will then cover modern-day clinical trials of psychedelic therapies in addiction from first-in-human to phase II clinical trials. Finally, we will provide an overview of the different translational human neuropsychopharmacology techniques, including functional magnetic resonance imaging (fMRI) and positron emission tomography (PET), that can be applied to foster a mechanistic understanding of therapeutic mechanisms. A more granular understanding of the treatment effects of psychedelics will facilitate the optimisation of the psychedelic therapy drug development landscape, and ultimately improve patient outcomes.
Richie-Halford A, Cieslak M, Ai L, et al., 2023, Author Correction: An analysis-ready and quality controlled resource for pediatric brain white-matter research., Sci Data, Vol: 10
Wall M, 2023, Shaking the kaleidoscope of the mind, Psychologist, Vol: 36, Pages: 40-44, ISSN: 0952-8229
Mills E, Ertl N, Wall M, et al., 2023, Effects of kisspeptin on sexual brain processing and penile tumescence in men with hypoactive sexual desire disorder: a randomized clinical trial, Jama Network Open, Vol: 6, Pages: 1-16, ISSN: 2574-3805
Importance The human physiological sexual response is crucial for reward, satisfaction, and reproduction. Disruption of the associated neurophysiological pathways predisposes to low sexual desire; the most prevalent psychological form is hypoactive sexual desire disorder (HSDD), which affects 8% of men but currently has no effective pharmacological treatment options. The reproductive neuropeptide kisspeptin offers a putative therapeutic target, owing to emerging understanding of its role in reproductive behavior.Objective To determine the physiological, behavioral, neural, and hormonal effects of kisspeptin administration in men with HSDD.Design, Setting, and Participants This double-blind, 2-way crossover, placebo-controlled randomized clinical trial was performed at a single academic research center in the UK. Eligible participants were right-handed heterosexual men with HSDD. Physiological, behavioral, functional magnetic resonance imaging (fMRI), and hormonal analyses were used to investigate the clinical and mechanistic effects of kisspeptin administration in response to visual sexual stimuli (short and long video tasks). The trial was conducted between January 11 and September 15, 2021, and data analysis was performed between October and November 2021.Interventions Participants attended 2 study visits at least 7 days apart, in balanced random order, for intravenous infusion of kisspeptin-54 (1 nmol/kg/h) for 75 minutes or for administration of a rate-matched placebo.Main Outcomes and Measures Changes in (1) brain activity on whole-brain analysis, as determined by fMRI blood oxygen level–dependent activity in response to visual sexual stimuli during kisspeptin administration compared with placebo, (2) physiological sexual arousal (penile tumescence), and (3) behavioral measures of sexual desire and arousal.Results Of the 37 men randomized, 32 completed the trial. Participants had a mean (SD) age of 37.9 (8.6) years and a mean (SD) body mass i
Skumlien M, Freeman TP, Hall D, et al., 2023, The Effects of Acute Cannabis With and Without Cannabidiol on Neural Reward Anticipation in Adults and Adolescents, BIOLOGICAL PSYCHIATRY-COGNITIVE NEUROSCIENCE AND NEUROIMAGING, Vol: 8, Pages: 219-229, ISSN: 2451-9022
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- Citations: 1
Skumlien M, Mokrysz C, Freeman TP, et al., 2023, Anhedonia, Apathy, Pleasure, and Effort-Based Decision-Making in Adult and Adolescent Cannabis Users and Controls, INTERNATIONAL JOURNAL OF NEUROPSYCHOPHARMACOLOGY, Vol: 26, Pages: 9-19, ISSN: 1461-1457
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- Citations: 4
Zahid U, Onwordi EC, Hedges EP, et al., 2023, Neurofunctional correlates of glutamate and GABA imbalance in psychosis: A systematic review, NEUROSCIENCE AND BIOBEHAVIORAL REVIEWS, Vol: 144, ISSN: 0149-7634
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- Citations: 2
Shukuroglou M, Roseman L, Wall M, et al., 2023, Changes in music-evoked emotion and ventral striatal functional connectivity after psilocybin therapy for depression, JOURNAL OF PSYCHOPHARMACOLOGY, Vol: 37, Pages: 70-79, ISSN: 0269-8811
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- Citations: 2
