Publications by authors named "Geor Bakker"

20 Publications

  • Page 1 of 1

Spatial Covariance of Cholinergic Muscarinic M /M Receptors in Parkinson's Disease.

Mov Disord 2021 May 11. Epub 2021 May 11.

Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Campus for Ageing and Vitality, Newcastle upon Tyne, United Kingdom.

Background: Parkinson's disease (PD) is associated with cholinergic dysfunction, although the role of M1 and M4 receptors remains unclear.

Objective: To investigate spatial covariance patterns of cholinergic muscarinic M /M receptors in PD and their relationship with cognition and motor symptoms.

Methods: Some 19 PD and 24 older adult controls underwent I-iodo-quinuclidinyl-benzilate (QNB) (M /M receptor) and Tc-exametazime (perfusion) single-photon emission computed tomography (SPECT) scanning. We implemented voxel principal components analysis, producing a series of images representing patterns of intercorrelated voxels across individuals. Linear regression analyses derived specific M /M spatial covariance patterns associated with PD.

Results: A cholinergic M /M pattern that converged onto key hubs of the default, auditory-visual, salience, and sensorimotor networks fully discriminated PD patients from controls (F  = 135.4, P < 0.001). In PD, we derived M /M patterns that correlated with global cognition (r = -0.62, P = 0.008) and motor severity (r = 0.53, P = 0.02). Both patterns emerged with a shared topography implicating the basal forebrain as well as visual, frontal executive, and salience circuits. Further, we found a M /M pattern that predicted global cognitive decline (r = 0.46, P = 0.04) comprising relative decreased binding within default and frontal executive networks.

Conclusions: Cholinergic muscarinic M /M modulation within key brain networks were apparent in PD. Cognition and motor severity were associated with a similar topography, inferring both phenotypes possibly rely on related cholinergic mechanisms. Relative decreased M /M binding within default and frontal executive networks could be an indicator of future cognitive decline. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.28564DOI Listing
May 2021

Effects of copy number variations on brain structure and risk for psychiatric illness: Large-scale studies from the ENIGMA working groups on CNVs.

Hum Brain Mapp 2021 Feb 21. Epub 2021 Feb 21.

Center for Neuroimaging, Genetics and Genomics, School of Psychology, NUI Galway, Galway, Ireland.

The Enhancing NeuroImaging Genetics through Meta-Analysis copy number variant (ENIGMA-CNV) and 22q11.2 Deletion Syndrome Working Groups (22q-ENIGMA WGs) were created to gain insight into the involvement of genetic factors in human brain development and related cognitive, psychiatric and behavioral manifestations. To that end, the ENIGMA-CNV WG has collated CNV and magnetic resonance imaging (MRI) data from ~49,000 individuals across 38 global research sites, yielding one of the largest studies to date on the effects of CNVs on brain structures in the general population. The 22q-ENIGMA WG includes 12 international research centers that assessed over 533 individuals with a confirmed 22q11.2 deletion syndrome, 40 with 22q11.2 duplications, and 333 typically developing controls, creating the largest-ever 22q11.2 CNV neuroimaging data set. In this review, we outline the ENIGMA infrastructure and procedures for multi-site analysis of CNVs and MRI data. So far, ENIGMA has identified effects of the 22q11.2, 16p11.2 distal, 15q11.2, and 1q21.1 distal CNVs on subcortical and cortical brain structures. Each CNV is associated with differences in cognitive, neurodevelopmental and neuropsychiatric traits, with characteristic patterns of brain structural abnormalities. Evidence of gene-dosage effects on distinct brain regions also emerged, providing further insight into genotype-phenotype relationships. Taken together, these results offer a more comprehensive picture of molecular mechanisms involved in typical and atypical brain development. This "genotype-first" approach also contributes to our understanding of the etiopathogenesis of brain disorders. Finally, we outline future directions to better understand effects of CNVs on brain structure and behavior.
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http://dx.doi.org/10.1002/hbm.25354DOI Listing
February 2021

Understanding Exposure-Receptor Occupancy Relationships for Metabotropic Glutamate Receptor 5 Negative Allosteric Modulators across a Range of Preclinical and Clinical Studies.

J Pharmacol Exp Ther 2021 04 4;377(1):157-168. Epub 2021 Feb 4.

Sosei Heptares, Cambridge, CB21 6DG, United Kingdom.

The metabotropic glutamate receptor 5 (mGlu) is a recognized central nervous system therapeutic target for which several negative allosteric modulator (NAM) drug candidates have or are continuing to be investigated for various disease indications in clinical development. Direct measurement of target receptor occupancy (RO) is extremely useful to help design and interpret efficacy and safety in nonclinical and clinical studies. In the mGlu field, this has been successfully achieved by monitoring displacement of radiolabeled ligands, specifically binding to the mGlu receptor, in the presence of an mGlu NAM using in vivo and ex vivo binding in rodents and positron emission tomography imaging in cynomolgus monkeys and humans. The aim of this study was to measure the RO of the mGlu NAM HTL0014242 in rodents and cynomolgus monkeys and to compare its plasma and brain exposure-RO relationships with those of clinically tested mGlu NAMs dipraglurant, mavoglurant, and basimglurant. Potential sources of variability that may contribute to these relationships were explored. Distinct plasma exposure-response relationships were found for each mGlu NAM, with >100-fold difference in plasma exposure for a given level of RO. However, a unified exposure-response relationship was observed when both unbound brain concentration and mGlu affinity were considered. This relationship showed <10-fold overall difference, was fitted with a Hill slope that was not significantly different from 1, and appeared consistent with a simple E model. This is the first time this type of comparison has been conducted, demonstrating a unified brain exposure-RO relationship across several species and mGlu NAMs with diverse properties. SIGNIFICANCE STATEMENT: Despite the long history of mGlu as a therapeutic target and progression of multiple compounds to the clinic, no formal comparison of exposure-receptor occupancy relationships has been conducted. The data from this study indicate for the first time that a consistent, unified relationship can be observed between exposure and mGlu receptor occupancy when unbound brain concentration and receptor affinity are taken into account across a range of species for a diverse set of mGlu negative allosteric modulators, including a new drug candidate, HTL0014242.
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http://dx.doi.org/10.1124/jpet.120.000371DOI Listing
April 2021

Cholinergic muscarinic M/M receptor networks in dementia with Lewy bodies.

