Cambridge Center for Brain Repair

Cambridge, United Kingdom

Cambridge Center for Brain Repair

Cambridge, United Kingdom
SEARCH FILTERS
Time filter
Source Type

Brundin P.,Lund University | Barker R.A.,Cambridge Center for Brain Repair | Parmar M.,Lund University
Progress in Brain Research | Year: 2010

Neural transplantation has emerged as a possible therapy for Parkinson's disease (PD). Clinical studies performed during the 1990s, where dopaminergic neurons derived from the human embryonic brain were transplanted into striatum of patients with PD, provided proof-of-principle that long-lasting therapeutic benefits can be achieved. Subsequent studies, in particular two that followed a double-blind, sham surgery, placebo-control design, showed variable and mostly negative results. They also revealed that some patients develop involuntary movements, so called graft-induced dyskinesias, as side effects. Thus, while nigral transplants clearly work well in select PD cases, the technique needs refinement before it can successfully be performed in a large series of patients. In this review, we describe the clinical neural transplantation trials in PD and the likely importance of factors such as patient selection, trial design, preparation of the donor tissue, and surgical techniques for successful outcome and avoiding unwanted side effects. We also highlight that it was recently found that neuropathological signs typical for PD can appear inside some of the grafted neurons over a decade after surgery. Finally, we discuss future possibilities offered by stem cells as potential sources of dopamine neurons that can be used for transplantation in PD. © 2010 Elsevier B.V.


Cools R.,Radboud University Nijmegen | Rogers R.,University of Oxford | Barker R.A.,Cambridge Center for Brain Repair | Robbins T.W.,University of Cambridge
Journal of Cognitive Neuroscience | Year: 2010

Cognitive dysfunction in Parkinson's disease (PD) has been hypothesized to reflect a failure of cortical control. In keeping with this hypothesis, some of the cognitive deficits in PD resemble those seen in patients with lesions in the lateral pFC, which has been associated with top-down attentional control. However, there is no direct evidence for a failure of top-down control mechanisms in PD. Here we fill this gap by demonstrating disproportionate control by bottom-up attention to dimensional salience during attentional set shifting. Patients needed significantly more trials to criterion than did controls when shifting to a low-salient dimension while, remarkably, needing significantly fewer trials to criterion than did controls when shifting to a highsalient dimension. Thus, attention was captured by bottom-up attention to salient information to a greater extent in patients than in controls. The results provide a striking reinterpretation of prior set-shifting data and provide the first direct evidence for a failure of top-down attentional control, resembling that seen after catecholamine depletion in the pFC. © 2009 Massachusetts Institute of Technology.


Nombela C.,Cambridge Center for Brain Repair | Hughes L.E.,MRC Cognition and Brain science Unit | Owen A.M.,University of Western Ontario | Grahn J.A.,University of Western Ontario
Neuroscience and Biobehavioral Reviews | Year: 2013

Previous research has noted that music can improve gait in several pathological conditions, including Parkinson's disease, Huntington's disease and stroke. Current research into auditory-motor interactions and the neural bases of musical rhythm perception has provided important insights for developing potential movement therapies. Specifically, neuroimaging studies show that rhythm perception activates structures within key motor networks, such as premotor and supplementary motor areas, basal ganglia and the cerebellum - many of which are compromised to varying degrees in Parkinson's disease. It thus seems likely that automatic engagement of motor areas during rhythm perception may be the connecting link between music and motor improvements in Parkinson's disease. This review seeks to describe the link, address core questions about its underlying mechanisms, and examine whether it can be utilized as a compensatory mechanism. © 2013 The Authors.


