Mgr. Tomáš Sieger, Ph.D.

Objective: Pathophysiology explanations for functional movement disorders often assume a role for emotional hyperarousal. Pupillometry is a validated method for evaluation of emotional arousal by detecting changes in pupil size in response to emotional stimuli. In a case-control study design, we aimed to study objective and subjective emotional arousal using pupillometry and affective ratings. To assess attentional engagement by affective stimuli, we used videooculographic tracking of eye movement patterns (scanpath). Methods: Twenty-five female patients with functional movement disorders (mean age: 40.9 [SD 12.7] years) and 23 age matched healthy female controls participated in the study. Using infrared high-resolution eye-tracker, both pupil size and eye movement pattern in response to emotionally charged erotic, adventure, threat, victim, and neutral pictures were recorded along with subjective ratings of emotional valence and arousal of the presented pictures. Results: A between-group comparison showed significantly smaller pupil dilation to adventure stimuli compared to neutral stimuli in patients compared to controls (P < 0.004, bootstrap, uncorr., adj. η2 = 0.00). No significant difference in pupillary response to other stimuli and scanpath parameters was found between the groups. Patients rated significantly lower emotional arousal to erotic pictures than controls (P < 0.001, bootstrap, uncorr., adj. η2 = 0.09). Conclusion: This study did not find evidence of autonomous or subjective emotional hyperarousal. The mismatch between objective autonomic measures and subjective arousal ratings in patients is of pathophysiological interest and in line with recent findings of impaired interoception in functional movement disorders.

Background: Abnormal findings at brain MRI in patients with neurologic Wilson disease (WD) are characterized by signal intensity changes and cerebral atrophy. T2 signal hypointensities and atrophy are largely irreversible with treatment; their relationship with permanent disability has not been systematically investigated. Purpose: To investigate associations of regional brain atrophy and iron accumulation at MRI with clinical severity in participants with neurologic WD who are undergoing long-term anti-copper treatment. Materials and Methods: Participants with WD and controls were compared in a prospective study performed from 2015 to 2019. MRI at 3.0 T included three-dimensional T1-weighted and six-echo multigradient-echo pulse sequences for morphometry and quantitative susceptibility mapping, respectively. Neurologic severity was assessed with the Unified WD Rating Scale (UWDRS). [...] Results: Twenty-nine participants with WD and 26 controls were evaluated. Whole-brain analysis demonstrated atrophy of the deep gray matter nuclei, brainstem, internal capsule, motor cortex and corticospinal pathway, and visual cortex and optic radiation in participants with WD (P < .05 at voxel level, corrected for family-wise error). The UWDRS score was negatively correlated with volumes of putamen, red nucleus, globus pallidus, and substantia nigra but not with susceptibilities. Only the putaminal volume was identified as a stable factor associated with the UWDRS score using least absolute shrinkage and selection operator regression. Conclusion: Individuals with Wilson disease (WD) had widespread brain atrophy most pronounced in the central structures. The putaminal volume was associated with the Unified WD Rating Scale score and can be used as a surrogate imaging marker of clinical severity.

We collected a multi-centric retrospective dataset of patients (N = 213) who were admitted to ten hospitals in Czech Republic and tested positive for SARS-CoV-2 during the early phases of the pandemic in March—October 2020. The dataset contains baseline patient characteristics, breathing support required, pharmacological treatment received and multiple markers on daily resolution. Patients in the dataset were treated with hydroxychloroquine (N = 108), azithromycin (N = 72), favipiravir (N = 9), convalescent plasma (N = 7), dexamethasone (N = 4) and remdesivir (N = 3), often in combination. To explore association between treatments and patient outcomes we performed multiverse analysis, observing how the conclusions change between defensible choices of statistical model, predictors included in the model and other analytical degrees of freedom. Weak evidence to constrain the potential efficacy of azithromycin and favipiravir can be extracted from the data. Additionally, we performed external validation of several proposed prognostic models for Covid-19 severity showing that they mostly perform unsatisfactorily on our dataset.

Hierarchical clustering is a common tool for simplifica- tion, exploration, and analysis of datasets in many areas of research. For data originating in flow cytometry, a specific variant of agglom- erative clustering based Mahalanobis-average linkage has been shown to produce results better than the common linkages. However, the high complexity of computing the distance limits the applicability of the algorithm to datasets obtained from current equipment. We pro- pose an optimized, GPU-accelerated open-source implementation of the Mahalanobis-average hierarchical clustering that improves the algorithm performance by over two orders of magnitude, thus allowing it to scale to the large datasets. We provide a detailed analysis of the optimiza- tions and collected experimental results that are also portable to other hierarchical clustering algorithms; and demonstrate the use on realistic high-dimensional datasets.

The nuclear pore complex (NPC) has emerged as a hub for the transcriptional regulation of a subset of genes, and this type of regulation plays an important role during differentiation. Nucleoporin TPR forms the nuclear basket of the NPC and is crucial for the enrichment of open chromatin around NPCs. TPR has been implicated in the regulation of transcription; however, the role of TPR in gene expression and cell differentiation has not been described. Here we show that depletion of TPR results in an aberrant morphology of murine proliferating C2C12 myoblasts (MBs) and differentiated C2C12 myotubes (MTs). The ChIP-Seq data revealed that TPR binds to genes linked to muscle formation and function, such as myosin heavy chain (Myh4), myocyte enhancer factor 2C (Mef2C) and a majority of olfactory receptor (Olfr) genes. We further show that TPR, possibly via lysine-specific demethylase 1 (LSD1), promotes the expression of Myh4 and Olfr376, but not Mef2C. This provides a novel insight into the mechanism of myogenesis; however, more evidence is needed to fully elucidate the mechanism by which TPR affects specific myogenic genes.

