Subthalamic oscillatory activity and connectivity during gait in Parkinson's disease

Local field potentials (LFP) of the subthalamic nucleus (STN) recorded during walking may provide clues for determining the function of the STN during gait and also, may be used as biomarker to steer adaptive brain stimulation devices. Here, we present LFP recordings from an implanted sensing neurostimulator (Medtronic Activa PC+S) during walking and rest with and without stimulation in 10 patients with Parkinson's disease and electrodes placed bilaterally in the STN. We also present recordings from two of these patients recorded with externalized leads. We analyzed changes in overall frequency power, bilateral connectivity, high beta frequency oscillatory characteristics and gait-cycle related oscillatory activity. We report that deep brain stimulation improves gait parameters. High beta frequency power (20-30 Hz) and bilateral oscillatory connectivity are reduced during gait, while the attenuation of high beta power is absent during stimulation. Oscillatory characteristics are affected in a similar way. We describe a reduction in overall high beta burst amplitude and burst lifetimes during gait as compared to rest off stimulation. Investigating gait cycle related oscillatory dynamics, we found that alpha, beta and gamma frequency power is modulated in time during gait, locked to the gait cycle. We argue that these changes are related to movement induced artifacts and that these issues have important implications for similar research

Improving the Standard for Deep Brain Stimulation Therapy: Target Structures and Feedback Signals for Adaptive Stimulation. Current Perspectives and Future Directions

Deep brain stimulation (DBS) is an established therapeutic option for the treatment of various neurological disorders and has been used successfully in movement disorders for over 25 years. However, the standard stimulation schemes have not changed substantially. Two major points of interest for the further development of DBS are target-structures and novel adaptive stimulation techniques integrating feedback signals. We describe recent research results on target structures and on neural and behavioural feedback signals for adaptive deep brain stimulation (aDBS), as well as outline future directions

Iron-mediated aggregation and toxicity in a novel neuronal cell culture model with inducible alpha-synuclein expression

Parkinson's disease (PD) represents an increasing problem in society. The oligomerization of alpha-synuclein (alpha Syn) is a suggested key event in its pathogenesis, yet the pathological modes of action remain to be fully elucidated. To identify potential disease-modifying therapeutics and to study alpha Syn-mediated toxic mechanisms, we established cell lines with inducible overexpression of different alpha Syn constructs: alpha Syn, alpha Syn coupled to the fluorescence protein Venus (alpha Syn-Venus), and alpha Syn coupled to the N-terminal or C-terminal part of Venus (V1S and SV2, respectively) for a bimolecular fluorescence complementation assay (BiFC). Inducibility was achieved by applying modified GAL4-UAS or Cre-loxP systems and addition of tebufenozide or 4-OH-tamoxifen, respectively. Expression constructs were stably integrated into the host genome of H4 neuroglioma cells by lentiviral transduction. We here demonstrate a detailed investigation of the expression characteristics of inducible H4 cells showing low background expression and high inducibility. We observed increased protein load and aggregation of alpha Syn upon incubation with DMSO and FeCl3 along with an increase in cytotoxicity. In summary, we present a system for the creation of inducibly alpha Syn-overexpressing cell lines holding high potential for the screening for modulators of alpha Syn aggregation and alpha Syn-mediated toxicity

Postural Stabilization Differences in Idiopathic Parkinson’s Disease and Progressive Supranuclear Palsy during Self-Triggered Fast Forward Weight Lifting

Progressive supranuclear palsy (PSP) and late-stage idiopathic Parkinson's disease (IPD) are neurodegenerative movement disorders resulting in different postural instability and falling symptoms. IPD falls occur usually forward in late stage, whereas PSP falls happen in early stages, mostly backward, unprovoked, and with high morbidity. Self-triggered, weighted movements appear to provoke falls in IPD, but not in PSP. Repeated self-triggered lifting of a 0.5-1-kg weight (<2% of body weight) with the dominant hand was performed in 17 PSP, 15 IPD with falling history, and 16 controls on a posturography platform. PSP showed excessive force scaling of weight and body motion with high-frequency multiaxial body sway, whereas IPD presented a delayed-onset forward body displacement. Differences in center of mass displacement apparent at very small weights indicate that both syndromes decompensate postural control already within stability limits. PSP may be subject to specific postural system devolution. IPD are susceptible to delayed forward falling. Differential physiotherapy strategies are suggested

Robust segmentation of various anatomies in 3D ultrasound using hough forests and learned data representations

3D ultrasound segmentation is a challenging task due to image artefacts, low signal-to-noise ratio and lack of contrast at anatomical boundaries. Current solutions usually rely on complex, anatomy-specific regularization methods to improve segmentation accuracy. In this work, we propose a highly adaptive learning-based method for fully automatic segmentation of ultrasound volumes. During training, anatomy-specific features are obtained through a sparse auto-encoder. The extracted features are employed in a Hough Forest based framework to retrieve the position of the target anatomy and its segmentation contour. The resulting method is fully automatic, i.e. it does not require any human interaction, and can robustly and automatically adapt to different anatomies yet enforcing appearance and shape constraints.We demonstrate the performance of the method for three different applications: segmentation of midbrain, left ventricle of the heart and prostate

Occupancy of pramipexole (Sifrol) at cerebral dopamine D2/3 receptors in Parkinson's disease patients

