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Parkinson Disease: HELP
Articles by Peter Brown
Based on 93 articles published since 2008
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Between 2008 and 2019, P. Brown wrote the following 93 articles about Parkinson Disease.
 
+ Citations + Abstracts
Pages: 1 · 2 · 3 · 4
1 Editorial Making use of pathological synchrony in Parkinson's disease. 2013

Brown, Peter. · ·Clin Neurophysiol · Pubmed #23177455.

ABSTRACT: -- No abstract --

2 Review Pedunculopontine Nucleus Region Deep Brain Stimulation in Parkinson Disease: Surgical Techniques, Side Effects, and Postoperative Imaging. 2016

Hamani, Clement / Lozano, Andres M / Mazzone, Paolo A M / Moro, Elena / Hutchison, William / Silburn, Peter A / Zrinzo, Ludvic / Alam, Mesbah / Goetz, Laurent / Pereira, Erlick / Rughani, Anand / Thevathasan, Wesley / Aziz, Tipu / Bloem, Bastiaan R / Brown, Peter / Chabardes, Stephan / Coyne, Terry / Foote, Kelly / Garcia-Rill, Edgar / Hirsch, Etienne C / Okun, Michael S / Krauss, Joachim K. ·Division of Neurosurgery, Toronto Western Hospital, University of Toronto, Toronto, Ont., Canada. ·Stereotact Funct Neurosurg · Pubmed #27728909.

ABSTRACT: The pedunculopontine nucleus (PPN) region has received considerable attention in clinical studies as a target for deep brain stimulation (DBS) in Parkinson disease. These studies have yielded variable results with an overall impression of improvement in falls and freezing in many but not all patients treated. We evaluated the available data on the surgical anatomy and terminology of the PPN region in a companion paper. Here we focus on issues concerning surgical technique, imaging, and early side effects of surgery. The aim of this paper was to gain more insight into the reasoning for choosing specific techniques and to discuss shortcomings of available studies. Our data demonstrate the wide range in almost all fields which were investigated. There are a number of important challenges to be resolved, such as identification of the optimal target, the choice of the surgical approach to optimize electrode placement, the impact on the outcome of specific surgical techniques, the reliability of intraoperative confirmation of the target, and methodological differences in postoperative validation of the electrode position. There is considerable variability both within and across groups, the overall experience with PPN DBS is still limited, and there is a lack of controlled trials. Despite these challenges, the procedure seems to provide benefit to selected patients and appears to be relatively safe. One important limitation in comparing studies from different centers and analyzing outcomes is the great variability in targeting and surgical techniques, as shown in our paper. The challenges we identified will be of relevance when designing future studies to better address several controversial issues. We hope that the data we accumulated may facilitate the development of surgical protocols for PPN DBS.

3 Review Pedunculopontine Nucleus Region Deep Brain Stimulation in Parkinson Disease: Surgical Anatomy and Terminology. 2016

Hamani, Clement / Aziz, Tipu / Bloem, Bastiaan R / Brown, Peter / Chabardes, Stephan / Coyne, Terry / Foote, Kelly / Garcia-Rill, Edgar / Hirsch, Etienne C / Lozano, Andres M / Mazzone, Paolo A M / Okun, Michael S / Hutchison, William / Silburn, Peter / Zrinzo, Ludvic / Alam, Mesbah / Goetz, Laurent / Pereira, Erlick / Rughani, Anand / Thevathasan, Wesley / Moro, Elena / Krauss, Joachim K. ·Division of Neurosurgery, Toronto Western Hospital, University of Toronto, Toronto, Ont., Canada. ·Stereotact Funct Neurosurg · Pubmed #27723662.

ABSTRACT: Several lines of evidence over the last few years have been important in ascertaining that the pedunculopontine nucleus (PPN) region could be considered as a potential target for deep brain stimulation (DBS) to treat freezing and other problems as part of a spectrum of gait disorders in Parkinson disease and other akinetic movement disorders. Since the introduction of PPN DBS, a variety of clinical studies have been published. Most indicate improvements in freezing and falls in patients who are severely affected by these problems. The results across patients, however, have been variable, perhaps reflecting patient selection, heterogeneity in target selection and differences in surgical methodology and stimulation settings. Here we outline both the accumulated knowledge and the domains of uncertainty in surgical anatomy and terminology. Specific topics were assigned to groups of experts, and this work was accumulated and reviewed by the executive committee of the working group. Areas of disagreement were discussed and modified accordingly until a consensus could be reached. We demonstrate that both the anatomy and the functional role of the PPN region need further study. The borders of the PPN and of adjacent nuclei differ when different brainstem atlases and atlas slices are compared. It is difficult to delineate precisely the PPN pars dissipata from the nucleus cuneiformis, as these structures partially overlap. This lack of clarity contributes to the difficulty in targeting and determining the exact localization of the electrodes implanted in patients with akinetic gait disorders. Future clinical studies need to consider these issues.

4 Review Adaptive deep brain stimulation in Parkinson's disease. 2016

Beudel, M / Brown, P. ·Department of Neurology, University Medical Centre Groningen, University of Groningen, Groningen, The Netherlands. · Nuffield Department of Clinical Neurosciences, John Radcliffe Hospital, University of Oxford, OX3 9DU, UK; The Medical Research Council Brain Network Dynamics Unit at the University of Oxford, OX1 3TH, UK. Electronic address: peter.brown@ndcn.ox.ac.uk. ·Parkinsonism Relat Disord · Pubmed #26411502.