Shatalina E, Ashok AH, Wall MB, et al., 2023, Reward processing in schizophrenia and its relation to Mu opioid receptor availability and negative symptoms: A [11C]-carfentanil PET and fMRI study, NEUROIMAGE-CLINICAL, Vol: 39, ISSN: 2213-1582
Lawn W, Mokrysz C, Lees R, et al., 2022, The CannTeen Study: Cannabis use disorder, depression, anxiety, and psychotic-like symptoms in adolescent and adult cannabis users and age-matched controls., J Psychopharmacol, Vol: 36, Pages: 1350-1361
BACKGROUND: Adolescence is characterised by psychological and neural development. Cannabis harms may be accentuated during adolescence. We hypothesised that adolescents would be more vulnerable to the associations between cannabis use and mental health and addiction problems than adults. METHOD: As part of the 'CannTeen' study, we conducted a cross-sectional analysis. There were 274 participants: split into groups of adolescent users (n = 76; 16-17 years old) and controls (n = 63), and adult users (n = 71; 26-29 years old) and controls (n = 64). Among users, cannabis use frequency ranged from 1 to 7 days/week, while controls had 0-10 lifetime exposures to cannabis. Adolescent and adult cannabis users were matched on cannabis use frequency (mean=4 days/week). We measured Diagnostic and Statistical Manual (DSM-5) Cannabis Use Disorder (CUD), Beck Depression Inventory, Beck Anxiety Inventory and Psychotomimetic States Inventory-adapted. RESULTS: After adjustment for covariates, adolescent users were more likely to have severe CUD than adult users (odd ratio = 3.474, 95% confidence interval (CI) = 1.501-8.036). Users reported greater psychotic-like symptoms than controls (b = 6.004, 95% CI = 1.211-10.796) and adolescents reported greater psychotic-like symptoms than adults (b = 5.509, 95% CI = 1.070-9.947). User-group was not associated with depression or anxiety. No significant interactions between age-group and user-group were identified. Exploratory analyses suggested that cannabis users with severe CUD had greater depression and anxiety levels than cannabis users without severe CUD. CONCLUSION: Adolescent cannabis users are more likely than adult cannabis users to have severe CUD. Adolescent cannabis users have greater psychotic-like symptoms than adult cannabis users and adolescent controls, through an addi
Richie-Halford A, Cieslak M, Ai L, et al., 2022, Author Correction: An analysis-ready and quality controlled resource for pediatric brain white-matter research., Sci Data, Vol: 9
Richie-Halford A, Cieslak M, Ai L, et al., 2022, Publisher Correction: An analysis-ready and quality controlled resource for pediatric brain white-matter research., Sci Data, Vol: 9
Thurston L, Hunjan T, Ertl N, et al., 2022, Effects of kisspeptin administration in women with hypoactive sexual desire disorder: a randomized clinical trial, Jama Network Open, Vol: 5, Pages: 1-14, ISSN: 2574-3805
Importance: The absence or deficiency of sexual desire leading to distress or interpersonal difficultydefines ‘hypoactive sexual desire disorder’ (HSDD). Despite being the most common female sexualhealth complaint worldwide, current treatment options for HSDD are limited in their safety andeffectiveness. The hormone kisspeptin is a key endogenous activator of the reproductive hormonalaxis with additional emerging roles in sexual and emotional behavior, however, its effects in womenwith HSDD are unknown.Objective: To test the hypothesis that kisspeptin enhances sexual and attraction brain processing inwomen with HSDD.Design: A randomized, double-blind, two-way crossover, placebo-controlled clinical trial. Functionalneuroimaging, psychometric and hormonal analyses were employed to investigate the effects ofkisspeptin administration on brain processing, in response to erotic stimuli (erotic videos) and facialattraction (face images of varying attractiveness).Setting: The trial was conducted in a university research setting from October 2020 to April 2021. Datawere analyzed from May to December 2021.Participants: 32 premenopausal women with HSDD for at least 6 months’ duration.Interventions: 75-minute intravenous infusion of kisspeptin-54 (1 nmol/kg/h) vs equivalent-rateplacebo infusion.Main Outcome and Measures: Blood oxygen level–dependent responses across the whole brain andregions of interest during kisspeptin vs placebo administration, in response to erotic and facialattraction stimuli.Results: Of the 40 participants who were randomized, 32 women completed both kisspeptin andplacebo visits, and the mean (SEM) age was 29.2 (1.2) years. Kisspeptin administration resulted inmodulations in sexual and facial attraction brain processing (all P<.05). Furthermore, positivecorrelations were observed between kisspeptin-enhanced hippocampal activity in response to eroticvideos, and baseline distress relating to sexual function (P<.01). In additio
