Fixed Dystonia in Complex Regional Pain Syndrome: a Descriptive and Computational Modeling Approach

Background: Complex regional pain syndrome (CRPS) may occur after trauma, usually to one limb, and is characterized by pain and disturbed blood flow, temperature regulation and motor control. Approximately 25% of cases develop fixed dystonia. Involvement of dysfunctional GABAergic interneurons has been suggested, however the mechanisms that underpin fixed dystonia are still unknown. We hypothesized that dystonia could be the result of aberrant proprioceptive reflex strengths of position, velocity or force feedback. Methods: We systematically characterized the pattern of dystonia in 85 CRPS-patients with dystonia according to the posture held at each joint of the affected limb. We compared the patterns with a neuromuscular computer model simulating aberrations of proprioceptive reflexes. The computer model consists of an antagonistic muscle pair with explicit contributions of the musculotendinous system and reflex pathways originating from muscle spindles and Golgi tendon organs, with time delays reflective of neural latencies. Three scenarios were simulated with the model: (i) increased reflex sensitivity (increased sensitivity of the agonistic and antagonistic reflex loops); (ii) imbalanced reflex sensitivity (increased sensitivity of the agonistic reflex loop); (iii) imbalanced reflex offset (an offset to the reflex output of the agonistic proprioceptors). Results: For the arm, fixed postures were present in 123 arms of 77 patients. The dominant pattern involved flexion of the fingers (116/123), the wrists (41/123) and elbows (38/123). For the leg, fixed postures were present in 114 legs of 77 patients. The dominant pattern was plantar flexion of the toes (55/114 legs), plantar flexion and inversion of the ankle (73/114) and flexion of the knee (55/114). Only the computer simulations of imbalanced reflex sensitivity to muscle force from Golgi tendon organs caused patterns that closely resembled the observed patient characteristics. In parallel experiments using robot manipulators we have shown that patients with dystonia were less able to adapt their force feedback strength. Conclusions: Findings derived from a neuromuscular model suggest that aberrant force feedback regulation from Golgi tendon organs involving an inhibitory interneuron may underpin the typical fixed flexion postures in CRPS patients with dystonia.Biomechanical EngineeringMechanical, Maritime and Materials Engineerin

Spreading of complex regional pain syndrome: not a random process

Complex regional pain syndrome (CRPS) generally remains restricted to one limb but occasionally may spread to other limbs. Knowledge of the spreading pattern of CRPS may lead to hypotheses about underlying mechanisms but to date little is known about this process. The objective is to study patterns of spread of CRPS from a first to a second limb and the factors associated with this process. One hundred and eighty-five CRPS patients were retrospectively evaluated. Cox’s proportional hazards model was used to evaluate factors that influenced spread of CRPS symptoms. Eighty-nine patients exhibited CRPS in multiple limbs. In 72 patients spread from a first to a second limb occurred showing a contralateral pattern in 49%, ipsilateral pattern in 30% and diagonal pattern in 14%. A trauma preceded the onset in the second limb in 37, 44 and 91%, respectively. The hazard of spread of CRPS increased with the number of limbs affected. Compared to patients with CRPS in one limb, patients with CRPS in multiple limbs were on average 7 years younger and more often had movement disorders. In patients with CRPS in multiple limbs, spontaneous spread of symptoms generally follows a contralateral or ipsilateral pattern whereas diagonal spread is rare and generally preceded by a new trauma. Spread is associated with a younger age at onset and a more severely affected phenotype. We argue that processes in the spinal cord as well as supraspinal changes are responsible for spontaneous spread in CRPS

Nonlinear Analysis of Motor Activity Shows Differences between Schizophrenia and Depression: A Study Using Fourier Analysis and Sample Entropy

The purpose of this study has been to describe motor activity data obtained by using wrist-worn actigraphs in patients with schizophrenia and major depression by the use of linear and non-linear methods of analysis. Different time frames were investigated, i.e., activity counts measured every minute for up to five hours and activity counts made hourly for up to two weeks. The results show that motor activity was lower in the schizophrenic patients and in patients with major depression, compared to controls. Using one minute intervals the depressed patients had a higher standard deviation (SD) compared to both the schizophrenic patients and the controls. The ratio between the root mean square successive differences (RMSSD) and SD was higher in the schizophrenic patients compared to controls. The Fourier analysis of the activity counts measured every minute showed that the relation between variance in the low and the high frequency range was lower in the schizophrenic patients compared to the controls. The sample entropy was higher in the schizophrenic patients compared to controls in the time series from the activity counts made every minute. The main conclusions of the study are that schizophrenic and depressive patients have distinctly different profiles of motor activity and that the results differ according to period length analysed

Muscle weakness and lack of reflex gain adaptation predominate during post-stroke posture control of the wrist