ABSTRACT: Although Deep Brain Stimulation (DBS) is an established treatment for Parkinson's disease (PD), there are still limitations in terms of effectivity, side-effects and battery consumption. One of the reasons for this may be that not only pathological but also physiological neural activity can be suppressed whilst stimulating. For this reason, adaptive DBS (aDBS), where stimulation is applied according to the level of pathological activity, might be advantageous. Initial studies of aDBS demonstrate effectiveness in PD, but there are still many questions to be answered before aDBS can be applied clinically. Here we discuss the feedback signals and stimulation algorithms involved in adaptive stimulation in PD and sketch a potential road-map towards clinical application.

5 Review The subthalamic nucleus, oscillations, and conflict. 2015

Zavala, Baltazar / Zaghloul, Kareem / Brown, Peter. ·Experimental Neurology Group, Nuffield Department of Clinical Neurology, University of Oxford John Radcliffe Hospital, Oxford, UK; Surgical Neurology Branch, National Institutes of Health, Bethesda, MD, USA. ·Mov Disord · Pubmed #25688872.

ABSTRACT: The subthalamic nucleus (STN), which is currently the most common target for deep brain stimulation (DBS) for Parkinson's disease (PD), has received increased attention over the past few years for the roles it may play in functions beyond simple motor control. In this article, we highlight several of the theoretical, interventional, and electrophysiological studies that have implicated the STN in response inhibition. Most influential among this evidence has been the reported effect of STN DBS in increasing impulsive responses in the laboratory setting. Yet, how this relates to pathological impulsivity in patients' everyday lives remains uncertain.

6 Review Focusing brain therapeutic interventions in space and time for Parkinson's disease. 2014

Little, S / Brown, P. ·Nuffield Department of Clinical Neurosciences, John Radcliffe Hospital, University of Oxford, OX3 9DU, UK. · Nuffield Department of Clinical Neurosciences, John Radcliffe Hospital, University of Oxford, OX3 9DU, UK. Electronic address: peter.brown@ndcn.ox.ac.uk. ·Curr Biol · Pubmed #25247369.

ABSTRACT: The last decade has seen major progress at all levels of neuroscience, from genes and molecules up to integrated systems-level models of brain function. In particular, there have been advances in the understanding of cell-type-specific contributions to function, together with a clearer account of how these contributions are coordinated from moment to moment to organise behavior. A major current endeavor is to leverage this knowledge to develop new therapeutic approaches. In Parkinson's disease, there are a number of promising emerging treatments. Here, we will highlight three ambitious novel therapeutic approaches for this condition, each robustly driven by primary neuroscience. Pharmacogenetics genetically re-engineers neurons to produce neurotrophins that are neuroprotective to vulnerable dopaminergic cells or to directly replace dopamine through enzyme transduction. Deep brain stimulation (DBS) is undergoing a transformation, with adaptive DBS controlled by neural signals resulting in better motor outcomes and significant reductions in overall stimulation that could reduce side effects. Finally, optogenetics presents the opportunity to achieve cell-type-specific control with a high temporal specification on a large enough scale to effectively repair network-level dysfunction.

7 Review The highs and lows of beta activity in cortico-basal ganglia loops. 2014

Brittain, John-Stuart / Sharott, Andrew / Brown, Peter. ·Experimental Neurology Group, Nuffield Department of Clinical Neuroscience, University of Oxford, Oxford, OX3 9DU, UK. ·Eur J Neurosci · Pubmed #24890470.

ABSTRACT: Oscillatory activity in the beta (13-30 Hz) frequency band is widespread in cortico-basal ganglia circuits, and becomes prominent in Parkinson's disease (PD). Here we develop the hypothesis that the degree of synchronization in this frequency band is a critical factor in gating computation across a population of neurons, with increases in beta band synchrony entailing a loss of information-coding space and hence computational capacity. Task and context drive this dynamic gating, so that for each state there will be an optimal level of network synchrony, and levels lower or higher than this will impair behavioural performance. Thus, both the pathological exaggeration of synchrony, as observed in PD, and the ability of interventions like deep brain stimulation (DBS) to excessively suppress synchrony can potentially lead to impairments in behavioural performance. Indeed, under physiological conditions, the manipulation of computational capacity by beta activity may itself present a mechanism of action selection and maintenance.

8 Review The functional role of beta oscillations in Parkinson's disease. 2014

Little, Simon / Brown, Peter. ·Nuffield Department of Clinical Neurosciences, John Radcliffe Hospital, University of Oxford. OX3 9DU, UK. ·Parkinsonism Relat Disord · Pubmed #24262186.

ABSTRACT: Modulations of beta oscillations (13-30 Hz) during normal motor control suggest that they may act to promote current motor set at the expense of new movements. These oscillations are greatly enhanced in Parkinson's disease (PD) and there is strong correlative evidence linking beta activity at rest and beta changes in response to treatment with bradykinesia and rigidity. Some evidence that this link may be mechanistically important or causal comes from studies in which either cortical or subcortical sites have been stimulated in the beta frequency range causing modest but significant slowing of movements. However, recent trials in which high frequency deep brain stimulation (DBS) has only been delivered during periods of elevated beta activity have demonstrated major clinical effects that even exceed those of standard continuous high frequency DBS. These studies suggest that beta activity may be both causally and quantitatively important in the motor impairment of PD, and demonstrate how improvements in the understanding of the pathophysiology of PD can lead to enhanced therapeutic interventions in this condition.

9 Review Synchronized neural oscillations and the pathophysiology of Parkinson's disease. 2013

Oswal, Ashwini / Brown, Peter / Litvak, Vladimir. ·aDepartment of Clinical Neurology, John Radcliffe Hospital, Oxford bWellcome Trust Centre for Neuroimaging, Institute of Neurology, London, UK. ·Curr Opin Neurol · Pubmed #24150222.

