Elective and Emergency Deep Brain Stimulation in Refractory Pediatric Monogenetic Movement Disorders Presenting with Dystonia: Current Practice Illustrated by Two Cases.

BACKGROUND: Dystonia is characterized by sustained or intermittent muscle contractions, leading to abnormal posturing and twisting movements. In pediatric patients, dystonia often negatively influences quality of life. Pharmacological treatment for dystonia is often inadequate and causes adverse effects. Deep brain stimulation (DBS) appears to be a valid therapeutic option for pharmacoresistant dystonia in children. METHODS: To illustrate the current clinical practice, we hereby describe two pediatric cases of monogenetic movement disorders presenting with dystonia and treated with DBS. We provide a literature review of similar previously described cases and on different clinical aspects of DBS in pediatric dystonia. RESULTS: The first patient, a 6-year-old girl with severe dystonia, chorea, and myoclonus due to an ADCY5 gene mutation, received DBS in an elective setting. The second patient, an 8-year-old boy with GNAO1-related dystonia and chorea, underwent emergency DBS due to a pharmacoresistant status dystonicus. A significant amelioration of motor symptoms (65% on the Burke-Fahn-Marsden Dystonia Rating Scale) was observed postoperatively in the first patient and her personal therapeutic goals were achieved. DBS was previously reported in five patients with ADCY5-related movement disorders, of which three showed objective improvement. Emergency DBS in our second patient resulted in the successful termination of his GNAO1-related status dystonicus, this being the eighth case reported in the literature. CONCLUSION: DBS can be effective in monogenetic pediatric dystonia and should be considered early in the disease course. To better evaluate the effects of DBS on patients' functioning, patient-centered therapeutic goals should be discussed in a multidisciplinary approach.

Electroencephalographic Findings in Posthypoxic Myoclonus.

The physical examination findings of early posthypoxic myoclonus (PHM) are associated with poor prognosis. Recent findings indicate that patients with multifocal PHM, assumed to have a cortical origin, have a comparable outcome to resuscitated patients without PHM. Generalized PHM, assumed to have a subcortical myoclonus origin, is still associated with a bad clinical outcome. It is not known whether the electroencephalographic (EEG) findings differ between the multifocal and generalized myoclonus groups nor is the clinical significance clearly defined. Forty-three patients with PHM were retrospectively derived from an EEG database. Patients were categorized as having multifocal (i), generalized (ii), or undetermined (iii) PHM. Outcome was expressed in cerebral performance category scores. The EEG background was categorized into isoelectric (I), low voltage (II), burst suppression (III), status epilepticus (SE; IV), diffuse slowing (V), and mild encephalopathic or normal (VI). 17 patients had generalized PHM and 23 had multifocal PHM (3 undetermined). The EEG showed more SE in generalized compared to multifocal PHM (64% vs 13%, P< .001). Diffuse slowing was more often present in multifocal PHM (52% vs 17%, P < .05). Early-onset myoclonus occurred significantly more often in generalized PHM, and early generalized PHM was invariantly associated with poor outcome. In conclusion, patients with generalized PHM showed more SE. These EEG findings might be either subcortical corollaries or primarily cortical phenomena. Our retrospective results conflict with currently used clinical criteria for myoclonus classification, and we suggest that more refined difference may be needed for accurate assessment of PHM. To better understand PHM, prospective research with standardized clinical assessment and quantitative EEG analysis is needed.

A comparison of methods to suppress electrocardiographic artifacts in local field potential recordings.