The study analyzes changes in lung function, pulmonary pressure and diffusing capacity of the lung in patients with mitral valve regurgitation (MR) treated by MitraClip implantation. A total of 43 patients (19 women and 24 men with an average age of 78.0 ± 6.6 years) who were able to perform pulmonary function testing including diffusing capacity of the lung for carbon monoxide (DLCO), vital capacity (VC), total lung capacity (TLC), residual volume (RV) and forced expiratory volume in 1 s (FEV1) before and 6 weeks after MitraClip implantation participated in this study. Furthermore, clinical and echocardiographic parameters including systolic pulmonary artery pressure (sPAP), left ventricular ejection fraction (LVEF) and left atrial diameter (LAD) measurements were recorded in all patients. The procedure was performed successfully in all 43 patients leading to a reduction of MR in 97.7% of cases. One patient died on day 4 after the intervention most likely due to pulmonary artery embolism. Six weeks after the implantation 79.1% of patients showed a MR of at most mild to moderate. Furthermore, we could demonstrate a significant reduction of systolic pulmonary artery pressure during follow-up (from 48.8 ± 11.4 mmHg to 42.9 ± 9.0 mmHg (t(41) = − 2.6, p = 0.01). However, no changes in LVEF were detected. Comparing pre and post implant lung function tests, no significant alterations were seen for VC, TLC, DLCO and FEV1. Though, in a subgroup of patients with moderate to severe preexisting deterioration of DLCO at the baseline (max. 50%) the MitraClip procedure resulted in a significant improvement in DLCO (37.8% ± 9.0 to 41.6% ± 10.0, p < 0.001). Treatment of MR with the MitraClip system successfully reduces MR severity in the vast majority of patients. Consecutively, a reduction in pulmonary pressure could be observed, however no changes in LVEF were obvious. Lung function tests remained unaltered during follow-up. [...]

Summary ShinySOM offers a user-friendly interface for reproducible, high-throughput analysis of high-dimensional flow and mass cytometry data guided by self-organizing maps. The software implements a FlowSOM-style workflow, with improvements in performance, visualizations and data dissection possibilities. The outputs of the analysis include precise statistical information about the dissected samples, and R-compatible metadata useful for the batch processing of large sample volumes. Availability and implementation ShinySOM is free and open-source, available online at gitlab.com/exaexa/ShinySOM.

The deep brain stimulation (DBS) is a treatment technique for late-stage Parkinson’s disease (PD), based on chronic electrical stimulation of neural tissue through implanted electrodes. To achieve high level of symptom suppression with low side effects, precise electrode placement is necessary, although difficult due to small size of the target nucleus and various sources of inaccuracy, especially brain shift and electrode bending. To increase accuracy of electrode placement, electrophysiological recording using several parallel microelectrodes (MER) is used intraoperatively in most centers. Location of the target nucleus is identified from manual expert evaluation of characteristic neuronal activity. Existing studies have presented several models to classify individual recordings or trajectories automatically. In this study, we extend this approach by fitting a 3D anatomical atlas to the recorded electrophysiological activity, thus adding topological information. Methods: We developed a probabilistic model of neuronal activity in the vicinity the subthalamic nucleus (STN), based on normalized signal energy. The model is used to find a maximum-likelihood transformation of an anatomical surface-based atlas to the recorded activity. The resulting atlas fit is compared to atlas position estimated from pre-operative MRI scans. Accuracy of STN classification is then evaluated in a leave-one-subject-out scenario using expert MER annotation. Results: In an evaluation on a set of 27 multi-electrode trajectories from 15 PD patients, the proposed method showed higher accuracy in STN-nonSTN classification (88.1%) compared to the reference methods (78.7%) with an even more pronounced advantage in sensitivity (69.0% vs 44.6%). Conclusion: The proposed method allows electrophysiology-based refinement of atlas position of the STN and represents a promising direction in refining accuracy of MER localization in clinical DBS setting, as well as in research of DBS mechanisms.

Abnormalities of eye movements have been reported in patients with Parkinson's disease (PD). However, it is unclear if they occur in the prodromal stage of synucleinopathy represented by idiopathic rapid eye movement sleep behaviour disorder (iRBD). We thus aimed to study eye movements in subjects with iRBD and in de novo PD, to assess if their abnormalities may serve as a clinical biomarker of neurodegeneration. Fifty subjects with polysomnography-confirmed iRBD (46 male, age 40-79 years), 18 newly diagnosed, untreated PD patients (13 male, age 43-75 years) and 25 healthy controls (20 male, age 42-79 years) were prospectively enrolled. Horizontal and vertical ocular prosaccades and antisaccades were investigated with video-oculography. All patients completed the MDS-UPDRS and the Montreal Cognitive Assessment. In addition, a neuropsychological battery was performed on iRBD subjects. When compared with healthy controls, both de novo PD patients and iRBD subjects showed increased error rates in the horizontal antisaccade task (p < 0.01, p < 0.05 respectively). In the iRBD group, the error rates in horizontal and vertical antisaccades correlated with performances in the Prague Stroop Test and the Grooved Pegboard Test, as well as with motor scores of the MDS-UPDRS. De novo PD patients showed a lower gain (p < 0.01) compared with controls. In conclusion, the increased error rate in the antisaccade task of iRBD and PD patients reflects a dysfunction of the dorsolateral prefrontal cortex and is related to the impairment of executive functions and attention.