ABSTRACT: PURPOSE OF THE REVIEW: Developments in functional neurosurgery for movement disorders and recent advances in electrophysiological techniques have allowed important insights into the role of oscillations in corticobasal ganglia circuits, both in health and in neurological disease states. Here we review recent developments in our understanding of how abnormally synchronized oscillatory activity within the corticobasal ganglia loop may play a key role in the pathophysiology of cognitive and motor phenotypes in Parkinson's disease. RECENT FINDINGS: Recent developments highlight the motor and non-motor roles of α, β and γ oscillations in the context of Parkinson's disease. They also emphasize the importance of oscillatory coupling between basal ganglia and cortex and draw attention to the importance of interactions between different frequency bands. SUMMARY: Oscillatory activities across multiple frequency bands and their cross-frequency interactions within spatially segregated loops of the basal ganglia-thalamo-cortical system may relate to distinct components of clinical impairment, both motor and non-motor. It is hoped that this characterization will lead to improved interventions like deep brain stimulation, tailored to specific components of clinical impairment and their associated spatial and spectral signatures.

10 Review γ oscillations in the human basal ganglia. 2013

Jenkinson, Ned / Kühn, Andrea A / Brown, Peter. ·Functional Neurosurgery and Experimental Neurology Group, University of Oxford, University Offices, Level 6, West Wing John Radcliffe Hospital, Oxford, OX3 9DU, UK. ned.jenkinson@dpag.ox.ac.uk ·Exp Neurol · Pubmed #22841500.

ABSTRACT: Interest in beta activity in the basal ganglia has mushroomed since it was first identified in the subthalamic nucleus of patients with Parkinson's disease in Jonathan Dostrovsky's landmark paper (Levy et al., 2000). Here we consider a less explored phenomenon; namely gamma frequency synchronisation of neurons in the basal ganglia. Gamma oscillations have been reported in a distributed network involving the basal ganglia, thalamus and motor cortex, and have been described in a wide range of diseases as well as during increased arousal and voluntary movement. In Parkinson's disease, gamma activity is promoted by dopaminergic therapy. These features suggest that its elevation may be involved in the production of movement and this hypothesis is supported by the correlation between the amplitude of gamma activity and limb kinematics. Here we review these data, discuss the functional anatomy of gamma activity in basal ganglia and question how closely it relates to the coding of movement parameters.

11 Clinical Trial Intact Acquisition and Short-Term Retention of Non-Motor Procedural Learning in Parkinson's Disease. 2016

Panouillères, Muriel T N / Tofaris, George K / Brown, Peter / Jenkinson, Ned. ·Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom. · School of Sport, Exercise and Rehabilitation Sciences, University of Birmingham, Birmingham, United Kingdom. ·PLoS One · Pubmed #26906905.

ABSTRACT: Procedural learning is a form of memory where people implicitly acquire a skill through repeated practice. People with Parkinson's disease (PD) have been found to acquire motor adaptation, a form of motor procedural learning, similarly to healthy older adults but they have deficits in long-term retention. A similar pattern of normal learning on initial exposure with a deficit in retention seen on subsequent days has also been seen in mirror-reading, a form of non-motor procedural learning. It is a well-studied fact that disrupting sleep will impair the consolidation of procedural memories. Given the prevalence of sleep disturbances in PD, the lack of retention on following days seen in these studies could simply be a side effect of this well-known symptom of PD. Because of this, we wondered whether people with PD would present with deficits in the short-term retention of a non-motor procedural learning task, when the test of retention was done the same day as the initial exposure. The aim of the present study was then to investigate acquisition and retention in the immediate short term of cognitive procedural learning using the mirror-reading task in people with PD. This task involved two conditions: one where triads of mirror-inverted words were always new that allowed assessing the learning of mirror-reading skill and another one where some of the triads were presented repeatedly during the experiment that allowed assessing the word-specific learning. People with PD both ON and OFF their normal medication were compared to healthy older adults and young adults. Participants were re-tested 50 minutes break after initial exposure to probe for short-term retention. The results of this study show that all groups of participants acquired and retained the two skills (mirror-reading and word-specific) similarly. These results suggest that neither healthy ageing nor the degeneration within the basal ganglia that occurs in PD does affect the mechanisms that underpin the acquisition of these new non-motor procedural learning skills and their short-term memories.

12 Clinical Trial A spatiotemporal analysis of gait freezing and the impact of pedunculopontine nucleus stimulation. 2012

Thevathasan, Wesley / Cole, Michael H / Graepel, Cara L / Hyam, Jonathan A / Jenkinson, Ned / Brittain, John-Stuart / Coyne, Terry J / Silburn, Peter A / Aziz, Tipu Z / Kerr, Graham / Brown, Peter. ·Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK. wesley.thevathasan@nds.ox.ac.uk ·Brain · Pubmed #22396391.

ABSTRACT: Gait freezing is an episodic arrest of locomotion due to an inability to take normal steps. Pedunculopontine nucleus stimulation is an emerging therapy proposed to improve gait freezing, even where refractory to medication. However, the efficacy and precise effects of pedunculopontine nucleus stimulation on Parkinsonian gait disturbance are not established. The clinical application of this new therapy is controversial and it is unknown if bilateral stimulation is more effective than unilateral. Here, in a double-blinded study using objective spatiotemporal gait analysis, we assessed the impact of unilateral and bilateral pedunculopontine nucleus stimulation on triggered episodes of gait freezing and on background deficits of unconstrained gait in Parkinson's disease. Under experimental conditions, while OFF medication, Parkinsonian patients with severe gait freezing implanted with pedunculopontine nucleus stimulators below the pontomesencephalic junction were assessed during three conditions; off stimulation, unilateral stimulation and bilateral stimulation. Results were compared to Parkinsonian patients without gait freezing matched for disease severity and healthy controls. Pedunculopontine nucleus stimulation improved objective measures of gait freezing, with bilateral stimulation more effective than unilateral. During unconstrained walking, Parkinsonian patients who experience gait freezing had reduced step length and increased step length variability compared to patients without gait freezing; however, these deficits were unchanged by pedunculopontine nucleus stimulation. Chronic pedunculopontine nucleus stimulation improved Freezing of Gait Questionnaire scores, reflecting a reduction of the freezing encountered in patients' usual environments and medication states. This study provides objective, double-blinded evidence that in a specific subgroup of Parkinsonian patients, stimulation of a caudal pedunculopontine nucleus region selectively improves gait freezing but not background deficits in step length. Bilateral stimulation was more effective than unilateral.

