Centre for Neuroscience - Research Publications
Now showing items 1-60 of 99
Alteration to hippocampal volume and shape confined to cannabis dependence: a multi-site study
Cannabis use is highly prevalent and often considered to be relatively harmless. Nonetheless, a subset of regular cannabis users may develop dependence, experiencing poorer quality of life and greater mental health problems relative to non-dependent users. The neuroanatomy characterizing cannabis use versus dependence is poorly understood. We aimed to delineate the contributing role of cannabis use and dependence on morphology of the hippocampus, one of the most consistently altered brain regions in cannabis users, in a large multi-site dataset aggregated across four research sites. We compared hippocampal volume and vertex-level hippocampal shape differences (1) between 121 non-using controls and 140 cannabis users; (2) between 106 controls, 50 non-dependent users and 70 dependent users; and (3) between a subset of 41 controls, 41 non-dependent users and 41 dependent users, matched on sample characteristics and cannabis use pattern (onset age and dosage). Cannabis users did not differ from controls in hippocampal volume or shape. However, cannabis-dependent users had significantly smaller right and left hippocampi relative to controls and non-dependent users, irrespective of cannabis dosage. Shape analysis indicated localized deflations in the superior-medial body of the hippocampus. Our findings support neuroscientific theories postulating dependence-specific neuroadaptations in cannabis users. Future efforts should uncover the neurobiological risk and liabilities separating dependent and non-dependent use of cannabis.
Modelling the distribution of white matter hyperintensities due to ageing on MRI images using Bayesian inference.
(Elsevier BV, 2019-01-15)
White matter hyperintensities (WMH), also known as white matter lesions, are localised white matter areas that appear hyperintense on MRI scans. WMH commonly occur in the ageing population, and are often associated with several factors such as cognitive disorders, cardiovascular risk factors, cerebrovascular and neurodegenerative diseases. Despite the fact that some links between lesion location and parametric factors such as age have already been established, the relationship between voxel-wise spatial distribution of lesions and these factors is not yet well understood. Hence, it would be of clinical importance to model the distribution of lesions at the population-level and quantitatively analyse the effect of various factors on the lesion distribution model. In this work we compare various methods, including our proposed method, to generate voxel-wise distributions of WMH within a population with respect to various factors. Our proposed Bayesian spline method models the spatio-temporal distribution of WMH with respect to a parametric factor of interest, in this case age, within a population. Our probabilistic model takes as input the lesion segmentation binary maps of subjects belonging to various age groups and provides a population-level parametric lesion probability map as output. We used a spline representation to ensure a degree of smoothness in space and the dimension associated with the parameter, and formulated our model using a Bayesian framework. We tested our algorithm output on simulated data and compared our results with those obtained using various existing methods with different levels of algorithmic and computational complexity. We then compared the better performing methods on a real dataset, consisting of 1000 subjects of the UK Biobank, divided in two groups based on hypertension diagnosis. Finally, we applied our method on a clinical dataset of patients with vascular disease. On simulated dataset, the results from our algorithm showed a mean square error (MSE) value of 7.27×10-5, which was lower than the MSE value reported in the literature, with the advantage of being robust and computationally efficient. In the UK Biobank data, we found that the lesion probabilities are higher for the hypertension group compared to the non-hypertension group and further verified this finding using a statistical t-test. Finally, when applying our method on patients with vascular disease, we observed that the overall probability of lesions is significantly higher in later age groups, which is in line with the current literature.
Separation of trait and state in stuttering.
Stuttering is a disorder in which the smooth flow of speech is interrupted. People who stutter show structural and functional abnormalities in the speech and motor system. It is unclear whether functional differences reflect general traits of the disorder or are specifically related to the dysfluent speech state. We used a hierarchical approach to separate state and trait effects within stuttering. We collected sparse-sampled functional MRI during two overt speech tasks (sentence reading and picture description) in 17 people who stutter and 16 fluent controls. Separate analyses identified indicators of: (1) general traits of people who stutter; (2) frequency of dysfluent speech states in subgroups of people who stutter; and (3) the differences between fluent and dysfluent states in people who stutter. We found that reduced activation of left auditory cortex, inferior frontal cortex bilaterally, and medial cerebellum were general traits that distinguished fluent speech in people who stutter from that of controls. The stuttering subgroup with higher frequency of dysfluent states during scanning (n = 9) had reduced activation in the right subcortical grey matter, left temporo-occipital cortex, the cingulate cortex, and medial parieto-occipital cortex relative to the subgroup who were more fluent (n = 8). Finally, during dysfluent states relative to fluent ones, there was greater activation of inferior frontal and premotor cortex extending into the frontal operculum, bilaterally. The above differences were seen across both tasks. Subcortical state effects differed according to the task. Overall, our data emphasise the independence of trait and state effects in stuttering.
Donepezil Enhances Frontal Functional Connectivity in Alzheimer's Disease: A Pilot Study.
(S. Karger AG, 2016-09)
BACKGROUND: We have previously shown that increased resting-state functional magnetic resonance imaging (fMRI)-based functional connectivity (FC) within the frontal resting-state networks in Alzheimer's disease (AD) patients reflects residual, possibly compensatory, function. This suggests that symptomatic treatments should aim to enhance FC specifically in these networks. METHODS: 18 patients with probable AD underwent brain MRI and neuropsychological assessment at baseline and after 12 weeks of treatment with donepezil. We tested if changes in cognitive performance after treatment correlated with changes in FC in resting-state networks known to be altered in AD. RESULTS: We found increases in FC in the orbitofrontal network that correlated with cognitive improvement after treatment. The increased FC was greatest in patients who responded most to treatment. CONCLUSION: This 'proof of concept' study suggests that changes in network-specific FC might be a biomarker of pharmacological intervention efficacy in AD.
A multi-modal parcellation of human cerebral cortex.
(Springer Science and Business Media LLC, 2016-08-11)
Understanding the amazingly complex human cerebral cortex requires a map (or parcellation) of its major subdivisions, known as cortical areas. Making an accurate areal map has been a century-old objective in neuroscience. Using multi-modal magnetic resonance images from the Human Connectome Project (HCP) and an objective semi-automated neuroanatomical approach, we delineated 180 areas per hemisphere bounded by sharp changes in cortical architecture, function, connectivity, and/or topography in a precisely aligned group average of 210 healthy young adults. We characterized 97 new areas and 83 areas previously reported using post-mortem microscopy or other specialized study-specific approaches. To enable automated delineation and identification of these areas in new HCP subjects and in future studies, we trained a machine-learning classifier to recognize the multi-modal 'fingerprint' of each cortical area. This classifier detected the presence of 96.6% of the cortical areas in new subjects, replicated the group parcellation, and could correctly locate areas in individuals with atypical parcellations. The freely available parcellation and classifier will enable substantially improved neuroanatomical precision for studies of the structural and functional organization of human cerebral cortex and its variation across individuals and in development, aging, and disease.
Multimodal population brain imaging in the UK Biobank prospective epidemiological study.
(Springer Science and Business Media LLC, 2016-11)
Medical imaging has enormous potential for early disease prediction, but is impeded by the difficulty and expense of acquiring data sets before symptom onset. UK Biobank aims to address this problem directly by acquiring high-quality, consistently acquired imaging data from 100,000 predominantly healthy participants, with health outcomes being tracked over the coming decades. The brain imaging includes structural, diffusion and functional modalities. Along with body and cardiac imaging, genetics, lifestyle measures, biological phenotyping and health records, this imaging is expected to enable discovery of imaging markers of a broad range of diseases at their earliest stages, as well as provide unique insight into disease mechanisms. We describe UK Biobank brain imaging and present results derived from the first 5,000 participants' data release. Although this covers just 5% of the ultimate cohort, it has already yielded a rich range of associations between brain imaging and other measures collected by UK Biobank.
Informatics and data mining tools and strategies for the human connectome project.
(Frontiers Media SA, 2011)
The Human Connectome Project (HCP) is a major endeavor that will acquire and analyze connectivity data plus other neuroimaging, behavioral, and genetic data from 1,200 healthy adults. It will serve as a key resource for the neuroscience research community, enabling discoveries of how the brain is wired and how it functions in different individuals. To fulfill its potential, the HCP consortium is developing an informatics platform that will handle: (1) storage of primary and processed data, (2) systematic processing and analysis of the data, (3) open-access data-sharing, and (4) mining and exploration of the data. This informatics platform will include two primary components. ConnectomeDB will provide database services for storing and distributing the data, as well as data analysis pipelines. Connectome Workbench will provide visualization and exploration capabilities. The platform will be based on standard data formats and provide an open set of application programming interfaces (APIs) that will facilitate broad utilization of the data and integration of HCP services into a variety of external applications. Primary and processed data generated by the HCP will be openly shared with the scientific community, and the informatics platform will be available under an open source license. This paper describes the HCP informatics platform as currently envisioned and places it into the context of the overall HCP vision and agenda.
Recommendations to improve imaging and analysis of brain lesion load and atrophy in longitudinal studies of multiple sclerosis
(SPRINGER HEIDELBERG, 2013-10-01)
Focal lesions and brain atrophy are the most extensively studied aspects of multiple sclerosis (MS), but the image acquisition and analysis techniques used can be further improved, especially those for studying within-patient changes of lesion load and atrophy longitudinally. Improved accuracy and sensitivity will reduce the numbers of patients required to detect a given treatment effect in a trial, and ultimately, will allow reliable characterization of individual patients for personalized treatment. Based on open issues in the field of MS research, and the current state of the art in magnetic resonance image analysis methods for assessing brain lesion load and atrophy, this paper makes recommendations to improve these measures for longitudinal studies of MS. Briefly, they are (1) images should be acquired using 3D pulse sequences, with near-isotropic spatial resolution and multiple image contrasts to allow more comprehensive analyses of lesion load and atrophy, across timepoints. Image artifacts need special attention given their effects on image analysis results. (2) Automated image segmentation methods integrating the assessment of lesion load and atrophy are desirable. (3) A standard dataset with benchmark results should be set up to facilitate development, calibration, and objective evaluation of image analysis methods for MS.
Gray matter volume is associated with rate of subsequent skill learning after a long term training intervention
(ACADEMIC PRESS INC ELSEVIER SCIENCE, 2014-08-01)
The ability to predict learning performance from brain imaging data has implications for selecting individuals for training or rehabilitation interventions. Here, we used structural MRI to test whether baseline variations in gray matter (GM) volume correlated with subsequent performance after a long-term training of a complex whole-body task. 44 naïve participants were scanned before undertaking daily juggling practice for 6weeks, following either a high intensity or a low intensity training regime. To assess performance across the training period participants' practice sessions were filmed. Greater GM volume in medial occipito-parietal areas at baseline correlated with steeper learning slopes. We also tested whether practice time or performance outcomes modulated the degree of structural brain change detected between the baseline scan and additional scans performed immediately after training and following a further 4weeks without training. Participants with better performance had higher increases in GM volume during the period following training (i.e., between scans 2 and 3) in dorsal parietal cortex and M1. When contrasting brain changes between the practice intensity groups, we did not find any straightforward effects of practice time though practice modulated the relationship between performance and GM volume change in dorsolateral prefrontal cortex. These results suggest that practice time and performance modulate the degree of structural brain change evoked by long-term training regimes.
