Showing papers by "Thomas Foltynie published in 2011"

Resting oscillatory cortico-subthalamic connectivity in patients with Parkinson's disease

Abstract: Both phenotype and treatment response vary in patients with Parkinson’s disease. Anatomical and functional imaging studies suggest that individual symptoms may represent malfunction of different segregated networks running in parallel through the basal ganglia. In this study, we use a newly described, electrophysiological method to describe cortico-subthalamic networks in humans. We performed combined magnetoencephalographic and subthalamic local field potential recordings in thirteen patients with Parkinson’s disease at rest. Two spatially and spectrally separated networks were identified. A temporoparietal-brainstem network was coherent with the subthalamic nucleus in the alpha (7–13 Hz) band, whilst a predominantly frontal network was coherent in the beta (15–35 Hz) band. Dopaminergic medication modulated the resting beta network, by increasing beta coherence between the subthalamic region and prefrontal cortex. Subthalamic activity was predominantly led by activity in the cortex in both frequency bands. The cortical topography and frequencies involved in the alpha and beta networks suggest that these networks may be involved in attentional and executive, particularly motor planning, processes, respectively. * Abbreviations : DICS : dynamic imaging of coherent sources LFP : local field potential SPM : statistical parametric mapping STN-LFP : subthalamic nucleus local field potential UPDRS : Unified Parkinson’s Disease Rating Scale

Deep brain stimulation can suppress pathological synchronisation in parkinsonian patients

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 ms; 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 11e30 Hz activity in the vicinity of stimulation in patients with Parkinson’s disease. This suppression occurs at stimulation voltages that are clinically effective.

A Two-Stage Meta-Analysis Identifies Several New Loci for Parkinson's Disease

Abstract: A previous genome-wide association (GWA) meta-analysis of 12,386 PD cases and 21,026 controls conducted by the International Parkinson's Disease Genomics Consortium (IPDGC) discovered or confirmed 11 Parkinson's disease (PD) loci. This first analysis of the two-stage IPDGC study focused on the set of loci that passed genome-wide significance in the first stage GWA scan. However, the second stage genotyping array, the ImmunoChip, included a larger set of 1,920 SNPs selected on the basis of the GWA analysis. Here, we analyzed this set of 1,920 SNPs, and we identified five additional PD risk loci (combined p<5x10(-10), PARK16/1q32, STX1B/16p11, FGF20/8p22, STBD1/4q21, and GPNMB/7p15). Two of these five loci have been suggested by previous association studies (PARK16/1q32, FGF20/8p22), and this study provides further support for these findings. Using a dataset of post-mortem brain samples assayed for gene expression (n = 399) and methylation (n = 292), we identified methylation and expression changes associated with PD risk variants in PARK16/1q32, GPNMB/7p15, and STX1B/16p11 loci, hence suggesting potential molecular mechanisms and candidate genes at these risk loci.

MRI-guided STN DBS in Parkinson's disease without microelectrode recording: efficacy and safety

Abstract: Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is a commonly employed therapeutic procedure for patients with Parkinson's disease uncontrolled by medical therapies. This series describes the outcomes of 79 consecutive patients that underwent bilateral STN DBS at the National Hospital for Neurology and Neurosurgery between November 2002 and November 2008 using an MRI-guided surgical technique without microelectrode recording. Patients underwent immediate postoperative stereotactic MR imaging. The mean (SD) error in electrode placement was 1.3 (0.6) mm. There were no haemorrhagic complications. At a median follow-up period of 12 months, there was a mean improvement in the off-medication motor part of the Unified Parkinson's Disease Rating Scale (UPDRS III) of 27.7 points (SD 13.8) equivalent to a mean improvement of 52% (p<0.0001). In addition, there were significant improvements in dyskinesia duration, disability and pain, with a mean reduction in on-medication dyskinesia severity (sum of dyskinesia duration, disability and pain from UPDRS IV) from 3.15 (SD 2.33) pre-operatively, to 1.56 (SD 1.92) post-operatively (p=0.0001). Quality of life improved by a mean of 5.5 points (median 7.9 points, SD 17.3) on the Parkinson's disease Questionnaire 39 summary index. This series confirms that image-guided STN DBS without microelectrode recording can lead to substantial improvements in motor disability of well-selected PD patients with accompanying improvements in quality of life and most importantly, with very low morbidity.