13 Clinical Trial A block to pre-prepared movement in gait freezing, relieved by pedunculopontine nucleus stimulation. 2011

Thevathasan, Wesley / Pogosyan, Alek / Hyam, Jonathan A / Jenkinson, Ned / Bogdanovic, Marko / Coyne, Terry J / Silburn, Peter A / Aziz, Tipu Z / Brown, Peter. ·Department of Clinical Neurology, University of Oxford, UK. ·Brain · Pubmed #21705424.

ABSTRACT: Gait freezing and postural instability are disabling features of Parkinsonian disorders, treatable with pedunculopontine nucleus stimulation. Both features are considered deficits of proximal and axial musculature, innervated predominantly by reticulospinal pathways and tend to manifest when gait and posture require adjustment. Adjustments to gait and posture are amenable to pre-preparation and rapid triggered release. Experimentally, such accelerated release can be elicited by loud auditory stimuli--a phenomenon known as 'StartReact'. We observed StartReact in healthy and Parkinsonian controls. However, StartReact was absent in Parkinsonian patients with severe gait freezing and postural instability. Pedunculopontine nucleus stimulation restored StartReact proximally and proximal reaction times to loud stimuli correlated with gait and postural disturbance. These findings suggest a relative block to triggered, pre-prepared movement in gait freezing and postural instability, relieved by pedunculopontine nucleus stimulation.

14 Clinical Trial Deep brain stimulation can suppress pathological synchronisation in parkinsonian patients. 2011

Eusebio, A / Thevathasan, W / Doyle Gaynor, L / Pogosyan, A / Bye, E / Foltynie, T / Zrinzo, L / Ashkan, K / Aziz, T / Brown, P. ·Sobell Department of Motor Neuroscience and Movement Disorders, Institute of Neurology, London, UK. ·J Neurol Neurosurg Psychiatry · Pubmed #20935326.

ABSTRACT: BACKGROUND: Although deep brain stimulation (DBS) of the subthalamic nucleus (STN) is a highly effective therapeutic intervention in severe Parkinson's disease, its mechanism of action remains unclear. One possibility is that DBS suppresses local pathologically synchronised oscillatory activity. METHODS: To explore this, the authors recorded from DBS electrodes implanted in the STN of 16 patients with Parkinson's disease during simultaneous stimulation (pulse width 60 μs; frequency 130 Hz) of the same target using a specially designed amplifier. The authors analysed data from 25 sides. RESULTS: The authors found that DBS progressively suppressed peaks in local field potential activity at frequencies between 11 and 30 Hz as voltage was increased beyond a stimulation threshold of 1.5 V. Median peak power had fallen to 54% of baseline values by a stimulation intensity of 3.0 V. CONCLUSION: The findings suggest that DBS can suppress pathological 11-30 Hz activity in the vicinity of stimulation in patients with Parkinson's disease. This suppression occurs at stimulation voltages that are clinically effective.

15 Clinical Trial Pathological synchronisation in the subthalamic nucleus of patients with Parkinson's disease relates to both bradykinesia and rigidity. 2009

Kühn, Andrea A / Tsui, Alexander / Aziz, Tipu / Ray, Nicola / Brücke, Christof / Kupsch, Andreas / Schneider, Gerd-Helge / Brown, Peter. ·Department of Neurology, Charité, University Medicine Berlin, Campus Virchow, Berlin, Germany. ·Exp Neurol · Pubmed #19070616.

ABSTRACT: Parkinson's disease (PD) is associated with exaggerated oscillatory synchrony in the basal ganglia at frequencies over 8-35 Hz. Studies have demonstrated a suppression of local field potential (LFP) activity in the subthalamic nucleus (STN) upon treatment with the dopamine prodrug, levodopa, with the degree of suppression of power in the 8-35 Hz band correlating with the improvement in combined measures of bradykinesia and rigidity. However, these studies do not explicitly address the question of what is more important in predicting clinical change - synchronisation of neuronal activity or the specific frequency within the 8-35 Hz band over which the latter occurs. In addition, they have not demonstrated a relationship between treatment-induced changes in synchronisation and changes in bradykinesia or rigidity on their own. To this end, we collected and analysed LFP and clinical data in 30 patients with PD. We found significant correlations between levodopa-induced power suppression and rigidity and bradykinesia, when these clinical features were considered separately, but only when power suppression profiles were re-aligned to the frequency of peak synchronisation. Under these circumstances correlations with rigidity persisted despite partialising out the effect of bradykinesia and vice versa. These data suggest that levodopa-induced improvements in both rigidity and bradykinesia scale with the degree of suppression of oscillatory power in the STN LFP, and that this is true irrespective of the frequency at which synchronisation occurs across a broad band from 8-35 Hz.

