Imperial College London

DrOliverHowes

Faculty of MedicineInstitute of Clinical Sciences

Visiting Professor
 
 
 
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Contact

 

+44 (0)20 3313 4318oliver.howes Website

 
 
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Location

 

Steiner MRI UnitHammersmith HospitalHammersmith Campus

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Summary

 

Publications

Publication Type
Year
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128 results found

Pillinger T, Osimo EF, de Marvao A, Berry MA, Whitehurst T, Statton B, Quinlan M, Brugger S, Vazir A, Cook SA, O'Regan DP, Howes ODet al., 2019, Cardiac structure and function in patients with schizophrenia taking antipsychotic drugs: an MRI study, Translational Psychiatry, Vol: 9, ISSN: 2158-3188

Cardiovascular disease (CVD) is a major cause of excess mortality in schizophrenia. Preclinical evidence shows antipsychotics can cause myocardial fibrosis and myocardial inflammation in murine models, but it is not known if this is the case in patients. We therefore set out to determine if there is evidence of cardiac fibrosis and/or inflammation using cardiac MRI in medicated patients with schizophrenia compared with matched healthy controls. Thirty-one participants (14 patients and 17 controls) underwent cardiac MRI assessing myocardial markers of fibrosis/inflammation, indexed by native myocardial T1 time, and cardiac structure (left ventricular (LV) mass) and function (left/right ventricular end-diastolic and end-systolic volumes, stroke volumes, and ejection fractions). Participants were physically fit, and matched for age, gender, smoking, blood pressure, BMI, HbA1c, ethnicity, and physical activity. Compared with controls, native myocardial T1 was significantly longer in patients with schizophrenia (effect size, d = 0.89; p = 0.02). Patients had significantly lower LV mass, and lower left/right ventricular end-diastolic and stroke volumes (effect sizes, d = 0.86-1.08; all p-values < 0.05). There were no significant differences in left/right end-systolic volumes and ejection fractions between groups (p > 0.05). These results suggest an early diffuse fibro-inflammatory myocardial process in patients that is independent of established CVD-risk factors and could contribute to the excess cardiovascular mortality associated with schizophrenia. Future studies are required to determine if this is due to antipsychotic treatment or is intrinsic to schizophrenia.

Journal article

Rizzo G, Veronese M, Tonietto M, Bodini B, Stankoff B, Wimberley C, Lavisse S, Bottlaender M, Bloomfield PS, Howes O, Zanotti-Fregonara P, Turkheimer FE, Bertoldo Aet al., 2019, Generalization of endothelial modelling of TSPO PET imaging: Considerations on tracer affinities., J Cereb Blood Flow Metab, Vol: 39, Pages: 874-885

The 18 kDa translocator protein (TSPO) is a marker of microglia activation and the main target of positron emission tomography (PET) ligands for neuroinflammation. Previous works showed that accounting for TSPO endothelial binding improves PET quantification for [11C]PBR28, [18F]DPA714 and [11C]-R-PK11195. It is still unclear, however, whether the vascular signal is tracer-dependent. This work aims to explore the relationship between the TSPO vascular and tissue components for PET tracers with varying affinity, also assessing the impact of affinity towards the differentiability amongst kinetics and the ensuing ligand amenability to cluster analysis for the extraction of a reference region. First, we applied the compartmental model accounting for vascular binding to [11C]-R-PK11195 data from six healthy subjects. Then, we compared the [11C]-R-PK11195 vascular binding estimates with previously published values for [18F]DPA714 and [11C]PBR28. Finally, we determined the suitability for reference region extraction by calculating the angle between grey and white matter kinetics. Our results showed that endothelial binding is common to all TSPO tracers and proportional to their affinity. By consequence, grey and white matter kinetics were most similar for the radioligand with the highest affinity (i.e. [11C]PBR28), hence poorly suited for the extraction of a reference region using supervised clustering.

Journal article

Lally J, Ajnakina O, Singh N, Gardner-Sood P, Stubbs B, Stringer D, Di Forti M, David AS, Smith S, Murray RM, Howes OD, Gaughran Fet al., 2019, Vitamin D and clinical symptoms in First Episode Psychosis (FEP): A prospective cohort study, SCHIZOPHRENIA RESEARCH, Vol: 204, Pages: 381-388, ISSN: 0920-9964

Journal article

Nour M, Dahoun T, Schwartenbeck P, Adams R, FitzGerald T, Coello C, Wall M, Dolan R, Howes Oet al., 2019, Dopamine modulates belief updating but not surprise in the midbrain and ventral striatum, 31st Congress of the European-College-of-Neuropsychopharmacology (ECNP), Publisher: ELSEVIER SCIENCE BV, Pages: S312-S313, ISSN: 0924-977X