Ali F.,Cambridge Center for Brain Repair | Stott S.R.W.,Cambridge Center for Brain Repair | Barker R.A.,Cambridge Center for Brain Repair
Experimental Neurology | Year: 2014

Progress in Parkinson's disease (PD) research has been hampered by the lack of an appropriate model which exhibits the core pathology seen in the human brain. Recent advances in deriving cells with neuronal phenotypes from patients with neurodegenerative disorders through cellular reprogramming offer a unique tool for disease modelling and may help shed light on the molecular pathogenesis that drives the progression of the disease. This technology may also help in establishing platforms for drug screening and open up exciting new prospects for cell grafting. In this review, we will discuss progress made in differentiating stem cells into authentic dopamine neurons and where we stand with respect to clinical trials with these cells in patients with PD. We will also examine the various approaches used in cellular reprogramming and their differentiation into patient-specific midbrain dopamine neurons, with an emphasis particularly on modelling familial cases of PD to recapitulate disease phenotypes. This review will highlight some of the challenges that need to be addressed for this technology to have any potential clinical application in cell therapy and personalised medicine. © 2013 Elsevier Inc.


Barker R.A.,Cambridge Center for Brain Repair | Barrett J.,Institute of Public Health | Mason S.L.,Cambridge Center for Brain Repair | Bjorklund A.,Lund University
The Lancet Neurology | Year: 2013

Clinical use of allografts of fetal ventral mesencephalic tissue as a treatment to replace dopaminergic neurons in patients with Parkinson's disease was first done more than 20 years ago. Since then, many patients have received transplants, with variable results. During this time, our knowledge of Parkinson's disease has changed and the nature and extent of problems associated with the disorder have been better defined. Our understanding on how best to implement this cell-replacement strategy for patients has grown, but gaining this insight has entailed critical reappraisal of data from transplant trials that have already been undertaken. © 2013 Elsevier Ltd.


Calder A.J.,MRC Cognition and Brain science Unit | Keane J.,MRC Cognition and Brain science Unit | Young A.W.,University of York | Lawrence A.D.,University of Cardiff | And 2 more authors.
Neuropsychologia | Year: 2010

Initial reports of emotion recognition in Huntington's disease (HD) found disproportionate impairments in recognising disgust. Not all subsequent studies have found this pattern, and a review of the literature to date shows that marked impairments in recognising anger are also often seen in HD. However, the majority of studies have based their conclusions on a single test of facial expression recognition. In the current study we revisit this issue of emotion recognition in HD to address whether the pattern found on one test of facial expression recognition generalised to another, and to different modalities using tests of emotion recognition from facial expressions, vocal expressions, and short verbal vignettes. The results showed evidence of impairments in recognising anger, fear and disgust across the three domains, with recognition of anger the most severely impaired. Given work identifying different subtypes of disgust that are associated with different facial features, a second study examined the recognition of three disgust expressions that healthy participants reliably associate with unpleasant tastes, unpleasant smells, and a more general elaborated or expanded form of disgust that includes reactions to violations of moral standards. The results showed a disproportionate impairment in recognising faces associated with the expanded form, the subtype most closely aligned with anger. We conclude that the related emotions of disgust and anger associated with social disapproval are frequently impaired in HD and discuss factors that might cause one emotion to show more severe impairments than the other. © 2010 Elsevier Ltd.


Barker R.A.,Cambridge Center for Brain Repair
Lancet neurology | Year: 2013

Clinical use of allografts of fetal ventral mesencephalic tissue as a treatment to replace dopaminergic neurons in patients with Parkinson's disease was first done more than 20 years ago. Since then, many patients have received transplants, with variable results. During this time, our knowledge of Parkinson's disease has changed and the nature and extent of problems associated with the disorder have been better defined. Our understanding on how best to implement this cell-replacement strategy for patients has grown, but gaining this insight has entailed critical reappraisal of data from transplant trials that have already been undertaken. Copyright © 2013 Elsevier Ltd. All rights reserved.


Rowe J.B.,University of Cambridge | Rowe J.B.,Medical Research Council Cognition and Brain science Unit | Hughes L.E.,University of Cambridge | Hughes L.E.,Medical Research Council Cognition and Brain science Unit | And 3 more authors.
NeuroImage | Year: 2010