Brain Commun 2020 15;2(2):fcaa098. Epub 2020 Jul 15.

Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Campus for Ageing and Vitality, Newcastle upon Tyne NE4 5PL, UK.

Cholinergic dysfunction is central in dementia with Lewy bodies, possibly contributing to the cognitive and psychiatric phenotypes of this condition. We investigated baseline muscarinic M/M receptor spatial covariance patterns in dementia with Lewy bodies and their association with changes in cognition and neuropsychiatric symptoms after 12 weeks of treatment with the cholinesterase inhibitor donepezil. Thirty-eight participants (14 cholinesterase inhibitor naive patients, 24 healthy older individuals) underwent I-iodo-quinuclidinyl-benzilate (M/M receptor assessment) and Tc-exametazime (perfusion) single-photon emission computed tomography scanning. We implemented voxel principal components analysis, producing a series of images representing patterns of inter-correlated voxels across individuals. Linear regression analyses derived specific M/M and perfusion spatial covariance patterns associated with patients. A discreet M/M pattern that distinguished patients from controls (W = 16.7,  = 0.001), showed relative decreased binding in right lateral temporal and insula, as well as relative preserved/increased binding in frontal, precuneus, lingual and cuneal regions, implicating nodes within attention and dorsal visual networks. We then derived from patients an M/M pattern that correlated with a positive change in mini-mental state examination ( = 0.52,  = 0.05), showing relative preserved/increased uptake in prefrontal, temporal pole and anterior cingulate, elements of attention-related networks. We also generated from patients an M/M pattern that correlated with a positive change in neuropsychiatric inventory score ( = 0.77,  = 0.002), revealing relative preserved/increased uptake within a bilateral temporal-precuneal-striatal system. Although in a small sample and therefore tentative, we posit that optimal response of donepezil on cognitive and neuropsychiatric signs in patients with dementia with Lewy bodies were associated with a maintenance of muscarinic M/M receptor expression within attentional/executive and ventral visual network hubs, respectively.
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http://dx.doi.org/10.1093/braincomms/fcaa098DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7475694PMC
July 2020

Virtual Histology of Cortical Thickness and Shared Neurobiology in 6 Psychiatric Disorders.

JAMA Psychiatry 2021 Jan;78(1):47-63

Department of Psychiatry and Neuropsychology, School of Mental Health and Neuroscience, Maastricht University, the Netherlands.

Importance: Large-scale neuroimaging studies have revealed group differences in cortical thickness across many psychiatric disorders. The underlying neurobiology behind these differences is not well understood.

Objective: To determine neurobiologic correlates of group differences in cortical thickness between cases and controls in 6 disorders: attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), bipolar disorder (BD), major depressive disorder (MDD), obsessive-compulsive disorder (OCD), and schizophrenia.

Design, Setting, And Participants: Profiles of group differences in cortical thickness between cases and controls were generated using T1-weighted magnetic resonance images. Similarity between interregional profiles of cell-specific gene expression and those in the group differences in cortical thickness were investigated in each disorder. Next, principal component analysis was used to reveal a shared profile of group difference in thickness across the disorders. Analysis for gene coexpression, clustering, and enrichment for genes associated with these disorders were conducted. Data analysis was conducted between June and December 2019. The analysis included 145 cohorts across 6 psychiatric disorders drawn from the ENIGMA consortium. The numbers of cases and controls in each of the 6 disorders were as follows: ADHD: 1814 and 1602; ASD: 1748 and 1770; BD: 1547 and 3405; MDD: 2658 and 3572; OCD: 2266 and 2007; and schizophrenia: 2688 and 3244.

Main Outcomes And Measures: Interregional profiles of group difference in cortical thickness between cases and controls.

Results: A total of 12 721 cases and 15 600 controls, ranging from ages 2 to 89 years, were included in this study. Interregional profiles of group differences in cortical thickness for each of the 6 psychiatric disorders were associated with profiles of gene expression specific to pyramidal (CA1) cells, astrocytes (except for BD), and microglia (except for OCD); collectively, gene-expression profiles of the 3 cell types explain between 25% and 54% of variance in interregional profiles of group differences in cortical thickness. Principal component analysis revealed a shared profile of difference in cortical thickness across the 6 disorders (48% variance explained); interregional profile of this principal component 1 was associated with that of the pyramidal-cell gene expression (explaining 56% of interregional variation). Coexpression analyses of these genes revealed 2 clusters: (1) a prenatal cluster enriched with genes involved in neurodevelopmental (axon guidance) processes and (2) a postnatal cluster enriched with genes involved in synaptic activity and plasticity-related processes. These clusters were enriched with genes associated with all 6 psychiatric disorders.

Conclusions And Relevance: In this study, shared neurobiologic processes were associated with differences in cortical thickness across multiple psychiatric disorders. These processes implicate a common role of prenatal development and postnatal functioning of the cerebral cortex in these disorders.
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http://dx.doi.org/10.1001/jamapsychiatry.2020.2694DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7450410PMC
January 2021

The muscarinic M receptor modulates associative learning and memory in psychotic disorders.