OBJECTIVE: Local field potential (LFP) recordings from deep brain stimulation (DBS) electrodes are often contaminated with electrocardiographic (ECG) artifacts that hinder the detection of disease-specific electrical brain activity. METHODS: Three ECG suppression methods were evaluated: (1) QRS interpolation of the Perceive toolbox, (2) template subtraction, and (3) singular value decomposition (SVD). LFPs were recorded with the Medtronic PerceptTM PC system in nine Parkinson's disease patients with stimulation OFF ("OFF-DBS"; anode disconnected) and ON at 0 mA ("ON-DBS 0 mA"; anode connected). Findings were verified with simulated ECG-contaminated time series. RESULTS: ECG artifacts were present in 10 out of 18 ON-DBS 0 mA recordings. All ECG suppression methods drastically reduced artifact-induced beta band (13-35 Hz) power and at least partly recovered the beta peak and beta burst dynamics. Using external ECG recordings and lengthening artifact epoch length improved the performance of the suppression methods. Increasing epoch length, however, elevated the risk of flattening the beta peak and losing beta burst dynamics. CONCLUSIONS: The SVD method formed the preferred trade-off between artifact cleaning and signal loss, as long as its parameter settings are adequately chosen. SIGNIFICANCE: ECG suppression methods enable analysis of disease-specific neural activity from signals affected by ECG artifacts.

Thalamic local field potentials recorded using the deep brain stimulation pulse generator.

Background: Essential tremor (ET) is one of the most common movement disorders, and continuous deep brain stimulation (DBS) is an established treatment for medication-refractory cases. However, the need for increasing stimulation intensities, with unpleasant side effects, and DBS tolerance over time can be problematic. The advent of novel DBS devices now provides the opportunity to longitudinally record LFPs using the implanted pulse generator, which opens up possibilities to implement adaptive DBS algorithms in a real-life setting. Methods: Here we report a case of thalamic LFP activity recorded using a commercially available sensing-enabled DBS pulse generator (Medtronic Percept PC). Results: In the OFF-stimulation condition, a peak tremor frequency of 3.8 Hz was identified during tremor evoking movements as assessed by video and accelerometers. Activity at the same and supraharmonic frequency was seen in the frequency spectrum of the LFP data from the left vim nucleus during motor tasks. Coherence analysis showed that peripherally recorded tremor was coherent with the LFP signal at the tremor frequency and supraharmonic frequency. Conclusion: This is the first report of recorded tremor-related thalamic activity using the electrodes and pulse generator of an implanted DBS system. Larger studies are needed to evaluate the clinical potential of these fully implantable systems, and ultimately pulse generators with sensing-coupled algorithms driving stimulation, to really close the loop.

Secondary sensory area SII is crucially involved in the preparation of familiar movements compared to movements never made before.

Secondary sensorimotor regions are involved in sensorimotor integration and movement preparation. These regions take part in parietal-premotor circuitry that is not only active during motor execution but also during movement observation and imagery. This activation particularly occurs when observed movements belong to one's own motor repertoire, consistent with the finding that motor imagery only improves performance when one can actually make such movement. We aimed to investigate whether imagery or observation of a movement that was never made before causes parietal-premotor activation or that the ability to perform this movement is indeed a precondition. Nine subjects [group Already Knowing It (AKI)] could abduct their hallux (moving big toe outward). Seven subjects initially failed to make such movement (Absolute Zero A0 group). They had to imagine, observe, or execute this movement, whereas fMRI data were obtained both before and after training. Contrasting abduction observation between the AKI-group and A0-group showed increased left SII and supplementary motor area activation. Comparing the observation of hallux flexion with abduction showed increased bilateral SII activation in the A0 and not in the AKI group. Prolonged training resulted in equal performance and similar cerebral activation patterns in the two groups. Thereby, conjunction analysis of the correlations on subject's range of abduction during execution, imagery, and observation of hallux abduction showed exclusive bilateral SII activation. The reduced SII involvement in A0 may imply that effective interplay between sensory predictions and feedback does not take place without actual movement experience. However, this can be acquired by training.

Overlap and segregation in predorsal premotor cortex activations related to free selection of self-referenced and target-based finger movements.