16 Clinical Trial High-frequency stimulation of the subthalamic nucleus suppresses oscillatory beta activity in patients with Parkinson's disease in parallel with improvement in motor performance. 2008

Kühn, Andrea A / Kempf, Florian / Brücke, Christof / Gaynor Doyle, Louise / Martinez-Torres, Irene / Pogosyan, Alek / Trottenberg, Thomas / Kupsch, Andreas / Schneider, Gerd-Helge / Hariz, Marwan I / Vandenberghe, Wim / Nuttin, Bart / Brown, Peter. ·Sobell Department of Motor Neuroscience and Movement Disorders, Institute of Neurology, London WC1N 3BG, United Kingdom. andrea.kuehn@charite.de ·J Neurosci · Pubmed #18550758.

ABSTRACT: High-frequency stimulation (HFS) of the subthalamic nucleus (STN) is a well-established therapy for patients with severe Parkinson's disease (PD), but its mechanism of action is unclear. Exaggerated oscillatory synchronization in the beta (13-30 Hz) frequency band has been associated with bradykinesia in patients with PD. Accordingly, we tested the hypothesis that the clinical benefit exerted by STN HFS is accompanied by suppression of local beta activity. To this end, we explored the after effects of STN HFS on the oscillatory local field potential (LFP) activity recorded from the STN immediately after the cessation of HFS in 11 PD patients. Only patients that demonstrated a temporary persistence of clinical benefit after cessation of HFS were analyzed. STN HFS led to a significant reduction in STN LFP beta activity for 12 s after the end of stimulation and a decrease in motor cortical-STN coherence in the beta band over the same time period. The reduction in LFP beta activity correlated with the movement amplitude during a simple motor task, so that a smaller amount of beta activity was associated with better task performance. These features were absent when power in the 5-12 Hz frequency band was considered. Our findings suggest that HFS may act by modulating pathological patterns of synchronized oscillations, specifically by reduction of pathological beta activity in PD.

17 Clinical Trial Oscillatory activity in the pedunculopontine area of patients with Parkinson's disease. 2008

Androulidakis, Alexandros G / Mazzone, Paolo / Litvak, Vladimir / Penny, Will / Dileone, Michele / Gaynor, Louise M F Doyle / Tisch, Stephen / Di Lazzaro, Vincenzo / Brown, Peter. ·Sobell Department of Motor Neuroscience and Movement Disorders, Institute of Neurology, University College London, Queen Square, London, UK. ·Exp Neurol · Pubmed #18282571.

ABSTRACT: The pedunculopontine nucleus (PPN) has recently been introduced as a new therapeutic target for deep brain stimulation (DBS) in patients suffering from Parkinson's disease (PD). In a recent case report it was demonstrated that alpha frequency oscillations appear in PPN after the administration of levodopa in PD, indicating a possible physiological role of these oscillations. Here we confirm this result and investigate the functional connectivity and reactivity of subcortical alpha activity by recording LFP activity from the PPN area and EEG in six patients with PD while at rest and in four of them while they performed ipsi- and contralateral self-paced joystick movements. Levodopa strongly promoted 7-11 Hz oscillatory synchronization in the region of PPN and coupling of this activity with similar activity in the cortical EEG. Such coupling was bidirectional. Moreover, the 7-11 Hz oscillatory synchronization in the PPN area increased about 3 s prior to self-paced movements, but only following levodopa treatment. These findings suggest that alpha oscillations in the PPN area may represent a physiological pattern of activity. The subcortical oscillations are coupled to cortical alpha activity and possibly allied to motor related attentional processes.

18 Article Beta burst dynamics in Parkinson's disease OFF and ON dopaminergic medication. 2017

Tinkhauser, Gerd / Pogosyan, Alek / Tan, Huiling / Herz, Damian M / Kühn, Andrea A / Brown, Peter. ·Medical Research Council Brain Network Dynamics Unit at the University of Oxford, Oxford, UK. · Nuffield Department of Clinical Neurosciences, John Radcliffe Hospital, University of Oxford, Oxford, UK. · Department of Neurology, Bern University Hospital and University of Bern, Switzerland. · Department of Neurology, Charitè, Universitätsmedizin Berlin, Germany. ·Brain · Pubmed #29053865.

ABSTRACT: Exaggerated basal ganglia beta activity (13-35 Hz) is commonly found in patients with Parkinson's disease and can be suppressed by dopaminergic medication, with the degree of suppression being correlated with the improvement in motor symptoms. Importantly, beta activity is not continuously elevated, but fluctuates to give beta bursts. The percentage number of longer beta bursts in a given interval is positively correlated with clinical impairment in Parkinson's disease patients. Here we determine whether the characteristics of beta bursts are dependent on dopaminergic state. Local field potentials were recorded from the subthalamic nucleus of eight Parkinson's disease patients during temporary lead externalization during surgery for deep brain stimulation. The recordings took place with the patient quietly seated following overnight withdrawal of levodopa and after administration of levodopa. Beta bursts were defined by applying a common amplitude threshold and burst characteristics were compared between the two drug conditions. The amplitude of beta bursts, indicative of the degree of local neural synchronization, progressively increased with burst duration. Treatment with levodopa limited this evolution leading to a relative increase of shorter, lower amplitude bursts. Synchronization, however, was not limited to local neural populations during bursts, but also, when such bursts were cotemporaneous across the hemispheres, was evidenced by bilateral phase synchronization. The probability of beta bursts and the proportion of cotemporaneous bursts were reduced by levodopa. The percentage number of longer beta bursts in a given interval was positively related to motor impairment, while the opposite was true for the percentage number of short duration beta bursts. Importantly, the decrease in burst duration was also correlated with the motor improvement. In conclusion, we demonstrate that long duration beta bursts are associated with an increase in local and interhemispheric synchronization. This may compromise information coding capacity and thereby motor processing. Dopaminergic activity limits this uncontrolled beta synchronization by terminating long duration beta bursts, with positive consequences on network state and motor symptoms.