Richie-Halford A, Cieslak M, Ai L, et al., 2022, An analysis-ready and quality controlled resource for pediatric brain white-matter research, SCIENTIFIC DATA, Vol: 9
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- Citations: 3
Thurston L, Hunjan T, Mills E, et al., 2022, Melanocortin 4 receptor agonism enhances sexual brain processing in women with hypoactive sexual desire disorder, Journal of Clinical Investigation, Vol: 132, Pages: 1-12, ISSN: 0021-9738
BACKGROUND. Hypoactive sexual desire disorder (HSDD) is characterized by a persistent deficiency of sexual fantasies and desire for sexual activity, causing marked distress and interpersonal difficulty. It is the most prevalent female sexual health problem globally, affecting approximately 10% of women, but has limited treatment options. Melanocortin 4 receptor (MC4R) agonists have emerged as a promising therapy for women with HSDD, through unknown mechanisms. Studying the pathways involved is crucial for our understanding of normal and abnormal sexual behavior.METHODS. Using psychometric, functional neuroimaging, and hormonal analyses, we conducted a randomized, double-blinded, placebo-controlled, crossover clinical study to assess the effects of MC4R agonism compared with placebo on sexual brain processing in 31 premenopausal heterosexual women with HSDD.RESULTS. MC4R agonism significantly increased sexual desire for up to 24 hours after administration compared with placebo. During functional neuroimaging, MC4R agonism enhanced cerebellar and supplementary motor area activity and deactivated the secondary somatosensory cortex, specifically in response to visual erotic stimuli, compared with placebo. In addition, MC4R agonism enhanced functional connectivity between the amygdala and the insula during visual erotic stimuli compared with placebo.CONCLUSION. These data suggest that MC4R agonism enhanced sexual brain processing by reducing self-consciousness, increasing sexual imagery, and sensitizing women with HSDD to erotic stimuli. These findings provide mechanistic insight into the action of MC4R agonism in sexual behavior and are relevant to the ongoing development of HSDD therapies and MC4R agonist development more widely.TRIAL REGISTRATION. ClinicalTrials.gov NCT04179734.FUNDING. This is an investigator-sponsored study funded by AMAG Pharmaceuticals Inc., the Medical Research Council (MRC) (MR/T006242/1), and the National Institute for Health Research (NIHR) (C
Skumlien M, Mokrysz C, Freeman TP, et al., 2022, Neural responses to reward anticipation and feedback in adult and adolescent cannabis users and controls, NEUROPSYCHOPHARMACOLOGY, Vol: 47, Pages: 1976-1983, ISSN: 0893-133X
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- Citations: 6
Borissova A, Soni S, Aston ER, et al., 2022, Age differences in the behavioural economics of cannabis use: Do adolescents and adults differ on demand for cannabis and discounting of future reward?, DRUG AND ALCOHOL DEPENDENCE, Vol: 238, ISSN: 0376-8716
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- Citations: 1
Wall MB, 2022, "Technical skills are always useful, no matter what you're actually working on", Academia and the World Beyond: Navigating Life after a PhD, Pages: 23-29, ISBN: 9783030826055
In our interview with Matthew Wall, we learn about the potential to work in a position that bridges between commercial and academic research. Using the cognitive neuroscience approach of functional magnetic resonance imaging (fMRI), Matt conducts research on the effects of drugs on the brain. After a difficult PhD studying implicit learning and resulting in no publications, technical experience with fMRI and programming acquired during his PhD laid the foundation for his career. While it is useful to have a career plan, you also need to be flexible and realistic about your options. Strong research skills and an interest in methods are valuable and could lead to a path like Matt's.
