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.
Nombela C.,University of Cambridge |
Rittman T.,University of Cambridge |
Robbins T.W.,University of Cambridge |
Robbins T.W.,Behavioural and Clinical Neuroscience Institute |
And 3 more authors.
PLoS ONE | Year: 2014
Cognitive problems are a major factor determining quality of life of patients with Parkinson's disease. These include deficits in inhibitory control, ranging from subclinical alterations in decision-making to severe impulse control disorders. Based on preclinical studies, we proposed that Parkinson's disease does not cause a unified disorder of inhibitory control, but rather a set of impulsivity factors with distinct psychological profiles, anatomy and pharmacology. We assessed a broad set of measures of the cognitive, behavioural and temperamental/trait aspects of impulsivity. Sixty adults, including 30 idiopathic Parkinson's disease patients (Hoehn and Yahr stage I-III) and 30 healthy controls, completed a neuropsychological battery, objective behavioural measures and self-report questionnaires. Univariate analyses of variance confirmed group differences in nine out of eleven metrics. We then used factor analysis (principal components method) to identify the structure of impulsivity in Parkinson's disease. Four principal factors were identified, consistent with four different mechanisms of impulsivity, explaining 60% of variance. The factors were related to (1) tests of response conflict, interference and self assessment of impulsive behaviours on the Barrett Impulsivity Scale, (2) tests of motor inhibitory control, and the self-report behavioural approach system, (3) time estimation and delay aversion, and (4) reflection in hypothetical scenarios including temporal discounting. The different test profiles of these four factors were consistent with human and comparative studies of the pharmacology and functional anatomy of impulsivity. Relationships between each factor and clinical and demographic features were examined by regression against factor loadings. Levodopa dose equivalent was associated only with factors (2) and (3). The results confirm that impulsivity is common in Parkinson's disease, even in the absence of impulse control disorders, and that it is not a unitary phenomenon. A better understanding of the structure of impulsivity in Parkinson's disease will support more evidence-based and effective strategies to treat impulsivity. © 2014 Nombela et al.
News Article | February 21, 2017
Cocaine addiction may affect how the body processes iron, leading to a build-up of the mineral in the brain, according to new research from the University of Cambridge. The study, published today in Translational Psychiatry, raises hopes that there may be a biomarker - a biological measure of addiction - that could be used as a target for future treatments. Cocaine is one of the most widely-used illicit drugs in the Western world and is highly addictive. A report last year by the UK government's Advisory Council on the Misuse of Drugs found that almost one in 10 of all 16-to 59-year-olds have used cocaine in their lifetime. Cocaine use was implicated in, but not necessarily the cause of 234 deaths in Scotland, England and Wales in 2013. However, despite significant advances in our understanding of the biology of addiction - including how the brains of people addicted to cocaine may differ in structure - there is currently no medical treatment for cocaine addiction; most individuals are treated with talking or cognitive therapies. A team of researchers led by Dr Karen Ersche from the Department of Psychiatry at Cambridge examined brain tissue in 44 people who were addicted to cocaine and 44 healthy control volunteers. In the cocaine group, they detected excessive amounts of iron in a region of the brain known as the globus pallidus, which ordinarily acts as a 'brake' for inhibiting behaviour. Particularly striking was the fact that the concentration of iron in this area was directly linked with the duration of cocaine use - in other words, the longer that participants had used cocaine, the greater the accumulation of iron. At the same time, the increased iron concentration in the brain was accompanied by mild iron deficiency in the rest of the body, suggesting that iron regulation in general is disrupted in people with cocaine addiction. "Given the important role that iron plays in both health and disease, iron metabolism is normally tightly regulated," explains Dr Karen Ersche from the Department of Psychiatry. "Long-term cocaine use, however, seems to disrupt this regulation, which may cause significant harm. "Iron is used to produce red blood cells, which help store and carry oxygen in the blood. So, iron deficiency in the blood means that organs and tissues may not get as much oxygen as they need. On the other hand, we know that excessive iron in the brain is associated with cell death, which is what we frequently see in neurodegenerative diseases such as Alzheimer's or Parkinson's disease." The Cambridge researchers now aim to identify the precise mechanisms by which cocaine interacts with iron regulation. Dr Ersche believes the most likely mechanism is that cocaine disrupts iron metabolism, possibly by reducing the absorption of iron from food, increasing the permeability of the blood-brain-barrier so that more iron enters the brain, where it can accumulate. Although excess iron in the brain is associated with neurodegeneration, there is no suggestion that cocaine addiction leads to an increased risk of Alzheimer's or Parkinson's disease. The mechanism underlying the increase in iron in the brain in Parkinson's disease, for example, is different to that in cocaine addiction, as are the affected brain regions. As an essential micronutrient, iron can only be obtained through our diet and cannot be excreted, other than through blood loss. The researchers now want to find out whether means of correcting the disruptions in iron metabolism might slow down or even reverse the accumulation of iron in the brain, and ultimately help affected individuals to successfully recover from cocaine addiction. This work was funded by the Medical Research Council and was conducted at the NIHR Cambridge Biomedical Research Centre and the Behavioural and Clinical Neuroscience Institute. Ersche, KD et al. Disrupted iron regulation in the brain and periphery in cocaine addiction. Translational Psychiatry; Date; DOI: 10.1038/tp.2016.271
News Article | November 17, 2015
