Spinal Cord Stimulation for Gait Disorders in Parkinson's Disease and Atypical Parkinsonism: A Systematic Review of Preclinical and Clinical Data.

BACKGROUND: Falls in extrapyramidal disorders, particularly Parkinson's disease (PD), multisystem atrophy (MSA), and progressive supranuclear palsy (PSP), are key milestones affecting patients' quality of life, incurring increased morbidity/mortality and high healthcare costs. Unfortunately, gait and balance in parkinsonisms respond poorly to currently available treatments. A serendipitous observation of improved gait and balance in patients with PD receiving spinal cord stimulation (SCS) for back pain kindled an interest in using SCS to treat gait disorders in parkinsonisms. OBJECTIVES: We reviewed preclinical and clinical studies of SCS to treat gait dysfunction in parkinsonisms, covering its putative mechanisms and efficacies. MATERIALS AND METHODS: Preclinical studies in animal models of PD and clinical studies in patients with PD, PSP, and MSA who received SCS for gait disorders were included. The main outcome assessed was clinical improvement in gait, together with outcome measures used and possible mechanism of actions. RESULTS: We identified 500 references, and 45 met the selection criteria and have been included in this study for analysis. Despite positive results in animal models, the outcomes in human studies are inconsistent. CONCLUSIONS: The lack of blind and statistically powered studies, the heterogeneity in patient selection and study outcomes, and the poor understanding of the underlying mechanisms of action of SCS are some of the limiting factors in the field. Addressing these limitations will allow us to draw more reliable conclusions on the effects of SCS on gait and balance in extrapyramidal disorders.

A Heterogeneous Sensing Suite for Multisymptom Quantification of Parkinson's Disease.

Parkinson's disease (PD) is the second most common neurodegenerative disease affecting millions worldwide. Bespoke subject-specific treatment (medication or deep brain stimulation (DBS)) is critical for management, yet depends on precise assessment cardinal PD symptoms - bradykinesia, rigidity and tremor. Clinician diagnosis is the basis of treatment, yet it allows only a cross-sectional assessment of symptoms which can vary on an hourly basis and is liable to inter- and intra-rater subjectivity across human examiners. Automated symptomatic assessment has attracted significant interest to optimise treatment regimens between clinician visits, however, no wearable has the capacity to simultaneously assess all three cardinal symptoms. Challenges in the measurement of rigidity, mapping muscle activity out-of-clinic and sensor fusion have inhibited translation. In this study, we address all through a novel wearable sensor system and machine learning algorithms. The sensor system is composed of a force-sensor, three inertial measurement units (IMUs) and four custom mechanomyography (MMG) sensors. The system was tested in its capacity to predict Unified Parkinson's Disease Rating Scale (UPDRS) scores based on quantitative assessment of bradykinesia, rigidity and tremor in PD patients. 23 PD patients were tested with the sensor system in parallel with exams conducted by treating clinicians and 10 healthy subjects were recruited as a comparison control group. Results prove the system accurately predicts UPDRS scores for all symptoms (85.4% match on average with physician assessment) and discriminates between healthy subjects and PD patients (96.6% on average). MMG features can also be used for remote monitoring of severity and fluctuations in PD symptoms out-of-clinic. This closed-loop feedback system enables individually tailored and regularly updated treatment, facilitating better outcomes for a very large patient population.

Traditional Trial and Error versus Neuroanatomic 3-Dimensional Image Software-Assisted Deep Brain Stimulation Programming in Patients with Parkinson Disease.

BACKGROUND: Programming deep brain stimulation (DBS) settings in patients with Parkinson disease (PD) is challenging and time consuming because of the vast number of possible parameter combinations. This results in long sessions that can be exhausting for the patients and physicians. GUIDE (Boston Scientific) is a 3-dimensional neuroanatomic visual software that precisely visualizes the location of the DBS electrode in the subthalamic nucleus (STN). The objective of this paper is to compare the duration and clinical effects of traditional trial and error versus GUIDE-assisted DBS programming in 10 patients with PD treated with STN DBS. METHODS: For each patient, neurostimulation parameters were selected with GUIDE to create a stimulation field encompassing the dorsal part of the STN. On programming day, each patient was assessed with both traditional and GUIDE approaches using a crossover design. For GUIDE-assisted sessions, the patients were programmed directly with the DBS settings obtained with the stimulated field model, and if necessary, parameters were adjusted to achieve optimal clinical response. Clinical improvement was assessed with Unified Parkinson's Disease Rating Scale scores for limb bradykinesia, tremor, and rigidity. RESULTS: In 7 patients, DBS settings obtained with GUIDE led to suboptimal clinical improvement and mild adjustments were required. After these adjustments, the magnitude of clinical improvement with the 2 approaches was comparable (P = 0.8219). Programming time with GUIDE was significantly shorter than with the traditional programming approach (P < 0.0001). CONCLUSIONS: Visualization of stimulation fields with GUIDE provides useful information to achieve a clinical improvement comparable with that obtained with the traditional trial and error approach, but with shorter and more efficient programming sessions.

