KMT2B-related disorders: expansion of the phenotypic spectrum and long-term efficacy of deep brain stimulation.

Heterozygous mutations in KMT2B are associated with an early-onset, progressive and often complex dystonia (DYT28). Key characteristics of typical disease include focal motor features at disease presentation, evolving through a caudocranial pattern into generalized dystonia, with prominent oromandibular, laryngeal and cervical involvement. Although KMT2B-related disease is emerging as one of the most common causes of early-onset genetic dystonia, much remains to be understood about the full spectrum of the disease. We describe a cohort of 53 patients with KMT2B mutations, with detailed delineation of their clinical phenotype and molecular genetic features. We report new disease presentations, including atypical patterns of dystonia evolution and a subgroup of patients with a non-dystonic neurodevelopmental phenotype. In addition to the previously reported systemic features, our study has identified co-morbidities, including the risk of status dystonicus, intrauterine growth retardation, and endocrinopathies. Analysis of this study cohort (n = 53) in tandem with published cases (n = 80) revealed that patients with chromosomal deletions and protein truncating variants had a significantly higher burden of systemic disease (with earlier onset of dystonia) than those with missense variants. Eighteen individuals had detailed longitudinal data available after insertion of deep brain stimulation for medically refractory dystonia. Median age at deep brain stimulation was 11.5 years (range: 4.5-37.0 years). Follow-up after deep brain stimulation ranged from 0.25 to 22 years. Significant improvement of motor function and disability (as assessed by the Burke Fahn Marsden's Dystonia Rating Scales, BFMDRS-M and BFMDRS-D) was evident at 6 months, 1 year and last follow-up (motor, P = 0.001, P = 0.004, and P = 0.012; disability, P = 0.009, P = 0.002 and P = 0.012). At 1 year post-deep brain stimulation, >50% of subjects showed BFMDRS-M and BFMDRS-D improvements of >30%. In the long-term deep brain stimulation cohort (deep brain stimulation inserted for >5 years, n = 8), improvement of >30% was maintained in 5/8 and 3/8 subjects for the BFMDRS-M and BFMDRS-D, respectively. The greatest BFMDRS-M improvements were observed for trunk (53.2%) and cervical (50.5%) dystonia, with less clinical impact on laryngeal dystonia. Improvements in gait dystonia decreased from 20.9% at 1 year to 16.2% at last assessment; no patient maintained a fully independent gait. Reduction of BFMDRS-D was maintained for swallowing (52.9%). Five patients developed mild parkinsonism following deep brain stimulation. KMT2B-related disease comprises an expanding continuum from infancy to adulthood, with early evidence of genotype-phenotype correlations. Except for laryngeal dysphonia, deep brain stimulation provides a significant improvement in quality of life and function with sustained clinical benefit depending on symptoms distribution.

Deep brain stimulation treated dystonia-trajectory via status dystonicus.

BACKGROUND: Status dystonicus (SD) is a life-threatening condition. OBJECTIVE AND METHODS: In a dystonia cohort who developed status dystonicus, we analyzed demographics, background dystonia phenomenology and complexity, trajectory previous to-, via status dystonicus episodes, and evolution following them. RESULTS: Over 20 years, 40 of 328 dystonia patients who were receiving DBS developed 58 status dystonicus episodes. Dystonia was of pediatric onset (95%), frequently complex, and had additional cognitive and pyramidal impairment (62%) and MRI alterations (82.5%); 40% of episodes occured in adults. Mean disease duration preceding status dystonicus was 10.3 ± 8 years. Evolution time to status dystonicus varied from days to weeks; however, 37.5% of patients exhibited progressive worsening over years. Overall, DBS was efficient in resolving 90% of episodes. CONCLUSION: Status dystonicus is potentially reversible and a result of heterogeneous conditions with nonuniform underlying physiology. Recognition of the complex phenomenology, morphological alterations, and distinct patterns of evolution, before and after status dystonicus, will help our understanding of these conditions. © 2018 International Parkinson and Movement Disorder Society.

Application of quantum machine learning using quantum kernel algorithms on multiclass neuron M-type classification.