The organization of the nuclear periphery is crucial for many nuclear functions. Nuclear lamins form dense network at the nuclear periphery and play a substantial role in chromatin organization, transcription regulation and in organization of nuclear pore complexes (NPCs). Here, we show that TPR, the protein located preferentially within the nuclear baskets of NPCs, associates with lamin B1. The depletion of TPR affects the organization of lamin B1 but not lamin A/C within the nuclear lamina as shown by stimulated emission depletion microscopy. Finally, reduction of TPR affects the distribution of NPCs within the nuclear envelope and the effect can be reversed by simultaneous knock-down of lamin A/C or the overexpression of lamin B1. Our work suggests a novel role for the TPR at the nuclear periphery: the TPR contributes to the organization of the nuclear lamina and in cooperation with lamins guards the interphase assembly of nuclear pore complexes.

Background Patients with functional movement disorders also typically have functional somatic symptoms, including pain, fatigue, and sensory disturbance. A potentially unifying mechanism for such symptoms is a failure in processing of sensory inputs. Prepulse inhibition is a neurophysiological method that allows for the study of preconscious somatosensory processing. Objective The objective of this study was to assess prepulse inhibition in patients with functional movement disorders and healthy control subjects. Methods We analyzed the effect of a weak electrical stimulus to the index finger (prepulse) on the magnitude of the R2 response of the blink reflex induced by electrical stimuli delivered to the supraorbital nerve in 22 patients with clinically established functional movement disorders and 22 matched controls. Pain, depression, anxiety, and obsessive‐compulsive symptoms were assessed using self‐rated questionnaires. In addition, in patients we assessed motor symptom severity. Results Prepulses suppressed the R2 response of the blink reflex in both groups, by 36.4% (standard deviation: 25.6) in patients and by 67.3% (standard deviation: 16.4) in controls. This difference was significant (P < 0.001). There was no significant correlation between motor and nonmotor symptom measures and prepulse inhibition size. Conclusions Impaired prepulse inhibition of the blink reflex suggests an abnormal preconscious processing of somatosensory inputs, which can be interpreted within predictive coding accounts of both functional movement disorders and functional somatic syndromes. Our results, along with previous findings of a reduced prepulse inhibition in fibromyalgia syndrome, support a possible unified pathophysiology across functional neurological and somatic syndromes with noteworthy implications for diagnostic classification and development of novel biomarkers and treatments.

Clinical motor and non-motor effects of deep brain stimulation (DBS) of the subthalamic nucleus (STN) in Parkinson's disease (PD) seem to depend on the stimulation site within the STN. We analysed the effects of the position of the stimulation electrode within the motor STN on subjective emotional experience, expressed as emotional valence and arousal ratings to pictures representing primary rewards and aversive fearful stimuli in 20 PD patients. Patients’ ratings from both aversive and erotic stimuli matched the mean ratings from a group of 20 control subjects at similar position within the STN. Patients with electrodes located more posteriorly reported both valence and arousal ratings from both the rewarding and aversive pictures as more extreme. Moreover, posterior electrode positions were associated with a higher occurrence of depression at a long-term follow-up. This brain–behavior relationship suggests a complex emotion topography in the motor part of the STN. Both valence and arousal representations overlapped and were uniformly arranged anterior-posteriorly in a gradient-like manner, suggesting a specific spatial organization needed for the coding of the motivational salience of the stimuli. This finding is relevant for our understanding of neuropsychiatric side effects in STN DBS and potentially for optimal electrode placement.

The deep brain stimulation (DBS) is a symptomatic treatment technique used mainly for movement disorders, consisting of chronic electrical stimulation of subcortical structures. To achieve very precise electrode implantation, which is necessary for a good clinical outcome, many surgical teams use electrophysiological recording around the assumed target, planned in pre-operative MRI images. In our previous work, we developed a probabilistic model to fit a 3D anatomical atlas of the subthalamic nucleus to the recorded microelectrode activity in Parkinson’s disease (PD) patients. In this paper, we extend the model to incorporate characteristic landmarks of the target nucleus, manually annotated in pre-operative MRI data. We validate the approach on a set of 27 exploration five-electrode trajectories from 15 PD patients. The results show that such combined approach may lead to a vast improvement in optimization reliability, while maintaining good fit to the electrophysiology data. The combination of electrophysiology and MRI-based data thus provides a promising approach for compensating brain shift, occuring during the surgery and achieving accurate localization of recording sites in DBS surgery.

Background: Detailed study of the period before schizophrenic relapse when early warning signs (EWS) are present is crucial to effective pre-emptive strategies. Aims: To investigate the temporal properties of EWS self-reported weekly via a telemedicine system. Method: EWS history was obtained for 61 relapses resulting in hospitalization involving 51 patients with schizophrenia. Up to 20 weeks of EWS history per case were evaluated using a non-parametric bootstrap test and generalized mixed-effects model to test the significance and homogeneity of the findings. Results: A statistically significant increase in EWS sum score was detectable 5 weeks before hospitalization. However, analysis of EWS dynamics revealed a gradual, monotonic increase in EWS score across during the 8 weeks before a relapse. Conclusions: The findings-in contrast to earlier studies-suggest that relapse is preceded by a lengthy period during which pathophysiological processes unfold; these changes are reflected in subjective EWS.

Nuclear periphery (NP) plays substantial role in chromatin organization. Heterochromatin at the NP is intermitted with active chromatin surrounding nuclear pore complexes (NPCs), however, details of the peripheral chromatin organization are missing. To discern the distributions of epigenetic marks at the NP of HeLa nuclei, we used structured illumination microscopy combined with a new MATLAB software tool for an automatic NP and NPC detection, measurements of fluorescent intensity and statistical analysis of measured data. Our results show that marks for both active and non-active chromatin associate differentially with NPCs. The incidence of heterochromatin marks such as H3K27me2 and H3K9me2 was significantly lower around NPCs. In contrast, the presence of marks of active chromatin H4K5Ac and H3K4me2 was only little decreased around the NPCs or not at all (H3K9Ac). Interestingly, histone demethylases LSD1 and KDM2a were enriched within the NPCs suggesting the presence of chromatin modifying mechanism at the NPCs. Inhibition of transcription resulted in larger drop in the distribution of H1, H3K9me2 and H3K23me2 which implies the role of transcription in the organization of heterochromatin at the NP.