Neuroimage Clin 2020 26;27:102278. Epub 2020 May 26.

Department of Psychiatry and Psychology, University of Maastricht, Maastricht, The Netherlands.

Background: Psychotic disorders are characterized by prominent deficits in associative learning and memory for which there are currently no effective treatments. Functional magnetic resonance imaging (fMRI) studies in psychotic disorders have identified deficits in fronto-temporal activation during associative learning and memory. The underlying pathology of these findings remains unclear. Postmortem data have suggested these deficits may be related to loss of muscarinic M receptor mediated signaling. This is supported by an in-vivo study showing improvements in these symptoms after treatment with the experimental M receptor agonist xanomeline. The current study tests whether reported deficits in fronto-temporal activation could be mediated by loss of M receptor signaling in psychotic disorders.

Methods: Twenty-six medication-free subjects diagnosed with a psychotic disorder and 29 age-, gender-, and IQ-matched healthy controls underwent two functional magnetic resonance imaging (fMRI) sessions, one under placebo and one under selective M antagonist biperiden, while performing the paired associated learning task. M binding potentials (BP) were measured in the dorsolateral prefrontal cortex (DLPFC) and hippocampus using I-IDEX single photon emission computed tomography.

Results: In the subjects with psychotic disorders DLPFC hypoactivation was only found in the memory phase of the task. In both learning and memory phases of the task, M antagonism by biperiden elicited significantly greater hyperactivation of the parahippocampal gyrus and superior temporal gyrus in subjects with a psychotic disorders compared to controls. Greater hyperactivation of these areas after biperiden was associated with greater hippocampal M receptor binding during learning, with no association found with M receptor binding in the DLPFC. M receptor binding in the DLPFC was related to greater functional sensitivity to biperiden of the cingulate gyrus during the memory phase.

Conclusion: The current study is the first to show differences in M receptor mediated functional sensitivity between subjects with a psychotic disorder and controls during a paired associate learning and memory task. Results point to subjects with psychotic disorders having a loss of M receptor reserve in temporal-limbic areas.
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http://dx.doi.org/10.1016/j.nicl.2020.102278DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7305431PMC
March 2021

Increased power by harmonizing structural MRI site differences with the ComBat batch adjustment method in ENIGMA.

Neuroimage 2020 09 26;218:116956. Epub 2020 May 26.

CIBERSAM, Madrid, Spain; FIDMAG Germanes Hospitalàries Research Foundation, Barcelona, Spain.

A common limitation of neuroimaging studies is their small sample sizes. To overcome this hurdle, the Enhancing Neuro Imaging Genetics through Meta-Analysis (ENIGMA) Consortium combines neuroimaging data from many institutions worldwide. However, this introduces heterogeneity due to different scanning devices and sequences. ENIGMA projects commonly address this heterogeneity with random-effects meta-analysis or mixed-effects mega-analysis. Here we tested whether the batch adjustment method, ComBat, can further reduce site-related heterogeneity and thus increase statistical power. We conducted random-effects meta-analyses, mixed-effects mega-analyses and ComBat mega-analyses to compare cortical thickness, surface area and subcortical volumes between 2897 individuals with a diagnosis of schizophrenia and 3141 healthy controls from 33 sites. Specifically, we compared the imaging data between individuals with schizophrenia and healthy controls, covarying for age and sex. The use of ComBat substantially increased the statistical significance of the findings as compared to random-effects meta-analyses. The findings were more similar when comparing ComBat with mixed-effects mega-analysis, although ComBat still slightly increased the statistical significance. ComBat also showed increased statistical power when we repeated the analyses with fewer sites. Results were nearly identical when we applied the ComBat harmonization separately for cortical thickness, cortical surface area and subcortical volumes. Therefore, we recommend applying the ComBat function to attenuate potential effects of site in ENIGMA projects and other multi-site structural imaging work. We provide easy-to-use functions in R that work even if imaging data are partially missing in some brain regions, and they can be trained with one data set and then applied to another (a requirement for some analyses such as machine learning).
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http://dx.doi.org/10.1016/j.neuroimage.2020.116956DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7524039PMC
September 2020

Mapping Subcortical Brain Alterations in 22q11.2 Deletion Syndrome: Effects of Deletion Size and Convergence With Idiopathic Neuropsychiatric Illness.

Am J Psychiatry 2020 07 12;177(7):589-600. Epub 2020 Feb 12.