The ENIGMA Consortium: large-scale collaborative analyses of neuroimaging and genetic data
The Enhancing NeuroImaging Genetics through Meta-Analysis (ENIGMA) Consortium is a collaborative network of researchers working together on a range of large-scale studies that integrate data from 70 institutions worldwide. Organized into Working Groups that tackle questions in neuroscience, genetics, and medicine, ENIGMA studies have analyzed neuroimaging data from over 12,826 subjects. In addition, data from 12,171 individuals were provided by the CHARGE consortium for replication of findings, in a total of 24,997 subjects. By meta-analyzing results from many sites, ENIGMA has detected factors that affect the brain that no individual site could detect on its own, and that require larger numbers of subjects than any individual neuroimaging study has currently collected. ENIGMA's first project was a genome-wide association study identifying common variants in the genome associated with hippocampal volume or intracranial volume. Continuing work is exploring genetic associations with subcortical volumes (ENIGMA2) and white matter microstructure (ENIGMA-DTI). Working groups also focus on understanding how schizophrenia, bipolar illness, major depression and attention deficit/hyperactivity disorder (ADHD) affect the brain. We review the current progress of the ENIGMA Consortium, along with challenges and unexpected discoveries made on the way.
Relaxin Signals through a RXFP1-pERK-nNOS-NO-cGMP-Dependent Pathway to Up-Regulate Matrix Metalloproteinases: The Additional Involvement of iNOS
(PUBLIC LIBRARY SCIENCE, 2012-08-22)
The hormone, relaxin, inhibits aberrant myofibroblast differentiation and collagen deposition by disrupting the TGF-β1/Smad2 axis, via its cognate receptor, Relaxin Family Peptide Receptor 1 (RXFP1), extracellular signal-regulated kinase (ERK)1/2 phosphorylation (pERK) and a neuronal nitric oxide (NO) synthase (nNOS)-NO-cyclic guanosine monophosphate (cGMP)-dependent pathway. However, the signalling pathways involved in its additional ability to increase matrix metalloproteinase (MMP) expression and activity remain unknown. This study investigated the extent to which the NO pathway was involved in human gene-2 (H2) relaxin's ability to positively regulate MMP-1 and its rodent orthologue, MMP-13, MMP-2 and MMP-9 (the main collagen-degrading MMPs) in TGF-β1-stimulated human dermal fibroblasts and primary renal myofibroblasts isolated from injured rats; by gelatin zymography (media) and Western blotting (cell layer). H2 relaxin (10-100 ng/ml) significantly increased MMP-1 (by ~50%), MMP-2 (by ~80%) and MMP-9 (by ~80%) in TGF-β1-stimulated human dermal fibroblasts; and MMP-13 (by ~90%), MMP-2 (by ~130%) and MMP-9 (by ~115%) in rat renal myofibroblasts (all p<0.01 vs untreated cells) over 72 hours. The relaxin-induced up-regulation of these MMPs, however, was significantly blocked by a non-selective NOS inhibitor (L-nitroarginine methyl ester (hydrochloride); L-NAME; 75-100 µM), and specific inhibitors to nNOS (N-propyl-L-arginine; NPLA; 0.2-2 µM), iNOS (1400W; 0.5-1 µM) and guanylyl cyclase (ODQ; 5 µM) (all p<0.05 vs H2 relaxin alone), but not eNOS (L-N-(1-iminoethyl)ornithine dihydrochloride; L-NIO; 0.5-5 µM). However, neither of these inhibitors affected basal MMP expression at the concentrations used. Furthermore, of the NOS isoforms expressed in renal myofibroblasts (nNOS and iNOS), H2 relaxin only stimulated nNOS expression, which in turn, was blocked by the ERK1/2 inhibitor (PD98059; 1 µM). These findings demonstrated that H2 relaxin signals through a RXFP1-pERK-nNOS-NO-cGMP-dependent pathway to mediate its anti-fibrotic actions, and additionally signals through iNOS to up-regulate MMPs; the latter being suppressed by TGF-β1 in myofibroblasts, but released upon H2 relaxin-induced inhibition of the TGF-β1/Smad2 axis.
TRPM8 and Na(v)1.8 sodium channels are required for transthyretin-induced calcium influx in growth cones of small-diameter TrkA-positive sensory neurons
(BIOMED CENTRAL LTD, 2011-03-04)
BACKGROUND: Familial amyloidotic polyneuropathy (FAP) is a peripheral neuropathy caused by the extracellular accumulation and deposition of insoluble transthyretin (TTR) aggregates. However the molecular mechanism that underlies TTR toxicity in peripheral nerves is unclear. Previous studies have suggested that amyloidogenic proteins can aggregate into oligomers which disrupt intracellular calcium homeostasis by increasing the permeability of the plasma membrane to extracellular calcium. The aim of the present study was to examine the effect of TTR on calcium influx in dorsal root ganglion neurons. RESULTS: Levels of intracellular cytosolic calcium were monitored in dorsal root ganglion (DRG) neurons isolated from embryonic rats using the calcium-sensitive fluorescent indicator Fluo4. An amyloidogenic mutant form of TTR, L55P, induced calcium influx into the growth cones of DRG neurons, whereas wild-type TTR had no significant effect. Atomic force microscopy and dynamic light scattering studies confirmed that the L55P TTR contained oligomeric species of TTR. The effect of L55P TTR was decreased by blockers of voltage-gated calcium channels (VGCC), as well as by blockers of Nav1.8 voltage-gated sodium channels and transient receptor potential M8 (TRPM8) channels. siRNA knockdown of TRPM8 channels using three different TRPM8 siRNAs strongly inhibited calcium influx in DRG growth cones. CONCLUSIONS: These data suggest that activation of TRPM8 channels triggers the activation of Nav1.8 channels which leads to calcium influx through VGCC. We suggest that TTR-induced calcium influx into DRG neurons may contribute to the pathophysiology of FAP. Furthermore, we speculate that similar mechanisms may mediate the toxic effects of other amyloidogenic proteins such as the β-amyloid protein of Alzheimer's disease.
Gas6 Increases Myelination by Oligodendrocytes and Its Deficiency Delays Recovery following Cuprizone-Induced Demyelination
(PUBLIC LIBRARY SCIENCE, 2011-03-10)
Multiple sclerosis (MS) is a complex demyelinating disease of the central nervous system. Current research has shown that at least in some cases, the primary insult in MS could be directed at the oligodendrocyte, and that the earliest immune responses are primarily via innate immune cells. We have identified a family of receptor protein tyrosine kinases, known as the TAM receptors (Tyro3, Axl and Mertk), as potentially important in regulating both the oligodendrocyte and immune responses. We have previously shown that Gas6, a ligand for the TAM receptors, can affect the severity of demyelination in mice, with a loss of signalling via Gas6 leading to decreased oligodendrocyte survival and increased microglial activation during cuprizone-induced demyelination. We hypothesised TAM receptor signalling would also influence the extent of recovery in mice following demyelination. A significant effect of the absence of Gas6 was detected upon remyelination, with a lower level of myelination after 4 weeks of recovery in comparison with wild-type mice. The delay in remyelination was accompanied by a reduction in oligodendrocyte numbers. To understand the molecular mechanisms that drive the observed effects, we also examined the effect of exogenous Gas6 in in vitro myelination assays. We found that Gas6 significantly increased myelination in a dose-dependent manner, suggesting that TAM receptor signalling could be directly involved in myelination by oligodendrocytes. The reduced rate of remyelination in the absence of Gas6 could thus result from a lack of Gas6 at a critical time during myelin production after injury. These findings establish Gas6 as an important regulator of both CNS demyelination and remyelination.
Functional Characterization of Friedreich Ataxia iPS-Derived Neuronal Progenitors and Their Integration in the Adult Brain
(PUBLIC LIBRARY SCIENCE, 2014-07-07)
Friedreich ataxia (FRDA) is an autosomal recessive disease characterised by neurodegeneration and cardiomyopathy that is caused by an insufficiency of the mitochondrial protein, frataxin. Our previous studies described the generation of FRDA induced pluripotent stem cell lines (FA3 and FA4 iPS) that retained genetic characteristics of this disease. Here we extend these studies, showing that neural derivatives of FA iPS cells are able to differentiate into functional neurons, which don't show altered susceptibility to cell death, and have normal mitochondrial function. Furthermore, FA iPS-derived neural progenitors are able to differentiate into functional neurons and integrate in the nervous system when transplanted into the cerebellar regions of host adult rodent brain. These are the first studies to describe both in vitro and in vivo characterization of FA iPS-derived neurons and demonstrate their capacity to survive long term. These findings are highly significant for developing FRDA therapies using patient-derived stem cells.
Optic Nerve Diffusion Tensor Imaging after Acute Optic Neuritis Predicts Axonal and Visual Outcomes
(PUBLIC LIBRARY SCIENCE, 2013-12-26)
BACKGROUND: Early markers of axonal and clinical outcomes are required for early phase testing of putative neuroprotective therapies for multiple sclerosis (MS). OBJECTIVES: To assess whether early measurement of diffusion tensor imaging (DTI) parameters (axial and radial diffusivity) within the optic nerve during and after acute demyelinating optic neuritis (ON) could predict axonal (retinal nerve fibre layer thinning and multi-focal visual evoked potential amplitude reduction) or clinical (visual acuity and visual field loss) outcomes at 6 or 12 months. METHODS: Thirty-seven patients presenting with acute, unilateral ON were studied at baseline, one, three, six and 12 months using optic nerve DTI, clinical and paraclinical markers of axonal injury and clinical visual dysfunction. RESULTS: Affected nerve axial diffusivity (AD) was reduced at baseline, 1 and 3 months. Reduced 1-month AD correlated with retinal nerve fibre layer (RNFL) thinning at 6 (R=0.38, p=0.04) and 12 months (R=0.437, p=0.008) and VEP amplitude loss at 6 (R=0.414, p=0.019) and 12 months (R=0.484, p=0.003). AD reduction at three months correlated with high contrast visual acuity at 6 (ρ = -0.519, p = 0.001) and 12 months (ρ = -0.414, p=0.011). The time-course for AD reduction for each patient was modelled using a quadratic regression. AD normalised after a median of 18 weeks and longer normalisation times were associated with more pronounced RNFL thinning and mfVEP amplitude loss at 12 months. Affected nerve radial diffusivity (RD) was unchanged until three months, after which time it remained elevated. CONCLUSIONS: These results demonstrate that AD reduces during acute ON. One month AD reduction correlates with the extent of axonal loss and persistent AD reduction at 3 months predicts poorer visual outcomes. This suggests that acute ON therapies that normalise optic nerve AD by 3 months could also promote axon survival and improve visual outcomes.