Disturbances of the gamma-aminobutyric-acid (GABA) system have been suspected of contributing to the pathophysiology of progressive supranuclear palsy (PSP). The ability to rapidly resolve competitive action decisions, such as shifting the gaze to one particular stimulus rather than another, can be predicted by the concentration of GABA in the region of the frontal cortex relevant to eye movements. For this reason, our study measured GABA levels in seven PSP patients and eight healthy controls, using proton magnetic resonance spectroscopy, and assessed the relationship of these measurements to the remote distractor effect (RDE), an eye-movement paradigm investigating competitive action decisions. No significant differences were found in either frontal-eye-field GABA levels or RDE between Distraction PSP patients and controls.

Hierarchical cluster analysis is a valuable tool for exploring data by describing their structure using a dendrogram. However, proper visualization and interactive inspection of the dendrogram are needed to unlock the information in the data. We describe a new R package, idendro, that enables the user to inspect dendrograms interactively: to select and color clusters, to zoom and pan the dendrogram, and to visualize the clustered data not only in a built-in heat map, but also in any interactive plot implemented in the cranvas package. A lightweight version idendr0 with reduced dependencies is also available from the Comprehensive R Archive Network.

BACKGROUND: Extracellular microelectrode recording (MER) is a prominent technique for studies of extracellular single-unit neuronal activity. In order to achieve robust results in more complex analysis pipelines, it is necessary to have high quality input data with a low amount of artifacts. We show that noise (mainly electromagnetic interference and motion artifacts) may affect more than 25% of the recording length in a clinical MER database. NEW METHOD: We present several methods for automatic detection of noise in MER signals, based on (i) unsupervised detection of stationary segments, (ii) large peaks in the power spectral density, and (iii) a classifier based on multiple time- and frequency-domain features. We evaluate the proposed methods on a manually annotated database of 5735 ten-second MER signals from 58 Parkinson's disease patients. COMPARISON WITH EXISTING METHODS: The existing methods for artifact detection in single-channel MER that have been rigorously tested, are based on unsupervised change-point detection. We show on an extensive real MER database that the presented techniques are better suited for the task of artifact identification and achieve much better results. RESULTS: The best-performing classifiers (bagging and decision tree) achieved artifact classification accuracy of up to 89% on an unseen test set and outperformed the unsupervised techniques by 5–10%. This was close to the level of agreement among raters using manual annotation (93.5%). CONCLUSION: We conclude that the proposed methods are suitable for automatic MER denoising and may help in the efficient elimination of undesirable signal artifacts.

Background: Convergence spasm was reported as a common eye movement (EM) abnormality in patients with functional movement disorders (FMD). We aimed to analyze horizontal reflexive, volitional and vergence EM in FMD using video-oculography (VOG). Methods: Twenty patients with FMD and 20 matched controls underwent VOG with tasks for prosaccades, antisaccades and vergence. Mean latency and velocities were analyzed in prosaccades and vergence. In antisaccades, error rate was evaluated. Results: Clinically manifested convergence spasm was found only in two patients, however, FMD patients showed prolonged latencies in divergence EM. Higher error rate in the antisaccade task and no differences in prosaccades in comparison to controls were found. Conclusions: Subclinical abnormalities in vergence EM along with normal reflexive EM are suggestive of explicit EM control failure in FMD. Consistently with current hypothesis of attention and response inhibition disorders in FMD, we found an increased error rate in antisaccades in FMD.

We present a probabilistic model for classification of micro- EEG signals, recorded during deep brain stimulation surgery for Parkinson’s disease. The model uses parametric representation of neuronal background activity, estimated using normalized root-mean-square of the signal. Contrary to existing solutions using Bayes classifiers or Hidden Markov Models, our model uses smooth state-transitions represented by sigmoid functions, which ensures flexible model structure in combination with general optimizers for parameter estimation and model fitting. The presented model can easily be extended with additional parameters and constraints and is intended for fitting of a 3D anatomical model to micro-EEG data in further perspective. In an evaluation on 260 trajectories from 61 patients, the model showed classification accuracy 90.0%, which was comparable to existing solutions. The evaluation proved the model successful in target identification and we conclude that its use for more complex tasks in the area of DBS planning and modeling is feasible.

Both animal studies and studies using deep brain stimulation in humans have demonstrated the involvement of the subthalamic nucleus (STN) in motivational and emotional processes; however, participation of this nucleus in processing human emotion has not been investigated directly at the single-neuron level. We analyzed the relationship between the neuronal firing from intraoperative microrecordings from the STN during affective picture presentation in patients with Parkinsons disease (PD) and the affective ratings of emotional valence and arousal performed subsequently. We observed that 17% of neurons responded to emotional valence and arousal of visual stimuli according to individual ratings. The activity of some neurons was related to emotional valence, whereas different neurons responded to arousal. In addition, 14% of neurons responded to visual stimuli. Our results suggest the existence of neurons involved in processing or transmission of visual and emotional information in the human STN, and provide evidence of separate processing of the affective dimensions of valence and arousal at the level of single neurons as well.

