Parkinson Disease: Owen AM

Grahn JA, Parkinson JA, Owen AM. · MRC Cognition and Brain Sciences Unit, Cambridge, UK. · Behav Brain Res. · Pubmed #19059285 No free full text.

Abstract: In recent years, a common approach to understanding how the basal ganglia contribute to learning and memory in humans has been to study the deficits that occur in patients with basal ganglia pathology, such as Parkinson's disease and Huntington's disease. Pharmacological manipulations in patients and in healthy volunteers have also been conducted to investigate the role of dopamine, a neurotransmitter that is crucial for normal striatal functioning. When combined with powerful functional neuroimaging methods such as positron emission tomography and functional magnetic resonance imaging, such studies can provide important new insights into striatal function and dysfunction in humans. In this review, we consider this broad literature in an attempt to define a specific role for the caudate nucleus in learning and memory, and in particular, how this role may differ from that of the putamen. We conclude that the caudate nucleus contributes to learning and memory through the excitation of correct action schemas and the selection of appropriate sub-goals based on an evaluation of action-outcomes; both processes that are fundamental to all tasks involve goal-directed action.

Owen AM. · Medical Research Council Cognition and Brain Sciences Unit, Cambridge, United Kingdom. · Neuroscientist. · Pubmed #15534038 No free full text.

Abstract: It has been known for many years that the classic motor symptoms of Parkinson's disease are accompanied by deficits of executive function that resemble those seen after frontal lobe damage in humans. What is less clear is how different components of frontostriatal circuitry contribute to these impairments. Recently, improved methods of clinical assessment and classification, combined with novel technical approaches, such as functional neuroimaging, have led to great advances in our understanding of the fundamental mechanisms that drive frontostriatal circuitry. As a direct result, it has been possible to redefine impairments of executive function in Parkinson's disease more precisely in terms of the specific neuropsychological, neuroanatomical, and psychopharmacological mechanisms involved.

Owen AM, Doyon J. · Cognition and Brain Sciences Unit, Medical Research Council Applied Psychology Unit, Cambridge, United Kingdom. · Adv Neurol. · Pubmed #10410702 No free full text.

This publication has no abstract.

Slabosz A, Lewis SJ, Smigasiewicz K, Szymura B, Barker RA, Owen AM. · MRC Cognition and Brain Sciences Unit, Cambridge, England. · Neuropsychology. · Pubmed #16938020 No free full text.

Abstract: In this study, the cognitive and neurochemical factors underlying learned irrelevance, one of the mechanisms thought to be responsible for attentional set-shifting deficits in Parkinson's disease (PD), were investigated. In a visual discrimination learning task, the extent to which a target dimension was irrelevant prior to an extra-dimensional shift was varied. Twenty patients with PD and 22 healthy participants performed the task twice, with patients tested on and off L-dopa. The patients made more errors than control participants in the condition in which the target dimension was completely irrelevant prior to the extradimensional shift, but not when it was partially reinforced. Moreover, L-dopa had no effect on the patients' task performance, despite improving their working memory. These results confirm that learned irrelevance is a significant factor in accounting for attentional set-shifting deficits in patients with PD, although unlike other executive impairments in this group, the phenomenon appears to be unrelated to their central dopaminergic deficit.

Lewis SJ, Slabosz A, Robbins TW, Barker RA, Owen AM. · Cambridge Centre for Brain Repair, Forvie Site, Addenbrooke's Hospital, Cambridge CB2 2PY, UK. · Neuropsychologia. · Pubmed #15716155 No free full text.

Abstract: Although Parkinson's disease is a common neurodegenerative disorder characterised by its motoric symptoms, there is an increasing recognition of accompanying impairments in cognition that have a profound impact on the quality of life of these patients. These deficits predominantly affect executive function and impairments of working memory have been frequently reported. However, the underlying neurochemical and pathological basis for these deficits are not well understood. In this study, 20 patients were tested 'on' and 'off' levodopa (L-dopa) medication on a task that allowed different aspects of working memory function such as maintenance, retrieval and manipulation to be tested within the same general paradigm as well as on an unrelated test of attentional set-shifting, which is known to be sensitive to deficits in early Parkinson's disease. Compared to healthy volunteers, PD patients were impaired at manipulation more than maintenance or retrieval of information within working memory. The patients were also impaired at the attentional set-shifting task. However, whereas L-dopa ameliorated the working memory deficit in manipulation (improving both accuracy and cognitive response time), it had no effect on the attentional set-shifting impairment. These results confirm that working memory deficits in PD are both psychologically specific and related to dopamine depletion. It is anticipated that greater understanding of these mechanisms will lead to future therapeutic improvements.

