ORCID Profile
0000-0001-9530-4848
Current Organisation
King's College London
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Publisher: Springer Science and Business Media LLC
Date: 27-10-2022
DOI: 10.1038/S41593-022-01186-3
Abstract: Neurotransmitter receptors support the propagation of signals in the human brain. How receptor systems are situated within macro-scale neuroanatomy and how they shape emergent function remain poorly understood, and there exists no comprehensive atlas of receptors. Here we collate positron emission tomography data from more than 1,200 healthy in iduals to construct a whole-brain three-dimensional normative atlas of 19 receptors and transporters across nine different neurotransmitter systems. We found that receptor profiles align with structural connectivity and mediate function, including neurophysiological oscillatory dynamics and resting-state hemodynamic functional connectivity. Using the Neurosynth cognitive atlas, we uncovered a topographic gradient of overlapping receptor distributions that separates extrinsic and intrinsic psychological processes. Finally, we found both expected and novel associations between receptor distributions and cortical abnormality patterns across 13 disorders. We replicated all findings in an independently collected autoradiography dataset. This work demonstrates how chemoarchitecture shapes brain structure and function, providing a new direction for studying multi-scale brain organization.
Publisher: Elsevier BV
Date: 04-2015
DOI: 10.1016/J.MEDIA.2014.12.003
Abstract: We propose a framework for the robust and fully-automatic segmentation of magnetic resonance (MR) brain images called "Multi-Atlas Label Propagation with Expectation-Maximisation based refinement" (MALP-EM). The presented approach is based on a robust registration approach (MAPER), highly performant label fusion (joint label fusion) and intensity-based label refinement using EM. We further adapt this framework to be applicable for the segmentation of brain images with gross changes in anatomy. We propose to account for consistent registration errors by relaxing anatomical priors obtained by multi-atlas propagation and a weighting scheme to locally combine anatomical atlas priors and intensity-refined posterior probabilities. The method is evaluated on a benchmark dataset used in a recent MICCAI segmentation challenge. In this context we show that MALP-EM is competitive for the segmentation of MR brain scans of healthy adults when compared to state-of-the-art automatic labelling techniques. To demonstrate the versatility of the proposed approach, we employed MALP-EM to segment 125 MR brain images into 134 regions from subjects who had sustained traumatic brain injury (TBI). We employ a protocol to assess segmentation quality if no manual reference labels are available. Based on this protocol, three independent, blinded raters confirmed on 13 MR brain scans with pathology that MALP-EM is superior to established label fusion techniques. We visually confirm the robustness of our segmentation approach on the full cohort and investigate the potential of derived symmetry-based imaging biomarkers that correlate with and predict clinically relevant variables in TBI such as the Marshall Classification (MC) or Glasgow Outcome Score (GOS). Specifically, we show that we are able to stratify TBI patients with favourable outcomes from non-favourable outcomes with 64.7% accuracy using acute-phase MR images and 66.8% accuracy using follow-up MR images. Furthermore, we are able to differentiate subjects with the presence of a mass lesion or midline shift from those with diffuse brain injury with 76.0% accuracy. The thalamus, putamen, pallidum and hippoc us are particularly affected. Their involvement predicts TBI disease progression.
Publisher: BMJ
Date: 09-2005
Publisher: Oxford University Press (OUP)
Date: 20-04-2005
DOI: 10.1093/BRAIN/AWH509
Abstract: Five to ten percent of amyotrophic lateral sclerosis (ALS) cases are associated with mutations of the superoxide dismutase-1 (SOD1) gene, and the 'D90A' mutation is associated with a unique phenotype and markedly slower disease progression (mean survival time 14 years). Relative sparing of inhibitory cortical neuronal circuits might be one mechanism contributing to the slower progression in patients homozygous for the D90A mutation (homD90A). The GABA(A) receptor PET ligand [11C]flumazenil has demonstrated motor and extra-motor cortical changes in sporadic ALS. In this study, we used [11C]flumazenil PET to explore differences in the pattern of cortical involvement between sporadic and genetically homogeneous ALS groups. Twenty-four sporadic ALS (sALS) and 10 homD90A patients underwent [11C]flumazenil PET of the brain. In addition, two subjects homozygous for the D90A mutation, but without symptoms or signs ('pre-symptomatic', psD90A), also underwent imaging. Results for each group were compared with those for 24 healthy controls of similar age. Decreases in the binding of [11C]flumazenil in the sALS group were found within premotor regions, motor cortex and posterior motor association areas. In the homD90A group of ALS patients, however, decreases were concentrated in the left fronto-temporal junction and anterior cingulate gyrus. In the two psD90A subjects, a small focus of reduced [11C]flumazenil binding at the left fronto-temporal junction was seen, similar to the pattern seen in the clinically affected patients. Within the sALS group, there was no statistically significant association between decreases in cortical [11C]flumazenil binding and revised ALS functional rating scale (ALSFRS-R score), whereas the upper motor neuron (UMN) score correlated with widespread and marked cortical decreases over the dominant hemisphere. In the homD90A group, there was a stronger statistical association between reduced cortical [11C]flumazenil binding and the ALSFRS-R, rather than the UMN, score, and also with disease duration. This study provides evidence for differences in the distribution of reduced cortical [11C]flumazenil binding in homD90A compared with sALS patients. We hypothesize that this might reflect differences in cortical neuronal vulnerability.