The natural history of treated Parkinson's disease in an incident, community based cohort

Abstract: Background Our understanding of the natural history of idiopathic Parkinson’s disease (PD) remains limited. In the era of potential disease modifying therapies, there is an urgent need for studies assessing the natural evolution of treated PD from onset so that relevant outcome measures can be identified for clinical trials. No previous studies have charted progression in unselected patients followed from the point of diagnosis. Methods A representative cohort of 132 PD patients was followed from diagnosis for up to 7.9 years (mean 5.2 years). Comprehensive clinical and neuropsychological evaluations were performed every 18 months. Disease progression was evaluated using well validated clinical measures (motor progression and development of dyskinesia on the Unified PD Rating Scale and HoehneYahr scale, dementia onset according to DSM-IV criteria). Multi-level linear modelling was used to chart the nature and rate of progression in parkinsonian symptoms and signs over time. The prognostic importance of baseline demogr‘aphic, clinical and genetic variables was evaluated using survival analysis. Results Axial (gait and postural) symptoms evolve more rapidly than other motor features of PD and appear to be the best index of disease progression. Conversely, conventional outcome measures are relatively insensitive to change over time. Earlier onset of postural instability (HoehneYahr stage 3) is strongly associated with increased age at disease onset and has a significant impact on quality of life. Conclusions Dementia risk is associated with increased age, impaired baseline semantic fluency and the MAPT H1/H1 genotype. The efficacy of disease modifying therapies may be more meaningfully assessed in terms of their effects in delaying the major milestones of PD, such as postural instability and dementia, since it is these that have the greatest impact on patients.

Effects of subthalamic stimulation on speech of consecutive patients with Parkinson disease.

Abstract: Objective: Subthalamic nucleus deep brain stimulation (STN-DBS) is an effective treatment for advanced Parkinson disease (PD). Following STN-DBS, speech intelligibility can deteriorate, limiting its beneficial effect. Here we prospectively examined the short- and long-term speech response to STN-DBS in a consecutive series of patients to identify clinical and surgical factors associated with speech change. Methods: Thirty-two consecutive patients were assessed before surgery, then 1 month, 6 months, and 1 year after STN-DBS in 4 conditions on- and off-medication with on- and off-stimulation using established and validated speech and movement scales. Fifteen of these patients were followed up for 3 years. A control group of 12 patients with PD were followed up for 1 year. Results: Within the surgical group, speech intelligibility significantly deteriorated by an average of 14.2% ± 20.15% off-medication and 16.9% ± 21.8% on-medication 1 year after STN-DBS. The medical group deteriorated by 3.6% ± 5.5% and 4.5% ± 8.8%, respectively. Seven patients showed speech amelioration after surgery. Loudness increased significantly in all tasks with stimulation. A less severe preoperative on-medication motor score was associated with a more favorable speech response to STN-DBS after 1 year. Medially located electrodes on the left STN were associated with a significantly higher risk of speech deterioration than electrodes within the nucleus. There was a strong relationship between high voltage in the left electrode and poor speech outcome at 1 year. Conclusion: The effect of STN-DBS on speech is variable and multifactorial, with most patients exhibiting decline of speech intelligibility. Both medical and surgical issues contribute to deterioration of speech in STN-DBS patients. Classification of evidence: This study provides Class III evidence that STN-DBS for PD results in deterioration in speech intelligibility in all combinations of medication and stimulation states at 1 month, 6 months, and 1 year compared to baseline and to control subjects treated with best medical therapy.

Deep brain stimulation for Gilles de la Tourette syndrome: a case series targeting subregions of the globus pallidus internus.

Abstract: Deep brain stimulation remains an experimental treatment for patients with Gilles de la Tourette syndrome. Currently, a major controversial issue is the choice of brain target that leads to optimal patient outcomes within a presumed network of basal ganglia and cortical pathways involved in tic pathogenesis. This report describes our experience with patients with severe refractory Gilles de la Tourette syndrome treated with globus pallidus internus deep brain stimulation. Five patients were selected for surgery, 2 targeting the posteroventral globus pallidus internus and 2 targeting the anteromedial region. The remaining patient was first targeted on the posterolateral region, but after 18 months the electrodes were relocated in the anteromedial area. Tics were clinically assessed in all patients pre- and postoperatively using the Modified Rush Video protocol and the Yale Global Tic Severity Scale. Obsessive-compulsive behaviors were quantified with the Yale-Brown Obsessive Compulsive Scale. The Gilles de la Tourette Syndrome-Quality of Life Scale was also completed. All patients experienced improvements in tic severity but to variable extents. More convincing improvements were seen in patients with electrodes sited in the anteromedial region of the globus pallidus internus than in those with posterolateral implants. Mean reduction in the Modified Rush Video Rating scale for each group was 54% and 37%, respectively. Our open-label limited experience supports the use of the anteromedial globus pallidus internus as a promising target for future planned randomized double-blind trials of deep brain stimulation for patients with Gilles de la Tourette syndrome.