Prediction of Gait Freezing in Parkinsonian Patients: A Binary Classification Augmented With Time Series Prediction.

This paper presents a novel technique to predict freezing of gait in advanced stage Parkinsonian patients using movement data from wearable sensors. A two-class approach is presented which consists of autoregressive predictive models to project the feature time series, followed by machine learning based classifiers to discriminate freezing from nonfreezing based on the predicted features. To implement and validate our technique a set of time domain and frequency domain features were extracted from the 3D acceleration data, which was then analyzed using information theoretic and feature selection approaches to determine the most discriminative features. Predictive models were trained to predict the features from their past values, then fed into binary classifiers based on support vector machines and probabilistic neural networks which were rigorously cross validated. We compared the results of this approach with a three-class classification approach proposed in previous literature, in which a pre-freezing class was introduced and the problem of prediction of the gait freezing incident was reduced to solving a three-class classification problem. The two-class approach resulted in a sensitivity of 93±4%, specificity of 91±6%, with an expected prediction horizon of 1.72 s. Our subject-specific gait freezing prediction algorithm outperformed existing algorithms, yields consistent results across different subjects and is robust against the choice of classifier, with slight variations in the selected features. In addition, we analyzed the merits and limitations of different families of features to predict gait freezing.

An unusual case of bilateral anterior opercular syndrome from a neuro-rehabilitation perspective.

Bilateral anterior opercular syndrome, also known as Foix-Chavany-Marie syndrome, is relatively rare and is characterized by inability of voluntary activation of facial, lingual, pharyngeal, and masticatory muscles with preserved automatic and reflex movements such as smiling and yawning. The syndrome is caused by bilateral lesions of the anterior opercula and results in severe impairments with speech and swallowing. This article describes a patient with bilateral anterior opercular syndrome secondary to embolic strokes and how neuro-rehabilitation improved symptoms.

Nigrosome Imaging and Neuromelanin Sensitive MRI in Diagnostic Evaluation of Parkinsonism.

BACKGROUND: Recent developments in magnetic resonance imaging (MRI) techniques have offered new research opportunities to visualize in vivo substantia nigra pathology in Parkinson's disease (PD). This paper summarizes the main findings of nigrosome imaging and neuromelanin sensitive MRI studies in patients with PD and other parkinsonisms. METHODS: The PubMed database was searched from 2005 to 2017 using the following keywords: Parkinson's disease and parkinsonism, in combination with MRI, nigrosome, neuromelanin, and iron. Only publications in English were included. RESULTS: Nigrosome or dorsal nigral hyperintensity abnormalities are studied using T2* and susceptibility weighted imaging MRI sequences in most studies, whereas Neuromelanin imaging is usually performed using T1-weighted fast spin echo sequence. Nigrosome abnormalities have been consistently demonstrated in PD patients, and nigrosome imaging has high sensitivity and specificity in distinguishing PD from healthy controls, though it is unable to reliably separate PD from atypical parkinsonisms. Reduced neuromelanin-related signals and/or volume loss in neuromelanin containing structures have been found in PD patients, and neuromelanin sensitive MRI imaging can also discriminate PD patients from healthy controls with high accuracy, though there is a degree of heterogeneity in the imaging findings. Preliminary findings suggested that longitudinal change of neuromelanin signal could be detected in PD, raising the possibility of using it as a marker of disease progression. CONCLUSION: Nigrosome imaging and neuromelanin sensitive MRI are promising tools to study nigral pathology and to improve the diagnosis of PD. However, further studies are required to standardize analysis approaches, confirm longitudinal changes, and assess their generalizability.