The functional characterization of different neuronal types has been a longstanding and crucial challenge. With the advent of physical quantum computers, it has become possible to apply quantum machine learning algorithms to translate theoretical research into practical solutions. Previous studies have shown the advantages of quantum algorithms on artificially generated datasets, and initial experiments with small binary classification problems have yielded comparable outcomes to classical algorithms. However, it is essential to investigate the potential quantum advantage using real-world data. To the best of our knowledge, this study is the first to propose the utilization of quantum systems to classify neuron morphologies, thereby enhancing our understanding of the performance of automatic multiclass neuron classification using quantum kernel methods. We examined the influence of feature engineering on classification accuracy and found that quantum kernel methods achieved similar performance to classical methods, with certain advantages observed in various configurations.

Shaping reversibility? Long-term deep brain stimulation in dystonia: the relationship between effects on electrophysiology and clinical symptoms.

Long-term results show that benefits from chronic deep brain stimulation in dystonia are maintained for many years. Despite this, the neurophysiological long-term consequences of treatment and their relationship to clinical effects are not well understood. Previous studies have shown that transcranial magnetic stimulation measures of abnormal long-term potentiation-like plasticity (paired associative stimulation) and GABAa-ergic inhibition (short-interval intracortical inhibition), which are seen in dystonia, normalize after several months of deep brain stimulation. In the present study, we examine the same measures in a homogenous group of 10 DYT1 gene-positive patients after long-term deep brain stimulation treatment for at least 4.5 years. Recordings were made 'on' deep brain stimulation and after stopping deep brain stimulation for 2 days. The results show that: (i) on average, prior to discontinuing deep brain stimulation, the paired associative stimulation response was almost absent and short-interval intracortical inhibition was reduced compared with normal. This pattern differs from that in both healthy volunteers and from the typical pattern of enhanced plasticity and reduced inhibition seen in deep brain stimulation-naïve dystonia. It is similar to that seen in untreated Parkinson's disease and may relate to thus far unexplained clinical phenomena like parkinsonian symptoms that have sometimes been observed in patients treated with deep brain stimulation. (ii) Overall, there was no change in average physiological or clinical status when deep brain stimulation was turned off for 2 days, suggesting that deep brain stimulation had produced long-term neural reorganization in the motor system. (iii) However, there was considerable variation between patients. Those who had higher levels of plasticity when deep brain stimulation was 'on', had the best retention of clinical benefit when deep brain stimulation was stopped and vice versa. This may indicate that better plasticity is required for longer term retention of normal movement when deep brain stimulation is off. (iv) Patients with the highest plasticity 'on' deep brain stimulation were those who had been receiving stimulation with the least current drain. This suggests that it might be possible to 'shape' deep brain stimulation of an individual patient to maximize beneficial neurophysiological patterns that have an impact on clinical status. The results are relevant for understanding long-term consequences and management of deep brain stimulation in dystonia.

Long-term follow-up of DYT1 dystonia patients treated by deep brain stimulation: an open-label study.

Long-term efficacy of internal globus pallidus (GPi) deep-brain stimulation (DBS) in DYT1 dystonia and disease progression under DBS was studied. Twenty-six patients of this open-label study were divided into two groups: (A) with single bilateral GPi lead, (B) with a second bilateral GPi lead implanted owning to subsequent worsening of symptomatology. Dystonia was assessed with the Burke Scale. Appearance of new symptoms and distribution according to body region were recorded. In the whole cohort, significant decreases in motor and disability subscores (P < 0.0001) were observed at 1 year and maintained up to 10 years. Group B showed worsening of the symptoms. At 1 year, there were no significant differences between Groups A (without subsequent worsening) and B; at 5 years, a significant difference was found for motor and disability scores. Within Group B, four patients exhibited additional improvement after the second DBS surgery. In the 26 patients, significant difference (P = 0.001) was found between the number of body regions affected by dystonia preoperatively and over the whole follow-up. DBS efficacy in DYT1 dystonia can be maintained up to 10 years (two patients). New symptoms appear with long-term follow-up and may improve with additional leads in a subgroup of patients.

A target-specific electrode and lead design for internal globus pallidus deep brain stimulation.

In nearly all deep brain stimulation (DBS) applications, the same quadripolar electrode design is used for different anatomical targets even if shape and volume differences exist between nuclei. Taking into account the electrode location within the internal globus pallidus (GPi) and the size of the GPi, 2 electrodes were designed in order to improve the therapeutic benefit, to minimize side effects from DBS and to obtain a more homogeneous electric field distribution. The electrodes were evaluated numerically by using a stereotactic model measuring the correlation between the electric field and the GPi. The model was applied to 26 dystonodyskinetic patients who underwent surgery for a bilateral lead implantation into the posteroventral part of the GPi. The designed electrodes produced a more homogeneous distribution of the electric field than the quadripolar electrode.