MRI-guided subthalamic nucleus deep brain stimulation without microelectrode recording: can we dispense with surgery under local anaesthesia?

Abstract: Aims: Subthalamic nucleus (STN) deep brain stimulation (DBS) for Parkinson's disease (PD) is traditionally performed under local anaesthetic (LA). STN visualization and routine validation of electrode location on stereotactic MRI may allow surgery under general anaesthesia (GA). This study compares the clinical outcome of MRI-guided STN DBS performed under LA or GA in a consecutive patient series. Methods: Unified Parkinson's Disease Rating Scale motor scores (UPDRS-III) in 14 GA patients (mean age 56.1 years, disease duration 13.8 years) were compared with those of 68 LA patients (mean age 57.5 years, disease duration 15.2 years). Results: Baseline UPDRS-III were worse in the GA group, both on medication (GA: 20.9 +/- 10.8; LA: 13.2 +/- 7.8, p < 0.01) and off medication (GA: 57.9 +/- 16.6; LA: 48.2 +/- 15.7, p < 0.05). On stimulation off medication motor scores significantly improved in both groups (GA: 27.3 +/- 11.8, mean 12-month follow-up; LA: 23.7 +/- 11.8, mean 14-month follow-up). The percentage improvement was similar in both groups (GA: 52.8%; LA: 50.8%, p = 0.96). Transient surgical complications occurred in 1 GA and 7 LA patients. Conclusions: MRI-guided STN DBS under GA with routine stereotactic verification of lead location did not have a negative effect on efficacy or safety. Surgery under GA is a viable option in patients who would find it hard to tolerate awake surgery due to disease severity, comorbidities or anxiety. Copyright (C) 2011 S. Karger AG, Basel

An approach to deep brain stimulation for severe treatment-refractory Tourette syndrome: the UK perspective

Abstract: Deep brain stimulation (DBS) is an emerging therapeutic option for severe, treatment-resistant Tourette Syndrome (TS), with about 40 cases reported in the scientific literature over the last decade. Despite the production of clinical guidelines for this procedure from both European and USA centres, a number of unresolved issues still persist, mainly in relation to eligibility criteria and brain targets. The present article illustrates the UK perspective on DBS in TS and proposes consensus-based recommendations for double-blind controlled trials.

Functional imaging of subthalamic nucleus deep brain stimulation in Parkinson's disease.

Abstract: Deep brain stimulation of the subthalamic nucleus is an accepted treatment for the motor complications of Parkinson's disease. The therapeutic mechanism of action remains incompletely understood. Although the results of deep brain stimulation are similar to the results that can be obtained by lesional surgery, accumulating evidence from functional imaging and clinical neurophysiology suggests that the effects of subthalamic nucleus-deep brain stimulation are not simply the result of inhibition of subthalamic nucleus activity. Positron emission tomography/single-photon emission computed tomography has consistently demonstrated changes in cortical activation in response to subthalamic nucleus-deep brain stimulation. However, the technique has limited spatial and temporal resolution, and therefore the changes in activity of subcortical projection sites of the subthalamic nucleus (such as the globus pallidus, substantia nigra, and thalamus) are not as clear. Clarifying whether clinically relevant effects from subthalamic nucleus-deep brain stimulation in humans are mediated through inhibition or excitation of orthodromic or antidromic pathways (or both) would contribute to our understanding of the precise mechanism of action of deep brain stimulation and may allow improvements in safety and efficacy of the technique. In this review we discuss the published evidence from functional imaging studies of patients with subthalamic nucleus-deep brain stimulation to date, together with how these data inform the mechanism of action of deep brain stimulation.

Urinary incontinence following deep brain stimulation of the pedunculopontine nucleus

Abstract: Low-frequency deep brain stimulation (DBS) of the pedunculopontine nucleus (PPN) has been reported to improve akinesia and gait difficulties in patients with Parkinson’s disease (PD). We report on a patient with PD and L-dopa refractory gait symptoms who developed detrusor over-activity immediately after right PPN DBS. Proximity between caudal PPN and brainstem structures implicated in control of micturition is a possible explanation.