Lewis SJ, Dove A, Robbins TW, Barker RA, Owen AM. · Cambridge Centre for Brain Repair and Department of Neurology, University of Cambridge, Cambridge, United Kingdom CB2 2EF. · J Neurosci. · Pubmed #12867520 links to  free full text

Abstract: Studies in patients with Parkinson's disease (PD) suggest that the characteristic motor symptoms of the disorder are frequently accompanied by impairments in cognition that are most profound in tasks of executive function. Neuropsychological deficits are not an inevitable consequence of the disease, yet the reasons underlying cognitive heterogeneity in PD are not well understood. To determine the underlying neural correlate of these cognitive deficits, we used event-related functional magnetic resonance imaging (fMRI) to compare groups of cognitively impaired and unimpaired patients, matched on all other clinical measures. fMRI revealed significant signal intensity reductions during a working-memory paradigm in specific striatal and frontal lobe sites in patients with cognitive impairment compared with those patients who were not cognitively unimpaired. These results demonstrate that cognitive deficits in PD are accompanied by neural changes that are related to, but distinct from, those changes that underlie motoric deficits in these patients. Furthermore, they suggest that fMRI may provide a valuable tool for identifying patients who may benefit from targeted therapeutic strategies.

Hodgson TL, Tiesman B, Owen AM, Kennard C. · Division of Neuroscience and Psychological Medicine, Faculty of Medicine, Imperial College, Charing Cross Hospital Campus, 10th Floor East Wing, St Dunstans Road, London W6 8RP, UK. · Neuropsychologia. · Pubmed #11684174 No free full text.

Abstract: We have taken a novel approach to the study of problem solving involving the detailed analysis of natural scanning eye movements during the 'one touch' Tower of London task. Control subjects and patients with idiopathic Parkinson's disease (PDs) viewed a series of pictures depicting two arrangements of coloured balls in pockets within the upper and lower halves of a computer display. The task was to plan (but not execute) the shortest movement sequence required to rearrange the balls in one half of the display (the Workspace) to match the arrangement in the opposite half (the Goalspace) and indicate the number of moves required for problem solution. As problem complexity increased, control subjects spent proportionally more time fixating the Workspace region. This pattern was found regardless of whether subjects were instructed to solve problems by rearranging balls in the lower or upper visual fields. The distribution of gaze within the Workspace was also found to be problem dependent, with gaze being selectively directed towards the problem critical balls. In contrast, PDs were found to make more errors in the task and failed to show any dissociation in the amount of time fixating the two halves of the display. This pattern suggests that the patients had difficulty in encoding and/or maintaining current goals during problem solving, consistent with a role for fronto-striatal circuits in mechanisms of working memory and attention.

Dagher A, Owen AM, Boecker H, Brooks DJ. · MRC Clinical Sciences Centre, Imperial College School of Medicine, Hammersmith Hospital, London, UK. · Brain. · Pubmed #11335704 links to  free full text

Abstract: Previous work has identified the prefrontal cortex (PFC) and striatum as participating in the planning and selection of movements. We compared the brain activation patterns during planning in Parkinson's disease patients and age-matched controls using H(2)(15)O-PET and the Tower of London (TOL) task. In this study, our mildly affected Parkinson's disease group performed as well as the control group but showed a different pattern of neuronal activation. In the two groups, overlapping areas of the PFC were activated but, whereas the right caudate nucleus was activated in the control group, this was not evident in the Parkinson's disease patients. This suggests that normal normal frontal lobe activation can occur in Parkinson's disease despite abnormal processing within the basal ganglia. Moreover, right hippocampus activity was suppressed in the controls and enhanced in the Parkinson's disease patients. This could represent a shift to the declarative memory system in Parkinson's disease during performance of the TOL task, possibly resulting from insufficient working memory capacity within the frontostriatal system.