A Rare Presentation of Orthostatic Tremor as Abdominal Tremor.

Background: Orthostatic tremor (OT) is a weight-bearing hyperkinetic disorder characterized by unsteadiness while standing that is relieved when sitting or walking. Case report: A 66-year-old male presented with a 5 year-history of tremor in his abdomen, but only when he stood in a stationary position. The tremor disappeared when he stood or walked. On examination, he had palpable tremor in his rectus abdominis and gastrocnemius virtually instantaneously after standing. His electromyography findings confirmed the presence of a 12-Hz tremor in the tibialis anterior while standing, with subharmonics recorded in the external obliques and rectus abdominis. Discussion: Our case illustrates an unusual presentation of OT. The diagnosis is supported by its characteristic frequency and specific appearance only during upright stance.

Restorative Strategies in Movement Disorders: the Contribution of Imaging.

PURPOSE OF REVIEW: The purpose of this review was to review the imaging, particularly positron emission tomography (PET), findings in neurorestoration studies in movement disorders, with specific focus on neural transplantation in Parkinson's disease (PD) and Huntington's disease (HD). RECENT FINDINGS: PET findings in PD transplantation studies have shown that graft survival as reflected by increases in dopaminergic PET markers does not necessarily correlate with clinical improvement. PD patients with more denervated ventral striatum and more imbalanced serotonin-to-dopamine ratio in the grafted neurons tended to have worse outcome. In HD transplantation studies, variable graft survival and clinical responses may be related to host inflammatory/immune responses to the grafts. Information gleaned from imaging findings in previous neural transplantation studies has been used to refine study protocol and patient selection in future trials. This includes identifying suitable candidates for transplantation using imaging markers, employing multiple and/or novel PET tracers to better assess graft functions and inflammatory responses to grafts.

Genetic and degenerative disorders primarily causing other movement disorders.

In this chapter, we will discuss the contributions of structural and functional imaging to the diagnosis and management of genetic and degenerative diseases that lead to the occurrence of movement disorders. We will mainly focus on Huntington's disease, Wilson's disease, dystonia, and neurodegeneration with brain iron accumulation, as they are the more commonly encountered clinical conditions within this group.

The long-term safety and efficacy of bilateral transplantation of human fetal striatal tissue in patients with mild to moderate Huntington's disease.

Huntington's disease (HD) is a fatal autosomal dominant neurodegenerative disease involving progressive motor, cognitive and behavioural decline, leading to death approximately 20 years after motor onset. The disease is characterised pathologically by an early and progressive striatal neuronal cell loss and atrophy, which has provided the rationale for first clinical trials of neural repair using fetal striatal cell transplantation. Between 2000 and 2003, the 'NEST-UK' consortium carried out bilateral striatal transplants of human fetal striatal tissue in five HD patients. This paper describes the long-term follow up over a 3-10-year postoperative period of the patients, grafted and non-grafted, recruited to this cohort using the 'Core assessment program for intracerebral transplantations-HD' assessment protocol. No significant differences were found over time between the patients, grafted and non-grafted, on any subscore of the Unified Huntington's Disease Rating Scale, nor on the Mini Mental State Examination. There was a trend towards a slowing of progression on some timed motor tasks in four of the five patients with transplants, but overall, the trial showed no significant benefit of striatal allografts in comparison with a reference cohort of patients without grafts. Importantly, no significant adverse or placebo effects were seen. Notably, the raclopride positron emission tomography (PET) signal in individuals with transplants, indicated that there was no obvious surviving striatal graft tissue. This study concludes that fetal striatal allografting in HD is safe. While no sustained functional benefit was seen, we conclude that this may relate to the small amount of tissue that was grafted in this safety study compared with other reports of more successful transplants in patients with HD.

Microglial activation in regions related to cognitive function predicts disease onset in Huntington's disease: a multimodal imaging study.