Blocking LINGO-1 in vivo reduces degeneration and enhances regeneration of the optic nerve.
(SAGE Publications, 2016-01)
BACKGROUND: Two ongoing phase II clinical trials (RENEW and SYNERGY) have been developed to test the efficacy of anti-LINGO-1 antibodies in acute optic neuritis and relapsing forms of multiple sclerosis, respectively. Across a range of experimental models, LINGO-1 has been found to inhibit neuron and oligodendrocyte survival, axon regeneration, and (re)myelination. The therapeutic effects of anti-LINGO-1 antibodies on optic nerve axonal loss and regeneration have not yet been investigated. OBJECTIVE: In this series of studies we investigate if LINGO-1 antibodies can prevent acute inflammatory axonal loss, and promote axonal regeneration after injury in rodent optic nerves. METHODS: The effects of anti-LINGO-1 antibody on optic nerve axonal damage were assessed using rodent myelin oligodendrocyte glycoprotein experimental autoimmune encephalomyelitis (EAE), and its effects on axonal regeneration were assessed in optic nerve crush injury models. RESULTS: In the optic nerve, anti-LINGO-1 antibody therapy was associated with improved optic nerve parallel diffusivity measures on MRI in mice with EAE and reduced axonal loss in rat EAE. Both anti-LINGO-1 antibody therapy and the genetic deletion of LINGO-1 reduced nerve crush-induced axonal degeneration and enhanced axonal regeneration. CONCLUSION: These data demonstrate that LINGO-1 blockade is associated with axonal protection and regeneration in the injured optic nerve.
Effectiveness of Workplace Interventions in Return-to-Work for Musculoskeletal, Pain-Related and Mental Health Conditions: An Update of the Evidence and Messages for Practitioners
(SPRINGER/PLENUM PUBLISHERS, 2018-03-01)
Purpose The objective of this systematic review was to synthesize evidence on the effectiveness of workplace-based return-to-work (RTW) interventions and work disability management (DM) interventions that assist workers with musculoskeletal (MSK) and pain-related conditions and mental health (MH) conditions with RTW. Methods We followed a systematic review process developed by the Institute for Work & Health and an adapted best evidence synthesis that ranked evidence as strong, moderate, limited, or insufficient. Results Seven electronic databases were searched from January 1990 until April 2015, yielding 8898 non-duplicate references. Evidence from 36 medium and high quality studies were synthesized on 12 different intervention categories across three broad domains: health-focused, service coordination, and work modification interventions. There was strong evidence that duration away from work from both MSK or pain-related conditions and MH conditions were significantly reduced by multi-domain interventions encompassing at least two of the three domains. There was moderate evidence that these multi-domain interventions had a positive impact on cost outcomes. There was strong evidence that cognitive behavioural therapy interventions that do not also include workplace modifications or service coordination components are not effective in helping workers with MH conditions in RTW. Evidence for the effectiveness of other single-domain interventions was mixed, with some studies reporting positive effects and others reporting no effects on lost time and work functioning. Conclusions While there is substantial research literature focused on RTW, there are only a small number of quality workplace-based RTW intervention studies that involve workers with MSK or pain-related conditions and MH conditions. We recommend implementing multi-domain interventions (i.e. with healthcare provision, service coordination, and work accommodation components) to help reduce lost time for MSK or pain-related conditions and MH conditions. Practitioners should also consider implementing these programs to help improve work functioning and reduce costs associated with work disability.
Automated segmentation of the substantia nigra, subthalamic nucleus and red nucleus in 7T data at young and old age.
(Elsevier BV, 2016-10-01)
With recent developments in MR acquisition at 7T, smaller brainstem structures such as the red nuclei, substantia nigra and subthalamic nuclei can be imaged with good contrast and resolution. These structures have important roles both in the study of the healthy brain and in diseases such as Parkinson's disease, but few methods have been described to automatically segment them. In this paper, we extend a method that we have previously proposed for segmentation of the striatum and globus pallidus to segment these deeper and smaller structures. We modify the method to allow more direct control over segmentation smoothness by using a Markov random field prior. We investigate segmentation performance in three age groups and show that the method produces consistent results that correspond well with manual segmentations. We perform a vertex-based analysis to identify changes with age in the shape of the structures and present results suggesting that the method may be at least as effective as manual delineation in capturing differences between subjects.
Quantitative assessment of the susceptibility artefact and its interaction with motion in diffusion MRI.
(Public Library of Science (PLoS), 2017)
In this paper we evaluate the three main methods for correcting the susceptibility-induced artefact in diffusion-weighted magnetic-resonance (DW-MR) data, and assess how correction is affected by the susceptibility field's interaction with motion. The susceptibility artefact adversely impacts analysis performed on the data and is typically corrected in post-processing. Correction strategies involve either registration to a structural image, the application of an acquired field-map or the use of additional images acquired with different phase-encoding. Unfortunately, the choice of which method to use is made difficult by the absence of any systematic comparisons of them. In this work we quantitatively evaluate these methods, by extending and employing a recently proposed framework that allows for the simulation of realistic DW-MR datasets with artefacts. Our analysis separately evaluates the ability for methods to correct for geometric distortions and to recover lost information in regions of signal compression. In terms of geometric distortions, we find that registration-based methods offer the poorest correction. Field-mapping techniques are better, but are influenced by noise and partial volume effects, whilst multiple phase-encode methods performed best. We use our simulations to validate a popular surrogate metric of correction quality, the comparison of corrected data acquired with AP and LR phase-encoding, and apply this surrogate to real datasets. Furthermore, we demonstrate that failing to account for the interaction of the susceptibility field with head movement leads to increased errors when analysing DW-MR data. None of the commonly used post-processing methods account for this interaction, and we suggest this may be a valuable area for future methods development.
Image processing and Quality Control for the first 10,000 brain imaging datasets from UK Biobank.
(Elsevier BV, 2018-02-01)
UK Biobank is a large-scale prospective epidemiological study with all data accessible to researchers worldwide. It is currently in the process of bringing back 100,000 of the original participants for brain, heart and body MRI, carotid ultrasound and low-dose bone/fat x-ray. The brain imaging component covers 6 modalities (T1, T2 FLAIR, susceptibility weighted MRI, Resting fMRI, Task fMRI and Diffusion MRI). Raw and processed data from the first 10,000 imaged subjects has recently been released for general research access. To help convert this data into useful summary information we have developed an automated processing and QC (Quality Control) pipeline that is available for use by other researchers. In this paper we describe the pipeline in detail, following a brief overview of UK Biobank brain imaging and the acquisition protocol. We also describe several quantitative investigations carried out as part of the development of both the imaging protocol and the processing pipeline.
BIANCA (Brain Intensity AbNormality Classification Algorithm): A new tool for automated segmentation of white matter hyperintensities.
(Elsevier BV, 2016-11-01)
Reliable quantification of white matter hyperintensities of presumed vascular origin (WMHs) is increasingly needed, given the presence of these MRI findings in patients with several neurological and vascular disorders, as well as in elderly healthy subjects. We present BIANCA (Brain Intensity AbNormality Classification Algorithm), a fully automated, supervised method for WMH detection, based on the k-nearest neighbour (k-NN) algorithm. Relative to previous k-NN based segmentation methods, BIANCA offers different options for weighting the spatial information, local spatial intensity averaging, and different options for the choice of the number and location of the training points. BIANCA is multimodal and highly flexible so that the user can adapt the tool to their protocol and specific needs. We optimised and validated BIANCA on two datasets with different MRI protocols and patient populations (a "predominantly neurodegenerative" and a "predominantly vascular" cohort). BIANCA was first optimised on a subset of images for each dataset in terms of overlap and volumetric agreement with a manually segmented WMH mask. The correlation between the volumes extracted with BIANCA (using the optimised set of options), the volumes extracted from the manual masks and visual ratings showed that BIANCA is a valid alternative to manual segmentation. The optimised set of options was then applied to the whole cohorts and the resulting WMH volume estimates showed good correlations with visual ratings and with age. Finally, we performed a reproducibility test, to evaluate the robustness of BIANCA, and compared BIANCA performance against existing methods. Our findings suggest that BIANCA, which will be freely available as part of the FSL package, is a reliable method for automated WMH segmentation in large cross-sectional cohort studies.
Evaluating fibre orientation dispersion in white matter: Comparison of diffusion MRI, histology and polarized light imaging.
(Elsevier BV, 2017-08-15)
Diffusion MRI is an exquisitely sensitive probe of tissue microstructure, and is currently the only non-invasive measure of the brain's fibre architecture. As this technique becomes more sophisticated and microstructurally informative, there is increasing value in comparing diffusion MRI with microscopic imaging in the same tissue samples. This study compared estimates of fibre orientation dispersion in white matter derived from diffusion MRI to reference measures of dispersion obtained from polarized light imaging and histology. Three post-mortem brain specimens were scanned with diffusion MRI and analyzed with a two-compartment dispersion model. The specimens were then sectioned for microscopy, including polarized light imaging estimates of fibre orientation and histological quantitative estimates of myelin and astrocytes. Dispersion estimates were correlated on region - and voxel-wise levels in the corpus callosum, the centrum semiovale and the corticospinal tract. The region-wise analysis yielded correlation coefficients of r = 0.79 for the diffusion MRI and histology comparison, while r = 0.60 was reported for the comparison with polarized light imaging. In the corpus callosum, we observed a pattern of higher dispersion at the midline compared to its lateral aspects. This pattern was present in all modalities and the dispersion profiles from microscopy and diffusion MRI were highly correlated. The astrocytes appeared to have minor contribution to dispersion observed with diffusion MRI. These results demonstrate that fibre orientation dispersion estimates from diffusion MRI represents the tissue architecture well. Dispersion models might be improved by more faithfully incorporating an informed mapping based on microscopy data.
Conditioned respiratory threat in the subdivisions of the human periaqueductal gray
(ELIFE SCIENCES PUBLICATIONS LTD, 2016-02-27)
The sensation of breathlessness is the most threatening symptom of respiratory disease. The different subdivisions of the midbrain periaqueductal gray (PAG) are intricately (and differentially) involved in integrating behavioural responses to threat in animals, while the PAG has previously only been considered as a single entity in human research. Here we investigate how these individual PAG columns are differently involved with respiratory threat. Eighteen healthy subjects were conditioned to associate shapes with certain or uncertain impending respiratory load, and scanned the following day during anticipation and application of inspiratory loading using 7 T functional MRI. We showed activity in the ventrolateral PAG (vlPAG) during anticipation of resistive loading, with activity in the lateral PAG (lPAG) during resistive loading, revealing spatially and temporally distinct functions within this structure. We propose that lPAG is involved with sensorimotor responses to breathlessness, while the vlPAG operates within the threat perception network for impending breathlessness.