Rowe JB, Hughes L, Ghosh BC, Eckstein D, Williams-Gray CH, Fallon S, Barker RA, Owen AM. · University of Cambridge Department of Clinical Neurosciences, Cambridge, CB2 7EF, UK. · Brain. · Pubmed #18577547 links to  free full text

Abstract: Cognitive deficits are very common in Parkinson's disease particularly for 'executive functions' associated with frontal cortico-striatal networks. Previous work has identified deficits in tasks that require attentional control like task-switching, and reward-based tasks like gambling or reversal learning. However, there is a complex relationship between the specific cognitive problems faced by an individual patient, their stage of disease and dopaminergic treatment. We used a bimodality continuous performance task during fMRI to examine how patients with Parkinson's disease represent the prospect of reward and switch between competing task rules accordingly. The task-switch was not separately cued but was based on the implicit reward relevance of spatial and verbal dimensions of successive compound stimuli. Nineteen patients were studied in relative 'on' and 'off' states, induced by dopaminergic medication withdrawal (Hoehn and Yahr stages 1-4). Patients were able to successfully complete the task and establish a bias to one or other dimension in order to gain reward. However the lateral prefrontal cortex and caudate nucleus showed a non-linear U-shape relationship between motor disease severity and regional brain activation. Dopaminergic treatment led to a shift in this U-shape function, supporting the hypothesis of differential neurodegeneration in separate motor and cognitive cortico-striato-thalamo-cortical circuits. In addition, anterior cingulate activation associated with reward expectation declined with more severe disease, whereas activation following actual rewards increased with more severe disease. This may facilitate a change in goal-directed behaviours from deferred predicted rewards to immediate actual rewards, particularly when on dopaminergic treatment. We discuss the implications for investigation and optimal treatment of this common condition at different stages of disease.

Williams-Gray CH, Hampshire A, Barker RA, Owen AM. · Cambridge Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, Forvie Site, Robinson Way, Cambridge, CB2 2PY, UK. · Brain. · Pubmed #18178571 links to  free full text

Abstract: Cognitive deficits occur even in the earliest stages of Parkinson's disease. Some such deficits are known to relate to dysfunction in dopaminergic frontostriatal networks, and may be influenced by a common functional polymorphism (val(158)met) within the catechol O-methyltransferase (COMT) gene. Abnormal attentional shifting behaviour is an important and well-recognized cognitive problem in PD, but nonetheless its precise cognitive and neural basis remains unclear. Here we explored this impairment in an fMRI study employing a recently developed cognitive task designed to fractionate components of attentional control. We investigated the impact of the COMT val(158)met genotype and dopaminergic medication on both patterns of behaviour and associated brain activation in 29 medicated patients with early PD. Genotype had a critical impact on task strategy: whilst patients with high activity COMT genotypes (val/val) adopted a typical approach of preferentially shifting attention within rather than between dimensions, those with low activity genotypes (met/met) failed to adopt such a strategy, suggesting an inability to form an attentional 'set'. Moreover, this behaviour was associated with significant underactivation across the frontoparietal attentional network. Furthermore, we demonstrated an interactive effect of COMT genotype and dopaminergic medication on task performance and BOLD response. Hence we have shown for the first time that attentional control in PD is critically determined by genetic and pharmacological influences on dopaminergic activity in frontoparietal networks. This has important implications for understanding the neurobiological basis of attentional control, and highlights the risk of medication-induced cognitive dysfunction in certain genotypic groups of PD patients, which may ultimately impact on clinical practice.

Williams-Gray CH, Hampshire A, Robbins TW, Owen AM, Barker RA. · Cambridge Centre for Brain Repair and Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom. · J Neurosci. · Pubmed #17475791 links to  free full text

Abstract: Cognitive dysfunction commonly occurs even in the early stages of Parkinson's disease (PD). Impairment on frontostriatally based executive tasks is particularly well described but affects only a proportion of early PD patients. Our previous work suggests that a common functional polymorphism (val(158)met) within the catechol O-methyltransferase (COMT) gene underlies some of this executive heterogeneity. In particular, an increasing number of methionine alleles, resulting in lower enzyme activity, is associated with impaired performance on the "Tower of London" planning task. The main objective of this study was to investigate the underlying neural basis of this genotype-phenotype effect in PD using functional magnetic resonance imaging. We scanned 31 patients with early PD who were homozygous for either valine (val) (n = 16) or methionine (met) (n = 15) at the COMT val(158)met polymorphism during performance of an executive task comprising both Tower of London (planning) and simple subtracting ("control") problems. A cross-group comparison between genetic subgroups revealed that response times for planning problems were significantly longer in met compared with val homozygotes, whereas response times for control problems did not differ. Furthermore, imaging data revealed a significant reduction in blood oxygen level-dependent signal across the frontoparietal network involved in planning in met/met compared with val/val patients. Hence, we have demonstrated that COMT genotype impacts on executive function in PD through directly influencing frontoparietal activation. Furthermore, the directionality of the genotype-phenotype effect observed in this study, when interpreted in the context of the existing literature, adds weight to the hypothesis that the relationship between prefrontal function and dopamine levels follows as an inverted U-shaped curve.