Huntington's disease (HD) is an inherited neurodegenerative disorder associated with motor, cognitive and psychiatric deficits. This study, using a multimodal imaging approach, aims to assess in vivo the functional and structural integrity of regions and regional networks linked with motor, cognitive and psychiatric function. Predicting disease onset in at risk individuals is problematic and thus we sought to investigate this by computing the 5-year probability of HD onset (p5 HD) and relating it to imaging parameters. Using MRI, (11)C-PK11195 and (11)C-raclopride PET, we have investigated volumes, levels of microglial activation and D2/D3 receptor binding in CAG repeat-matched groups of premanifest and symptomatic HD gene carriers. Findings were correlated with disease-burden and UHDRS scores. Atrophy was detected in sensorimotor striatum (SMST), substantia nigra, orbitofrontal and anterior prefrontal cortex in the premanifest HD. D2/D3 receptor binding was reduced and microglial activation increased in SMST and associative striatum (AST), bed nucleus of the stria terminalis, the amygdala and the hypothalamus. In symptomatic HD cases this extended to involve atrophy in globus pallidus, limbic striatum, the red nuclei, anterior cingulate cortex, and insula. D2/D3 receptor binding was additionally reduced in substantia nigra, globus pallidus, limbic striatum, anterior cingulate cortex and insula, and microglial activation increased in globus pallidus, limbic striatum and anterior prefrontal cortex. In premanifest HD, increased levels of microglial activation in the AST and in the regional network associated with cognitive function correlated with p5 HD onset. These data suggest that pathologically activated microglia in AST and other areas related to cognitive function, maybe better predictors of clinical onset and stresses the importance of early cognitive assessment in HD.

Global-two-stage filtering of clinical PET parametric maps: application to [(11)C]-(R)-PK11195.

INTRODUCTION: In Positron Emission Tomography (PET) quantification of physiological parameters at the voxel level may result in unreliable estimates due to the high noise of voxel time activity curves. Global-Two-Stage (GTS), an estimation technique belonging to the group of "population approaches", can be used to tackle this problem. GTS was previously tested on simulated PET data and yielded substantial improvements when compared to standard estimation approaches such as Weighted NonLinear Least Squares (WNLLS) and Basis Function Method (BFM). In this work GTS performance is assessed in a clinical context using the neuroinflammation marker [(11)C]-(R)-PK11195 applied to a cohort of Huntington's disease (HD) patients with and without symptoms. MATERIALS AND METHODS: Parametric maps of binding potential (BP(ND)) of 12 normal controls (NC), 9 symptomatic and 9 presymptomatic HD patients were generated by applying a modified reference tissue model that accounts for tracer vascular activity in both reference and target tissues (SRTMV). GTS was then applied to SRTMV maps and its performance compared with that of SRTMV. Three smoothed versions of SRTMV, obtained by filtering the original SRTMV maps with Gaussian filters of 3 mm, 5 mm and 7 mm Full Width Half Maximum (FWHM), were also included in the comparison. Since striatal degeneration is the hallmark of HD, sensitivity was assessed for all methods by computing the mean of z-scores in caudate, putamen and globus pallidus in the voxel-by-voxel statistical comparison of BP(ND) between HD and NC. RESULTS: Application of GTS to parametric maps brought a substantial qualitative improvement to SRTMV maps to the extent that anatomical structures often became visible. In addition, most parameter estimates that were outside the physiological range with SRTMV were corrected by GTS. GTS yielded a 2.3-fold increase in sensitivity with respect to SRTMV for the symptomatic cohort (mean of striatal z-scores of 0.76 for SRTMV and 1.79 for GTS) and an even more substantial increase for the presymptomatic cohort (mean of striatal z-scores of 0.34 for SRTMV and 0.96 for GTS). The sensitivity of GTS was similar to the one obtained with a filter of 7 mm FWHM applied to the initial SRTMV maps but GTS images were not characterized by the notable loss of resolution typical of smoothed maps. GTS, additionally, does not require to change/define settings according to the tracer and level of noise, whereas the choice of the FWHM value of the Gaussian filter normally employed in the smoothing procedure is typically arbitrary. CONCLUSIONS: GTS is a powerful and robust tool for improving the quality of parametric maps in PET. The method is particularly appealing in that it can be applied to any tracer and estimation method, provided that initial estimates of the parameter vector and of its covariance are available. Although the benefits of GTS are far from being exhaustively assessed, the significant improvements obtained both on real and simulated data suggest that it could become an important tool for dynamic PET in the future.

Persistent nigrostriatal dopaminergic abnormalities in ex-users of MDMA ('Ecstasy'): an 18F-dopa PET study.