Conference paper

McGinnity CJ, Arstad E, Beck K, Brooks DJ, Coles JP, Duncan JS, Galovic M, Hinz R, Hirani E, Howes OD, Jones PA, Koepp MJ, Luo F, Barros DAR, Singh N, Trigg W, Hammers Aet al., 2019, Comment on "In Vivo [F-18]GE-179 Brain Signal Does Not Show NMDA-Specific Modulation with Drug Challenges in Rodents and Nonhuman Primates", ACS CHEMICAL NEUROSCIENCE, Vol: 10, Pages: 768-772, ISSN: 1948-7193

Journal article

Bloomfield PS, Bonsall D, Wells L, Dormann D, Howes O, De Paola Vet al., 2018, The effects of haloperidol on microglial morphology and translocator protein levels: An in vivo study in rats using an automated cell evaluation pipeline, Journal of Psychopharmacology, Vol: 32, Pages: 1264-1272, ISSN: 1461-7285

BACKGROUND: Altered microglial markers and morphology have been demonstrated in patients with schizophrenia in post-mortem and in vivo studies. However, it is unclear if changes are due to antipsychotic treatment. AIMS: Here we aimed to determine whether antipsychotic medication affects microglia in vivo. METHODS: To investigate this we administered two clinically relevant doses (0.05 mg n=12 and 2.5 mg n=7 slow-release pellets, placebo n=20) of haloperidol, over 2 weeks, to male Sprague Dawley rats to determine the effect on microglial cell density and morphology (area occupied by processes and microglial cell area). We developed an analysis pipeline for the automated assessment of microglial cells and used lipopolysaccharide (LPS) treatment ( n=13) as a positive control for analysis. We also investigated the effects of haloperidol ( n=9) or placebo ( n=10) on the expression of the translocator protein 18 kDa (TSPO) using autoradiography with [3H]PBR28, a TSPO ligand used in human positron emission tomography (PET) studies. RESULTS: Here we demonstrated that haloperidol at either dose does not alter microglial measures compared with placebo control animals ( p > 0.05). Similarly there was no difference in [3H]PBR28 binding between placebo and haloperidol tissue ( p > 0.05). In contrast, LPS was associated with greater cell density ( p = 0.04) and larger cell size ( p = 0.01). CONCLUSION: These findings suggest that haloperidol does not affect microglial cell density, morphology or TSPO expression, indicating that clinical study alterations are likely not the consequence of antipsychotic treatment. The automated cell evaluation pipeline was able to detect changes in microglial morphology induced by LPS and is made freely available for future use.

Journal article

Reis Marques T, Ashok A, Pillinger T, Veronese M, Turkheimer F, Dazzan P, Sommer I, Howes Oet al., 2018, Neuroinflammation in schizophrenia: meta-analysis of in-vivo microglial imaging studies, Psychological Medicine, ISSN: 0033-2917

AbstractBackgroundConverging lines of evidence implicate an important role for the immune system in schizophrenia. Microglia are the resident immune cells of the central nervous system and have many functions including neuroinflammation, axonal guidance and neurotrophic support. We aimed to provide a quantitative review of in vivo PET imaging studies of microglia activation in patients with schizophrenia compared with healthy controls.MethodsDemographic, clinical and imaging measures were extracted from each study and meta-analysis was conducted using a random-effects model (Hedge's g). The difference in 18-kDa translocator protein (TSPO) binding between patients with schizophrenia and healthy controls, as quantified by either binding potential (BP) or volume of distribution (VT), was used as the main outcome. Sub-analysis and sensitivity analysis were carried out to investigate the effects of genotype, ligand and illness stage.ResultsIn total, 12 studies comprising 190 patients with schizophrenia and 200 healthy controls met inclusion criteria. There was a significant elevation in tracer binding in schizophrenia patients relative to controls when BP was used as an outcome measure, (Hedge's g = 0.31; p = 0.03) but no significant differences when VT was used (Hedge's g = −0.22; p = 0.29).ConclusionsIn conclusion, there is evidence for moderate elevations in TSPO tracer binding in grey matter relative to other brain tissue in schizophrenia when using BP as an outcome measure, but no difference when VT is the outcome measure. We discuss the relevance of these findings as well as the methodological issues that may underlie the contrasting difference between these outcomes.

