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Herz D.M.,Copenhagen University | Haagensen B.N.,Copenhagen University | Christensen M.S.,Copenhagen University | Madsen K.H.,Copenhagen University | And 6 more authors.
Annals of Neurology | Year: 2014

Objective In Parkinson disease (PD), long-term treatment with the dopamine precursor levodopa gradually induces involuntary "dyskinesia" movements. The neural mechanisms underlying the emergence of levodopa-induced dyskinesias in vivo are still poorly understood. Here, we applied functional magnetic resonance imaging (fMRI) to map the emergence of peak-of-dose dyskinesias in patients with PD. Methods Thirteen PD patients with dyskinesias and 13 PD patients without dyskinesias received 200mg fast-acting oral levodopa following prolonged withdrawal from their normal dopaminergic medication. Immediately before and after levodopa intake, we performed fMRI, while patients produced a mouse click with the right or left hand or no action (No-Go) contingent on 3 arbitrary cues. The scan was continued for 45 minutes after levodopa intake or until dyskinesias emerged. Results During No-Go trials, PD patients who would later develop dyskinesias showed an abnormal gradual increase of activity in the presupplementary motor area (preSMA) and the bilateral putamen. This hyperactivity emerged during the first 20 minutes after levodopa intake. At the individual level, the excessive No-Go activity in the predyskinesia period predicted whether an individual patient would subsequently develop dyskinesias (p < 0.001) as well as severity of their day-to-day symptomatic dyskinesias (p < 0.001). Interpretation PD patients with dyskinesias display an immediate hypersensitivity of preSMA and putamen to levodopa, which heralds the failure of neural networks to suppress involuntary dyskinetic movements. Ann Neurol 2014;75:829-836 © 2014 American Neurological Association.


Zhang J.,Cognition and Brain science Unit | Rowe J.B.,Cognition and Brain science Unit | Rowe J.B.,University of Cambridge | Rowe J.B.,Behavioural and Clinical Neuroscience Institute
NeuroImage | Year: 2015

Statistical regularities exist at different timescales in temporally unfolding event sequences. Recent studies have identified brain regions that are sensitive to the levels of regularity in sensory inputs, enabling the brain to construct a representation of environmental structure and adaptively generate actions or predictions. However, the temporal specificity of the statistical regularity to which the brain responds remains largely unknown. This uncertainty applies to the regularities of sensory inputs as well as instrumental actions. Here, we used fMRI to investigate the neural correlates of regularity in sequences of task events and action selections in a visuomotor choice task. We quantified timescale-dependent regularity measures by calculating Shannon's entropy and surprise from a sliding-window of consecutive task events and actions. Activity in the frontopolar cortex negatively correlated with the entropy in action selection, while activity in the temporoparietal junction, the striatum, and the cerebellum negatively correlated with the entropy in stimulus events at longer timescales. In contrast, activity in the supplementary motor area, the superior frontal gyrus, and the superior parietal lobule was positively correlated with the surprise of each stimulus across different timescales. The results suggest a spatial distribution of regions sensitive to various information regularities according to a temporal hierarchy, which may play a central role in concurrently monitoring the regularity in previous and current events over different timescales to optimize behavioral control in a dynamic environment. © 2014.


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.


Mehta A.R.,University of Oxford | Rowe J.B.,University of Cambridge | Rowe J.B.,Medical Research Council Cognition and Brain science Unit | Rowe J.B.,Behavioural and Clinical Neuroscience Institute | Schrag A.E.,University College London
Current Neurology and Neuroscience Reports | Year: 2013

The neurobiological basis of psychogenic movement disorders (PMDs) has been elusive, and they remain difficult to treat. In the last few years, functional neuroimaging studies have provided insight into their pathophysiology and neural correlates. Here, we review the various methodological approaches that have been used in both clinical and research practice to address neural correlates of functional disorders. We then review the dominant hypotheses generated from the literature on psychogenic paralysis. Overall, these studies emphasize abnormalities in the prefrontal and anterior cingu-late cortices. Recently, functional neuroimaging has been used to specifically examine PMDs. These studies have addressed a major point of controversy: whether higher frontal brain areas are directly responsible for inhibiting motor areas or whether they reflect modulation by attentional and/or emotional processes. In addition to elucidating the mechanism and cause, recent work has also explored the lack of agency that characterizes PMDs. We describe the results and implications of the results of these imaging studies and discuss possible interpretations © The Author(s) 2013.


Hughes L.E.,University of Cambridge | Hughes L.E.,Medical Research Council Cognition and Brain science Unit | Ghosh B.C.P.,Wessex Neuroscience Center | Rowe J.B.,University of Cambridge | And 2 more authors.
NeuroImage: Clinical | Year: 2013

The disruption of large-scale brain networks is increasingly recognised as a consequence of neurodegenerative dementias. We assessed adults with behavioural variant frontotemporal dementia and progressive supranuclear palsy using magnetoencephalography during an auditory oddball paradigm. Network connectivity among bilateral temporal, frontal and parietal sources was examined using dynamic causal modelling. We found evidence for a systematic change in effective connectivity in both diseases. Compared with healthy subjects, who had focal modulation of intrahemispheric frontal-temporal connections, the patient groups showed abnormally extensive and inefficient networks. The changes in connectivity were accompanied by impaired responses of the auditory cortex to unexpected deviant tones (MMNm), despite normal responses to standard stimuli. Together, these results suggest that neurodegeneration in two distinct clinical syndromes with overlapping profiles of prefrontal atrophy, causes a similar pattern of reorganisation of large-scale networks. We discuss this network reorganisation in the context of other focal brain disorders and the specific vulnerability of functional brain networks to neurodegenerative disease. © 2013 The Authors.

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