19 Article Long term correlation of subthalamic beta band activity with motor impairment in patients with Parkinson's disease. 2017

Neumann, Wolf-Julian / Staub-Bartelt, Franziska / Horn, Andreas / Schanda, Julia / Schneider, Gerd-Helge / Brown, Peter / Kühn, Andrea A. ·Movement Disorders and Neuromodulation Unit, Department of Neurology, Charité Campus Mitte, Charité - Universitätsmedizin Berlin, Berlin, Germany. · Department of Neurosurgery, Charité Campus Mitte, Charité - Universitätsmedizin Berlin, Berlin, Germany. · MRC Brain Network Dynamics Unit and Nuffield Department of Clinical Neuroscience, University of Oxford, Oxford, United Kingdom. · Movement Disorders and Neuromodulation Unit, Department of Neurology, Charité Campus Mitte, Charité - Universitätsmedizin Berlin, Berlin, Germany; Berlin School of Mind and Brain, Charité - Universitätsmedizin Berlin, Berlin, Germany; NeuroCure, Charité - Universitätsmedizin Berlin, Berlin, Germany. Electronic address: andrea.kuehn@charite.de. ·Clin Neurophysiol · Pubmed #29031219.

ABSTRACT: OBJECTIVES: To investigate the long term association of subthalamic beta activity with parkinsonian motor signs. METHODS: We recruited 15 patients with Parkinson's disease undergoing subthalamic DBS for local field potential recordings after electrode implantation, and at 3 and 8months post-operatively using the implantable sensing enabled Activa PC+S (Medtronic). Three patients dropped out leaving 12 patients. Recordings were conducted ON and OFF levodopa at rest. Beta (13-35Hz) peak amplitudes were extracted, compared across time points and correlated with UPDRS-III hemibody scores. RESULTS: Peaks in the beta frequency band (13-35Hz) in the OFF medication state were found in all hemispheres. Mean beta activity was significantly suppressed by levodopa at all recorded time points (P<0.007) and individual beta power amplitude correlated with parkinsonian motor impairment across time points and dopaminergic states (pooled data; ρ=0.25, P<0.001). CONCLUSIONS: Our results indicate that beta-activity is correlated with parkinsonian motor signs over a time period of 8months. SIGNIFICANCE: Beta-activity may be a chronically detectable biomarker of symptom severity in PD that should be further evaluated under ongoing DBS.

20 Article Localization of beta and high-frequency oscillations within the subthalamic nucleus region. 2017

van Wijk, B C M / Pogosyan, A / Hariz, M I / Akram, H / Foltynie, T / Limousin, P / Horn, A / Ewert, S / Brown, P / Litvak, V. ·Department of Neurology, Charité - University Medicine Berlin, Berlin, Germany. · Wellcome Trust Centre for Neuroimaging, UCL Institute of Neurology, London, United Kingdom. · Nuffield Department of Clinical Neuroscience, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom. · Unit of Functional Neurosurgery, Sobell Department of Motor Neuroscience and Movement Disorders, UCL Institute of Neurology, London, United Kingdom. · Department of Clinical Neuroscience, Umeå University, Umeå, Sweden. · Victor Horsley Department of Neurosurgery, National Hospital for Neurology and Neurosurgery, London, United Kingdom. · Berenson-Allen Center for Non-Invasive Brain Stimulation and Division of Cognitive Neurology, Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA. · Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. · Medical Research Council Brain Network Dynamics Unit at the University of Oxford, Oxford, United Kingdom. ·Neuroimage Clin · Pubmed #28794978.

ABSTRACT: Parkinsonian bradykinesia and rigidity are typically associated with excessive beta band oscillations in the subthalamic nucleus. Recently another spectral peak has been identified that might be implicated in the pathophysiology of the disease: high-frequency oscillations (HFO) within the 150-400 Hz range. Beta-HFO phase-amplitude coupling (PAC) has been found to correlate with severity of motor impairment. However, the neuronal origin of HFO and its usefulness as a potential target for deep brain stimulation remain to be established. For example, it is unclear whether HFO arise from the same neural populations as beta oscillations. We intraoperatively recorded local field potentials from the subthalamic nucleus while advancing DBS electrodes in 2 mm steps from 4 mm above the surgical target point until 2 mm below, resulting in 4 recording sites. Data from 26 nuclei from 14 patients were analysed. For each trajectory, we identified the recording site with the largest spectral peak in the beta range (13-30 Hz), and the largest peak in the HFO range separately. In addition, we identified the recording site with the largest beta-HFO PAC. Recording sites with largest beta power and largest HFO power coincided in 50% of cases. In the other 50%, HFO was more likely to be detected at a more superior recording site in the target area. PAC followed more closely the site with largest HFO (45%) than beta power (27%). HFO are likely to arise from spatially close, but slightly more superior neural populations than beta oscillations. Further work is necessary to determine whether the different activities can help fine-tune deep brain stimulation targeting.

21 Article Subthalamic nucleus gamma activity increases not only during movement but also during movement inhibition. 2017

Fischer, Petra / Pogosyan, Alek / Herz, Damian M / Cheeran, Binith / Green, Alexander L / Fitzgerald, James / Aziz, Tipu Z / Hyam, Jonathan / Little, Simon / Foltynie, Thomas / Limousin, Patricia / Zrinzo, Ludvic / Brown, Peter / Tan, Huiling. ·Medical Research Council Brain Network Dynamics Unit at the University of Oxford, Oxford, United Kingdom. · Nuffield Department of Clinical Neurosciences, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom. · Unit of Functional Neurosurgery, Sobell Department of Motor Neuroscience and Movement Disorders, University College London Institute of Neurology, London, United Kingdom. ·Elife · Pubmed #28742498.