Journal article

Nour MM, Dahoun T, Schwartenbeck P, Adams RA, FitzGerald THB, Coello C, Wall MB, Dolan RJ, Howes ODet al., 2018, Dopaminergic basis for signaling belief updates, but not surprise, and the link to paranoia, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, Vol: 115, Pages: E10167-E10176, ISSN: 0027-8424

Journal article

Horder J, Andersson M, Mendez MA, Singh N, Tangen A, Lundberg J, Gee A, Halldin C, Veronese M, Bolte S, Farde L, Sementa T, Cash D, Higgins K, Spain D, Turkheimer F, Mick I, Selvaraj S, Nutt DJ, Lingford-Hughes A, Howes OD, Murphy DG, Borg Jet al., 2018, GABA(A) receptor availability is not altered in adults with autism spectrum disorder or in mouse models, Science Translational Medicine, Vol: 10, ISSN: 1946-6234

Preliminary studies have suggested that γ-aminobutyric acid type A (GABAA) receptors, and potentially the GABAA α5 subtype, are deficient in autism spectrum disorder (ASD). However, prior studies have been confounded by the effects of medications, and these studies did not compare findings across different species. We measured both total GABAA and GABAA α5 receptor availability in two positron emission tomography imaging studies. We used the tracer [11C]flumazenil in 15 adults with ASD and in 15 control individuals without ASD and the tracer [11C]Ro15-4513 in 12 adults with ASD and in 16 control individuals without ASD. All participants were free of medications. We also performed autoradiography, using the same tracers, in three mouse models of ASD: the Cntnap2 knockout mouse, the Shank3 knockout mouse, and mice carrying a 16p11.2 deletion. We found no differences in GABAA receptor or GABAA α5 subunit availability in any brain region of adults with ASD compared to those without ASD. There were no differences in GABAA receptor or GABAA α5 subunit availability in any of the three mouse models. However, adults with ASD did display altered performance on a GABA-sensitive perceptual task. Our data suggest that GABAA receptor availability may be normal in adults with ASD, although GABA signaling may be functionally impaired.

Journal article

McCutcheon RA, Nour MM, Dahoun T, Jauhar S, Pepper F, Expert P, Veronese M, Adams RA, Turkheimer F, Mehta MA, Howes Oet al., 2018, Mesolimbic dopamine function is related to salience network connectivity: an integrative PET and MR study, Biological Psychiatry, ISSN: 0006-3223

BackgroundA wide range of neuropsychiatric disorders, from schizophrenia to drug addiction, involve abnormalities in both the mesolimbic dopamine system and the cortical salience network. Both systems play a key role in the detection of behaviorally relevant environmental stimuli. Although anatomical overlap exists, the functional relationship between these systems remains unknown. Preclinical research has suggested that the firing of mesolimbic dopamine neurons may activate nodes of the salience network, but in vivo human research is required given the species-specific nature of this network.MethodsWe employed positron emission tomography to measure both dopamine release capacity (using the D2/3 receptor ligand 11C-PHNO, n = 23) and dopamine synthesis capacity (using 18F-DOPA, n = 21) within the ventral striatum. Resting-state functional magnetic resonance imaging was also undertaken in the same individuals to investigate salience network functional connectivity. A graph theoretical approach was used to characterize the relationship between dopamine measures and network connectivity.ResultsDopamine synthesis capacity was associated with greater salience network connectivity, and this relationship was particularly apparent for brain regions that act as information-processing hubs. In contrast, dopamine release capacity was associated with weaker salience network connectivity. There was no relationship between dopamine measures and visual and sensorimotor networks, indicating specificity of the findings.ConclusionsOur findings demonstrate a close relationship between the salience network and mesolimbic dopamine system, and they are relevant to neuropsychiatric illnesses in which aberrant functioning of both systems has been observed.

Journal article

Plavén-Sigray P, Matheson GJ, Collste K, Ashok AH, Coughlin JM, Howes OD, Mizrahi R, Pomper MG, Rusjan P, Veronese M, Wang Y, Cervenka Set al., 2018, Positron emission tomography studies of the Glial cell marker translocator protein in patients with psychosis: a meta-analysis using individual participant data, Biological Psychiatry, Vol: 84, Pages: 433-442, ISSN: 0006-3223