Imaging Genetics Center, Mark and Mary Stevens Institute for Neuroimaging and Informatics, Keck School of Medicine, Los Angeles (Ching, Villalon Reina, Zavaliangos-Petropulu, Thompson); Department of Biomedical Engineering, Armour College of Engineering, Illinois Institute of Technology, Chicago (Gutman); Department of Psychiatry and Biobehavioral Sciences, Semel Institute for Neuroscience and Human Behavior, Los Angeles (Ching, Sun, Lin, Jonas, Pacheco-Hansen, Vajdi, Forsyth, Bearden); Department of Psychology, UCLA, Los Angeles (Ching, Forsyth, Bearden); Department of Biomedical Engineering, Oregon Health and Science University, Portland (Ragothaman); Department of Biomedical Engineering, Duke University, Durham, N.C. (Isaev); Graduate Interdepartmental Program in Neuroscience, UCLA School of Medicine, Los Angeles (Lin, Jonas); Department of Psychiatry, University of Pittsburgh, Pittsburgh (Jalbrzikowski); Department of Psychiatry and Neuropsychology, Maastricht University, Maastricht, the Netherlands (Bakker, van Amelsvoort); Department of Radiology and Nuclear Medicine, Amsterdam University Medical Centers, Amsterdam (Bakker); Department of Psychology, Syracuse University, Syracuse, N.Y. (Antshel); Department of Psychiatry and Behavioral Sciences, SUNY Upstate Medical University, Syracuse (Fremont, Kates); School of Psychology, University of Newcastle, Newcastle, Australia (Campbell, McCabe); MIND Institute and Department of Psychiatry and Behavioral Sciences, University of California Davis, Davis (McCabe, Durdle, Goodrich-Hunsaker, Simon); Institute of Psychiatry, Psychology, and Neuroscience, Sackler Institute for Translational Neurodevelopment, and Department of Forensic and Neurodevelopmental Sciences, King's College London (Craig, Daly, Gudbrandsen, C.M. Murphy, D.G. Murphy); Bethlem Royal Hospital, National Institute for Health Research Maudsley Biomedical Research Centre, and SLaM NHS Foundation Trust, National Autism Unit, London (Craig); Behavioural Genetics Clinic, Adult Autism Service, Behavioural and Developmental Psychiatry Clinical Academic Group, South London and Maudsley NHS Foundation Trust, London (C.M. Murphy, D.G. Murphy); Department of Psychiatry, Royal College of Surgeons in Ireland, and Education and Research Centre, Beaumont Hospital, Dublin (K.C. Murphy); Department of Psychiatry, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, the Netherlands (Fiksinski, Koops, Vorstman); Clinical Genetics Research Program (Bassett, Fiksinski, Chow), Clinical Genetics Service (Chow), Campbell Family Mental Health Research Institute (Bassett), Centre for Addiction and Mental Health, Toronto; Dalglish Family 22q Clinic (Bassett, Fiksinski), Department of Mental Health, and Toronto General Hospital Research Institute (Bassett); University Health Network, Toronto (Fiksinski, Bassett); Department of Psychiatry, University of Toronto, Toronto (Bassett, Vorstman, Chow); Program in Genetics and Genome Biology, Research Institute, and Department of Psychiatry, Hospital for Sick Children, Toronto (Vorstman); Division of Human Genetics and 22q and You Center, Children's Hospital of Philadelphia, Philadelphia (Crowley, Emanuel, McDonald-McGinn, Zackai); Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia (Emanuel, McDonald-McGinn, Zackai); Department of Psychiatry, University of Pennsylvania Perelman School of Medicine and Children's Hospital of Philadelphia, Philadelphia (Gur); Department of Psychiatry, University of Pennsylvania Perelman School of Medicine, Philadelphia (Roalf, Ruparel); Departments of Radiology and Psychiatry, Hospital of the University of Pennsylvania, Philadelphia (Schmitt); Department of Psychological and Brain Sciences, University of California, Santa Barbara (Durdle); Department of Neurology, University of Utah, Salt Lake City (Goodrich-Hunsaker); Child Health Evaluative Sciences, Hospital for Sick Children Research Institute, Toronto (Butcher); Department Psychiatry, University of British Columbia, Vancouver (Vila-Rodriguez); MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, U.K. (Cunningham, Doherty, Linden, Moss, Owen, van den Bree); Cardiff University Brain Research Imaging Centre, Cardiff, U.K. (Doherty, Linden); Department of Psychiatry, Pontificia Universidad Católica de Chile, Santiago (Crossley); Clinica Alemana, Universidad del Desarrollo, Centro de Genética y Genomica, Facultad de Medicina, Santiago (Repetto); Departments of Neurology, Psychiatry, Radiology, Engineering, Pediatrics, and Ophthalmology, University of Southern California, Los Angeles (Thompson).

Objective: 22q11.2 deletion syndrome (22q11DS) is among the strongest known genetic risk factors for schizophrenia. Previous studies have reported variable alterations in subcortical brain structures in 22q11DS. To better characterize subcortical alterations in 22q11DS, including modulating effects of clinical and genetic heterogeneity, the authors studied a large multicenter neuroimaging cohort from the ENIGMA 22q11.2 Deletion Syndrome Working Group.

Methods: Subcortical structures were measured using harmonized protocols for gross volume and subcortical shape morphometry in 533 individuals with 22q11DS and 330 matched healthy control subjects (age range, 6-56 years; 49% female).

Results: Compared with the control group, the 22q11DS group showed lower intracranial volume (ICV) and thalamus, putamen, hippocampus, and amygdala volumes and greater lateral ventricle, caudate, and accumbens volumes (Cohen's d values, -0.90 to 0.93). Shape analysis revealed complex differences in the 22q11DS group across all structures. The larger A-D deletion was associated with more extensive shape alterations compared with the smaller A-B deletion. Participants with 22q11DS with psychosis showed lower ICV and hippocampus, amygdala, and thalamus volumes (Cohen's d values, -0.91 to 0.53) compared with participants with 22q11DS without psychosis. Shape analysis revealed lower thickness and surface area across subregions of these structures. Compared with subcortical findings from other neuropsychiatric disorders studied by the ENIGMA consortium, significant convergence was observed between participants with 22q11DS with psychosis and participants with schizophrenia, bipolar disorder, major depressive disorder, and obsessive-compulsive disorder.

Conclusions: In the largest neuroimaging study of 22q11DS to date, the authors found widespread alterations to subcortical brain structures, which were affected by deletion size and psychotic illness. Findings indicate significant overlap between 22q11DS-associated psychosis, idiopathic schizophrenia, and other severe neuropsychiatric illnesses.
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http://dx.doi.org/10.1176/appi.ajp.2019.19060583DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7419015PMC
July 2020

Lessons learned from using fMRI in the early clinical development of a mu-opioid receptor antagonist for disorders of compulsive consumption.