Treatment of dysarthria following subthalamic nucleus deep brain stimulation for Parkinson's disease.

Abstract: Deep brain stimulation of the subthalamic nucleus (STN-DBS) is an established treatment for patients with Parkinson’s disease (PD). Speech impairment is a frequent side effect of the surgery. This study examined the efficacy of an intensive speech treatment (the Lee Silverman Voice Treatment, LSVT) on dysarthria after STN-DBS. The LSVT was administered in ten patients with STN-DBS (surgical group) and ten patients without (medical group). Patients were assessed before, immediately after and six months following the speech treatment using sustained phonation, a speech intelligibility scale and monologue. Vocal loudness, speech intelligibility and perceptual ratings were the primary outcome measures. Vocal loudness and perceptual scores improved significantly across tasks for the medical group only. Speech intelligibility did not significantly change for either group. Results in the surgical group were variable with some patients deteriorating. Treatment of dysarthria following STN-DBS needs further investigation due to the variable response to LSVT.

Gene therapy: a viable therapeutic strategy for Parkinson’s disease?

Abstract: Gene therapy represents a potentially useful additional technique to ameliorate the motor symptoms of Parkinson's disease (PD), and the motor complications of its treatment. The neurodegenerative process itself, as well as the non-motor symptoms of PD, both remain less amenable to most of the current gene therapy approaches. This review presents an overview of the four gene therapies in phase I/II clinical trials, outlines some of the challenges they face, and proposes additional alternative strategies that might improve the clinical prospects of gene therapy for PD. In so doing, we hope to highlight the issue of the current absence of effective treatment for non-motor symptoms of PD and the potential of further candidate targets for gene therapy intervention that might improve upon this, for both specific individuals with genetic forms of PD as well as "sporadic" PD patients.

The factor structure of the UPDRS as an index of disease progression in Parkinson's disease.

Abstract: The optimum method for evaluating disease progression in Parkinson's disease (PD) has not been established, and this has implications for clinical trials. The majority of previous studies have utilized change on the Unified Parkinson's disease Rating Scale (UPDRS) as an index of progression. However, the UPDRS has not been validated for this purpose. We utilized exploratory factor analysis (EFA) to evaluate the longitudinal properties of the UPDRS as an index of disease progression in PD. Data was derived from a representative cohort of 122 PD patients followed from diagnosis and assessed every 18-24 months for up to 7.9 years. For each subject the rate of change of each item on the UPDRS-3 was calculated and an EFA was performed using this data. Results were compared with those of previously published EFAs in cross-sectional PD cohorts. The UPDRS-3 retains a stable factor structure when used as an index of disease evolution. The 27 items reduced to 6 factors which accounted for 61.0% of the variance in disease progression. A dominant factor was identified which incorporated axial (gait/postural stability) symptoms and signs. Our analysis indicates that the UPDRS captures meaningful aspects of disease progression in PD, and that it is possible to identify symptom/sign complexes which evolve independently of one another. Progression in PD is predominantly characterized by the development of axial symptoms and signs. This result has implications for pathogenesis and should also inform natural history models of PD thereby allowing identification of meaningful outcome measures for clinical trials of disease-modifying therapies.

Critical Aspects of Clinical Trial Design for Novel Cell and Gene Therapies

Abstract: Neural cell transplantation and gene therapy have attracted considerable interest as promising therapeutic alternatives for patients with Parkinson's disease (PD). Preclinical and open-label studies have suggested that grafted fetal neural tissue or viral vector gene transfer can achieve considerable biochemical and clinical improvements, whereas subsequent double-blind, placebo-controlled protocols have produced rather more modest and variable results. Detailed evaluation of these discordant findings has highlighted several crucial issues such as patient selection criteria, details surrounding transplantation or gene therapy methodologies, as well as the study designs themselves that ought to be carefully considered in the planning phases of future clinical trials. Beyond the provision of symptomatic efficacy and safety data, it also remains to be identified whether the possibilities offered by stem cell and gene therapy technological advances might translate to meaningful neuroprotection and/or disease-modifying effects or alleviate the nonmotor aspects of PD and thus offer additional benefits beyond those achieved through conventional pharmacotherapy or deep brain stimulation (DBS).

Skewering the subthalamic nucleus via a parietal approach.

Abstract: Background/Aims: A frontal burr hole around the level of the coronal suture is the conventional entry point when performing subthalamic nucleus (STN) deep brain stimulation (DBS). H