BACKGROUND: Accumulating evidence suggests that the immune system may be an important target for new treatment approaches in schizophrenia. Positron emission tomography and radioligands binding to the translocator protein (TSPO), which is expressed in glial cells in the brain including immune cells, represents a potential method for patient stratification and treatment monitoring. This study examined whether patients with first-episode psychosis and schizophrenia had altered TSPO levels compared with healthy control subjects. METHODS: PubMed was searched for studies comparing patients with psychosis with healthy control subjects using second-generation TSPO radioligands. The outcome measure was total distribution volume (VT), an index of TSPO levels, in frontal cortex, temporal cortex, and hippocampus. Bayes factors (BFs) were applied to examine the relative support for higher, lower, or no difference in patients' TSPO levels compared with healthy control subjects. RESULTS: Five studies, with 75 participants with first-episode psychosis or schizophrenia and 77 healthy control subjects, were included. BFs showed strong support for lower VT in patients relative to no difference (all BFs > 32), or relative to higher VT (all BFs > 422), in all brain regions. From the posterior distributions, mean patient-control differences in standardized VT values were -0.48 for frontal cortex (95% credible interval [CredInt] = -0.88 to 0.09), -0.47 for temporal cortex (CredInt = -0.87 to -0.07), and -0.63 for hippocampus (CredInt = -1.00 to -0.25). CONCLUSIONS: The lower levels of TSPO observed in patients may correspond to altered function or lower density of brain immune cells. Future studies should focus on investigating the underlying biological mechanisms and their relevance for treatment.

Journal article

Winton-Brown T, Schmidt A, Roiser JP, Howes OD, Egerton A, Fusar-Poli P, Bunzeck N, Grace AA, Duzel E, Kapur S, McGuire Pet al., 2018, Altered activation and connectivity in a hippocampal-basal ganglia-midbrain circuit during salience processing in subjects at ultra high risk for psychosis (vol 7, e1245, 2017), TRANSLATIONAL PSYCHIATRY, Vol: 8, ISSN: 2158-3188

Journal article

Veronese M, Marques TR, Bloomfield PS, Rizzo G, Singh N, Jones D, Agushi E, Mosses D, Bertoldo A, Howes O, Roncaroli F, Turkheimer FEet al., 2018, Kinetic modelling of [C-11]PBR28 for 18kDa translocator protein PET data: A validation study of vascular modelling in the brain using XBD173 and tissue analysis, JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM, Vol: 38, Pages: 1227-1242, ISSN: 0271-678X

Journal article

Selvaraj S, Bloomfield PS, Cao B, Veronese M, Turkheimer F, Howes ODet al., 2018, Brain TSPO imaging and gray matter volume in schizophrenia patients and in people at ultra high risk of psychosis: An [11C]PBR28 study., Schizophr Res, Vol: 195, Pages: 206-214

Patients with schizophrenia show whole brain and cortical gray matter (GM) volume reductions which are progressive early in their illness. Microglia, the resident immune cells in the CNS, phagocytose neurons and synapses. Some post mortem and in vivo studies in schizophrenia show evidence for elevated microglial activation compared to matched controls. However, it is currently unclear how these results relate to changes in cortical structure. METHODS: Fourteen patients with schizophrenia and 14 ultra high risk for psychosis (UHR) subjects alongside two groups of age and genotype matched healthy controls received [11C]PBR28 PET scans to index TSPO expression, a marker of microglial activation and a 3T MRI scan. We investigated the relationship between the volume changes of cortical regions and microglial activation in cortical GM (as indexed by [11C]PBR28 distribution volume ratio (DVR). RESULTS: The total cortical GM volume was significantly lower in SCZ than the controls [mean (SD)/cm3: SCZ=448.83 (39.2) and controls=499.6 (59.2) (p=0.02) but not in UHR (mean (SD)=503.06 (57.9) and controls=524.46 (45.3) p=0.3). Regression model fitted the total cortical GM DVR values with the cortical regional volumes in SCZ (r=0.81; p<0.001) and in UHR (r=0.63; p=0.02). We found a significant negative correlation between the TSPO signal and total cortical GM volume in SCZ with the highest absolute correlation coefficient in the right superior-parietal cortex (r=-0.72; p=0.006). CONCLUSIONS: These findings suggest that microglial activity is related to the altered cortical volume seen in schizophrenia. Longitudinal investigations are required to determine whether microglial activation leads to cortical gray matter loss.