Study protocol: the Whitehall II imaging sub-study
BACKGROUND: The Whitehall II (WHII) study of British civil servants provides a unique source of longitudinal data to investigate key factors hypothesized to affect brain health and cognitive ageing. This paper introduces the multi-modal magnetic resonance imaging (MRI) protocol and cognitive assessment designed to investigate brain health in a random sample of 800 members of the WHII study. METHODS/DESIGN: A total of 6035 civil servants participated in the WHII Phase 11 clinical examination in 2012-2013. A random sample of these participants was included in a sub-study comprising an MRI brain scan, a detailed clinical and cognitive assessment, and collection of blood and buccal mucosal samples for the characterisation of immune function and associated measures. Data collection for this sub-study started in 2012 and will be completed by 2016. The participants, for whom social and health records have been collected since 1985, were between 60-85 years of age at the time the MRI study started. Here, we describe the pre-specified clinical and cognitive assessment protocols, the state-of-the-art MRI sequences and latest pipelines for analyses of this sub-study. DISCUSSION: The integration of cutting-edge MRI techniques, clinical and cognitive tests in combination with retrospective data on social, behavioural and biological variables during the preceding 25 years from a well-established longitudinal epidemiological study (WHII cohort) will provide a unique opportunity to examine brain structure and function in relation to age-related diseases and the modifiable and non-modifiable factors affecting resilience against and vulnerability to adverse brain changes.
Target Identification for Stereotactic Thalamotomy Using Diffusion Tractography
(PUBLIC LIBRARY SCIENCE, 2012-01-04)
BACKGROUND: Stereotactic targets for thalamotomy are usually derived from population-based coordinates. Individual anatomy is used only to scale the coordinates based on the location of some internal guide points. While on conventional MR imaging the thalamic nuclei are indistinguishable, recently it has become possible to identify individual thalamic nuclei using different connectivity profiles, as defined by MR diffusion tractography. METHODOLOGY AND PRINCIPAL FINDINGS: Here we investigated the inter-individual variation of the location of target nuclei for thalamotomy: the putative ventralis oralis posterior (Vop) and the ventral intermedius (Vim) nucleus as defined by probabilistic tractography. We showed that the mean inter-individual distance of the peak Vop location is 7.33 mm and 7.42 mm for Vim. The mean overlap between individual Vop nuclei was 40.2% and it was 31.8% for Vim nuclei. As a proof of concept, we also present a patient who underwent Vop thalamotomy for untreatable tremor caused by traumatic brain injury and another patient who underwent Vim thalamotomy for essential tremor. The probabilistic tractography indicated that the successful tremor control was achieved with lesions in the Vop and Vim respectively. CONCLUSIONS: Our data call attention to the need for a better appreciation of the individual anatomy when planning stereotactic functional neurosurgery.
Allostatic load as a predictor of grey matter volume and white matter integrity in old age: The Whitehall II MRI study.
(Springer Science and Business Media LLC, 2018-04-23)
The allostatic load index quantifies the cumulative multisystem physiological response to chronic everyday stress, and includes cardiovascular, metabolic and inflammatory measures. Despite its central role in the stress response, research of the effect of allostatic load on the ageing brain has been limited. We investigated the relation of mid-life allostatic load index and multifactorial predictors of stroke (Framingham stroke risk) and diabetes (metabolic syndrome) with voxelwise structural grey and white matter brain integrity measures in the ageing Whitehall II cohort (N = 349, mean age = 69.6 (SD 5.2) years, N (male) = 281 (80.5%), mean follow-up before scan = 21.4 (SD 0.82) years). Higher levels of all three markers were significantly associated with lower grey matter density. Only higher Framingham stroke risk was significantly associated with lower white matter integrity (low fractional anisotropy and high mean diffusivity). Our findings provide some empirical support for the concept of allostatic load, linking the effect of everyday stress on the body with features of the ageing human brain.
fMRI reveals neural activity overlap between adult and infant pain
(ELIFE SCIENCES PUBLICATIONS LTD, 2015-04-21)
Limited understanding of infant pain has led to its lack of recognition in clinical practice. While the network of brain regions that encode the affective and sensory aspects of adult pain are well described, the brain structures involved in infant nociceptive processing are completely unknown, meaning we cannot infer anything about the nature of the infant pain experience. Using fMRI we identified the network of brain regions that are active following acute noxious stimulation in newborn infants, and compared the activity to that observed in adults. Significant infant brain activity was observed in 18 of the 20 active adult brain regions but not in the infant amygdala or orbitofrontal cortex. Brain regions that encode sensory and affective components of pain are active in infants, suggesting that the infant pain experience closely resembles that seen in adults. This highlights the importance of developing effective pain management strategies in this vulnerable population.
Automatic segmentation of the striatum and globus pallidus using MIST: Multimodal Image Segmentation Tool.
(Elsevier BV, 2016-01-15)
Accurate segmentation of the subcortical structures is frequently required in neuroimaging studies. Most existing methods use only a T1-weighted MRI volume to segment all supported structures and usually rely on a database of training data. We propose a new method that can use multiple image modalities simultaneously and a single reference segmentation for initialisation, without the need for a manually labelled training set. The method models intensity profiles in multiple images around the boundaries of the structure after nonlinear registration. It is trained using a set of unlabelled training data, which may be the same images that are to be segmented, and it can automatically infer the location of the physical boundary using user-specified priors. We show that the method produces high-quality segmentations of the striatum, which is clearly visible on T1-weighted scans, and the globus pallidus, which has poor contrast on such scans. The method compares favourably to existing methods, showing greater overlap with manual segmentations and better consistency.
Imaging Surrogates of Disease Activity in Neuromyelitis Optica Allow Distinction from Multiple Sclerosis.
(Public Library of Science (PLoS), 2015)
Inflammatory demyelinating lesions of the central nervous system are a common feature of both neuromyelitis optica and multiple sclerosis. Despite this similarity, it is evident clinically that the accumulation of disability in patients with neuromyelitis optica is relapse related and that a progressive phase is very uncommon. This poses the question whether there is any pathological evidence of disease activity or neurodegeneration in neuromyelitis optica between relapses. To investigate this we conducted a longitudinal advanced MRI study of the brain and spinal cord in neuromyelitis optica patients, comparing to patients with multiple sclerosis and controls. We found both cross-sectional and longitudinal evidence of diffusely distributed neurodegenerative surrogates in the multiple sclerosis group (including thalamic atrophy, cervical cord atrophy and progressive widespread diffusion and myelin water imaging abnormalities in the normal appearing white matter) but not in those with neuromyelitis optica, where localised abnormalities in the optic radiations of those with severe visual impairment were noted. In addition, between relapses, there were no new silent brain lesions in the neuromyelitis optica group. These findings indicate that global central nervous system neurodegeneration is not a feature of neuromyelitis optica. The work also questions the theory that neurodegeneration in multiple sclerosis is a chronic sequela to prior inflammatory and demyelinating pathology, as this has not been found to be the case in neuromyelitis optica where the lesions are often more destructive.
Sharing brain mapping statistical results with the neuroimaging data model.
(Springer Science and Business Media LLC, 2016-12-06)
Only a tiny fraction of the data and metadata produced by an fMRI study is finally conveyed to the community. This lack of transparency not only hinders the reproducibility of neuroimaging results but also impairs future meta-analyses. In this work we introduce NIDM-Results, a format specification providing a machine-readable description of neuroimaging statistical results along with key image data summarising the experiment. NIDM-Results provides a unified representation of mass univariate analyses including a level of detail consistent with available best practices. This standardized representation allows authors to relay methods and results in a platform-independent regularized format that is not tied to a particular neuroimaging software package. Tools are available to export NIDM-Result graphs and associated files from the widely used SPM and FSL software packages, and the NeuroVault repository can import NIDM-Results archives. The specification is publically available at: http://nidm.nidash.org/specs/nidm-results.html.
Dissecting the pathobiology of altered MRI signal in amyotrophic lateral sclerosis: A post mortem whole brain sampling strategy for the integration of ultra-high-field MRI and quantitative neuropathology.
(Springer Science and Business Media LLC, 2018-03-13)
BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a clinically and histopathologically heterogeneous neurodegenerative disorder, in which therapy is hindered by the rapid progression of disease and lack of biomarkers. Magnetic resonance imaging (MRI) has demonstrated its potential for detecting the pathological signature and tracking disease progression in ALS. However, the microstructural and molecular pathological substrate is poorly understood and generally defined histologically. One route to understanding and validating the pathophysiological correlates of MRI signal changes in ALS is to directly compare MRI to histology in post mortem human brains. RESULTS: The article delineates a universal whole brain sampling strategy of pathologically relevant grey matter (cortical and subcortical) and white matter tracts of interest suitable for histological evaluation and direct correlation with MRI. A standardised systematic sampling strategy that was compatible with co-registration of images across modalities was established for regions representing phosphorylated 43-kDa TAR DNA-binding protein (pTDP-43) patterns that were topographically recognisable with defined neuroanatomical landmarks. Moreover, tractography-guided sampling facilitated accurate delineation of white matter tracts of interest. A digital photography pipeline at various stages of sampling and histological processing was established to account for structural deformations that might impact alignment and registration of histological images to MRI volumes. Combined with quantitative digital histology image analysis, the proposed sampling strategy is suitable for routine implementation in a high-throughput manner for acquisition of large-scale histology datasets. Proof of concept was determined in the spinal cord of an ALS patient where multiple MRI modalities (T1, T2, FA and MD) demonstrated sensitivity to axonal degeneration and associated heightened inflammatory changes in the lateral corticospinal tract. Furthermore, qualitative comparison of R2* and susceptibility maps in the motor cortex of 2 ALS patients demonstrated varying degrees of hyperintense signal changes compared to a control. Upon histological evaluation of the same region, intensity of signal changes in both modalities appeared to correspond primarily to the degree of microglial activation. CONCLUSION: The proposed post mortem whole brain sampling methodology enables the accurate intraindividual study of pathological propagation and comparison with quantitative MRI data, to more fully understand the relationship of imaging signal changes with underlying pathophysiology in ALS.