Instead of hyper-reflexia as sole paradigm, post-stroke movement disorders are currently considered the result of a complex interplay between neuronal and muscular properties, modified by level of activity. We used a closed loop system identification technique to quantify individual contributors to wrist joint stiffness during an active posture task. Continuous random torque perturbations applied to the wrist joint by a haptic manipulator had to be resisted maximally. Reflex provoking conditions were applied i.e. additional viscous loads and reduced perturbation signal bandwidth. Linear system identification and neuromuscular modeling were used to separate joint stiffness into the intrinsic resistance of the muscles including co-contraction and the reflex mediated contribution. Compared to an age and sex matched control group, patients showed an overall 50% drop in intrinsic elasticity while their reflexive contribution did not respond to provoking conditions. Patients showed an increased mechanical stability compared to control subjects. Post stroke, we found active posture tasking to be dominated by: 1) muscle weakness and 2) lack of reflex adaptation. This adds to existing doubts on reflex blocking therapy as the sole paradigm to improve active task performance and draws attention to muscle strength and power recovery and the role of the inability to modulate reflexes in post stroke movement disorders.Mechanical, Maritime and Materials Engineerin

Physical inactivity in Parkinson’s disease

Patients with Parkinson’s disease (PD) are likely to become physically inactive, because of their motor, mental, and emotional symptoms. However, specific studies on physical activity in PD are scarce, and results are conflicting. Here, we quantified daily physical activities in a large cohort of PD patients and another large cohort of matched controls. Moreover, we investigated the influence of disease-related factors on daily physical activities in PD patients. Daily physical activity data of PD patients (n = 699) were collected in the ParkinsonNet trial and of controls (n = 1,959) in the Longitudinal Aging Study Amsterdam (LASA); data were determined using the LAPAQ, a validated physical activity questionnaire. In addition, variables that may affect daily physical activities in PD were recorded, including motor symptoms, depression, disability in daily life, and comorbidity. Patients were physically less active; a reduction of 29% compared to controls (95% CI, 10–44%). Multivariate regression analyses demonstrated that greater disease severity, gait impairment, and greater disability in daily living were associated with less daily physical activity in PD (R2 = 24%). In this large study, we show that PD patients are about one-third less active compared to controls. While disease severity, gait, and disability in daily living predicted part of the inactivity, a portion of the variance remained unexplained, suggesting that additional determinants may also affect daily physical activities in PD. Because physical inactivity has many adverse consequences, work is needed to develop safe and enjoyable exercise programs for patients with PD

Prediction of cognition in Parkinson's disease with a clinical-genetic score: a longitudinal analysis of nine cohorts