Journal article

Sandhu EC, Fernando ABP, Irvine E, Tossell K, Kokkinou M, Glegola J, Smith M, Howes O, Withers DJ, Ungless MAet al., 2018, Phasic stimulation of midbrain dopamine neuron activity reduces salt consumption, eNeuro, Vol: 5, ISSN: 2373-2822

Salt intake is an essential dietary requirement, but excessive consumption is implicated in hypertension and associated conditions. Little is known about the neural circuit mechanisms that control motivation to consume salt, although the midbrain dopamine system, which plays a key role in other reward-related behaviours, has been implicated. We, therefore, examined the effects on salt consumption of either optogenetic excitation or chemogenetic inhibition of ventral tegmental area (VTA) dopamine neurons in male mice. Strikingly, optogenetic excitation of dopamine neurons decreased salt intake in a rapid and reversible manner, despite a strong salt appetite. Importantly, optogenetic excitation was not aversive, did not induce hyperactivity, and did not alter salt concentration preferences in a need-free state. In addition, we found that chemogenetic inhibition of dopamine neurons had no effect on salt intake. Lastly, optogenetic excitation of dopamine neurons reduced consumption of sucrose following an overnight fast, suggesting a more general role of VTA dopamine neuron excitation in organising motivated behaviors.

Journal article

Osimo E, Beck K, Reis Marques T, Howes ODet al., Synaptic loss in schizophrenia: a meta-analysis and systematic review of synaptic protein and mRNA measures, Molecular Psychiatry, ISSN: 1359-4184

Although synaptic loss is thought to be core to the pathophysiology of schizophrenia, the nature, consistency and magnitude of synaptic protein and mRNA changes has not been systematically appraised. Our objective was thus to systematically review and meta-analyse findings. The entire PubMed database was searched for studies from inception date to the 1st of July 2017. We selected case-control postmortem studies in schizophrenia quantifying synaptic protein or mRNA levels in brain tissue. The difference in protein and mRNA levels between cases and controls was extracted and meta-analysis conducted. Among the results, we found a significant reduction in synaptophysin in schizophrenia in the hippocampus (effect size: −0.65, p < 0.01), frontal (effect size: −0.36, p = 0.04), and cingulate cortices (effect size: −0.54, p = 0.02), but no significant changes for synaptophysin in occipital and temporal cortices, and no changes for SNAP-25, PSD-95, VAMP, and syntaxin in frontal cortex. There were insufficient studies for meta-analysis of complexins, synapsins, rab3A and synaptotagmin and mRNA measures. Findings are summarised for these, which generally show reductions in SNAP-25, PSD-95, synapsin and rab3A protein levels in the hippocampus but inconsistency in other regions. Our findings of moderate–large reductions in synaptophysin in hippocampus and frontal cortical regions, and a tendency for reductions in other pre- and postsynaptic proteins in the hippocampus are consistent with models that implicate synaptic loss in schizophrenia. However, they also identify potential differences between regions and proteins, suggesting synaptic loss is not uniform in nature or extent.

Journal article

Nour M, Dahoun T, Schwartenbeck P, Adams R, Coello C, Wall M, FitzGerald T, Dolan R, Howes Oet al., 2018, Dopamine modulates belief updating but not surprise in the midbrain and ventral striatum, European-College-of-Neuropsychopharmacology Workshop for Junior Scientists in Europe, Publisher: ELSEVIER SCIENCE BV, Pages: S26-S27, ISSN: 0924-977X

Conference paper

McCutcheon R, Beck K, D'Ambrosio E, Donocik J, Gobjila C, Jauhar S, Kaar S, Pillinger T, Marques TR, Rogdaki M, Howes ODet al., 2018, Antipsychotic plasma levels in the assessment of poor treatment response in schizophrenia, ACTA PSYCHIATRICA SCANDINAVICA, Vol: 137, Pages: 39-46, ISSN: 0001-690X

Journal article

Howes O, Allen P, Azis M, Modinos G, Bossong MGet al., Increased Resting Hippocampal and Basal Ganglia Perfusion in People at Ultra High Risk for Psychosis: Replication in a Second Cohort., Schizophrenia Bulletin, ISSN: 1745-1701

Journal article

Scott GPT, Zetterberg H, Jolly A, Cole JH, De Simoni S, Jenkins PO, Feeney C, Owen DR, Lingford-Hughes A, Howes O, Patel MC, Goldstone AP, Gunn RN, Blennow K, Matthews PM, Sharp DJet al., 2017, Minocycline reduces chronic microglial activation after brain trauma but increases neurodegeneration, Brain, Vol: 141, Pages: 459-471, ISSN: 1460-2156