Publisher: Oxford University Press (OUP)
Date: 02-02-2005
DOI: 10.1093/BRAIN/AWH428
Abstract: The pathogenesis of amyotrophic lateral sclerosis (ALS) remains obscure, but it is now clear that neuronal loss is not confined to the motor cortex, even in cases without dementia. A reliable method of assessing cortical involvement in vivo remains elusive. WAY100635 binds selectively to the 5-hydroxytryptamine (5-HT1A) receptor, which is expressed on pyramidal neurones present throughout the cortex. [11C]-WAY100635 PET is, therefore, a potential marker of cerebral neuronal loss or dysfunction in ALS. Twenty-one ALS subjects and 19 healthy volunteers underwent [11C]-WAY100635 PET of the brain. A cortical template consisting of multiple volumes of interest (VOI) was applied to each in idual's [11C]-WAY100635 binding potential (BP) image to determine the regional reduction in binding in ALS patients compared to controls. There was a marked reduction (21%) in both the global cortical and raphe BP of [11C]-WAY100635 in ALS patients (P < 0.001), with regional variations in the VOI analysis that ranged from 16% to 29% decrease compared with the control group, and trends to greater reductions in those with bulbar involvement. To clarify the significance of the global cortical reductions, statistical parametric mapping was used as an alternative method to identify the cortical regions with the most significant decreases in [11C]-WAY100635 binding. SPM analysis revealed the greatest differences between ALS cases and controls in frontotemporal regions, cingulate and lateral precentral gyri. The reductions in cortical [11C]-WAY100635 binding were not related to depression, riluzole or other drug use. We postulate that the reduction of 5-HT1A binding represents loss of, or damage to, neurones bearing these receptors although we cannot exclude the possibility that these reductions reflect alterations in receptor expression or function. Further investigation into the role of the 5-HT1A receptor and the potential of [11C]-WAY100635 PET as a marker of cortical dysfunction in ALS is warranted.
Publisher: Wiley
Date: 03-04-2014
DOI: 10.1002/HBM.22522
Publisher: Royal College of Psychiatrists
Date: 07-2007
DOI: 10.1192/BJP.BP.106.031120
Abstract: Although opioid receptor function in humans is clearly reduced during opioid dependence, what happens to the receptor in early abstinence is not understood. This study sought to examine changes in opioid receptor availability in early abstinence from opioid dependence. Ten people with opioid dependence who had completed inpatient detoxification and 20 healthy controls underwent [ 11 C]-diprenorphine positron emission tomography. Clinical variables were assessed with structured questionnaires. Opioid receptor binding was characterised as the volume of distribution of [ 11 C]-diprenorphine using a template of predefined brain volumes and an exploratory voxel-by-voxel analysis. Compared with controls, participants with opioid dependence had increased [ 11 C]-diprenorphine binding in the whole brain and in 15 of the 21 a priori regions studied. This study suggests that opioid receptor binding is increased throughout the brain in early abstinence from dependent opioid use. These data complement the findings in cocaine and alcohol dependence.
