Publications by authors named "Tomas Sieger"

29 Publications

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ShinySOM: graphical SOM-based analysis of single-cell cytometry data.

Bioinformatics 2020 05;36(10):3288-3289

Institute of Organic Chemistry and Biochemistry AS CR, 166 10 Praha 6, Czech Republic.

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.

Supplementary Information: Supplementary data are available at Bioinformatics online.
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http://dx.doi.org/10.1093/bioinformatics/btaa091DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7214046PMC
May 2020

Topography of emotional valence and arousal within the motor part of the subthalamic nucleus in Parkinson's disease.

Sci Rep 2019 12 27;9(1):19924. Epub 2019 Dec 27.

Department of Neurology and Center of Clinical Neuroscience, Charles University, 1st Faculty of Medicine and General University Hospital, Kateřinská 30, 128 08, Prague, Czech Republic.

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.
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http://dx.doi.org/10.1038/s41598-019-56260-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6934686PMC
December 2019

Prepulse inhibition of the blink reflex is abnormal in functional movement disorders.

Mov Disord 2019 07 2;34(7):1022-1030. Epub 2019 May 2.

Department of Neurology and Center of Clinical Neuroscience, Charles University in Prague, 1st Faculty of Medicine and General University Hospital, Prague, Czech Republic.

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. © 2019 International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.27706DOI Listing
July 2019

Nuclear pore protein TPR associates with lamin B1 and affects nuclear lamina organization and nuclear pore distribution.

Cell Mol Life Sci 2019 Jun 14;76(11):2199-2216. Epub 2019 Feb 14.

Department of Biology of the Cell Nucleus, Institute of Molecular Genetics CAS, v.v.i., Vídeňská 1083, 142 00, Prague, Czech Republic.

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.
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http://dx.doi.org/10.1007/s00018-019-03037-0DOI Listing
June 2019

Eye movements in idiopathic rapid eye movement sleep behaviour disorder: High antisaccade error rate reflects prefrontal cortex dysfunction.

J Sleep Res 2019 10 25;28(5):e12742. Epub 2018 Jul 25.

Department of Neurology and Centre of Clinical Neuroscience, 1st Faculty of Medicine, Charles University and General University Hospital, Prague, Czech Republic.

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.
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http://dx.doi.org/10.1111/jsr.12742DOI Listing
October 2019

Methods for automatic detection of artifacts in microelectrode recordings.

J Neurosci Methods 2017 Oct 20;290:39-51. Epub 2017 Jul 20.

Department of Neurology and Center of Clinical Neuroscience, First Faculty of Medicine and General University Hospital, Charles University, Prague, Czech Republic.

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.
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http://dx.doi.org/10.1016/j.jneumeth.2017.07.012DOI Listing
October 2017

Chromatin organization at the nuclear periphery as revealed by image analysis of structured illumination microscopy data.

J Cell Sci 2017 Jun 5;130(12):2066-2077. Epub 2017 May 5.

Department of Biology of the Cell Nucleus, Institute of Molecular Genetics CAS, v.v.i., Vídeňská 1083, Prague 142 00, Czech Republic.

The nuclear periphery (NP) plays a substantial role in chromatin organization. Heterochromatin at the NP is interspersed with active chromatin surrounding nuclear pore complexes (NPCs); however, details of the peripheral chromatin organization are missing. To discern the distribution of epigenetic marks at the NP of HeLa nuclei, we used structured illumination microscopy combined with a new MATLAB software tool for 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 such as H3K4me2 was only decreased very slightly around the NPCs or not at all (H3K9Ac). Interestingly, the histone demethylases LSD1 (also known as KDM1A) and KDM2A were enriched within the NPCs, suggesting that there was a chromatin-modifying mechanism at the NPCs. Inhibition of transcription resulted in a larger drop in the distribution of H1, H3K9me2 and H3K23me2, which implies that transcription has a role in the organization of heterochromatin at the NP.
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http://dx.doi.org/10.1242/jcs.198424DOI Listing
June 2017

Relapse in schizophrenia: Definitively not a bolt from the blue.

Neurosci Lett 2018 03 22;669:68-74. Epub 2016 Apr 22.