Survivors of a traumatic brain injury can deteriorate years later, developing brain atrophy and dementia. Traumatic brain injury triggers chronic microglial activation, but it is unclear whether this is harmful or beneficial. A successful chronic-phase treatment for traumatic brain injury might be to target microglia. In experimental models, the antibiotic minocycline inhibits microglial activation. We investigated the effect of minocycline on microglial activation and neurodegeneration using PET, MRI, and measurement of the axonal protein neurofilament light in plasma. Microglial activation was assessed using 11C-PBR28 PET. The relationships of microglial activation to measures of brain injury, and the effects of minocycline on disease progression, were assessed using structural and diffusion MRI, plasma neurofilament light, and cognitive assessment. Fifteen patients at least 6 months after a moderate-to-severe traumatic brain injury received either minocycline 100 mg orally twice daily or no drug, for 12 weeks. At baseline, 11C-PBR28 binding in patients was increased compared to controls in cerebral white matter and thalamus, and plasma neurofilament light levels were elevated. MRI measures of white matter damage were highest in areas of greater 11C-PBR28 binding. Minocycline reduced 11C-PBR28 binding (mean Δwhite matter binding = −23.30%, 95% confidence interval −40.9 to −5.64%, P = 0.018), but increased plasma neurofilament light levels. Faster rates of brain atrophy were found in patients with higher baseline neurofilament light levels. In this experimental medicine study, minocycline after traumatic brain injury reduced chronic microglial activation while increasing a marker of neurodegeneration. These findings suggest that microglial activation has a reparative effect in the chronic phase of traumatic brain injury.

Journal article

Bhattacharyya S, Egerton A, Kim E, Rosso L, Riano Barros D, Hammers A, Brammer M, Turkheimer FE, Howes OD, McGuire Pet al., 2017, Acute induction of anxiety in humans by delta-9-tetrahydrocannabinol related to amygdalar cannabinoid-1 (CB1) receptors., Scientific Reports, Vol: 7, ISSN: 2045-2322

Use of Cannabis, the most widely used illicit drug worldwide, is associated with acute anxiety, and anxiety disorders following regular use. The precise neural and receptor basis of these effects have not been tested in man. Employing a combination of functional MRI (fMRI) and positron emission tomography (PET), we investigated whether the effects of delta-9-tetrahydrocannabinol (delta-9-THC), the main psychoactive ingredient of cannabis, on anxiety and on amygdala response while processing fearful stimuli were related to local availability of its main central molecular target, cannabinoid-1 (CB1) receptors in man. Fourteen healthy males were studied with fMRI twice, one month apart, following an oral dose of either delta-9-THC (10 mg) or placebo, while they performed a fear-processing task. Baseline availability of the CB1 receptor was studied using PET with [(11)C]MePPEP, a CB1 inverse agonist radioligand. Relative to the placebo condition, delta-9-THC induced anxiety and modulated right amygdala activation while processing fear. Both these effects were positively correlated with CB1 receptor availability in the right amygdala. These results suggest that the acute effects of cannabis on anxiety in males are mediated by the modulation of amygdalar function by delta-9-THC and the extent of these effects are related to local availability of CB1 receptors.

Journal article

Jauhar S, Nour MM, Veronese M, Rogdaki M, Bonoldi I, Azis M, Turkheimer F, McGuire P, Young AH, Howes ODet al., 2017, A Test of the Transdiagnostic Dopamine Hypothesis of Psychosis Using Positron Emission Tomographic Imaging in Bipolar Affective Disorder and Schizophrenia, JAMA Psychiatry, Vol: 74, Pages: 1206-1213, ISSN: 2168-622X

Importance The dopamine hypothesis suggests that dopamine abnormalities underlie psychosis, irrespective of diagnosis, implicating dopamine dysregulation in bipolar affective disorder and schizophrenia, in line with the research domain criteria approach. However, this hypothesis has not been directly examined in individuals diagnosed with bipolar disorder with psychosis.Objectives To test whether dopamine synthesis capacity is elevated in bipolar disorder with psychosis and how this compares with schizophrenia and matched controls and to examine whether dopamine synthesis capacity is associated with psychotic symptom severity, irrespective of diagnostic class.Design, Setting, and Participants This cross-sectional case-control positron emission tomographic study was performed in the setting of first-episode psychosis services in an inner-city area (London, England). Sixty individuals participated in the study (22 with bipolar psychosis [18 antipsychotic naive or free], 16 with schizophrenia [14 antipsychotic naive or free], and 22 matched controls) and underwent fluorodihydroxyphenyl-l-alanine ([18F]-DOPA) positron emission tomography to examine dopamine synthesis capacity. Standardized clinical measures, including the Positive and Negative Syndrome Scale, Young Mania Rating Scale, and Global Assessment of Functioning, were administered. The study dates were March 2013 to November 2016.Main Outcomes and Measures Dopamine synthesis capacity (Kicer) and clinical measures (Positive and Negative Syndrome Scale, Young Mania Rating Scale, and Global Assessment of Functioning).Results The mean (SD) ages of participants were 23.6 (3.6) years in 22 individuals with bipolar psychosis (13 male), 26.3 (4.4) years in 16 individuals with schizophrenia (14 male), and 24.5 (4.5) years in controls (14 male). There was a significant group difference in striatal dopamine synthesis capacity (Kicer) (F2,57 = 6.80, P = .002). Kicer was significantly elevat