Introduction Historical nomograms for the prediction of cancer on prostate biopsy, developed in the sex- tant biopsy era are no more accurate today. The aim of this study was an independent external validation of a 10-core biopsy nomogram by Chun et al. (2007). Material and methods A total of 322 patients who presented for their initial biopsy in a tertiary care center and had all the necessary data available were included in the retrospective analysis. To validate the nomogram, receiver operator characteristic (ROC) curves and calibration plots were constructed. Results Area under the ROC curve calculated for our data using the nomogram was 0.773, similar to that reported originally. However, the nomogram systematically overestimated prostate cancer risk, which, for our data, could be resolved by subtracting 24 points from the total number of points of the nomogram. Conclusions The nomogram yielded overall good predictive accuracy as measured by the area under the ROC curve, but it systematically overestimated PC probability in individual patients. However, we showed how the nomogram could easily be adapted to our patient sample, resolving the bias issue.

Introduction Historical nomograms for the prediction of cancer on prostate biopsy, developed in the sex- tant biopsy era are no more accurate today. The aim of this study was an independent external validation of a 10-core biopsy nomogram by Chun et al. (2007). Material and methods A total of 322 patients who presented for their initial biopsy in a tertiary care center and had all the necessary data available were included in the retrospective analysis. To validate the nomogram, receiver operator characteristic (ROC) curves and calibration plots were constructed. Results Area under the ROC curve calculated for our data using the nomogram was 0.773, similar to that reported originally. However, the nomogram systematically overestimated prostate cancer risk, which, for our data, could be resolved by subtracting 24 points from the total number of points of the nomogram. Conclusions The nomogram yielded overall good predictive accuracy as measured by the area under the ROC curve, but it systematically overestimated PC probability in individual patients. However, we showed how the nomogram could easily be adapted to our patient sample, resolving the bias issue.

Background: Blurred near vision is a common non-motor symptom in patients with Parkinson's disease (PD), however detailed characterization of vergence eye movements (VEM) is lacking. Methods: Convergence and divergence were examined in 18 patients with PD and 18 control subjects using infrared video-oculography. VEM metrics analyzed included latency, velocity and accuracy, in vertical and horizontal planes. Results: The latency of convergence and divergence was significantly increased in PD subjects. Additionally, divergence was slow and hypometric, while other convergence metrics were similar to controls. Conclusion: We provide evidence in favor of disrupted VEM in PD.

Background Falls are a common complication of advancing Parkinson's disease (PD). Although numer- ous risk factors are known, reliable predictors of future falls are still lacking. The objective of this prospective study was to investigate clinical and instrumented tests of balance and gait in both OFF and ON medication states and to verify their utility in the prediction of future falls in PD patients. Methods Forty-five patients with idiopathic PD were examined in defined OFF and ON medication states within one examination day including PD-specific clinical tests, instrumented Timed Up and Go test (iTUG) and computerized dynamic posturography. The same gait and bal- ance tests were performed in 22 control subjects of comparable age and sex. Participants were then followed-up for 6 months using monthly fall diaries and phone calls. Results During the follow-up period, 27/45 PD patients and 4/22 control subjects fell one or more times. Previous falls, fear of falling, more severe motor impairment in the OFF state, higher PD stage, more pronounced depressive symptoms, higher daily levodopa dose and stride time variability in the OFF state were significant risk factors for future falls in PD patients. Increased stride time variability in the OFF state in combination with faster walking cadence appears to be the most significant predictor of future falls, superior to clinical predictors. Conclusion Incorporating instrumented gait measures into the baseline assessment battery as well as accounting for both OFF and ON medication states might improve future fall prediction in PD patients. However, instrumented testing in the OFF state is not routinely performed in clinical practice and has not been used in the development of fall prevention programs in PD. New assessment methods for daylong monitoring of gait, balance and falls are thus required to more effectively address the risk of falling in PD patients.

Appropriate detection of clean signal segments in extracellular microelectrode recordings (MER) is vital for maintaining high signal-to-noise ratio in MER studies. Existing alternatives to manual signal inspection are based on unsupervised change-point detection. We present a method of supervised MER artifact classification, based on power spectral density (PSD) and evaluate its performance on a database of 95 labelled MER signals. The proposed method yielded test-set accuracy of 90%, which was close to the accuracy of annotation (94%). The unsupervised methods achieved accuracy of about 77% on both training and testing data.

Patients with ephedrone parkinsonism (EP) show a complex, rapidly progressive, irreversible, and levodopa non-responsive parkinsonian and dystonic syndrome due to manganese intoxication. Eye movements may help to differentiate parkinsonian syndromes providing insights into which brain networks are affected in the underlying disease, but they have never been systematically studied in EP. Horizontal and vertical eye movements were recorded in 28 EP and compared to 21 Parkinson's disease (PD) patients, and 27 age- and gender-matched healthy subjects using standardized oculomotor tasks with infrared videooculography. EP patients showed slow and hypometric horizontal saccades, an increased occurrence of square wave jerks, long latencies of vertical antisaccades, a high error rate in the horizontal antisaccade task, and made more errors than controls when pro- and antisaccades were mixed. Based on oculomotor performance, a direct differentiation between EP and PD was possible only by the velocity of horizontal saccades. All remaining metrics were similar between both patient groups. EP patients present extensive oculomotor disturbances probably due to manganese-induced damage to the basal ganglia, reflecting their role in oculomotor system.

The oculomotor role of the basal ganglia has been supported by extensive evidence, although their role in scanning eye movements is poorly understood. Nineteen Parkinsońs disease patients, which underwent implantation of deep brain stimulation electrodes, were investigated with simultaneous intraoperative microelectrode recordings and single channel electrooculography in a scanning eye movement task by viewing a series of colored pictures selected from the International Affective Picture System. Four patients additionally underwent a visually guided saccade task. Microelectrode recordings were analyzed selectively from the subthalamic nucleus, substantia nigra pars reticulata and from the globus pallidus by the WaveClus program which allowed for detection and sorting of individual neurons. The relationship between neuronal firing rate and eye movements was studied by crosscorrelation analysis. Out of 183 neurons that were detected, 130 were found in the subthalamic nucleus, 30 in the substantia nigra and 23 in the globus pallidus. Twenty percent of the neurons in each of these structures showed eye movement-related activity. Neurons related to scanning eye movements were mostly unrelated to the visually guided saccades. We conclude that a relatively large number of basal ganglia neurons are involved in eye motion control. Surprisingly, neurons related to scanning eye movements differed from neurons activated during saccades suggesting functional specialization and segregation of both systems for eye movement control.