In reaching movements, parietal contributions can be distinguished that are based on representations of external space and body scheme. By functional magnetic resonance imaging, we examined 16 healthy subjects to see whether such segregation similarly exists in the frontal lobes when visuomotor actions are not specified but when free choices are allowed. Free selection was button based (target based) or finger based (self-referenced), with invariant instructions as control. To avoid a visual attention bias, instructions were auditory presented. Statistical parametric mapping revealed that free button selection with the same finger was associated with increased activations in the anterior cingulate cortex (ACC), right posterodorsal prefrontal cortex (PFC) including the rostral extension of the dorsal premotor cortex (pre-PMd), and the anterodorsal PFC. Prefrontal activation related to free finger selection (pressing the same button) was restricted to an anteromedial segment of the posterodorsal PFC/pre-PMd. Bilateral inferior parietal activations were present in both free-choice conditions. Pre-PMd and parietal contributions to free selection support concepts on early-stage action selection in dorsal visuomotor pathways. The rostral-caudal segregation in pre-PMd activations reflected that in anterior direction, frontal processing is gradually less involved in selection of environmental information but increasingly committed to self-referenced selection. ACC particularly contributes to free selection between external goals.

Low-frequency oscillation suppression in dystonia: Implications for adaptive deep brain stimulation.

BACKGROUND: Low-frequency oscillations (LFO) detected in the internal globus pallidus of dystonia patients have been identified as a physiomarker for adaptive Deep Brain Stimulation (aDBS), since LFO correlate with dystonic symptoms and are rapidly suppressed by continuous DBS (cDBS). However, it is as yet unclear how LFO should be incorporated as feedback for aDBS. OBJECTIVES: to test the acute effects of aDBS, using the amplitude of short-lived LFO-bursts to titrate stimulation, to explore the immediate effects of cDBS on LFO-modulation and dystonic symptoms, and to investigate whether a difference in the resting-state LFO is present between DBS-naïve patients and patients with chronic DBS. METHODS: seven patients were assessed during either DBS-implantation (n = 2) or battery replacement surgery (n = 5), and pseudorandomized in three conditions: no stimulation, cDBS, and aDBS. Additionally, resting-state LFP-recordings from patients undergoing battery replacement were compared to those obtained during DBS-implantation; LFP-recordings from a previous cohort of six dystonia patients undergoing DBS-implantation were incorporated into this analysis (total n = 8 newly implanted patients). RESULTS: we corroborated that a mild LFO-suppression rapidly occurs during cDBS. However, no acute changes in clinical symptoms were observed after cDBS or aDBS. Remarkably, we observed that resting-state LFO were significantly lower in patients who had been effectively treated with chronic cDBS compared to those of newly implanted patients, even when stimulation was suspended. CONCLUSIONS: our results indicate that LFO-suppression in dystonia, similar to symptom response to cDBS, might be gradual, and remain after stimulation is suspended. Therefore, tracking gradual changes in LFO may be required for aDBS implementation.

Cerebral representations of space and time.

A link between perception of time and spatial change is particularly revealed in dynamic conditions. By fMRI, we identified regional segregation as well as overlap in activations related to spatial and temporal processing. Using spatial and temporal anticipation concerning movements of a ball provided a balanced paradigm for contrasting spatial and temporal conditions. In addition, momentary judgments were assessed. Subjects watched a monitor-display with a moving ball that repeatedly disappeared. Ordered in 4 conditions, they indicated either where or when the ball would hit the screen bottom, where it actually disappeared or what its speed was. Analysis with SPM showed posterior parietal activations related to both spatial- and temporal predictions. After directly contrasting these two conditions, parietal activations remained robust in spatial prediction but virtually disappeared in temporal prediction, while additional left cerebellar-right prefrontal and pre-SMA activations in temporal prediction remained unchanged. Speed contrasted to the location of disappearance showed similar parietal decrease with maintained cerebellar-prefrontal activations, but also increased caudate activation. From these results we inferred that parietal-based spatial information was a prerequisite for temporal processing, while prefrontal-cerebellar activations subsequently reflected working memory and feedforward processing for the assessment of differences between past and future spatial states. We propose that a temporal component was extracted from speed, i.e. approximated momentary time, which demarcated minimal intervals of spatial change (defined by neuronal processing time). The caudate association with such interval demarcation provided an argument to integrate concepts of space-referenced time processing and a clock-like processing model.

A Clinical Applicable Smartwatch Application for Measuring Hyperkinetic Movement Disorder Severity.