Cheesman AL, Barker RA, Lewis SJ, Robbins TW, Owen AM, Brooks DJ. · Medical Research Council Clinical Sciences Centre, Imperial College, Hammersmith Hospital, Du Cane Road, London W12 0NN, UK. · J Neurol Neurosurg Psychiatry. · Pubmed #16107352 links to  free full text

Abstract: OBJECTIVES: The aetiology of the cognitive changes seen in Parkinson's disease (PD) is multifactorial but it is likely that a significant contribution arises from the disruption of dopaminergic pathways. This study aimed to investigate the contribution of the dopaminergic system to performance on two executive tasks using (18)F-6-fluorodopa positron emission tomography ((18)F-dopa PET) in PD subjects with early cognitive changes. METHODS: 16 non-demented, non-depressed PD subjects were evaluated with the Tower of London (TOL) spatial planning task, a verbal working memory task (VWMT) and (18)F-dopa PET, all known to be affected in early PD. Statistical parametric mapping (SPM) localised brain regions in which (18)F-dopa uptake covaried with performance scores. Frontal cortical resting glucose metabolism was assessed with (18)F-fluoro-2-deoxy-D-glucose ((18)F-FDG) PET. RESULTS: SPM localised significant covariation between right caudate (18)F-dopa uptake (Ki) and TOL scores and between left anterior putamen Ki and VWMT performance. No significant covariation was found between task scores and (18)F-dopa Ki values in either limbic or cortical regions. Frontal cortical glucose metabolism was preserved in all cases. CONCLUSIONS: These findings support a causative role of striatal dopaminergic depletion in the early impairment of executive functions seen in PD. They suggest that spatial and verbal executive tasks require integrity of the right and left striatum, respectively, and imply that the pattern of cognitive changes manifest by a patient with PD may reflect differential dopamine loss in the two striatal complexes.

Lewis SJ, Foltynie T, Blackwell AD, Robbins TW, Owen AM, Barker RA. · Cambridge Centre for Brain Repair, Forvie Site, Addenbrooke's Hospital, Cambridge, CB2 2PY, UK. · J Neurol Neurosurg Psychiatry. · Pubmed #15716523 links to  free full text

Abstract: OBJECTIVE: To investigate the heterogeneity of idiopathic Parkinson's disease (PD) in a data driven manner among a cohort of patients in the early clinical stages of the disease meeting established diagnostic criteria. METHODS: Data on demographic, motor, mood, and cognitive measures were collected from 120 consecutive patients in the early stages of PD (Hoehn and Yahr I-III) attending a specialist PD research clinic. Statistical cluster analysis of the data allowed the existence of the patient subgroups generated to be explored. RESULTS: The analysis revealed four main subgroups: (a) patients with a younger disease onset; (b) a tremor dominant subgroup of patients; (c) a non-tremor dominant subgroup with significant levels of cognitive impairment and mild depression; and (d) a subgroup with rapid disease progression but no cognitive impairment. CONCLUSIONS: This study complements and extends previous research by using a data driven approach to define the clinical heterogeneity of early PD. The approach adopted in this study for the identification of subgroups of patients within Parkinson's disease has important implications for generating testable hypotheses on defining the heterogeneity of this common condition and its aetiopathological basis and thus its treatment.

Lewis SJ, Cools R, Robbins TW, Dove A, Barker RA, Owen AM. · Cambridge Centre for Brain Repair, Forvie Site, Addenbrooke's Hospital, University of Cambridge, CB2 2PY, UK. · Neuropsychologia. · Pubmed #12591022 No free full text.