Disorders of balance and gait have been observed in patients with essential tremor (ET), but their association with tremor severity remains unclear. This study aimed to evaluate postural instability and gait changes in ET patients and to investigate their relationship to tremor characteristics with regard to cerebellar dysfunction as a possible common pathogenetic mechanism in ET. Thirty ET patients (8F, mean (SD) age 55.8 (17.8), range 19-81 years) and 25 normal controls (7F, 53.0 (17.7), 19-81) were tested with the scales of Activities-specific Balance Confidence (ABC), Fullerton Advanced Balance (FAB), and International Cooperative Ataxia Rating Scale (ICARS). Posturography and gait were assessed using a Footscan® system. Tremor was evaluated by the Fahn-Tolosa-Marin Tremor Rating Scale (TRS) and accelerometry in five upper limb positions. A mean (SD) TRS sum score of 27.0 (13.2) corresponded to mild to moderate tremor severity in most patients. In comparison with controls, ET subjects exhibited lower tandem gait velocity (0.21 vs. 0.26 m/s, P = 0.028), more missteps (0.57 vs. 0.12, P = 0.039), and increased postural sway in tandem stance (sway area 301.1 vs. 202.9 mm(2), P = 0.045). In normal gait, step width increased with the midline tremor subscore of TRS (Pearson r = 0.60, P = 0.046). Moreover, significant correlations were found between age and quantitative measures of normal and tandem gait in ET patients but not in controls. ABC, FAB, and ICARS scores did not significantly differ between patients and controls. In conclusion, gait and balance alterations in ET patients occur even without subjective complaints. Their relationship with midline tremor and dependence on age suggest a connection with cerebellar dysfunction.

Objective: To assist other eye movement investigators in the design and analysis of their studies.Methods: We examined basic saccadic eye movements and smooth pursuit in the horizontal and vertical directions with video-oculography in a group of 145 healthy subjects between 19 and 82 years of age.Results: Gender and education level did not influence eye movement metrics. With age, the latency of leftward and vertical pro- and antisaccades increased (p < 0.001), velocity of upward prosaccades decreased (p < 0.001), gain of rightward and upward prosaccades diminished (p < 0.001), and the error rate of antisaccades increased (p < 0.001). Prosaccades and antisaccades were influenced by the direction of the target, resulting in a right/left and up/down asymmetry. The skewness of the saccade velocity pro-file was stable throughout the lifespan, and within the range of saccades analyzed in the present study, correlated with amplitude and duration only for antisaccades (p < 0.001).Conclusions: Some eye movement metrics must be separated by the direction of movement, others according to subject age, while others may be pooled.Significance: This study provides important information for new oculomotor laboratories concerning the constitution of subject groups and the analysis of eye movement metrics.

To tackle the heterogeneity of Parkinson’s disease symptoms, most functional imaging studies tend to select a uniform group of subjects. We hypothesize that more profound considerations are needed to account for intra/inter-subject clinical variability and possibly for differing pathophysiological processes. Twelve patients were investigated using functional magnetic resonance imaging during visually-guided finger tapping. To account for disease heterogeneity, the motor score and individual symptom scores from the Unified Parkinson’s Disease Rating Scale (UPDRS-III) were utilized in the group-level model using two approaches either as the explanatory variable or as the effect of interest. Employment of the UPDRS-III score and symptom scores was systematically tested on the resulting group response to the levodopa challenge, which further accentuated the diversity of the diseased state of participants. Statistics revealed a bilateral group response to levodopa in the basal ganglia. Interestingly, systematic incorporation of individual motor aspects of the disease in the modelling amended the resulting activity patterns conspicuously, evidencing a manifold amount of explained variability by the particular score. In conclusion, the severity of clinical symptoms expressed in the UPDRS-III scores should be considered in the analysis to attain unbiased statistics, draw reliable conclusions and allow for comparisons between research groups studying Parkinson’s disease using functional magnetic resonance imaging.

Changes in motivational processing may play a role in weight gain and other non-motor side effects in Parkinson's disease (PD) patients treated with deep brain stimulation of the subthalamic nucleus. We aimed to assess changes in aversive and appetitive motivational activation using modulation of the acoustic blink reflex (ABR) by rewarding and aversive stimuli. ABR elicited during the viewing of erotic, food, aversive and neutral pictures was recorded in 11 off-medicated patients with the subthalamic stimulation switched ON and OFF, and in 11 control subjects. ABR to erotic stimuli was larger in patients in the ON compared to the OFF condition and controls (P < 0.01). Aversive stimuli caused a larger increase in the ABR in patients with the ON condition than in controls (P < 0.05). Additionally, we found a negative correlation of the ABR magnitude to food pictures in the ON condition with weight gain following subthalamic stimulation (P < 0.01, after adjustment to OFF condition). Our results suggest that subthalamic stimulation affects motivational processing. Subthalamic stimulation may disturb appetitive engagement by erotic cues and increase aversive activation in PD patients. Additionally, postoperative weight gain may be related to changes in the processing of food cues due to subthalamic stimulation.