A combined post-mortem magnetic resonance imaging and quantitative histological study of multiple sclerosis pathology
(OXFORD UNIV PRESS, 2012-10-01)
Multiple sclerosis is a chronic inflammatory neurological condition characterized by focal and diffuse neurodegeneration and demyelination throughout the central nervous system. Factors influencing the progression of pathology are poorly understood. One hypothesis is that anatomical connectivity influences the spread of neurodegeneration. This predicts that measures of neurodegeneration will correlate most strongly between interconnected structures. However, such patterns have been difficult to quantify through post-mortem neuropathology or in vivo scanning alone. In this study, we used the complementary approaches of whole brain post-mortem magnetic resonance imaging and quantitative histology to assess patterns of multiple sclerosis pathology. Two thalamo-cortical projection systems were considered based on their distinct neuroanatomy and their documented involvement in multiple sclerosis: lateral geniculate nucleus to primary visual cortex and mediodorsal nucleus of the thalamus to prefrontal cortex. Within the anatomically distinct thalamo-cortical projection systems, magnetic resonance imaging derived cortical thickness was correlated significantly with both a measure of myelination in the connected tract and a measure of connected thalamic nucleus cell density. Such correlations did not exist between these markers of neurodegeneration across different thalamo-cortical systems. Magnetic resonance imaging lesion analysis depicted clearly demarcated subcortical lesions impinging on the white matter tracts of interest; however, quantitation of the extent of lesion-tract overlap failed to demonstrate any appreciable association with the severity of markers of diffuse pathology within each thalamo-cortical projection system. Diffusion-weighted magnetic resonance imaging metrics in both white matter tracts were correlated significantly with a histologically derived measure of tract myelination. These data demonstrate for the first time the relevance of functional anatomical connectivity to the spread of multiple sclerosis pathology in a 'tract-specific' pattern. Furthermore, the persisting relationship between metrics from post-mortem diffusion-weighted magnetic resonance imaging and histological measures from fixed tissue further validates the potential of imaging for future neuropathological studies.
Physiological noise in brainstem fMRI
(FRONTIERS MEDIA SA, 2013-10-04)
The brainstem is directly involved in controlling blood pressure, respiration, sleep/wake cycles, pain modulation, motor, and cardiac output. As such it is of significant basic science and clinical interest. However, the brainstem's location close to major arteries and adjacent pulsatile cerebrospinal fluid filled spaces, means that it is difficult to reliably record functional magnetic resonance imaging (fMRI) data from. These physiological sources of noise generate time varying signals in fMRI data, which if left uncorrected can obscure signals of interest. In this Methods Article we will provide a practical introduction to the techniques used to correct for the presence of physiological noise in time series fMRI data. Techniques based on independent measurement of the cardiac and respiratory cycles, such as retrospective image correction (RETROICOR, Glover et al., 2000), will be described and their application and limitations discussed. The impact of a physiological noise model, implemented in the framework of the general linear model, on resting fMRI data acquired at 3 and 7 T is presented. Data driven approaches based such as independent component analysis (ICA) are described. MR acquisition strategies that attempt to either minimize the influence of physiological fluctuations on recorded fMRI data, or provide additional information to correct for their presence, will be mentioned. General advice on modeling noise sources, and its effect on statistical inference via loss of degrees of freedom, and non-orthogonality of regressors, is given. Lastly, different strategies for assessing the benefit of different approaches to physiological noise modeling are presented.
Large-scale Probabilistic Functional Modes from resting state fMRI
(ACADEMIC PRESS INC ELSEVIER SCIENCE, 2015-04-01)
It is well established that it is possible to observe spontaneous, highly structured, fluctuations in human brain activity from functional magnetic resonance imaging (fMRI) when the subject is 'at rest'. However, characterising this activity in an interpretable manner is still a very open problem. In this paper, we introduce a method for identifying modes of coherent activity from resting state fMRI (rfMRI) data. Our model characterises a mode as the outer product of a spatial map and a time course, constrained by the nature of both the between-subject variation and the effect of the haemodynamic response function. This is presented as a probabilistic generative model within a variational framework that allows Bayesian inference, even on voxelwise rfMRI data. Furthermore, using this approach it becomes possible to infer distinct extended modes that are correlated with each other in space and time, a property which we believe is neuroscientifically desirable. We assess the performance of our model on both simulated data and high quality rfMRI data from the Human Connectome Project, and contrast its properties with those of both spatial and temporal independent component analysis (ICA). We show that our method is able to stably infer sets of modes with complex spatio-temporal interactions and spatial differences between subjects.
Feasibility of Diffusion Tensor and Morphologic Imaging of Peripheral Nerves at Ultra-High Field Strength.
(Ovid Technologies (Wolters Kluwer Health), 2018-12)
OBJECTIVES: The aim of this study was to describe the development of morphologic and diffusion tensor imaging sequences of peripheral nerves at 7 T, using carpal tunnel syndrome (CTS) as a model system of focal nerve injury. MATERIALS AND METHODS: Morphologic images were acquired at 7 T using a balanced steady-state free precession sequence. Diffusion tensor imaging was performed using single-shot echo-planar imaging and readout-segmented echo-planar imaging sequences. Different acquisition and postprocessing methods were compared to describe the optimal analysis pipeline. Magnetic resonance imaging parameters including cross-sectional areas, signal intensity, fractional anisotropy (FA), as well as mean, axial, and radial diffusivity were compared between patients with CTS (n = 8) and healthy controls (n = 6) using analyses of covariance corrected for age (significance set at P < 0.05). Pearson correlations with Bonferroni correction were used to determine association of magnetic resonance imaging parameters with clinical measures (significance set at P < 0.01). RESULTS: The 7 T acquisitions with high in-plane resolution (0.2 × 0.2mm) afforded detailed morphologic resolution of peripheral nerve fascicles. For diffusion tensor imaging, single-shot echo-planar imaging was more efficient than readout-segmented echo-planar imaging in terms of signal-to-noise ratio per unit scan time. Distortion artifacts were pronounced, but could be corrected during postprocessing. Registration of FA maps to the morphologic images was successful. The developed imaging and analysis pipeline identified lower median nerve FA (pisiform bone, 0.37 [SD 0.10]) and higher radial diffusivity (1.08 [0.20]) in patients with CTS compared with healthy controls (0.53 [0.06] and 0.78 [0.11], respectively, P < 0.047). Fractional anisotropy and radial diffusivity strongly correlated with patients' symptoms (r = -0.866 and 0.866, respectively, P = 0.005). CONCLUSIONS: Our data demonstrate the feasibility of morphologic and diffusion peripheral nerve imaging at 7 T. Fractional anisotropy and radial diffusivity were found to be correlates of symptom severity.
Artificial intelligence for clinical decision support in neurology
(OXFORD UNIV PRESS, 2020-01-01)
Artificial intelligence is one of the most exciting methodological shifts in our era. It holds the potential to transform healthcare as we know it, to a system where humans and machines work together to provide better treatment for our patients. It is now clear that cutting edge artificial intelligence models in conjunction with high-quality clinical data will lead to improved prognostic and diagnostic models in neurological disease, facilitating expert-level clinical decision tools across healthcare settings. Despite the clinical promise of artificial intelligence, machine and deep-learning algorithms are not a one-size-fits-all solution for all types of clinical data and questions. In this article, we provide an overview of the core concepts of artificial intelligence, particularly contemporary deep-learning methods, to give clinician and neuroscience researchers an appreciation of how artificial intelligence can be harnessed to support clinical decisions. We clarify and emphasize the data quality and the human expertise needed to build robust clinical artificial intelligence models in neurology. As artificial intelligence is a rapidly evolving field, we take the opportunity to iterate important ethical principles to guide the field of medicine is it moves into an artificial intelligence enhanced future.
White matter changes in the perforant path area in patients with amyotrophic lateral sclerosis.
OBJECTIVE: The aim of this study was to test the hypothesis that white matter degeneration of the perforant path - as part of the Papez circuit - is a key feature of amyotrophic lateral sclerosis (ALS), even in the absence of frontotemporal dementia (FTD) or deposition of pTDP-43 inclusions in hippocampal granule cells. METHODS: We used diffusion Magnetic Resonance Imaging (dMRI), polarized light imaging (PLI) and immunohistochemical analysis of post mortem hippocampus specimens from controls (n = 5) and ALS patients (n = 14) to study white matter degeneration in the perforant path. RESULTS: diffusion Magnetic Resonance Imaging demonstrated a decrease in fractional anisotropy (P = 0.01) and an increase in mean diffusivity (P = 0.01) in the perforant path in ALS compared to controls. PLI-myelin density was lower in ALS (P = 0.05) and correlated with fractional anisotropy (r = 0.52, P = 0.03). These results were confirmed by immunohistochemistry; both myelin (proteolipid protein, P = 0.03) and neurofilaments (SMI-312, P = 0.02) were lower in ALS. Two out of the fourteen ALS cases showed pTDP-43 pathology in the dentate gyrus, but with comparable myelination levels in the perforant path to other ALS cases. CONCLUSION: We conclude that degeneration of the perforant path occurs in ALS patients and that this may occur before, or independent of, pTDP-43 aggregation in the dentate gyrus of the hippocampus. Future research should focus on correlating the degree of cognitive decline to the amount of white matter atrophy in the perforant path.
Optimising neonatal fMRI data analysis: Design and validation of an extended dHCP preprocessing pipeline to characterise noxious-evoked brain activity in infants.
(Elsevier BV, 2019-02-01)
The infant brain is unlike the adult brain, with considerable differences in morphological, neurodynamic, and haemodynamic features. As the majority of current MRI analysis tools were designed for use in adults, a primary objective of the Developing Human Connectome Project (dHCP) is to develop optimised methodological pipelines for the analysis of neonatal structural, resting state, and diffusion MRI data. Here, in an independent neonatal dataset we have extended and optimised the dHCP fMRI preprocessing pipeline for the analysis of stimulus-response fMRI data. We describe and validate this extended dHCP fMRI preprocessing pipeline to analyse changes in brain activity evoked following an acute noxious stimulus applied to the infant's foot. We compare the results obtained from this extended dHCP pipeline to results obtained from a typical FSL FEAT-based analysis pipeline, evaluating the pipelines' outputs using a wide range of tests. We demonstrate that a substantial increase in spatial specificity and sensitivity to signal can be attained with a bespoke neonatal preprocessing pipeline through optimised motion and distortion correction, ICA-based denoising, and haemodynamic modelling. The improved sensitivity and specificity, made possible with this extended dHCP pipeline, will be paramount in making further progress in our understanding of the development of sensory processing in the infant brain.