National Institute of Mental Health, Klecany, Czech Republic; 3rd Faculty of Medicine, Charles University, Prague, Czech Republic.

Detailed study of the period before schizophrenic relapse when early warning signs (EWS) are present is crucial to effective pre-emptive strategies. To investigate the temporal properties of EWS self-reported weekly via a telemedicine system. 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. 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. 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.
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http://dx.doi.org/10.1016/j.neulet.2016.04.044DOI Listing
March 2018

Antisaccades and vergence abnormalities in functional movement disorders: A video-oculographic study.

Mov Disord 2016 07 19;31(7):1072-3. Epub 2016 Apr 19.

Department of Neurology and Center of Clinical Neuroscience, Charles University in Prague, 1st Faculty of Medicine and General University Hospital, Prague, Czech Republic.

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http://dx.doi.org/10.1002/mds.26641DOI Listing
July 2016

Supervised segmentation of microelectrode recording artifacts using power spectral density.

Annu Int Conf IEEE Eng Med Biol Soc 2015 Aug;2015:1524-7

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.
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http://dx.doi.org/10.1109/EMBC.2015.7318661DOI Listing
August 2015

Predicting Falls in Parkinson Disease: What Is the Value of Instrumented Testing in OFF Medication State?

PLoS One 2015 7;10(10):e0139849. Epub 2015 Oct 7.

Department of Neurology and Centre of Clinical Neuroscience, First Faculty of Medicine and General University Hospital in Prague, Charles University in Prague, Prague, Czech Republic.

Background: Falls are a common complication of advancing Parkinson's disease (PD). Although numerous 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 balance 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.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0139849PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4596567PMC
June 2016

External validation of extended prostate biopsy nomogram.

Cent European J Urol 2015 18;68(2):148-52. Epub 2015 May 18.

Department of Urology, 2 Faculty of Medicine and Motol University Hospital, Charles University Praha, Czech Republic.

Introduction: Historical nomograms for the prediction of cancer on prostate biopsy, developed in the sextant 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.
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http://dx.doi.org/10.5173/ceju.2015.610DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4526620PMC
August 2015

Fast vergence eye movements are disrupted in Parkinson's disease: A video-oculography study.

Parkinsonism Relat Disord 2015 Jul 23;21(7):797-9. Epub 2015 Apr 23.

Dept. of Neurology and Center of Clinical Neuroscience, Charles University in Prague, 1st Faculty of Medicine and General University Hospital, Prague, Czech Republic. Electronic address:

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.
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http://dx.doi.org/10.1016/j.parkreldis.2015.04.014DOI Listing
July 2015

Distinct populations of neurons respond to emotional valence and arousal in the human subthalamic nucleus.

Proc Natl Acad Sci U S A 2015 Mar 23;112(10):3116-21. Epub 2015 Feb 23.

Department of Neurology and Center of Clinical Neuroscience, First Faculty of Medicine and General University Hospital, Charles University in Prague, 128 21, Prague, Czech Republic;

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 Parkinson's 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.
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http://dx.doi.org/10.1073/pnas.1410709112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4364224PMC
March 2015

Eye movements in ephedrone-induced parkinsonism.

PLoS One 2014 12;9(8):e104784. Epub 2014 Aug 12.

Department of Neurology and Centre of Clinical Neuroscience, Charles University in Prague, 1st Faculty of Medicine and General University Hospital, Prague, Czech Republic.

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.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0104784PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4130591PMC
February 2016

Basal ganglia neuronal activity during scanning eye movements in Parkinson's disease.

PLoS One 2013 6;8(11):e78581. Epub 2013 Nov 6.

Department of Neurology and Center of Clinical Neuroscience, Charles University in Prague, 1st Faculty of Medicine and General University Hospital, Prague, Czech Republic ; Department of Cybernetics, Faculty of Electrical Engineering, Czech Technical University, Prague, Czech Republic.

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.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0078581PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3819366PMC
August 2014

Horizontal and vertical eye movement metrics: what is important?

Clin Neurophysiol 2013 Nov 25;124(11):2216-29. Epub 2013 Jun 25.