Journal article

Kokkinou M, Ashok AH, Howes OD, 2017, The effects of ketamine on dopaminergic function: meta-analysis and review of the implications for neuropsychiatric disorders, Molecular Psychiatry, Vol: 23, Pages: 59-69, ISSN: 1476-5578

Ketamine is a non-competitive antagonist at the N-methyl-d-aspartate receptor. It has recently been found to have antidepressant effects and is a drug of abuse, suggesting it may have dopaminergic effects. To examine the effect of ketamine on the dopamine systems, we carried out a systematic review and meta-analysis of dopamine measures in the rodent, human and primate brain following acute and chronic ketamine administration relative to a drug-free baseline or control condition. Systematic search of PubMed and PsychInfo electronic databases yielded 40 original peer-reviewed studies. There were sufficient rodent studies of the acute effects of ketamine at sub-anaesthetic doses for meta-analysis. Acute ketamine administration in rodents is associated with significantly increased dopamine levels in the cortex (Hedge’s g= 1.33, P<0.01), striatum (Hedge’s g=0.57, P<0.05) and the nucleus accumbens (Hedge’s g=1.30, P<0.05) compared to control conditions, and 62–180% increases in dopamine neuron population activity. Sub-analysis indicated elevations were more marked in in vivo (g=1.93) than ex vivo (g=0.50) studies. There were not enough studies for meta-analysis in other brain regions studied (hippocampus, ventral pallidum and cerebellum), or of the effects of chronic ketamine administration, although consistent increases in cortical dopamine levels (from 88 to 180%) were reported in the latter studies. In contrast, no study showed an effect of anaesthetic doses (>100 mg kg−1) of ketamine on dopamine levels ex vivo, although this remains to be tested in vivo. Findings in non-human primates and in human studies using positron emission tomography were not consistent. The studies reviewed here provide evidence that acute ketamine administration leads to dopamine release in the rodent brain. We discuss the inter-species variation in the ketamine induced dopamine release as well as the implications for understanding psych

Journal article

Winton-Brown T, Schmidt A, Roiser JP, Howes OD, Egerton A, Fusar-Poli P, Bunzeck N, Grace AA, Duzel E, Kapur S, McGuire Pet al., 2017, Altered activation and connectivity in a hippocampal-basal ganglia-midbrain circuit during salience processing in subjects at ultra high risk for psychosis, TRANSLATIONAL PSYCHIATRY, Vol: 7, ISSN: 2158-3188

Journal article

Kokkinou M, Irvine EE, Bonsall DR, Ungless MA, Withers DJ, Howes ODet al., 2017, Modulation of sub-chronic ketamine-induced locomotor sensitisation by midbrain dopamine neuron firing, 30th Congress of the European-College-of-Neuropsychopharmacology (ECNP), Publisher: ELSEVIER SCIENCE BV, Pages: S925-S926, ISSN: 0924-977X

Conference paper

Bonsall DR, Kokkinou M, Veronese M, Coello C, Wells L, Howes ODet al., 2017, Single cocaine exposure does not alter striatal presynaptic dopamine function in mice: an [18F]-FDOPA PET study, Journal of Neurochemistry, Vol: 143, Pages: 551-560, ISSN: 1471-4159

Cocaine is a recreational drug of abuse that binds to the dopamine transporter (DAT), preventing reuptake of dopamine into presynaptic terminals. The increased presence of synaptic dopamine results in stimulation of both pre- and postsynaptic dopamine receptors, considered an important mechanism by which cocaine elicits its reinforcing properties. However, the effects of acute cocaine administration on presynaptic dopamine function remain unclear. Non-invasive imaging techniques such as positron emission tomography (PET) have revealed impaired presynaptic dopamine function in chronic cocaine users. Similar impairments have been seen in animal studies, with microdialysis experiments indicating decreased basal dopamine release. Here we use μ-PET imaging techniques in mice to measure dopamine synthesis capacity and determine the effect of acute cocaine administration of presynaptic dopamine function. We show that a dose of 20mg/kg cocaine is sufficient to elicit hyperlocomotor activity, peaking 15-20 min post treatment (p<0.001). However, dopamine synthesis capacity in the striatum was not significantly altered by acute cocaine treatment (KiCer: 0.0097 min−1 vs. 0.0112 min−1 in vehicle controls, p>0.05). Furthermore, expression levels of two key enzymes related to dopamine synthesis, tyrosine hydroxylase and aromatic l-amino acid decarboxylase, within the striatum of scanned mice were not significantly affected by acute cocaine pre-treatment (p>0.05). Our findings suggest that while the regulation of dopamine synthesis and release in the striatum have been shown to change with chronic cocaine use, leading to a reduced basal tone, these adaptations to presynaptic dopaminergic neurons are not initiated following a single exposure to the drug.