Publisher: SAGE Publications
Date: 09-2022
DOI: 10.1177/02698811221099643
Abstract: Evidence from post-mortem studies and in vivo imaging studies suggests there may be reduced N-methyl-d-aspartate receptor (NMDAR) levels in the hippoc us in patients with schizophrenia. Other studies have reported increased glutamate in striatum in schizophrenia patients. It has been hypothesised that NMDAR hypofunction leads to the disinhibition of glutamatergic signalling however, this has not been tested in vivo. In this study, we investigated the relationship between hippoc al NMDAR and striatal glutamate using simultaneous positron emission tomography-magnetic resonance (PET-MR) imaging. We recruited 40 volunteers to this cross-sectional study 21 patients with schizophrenia, all in their first episode of illness, and 19 healthy controls. We measured hippoc al NMDAR availability using the PET ligand [ 18 F]GE179. This was indexed relative to whole brain as the distribution volume ratio (DVR). Striatal glutamatergic indices (glutamate and Glx) were acquired simultaneously, using combined PET-MR proton magnetic resonance spectroscopy ( 1 H-MRS). A total of 33 in iduals (15 healthy controls, 18 patients) were included in the analyses (mean (SD) age of controls, 27.31 (4.68) years mean (SD) age of patients, 24.75 (4.33), 27 male and 6 female). We found an inverse relationship between hippoc al DVR and striatal glutamate levels in people with first-episode psychosis (rho = −0.74, p 0.001) but not in healthy controls (rho = −0.22, p = 0.44). This study show that lower relative NMDAR availability in the hippoc us may drive increased striatal glutamate levels in patients with schizophrenia. Further work is required to determine whether these findings may yield new targets for drug development in schizophrenia.
Publisher: Cold Spring Harbor Laboratory
Date: 19-03-2023
DOI: 10.1101/2023.03.14.23287211
Abstract: Cognitive impairment has been reported after many types of infection, including SARS-CoV-2. Whether deficits following SARS-CoV-2 improve over time is unclear. Studies to date have focused on hospitalised in iduals with up to a year follow-up. The presence, magnitude, persistence and correlations of effects in community-based cases remain relatively unexplored. Cognitive performance (working memory, attention, reasoning, motor control) was assessed in participants of a voluntary biobank in July, 2021 (Round 1), and April, 2022 (Round 2). Participants, drawn from the COVID Symptom Study smartphone app, comprised in iduals with and without SARS-CoV-2 infection and varying symptom duration. Effects of COVID-19 exposures on cognitive accuracy and reaction time scores were estimated using multivariable ordinary least squares linear regression models weighted for inverse probability of participation, adjusting for potential confounders and mediators. The role of ongoing symptoms after COVID-19 infection was examined stratifying for self-perceived recovery. Longitudinal analysis assessed change in cognitive performance between rounds. 3335 in iduals completed Round 1, of whom 1768 also completed Round 2. At Round 1, in iduals with previous positive SARS-CoV-2 tests had lower cognitive accuracy (N = 1737, β = −0.14 standard deviations, SDs) than negative controls. Deficits were largest for positive in iduals with ≥ 12 weeks of symptoms (N = 495, β = −0.22 SDs). Effects were comparable to hospital presentation during illness (N = 281, β = −0.31 SDs), and 10 years age difference (60-70 years vs. 50-60 years, β = −0.21 SDs) in the whole study population. Stratification by self-reported recovery revealed that deficits were only detectable in SARS-CoV-2 positive in iduals who did not feel recovered from COVID-19, whereas in iduals who reported full recovery showed no deficits. Longitudinal analysis showed no evidence of cognitive change over time, suggesting that cognitive deficits for affected in iduals persisted at almost 2 years since initial infection. Cognitive deficits following SARS-CoV-2 infection were detectable nearly two years post infection, and largest for in iduals with longer symptom durations, ongoing symptoms, and/or more severe infection. However, no such deficits were detected in in iduals who reported full recovery from COVID-19. Further work is needed to monitor and develop understanding of recovery mechanisms for those with ongoing symptoms. Chronic Disease Research Foundation, Wellcome Trust, National Institute for Health and Care Research, Medical Research Council, British Heart Foundation, Alzheimer’s Society, European Union, COVID-19 Driver Relief Fund, French National Research Agency. Abstracts were screened from a PubMed search query (COVID-19) AND (long COVID) AND (cognitive impairment), which returned 409 results between 2020 and January 20, 2023. Multiple systematic reviews and meta-analyses reported consistent observation of cognitive deficits following SARS-CoV-2 infection. Most studies of cognitive impairment have used small s les of less than 200 participants (including any controls), hospitalised cohorts, and measured cognitive impairment through self-report or dichotomised quantitative scales. Only one study was found with a s le size of more than 1,000 in