Measuring the severity of hyperkinetic movement disorders like tremor and myoclonus is challenging. Although many accelerometers are available to quantify movements, the vast majority lacks real-time analysis and an interface that makes it possible to real-time adjust therapy like deep brain stimulation (DBS). Here, we developed a smartwatch/smartphone application that is capable of real-time analysing movement disorder severity. Movement analysis was realised by integrating acceleration values, to velocity and subsequently to distance. Measured distances were compared with a validated accelerometer already applied for quantifying movement disorders. Further validation was done by quantitative assessment of simulated movement disorders in 10 healthy volunteers. Finally, the approach was tested in two patients treated with DBS to quantify the effect of different DBS settings on myoclonus and tremor severity, respectively. The distance measured with the application had a 96% accuracy. This was non-inferior (p = 0.76) compared to accelerometers already clinically applied. Furthermore, (simulated) movement disorder severity could be classified correctly in 93% of the cases. Finally, the method was capable of distinguishing effective from non-effective DBS parameters in two patients. In summary, with our approach we realised an instantaneous and reliable estimation of the severity of movement disorders which can assist in real time titrating therapy like DBS.

Direct comparison of oscillatory activity in the motor system of Parkinson's disease and dystonia: A review of the literature and meta-analysis.

OBJECTIVE: To outline the current knowledge of (sub)cortical oscillations in Parkinson's Disease (PD) and dystonia, and to quantitatively summarize the results of direct comparisons of local oscillatory power between both diseases in the resting state, without medication or stimulation, in both the low-frequency (LF, ±4-12 Hz) and beta (±13 to ∼30 Hz) range. METHODS: Eight relevant studies were included. Recordings from 127 dystonia-, and 144 PD-patient hemispheres were analyzed. Ratios of LF and beta power between diseases were obtained. RESULTS: Beta oscillations in dystonia were lower when compared to beta oscillations in PD, ratio = 0.72, Z = 3.56, p = 0.0004, 95% CI [0.60, 0.86]. Subgroup analyses showed significant differences only in the GPi, whilst conflicting evidence was shown in the STN. LF oscillations in PD were lower when compared to LF oscillations in dystonia, ratio = 0.77, Z = 2.45, p = 0.01, 95% CI [0.63, 0.95]. Subgroup analyses showed significant differences in the GPi and the STN, but not in the M1. CONCLUSIONS: LF and beta oscillations are present in the resting-state motor network of both PD and dystonia patients. However, the power distribution of those oscillations differs between diseases. SIGNIFICANCE: This meta-analysis provides high-level evidence which supports the presence of exaggerated oscillations across the parkinsonian/dystonic motor networks.

Intermuscular coherence as biomarker for pallidal deep brain stimulation efficacy in dystonia.

OBJECTIVE: Finding a non-invasive biomarker for Globus Pallidus interna Deep Brain Stimulation (GPi-DBS) efficacy. Dystonia heterogeneity leads to a wide variety of clinical response to GPi-DBS, making it hard to predict GPi-DBS efficacy for individual patients. METHODS: EEG-EMG recordings of twelve dystonia patients who received bilateral GPi-DBS took place pre- and 1 year post-surgery ON and OFF stimulation, during a rest, pinch, and flexion task. Dystonia severity was assessed using the BFMDRS and TWSTRS (pre- and post-surgery ON stimulation). Intermuscular coherence (IMC) and motorcortex corticomuscular coherence (CMC) were calculated. Low frequency (4-12 Hz) and beta band (13-30 Hz) peak coherences were studied. RESULTS: Dystonia severity improved after 1 year GPi-DBS therapy (BFMDRS: 30%, median 7.8 (IQR 3-10), TWSTRS: 22%, median 6.8 (IQR 4-9)). 86% of IMC were above the 95% confidence limit. The highest IMC peak decreased significantly with GPi-DBS in the low frequency and beta band. Low frequency and beta band IMC correlated partly with dystonia severity and severity improvement. CMC generally were below the 95% confidence limit. CONCLUSIONS: Peak low frequency IMC functioned as biomarker for GPi-DBS efficacy, and partly correlated with dystonia severity. SIGNIFICANCE: IMC can function as biomarker. Confirmation in a larger study is needed for use in clinical practice.