Dept. of Neurology and Centre of Clinical Neuroscience, Charles University in Prague, 1st Faculty of Medicine and General University Hospital, Prague, Czech Republic. Electronic address:

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 profile 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.
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http://dx.doi.org/10.1016/j.clinph.2013.05.002DOI Listing
November 2013

Sex, food and threat: startling changes after subthalamic stimulation in Parkinson's disease.

Brain Stimul 2013 Sep 6;6(5):740-5. Epub 2013 Apr 6.

Department of Neurology and Center of Clinical Neuroscience, Charles University in Prague, 1st Faculty of Medicine and General University Hospital, Prague, Czech Republic. Electronic address:

Background: 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.

Objective/hypothesis: We aimed to assess changes in aversive and appetitive motivational activation using modulation of the acoustic blink reflex (ABR) by rewarding and aversive stimuli.

Methods: 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.

Results: 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).

Conclusions: 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.
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http://dx.doi.org/10.1016/j.brs.2013.03.009DOI Listing
September 2013

Motor matters: tackling heterogeneity of Parkinson's disease in functional MRI studies.

PLoS One 2013 13;8(2):e56133. Epub 2013 Feb 13.

Max Planck Institute for Human Cognitive and Brain Sciences, Leipzig, Germany.

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.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0056133PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3572025PMC
August 2013

The subthalamic microlesion story in Parkinson's disease: electrode insertion-related motor improvement with relative cortico-subcortical hypoactivation in fMRI.

PLoS One 2012 7;7(11):e49056. Epub 2012 Nov 7.

Dept. of Neurology and Center of Clinical Neuroscience, Charles University in Prague, 1st Faculty of Medicine and General University Hospital, Prague, Czech Republic.

Electrode implantation into the subthalamic nucleus for deep brain stimulation in Parkinson's 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 Parkinson's Disease Rating Scale (UPDRS-III) and collateral oedema. Twelve patients with PD (age 55.9± (SD)6.8 years, PD duration 9-15 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 33.8±8.7 before to 23.3±4.8 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 (35.8±7.0, 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.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0049056PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3492182PMC
July 2013

A loud auditory stimulus overcomes voluntary movement limitation in cervical dystonia.

PLoS One 2012 16;7(10):e46586. Epub 2012 Oct 16.

Department of Neurology and Centre of Clinical Neuroscience, 1st Medical Faculty, Charles University in Prague, Prague, Czech Republic.

Background: 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.

Methods: Fifteen CD patients and 15 age matched control subjects (CS) were asked to perform a rotational movement (RM) to either side as quick as possible immediately after IS perception (a low intensity electrical stimulus to the II finger). In randomly interspersed test trials (25%) a 130 dB SAS was delivered simultaneously with the IS. We recorded RMs in the horizontal plane with a high speed video camera (2.38 ms per frame) in synchronization with the IS. The RM kinematic-parameters (latency, velocity, duration and amplitude) were analyzed using video-editing software and screen protractor. Patients were asked to rate the difficulty of their RMs in a numerical rating scale.

Results: In control trials, CD patients executed slower RMs (repeated measures ANOVA, p<0.10(-5)), and reached a smaller final head position angle relative to the midline (p<0.05), than CS. In test trials, SAS improved all RMs in both groups (p<0.10(-14)). In addition, patients were more likely to reach beyond their baseline RM than CS (χ(2), p<0.001) and rated their performance better than in control trials (t-test, p<0.01).

Conclusion: We found improvement of kinematic parameters and subjective perception of motor performance in CD patients with StartReact testing. Our results suggest that CD patients reach an adequate level of motor preparation before task execution.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0046586PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3473053PMC
March 2013

Accounting for movement increases sensitivity in detecting brain activity in Parkinson's disease.

PLoS One 2012 1;7(5):e36271. Epub 2012 May 1.

Max Planck Institute for Human Cognitive and Brain Sciences, Leipzig, Germany.

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.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0036271PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3341369PMC
September 2012

Disorders of balance and gait in essential tremor are associated with midline tremor and age.

Cerebellum 2013 Feb;12(1):27-34

Department of Neurology and Centre of Clinical Neuroscience, First Faculty of Medicine and General University Hospital in Prague, Charles University in Prague, Kateřinská 30, Prague, 128 21, Czech Republic.