Patients with cervical dystonia (CD) present with an impaired performance of voluntary neck movements, which are usually slow and limited. We hypothesized that such abnormality could involve defective preparation for task execution. Therefore, we examined motor preparation in CD patients using the StartReact method. In this test, a startling auditory stimulus (SAS) is delivered unexpectedly at the time of the imperative signal (IS) in a reaction time task to cause a faster execution of the prepared motor programme. We expected that CD patients would show an abnormal StartReact phenomenon.

Background: Parkinsons disease (PD) patients are deficient in time estimation. This deficit improves after dopamine (DA) treatment and it has been associated with decreased internal timekeeper speed, disruption of executive function and memory retrieval dysfunction. Methodology/Findings: The aim of the present study was to explore the neurophysiologic correlates of this deficit. We performed functional magnetic resonance imaging on twelve PD patients while they were performing a time reproduction task (TRT). The TRT consisted of an encoding phase (during which visual stimuli of durations from 5s to 16.6s, varied at 8 levels were presented) and a reproduction phase (during which interval durations were reproduced by a button pressing) Patients were scanned twice, once while on their DA medication (ON condition) and once after medication withdrawal (OFF condition). Differences in Blood-Oxygenation-Level-Dependent (BOLD) signal in ON and OFF conditions were evaluated. The time course of activation in the brain areas with different BOLD signal was plotted. There were no significant differences in the behavioral results, but a trend toward overestimation of intervals #11.9s and underestimation of intervals $14.1s in the OFF condition (p,0.088).

Parkinson's disease (PD) is manifested by motor impairment, which may impede the ability to accurately perform motor tasks during functional magnetic resonance imaging (fMRI). Both temporal and amplitude deviations of movement performance affect the blood oxygenation level-dependent (BOLD) response. We present a general approach for assessing PD patients' movement control employing simultaneously recorded fMRI time series and behavioral data of the patients' kinematics using MR-compatible gloves. Twelve male patients with advanced PD were examined with fMRI at 1.5T during epoch-based visually paced finger tapping. MR-compatible gloves were utilized online to quantify motor outcome in two conditions with or without dopaminergic medication. Modeling of individual-level brain activity included (i) a predictor consisting of a condition-specific, constant-amplitude boxcar function convolved with the canonical hemodynamic response function (HRF) as commonly used in fMRI statistics (standard model), or (ii) a custom-made predictor computed from glove time series convolved with the HRF (kinematic model). Factorial statistics yielded a parametric map for each modeling technique, showing the medication effect on the group level. Patients showed bilateral response to levodopa in putamen and globus pallidus during the motor experiment. Interestingly, kinematic modeling produced significantly higher activation in terms of both the extent and amplitude of activity. Our results appear to account for movement performance in fMRI motor experiments with PD and increase sensitivity in detecting brain response to levodopa. We strongly advocate quantitatively controlling for motor performance to reach more reliable and robust analyses in fMRI with PD patients.

Patients with writer's cramp (WC) were studied for differences in cortical activation during movements likely to induce WC (complex movements) and movements which rarely lead to dystonia (simple movements). Eleven WC patients (10F, 1M, mean age 41.5±(SD)7.2years) and eleven age matched controls were examined for Blood oxygenation-level dependent (BOLD) 1.5 T fMRI. The complex task consisted of writing a single letter or random drawing using an especially adapted joystick with the line of trajectory visualized or hidden. The simple task consisted of self-initiated fingers flexion/extension using the affected hand Unlike the controls, WC patients performing complex movements exhibited a lower BOLD signal in the primary sensorimotor cortex and in the posterior parietal cortex bilaterally. A hypoactivation was also observed in the right secondary somatosensory area, in the right anterior insula and in the left premotor cortex (p<0.05 corrected).

Proper classification of action potentials from extracellular recordings is essential for making an accurate study of neuronal behavior. Many spike sorting algorithms have been presented in the technical literature. However, no comparative analysis has hitherto been performed. In our study, three widely-used publicly-available spike sorting algorithms (WaveClus, KlustaKwik, OSort) were compared with regard to their parameter settings. The algorithms were evaluated using 112 artificial signals (publicly available online) with 2-9 different neurons and varying noise levels between 0.00 and 0.60.

Electrode implantation into the subthalamic nucleus for deep brain stimulation in Parkinsons disease (PD) is associated with a temporary motor improvement occurring prior to neurostimulation. We studied this phenomenon by functional magnetic resonance imaging (fMRI) when considering the Unified Parkinsons Disease Rating Scale (UPDRS-III) and collateral oedema. Twelve patients with PD (age 55.96 (SD)6.8 years, PD duration 915 years) underwent bilateral electrode implantation into the subthalamic nucleus. The fMRI was carried out after an overnight withdrawal of levodopa (OFF condition): (i) before and (ii) within three days after surgery in absence of neurostimulation. The motor task involved visually triggered finger tapping. The OFF/UPDRS-III score dropped from 33.868.7 before to 23.364.8 after the surgery (p<0.001), correlating with the postoperative oedema score (p<0.05). During the motor task, bilateral activation of the thalamus and basal ganglia, motor cortex and insula were preoperatively higher than after surgery (p<0.001). The results became more enhanced after compensation for the oedema and UPDRS-III scores. In addition, the rigidity and axial symptoms score correlated inversely with activation of the putamen and globus pallidus (p<0.0001). One month later, the OFF/UPDRS-III score had returned to the preoperative level (35.867.0, p = 0.4). In conclusion, motor improvement induced by insertion of an inactive electrode into the subthalamic nucleus caused an acute microlesion which was at least partially related to the collateral oedema and associated with extensive impact on the motor network. This was postoperatively manifested as lowered movement-related activation at the cortical and subcortical levels and differed from the known effects of neurostimulation or levodopa. The motor system finally adapted to the microlesion within one month as suggested by loss of motor improvement and good efficacy of deep brain stimulation.