Journal article

Demjaha A, Lappin JM, Stahl D, Patel MX, MacCabe JH, Howes OD, Heslin M, Reininghaus UA, Donoghue K, Lomas B, Charalambides M, Onyejiaka A, Fearon P, Jones P, Doody G, Morgan C, Dazzan P, Murray RMet al., 2017, Antipsychotic treatment resistance in first-episode psychosis: prevalence, subtypes and predictors, PSYCHOLOGICAL MEDICINE, Vol: 47, Pages: 1981-1989, ISSN: 0033-2917

Journal article

Ashok AH, Mizuno Y, Volkow ND, Howes ODet al., 2017, Association of stimulants use with dopaminergic alterations in users of cocaine, amphetamine, or methamphetamine: a systematic review and meta-analysis, JAMA Psychiatry, Vol: 74, Pages: 511-519, ISSN: 2168-6238

Importance Stimulant use disorder is common, affecting between 0.3% and 1.1% of the population, and costs more than $85 billion per year globally. There are no licensed treatments to date. Several lines of evidence implicate the dopamine system in the pathogenesis of substance use disorder. Therefore, understanding the nature of dopamine dysfunction seen in stimulant users has the potential to aid the development of new therapeutics.Objective To comprehensively review the in vivo imaging evidence for dopaminergic alterations in stimulant (cocaine, amphetamine, or methamphetamine) abuse or dependence.Data Sources The entire PubMed, EMBASE, and PsycINFO databases were searched for studies from inception date to May 14, 2016.Study Selection Case-control studies were identified that compared dopaminergic measures between stimulant users and healthy controls using positron emission tomography or single-photon emission computed tomography to measure striatal dopamine synthesis or release or to assess dopamine transporter availability or dopamine receptor availability.Data Extraction and Synthesis Demographic, clinical, and imaging measures were extracted from each study, and meta-analyses and sensitivity analyses were conducted for stimulants combined, as well as for cocaine and for amphetamine and methamphetamine separately if there were sufficient studies.Main Outcomes and Measures Differences were measured in dopamine release (assessed using change in the D2/D3 receptor availability after administration of amphetamine or methylphenidate), dopamine transporter availability, and dopamine receptor availability in cocaine users, amphetamine and methamphetamine users, and healthy controls.Results A total of 31 studies that compared dopaminergic measures between 519 stimulant users and 512 healthy controls were included in the final analysis. In most of the studies, the duration of abstinence varied from 5 days to 3 weeks. There was a significant decrease in striatal

Journal article

Lapa CDO, Rocha GP, Marques TR, Howes O, Smith S, Monteiro RT, Zorzetti R, Spanemberg Let al., 2017, Translation and cross-cultural adaptation of the Sexual Function Questionnaire (SFQ) into Brazilian Portuguese., Trends Psychiatry Psychother, Vol: 39, Pages: 110-115

Introduction: Sexual dysfunction is common in patients with psychotic illness. This article describes the translation and cross-cultural adaptation of the Sexual Function Questionnaire (SFQ) into Brazilian Portuguese. Methods: The translation and cross-cultural adaptation followed the guidelines for adapting self-report instruments proposed by the Task Force of the International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Briefly, ISPOR steps include: preparation, forward translation, reconciliation, back-translation, back-translation review, harmonization, cognitive debriefing, review of cognitive debriefing and finalization, before proofreading and final version. The original authors authorized the translation and participated in the study. Results: There was good agreement between translations and between the back-translation and the original English version of the SFQ. The final version was prepared with certificated evaluators in the original language and in Portuguese. Few changes were necessary to the new version in Portuguese. Conclusion: The translated and adapted Brazilian Portuguese version of the SFQ is reliable and semantically equivalent to the original version. Studies on psychotropic-related sexual dysfunction may now test the validity of the instrument and can investigate sexual dysfunction in Portuguese-speaking patients.

Journal article

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