Psychopharmacology (Berl) 2021 May 4;238(5):1255-1263. Epub 2020 Jan 4.

Experimental Medicine (Neuroscience), Sosei Heptares, Cambridge, UK.

Functional magnetic resonance imaging (fMRI) has been widely used to gain a greater understanding of brain circuitry abnormalities in CNS disorders. fMRI has also been used to examine pharmacological modulation of brain circuity and is increasingly being used in early clinical drug development as functional pharmacodynamic index of target engagement, and to provide early indication of clinical efficacy. In this short review, we summarize data from experimental medicine and early clinical development studies of a mu-opioid receptor antagonist, GSK1521498 developed for disorders of compulsive consumption including binge eating in obesity. We demonstrate how fMRI can be used to answer important questions of early clinical drug development relating to; (1) target engagement, (2) dose response relationships, (3) differential efficacy and (4) prediction of behavioural and clinically relevant outcomes. We also highlight important methodological factors that need to be considered when conducting fMRI studies in drug development given the challenges faced with small sample sizes in Phase 1 and early proof of mechanism studies. While these data highlight the value of fMRI as a biomarker in drug development, its use for making Go/No-go decisions is still faced with challenges given the variability of responses, interpretation of brain activation changes and the limited data linking drug induced changes in brain activity to clinical or behavioural outcome. These challenges need to be addressed to fulfil the promise of fMRI as a tool in clinical drug development.
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http://dx.doi.org/10.1007/s00213-019-05427-5DOI Listing
May 2021

Cholinergic muscarinic M and M receptors as therapeutic targets for cognitive, behavioural, and psychological symptoms in psychiatric and neurological disorders.

Drug Discov Today 2019 12 6;24(12):2307-2314. Epub 2019 Sep 6.

Sosei Heptares, Cambridge, UK; Department of Psychiatry, University of Cambridge, Cambridge, UK; School of Psychological Sciences, Monash University, Melbourne, VIC, Australia. Electronic address:

Cholinergic dysfunction is involved in a range of neurological and psychiatric disorders, including schizophrenia, dementia and Lewy body disease (LBD), leading to widespread use of cholinergic therapies. However, such drugs have focused on increasing the availability of acetylcholine (ACh) generally, with relatively little work done on the muscarinic system and specific muscarinic receptor subtypes. In this review, we provide an overview of the major cholinergic pathways and cholinergic muscarinic receptors in the human brain and evidence for their dysfunction in several neurological and psychiatric disorders. We discuss how the selectivity of cholinergic system dysfunction suggests that targeted cholinergic therapeutics to the muscarinic receptor subtypes will be vital in treating several disorders associated with cognitive dysfunction and behavioural and psychological symptoms.
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http://dx.doi.org/10.1016/j.drudis.2019.08.009DOI Listing
December 2019

Altered white matter microstructure in 22q11.2 deletion syndrome: a multisite diffusion tensor imaging study.

Mol Psychiatry 2020 11 29;25(11):2818-2831. Epub 2019 Jul 29.

Department of Psychiatry, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands.

22q11.2 deletion syndrome (22q11DS)-a neurodevelopmental condition caused by a hemizygous deletion on chromosome 22-is associated with an elevated risk of psychosis and other developmental brain disorders. Prior single-site diffusion magnetic resonance imaging (dMRI) studies have reported altered white matter (WM) microstructure in 22q11DS, but small samples and variable methods have led to contradictory results. Here we present the largest study ever conducted of dMRI-derived measures of WM microstructure in 22q11DS (334 22q11.2 deletion carriers and 260 healthy age- and sex-matched controls; age range 6-52 years). Using harmonization protocols developed by the ENIGMA-DTI working group, we identified widespread reductions in mean, axial and radial diffusivities in 22q11DS, most pronounced in regions with major cortico-cortical and cortico-thalamic fibers: the corona radiata, corpus callosum, superior longitudinal fasciculus, posterior thalamic radiations, and sagittal stratum (Cohen's d's ranging from -0.9 to -1.3). Only the posterior limb of the internal capsule (IC), comprised primarily of corticofugal fibers, showed higher axial diffusivity in 22q11DS. 22q11DS patients showed higher mean fractional anisotropy (FA) in callosal and projection fibers (IC and corona radiata) relative to controls, but lower FA than controls in regions with predominantly association fibers. Psychotic illness in 22q11DS was associated with more substantial diffusivity reductions in multiple regions. Overall, these findings indicate large effects of the 22q11.2 deletion on WM microstructure, especially in major cortico-cortical connections. Taken together with findings from animal models, this pattern of abnormalities may reflect disrupted neurogenesis of projection neurons in outer cortical layers.
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http://dx.doi.org/10.1038/s41380-019-0450-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6986984PMC
November 2020

Influence of muscarinic M receptor antagonism on brain choline levels and functional connectivity in medication-free subjects with psychosis: A placebo controlled, cross-over study.

Psychiatry Res Neuroimaging 2019 08 23;290:5-13. Epub 2019 Jun 23.

Department of Psychiatry and Neuropsychology, Maastricht University, Maastricht, the Netherlands.