Factors predicting improvement in primary generalized dystonia treated by pallidal deep brain stimulation.

Despite the beneficial effects of Globus Pallidus internus (GPi) deep brain stimulation (DBS) in patients with primary generalized dystonia (PGD), the degree of improvement varies from one patient to another. The objective of this study was to examine the effects of clinical, anatomical (volume of the GPi), and electrical variables on the postoperative Burke-Fahn-Marsden Dystonia rating scale (BFMDRS) motor score to identify which factors may be predictive of the degree of improvement. We reviewed retrospectively the clinical records of 40 steady-state patients with PGD who had been treated by bilateral GPi lead implantation. The follow-up period was 2 to 8 years. The correlation between the electrical parameters (voltage, impedance, and current) and the clinical outcome was studied. An analysis of covariance was performed to identify factors predictive of the magnitude of improvement. The most influential factors according to the model are as follows: the preoperative BFMDRS score (P < 0.0001); age at surgery (P < 0.0001); the right GPi volume (P = 0.002); the left stimulated GPi volume (P = 0.005). No significant correlation was found between the electrical parameters used and the mean motor scores in steady state.

Stereotactic model of the electrical distribution within the internal globus pallidus during deep brain stimulation.

Deep brain stimulation (DBS) of the internal globus pallidus (GPi) is an established surgical technique for the treatment of movement disorders. The objective of this study was to propose a computational stereotactic model of the electrical distribution around the electrode within the targeted GPi in order to optimize parameter adjustment in clinical practice. The outline of the GPi can be defined precisely by using stereotactic magnetic resonance imaging (MRI) and from this it is possible to model its three-dimensional structure. The electrode and the distribution of the patient-specific parameters can then be co-registered with the GPi volume. By using this methodology, it is possible to visualize and measure the relationship between the electrical distribution of patient-specific parameters and the morphology of the GPi. The model could be applied in clinical practice to help determine the threshold for achieving a therapeutic effect and consequently may aid in optimizing parameter settings for individual patients.

Prognostic value of globus pallidus internus volume in primary dystonia treated by deep brain stimulation.

OBJECT: Given that improvement is variable from one patient to another, the authors analyzed the impact of globus pallidus internus (GPi) volume on the result of deep brain stimulation (DBS) by comparing highly and less improved patients with primary dystonodyskinetic syndromes. METHODS: A stereotactic model was developed to visualize and quantify the relationship between the isofield lines generated by the DBS lead and GPi target. The model was used in 30 right-handed selected patients with primary dystonodyskinetic syndromes who had been treated using bilateral stimulation of the sensorimotor GPi. Ten healthy control individuals were also included in the study. First, the authors compared the GPi volumes between patients and healthy controls. Second, the stimulated GPi volumes, that is, the intersection between the volume of each isofield value and the GPi volumes, were compared between less improved and highly improved patients. RESULTS: Improvement in the Burke-Fahn-Marsden Dystonia Rating Scale's motor score was rated > 90% in 20 patients (97 +/- 4.6%) and < 60% in 10 patients (56.9 +/- 6%). The mean volume of the right (461.8 +/- 81.8 mm(3)) and left (406.6 +/- 113.2 mm(3)) GPi in patients showing less response to DBS was significantly smaller than the GPi volume of patients who responded well (right 539.9 +/- 86.6 mm(3), left 510.6 +/- 88.7 mm(3)) and healthy controls (right 557.8 +/- 109.1 mm(3), left 525.1 +/- 40.8 mm(3)). CONCLUSIONS: On the left side, the mean stimulated volumes (isofield line range 0.2-1 V/mm) were significantly larger in highly improved than in less improved patients. In this model, the threshold for functional effect was calculated at 0.2 V/mm.

Morphological Neuron Classification Using Machine Learning.