Genes implicated in multiple sclerosis pathogenesis from consilience of genotyping and expression profiles in relapse and remission
BACKGROUND: Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS). Although the pathogenesis of MS remains unknown, it is widely regarded as an autoimmune disease mediated by T-lymphocytes directed against myelin proteins and/or other oligodendrocyte epitopes. METHODS: In this study we investigated the gene expression profiles of peripheral blood cells from patients with RRMS during the relapse and the remission phases utilizing gene microarray technology. Dysregulated genes encoded in regions associated with MS susceptibility from genomic screens or previous transcriptomic studies were identified. The proximal promoter region polymorphisms of two genes were tested for association with disease and expression level. RESULTS: Distinct sets of dysregulated genes during the relapse and remission phases were identified including genes involved in apoptosis and inflammation. Three of these dysregulated genes have been previously implicated with MS susceptibility in genomic screens: TGFbeta1, CD58 and DBC1. TGFbeta1 has one common SNP in the proximal promoter: -508 T>C (rs1800469). Genotyping two Australian trio sets (total 620 families) found a trend for over-transmission of the T allele in MS in females (p < 0.13). Upregulation of CD58 and DBC1 in remission is consistent with their putative roles in promoting regulatory T cells and reducing cell proliferation, respectively. A fourth gene, ALOX5, is consistently found over-expressed in MS. Two common genetic variants were confirmed in the ALOX5 putative promoter: -557 T>C (rs12762303) and a 6 bp tandem repeat polymorphism (GGGCGG) between position -147 and -176; but no evidence for transmission distortion found. CONCLUSION: The dysregulation of these genes tags their metabolic pathways for further investigation for potential therapeutic intervention.
The HSA21 gene EURL/C21ORF91 controls neurogenesis within the cerebral cortex and is implicated in the pathogenesis of Down Syndrome
(NATURE PUBLISHING GROUP, 2016-07-11)
Copy number variations to chromosome 21 (HSA21) cause intellectual disability and Down Syndrome, but our understanding of the HSA21 genetic factors which contribute to fetal brain development remains incomplete. Here, we focussed on the neurodevelopmental functions for EURL (also known as C21ORF91, Refseq Gene ID:54149), a protein-coding gene at the centromeric boundary of the Down Syndrome Critical Region (DSCR) of HSA21. We report that EURL is expressed during human and mouse cerebral cortex development, and we report that alterations to EURL mRNA levels within the human brain underlie Down Syndrome. Our gene perturbation studies in mice demonstrate that disruptions to Eurl impair progenitor proliferation and neuronal differentiation. Also, we find that disruptions to Eurl impair the long-term positioning and dendritic spine densities of cortical projection neurons. We provide evidence that EURL interacts with the coiled-coil domain-containing protein CCDC85B so as to modulate β-catenin levels in cells. Further, we utilised a fluorescent reporter (8xTOPFLASHd2EGFP) to demonstrate that disruptions to Eurl alter β-catenin signalling in vitro as well as in vivo. Together, these studies highlight EURL as an important new player in neuronal development that is likely to impact on the neuropathogenesis of HSA21-related disorders including Down Syndrome.
Optic Nerve Magnetisation Transfer Ratio after Acute Optic Neuritis Predicts Axonal and Visual Outcomes
(PUBLIC LIBRARY SCIENCE, 2012-12-18)
Magnetisation transfer ratio (MTR) can reveal the degree of proton exchange between free water and macromolecules and was suggested to be pathological informative. We aimed to investigate changes in optic nerve MTR over 12 months following acute optic neuritis (ON) and to determine whether MTR measurements can predict clinical and paraclinical outcomes at 6 and 12 months. Thirty-seven patients with acute ON were studied within 2 weeks of presentation and at 1, 3, 6 and 12 months. Assessments included optic nerve MTR, retinal nerve fibre layer (RNFL) thickness, multifocal visual evoked potential (mfVEP) amplitude and latency and high (100%) and low (2.5%) contrast letter acuity. Eleven healthy controls were scanned twice four weeks apart for comparison with patients. Patient unaffected optic nerve MTR did not significantly differ from controls at any time-point. Compared to the unaffected nerve, affected optic nerve MTR was significantly reduced at 3 months (mean percentage interocular difference = -9.24%, p = 0.01), 6 months (mean = -12.48%, p<0.0001) and 12 months (mean = -7.61%, p = 0.003). Greater reduction in MTR at 3 months in patients was associated with subsequent loss of high contrast letter acuity at 6 (ρ = 0.60, p = 0.0003) and 12 (ρ = 0.44, p = 0.009) months, low contrast letter acuity at 6 (ρ = 0.35, p = 0.047) months, and RNFL thinning at 12 (ρ = 0.35, p = 0.044) months. Stratification of individual patient MTR time courses based on flux over 12 months (stable, putative remyelination and putative degeneration) predicted RNFL thinning at 12 months (F(2,32) = 3.59, p = 0.02). In conclusion, these findings indicate that MTR flux after acute ON is predictive of axonal degeneration and visual disability outcomes.
Parallel Changes in Structural and Functional Measures of Optic Nerve Myelination after Optic Neuritis
(PUBLIC LIBRARY SCIENCE, 2015-05-28)
INTRODUCTION: Visual evoked potential (VEP) latency prolongation and optic nerve lesion length after acute optic neuritis (ON) corresponds to the degree of demyelination, while subsequent recovery of latency may represent optic nerve remyelination. We aimed to investigate the relationship between multifocal VEP (mfVEP) latency and optic nerve lesion length after acute ON. METHODS: Thirty acute ON patients were studied at 1, 3, 6 and 12 months using mfVEP and at 1 and 12 months with optic nerve MRI. LogMAR and low contrast visual acuity were documented. By one month, the mfVEP amplitude had recovered sufficiently for latency to be measured in 23 (76.7%) patients with seven patients having no recordable mfVEP in more than 66% of segments in at least one test. Only data from these 23 patients was analysed further. RESULTS: Both latency and lesion length showed significant recovery during the follow-up period. Lesion length and mfVEP latency were highly correlated at 1 (r = 0.94, p = <0.0001) and 12 months (r = 0.75, p < 0.001). Both measures demonstrated a similar trend of recovery. Speed of latency recovery was faster in the early follow-up period while lesion length shortening remained relatively constant. At 1 month, latency delay was worse by 1.76 ms for additional 1mm of lesion length while at 12 months, 1mm of lesion length accounted for 1.94 ms of latency delay. CONCLUSION: A strong association between two putative measures of demyelination in early and chronic ON was found. Parallel recovery of both measures could reflect optic nerve remyelination.
Bim Links ER Stress and Apoptosis in Cells Expressing Mutant SOD1 Associated with Amyotrophic Lateral Sclerosis
(PUBLIC LIBRARY SCIENCE, 2012-04-16)
Endoplasmic reticulum (ER) stress is an important pathway to cell death in amyotrophic lateral sclerosis (ALS). We previously demonstrated that ER stress is linked to neurotoxicity associated with formation of inclusions of mutant Cu,Zn-superoxide dismutase 1 (SOD1). Cells bearing mutant inclusions undergo mitochondrial apoptotic signalling. Here, we demonstrate that the BH3-only protein, Bim, is a direct link between ER stress and mitochondrial apoptosis. In the murine neuroblastoma cell line, Neuro2a, bearing mutant SOD1 inclusions, indicators of both ER stress and apoptosis are expressed. Bim knockdown by siRNA significantly reduced nuclear apoptotic features in these inclusion-bearing cells (but did not affect the proportion of cells overall that bear inclusions). Further, both Bax recruitment to mitochondria and cytochrome c redistribution were also decreased under Bim-depletion conditions. However, upregulation of CHOP, a marker of ER stress, was not reduced by Bim knockdown. Significantly, knockdown of CHOP by siRNA reduced the extent of apoptosis in cells bearing mutant SOD1 inclusions. These sequential links between ER stress, CHOP upregulation, and Bim activation of mitochondrial apoptotic signalling indicate a clear pathway to cell death mediated by mutant SOD1.
High Order W02-Reactive Stable Oligomers of Amyloid-beta are Produced in vivo and in vitro via Dialysis and Filtration of Synthetic Amyloid-beta Monomer
(IOS PRESS, 2015-01-01)
Oligomeric forms of amyloid-β (Aβ) are thought to be responsible for the pathogenesis of Alzheimer's disease. While many oligomers of Aβ are thought to be naturally occurring in the brain of humans and/or transgenic animals, it is well known that Aβ oligomers are also readily produced in vitro in the laboratory. In recent studies, we discovered that synthetic monomeric Aβ (4.7 kDa) could be transformed by microdialysis to higher molecular weight species (approximately 56 kDa, by western blot). Surface-enhanced laser desorption/ionization mass spectrometry and electron microscopy further identified these species' as potential Aβ oligomers. The production of similar species could also be produced by centrifugal filtration and this formation was concentration and pore-size dependent. These higher order species of Aβ were resistant to dissolution in NaOH, HFIP, formic acid, urea, and guanidine. We postulate that we have identified a novel way of producing a high order species of oligomeric Aβ and we provide evidence to suggest that Aβ oligomers can quite easily be a product of normal laboratory practices. These data suggest that the experimental detection of higher order oligomers in tissues derived from Alzheimer's disease brains or from animal models of disease could, in some cases, be a product the method of analysis.
Variants of ST8SIA1 Are Associated with Risk of Developing Multiple Sclerosis
(PUBLIC LIBRARY SCIENCE, 2008-07-09)
Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system of unknown etiology with both genetic and environmental factors playing a role in susceptibility. To date, the HLA DR15/DQ6 haplotype within the major histocompatibility complex on chromosome 6p, is the strongest genetic risk factor associated with MS susceptibility. Additional alleles of IL7 and IL2 have been identified as risk factors for MS with small effect. Here we present two independent studies supporting an allelic association of MS with polymorphisms in the ST8SIA1 gene, located on chromosome 12p12 and encoding ST8 alpha-N-acetyl-neuraminide alpha-2,8-sialyltransferase 1. The initial association was made in a single three-generation family where a single-nucleotide polymorphism (SNP) rs4762896, was segregating together with HLA DR15/DQ6 in MS patients. A study of 274 family trios (affected child and both unaffected parents) from Australia validated the association of ST8SIA1 in individuals with MS, showing transmission disequilibrium of the paternal alleles for three additional SNPs, namely rs704219, rs2041906, and rs1558793, with p = 0.001, p = 0.01 and p = 0.01 respectively. These findings implicate ST8SIA1 as a possible novel susceptibility gene for MS.