ABSTRACT: Gamma activity in the subthalamic nucleus (STN) is widely viewed as a pro-kinetic rhythm. Here we test the hypothesis that rather than being specifically linked to movement execution, gamma activity reflects dynamic processing in this nucleus. We investigated the role of gamma during fast stopping and recorded scalp electroencephalogram and local field potentials from deep brain stimulation electrodes in 9 Parkinson's disease patients. Patients interrupted finger tapping (paced by a metronome) in response to a stop-signal sound, which was timed such that successful stopping would occur only in ~50% of all trials. STN gamma (60-90 Hz) increased most strongly when the tap was successfully stopped, whereas phase-based connectivity between the contralateral STN and motor cortex decreased. Beta or theta power seemed less directly related to stopping. In summary, STN gamma activity may support flexible motor control as it did not only increase during movement execution but also during rapid action-stopping.

22 Article Subthalamic beta dynamics mirror Parkinsonian bradykinesia months after neurostimulator implantation. 2017

Steiner, Leon Amadeus / Neumann, Wolf-Julian / Staub-Bartelt, Franziska / Herz, Damian M / Tan, Huiling / Pogosyan, Alek / Kuhn, Andrea A / Brown, Peter. ·Department of Neurology, Charité, Campus Virchow Klinikum, University Medicine Berlin, Berlin, Germany. · Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK. · Medical Research Council Brain Network Dynamics Unit, University of Oxford, Oxford, UK. · NeuroCure, Charité, University Medicine Berlin, Berlin, Germany. ·Mov Disord · Pubmed #28639263.

ABSTRACT: BACKGROUND: Exaggerated oscillatory activity in the beta frequency band in the subthalamic nucleus has been suggested to be related to bradykinesia in Parkinson's disease (PD). However, studies seeking correlations between such activity in the local field potential and motor performance have been limited to the immediate postoperative period, which may be confounded by a stun effect that leads to the temporary alleviation of PD deficits. METHODS: Local field potentials were recorded simultaneously with motor performance in PD patients several months after neurostimulator implantation. This was enabled by the chronic implantation of a pulse generator with the capacity to record and transmit local field potentials from deep brain stimulation electrodes. Specifically, we investigated oscillatory beta power dynamics and objective measures of bradykinesia during an upper limb alternating pronation and supination task in 9 patients. RESULTS: Although beta power was suppressed during continuously repeated movements, this suppression progressively diminished over time in tandem with a progressive decrement in the frequency and amplitude of movements. The relationship between changes within local field potentials and movement parameters was significant across patients, and not present for theta/alpha frequencies (5-12 Hz). Change in movement frequency furthermore related to beta power dynamics within patients. CONCLUSIONS: Changes in beta power are linked to changes in movement performance and the sequence effect of bradykinesia months after neurostimulator implantation. These findings provide further evidence that beta power may serve as a biomarker for bradykinesia and provide a suitable substrate for feedback control in chronic adaptive deep brain stimulation. © 2017 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

23 Article Tremor stability index: a new tool for differential diagnosis in tremor syndromes. 2017

di Biase, Lazzaro / Brittain, John-Stuart / Shah, Syed Ahmar / Pedrosa, David J / Cagnan, Hayriye / Mathy, Alexandre / Chen, Chiung Chu / Martín-Rodríguez, Juan Francisco / Mir, Pablo / Timmerman, Lars / Schwingenschuh, Petra / Bhatia, Kailash / Di Lazzaro, Vincenzo / Brown, Peter. ·Neurology Unit, Campus Bio-Medico University of Rome, Via Alvaro del Portillo 200, 00128, Rome, Italy. · Nuffield Department of Clinical Neurosciences, University of Oxford, Level 6, West Wing, John Radcliffe Hospital, OX3 9DU, Oxford, UK. · Medical Research Council Brain Network Dynamics Unit, Department of Pharmacology, University of Oxford, Mansfield Road, OX1 3TH, Oxford, UK. · Department of Neurology, University Hospital of Cologne, Kerpener Straße 62, 50924 Cologne, Germany. · Department of Neurology and Neuroscience Research Center, Chang Gung Memorial Hospital and University, Taipei, Taiwan. · Unidad de Trastornos del Movimiento, Servicio de Neurología y Neurofisiología Clínica, Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Seville, Spain. · Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Spain. · Department of Neurology, University Hospital Marburg, Germany. · Department of Neurology, Medical University of Graz, Auenbruggerplatz 22, 8036 Graz, Austria. · Sobell Department of Motor Neuroscience and Movement Disorders, University College London, Queen Square, WC1N 3BG, London, UK. ·Brain · Pubmed #28459950.

ABSTRACT: See Vidailhet et al. (doi:10.1093/brain/awx140) for a scientific commentary on this article.Misdiagnosis among tremor syndromes is common, and can impact on both clinical care and research. To date no validated neurophysiological technique is available that has proven to have good classification performance, and the diagnostic gold standard is the clinical evaluation made by a movement disorders expert. We present a robust new neurophysiological measure, the tremor stability index, which can discriminate Parkinson's disease tremor and essential tremor with high diagnostic accuracy. The tremor stability index is derived from kinematic measurements of tremulous activity. It was assessed in a test cohort comprising 16 rest tremor recordings in tremor-dominant Parkinson's disease and 20 postural tremor recordings in essential tremor, and validated on a second, independent cohort comprising a further 55 tremulous Parkinson's disease and essential tremor recordings. Clinical diagnosis was used as gold standard. One hundred seconds of tremor recording were selected for analysis in each patient. The classification accuracy of the new index was assessed by binary logistic regression and by receiver operating characteristic analysis. The diagnostic performance was examined by calculating the sensitivity, specificity, accuracy, likelihood ratio positive, likelihood ratio negative, area under the receiver operating characteristic curve, and by cross-validation. Tremor stability index with a cut-off of 1.05 gave good classification performance for Parkinson's disease tremor and essential tremor, in both test and validation datasets. Tremor stability index maximum sensitivity, specificity and accuracy were 95%, 95% and 92%, respectively. Receiver operating characteristic analysis showed an area under the curve of 0.916 (95% confidence interval 0.797-1.000) for the test dataset and a value of 0.855 (95% confidence interval 0.754-0.957) for the validation dataset. Classification accuracy proved independent of recording device and posture. The tremor stability index can aid in the differential diagnosis of the two most common tremor types. It has a high diagnostic accuracy, can be derived from short, cheap, widely available and non-invasive tremor recordings, and is independent of operator or postural context in its interpretation.