An increasing number of studies implicate the muscarinic cholinergic system in cognitive dysfunction associated with psychosis. This study examined the effect of muscarinic M receptor modulation on anterior cingulate cortex (ACC) and striatal choline concentrations and the relation with cognitive performance, as well as functional connectivity of cognitive networks. Thirty medication-free subjects with a psychosis spectrum disorder and 30 gender, age and IQ-matched healthy control subjects underwent H-proton magnetic resonance spectroscopy (H-MRS) twice, once after placebo and once after a single dose of biperiden (M receptor antagonist, 4 mg). A subset of 19 psychotic subjects and 28 controls underwent resting-state functional magnetic resonance imaging (rs-fMRI) as well. No significant differences were found in ACC and striatal choline levels, nor in functional connectivity, between the two groups after placebo. Moreover, M antagonism did not significantly affect choline levels or functional connectivity. No correlations were found between choline levels and cognition as well as psychotic symptoms. Our findings do not support an association between the cholinergic system and cognition and psychotic symptoms. However, the lack of group differences in choline concentrations and functional connectivity, both after biperiden and placebo, may indicate that there were no severe cholinergic abnormalities present in our sample.
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http://dx.doi.org/10.1016/j.pscychresns.2019.06.005DOI Listing
August 2019

Large-scale mapping of cortical alterations in 22q11.2 deletion syndrome: Convergence with idiopathic psychosis and effects of deletion size.

Mol Psychiatry 2020 08 13;25(8):1822-1834. Epub 2018 Jun 13.

Department of Radiology, Division of Neuroradiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.

The 22q11.2 deletion (22q11DS) is a common chromosomal microdeletion and a potent risk factor for psychotic illness. Prior studies reported widespread cortical changes in 22q11DS, but were generally underpowered to characterize neuroanatomic abnormalities associated with psychosis in 22q11DS, and/or neuroanatomic effects of variability in deletion size. To address these issues, we developed the ENIGMA (Enhancing Neuro Imaging Genetics Through Meta-Analysis) 22q11.2 Working Group, representing the largest analysis of brain structural alterations in 22q11DS to date. The imaging data were collected from 10 centers worldwide, including 474 subjects with 22q11DS (age = 18.2 ± 8.6; 46.9% female) and 315 typically developing, matched controls (age = 18.0 ± 9.2; 45.9% female). Compared to controls, 22q11DS individuals showed thicker cortical gray matter overall (left/right hemispheres: Cohen's d = 0.61/0.65), but focal thickness reduction in temporal and cingulate cortex. Cortical surface area (SA), however, showed pervasive reductions in 22q11DS (left/right hemispheres: d = -1.01/-1.02). 22q11DS cases vs. controls were classified with 93.8% accuracy based on these neuroanatomic patterns. Comparison of 22q11DS-psychosis to idiopathic schizophrenia (ENIGMA-Schizophrenia Working Group) revealed significant convergence of affected brain regions, particularly in fronto-temporal cortex. Finally, cortical SA was significantly greater in 22q11DS cases with smaller 1.5 Mb deletions, relative to those with typical 3 Mb deletions. We found a robust neuroanatomic signature of 22q11DS, and the first evidence that deletion size impacts brain structure. Psychotic illness in this highly penetrant deletion was associated with similar neuroanatomic abnormalities to idiopathic schizophrenia. These consistent cross-site findings highlight the homogeneity of this single genetic etiology, and support the suitability of 22q11DS as a biological model of schizophrenia.
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http://dx.doi.org/10.1038/s41380-018-0078-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6292748PMC
August 2020

Relationship between muscarinic M receptor binding and cognition in medication-free subjects with psychosis.

Neuroimage Clin 2018 3;18:713-719. Epub 2018 Mar 3.

Department of Psychiatry & Psychology, University of Maastricht, The Netherlands.

Background: It is still unclear which underlying mechanisms are involved in cognitive deficits of psychotic disorders. Pro-cognitive effects of muscarinic M receptor agonists suggest alterations in M receptor functioning may modulate these symptoms. Post mortem studies in patients with schizophrenia have shown significantly reduced M receptor expression rates in the dorsolateral prefrontal cortex (DLPFC) compared to controls. To date no in-vivo examinations of M receptor binding in relation to cognitive impairments have been done. As cognitive deficits have similar course and prognostic relevance across psychotic disorders, the current study assessed M receptor binding in the DLPFC and hippocampus in relation to cognitive functioning.

Methods: Muscarinic M receptor binding potential (BP) was measured using I-IDEX, single photon emission computed tomography (SPECT) in 30 medication-free subjects diagnosed with a psychotic disorder. A computerized neuropsychological test battery was used to assess cognition, and the positive and negative syndrome scale (PANSS) to assess severity of psychotic symptoms.

Results: Assessment of cognitive domains showed that lower M BP in the DLPFC was related to overall lower performance in verbal learning and memory. In addition, lower M BP in the DLPFC was related to greater negative symptom severity. Lastly, lower M BP in the hippocampus was related to worse delayed recognition of verbal memory.

Conclusion: This is the first study to show that variation in M receptors in the DLPFC is related to cognitive and negative symptom outcome in psychotic disorders. The M receptor may be an important biomarker in biological stratification of patients with psychotic disorders.
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http://dx.doi.org/10.1016/j.nicl.2018.02.030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5857491PMC
January 2019

Dopamine in high-risk populations: A comparison of subjects with 22q11.2 deletion syndrome and subjects at ultra high-risk for psychosis.

Psychiatry Res Neuroimaging 2018 02 21;272:65-70. Epub 2017 Nov 21.

Maastricht University, Department of Psychiatry and Psychology, Maastricht, The Netherlands.

