Modeling movement disorders - CRPS-related dystonia explained by abnormal proprioceptive reflexes

AbstractHumans control their movements using adaptive proprioceptive feedback from muscle afferents. The interaction between proprioceptive reflexes and biomechanical properties of the limb is essential in understanding the etiology of movement disorders. A non-linear neuromuscular model of the wrist incorporating muscle dynamics and neural control was developed to test hypotheses on fixed dystonia. Dystonia entails sustained muscle contractions resulting in abnormal postures. Lack of inhibition is often hypothesized to result in hyperreflexia (exaggerated reflexes), which may cause fixed dystonia. In this study the model-simulated behavior in case of several abnormal reflex settings was compared to the clinical features of dystonia: abnormal posture, sustained muscle contraction, increased stiffness, diminished voluntary control and activity-aggravation.The simulation results were rated to criteria based on characteristic features of dystonia. Three abnormal reflex scenarios were tested: (1) increased reflex sensitivity—increased sensitivity of both the agonistic and antagonistic reflex pathways; (2) imbalanced reflex offset—a static offset to the reflex pathways on the agonistic side only; and (3) imbalanced reflex sensitivity—increased sensitivity of only the agonistic reflex pathways.Increased reflex sensitivity did not fully account for the features of dystonia, despite distinct motor dysfunction, since no abnormal postures occurred. Although imbalanced reflex offset did result in an abnormal posture, it could not satisfy other criteria. Nevertheless, imbalanced reflex sensitivity with unstable force feedback in one of the antagonists closely resembled all features of dystonia. The developed neuromuscular model is an effective tool to test hypotheses on the underlying pathophysiology of movement disorders

Cost-Effectiveness and Cost-Utility of Early Levodopa in Parkinson's Disease

Background: In the Levodopa in EArly Parkinson's disease (LEAP) study, 445 patients were randomized to levodopa/carbidopa 100/25 mg three times per day for 80 weeks (early-start) or placebo for 40 weeks followed by levodopa/carbidopa 100/25 mg three times per day for 40 weeks (delayed-start).Objective: This paper reports the results of the economic evaluation performed alongside the LEAP-study.Methods: Early-start treatment was evaluated versus delayed-start treatment, in which the cost-effectiveness analysis (CEA) and the cost-utility analysis (CUA) were performed from the societal perspective, including health care costs among providers, non-reimbursable out-of-pocket expenses of patients, employer costs of sick leave, and lowered productivity while at work. The outcome measure for the CEA was the extra cost per unit decrease on the Unified Parkinson's Disease Rating Scale 80 weeks after baseline. The outcome measure for the CUA was the extra costs per additional quality adjusted life year (QALY) during follow-up.Results: 212 patients in the early-start and 219 patients in the delayed-start group reported use of health care resources. With savings of D 59 per patient (BCa 95% CI: -829, 788) in the early-start compared to the delayed-start group, societal costs were balanced. The early-start group showed a mean of 1.30 QALYs (BCa 95% CI: 1.26, 1.33) versus 1.30 QALYs (BCa 95% CI: 1.27, 1.33) for the delayed-start group. Because of this negligible difference, incremental cost-effectiveness and cost-utility ratios were not calculated.Conclusion: From an economic point of view, this study suggests that early treatment with levodopa is not more expensive than delayed treatment with levodopa.Neurological Motor Disorder

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

Highlighting the Role of Biomarkers of Inflammation in the Diagnosis and Management of Complex Regional Pain Syndrome

Complex regional pain syndrome (CRPS) is characterized by continuous pain that is often accompanied by sensory, motor, vasomotor, sudomotor, and trophic disturbances. If left untreated, it can have a significant impact on the quality of life of patients. The diagnosis of CRPS is currently based on a set of relatively subjective clinical criteria: the New International Association for the Study of Pain clinical diagnostic criteria for CRPS. There are still no objective laboratory tests to diagnose CRPS and there is a great need for simple, objective, and easily measurable biomarkers in the diagnosis and management of this disease. In this review, we discuss the role of inflammation in the multi-mechanism pathophysiology of CRPS and highlight the application of potential biomarkers of inflammation in the diagnosis and management of this disease

Metabolic alterations in a rat model of Takotsubo syndrome

This work was supported by British Heart Foundation, Award FS/16/39/32174 [Early Metabolic Intervention in Acute Stress-Induced (Tako-tsubo) Cardiomyopathy] to D.K.D. D.K.D. is supported by the British Heart Foundation (FS/RTF/20/30009, NH/19/1/34595, PG/18/35/33786, CS/17/4/32960, PG/15/88/31780, PG/17/64/33205), Chest Heart and Stroke Scotland (19/53), Tenovus Scotland (G.18.01), Friends of Anchor, and Grampian NHS-Endowments. C.M. is supported by the Deutsche Forschungsgemeinschaft (Ma 2528/7-1; SFB 894; TRR-219), the Federal Ministry of Education and Research (BMBF; 01EO1504), and the Barth syndrome foundation.Peer reviewedPublisher PD

Metabolic alterations in a rat model of Takotsubo syndrome

AIMS: Cardiac energetic impairment is a major finding in takotsubo patients. We investigate specific metabolic adaptations to direct future therapies. METHODS AND RESULTS: An isoprenaline-injection female rat model (versus sham) was studied at day-3; recovery assessed at day-7. Substrate uptake, metabolism, inflammation and remodelling were investigated by 18F-FDG-PET, metabolomics, qPCR and WB. Isolated cardiomyocytes were patch-clamped during stress protocols for redox states of NAD(P)H/FAD or [Ca2+]c, [Ca2+]m and sarcomere length. Mitochondrial respiration was assessed by seahorse/Clark electrode (glycolytic and β-oxidation substrates).Cardiac 18F-FDG metabolic rate was increased in takotsubo (p = 0.006), as were expression of GLUT4-RNA/GLUT1/HK2-RNA and HK activity (all p  0.0001). Both lactate and pyruvate were lower (p < 0.05) despite increases in LDH-RNA and PDH (p < 0.05 both). β-oxidation enzymes CPT1b-RNA and 3KAT were increased (p < 0.01) but malonyl-CoA (CPT-1 regulator) was upregulated (p = 0.01) with decreased fatty acids and acyl-carnitines levels (p = 0.0001-0.02). Krebs cycle intermediates α-ketoglutarate and succinyl-carnitine were reduced (p < 0.05) as was cellular ATP reporter dihydroorotate (p = 0.003). Mitochondrial Ca2+ uptake during high workload was impaired on day-3 (p < 0.0001), inducing oxidation of NAD(P)H and FAD (p = 0.03) but resolved by day-7. There were no differences in mitochondrial respiratory function, sarcomere shortening or [Ca2+] transients of isolated cardiomyocytes, implying preserved integrity of both mitochondria and cardiomyocyte. Inflammation and remodelling were upregulated - increased CD68-RNA, collagen RNA/protein and skeletal actin RNA (all p < 0.05). CONCLUSION: Dys-regulation of glucose and lipid metabolic pathways with decreases in final glycolytic and β-oxidation metabolites and reduced availability of Krebs intermediates characterises takotsubo myocardium. The energetic deficit accompanies defective Ca2+ handling, inflammation and upregulation of remodelling pathways, with preservation of sarcomeric and mitochondrial integrity. TRANSLATIONAL PERSPECTIVE: The simultaneous dysregulation in the glycolytic and beta-oxidation pathways which underlies the energetic deficit of the takotsubo heart supports further testing of currently available metabolic modulators as possible candidates for successful therapy, as well as targeting the inflammatory and remodelling pathways