People diagnosed with schizophrenia who are prone to hallucinations are likely to have structural differences in a key region of the brain compared to both healthy individuals and people diagnosed with schizophrenia who do not hallucinate, according to research published recently. The study, led by the University of Cambridge in collaboration with Durham University, Macquarie University, and Trinity College Dublin, found that reductions in the length of the paracingulate sulcus (PCS), a fold towards the front of the brain, were associated with increased risk of hallucinations in people diagnosed with schizophrenia. The PCS is one of the last structural folds to develop in the brain before birth, and varies in size between individuals. In a previous study, a team of researchers led by Dr. Jon Simons from the Department of Psychology at the University of Cambridge, found that variation in the length of the PCS in healthy individuals was linked to the ability to distinguish real from imagined information, a process known as ‘reality monitoring’. In this new study, published today in the journal Nature Communications, Dr. Simons and his colleagues analyzed 153 structural MRI scans of people diagnosed with schizophrenia and matched control participants, measuring the length of the PCS in each participant’s brain. As difficulty distinguishing self-generated information from that perceived in the outside world may be responsible for many kinds of hallucinations, the researchers wanted to assess whether there was a link between length of the PCS and propensity to hallucinate. The researchers found that in people diagnosed with schizophrenia, a 1 cm reduction in the fold’s length increased the likelihood of hallucinations by nearly 20%. The effect was observed regardless of whether hallucinations were auditory or visual in nature, consistent with a reality monitoring explanation. “Schizophrenia is a complex spectrum of conditions that is associated with many differences throughout the brain, so it can be difficult to make specific links between brain areas and the symptoms that are often observed,” said Dr. Simons. “By comparing brain structure in a large number of people diagnosed with schizophrenia with and without the experience of hallucinations, we have been able to identify a particular brain region that seems to be associated with a key symptom of the disorder.” The researchers believe that changes in other areas of the brain are likely also important in generating the complex phenomena of hallucinations, possibly including regions that process visual and auditory perceptual information. In people who experience hallucinations, these areas may produce altered perceptions which, due to differences in reality monitoring processes supported by regions around the PCS, may be misattributed as being real. For example, a person may vividly imagine a voice but judge that it arises from the outside world, experiencing the voice as a hallucination. “We think that the PCS is involved in brain networks that help us recognize information that has been generated ourselves,” adds Dr. Jane Garrison, first author of the study, “People with a shorter PCS seem less able to distinguish the origin of such information, and appear more likely to experience it as having been generated externally. “Hallucinations are very complex phenomena that are a hallmark of mental illness and, in different forms, are also quite common across the general population. There is likely to be more than one explanation for why they arise, but this finding seems to help explain why some people experience things that are not actually real.” The research was primarily supported by the University of Cambridge Behavioural and Clinical Neuroscience Institute, funded by a joint award from the UK Medical Research Council and the Wellcome Trust.
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.
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.
Morein-Zamir S.,University of Cambridge |
Morein-Zamir S.,Behavioural and Clinical Neuroscience Institute |
Robbins T.W.,University of Cambridge
Brain Research | Year: 2015
Disruptions to inhibitory control are believed to contribute to multiple aspects of drug abuse, from preexisting vulnerability in at-risk individuals, through escalation to dependence, to promotion of relapse in chronic users. Paradigms investigating the suppression of actions have been investigated in animal and human research on drug addiction. Rodent research has focused largely on impulsive behaviors, often gauged by premature responding, as a viable model highlighting the relevant role of dopamine and other neurotransmitters primarily in the striatum. Human research on action inhibition in stimulant dependence has highlighted impaired performance and largely prefrontal cortical abnormalities as part of a broader pattern of cognitive abnormalities. Animal and human research implicate inhibitory difficulties mediated by fronto-striatal circuitry both preceding and as a result of excessive stimulus use. In this regard, response-inhibition has proven a useful cognitive function to gauge the integrity of fronto-striatal systems and their role in contributing to impulsive and compulsive features of drug dependence. This article is part of a Special Issue entitled SI:Addiction circuits. © 2014 The Authors. Published by Elsevier B.V.
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.
Smith D.G.,University of Cambridge |
Smith D.G.,Behavioural and Clinical Neuroscience Institute |
Jones P.S.,University of Cambridge |
Bullmore E.T.,University of Cambridge |
And 4 more authors.
Translational Psychiatry | Year: 2013
Cognitive and neural abnormalities are known to accompany chronic drug abuse, with impairments in cognition and changes in cortical structure seen in stimulant-dependent individuals. However, premorbid differences have also been observed in the brains and behavior of individuals at risk for substance abuse, before they develop dependence. Endophenotype research has emerged as a useful method for assessing preclinical traits that may be risk factors for pathology by studying patient populations and their undiagnosed first-degree relatives. This study used the color-word Stroop task to assess executive functioning in stimulant-dependent individuals, their unaffected biological siblings and unrelated healthy control volunteers using a functional magnetic resonance imaging paradigm. Both the stimulant-dependent and sibling participants demonstrated impairments in cognitive control and processing speed on the task, registering significantly longer response latencies. However, the two groups generated very different neural responses, with the sibling participants exhibiting a significant decrease in activation in the inferior frontal gyrus compared with both stimulant-dependent individuals and control participants. Both target groups also demonstrated a decrease in hemispheric laterality throughout the task, exhibiting a disproportionate increase in right hemispheric activation, which was associated with their behavioral inefficiencies. These findings not only suggest a possible risk factor for stimulant abuse of poor inhibitory control and cortical inefficiency but they also demonstrate possible adaptations in the brains of stimulant users. © 2013 Macmillan Publishers Limited.