Comparing genotyping algorithms for Illumina's Infinium whole-genome SNP BeadChips
BACKGROUND: Illumina's Infinium SNP BeadChips are extensively used in both small and large-scale genetic studies. A fundamental step in any analysis is the processing of raw allele A and allele B intensities from each SNP into genotype calls (AA, AB, BB). Various algorithms which make use of different statistical models are available for this task. We compare four methods (GenCall, Illuminus, GenoSNP and CRLMM) on data where the true genotypes are known in advance and data from a recently published genome-wide association study. RESULTS: In general, differences in accuracy are relatively small between the methods evaluated, although CRLMM and GenoSNP were found to consistently outperform GenCall. The performance of Illuminus is heavily dependent on sample size, with lower no call rates and improved accuracy as the number of samples available increases. For X chromosome SNPs, methods with sex-dependent models (Illuminus, CRLMM) perform better than methods which ignore gender information (GenCall, GenoSNP). We observe that CRLMM and GenoSNP are more accurate at calling SNPs with low minor allele frequency than GenCall or Illuminus. The sample quality metrics from each of the four methods were found to have a high level of agreement at flagging samples with unusual signal characteristics. CONCLUSIONS: CRLMM, GenoSNP and GenCall can be applied with confidence in studies of any size, as their performance was shown to be invariant to the number of samples available. Illuminus on the other hand requires a larger number of samples to achieve comparable levels of accuracy and its use in smaller studies (50 or fewer individuals) is not recommended.
Genome-wide association study identifies new multiple sclerosis susceptibility loci on chromosomes 12 and 20
(NATURE PUBLISHING GROUP, 2009-07-01)
To identify multiple sclerosis (MS) susceptibility loci, we conducted a genome-wide association study (GWAS) in 1,618 cases and used shared data for 3,413 controls. We performed replication in an independent set of 2,256 cases and 2,310 controls, for a total of 3,874 cases and 5,723 controls. We identified risk-associated SNPs on chromosome 12q13-14 (rs703842, P = 5.4 x 10(-11); rs10876994, P = 2.7 x 10(-10); rs12368653, P = 1.0 x 10(-7)) and upstream of CD40 on chromosome 20q13 (rs6074022, P = 1.3 x 10(-7); rs1569723, P = 2.9 x 10(-7)). Both loci are also associated with other autoimmune diseases. We also replicated several known MS associations (HLA-DR15, P = 7.0 x 10(-184); CD58, P = 9.6 x 10(-8); EVI5-RPL5, P = 2.5 x 10(-6); IL2RA, P = 7.4 x 10(-6); CLEC16A, P = 1.1 x 10(-4); IL7R, P = 1.3 x 10(-3); TYK2, P = 3.5 x 10(-3)) and observed a statistical interaction between SNPs in EVI5-RPL5 and HLA-DR15 (P = 0.001).
Chronic intermittent toluene inhalation in adolescent rats alters behavioural responses to amphetamine and MK801
(ELSEVIER SCIENCE BV, 2014-03-01)
Abuse of toluene-containing inhalants is common during adolescence, with ongoing chronic misuse associated with adverse outcomes and increased risk for addictive behaviours in adulthood. However, the mechanisms mediating the adaptive processes related to these outcomes are not well defined. To model human abuse patterns we exposed male adolescent Wistar rats (postnatal day 27) to chronic intermittent inhaled toluene (CIT, 10,000 ppm) or air (control) for 1h/day, three times/week for 3 weeks. The effects of CIT on behaviour and recovery were monitored. Locomotor activity was recorded following two consecutive injections of amphetamine (1mg/kg, i.p.) 72 and 96 h after the last exposure. This was followed with injection of the NMDA receptor antagonist MK801 (0.5mg/kg, i.p.) 20 days after the last exposure. CIT resulted in a significant and persistent retardation in weight gain during the exposure period and abstinence (p<0.05). Repeated exposure resulted in tolerance to the onset of toluene-induced behaviours and recovery latency. There was a reduction in the acute stimulant effects of amphetamine in CIT-exposed animals and an increase in the magnitude of locomotor activity (p<0.0125) following a subsequent exposure when compared to the responses observed in controls; this was associated with altered locomotor responses to MK801. Repeated exposure to CIT during adolescence alters parameters of growth, as measured by body weight, and leads to tolerance, indicating that increasing concentrations of the compound may be needed to reach the same behavioural state. Toluene during this period also alters responses to a psychostimulant which may be related to long-term glutamatergic dysfunction.
Maintenance N-acetyl cysteine treatment for bipolar disorder: A double-blind randomized placebo controlled trial
BACKGROUND: N-acetyl cysteine (NAC) is a glutathione precursor that has been shown to have antidepressant efficacy in a placebo-controlled trial. The current study aimed to investigate the maintenance effects of NAC following eight weeks of open-label treatment for bipolar disorder. METHOD: The efficacy of a double blind randomized placebo controlled trial of 2 g/day NAC as adjunct maintenance treatment for bipolar disorder was examined. Participants (n = 149) had a Montgomery Asberg Depression Rating Score of ≥12 at trial entry and, after eight weeks of open-label NAC treatment, were randomized to adjunctive NAC or placebo, in addition to treatment as usual. Participants (primarily outpatients) were recruited through public and private services and through newspaper advertisements. Time to intervention for a mood episode was the primary endpoint of the study, and changes in mood symptoms, functionality and quality of life measures were secondary outcomes. RESULTS: There was a substantial decrease in symptoms during the eight-week open-label NAC treatment phase. During the subsequent double-blind phase, there was minimal further change in outcome measures with scores remaining low. Consequently, from this low plateau, between-group differences did not emerge on recurrence, clinical functioning or quality of life measures. CONCLUSIONS: There were no significant between-group differences in recurrence or symptomatic outcomes during the maintenance phase of the trial; however, these findings may be confounded by limitations. TRIAL REGISTRATION: The trial was registered with the Australian New Zealand Clinical Trials Registry (ACTRN12607000074493).
Endogenously regulated Dab2 worsens inflammatory injury in experimental autoimmune encephalomyelitis
(BIOMED CENTRAL LTD, 2013-01-01)
BACKGROUND: Neuroinflammation regulates both disease pathogenesis and repair in multiple sclerosis. In early multiple sclerosis lesion development, neuroinflammation causes demyelination and axonal injury, the likely final common determinant of disability. Here we report the identification of a novel neuroinflammatory mediator, Disabled-2 (Dab2). Dab2 is an intracellular adaptor protein with previously unknown function in the central nervous system. RESULTS: We report that Dab2 is up-regulated in lesional macrophages/microglia in the spinal cord in murine experimental autoimmune encephalomyelitis, a model of multiple sclerosis. We demonstrate that dab2 expression is positively correlated with experimental autoimmune encephalomyelitis disease severity during the acute disease phase. Furthermore, dab2-deficient mice have a less severe experimental autoimmune encephalomyelitis disease course and suffer less neuroinflammation and less axonal injury than their wild-type littermates. We demonstrate that dab2 expression is strongly associated with the expression of inducible nitric oxide synthase. We further demonstrate that Dab2 is expressed at the protein level by macrophages in early acute human multiple sclerosis lesions and that this correlates with axonal injury. CONCLUSIONS: Together, these results suggest that endogenous Dab2 exacerbates central nervous system inflammation, potentially acting to up-regulate reactive oxygen species expression in macrophages and microglia, and that it is of potential pathogenic relevance in Multiple Sclerosis.
Hippocampal shape variations at term equivalent age in very preterm infants compared with term controls: Perinatal predictors and functional significance at age 7
(ACADEMIC PRESS INC ELSEVIER SCIENCE, 2013-04-15)
The hippocampus undergoes rapid growth and development in the perinatal months. Infants born very preterm (VPT) are vulnerable to hippocampal alterations, and can provide a model of disturbed early hippocampal development. Hippocampal shape alterations have previously been associated with memory impairment, but have never been investigated in infants. The aims of this study were to determine hippocampal shape differences between 184 VPT infants (<30 weeks' gestation or <1250 g at birth) and 32 full-term infants, effects of perinatal factors, and associations between infant hippocampal shape and volume, and 7 year verbal and visual memory (California Verbal Learning Test - Children's Version and Dot Locations). Infants underwent 1.5 T magnetic resonance imaging at term equivalent age. Hippocampi were segmented, and spherical harmonics-point distribution model shape analysis was undertaken. VPT infants' hippocampi were less infolded than full-term infants, being less curved toward the midline and less arched superior-inferiorly. Straighter hippocampi were associated with white matter injury and postnatal corticosteroid exposure. There were no significant associations between infant hippocampal shape and 7 year memory measures. However, larger infant hippocampal volumes were associated with better verbal memory scores. Altered hippocampal shape in VPT infants at term equivalent age may reflect delayed or disrupted development. This study provides further insight into early hippocampal development and the nature of hippocampal abnormalities in prematurity.
Manganese-enhanced MRI reflects seizure outcome in a model for mesial temporal lobe epilepsy
(ACADEMIC PRESS INC ELSEVIER SCIENCE, 2013-03-01)
The neurobiological processes resulting in epilepsy, known as epileptogenesis, are incompletely understood. Manganese-enhanced MRI (MEMRI) can potentially aide in this quest as it provides superior tissue contrast, particularly of the hippocampal subregions. This longitudinal study aims to characterise the changes in the hippocampus of the post kainic acid-induced status epilepticus (KASE) rat model of mesial temporal lobe epilepsy using MEMRI in vivo. Serial acquisition of T(1)-weighted MEMRI images were taken before, 2 days and 6 weeks after KASE (10-30 mg/kg, i.p.) in 14 rats and in 11 control rats, while a second cohort of control (N=6) and epileptic animals (N=10) was imaged at 2 months post KASE only. MnCl(2) (50 mM, 10 μl) was administered in the right lateral ventricle 1 day before scanning. Regions of interest were drawn around the hippocampus and several subregions of the hippocampus (CA1, CA3 and dentate gyrus). Markers of epilepsy such as spontaneous recurrent seizures, hippocampal neuronal loss and mossy fiber sprouting were quantified. A persistent increase in MEMRI signal intensity was found in the hippocampus, CA1 and dentate gyrus in the KASE group compared to the control group (ANOVA P<0.05). The intensity signal in the hippocampus and subregions correlated inversely with the frequency of spontaneous recurrent seizures in the chronic epileptic phase, however there was no relationship observed between histopathological changes such as cell loss and mossy fiber sprouting with seizures. This study demonstrates that MEMRI is able to detect imaging changes in the hippocampus during the course of epileptogenesis relevant for seizure expression. These data strongly indicate a relationship between manganese enhancement and spontaneous seizure outcome, suggesting that MEMRI could provide a preclinical biomarker for the severity of epileptogenesis in vivo in animal models.