Dynamic causal modelling (DCM) of functional magnetic resonance imaging (fMRI) data offers new insights into the pathophysiology of neurological disease and mechanisms of effective therapies. Current applications can be used both to identify the most likely functional brain network underlying observed data and estimate the networks' connectivity parameters. We examined the reproducibility of DCM in healthy subjects (young 18-48 years, n=27; old 50-80 years, n=15) in the context of action selection. We then examined the effects of Parkinson's disease (50-78 years, Hoehn and Yahr stage 1-2.5, n=16) and dopaminergic therapy. Forty-eight models were compared, for each of 90 sessions from 58 subjects. Model-evidences clustered according to sets of structurally similar models, with high correlations over two sessions in healthy older subjects. The same model was identified as most likely in healthy controls on both sessions and in medicated patients. In this most likely network model, the selection of action was associated with enhanced coupling between prefrontal cortex and the pre-supplementary motor area. However, the parameters for intrinsic connectivity and contextual modulation in this model were poorly correlated across sessions. A different model was identified in patients with Parkinson's disease after medication withdrawal. In "off" patients, action selection was associated with enhanced connectivity from prefrontal to lateral premotor cortex. This accords with independent evidence of a dopamine-dependent functional disconnection of the SMA in Parkinson's disease. Together, these results suggest that DCM model selection is robust and sensitive enough to study clinical populations and their pharmacological treatment. For critical inferences, model selection may be sufficient. However, caution is required when comparing groups or drug effects in terms of the connectivity parameter estimates, if there are significant posterior covariances among parameters. © 2009 Elsevier Inc.


Kehagia A.A.,University of St. Andrews | Barker R.A.,Cambridge Center for Brain Repair | Robbins T.W.,Behavioural and Clinical Neuroscience Institute | Robbins T.W.,University of Cambridge
Neurodegenerative Diseases | Year: 2013

Research into the heterogeneous nature of cognitive impairment documented in patients with Parkinson's disease (PD) has focused on disentangling deficits that vary between individuals, evolve and respond differentially to pharmacological treatments, and relate differentially to PD dementia (PDD). We summarise studies conducted in our laboratory over the last 2 decades, outlining the incremental development of our hypotheses, the starting point for which is our early work on executive deficits mirroring fronto-striatal dysfunction. We present subsequent findings linking these deficits to a model of dopaminergic function that conforms to an inverted curvilinear function. We review studies that investigated the range of dopamine-independent attentional and visuospatial memory deficits seen in PD, demonstrating that abnormalities in these domains more accurately predict PDD. We conclude with an exposition of the dual syndrome hypothesis, which distinguishes between dopaminergically mediated fronto-striatal executive impairments and a dementia syndrome with distinctive prodromal visuospatial deficits in which cholinergic treatments offer some clinical benefits. Copyright © 2012 S. Karger AG, Basel.


Goodyer I.M.,University of Cambridge | Croudace T.,University of Cambridge | Dudbridge F.,London School of Hygiene and Tropical Medicine | Ban M.,University of Cambridge | Herbert J.,Cambridge Center for Brain Repair
British Journal of Psychiatry | Year: 2010

Background: There is increasing evidence for genetic effects on the hypothalamic-pituitary axis system. More than one gene is likely to moderate corticoid-mediated activity. Aims: To investigate whether the brain-derived neurotrophic factor (BDNF) polymorphism (rs6265, Val66Met) is associated with morning waking salivary cortisol and moderates the corticoid-mediated risk for subsequent depressive episode onset independently of the known effects of 5-HTTLPR (the serotonin transporter gene promoter). Method: High-risk adolescents (n = 401) were genotyped for Val66Met BDNF and 5-HTTLPR. Salivary samples were obtained on four consecutive school days within 1 h of waking. There were 365 (91%) remaining participants reassessed at 12 months for episodes of psychiatric disorder in the follow-up period. Of these, 357 (89%) had complete data for multivariate modelling. Results: There were 41 (11.2%) individuals who reported a new episode of clinical depression over the follow-up period. Increased risk for subsequent depression was found in carriers of the Val66Val genotype in BDNF with higher morning waking cortisol. This remained present when the known interaction between carriers of a short allele of 5-HTTLPR with higher morning salivary cortisol was taken into account. Conclusions: Both BDNF and 5-HTTLPR genes show evidence of modifying the risk of a subsequent new depressive episode associated with elevated morning salivary cortisol. In adolescents morning salivary cortisol levels may constitute a biomarker for some forms of unipolar depression.

Loading Cambridge Center for Brain Repair collaborators
Loading Cambridge Center for Brain Repair collaborators