Striatal dopamine (DA) dysfunction has been consistently reported in psychotic disorders. Differences and similarities in the pathogenesis between populations at clinical and genetic risk for developing psychosis are yet to be established. Here we explored markers of dopamine (DA) function in subjects meeting clinically ultra-high risk criteria for psychosis (UHR) and in subjects with 22q11.2 deletion syndrome (22q11DS), a genetic condition associated with significant risk for developing psychotic disorders. Single Photon Emission Computed Tomography (SPECT) with I-labelled iodobenzamide ([I]IBZM) was used to measure striatal DA D receptor binding potential (DR BP). Also, peripheral DAergic markers were assessed in serum and urine (plasma prolactin (pPRL), plasma homovanillic acid (pHVA) and urine DA(uDA)). No significant difference in striatal DR BP was found between UHR and 22q11DS subjects. Compared to UHR subjects, pPRL and pHVA were lower and uDA levels were higher in the 22q11DS subjects. However, after correcting for age and gender, only pPRL as significantly lower in the 22q11DS patients. These results may suggest that there are differences in DAergic markers between subjects with UHR and with 22q11DS that may reflect differences in the pathways to psychosis. However, bigger samples are needed to replicate these findings.
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http://dx.doi.org/10.1016/j.pscychresns.2017.11.014DOI Listing
February 2018

The effect of the muscarinic M receptor antagonist biperiden on cognition in medication free subjects with psychosis.

Eur Neuropsychopharmacol 2017 09 6;27(9):854-864. Epub 2017 Jul 6.

Maastricht University, Department of Psychiatry and Psychology, Maastricht, The Netherlands.

The acetylcholine muscarinic M receptor has been implicated in both psychosis and cognition. Post-mortem research has shown reduced muscarinic M receptor density in 25% of chronic patients with schizophrenia. It is unknown whether reduced M receptor density is related to cognitive symptoms of psychosis. We investigated the role of the M receptor in separate cognitive domains in subjects with a psychotic disorder using a muscarinic M antagonist as an acute pharmacological challenge. 33 young subjects with a psychotic disorder and 30 gender, age and IQ matched healthy controls were enrolled. All participants completed a comprehensive cognitive test battery twice: once after placebo and once after oral administration of 4mg. biperiden (M antagonist). The order of drug administration was counterbalanced. Biperiden significantly negatively influenced both verbal (p< 0.001 and p=0.032) and visual learning and memory (p=0.028) in both groups. A medication x group interaction effect was found for reasoning and problem solving (p=0.005). No main or interaction effects were found for other cognitive domains. These results provide further in-vivo evidence that the M receptor is involved in cognitive functioning, particularly verbal and visual memory processes. Lack of differential effects of biperiden between psychotic subjects and healthy controls may suggest that decreased M receptor density is only present in chronic, older schizophrenia patients. However, it remains possible that differential effects of biperiden would be present in more severe cognitive impaired subjects with psychosis after several doses of biperiden instead of a single administration.
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http://dx.doi.org/10.1016/j.euroneuro.2017.06.014DOI Listing
September 2017

Cortical Morphology Differences in Subjects at Increased Vulnerability for Developing a Psychotic Disorder: A Comparison between Subjects with Ultra-High Risk and 22q11.2 Deletion Syndrome.

PLoS One 2016 9;11(11):e0159928. Epub 2016 Nov 9.

Department of Psychiatry & Psychology, University of Maastricht, Maastricht, The Netherlands.

Introduction: Subjects with 22q11.2 deletion syndrome (22q11DS) and subjects with ultra-high risk for psychosis (UHR) share a risk of approximately 30% to develop a psychotic disorder. Studying these groups helps identify biological markers of pathophysiological processes involved in the development of psychosis. Total cortical surface area (cSA), total cortical grey matter volume (cGMV), cortical thickness (CT), and local gyrification index (LGI) of the cortical structure have a distinct neurodevelopmental origin making them important target markers to study in relation to the development of psychosis.

Materials And Methods: Structural T1-weighted high resolution images were acquired using a 3 Tesla Intera MRI system in 18 UHR subjects, 18 22q11DS subjects, and 24 matched healthy control (HC) subjects. Total cSA, total cGMV, mean CT, and regional vertex-wise differences in CT and LGI were assessed using FreeSurfer software. The Positive and Negative Syndrome Scale was used to assess psychotic symptom severity in UHR and 22q11DS subjects at time of scanning.

Results: 22q11DS subjects had lower total cSA and total cGMV compared to UHR and HC subjects. The 22q11DS subjects showed bilateral lower LGI in the i) prefrontal cortex, ii) precuneus, iii) precentral gyrus and iv) cuneus compared to UHR subjects. Additionally, lower LGI was found in the left i) fusiform gyrus and right i) pars opercularis, ii) superior, and iii) inferior temporal gyrus in 22q11DS subjects compared to HC. In comparison to 22q11DS subjects, the UHR subjects had lower CT of the insula. For both risk groups, positive symptom severity was negatively correlated to rostral middle frontal gyrus CT.

Conclusion: A shared negative correlation between positive symptom severity and rostral middle frontal gyrus CT in UHR and 22q11DS may be related to their increased vulnerability to develop a psychotic disorder. 22q11DS subjects were characterised by widespread lower degree of cortical gyrification linked to early and postnatal neurodevelopmental pathology. No implications for early neurodevelopmental pathology were found for the UHR subjects, although they did have distinctively lower insula CT which may have arisen from defective pruning processes during adolescence. Implications of these findings in relation to development of psychotic disorders are in need of further investigation in longitudinal studies.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0159928PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5102447PMC
July 2017

123I-iododexetimide preferentially binds to the muscarinic receptor subtype M1 in vivo.

J Nucl Med 2015 Feb 15;56(2):317-22. Epub 2015 Jan 15.

Department of Nuclear Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.