Ecstasy (±3,4-methylenedioxymethamphetamine, MDMA) is a popular recreational drug with known serotonergic neurotoxicity. Its long-term effects on dopaminergic function are less certain. Studying the long-term effects of ecstasy is often confounded by concomitant polydrug use and the short duration of abstinence. We used (18)F-dopa positron emission tomography (PET) to investigate the long-term effects of ecstasy on nigrostriatal dopaminergic function in a group of male ex-recreational users of ecstasy who had been abstinent for a mean of 3.22 years. We studied 14 ex-ecstasy users (EEs), 14 polydrug-using controls (PCs) (matched to the ex-users for other recreational drug use), and 12 drug-naive controls (DCs). Each participant underwent one (18)F-dopa PET, cognitive assessments, and hair and urinary analyses to corroborate drug-use history. The putamen (18)F-dopa uptake of EEs was 9% higher than that of DCs (p=0.021). The putamen uptake rate of PCs fell between the other two groups, suggesting that the hyperdopaminergic state in EEs may be due to the combined effects of ecstasy and polydrug use. There was no relationship between the amount of ecstasy used and striatal (18)F-dopa uptake. Increased putaminal (18)F-dopa uptake in EEs after an abstinence of >3 years (mean) suggests that the effects are long lasting. Our findings suggest potential long-term effects of ecstasy use, in conjunction with other recreational drugs, on nigrostriatal dopaminergic functions. Further longitudinal studies are required to elucidate the significance of these findings as they may have important public health implications.

Cortical dopamine dysfunction in symptomatic and premanifest Huntington's disease gene carriers.

We used (11)C-raclopride PET, a marker of D(2) dopamine receptor binding, and statistical parametric mapping (SPM) to localise cortical D(2) receptor dysfunction in individual Huntington's disease (HD) gene carriers (16 symptomatic and 11 premanifest subjects) and assess its clinical significance. 62.5% of symptomatic HD patients and 54.5% of premanifest carriers showed cortical reductions in D(2) binding. The most frequent decreases in cortical binding in individual HD subjects were seen in temporal and frontal areas. Symptomatic HD subjects with decreased cortical D(2) binding had worse scores on neuropsychological tests assessing attention and executive functions than subjects without cortical dopamine dysfunction, notwithstanding comparable reduction in striatal D(2) binding and motor disability. Our results indicate that cortical dopaminergic dysfunction is common in both symptomatic and premanifest HD gene carriers. It is an early event in HD pathophysiology and could contribute to the impairment in neuropsychological performance in these patients.

Hypothalamic involvement in Huntington's disease: an in vivo PET study.

Recent studies have shown alterations in metabolism, sleep and circadian rhythms as well as in several neuropeptides derived from the hypothalamic-pituitary axis in Huntington's disease patients; however, the pathology underlying these abnormalities is not known. Our aim was to assess in vivo D(2) receptor's loss/dysfunction and increases in microglial activation in the hypothalamus of symptomatic Huntington's disease patients and premanifest Huntington's disease gene carriers using PET with (11)C-raclopride (RAC), a specific D(2) receptor ligand and (11)C-(R)-PK11195 (PK), a marker of microglial activation. We have studied 9 symptomatic Huntington's disease patients (age = 46.8 +/- 4.7 years; mean +/- SD) and 10 premanifest Huntington's disease gene carriers (age = 41.9 +/- 8.2 years; mean +/- SD). RAC and PK findings for these subjects were compared with those of a group of normal controls (RAC, n = 9; PK, n = 10). In the symptomatic Huntington's disease group, we found a significant decrease (P = 0.0012) in mean hypothalamic RAC binding potential (BP) and a significant increase in mean hypothalamic PK BP (P = 0.0008). Similarly, a significant decrease (P = 0.0143) in mean hypothalamic RAC BP and a significant increase in mean hypothalamic PK BP (P = 0.0057) were observed in the premanifest Huntington's disease group. Hypothalamic RAC and PK BP values correlated with each other in combined Huntington's disease groups (r = -0.6180, P = 0.0048) but not with striatal RAC and PK BP values. Our data demonstrate, for the first time, significant D(2) receptor loss and microglia activation in the hypothalamus of Huntington's disease. These pathological changes occur very early in the course of the disease and may partly explain the development of commonly reported symptoms in Huntington's disease including progressive weight loss, alterations in sexual behaviour and disturbances in the wake-sleep cycle.