Lawn W, Fernandez-Vinson N, Mokrysz C, et al., 2022, Correction to: The CannTeen study: verbal episodic memory, spatial working memory, and response inhibition in adolescent and adult cannabis users and age‑matched controls., Psychopharmacology (Berl), Vol: 239
Hunjan T, Thurston L, Ertl N, et al., 2022, Kisspeptin modulates sexual brain processing in women with low sexual desire, Publisher: WILEY, Pages: 200-200, ISSN: 1470-0328
Wall MB, Freeman TP, Hindocha C, et al., 2022, Individual and combined effects of cannabidiol and Δ<SUP>9</SUP>-tetrahydrocannabinol on striato-cortical connectivity in the human brain, JOURNAL OF PSYCHOPHARMACOLOGY, Vol: 36, Pages: 732-744, ISSN: 0269-8811
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- Citations: 7
Lawn W, Fernandez-Vinson N, Mokrysz C, et al., 2022, The CannTeen study: verbal episodic memory, spatial working memory, and response inhibition in adolescent and adult cannabis users and age-matched controls., Psychopharmacology (Berl), Vol: 239, Pages: 1629-1641
BACKGROUND: Preclinical and human studies suggest that adolescent cannabis use may be associated with worse cognitive outcomes than adult cannabis use. We investigated the associations between chronic cannabis use and cognitive function in adolescent and adult cannabis users and controls. We hypothesised user-status would be negatively associated with cognitive function and this relationship would be stronger in adolescents than adults. METHODS: As part of the 'CannTeen' project, this cross-sectional study assessed cognitive performance in adolescent cannabis users (n = 76; 16-17-year-olds), adolescent controls (n = 63), adult cannabis users (n = 71; 26-29-year-olds) and adult controls (n = 64). Users used cannabis 1-7 days/week. Adolescent and adult cannabis users were matched on cannabis use frequency (4 days/week) and time since last use (2.5 days). Verbal episodic memory (VEM) was assessed using the prose recall task, spatial working memory (SWM) was assessed using the spatial n-back task, and response inhibition was assessed with the stop-signal task. Primary outcome variables were: delayed recall, 3-back discriminability, and stop signal reaction time, respectively. RESULTS: Users had worse VEM than controls (F(1,268) = 7.423, p = 0.007). There were no significant differences between user-groups on SWM or response inhibition. Null differences were supported by Bayesian analyses. No significant interactions between age-group and user-group were found for VEM, SWM, or response inhibition. CONCLUSIONS: Consistent with previous research, there was an association between chronic cannabis use and poorer VEM, but chronic cannabis use was not associated with SWM or response inhibition. We did not find evidence for heightened adolescent vulnerability to cannabis-related cognitive impairment.
Bloomfield MAP, Yamamori Y, Hindocha C, et al., 2022, The acute effects of cannabidiol on emotional processing and anxiety: a neurocognitive imaging study, PSYCHOPHARMACOLOGY, Vol: 239, Pages: 1539-1549, ISSN: 0033-3158
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- Citations: 4
Daws R, Timmermann C, Giribaldi B, et al., 2022, Increased global integration in the brain after psilocybin therapy for depression, Nature Medicine, Vol: 28, ISSN: 1078-8956
Psilocybin therapy shows antidepressant potential, but its therapeutic actions are not well understood. We assessed the sub-acute impact of psilocybin on brain function in two clinical trials of depression. The first was an open-label trial of orally administered psilocybin (10mg and 25mg, 7 days apart) in treatment-resistant depression (TRD). fMRI was recorded at baseline and one day after the 25mg dose. Beck’s depression inventory (BDI) was the primary outcome measure (MR/J00460X/1). The second trial was a double-blind phase 2 randomised control trial (DB-RCT) comparing psilocybin therapy with escitalopram. Major depressive disorder (MDD) patients received either: 2 x 25mg oral psilocybin, 3 weeks apart, plus 6 weeks of daily placebo (‘psilocybin-arm’); or 2 x 1mg oral psilocybin, 3 weeks apart, plus 6 weeks of daily escitalopram [10-20mg] (‘escitalopram-arm’). fMRI wasrecorded at baseline and 3 weeks after the 2nd psilocybin dose (NCT03429075). In both trials, the antidepressant response to psilocybin was rapid, sustained and correlated with decreases in functional MRI (fMRI) brain network modularity, implying that psilocybin’s antidepressant action may depend on a global increase in brainnetwork integration. Network cartography analyses indicated that 5-HT2A receptor rich higher-order functional networks became more functionally inter-connected and flexible post psilocybin. The antidepressant response to escitalopram was milder and no changes in brain network organisation were observed. Consistent efficacy related brain changes, correlating with robust antidepressant effects across two studies, suggest an antidepressant mechanism for psilocybin therapy: Global increases in brain network integration.
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