24 Article Subthalamic nucleus beta and gamma activity is modulated depending on the level of imagined grip force. 2017

Fischer, Petra / Pogosyan, Alek / Cheeran, Binith / Green, Alexander L / Aziz, Tipu Z / Hyam, Jonathan / Little, Simon / Foltynie, Thomas / Limousin, Patricia / Zrinzo, Ludvic / Hariz, Marwan / Samuel, Michael / Ashkan, Keyoumars / Brown, Peter / Tan, Huiling. ·Medical Research Council Brain Network Dynamics Unit at the University of Oxford, OX1 3TH Oxford, United Kingdom; Nuffield Department of Clinical Neurosciences, John Radcliffe Hospital, University of Oxford, OX3 9DU Oxford, United Kingdom. Electronic address: petra.fischer@ndcn.ox.ac.uk. · Medical Research Council Brain Network Dynamics Unit at the University of Oxford, OX1 3TH Oxford, United Kingdom; Nuffield Department of Clinical Neurosciences, John Radcliffe Hospital, University of Oxford, OX3 9DU Oxford, United Kingdom. · Nuffield Department of Clinical Neurosciences, John Radcliffe Hospital, University of Oxford, OX3 9DU Oxford, United Kingdom. · Unit of Functional Neurosurgery, Sobell Department of Motor Neuroscience and Movement Disorders, University College London Institute of Neurology, WC1N 3BG London, United Kingdom. · Departments of Neurology and Neurosurgery, King's College Hospital, King's College London, United Kingdom. ·Exp Neurol · Pubmed #28342747.

ABSTRACT: Motor imagery involves cortical networks similar to those activated by real movements, but the extent to which the basal ganglia are recruited is not yet clear. Gamma and beta oscillations in the subthalamic nucleus (STN) vary with the effort of sustained muscle activity. We recorded local field potentials in Parkinson's disease patients and investigated if similar changes can be observed during imagined gripping at three different 'forces'. We found that beta activity decreased significantly only for imagined grips at the two stronger force levels. Additionally, gamma power significantly scaled with increasing imagined force. Thus, in combination, these two spectral features can provide information about the intended force of an imaginary grip even in the absence of sensory feedback. Modulations in the two frequency bands during imaginary movement may explain the rehabilitating benefit of motor imagery to improve motor performance. The results also suggest that STN LFPs may provide useful information for brain-machine interfaces.

25 Article The modulatory effect of adaptive deep brain stimulation on beta bursts in Parkinson's disease. 2017

Tinkhauser, Gerd / Pogosyan, Alek / Little, Simon / Beudel, Martijn / Herz, Damian M / Tan, Huiling / Brown, Peter. ·Medical Research Council Brain Network Dynamics Unit at the University of Oxford, Oxford, UK. · Nuffield Department of Clinical Neurosciences, John Radcliffe Hospital, University of Oxford, Oxford, UK. · Department of Neurology, Bern University Hospital and University of Bern, Switzerland. · Sobell Department of Motor Neuroscience and Movement Disorders, UCL Institute of Neurology, London, UK. · University Medical Center Groningen, 9700 RB Groningen, The Netherlands. ·Brain · Pubmed #28334851.

ABSTRACT: Adaptive deep brain stimulation uses feedback about the state of neural circuits to control stimulation rather than delivering fixed stimulation all the time, as currently performed. In patients with Parkinson's disease, elevations in beta activity (13-35 Hz) in the subthalamic nucleus have been demonstrated to correlate with clinical impairment and have provided the basis for feedback control in trials of adaptive deep brain stimulation. These pilot studies have suggested that adaptive deep brain stimulation may potentially be more effective, efficient and selective than conventional deep brain stimulation, implying mechanistic differences between the two approaches. Here we test the hypothesis that such differences arise through differential effects on the temporal dynamics of beta activity. The latter is not constantly increased in Parkinson's disease, but comes in bursts of different durations and amplitudes. We demonstrate that the amplitude of beta activity in the subthalamic nucleus increases in proportion to burst duration, consistent with progressively increasing synchronization. Effective adaptive deep brain stimulation truncated long beta bursts shifting the distribution of burst duration away from long duration with large amplitude towards short duration, lower amplitude bursts. Critically, bursts with shorter duration are negatively and bursts with longer duration positively correlated with the motor impairment off stimulation. Conventional deep brain stimulation did not change the distribution of burst durations. Although both adaptive and conventional deep brain stimulation suppressed mean beta activity amplitude compared to the unstimulated state, this was achieved by a selective effect on burst duration during adaptive deep brain stimulation, whereas conventional deep brain stimulation globally suppressed beta activity. We posit that the relatively selective effect of adaptive deep brain stimulation provides a rationale for why this approach could be more efficacious than conventional continuous deep brain stimulation in the treatment of Parkinson's disease, and helps inform how adaptive deep brain stimulation might best be delivered.

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