Unlabelled: The muscarinic M1 receptor (M1R) is highly involved in cognition, and selective M1 agonists have procognitive properties. Loss of M1R has been found in postmortem brain tissue for several neuropsychiatric disorders and may be related to symptoms of cognitive dysfunction. (123)I-iododexetimide is used for imaging muscarinic acetylcholine receptors (mAchRs). Considering its high brain uptake and intense binding in M1R-rich brain areas, (123)I-iododexetimide may be an attractive radiopharmaceutical to image M1R. To date, the binding affinity and selectivity of (123)I-iododexetimide for the mAchR subtypes has not been characterized, nor has its brain distribution been studied intensively. Therefore, this study aimed to address these topics.

Methods: The in vitro affinity and selectivity of (127)I-iododexetimide (cold-labeled iododexetimide), as well as its functional antagonist properties (guanosine 5'-[γ-(35)S-thio]triphosphate [GTPγ(35)S] assay), were assessed on recombinant human M1R-M5R. Distributions of (127)I-iododexetimide and (123)I-iododexetimide in the brain were evaluated using liquid chromatography-mass spectrometry and storage phosphor imaging, respectively, ex vivo in rats, wild-type mice, and M1-M5 knock-out (KO) mice. Inhibition of (127)I-iododexetimide and (123)I-iododexetimide binding in M1R-rich brain areas by the M1R/M4R agonist xanomeline, or the antipsychotics olanzapine (M1R antagonist) and haloperidol (low M1R affinity), was assessed in rats ex vivo.

Results: In vitro, (127)I-iododexetimide displayed high affinity for M1R (pM range), with modest selectivity over other mAchRs. In biodistribution studies on rats, ex vivo (127)I-iododexetimide binding was much higher in M1R-rich brain areas, such as the cortex and striatum, than in cerebellum (devoid of M1Rs). In M1 KO mice, but not M2-M5 KO mice, (127)I-iododexetimide binding was strongly reduced in the frontal cortex compared with wild-type mice. Finally, acute administration of both an M1R/M4R agonist xanomeline and the M1R antagonist olanzapine was able to inhibit (123)I-iododexetimide ex vivo, and (123)I-iododexetimide binding in M1-rich brain areas in rats, whereas administration of haloperidol had no effect.

Conclusion: The current results suggest that (123)I-iododexetimide preferentially binds to M1R in vivo and can be displaced by M1R ligands. (123)I-iododexetimide may therefore be a useful imaging tool as a way to further evaluate M1R changes in neuropsychiatric disorders, as a potential stratifying biomarker, or as a clinical target engagement biomarker to assess M1R.
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http://dx.doi.org/10.2967/jnumed.114.147488DOI Listing
February 2015

Pharmacological Interventions for the MATRICS Cognitive Domains in Schizophrenia: What's the Evidence?

Front Psychiatry 2013 Dec 4;4:157. Epub 2013 Dec 4.

Department of Psychiatry and Psychology, Maastricht University , Maastricht , Netherlands.

Schizophrenia is a disabling, chronic psychiatric disorder with a prevalence rate of 0.5-1% in the general population. Symptoms include positive (e.g., delusions, hallucinations), negative (e.g., blunted affect, social withdrawal), as well as cognitive symptoms (e.g., memory and attention problems). Although 75-85% of patients with schizophrenia report cognitive impairments, the underlying neuropharmacological mechanisms are not well understood and currently no effective treatment is available for these impairments. This has led to the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) initiative, which established seven cognitive domains that are fundamentally impaired in schizophrenia. These domains include verbal learning and memory, visual learning and memory, working memory, attention and vigilance, processing speed, reasoning and problem solving, and social cognition. Recently, a growing number of studies have been conducted trying to identify the underlying neuropharmacological mechanisms of cognitive impairments in schizophrenia patients. Specific cognitive impairments seem to arise from different underlying neuropharmacological mechanisms. However, most review articles describe cognition in general and an overview of the mechanisms involved in these seven separate cognitive domains is currently lacking. Therefore, we reviewed the underlying neuropharmacological mechanisms focusing on the domains as established by the MATRICS initiative which are considered most crucial in schizophrenia.
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http://dx.doi.org/10.3389/fpsyt.2013.00157DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3849802PMC
December 2013

Dopaminergic modulation of the reward system in schizophrenia: a placebo-controlled dopamine depletion fMRI study.

Eur Neuropsychopharmacol 2013 Nov 24;23(11):1577-86. Epub 2013 Aug 24.

Department of Psychiatry, Academic Medical Centre Amsterdam, The Netherlands. Electronic address:

Background: The brain reward circuitry innervated by dopamine is critically disturbed in schizophrenia. This study aims to investigate the role of dopamine-related brain activity during prediction of monetary reward and loss in first episode schizophrenia patients.

Methods: We measured blood-oxygen-level dependent (BOLD) activity in 10 patients with schizophrenia (SCH) and 12 healthy controls during dopamine depletion with α-methylparatyrosine (AMPT) and during a placebo condition (PLA).

Results: AMPT reduced the activation of striatal and cortical brain regions in SCH. In SCH vs. controls reduced activation was found in the AMPT condition in several regions during anticipation of reward and loss, including areas of the striatum and frontal cortex. In SCH vs. controls reduced activation of the superior temporal gyrus and posterior cingulate was observed in PLA during anticipation of rewarding stimuli. PLA patients had reduced activation in the ventral striatum, frontal and cingulate cortex in anticipation of loss. The findings of reduced dopamine-related brain activity during AMPT were verified by reduced levels of dopamine in urine, homovanillic-acid in plasma and increased prolactin levels.

Conclusions: Our results indicate that dopamine depletion affects functioning of the cortico-striatal reward circuitry in SCH. The findings also suggest that neuronal functions associated with dopamine neurotransmission and attribution of salience to reward predicting stimuli are altered in schizophrenia.
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http://dx.doi.org/10.1016/j.euroneuro.2013.06.008DOI Listing
November 2013
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