Classification and quantitative characterization of neuronal morphologies from histological neuronal reconstruction is challenging since it is still unclear how to delineate a neuronal cell class and which are the best features to define them by. The morphological neuron characterization represents a primary source to address anatomical comparisons, morphometric analysis of cells, or brain modeling. The objectives of this paper are (i) to develop and integrate a pipeline that goes from morphological feature extraction to classification and (ii) to assess and compare the accuracy of machine learning algorithms to classify neuron morphologies. The algorithms were trained on 430 digitally reconstructed neurons subjectively classified into layers and/or m-types using young and/or adult development state population of the somatosensory cortex in rats. For supervised algorithms, linear discriminant analysis provided better classification results in comparison with others. For unsupervised algorithms, the affinity propagation and the Ward algorithms provided slightly better results.

Automatic target validation based on neuroscientific literature mining for tractography.

Target identification for tractography studies requires solid anatomical knowledge validated by an extensive literature review across species for each seed structure to be studied. Manual literature review to identify targets for a given seed region is tedious and potentially subjective. Therefore, complementary approaches would be useful. We propose to use text-mining models to automatically suggest potential targets from the neuroscientific literature, full-text articles and abstracts, so that they can be used for anatomical connection studies and more specifically for tractography. We applied text-mining models to three structures: two well-studied structures, since validated deep brain stimulation targets, the internal globus pallidus and the subthalamic nucleus and, the nucleus accumbens, an exploratory target for treating psychiatric disorders. We performed a systematic review of the literature to document the projections of the three selected structures and compared it with the targets proposed by text-mining models, both in rat and primate (including human). We ran probabilistic tractography on the nucleus accumbens and compared the output with the results of the text-mining models and literature review. Overall, text-mining the literature could find three times as many targets as two man-weeks of curation could. The overall efficiency of the text-mining against literature review in our study was 98% recall (at 36% precision), meaning that over all the targets for the three selected seeds, only one target has been missed by text-mining. We demonstrate that connectivity for a structure of interest can be extracted from a very large amount of publications and abstracts. We believe this tool will be useful in helping the neuroscience community to facilitate connectivity studies of particular brain regions. The text mining tools used for the study are part of the HBP Neuroinformatics Platform, publicly available at http://connectivity-brainer.rhcloud.com/.

Longterm deep brain stimulation withdrawal: clinical stability despite electrophysiological instability.

Deep brain stimulation (DBS) is a powerful treatment option for movement disorders, including severe generalised dystonia. After several years of treatment, cases have been reported in which DBS has been stopped without any deterioration in clinical benefit. This might indicate that DBS can restore function in some cases. The mechanism of DBS induced clinical retention effects has been addressed before. Here, the question we asked was if such clinical stability is reflected at the underlying physiology level or whether there is indication to believe that a stand-still of symptoms might be at risk because of neurophysiological instability. We recorded patients with pre-intervention life-threatening or severe genetic dystonia with long lasting clinical benefit when turned off DBS. Despite clinical stability, our physiological studies revealed large changes in the excitability of excitatory and inhibitory motor circuits in the cortex, which exceed normal fluctuation. This discrepancy between instability in the motor network physiology caused by removal of DBS and clinical stability alerts as it potentially indicates a risk to fail and cause symptoms to return.

The influence of deep brain stimulation intensity and duration on symptoms evolution in an OFF stimulation dystonia study.

BACKGROUND: Deep brain stimulation (DBS) of the internal globus pallidus (GPi) is an established therapy for primary generalized dystonia. However, the evolution of dystonia symptoms after DBS discontinuation after years of therapy has only rarely been reported. We therefore longitudinally studied the main physiological measurements known to be impaired in dystonia, with DBS ON and then again after termination of DBS, after at least five years of continuous DBS. OBJECTIVE: We studied whether dystonia evolution after DBS discontinuation in patients benefiting from long-term GPi DBS is different from that observed in earlier stages of the therapy. METHODS: In eleven DYT1 patients treated with bilateral GPi DBS for at least 5 years, dystonia was assessed ON-DBS, immediately after switch-off (OFF-DBS1) and 48 h after DBS termination (OFF-DBS2). We studied the influence of DBS intensity on dystonia when DBS was discontinued. RESULTS: On average a significant difference in symptoms was measured only between ON-DBS and OFF-DBS1 conditions. Importantly, none of the patients returned to their preoperative dystonia severity, even 48 h after discontinuation. The amount of clinical deterioration in the OFF conditions positively correlated with higher stimulation current in the chronic ON-DBS condition. CONCLUSIONS: The duration of DBS application influences symptom evolution after DBS termination. DBS intensity seems to have a prominent role on evolution of dystonic symptoms when DBS is discontinued. In conclusion, DBS induces changing modulation of the motor network with less worsening of symptoms after long term stimulation, when DBS is stopped.