iduals, included cases and controls across both community and hospital settings, and used objective cognitive testing that allowed quantitative estimation of the scale of any cognitive impairment. Previous studies have also been limited insofar as focusing on earlier infections in the first year of the COVID-19 pandemic, prior to introduction of vaccination and emerging variants. Studies focusing on longitudinal follow-up for those hospitalised with COVID-19 or with long COVID have found low rates of full recovery from long-term symptoms at up to one year since infection, including cognitive impairment. We report quantitatively on cognitive impairment following SARS-CoV-2 infection, from a large dataset of 4,000 in iduals with and without test-confirmed SARS-CoV-2 infection and a range of associated symptom durations, with mostly community-based cases. Importantly, we undertook two rounds of cognitive testing allowing longitudinal tracking of cognitive performance. Our longitudinal methods allowed us to report on deficits up to two years since infection, and following infections with SARS-CoV-2 variants that have emerged over 2021 and 2022, not previously studied in the context of COVID-19 and cognition. This study adds to existing evidence of cognitive deficits following SARS-CoV-2 infection, but finds important exceptions. At initial testing in mid-2021, cognitive deficits are not found for in iduals who self-report as feeling recovered from COVID-19, even for those with longest symptom duration. In follow-up testing in mid-2022, we find that deficits appear persistent for those with earlier infections and ongoing symptoms, consistent with previous smaller studies. More research is required to monitor those experiencing persistent cognitive impairment and understand the mechanisms underlying recovery.
Publisher: Elsevier BV
Date: 10-2009
DOI: 10.1016/J.EURONEURO.2009.06.007
Abstract: The importance of the opioid receptor system in substance dependence is increasingly recognised. We used PET with the non-selective tracer [11C]diprenorphine to examine opioid receptor binding in early abstinence from alcohol dependence and the relationship to craving. We recruited 11 alcohol dependent patients and 13 controls. Subjects underwent one [11C]diprenorphine PET scan in early abstinence from dependent alcohol use (approximately 2 weeks) and 2 months later if continuously abstinent. Global and regional [11C]diprenorphine volumes of distribution (VD) were increased in alcohol dependent patients compared with controls but did not reach significance. We demonstrated a correlation between global and regional [11C]diprenorphine VD and craving in alcohol dependent patients which persisted in the anterior cingulate cortex into extended abstinence. This confirms previous work showing increased opioid receptor availability in early abstinence from substances of abuse and correlation with craving suggesting that the opioid system plays a fundamental role in this phase of addiction.
Publisher: Cold Spring Harbor Laboratory
Date: 30-10-2021
DOI: 10.1101/2021.10.28.466336
Abstract: Neurotransmitter receptors support the propagation of signals in the human brain. How receptor systems are situated within macroscale neuroanatomy and how they shape emergent function remains poorly understood, and there exists no comprehensive atlas of receptors. Here we collate positron emission tomography data from 200 healthy in iduals to construct a whole-brain 3-D normative atlas of 19 receptors and transporters across 9 different neurotransmitter systems. We find that receptor profiles align with structural connectivity and mediate function, including neurophysiological oscillatory dynamics and resting state hemodynamic functional connectivity. Using the Neurosynth cognitive atlas, we uncover a topographic gradient of overlapping receptor distributions that separates extrinsic and intrinsic psychological processes. Finally, we find both expected and novel associations between receptor distributions and cortical thinning patterns across 13 disorders. We replicate all findings in an independently collected autoradiography dataset. This work demonstrates how chemoarchitecture shapes brain structure and function, providing a new direction for studying multi-scale brain organization.
Publisher: Elsevier BV
Date: 08-2023
Publisher: Springer Science and Business Media LLC
Date: 09-02-2007
DOI: 10.1007/S00415-006-0482-7
Abstract: Four PLS patients underwent cerebral [(11)C]-flumazenil PET. They were compared firstly with a group of controls, then later directly with a group of sporadic ALS patients and a familial ALS group homozygous for the 'D90A' SOD1 gene mutation. There was a similar pattern of decreased binding in PLS patients when compared to controls as that seen in a previous study of sporadic ALS patients, supporting the concept that PLS is part of the same overall spectrum of MND. However, in direct group comparisons, both sporadic and homD90A ALS patients demonstrated relative decreases in anterior and orbito-frontal binding compared to PLS patients, suggesting that there may be differences in cortical vulnerability between phenotypic groups.
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Alexander Hammers.