Cognitive decline is a debilitating manifestation of disease progression in Parkinson's disease. We aimed to develop a clinical-genetic score to predict global cognitive impairment in patients with the disease.In this longitudinal analysis, we built a prediction algorithm for global cognitive impairment (defined as Mini Mental State Examination [MMSE] ≤25) using data from nine cohorts of patients with Parkinson's disease from North America and Europe assessed between 1986 and 2016. Candidate predictors of cognitive decline were selected through a backward eliminated Cox's proportional hazards analysis using the Akaike's information criterion. These were used to compute the multivariable predictor on the basis of data from six cohorts included in a discovery population. Independent replication was attained in patients from a further three independent longitudinal cohorts. The predictive score was rebuilt and retested in 10 000 training and test sets randomly generated from the entire study population.3200 patients with Parkinson's disease who were longitudinally assessed with 27 022 study visits between 1986 and 2016 in nine cohorts from North America and Europe were assessed for eligibility. 235 patients with MMSE ≤25 at baseline and 135 whose first study visit occurred more than 12 years from disease onset were excluded. The discovery population comprised 1350 patients (after further exclusion of 334 with missing covariates) from six longitudinal cohorts with 5165 longitudinal visits over 12·8 years (median 2·8, IQR 1·6-4·6). Age at onset, baseline MMSE, years of education, motor exam score, sex, depression, and β-glucocerebrosidase (GBA) mutation status were included in the prediction model. The replication population comprised 1132 patients (further excluding 14 patients with missing covariates) from three longitudinal cohorts with 19 127 follow-up visits over 8·6 years (median 6·5, IQR 4·1-7·2). The cognitive risk score predicted cognitive impairment within 10 years of disease onset with an area under the curve (AUC) of more than 0·85 in both the discovery (95% CI 0·82-0·90) and replication (95% CI 0·78-0·91) populations. Patients scoring in the highest quartile for cognitive risk score had an increased hazard for global cognitive impairment compared with those in the lowest quartile (hazard ratio 18·4 [95% CI 9·4-36·1]). Dementia or disabling cognitive impairment was predicted with an AUC of 0·88 (95% CI 0·79-0·94) and a negative predictive value of 0·92 (95% 0·88-0·95) at the predefined cutoff of 0·196. Performance was stable in 10 000 randomly resampled subsets.Our predictive algorithm provides a potential test for future cognitive health or impairment in patients with Parkinson's disease. This model could improve trials of cognitive interventions and inform on prognosis.National Institutes of Health, US Department of Defense.We thank all study participants, their families, and friends for their support and participation, and our study coordinators. The co-investigators and contributors from Parkinson's Disease Biomarkers Program, Harvard Biomarkers Study, Drug Interaction with Genes in Parkinson's Disease (DIGPD), Parkinson Research Examination of CEP-1347 Trial (PreCEPT) and a longitudinal follow-up of the PRECEPT study cohort (PostCEPT), Parkinsonism Incidence, Cognition and Non-motor heterogeneity in Cambridgeshire (PICNICS), Cambridgeshire Parkinson's Incidence from GP to Neurologist (CamPaIGN), PROfiling PARKinson's disease study (PROPARK), as well as acknowledgments for Parkinson's Progression Marker Initiative and Deprenyl and Tocopherol Antioxidative Therapy of Parkinsonism (DATATOP) are listed in the appendix. This work was supported in part by National Institutes of Health grants U01 NS082157, U01NS095736 (to CRS), US Department of Defense grants W81XWH-1–0007 (BR) and W81XWH-15–10007 (to CRS); MEMO Hoffman Foundation (to CRS); Brigham and Women's Hospital Departmental Funds (to BB). The Harvard Biomarkers Study is supported by the Harvard NeuroDiscovery Center, the Parkinson's Disease Biomarkers Program U01 NS082157, U01NS100603 of the National Institute of Neurological Disorders and Stroke (NINDS), and the Massachusetts Alzheimer's Disease Research Center P50 AG005134 grant of the National Institute on Aging, Harvard Aging Brain Study grant P01 AG036694. The PreCEPT and PostCEPT cohort was funded by Cephalon Inc and Lundbeck for the parent PRECEPT clinical trial and follow-up PostCEPT cohort, and the Department of Defense Neurotoxin Exposure Treatment Parkinson's Research Program (W23RRYX7022N606), NINDS Data and Organizing Center's (NS050095), the Parkinson's Disease Foundation (New York, NY, USA). Additional funding information for the PreCEPT and PostCEPT cohort and corresponding investigators is listed in Ravina et al. The CamPaIGN and PICNICS studies received funding support from the Wellcome Trust, MRC, Parkinson's UK, Cure-PD, the Patrick Berthoud Trust, the Van Geest Foundation, and National Institute for Health Research funding of a Biomedical Research Centre at the University of Cambridge and Addenbrooke's Hospital. DIGPD cohort was promoted by the Assistance Publique Hôpitaux de Paris, and funded by the French clinical research hospital programme (code AOR08010). The research leading to these results has received funding from the programme Investissements d'Avenir ANR-10-IAIHU-06. DATATOP was supported by NIH grant NS24778. The PROPARK study was funded by the Prinses Beatrix Fonds (project number WAR05–0120), the van Alkemade-Keuls Foundation (Stichting Alkemade-Keuls), and the International Parkinson Foundation (Stichting ParkinsonFonds)

Motivational modulation of bradykinesia in Parkinson's disease off and on dopaminergic medication.

Motivational influence on bradykinesia in Parkinson's disease may be observed in situations of emotional and physical stress, a phenomenon known as paradoxical kinesis. However, little is known about motivational modulation of movement speed beyond these extreme circumstances. In particular, it is not known if motivational factors affect movement speed by improving movement preparation/initiation or execution (or both) and how this effect relates to the patients' medication state. In the present study, we tested if provision of motivational incentive through monetary reward would speed-up movement initiation and/or execution in Parkinson's disease patients and if this effect depended on dopaminergic medication. We studied the effect of monetary incentive on simple reaction time in 11 Parkinson's disease patients both "off" and "on" dopaminergic medication and in 11 healthy participants. The simple reaction time task was performed across unrewarded and rewarded blocks. The initiation time and movement time were quantified separately. Anticipation errors and long responses were also recorded. The prospect of reward improved initiation times in Parkinson's disease patients both "off" and "on" dopaminergic medication, to a similar extent as in healthy participants. However, for "off" medication, this improvement was associated with increased frequency of anticipation errors, which were eliminated by dopamine replacement. Dopamine replacement had an additional, albeit small effect, on reward-related improvement of movement execution. Motivational strategies are helpful in overcoming bradykinesia in Parkinson's disease. Motivational factors may have a greater effect on bradykinesia when patients are "on" medication, as dopamine appears to be required for overcoming speed-accuracy trade-off and for improvement of movement execution. Thus, medication status should be an important consideration in movement rehabilitation programmes for patients with Parkinson's disease

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

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