Staged implantation of multiple electrodes in the internal globus pallidus in the treatment of primary generalized dystonia.

OBJECT: Deep brain stimulation (DBS) is used for treating various types of dystonia. Multiple electrodes could be proposed to improve the therapeutic outcome enabling the targeting of specific neuronal populations not reached by the electrical field generated by the initially implanted electrode. The authors address the question of the feasibility and safety of staged multiple lead implantations in the sensorimotor internal globus pallidus (GPi) in primary generalized dystonia (PGD). Criteria for patient selection, surgical technique, target selection, electrical settings management, and clinical outcome are presented. METHODS: Sixteen patients (8 harbored the DYT1 gene mutation) presented with PGD and were enrolled in this study. Patients underwent clinical assessment using the Burke-Fahn-Marsden Dystonia Rating Scale preoperatively and during follow-up with DBS. Prior to the addition of electrodes, the authors confirmed, by turning off stimulation, that the patient was still benefiting from DBS and that DBS settings adjustment did not provide further improvement. The second target was defined according to the position of the first electrode, to the residual volume within the sensorimotor GPi, and according to residual symptoms. The second surgery followed the same protocol as the first and the new electrode were inserted using the same bur hole as the first electrode. RESULTS: The addition of a new pair of electrodes was followed by significant improvement in the whole population (p = 0.005), as well as in the DYT1-negative subgroup (p = 0.012) but not in the DYT1 subgroup (p = not significant). Nevertheless, some patients did not exhibit significant additional benefit. Seven hardware-related complications occurred during the entire follow-up, 3 prior to it, and 4 after the addition of the second pair of electrodes. CONCLUSIONS: The addition of a second pair of electrodes in the GPi in patients with PGD with suboptimal or decaying benefit following the first surgery seems to be a safe procedure and is not followed by an increase in surgery-related complications. This staged procedure may provide further clinical improvement in patients with PGD in whom DBS effect is initially incomplete or when disease progression occurs over time. The position of the additional electrode within the GPi is determined by the available volume within the posteroventral GPi and by the distribution of the dystonic symptoms that need to be controlled.

Magnetic resonance-based deep brain stimulation technique: a series of 478 consecutive implanted electrodes with no perioperative intracerebral hemorrhage.

OBJECTIVE: The aim of this study was to determine the safety of a deep brain stimulation technique consisting of a combination of routine general anesthesia, magnetic resonance imaging direct targeting, and a single penetration technique in a large population of patients undergoing operation for movement disorders. METHODS: One hundred ninety-four patients treated with deep brain stimulation between 1996 and 2007 were assessed via a computerized database for intra- and perioperative events. Most patients were young; only 62 of them were older than 40 years (mean age, 31.1 years). General anesthesia was induced in all cases before placement of a magnetic resonance imaging-compatible stereotactic frame. Electrode implantation was done under radioscopic control via a rigid immobile cannula using a single cerebral perforation. No perioperative microelectrode recording or neurostimulation testing was used. Systematic postoperative magnetic resonance imaging was performed before frame removal. RESULTS: A total of 478 electrodes were implanted in 220 procedures: 426 for dystonic-dyskinetic syndromes and 52 for Parkinson disease. The mean number of parenchymal penetrations per patient was 2.5 for the dystonic-dyskinetic syndrome group and 2.08 for the Parkinson disease group. Postimplantation magnetic resonance imaging detected no perioperative intraparenchymal hemorrhages. CONCLUSION: We consider that the risk of hemorrhagic complication is multifactorial but closely related to the chosen technique.

Antero-ventral internal pallidum stimulation improves behavioral disorders in Lesch-Nyhan disease.

The Lesch-Nyhan syndrome is an X-linked recessive disorder caused by a deficiency in hypoxanthine-guanine phosphoribosyl transferase, a purine salvage enzyme. Affected individuals exhibit a characteristic neurobehavioral disorder with delayed acquisition of motor skills, dystonia, severe self-mutilations, and aggressive behavior. Deep brain stimulation has been previously proposed for controlling isolated involuntary movements and psychiatric disorders. We applied a double bilateral simultaneous stimulation to limbic and motor internal pallidum in one patient for controlling both behavioral and movement disorders, respectively. The injurious compulsions disappeared; dystonia and dyskinesia were decreased at 28 months follow-up.