This paper focuses on wrapper-based feature selection for a 1-nearest neighbor classifier. We consider in particular the case of a small sample size with a few hundred instances, which is common in biomedical applications. We propose a technique for calculating the complete bootstrap for a 1-nearest-neighbor classifier (i.e., averaging over all desired test/train partitions of the data). The complete bootstrap and the complete cross-validation error estimate with lower variance are applied as novel selection criteria and are compared with the standard bootstrap and cross-validation in combination with three optimization techniques - sequential forward selection (SFS), binary particle swarm optimization (BPSO) and simplified social impact theory based optimization (SSITO). The experimental comparison based on ten datasets draws the following conclusions: for all three search methods examined here, the complete criteria are a significantly better choice than standard 2-fold cross-validation, 10-fold cross-validation and bootstrap with 50 trials irrespective of the selected output number of iterations. All the complete criterion-based 1NN wrappers with SFS search performed better than the widely-used FILTER and SIMBA methods. We also demonstrate the benefits and properties of our approaches on an important and novel real-world application of automatic detection of the subthalamic nucleus.

Flow cytometry is a valuable tool in research and diagnostics including minimal residual disease (MRD) monitoring of hematologic malignancies. However, its gradual advancement toward increasing numbers of fluorescent parameters leads to information rich datasets, which are challenging to analyze by standard gating and do not reflect the multidimensionality of the data. We have developed a novel method to analyze complex flow cytometry data, based on hierarchical clustering analysis (HCA) but with a new underlying algorithm, using Mahalanobis distance measure. HCA is scalable to analyze complex multiparameter datasets (here demonstrated on up to 12 color flow cytometry and on a 20-parameter synthetic dataset).

The basal ganglia and the thalamus are involved in eye motion (EM) control. It has been shown that deep brain stimulation (DBS) of the subthalamic nucleus (STN) affects EM in patients with Parkinson's disease (PD), and that the STN contains neurons activated during voluntary saccades or pursuit EM. Our results suggested that each of the explored structures - STN, SNr and GPi contain relatively high ratios of neurons involved in the execution and/or control of eye movements.

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) can induce nonmotor side effects such as behavioral and mood disturbances or body weight gain in Parkinson's disease (PD) patients. We hypothesized that some of these problems could be related to an altered attribution of incentive salience (ie, emotional relevance) to rewarding and aversive stimuli. Twenty PD patients (all men; mean age ± SD, 58.3 ± 6 years) in bilateral STN DBS switched ON and OFF conditions and 18 matched controls rated pictures selected from the International Affective Picture System according to emotional valence (unpleasantness/pleasantness) and arousal on 2 independent visual scales ranging from 1 to 9. Eighty-four pictures depicting primary rewarding (erotica and food) and aversive fearful (victims and threat) and neutral stimuli were selected for this study.

The acoustic startle eye blink (ASB) potentiation during unpleasant stimuli and inhibition during pleasant stimuli reflects activation of the aversive and appetitive motivational systems. Deep brain stimulation (DBS) of the Subthalamic Nucleus (STN) seems to dissociate the processing of different reward cue categories. STN DBS disturbed the pleasure inhibition of the ASB only from erotic with ASBs paradoxically potentiated as they were aversive stimuli. The correlation analysis further suggests that postoperative weight gain might be related to changes in processing of food reward cues due to STN DBS.

Jeden z hlavních problémů současné neuroinformatiky je plně automaticky ale přesto spolehlivě extrahovat a roztřídit akční potenciály z extracelularního záznamu. Tímto problémem se však zabývá hned několik algoritmů, přičemž každý je potřeba před samotným použitím nakonfigurovat s ohledem na druh zpracovávaného záznamu. Provedli jsme nezávislé výkonnostní porovnání tří nejčastěji používaných algoritmů - KlustaKwik, WaveClus a OSort - a doplnili jej o metodiku optimalizace jejich nastavení.

Hluboké mozková stimulace (DBS) subthalamického jádra (STN) v léčbě Parkinsonovy nemoci může způsobovat paréza očních pohybů a diplopii. Vyhledávali jsem proto neurony, jejichž aktivita by souvisela s vykonáváním očních pohybů. Neuronální aktivitu jsme kromě v STN analyzovali také v substantia nigra (SNr) a ve vnitřním pallidu (GPi). Výsledky naznačují, že jádra STN, SNr a GPi obsahují vysoký počet neuronů, jejichž aktivita souvisí s vykonáváním očních pohybů.

Parkinsonova nemoc (PN) vede ke zhoršeným odhadům času. V naší studii jsme porovnávali odhady času v několika úlohách.Výsledky svědčí pro specifickou poruchu PN vázanou na vyšší nároky na pracovní paměť.

V naší studii jsme se pokusili objektivizovat hypokinezi pacientů s PN pomocí detekčních rukavic při provádění jednoduchého pohybu ruky po celonočním vysazení dopaminergní medikace (stav OFF) a následně po podání 250 mg L-DOPA (stav ON). Vlivem L-DOPA dochází ke zvýšení variability amplitudy a rychlosti pohybu prstů.

One of the most difficult aspects of spike sorting is choosing the number of neurons in extracellular recording. The paper proposes a methodology for estimating the number of neurons based on the Gaussian mixture model. The following criteria have been examined: Bayesian selection method, Akaikes information criteria, minimum description length, minimum message length, fuzzy hyper volume, evidence density and partition coefficient. In order to validate the procedure, an experimental comparative study was carried out, comparing the proposed methodology with three spike sorting algorithms. The proposed methodology has an advantage of setting the minimum number of parameters and is very robust to background noise. We conclude that only fuzzy hyper volume and evidence density criteria are able to identify the correct number of neurons across different noise levels.