Improving neurophysiological biomarkers for functional myoclonic movements.

INTRODUCTION: Differentiating between functional jerks (FJ) and organic myoclonus can be challenging. At present, the only advanced diagnostic biomarker to support FJ is the Bereitschaftspotential (BP). However, its sensitivity is limited and its evaluation subjective. Recently, event related desynchronisation in the broad beta range (13-45 Hz) prior to functional generalised axial (propriospinal) myoclonus was reported as a possible complementary diagnostic marker for FJ. Here we study the value of ERD together with a quantified BP in clinical practice. METHODS: Twenty-nine patients with FJ and 16 patients with cortical myoclonus (CM) were included. Jerk-locked back-averaging for determination of the 'classical' and quantified BP, and time-frequency decomposition for the event related desynchronisation (ERD) were performed. Diagnostic gain, sensitivity and specificity were obtained for individual and combined techniques. RESULTS: We detected a classical BP in 14/29, a quantitative BP in 15/29 and an ERD in 18/29 patients. At group level we demonstrate that ERD in the broad beta band preceding a jerk has significantly higher amplitude in FJ compared to CM (respectively -0.14 ± 0.13 and +0.04 ± 0.09 (p < 0.001)). Adding ERD to the classical BP achieved an additional diagnostic gain of 53%. Furthermore, when combining ERD with quantified and classical BP, an additional diagnostic gain of 71% was achieved without loss of specificity. CONCLUSION: Based on the current findings we propose to the use of combined beta ERD assessment and quantitative BP analyses in patients with a clinical suspicion for all types of FJ with a negative classical BP.

Adaptive deep brain stimulation in Parkinson's disease.

Although Deep Brain Stimulation (DBS) is an established treatment for Parkinson's disease (PD), there are still limitations in terms of effectivity, side-effects and battery consumption. One of the reasons for this may be that not only pathological but also physiological neural activity can be suppressed whilst stimulating. For this reason, adaptive DBS (aDBS), where stimulation is applied according to the level of pathological activity, might be advantageous. Initial studies of aDBS demonstrate effectiveness in PD, but there are still many questions to be answered before aDBS can be applied clinically. Here we discuss the feedback signals and stimulation algorithms involved in adaptive stimulation in PD and sketch a potential road-map towards clinical application.

Hippocampus activation related to 'real-time' processing of visuospatial change.

The delay associated with cerebral processing time implies a lack of real-time representation of changes in the observed environment. To bridge this gap for motor actions in a dynamical environment, the brain uses predictions of the most plausible future reality based on previously provided information. To optimise these predictions, adjustments to actual experiences are necessary. This requires a perceptual memory buffer. In our study we gained more insight how the brain treats (real-time) information by comparing cerebral activations related to judging past-, present- and future locations of a moving ball, respectively. Eighteen healthy subjects made these estimations while fMRI data was obtained. All three conditions evoked bilateral dorsal-parietal and premotor activations, while judgment of the location of the ball at the moment of judgment showed increased bilateral posterior hippocampus activation relative to making both future and past judgments at the one-second time-sale. Since the condition of such 'real-time' judgments implied undistracted observation of the ball's actual movements, the associated hippocampal activation is consistent with the concept that the hippocampus participates in a top-down exerted sensory gating mechanism. In this way, it may play a role in novelty (saliency) detection.

A Method for Automatic and Objective Scoring of Bradykinesia Using Orientation Sensors and Classification Algorithms.