DISTRIBUTION OF OREXIN-1 RECEPTOR-GREEN FLUORESCENT PROTEIN- (OX1-GFP) EXPRESSING NEURONS IN THE MOUSE BRAIN STEM AND PONS: CO-LOCALIZATION WITH TYROSINE HYDROXYLASE AND NEURONAL NITRIC OXIDE SYNTHASE
(PERGAMON-ELSEVIER SCIENCE LTD, 2014-10-10)
We used a reporter mouse line in which green fluorescent protein (GFP) was inserted into the orexin-1 receptor (OX1) locus to systematically map the neuroanatomical distribution of the OX1 receptor in the mouse brainstem and pons. Here, we show that the OX1 receptor is expressed in a select subset of medullary and pontine nuclei. In the medulla, we observed OX1-GFP expression in the cuneate, gracile, dorsal motor nucleus of the vagus (10N), nucleus of the solitary tract and medullary raphe areas. In the pons, the greatest expression was found in the locus coeruleus (LC) and dorsal raphe nucleus (DRN). High to moderate expression was found in the pedunculopontine tegmental nucleus (PPTg), laterodorsal tegmental nucleus, A5 noradrenergic cell group (A5) and the periaqueductal gray. Double-labeling with neuronal nitric oxide synthase (NOS1) revealed extensive co-localization in cell bodies and fibers of the 10N, A5 cell group and the PPTg. Double-staining with tyrosine hydroxylase revealed extensive co-expression in the LC, DRN and the lateral paragigantocellularis cell group in the ventral medulla. Our findings faithfully recapitulate the findings of OX1 mRNA expression previously reported. This is the first study to systematically map the neuroanatomical distribution of OX1 receptors within the mouse hindbrain and suggest that this OX1-GFP transgenic reporter mouse line might be a useful tool with which to study the neuroanatomy and physiology of OX1 receptor-expressing cells.
Reduction of p75 neurotrophin receptor ameliorates the cognitive deficits in a model of Alzheimer's disease
(ELSEVIER SCIENCE INC, 2015-02-01)
Alzheimer's disease (AD) is an extremely prevalent cause of dementia. It is characterized by progressive memory loss, confusion, and other behavioral and physiological problems. The amyloid-β (Aβ) protein is thought to be involved in the pathogenesis of AD, and there is evidence that Aβ may act through the p75 neurotrophin receptor (p75) to mediate its pathogenic effects. This raises the possibility that reducing levels of p75 could be a treatment for AD by preventing the effects of Aβ. In this study, we have crossed the transgenic AD model mice, Tg2576, with p75(-/-) mice to generate Tg2576/p75(+/-) mice with reduced levels of p75. These mice are rescued from the deficits in learning and memory and hippocampal function which were found in the Tg2576 mice. These findings suggest that reduction of p75 can ameliorate some of the primary symptoms of AD.
3D Electrospun scaffolds promote a cytotrophic phenotype of cultured primary astrocytes
Astrocytes are a target for regenerative neurobiology because in brain injury their phenotype arbitrates brain integrity, neuronal death and subsequent repair and reconstruction. We explored the ability of 3D scaffolds to direct astrocytes into phenotypes with the potential to support neuronal survival. Poly-ε-caprolactone scaffolds were electrospun with random and aligned fibre orientations on which murine astrocytes were sub-cultured and analysed at 4 and 12 DIV. Astrocytes survived, proliferated and migrated into scaffolds adopting 3D morphologies, mimicking in vivo stellated phenotypes. Cells on random poly-ε-caprolactone scaffolds grew as circular colonies extending processes deep within sub-micron fibres, whereas astrocytes on aligned scaffolds exhibited rectangular colonies with processes following not only the direction of fibre alignment but also penetrating the scaffold. Cell viability was maintained over 12 DIV, and cytochemistry for F-/G-actin showed fewer stress fibres on bioscaffolds relative to 2D astrocytes. Reduced cytoskeletal stress was confirmed by the decreased expression of glial fibrillary acidic protein. PCR demonstrated up-regulation of genes (excitatory amino acid transporter 2, brain-derived neurotrophic factor and anti-oxidant) reflecting healthy biologies of mature astrocytes in our extended culture protocol. This study illustrates the therapeutic potential of bioengineering strategies using 3D electrospun scaffolds which direct astrocytes into phenotypes supporting brain repair. Astrocytes exist in phenotypes with pro-survival and destructive components, and their biology can be modulated by changing phenotype. Our findings demonstrate murine astrocytes adopt a healthy phenotype when cultured in 3D. Astrocytes proliferate and extend into poly-ε-caprolactone scaffolds displaying 3D stellated morphologies with reduced GFAP expression and actin stress fibres, plus a cytotrophic gene profile. Bioengineered 3D scaffolds have potential to direct inflammation to aid regenerative neurobiology.
Evaluation of the acceptability and usefulness of an information website for caregivers of people with bipolar disorder
BACKGROUND: Bipolar disorder is associated with extreme mood symptoms, disability and suicide risk. Close family or friends often have a primary role in supporting an adult with bipolar disorder. However, not all support is helpful and there is little publicly accessible evidence-based information to guide caregivers. Caregiver burden increases the risk of caregiver depression and health problems. To help fill the information gap, expert clinicians, caregivers and consumers contributed to the development of guidelines for caregivers of adults with bipolar disorder using the Delphi consensus method. This paper reports on an evaluation of the acceptability and usefulness of the online version of the guidelines, http://www.bipolarcaregivers.org. METHODS: Visitors to the website responded to an initial online survey about the usefulness of the information (N=536). A more detailed follow-up feedback survey was emailed to web users who were adult caregivers of adults with bipolar disorder a month later (N=121). The feedback was analyzed quantitatively and qualitatively to establish user appraisals of the online information, whether and how caregivers applied the information and ways it could be improved. RESULTS: The majority of users (86.4% to 97.4%) found the various sections of the website useful. At follow-up, nearly 93% of caregivers reported that the information was relevant to them and 96% thought it would help others. Most respondents said that the information was supportive and encouraged adaptive control appraisals. However, a few respondents who were experiencing complex family problems, or who cared for a person with severe chronic bipolar disorder did not appraise it as positively. Nevertheless, over two-thirds of the caregivers reported using the information. Optional interactive features were recommended to maximize benefits. CONCLUSIONS: Overall, http://www.bipolarcaregivers.org was appraised positively and used. It appears useful to close family and friends seeking basic information and reassurance, and may be an inexpensive way to disseminate guidelines for caregivers. Those who care for people with more severe and chronic bipolar disorder, or who have complex family problems might benefit from more specialized interventions, suggesting the importance of a stepped-care approach to supporting caregivers. The potential of evidence-based, collaboratively developed information websites to enhance caregiver and consumer outcomes merits further investigation.
Brain Activity Associated with Placebo Suppression of the Urge-to-Cough in Humans
(AMER THORACIC SOC, 2013-11-01)
RATIONALE: Antitussive therapies are accompanied by a substantial placebo effect, indicating that inhibitory circuits in the brain have a significant capacity to regulate cough neural processing. However, essentially nothing is known about the identity of these inhibitory circuits or how they reduce coughing. Understanding these processes may help develop more effective antitussive therapies in the future. OBJECTIVES: To identify regional changes in human brain activity related to the urge-to-cough after placebo antitussive administration. METHODS: Seventeen healthy participants undertook functional magnetic resonance imaging while completing a series of inhalations of capsaicin to induce the urge-to-cough. The resultant brain responses associated with capsaicin inhalation without any treatment were compared with those induced by capsaicin after placebo antitussive administration. MEASUREMENTS AND MAIN RESULTS: There was a significant decrease in participants' ratings of urge-to-cough after the placebo antitussive administration. Brain activity associated with capsaicin inhalation was less in the somatosensory, primary motor, insula, and cingulate cortices during placebo antitussive trials compared with no treatment control subjects. By contrast, placebo trials were associated with increased activation in the prefrontal and left parietal cortices. CONCLUSIONS: Placebo-related decreases in urge-to-cough are accompanied by commensurate decreases in several brain regions activated during capsaicin inhalation, suggesting that beliefs about treatment can modify the central processing of inputs arising from the airways. The prefrontal cortex and posterior parietal cortex are likely to play an active role in the modification of airway sensory processing after administration of a placebo.
The Effect of Placebo Conditioning on Capsaicin-Evoked Urge to Cough
(ELSEVIER SCIENCE BV, 2012-10-01)
BACKGROUND: The urge to cough is a clinical symptom of respiratory disease that precedes the motor act of coughing. Although previous studies have shown that cough is particularly susceptible to placebo suppression, it is unclear whether the perception of an urge to cough is also modifiable by placebo. Therefore, we tested the hypothesis that capsaicin-evoked urge to cough could be suppressed by placebo conditioning. METHODS: Eleven healthy participants were unknowingly conditioned to believe that an inert inhaler temporarily suppressed capsaicin-induced urge to cough by deceptively modifying the challenge concentration of capsaicin. In subsequent testing, capsaicin-evoked urge-to-cough subjective ratings were assessed in four challenges with a single dose of inhaled capsaicin following no treatment or the placebo metered-dose inhaler. An additional 10 participants were informed that the inhaler therapy was inert prior to receiving capsaicin challenges with and without inhaler treatment. RESULTS: There was a significant decrease in mean urge-to-cough ratings to capsaicin challenge following placebo compared with no treatment followed by capsaicin challenge (P < .001), with a peak decrease of 45%. The placebo inhaler alone had no effect on urge-to-cough subjective ratings when participants were aware that it contained no active medication. CONCLUSIONS: These data confirm that the urge to cough is susceptible to placebo inhibition. This provides further evidence that higher brain networks are involved in the processing of respiratory sensations related to airway irritation.
A small peptide mimetic of brain-derived neurotrophic factor promotes peripheral myelination
The expression of the neurotrophins and their receptors is essential for peripheral nervous system development and myelination. We have previously demonstrated that brain-derived neurotrophic factor (BDNF) exerts contrasting influences upon Schwann cell myelination in vitro - promoting myelination via neuronally expressed p75NTR, but inhibiting myelination via neuronally expressed TrkB. We have generated a small peptide called cyclo-dPAKKR that structurally mimics the region of BDNF that binds p75NTR. Here, we have investigated whether utilizing cyclo-dPAKKR to selectively target p75NTR is an approach that could exert a unified promyelinating response. Like BDNF, cyclo-dPAKKR promoted myelination of nerve growth factor-dependent neurons in vitro, an effect dependent on the neuronal expression of p75NTR. Importantly, cyclo-dPAKKR also significantly promoted the myelination of tropomyosin-related kinase receptor B-expressing neurons in vitro, whereas BDNF exerted a significant inhibitory effect. This indicated that while BDNF exerted a contrasting influence upon the myelination of distinct subsets of dorsal root ganglion (DRG) neurons in vitro, cyclo-dPAKKR uniformly promoted their myelination. Local injection of cyclo-dPAKKR adjacent to the developing sciatic nerve in vivo significantly enhanced myelin protein expression and significantly increased the number of myelinated axons. These results demonstrate that cyclo-dPAKKR promotes peripheral myelination in vitro and in vivo, suggesting it is a strategy worthy of further investigation for the treatment of peripheral demyelinating diseases.