Abstract: Idiopathic Parkinson's disease (IPD) is characterised by a triad of motor symptoms, namely bradykinesia, rigidity and resting tremor, although cognitive impairment is a common feature of the disease and has been accepted as one of the strong predictors of quality of life in such patients. Neuropsychological testing in Parkinson's disease often reveals a pattern of cognitive impairment similar to that observed in patients with frontal lobe lesions, although clear differences between the two groups have also often been reported. This apparent inconsistency in the literature may reflect heterogeneity among different groups of patients with Parkinson's disease, although to date this possibility has not been formally addressed. In this study, two groups of patients with Parkinson's disease were assessed on a novel verbal memory task, which allowed different aspects of working memory function such as maintenance, retrieval and manipulation to be tested within the same general paradigm. The two groups were selected according to either good or bad performance on a 'standard', visuospatial test of executive function (The Tower of London Task), but were well matched on all other demographic and cognitive measures tested. The sub-group of Parkinson's disease patients with Tower of London defined executive deficit were specifically impaired at manipulating information within verbal working memory, both compared to controls and to the group of patients with no predefined executive impairments. In contrast, the three groups did not differ in their ability to maintain or retrieve information within verbal working memory. Given the known preferential role of the dorsolateral frontal cortex in higher executive functions, (including both planning and the manipulation of information within working memory), these results suggest that, in a subset of Parkinson's disease patients, it is the frontostriatal circuitry involving this region which is primarily affected, while other components of this circuitry may be relatively spared. The results also suggest that performance on the Tower of London task may prove to be a useful discriminant variable in defining the nature of cognitive heterogeneity in Parkinson's disease.

Cools R, Stefanova E, Barker RA, Robbins TW, Owen AM. · Department of Experimental Psychology, University of Cambridge, Cambridge, UK. · Brain. · Pubmed #11872615 links to  free full text

Abstract: This study examined the effects of L-dopa medication in patients with Parkinson's disease on cortical and subcortical blood flow changes during two tasks known to involve frontostriatal circuitry. Eleven patients with Parkinson's disease were scanned on two occasions, one ON L-dopa medication and one OFF L-dopa medication, during performance of the Tower of London planning task and a related test that emphasized aspects of spatial working memory. L-dopa-induced decreases were observed in the right dorsolateral prefrontal cortex during performance of both the planning and the spatial working memory tasks compared with the visuomotor control task. Conversely, L-dopa-induced blood flow increases were observed in the right occipital lobe during the memory task relative to the control task. Data from age-matched healthy volunteers demonstrated that L-dopa effectively normalized blood flow in these regions in the patient group. Moreover, a significant correlation was found between L-dopa-induced, planning related blood flow decreases in the right dorsolateral prefrontal cortex and L-dopa-induced changes in performance on the planning task. These data suggest that L-dopa ameliorates high-level cognitive deficits in Parkinson's disease by inducing relative blood flow changes in the right dorsolateral prefrontal cortex.

Cox SM, Stefanova E, Johnsrude IS, Robbins TW, Owen AM. · Medical Research Council Cognition and Brain Sciences Unit, 15 Chaucer Road, CB2 2EF, Cambridge, UK. · Neuropsychologia. · Pubmed #11684164 No free full text.

Abstract: Recent studies in rats have suggested that the amygdala and the dorsal striatum may be differentially involved in the formation of stimulus-reward associations and stimulus-response associations, respectively. In a recent study in humans, conditioned preference learning deficits were observed in a group of patients with damage to the amygdala formation. In this study, patients with Parkinson's disease, which is known to involve pathology of the dorsal striatum, were tested on the same conditioned preference task, together with a group of patients with circumscribed lesions of the frontal lobe. Unlike patients with frontal lobe damage, patients with Parkinson's disease did not exhibit conditioned preferences. However, in this respect their behaviour was indistinguishable from that of age-matched (older) control subjects. In keeping with previous literature, working memory deficits were observed in both patients with Parkinson's disease and patients with frontal-lobe lesions. Compared to young control subjects, a strong increase in preference for familiar, versus novel, items was observed in both patients with Parkinson's disease and in older control subjects. Such a familiarity effect appears to overshadow the conditioning manipulation employed in this task and, therefore, preclude the expression of conditioned preferences in older subjects. These results suggest that there is a developmental progression in the degree to which different mechanisms of 'learning to like' are important over the life span.