Whereas positron emission tomography (PET) with the antagonist ligand [18F]fallypride reveals the composite of dopamine D2 and D3 receptors in brain, treatment of Parkinson's disease (PD) patients with the D3-prefering agonist pramipexole should result in preferential occupancy in the nucleus accumbens, where the D3-subtype is most abundant. To test this prediction we obtained pairs of [18F]fallypride PET recordings in a group of nine PD patients, first in a condition of treatment as usual with pramipexole (ON-Sifrol; 3 × 0.7 mg p.d.), and again at a later date, after withholding pramipexole 48–72 h (OFF-Sifrol); in that condition the serum pramipexole concentration had declined by 90% and prolactin levels had increased four-fold, in conjunction with a small but significant worsening of PD motor symptoms. Exploratory comparison with historical control material showed 14% higher dopamine D2/3 availability in the more-affected putamen of patients OFF medication. On-Sifrol there was significant (p ˂ 0.01) occupancy at [18F]fallypride binding sites in globus pallidus (8%) thalamus (9%) and substantia nigra (19%), as well as marginally significant occupancy in frontal and temporal cortex of patients. Contrary to expectation, comparison of ON- and OFF-Sifrol results did not reveal any discernible occupancy in nucleus accumbens, or elsewhere in the extended striatum; present methods should be sensitive to a 10% change in dopamine D2/3 receptor availability in striatum; the significant findings elsewhere in the basal ganglia and in cerebral cortex are consistent with a predominance of D3 receptors in those structures, especially in substantia nigra, and imply that therapeutic effects of pramipexole may be obtained at sites outside the extended striatum

Robust segmentation of various anatomies in 3D ultrasound using hough forests and learned data representations

3D ultrasound segmentation is a challenging task due to image artefacts, low signal-to-noise ratio and lack of contrast at anatomical boundaries. Current solutions usually rely on complex, anatomy-specific regularization methods to improve segmentation accuracy. In this work, we propose a highly adaptive learning-based method for fully automatic segmentation of ultrasound volumes. During training, anatomy-specific features are obtained through a sparse auto-encoder. The extracted features are employed in a Hough Forest based framework to retrieve the position of the target anatomy and its segmentation contour. The resulting method is fully automatic, i.e. it does not require any human interaction, and can robustly and automatically adapt to different anatomies yet enforcing appearance and shape constraints.We demonstrate the performance of the method for three different applications: segmentation of midbrain, left ventricle of the heart and prostate

Negative impact of borderline global cognitive scores on quality of life after subthalamic nucleus stimulation in Parkinson's disease

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) significantly improves quality of life (QoL) in Parkinson's disease (PD). Dementia is considered as a contraindication for STN-DBS. However, no controlled study assessed the impact of STN-DBS on the QoL and motor outcome in PD patients with a borderline global cognitive impairment. We studied clinical baseline and progression parameters in a cohort of STN-DBS patients with a global cognitive score still in the non-demented range but scoring in the lowest quartile of the Mattis Dementia Rating Scale (MDRS), a measure of global cognitive functioning. Data from a German randomised controlled study comparing DBS (60 patients) with best medical treatment (BMT, 59 patients) were analysed. Changes in patients' QoL scores were assessed using the Parkinson's disease questionnaire (PDQ-39) at baseline and at the 6 months follow up. Patients were split into four groups according to their MDRS performance at baseline and these groups were compared in the context of motor outcome and QoL Twelve out of sixty patients of the STN-DBS group scored in the lowest quartile of the MDRS (range between one hundred thirty and one hundred thirty seven points). An individual analysis revealed that 3 of 12 patients showed a clinical relevant improvement in QoL whereas the group statistics did not reveal any significant improvement in QoL measures after STN-DBS compared to the BMT group. Since this failure to improve in QoL cannot be explained by a failure to improve in motor functions, stimulation settings and psychiatric scales after STN-DBS, the failure to improve in QoL in patients with a borderline global cognitive score might be specifically related to lower cognitive functioning. (C) 2011 Elsevier B.V. All rights reserved

Health-economic burden of Parkinson's disease in Portugal:a cohort study

Introduction. Parkinson's disease (PD) is a common neurodegenerative disorder with a considerable socioeconomic burden. Health-economic evaluations of PD in the Southern European countries are limited. Aim. To evaluate the costs of PD in an outpatient cohort in Portugal. Patients and methods. 49 consecutive PD patients were recruited at the neurological outpatient clinic of the University of Lisbon between October 2004 and December 2005. Clinical status was evaluated using the Unified Parkinson's Disease Rating Scale and the Hoehn & Yahr stages. Costs were assessed from the societal perspective using health-economic questionnaires. Human capital approach was used to estimate indirect costs. Health-related quality of life was evaluated by means of the EQ-5D. Results. Direct costs were 2,717 euros (95% Cl = 1,147-3,351) per patient for a six-month period. Main contributors to the direct costs included drugs (544 euros; 95% CI = 426-6,940) and hospitalizations (690 euros; 95% CI = 229-1,944). Indirect costs amounted to 850 euros (95% Cl = 397-1,529), whereas patient expenditures constituted 12% of direct costs. Assistance by family and other relatives played a major role. In general, costs were lower than in other Western countries. Conclusions. The economic burden of PD in Portugal is considerable. Important cost components include medications and hospitalizations. More research is needed in order to describe a comprehensive health service patterns in Portugal and to guide health policy decisions more effectively