Correct assessment of bradykinesia is a key element in the diagnosis and monitoring of Parkinson's disease. Its evaluation is based on a careful assessment of symptoms and it is quantified using rating scales, where the Movement Disorders Society-Sponsored Revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) is the gold standard. Regardless of their importance, the bradykinesia-related items show low agreement between different evaluators. In this study, we design an applicable tool that provides an objective quantification of bradykinesia and that evaluates all characteristics described in the MDS-UPDRS. Twenty-five patients with Parkinson's disease performed three of the five bradykinesia-related items of the MDS-UPDRS. Their movements were assessed by four evaluators and were recorded with a nine degrees-of-freedom sensor. Sensor fusion was employed to obtain a 3-D representation of movements. Based on the resulting signals, a set of features related to the characteristics described in the MDS-UPDRS was defined. Feature selection methods were employed to determine the most important features to quantify bradykinesia. The features selected were used to train support vector machine classifiers to obtain an automatic score of the movements of each patient. The best results were obtained when seven features were included in the classifiers. The classification errors for finger tapping, diadochokinesis and toe tapping were 15-16.5%, 9.3-9.8%, and 18.2-20.2% smaller than the average interrater scoring error, respectively. The introduction of objective scoring in the assessment of bradykinesia might eliminate inconsistencies within evaluators and interrater assessment disagreements and might improve the monitoring of movement disorders.

Parkinson bradykinesia correlates with EEG background frequency and perceptual forward projection.

BACKGROUND: To deal with processing-time in the nervous system, visuomotor control requires anticipation. An index for such anticipation is provided by the 'flash-lag illusion' in which moving objects are perceived ahead of static objects while actually being in the same place. We investigated the neurophysiological relation between visuomotor anticipation and motor velocity in Parkinson's disease (PD) and controls. METHODS: Motor velocity was assessed by the number of keystrokes in 30s ('kinesia score') and visuomotor anticipation in a behavioural flash-lag paradigm while electroencephalography data was obtained. PD patients (n = 24) were divided in a 'PDslow' and a 'PDfast' group based on kinesia score. RESULTS: The PDslow group had a lower kinesia score than controls (resp. 40.3 ± 1.7 and 64.9 ± 4.6, p < 0.001). The flash-lag illusion was weaker in the PDslow group than in controls (resp. fractions 0.32 ± 0.04 and 0.50 ± 0.09 of the responses indicating perceived lagging, p = 0.03). Furthermore, the magnitude of the flash-lag illusion correlated with the kinesia score (cc = 0.45, p = 0.02). Finally, electroencephalography background frequency was lower in the PDslow group than in controls (resp 8.24 ± 0.24 and 9.1 ± 0.32 Hz, p = 0.01) and background frequency correlated with the kinesia score (cc = 0.58, p = 0.001). CONCLUSIONS: The decreased flash-lag illusion and lower electroencephalography background frequency in more bradykinetic PD patients provides support for disturbed visuomotor anticipations, putatively caused by reduced, sub-cortically mediated, network efficiency. This suggests a link between anticipation in early-stage visual motion processing and motor preparation.

Interruption of visually perceived forward motion in depth evokes a cortical activation shift from spatial to intentional motor regions.

Forward locomotion generates a radially expanding flow of visual motion which supports goal-directed walking. In stationary mode, wide-field visual presentation of optic flow stimuli evokes the illusion of forward self-motion. These effects illustrate an intimate relation between visual and motor processing. In the present fMRI study, we applied optic flow to identify distinct interfaces between circuitries implicated in vision and movement. The dorsal premotor cortex (PMd) was expected to contribute to wide-field forward motion flow (FFw), reflecting a pathway for externally triggered motor control. Medial prefrontal activation was expected to follow interrupted optic flow urging internally generated action. Data of 15 healthy subjects were analyzed with Statistical Parametric Mapping and confirmed this hypothesis. Right PMd activation was seen in FFw, together with activations of posterior parietal cortex, ventral V5, and the right fusiform gyrus. Conjunction analysis of the transition from wide to narrow forward flow and reversed wide-field flow revealed selective dorsal medial prefrontal activation. These findings point at equivalent visuomotor transformations in locomotion and goal-directed hand movement, in which parietal-premotor circuitry is crucially implicated. Possible implications of an activation shift from spatial to intentional motor regions for understanding freezing of gait in Parkinson's disease are discussed: impaired medial prefrontal function in Parkinson's disease may reflect an insufficient internal motor drive when visual support from optic flow is reduced at the entrance of a narrow corridor.