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.
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http://dx.doi.org/10.1007/s12311-012-0384-4DOI Listing
February 2013

Wrapper feature selection for small sample size data driven by complete error estimates.

Comput Methods Programs Biomed 2012 Oct 1;108(1):138-50. Epub 2012 Apr 1.

Czech Technical University, Faculty of Electrical Engineering, Department of Cybernetics, Karlovo Namesti 13, 12135 Prague, Czech Republic.

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.
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http://dx.doi.org/10.1016/j.cmpb.2012.02.006DOI Listing
October 2012

Abnormal activity in the precuneus during time perception in Parkinson's disease: an fMRI study.

PLoS One 2012 6;7(1):e29635. Epub 2012 Jan 6.

Department of Neurology and Center of Clinical Neuroscience, Charles University in Prague, 1st Faculty of Medicine and General University Hospital, Prague, Czech Republic.

Background: Parkinson's 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 5 s to 16.6 s, 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 ≤11.9 s and underestimation of intervals ≥14.1 s in the OFF condition (p<0.088). During the reproduction phase, higher activation in the precuneus was found in the ON condition (p<0.05 corrected). Time course was plotted separately for long (≥14.1 s) and short (≤11.9 s) intervals. Results showed that there was a significant difference only in long intervals, when activity gradually decreased in the OFF, but remained stable in the ON condition. This difference in precuneus activation was not found during random button presses in a control task.

Conclusions/significance: Our results show that differences in precuneus activation during retrieval of a remembered duration may underlie some aspects of time perception deficit in PD patients. We suggest that DA medication may allow compensatory activation in the precuneus, which results in a more accurate retrieval of remembered interval duration.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0029635PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3253091PMC
May 2012

Performance comparison of extracellular spike sorting algorithms for single-channel recordings.

J Neurosci Methods 2012 Jan 21;203(2):369-76. Epub 2011 Oct 21.

Department of Cybernetics, Faculty of Electrical Engineering, Czech Technical University, Karlovo nam. 13, 121 35 Praha 2, Czech Republic.

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. An optimization technique based on Adjusted Mutual Information was employed to find near-optimal parameter settings for a given artificial signal and algorithm. All three algorithms performed significantly better (p<0.01) with optimized parameters than with the default ones. WaveClus was the most accurate spike sorting algorithm, receiving the best evaluation score for 60% of all signals. OSort operated at almost five times the speed of the other algorithms. In terms of accuracy, OSort performed significantly less well (p<0.01) than WaveClus for signals with a noise level in the range 0.15-0.30. KlustaKwik achieved similar scores to WaveClus for signals with low noise level 0.00-0.15 and was worse otherwise. In conclusion, none of the three compared algorithms was optimal in general. The accuracy of the algorithms depended on proper choice of the algorithm parameters and also on specific properties of the examined signal.
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http://dx.doi.org/10.1016/j.jneumeth.2011.10.013DOI Listing
January 2012

Detection and monitoring of normal and leukemic cell populations with hierarchical clustering of flow cytometry data.

Cytometry A 2012 Jan 11;81(1):25-34. Epub 2011 Oct 11.

Northern Institute for Cancer Research, Newcastle University, Newcastle, United Kingdom.

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). We have validated this method by comparison with standard gating approaches when performed independently by expert cytometrists. Acute lymphoblastic leukemia blast populations were analyzed in diagnostic and follow-up datasets (n = 123) from three centers. HCA results correlated very well (Passing-Bablok correlation coefficient = 0.992, slope = 1, intercept = -0.01) with standard gating data obtained by the I-BFM FLOW-MRD study group. To further improve the performance in follow-up samples with low MRD levels and to automate MRD detection, we combined HCA with support vector machine (SVM) learning. HCA in combination with SVM provides a novel diagnostic tool that not only allows analysis of increasingly complex flow cytometry data but also is less observer-dependent compared with classical gating and has potential for automation.
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http://dx.doi.org/10.1002/cyto.a.21148DOI Listing
January 2012

Cortical pattern of complex but not simple movements is affected in writer's cramp: a parametric event-related fMRI study.

Clin Neurophysiol 2012 Apr 7;123(4):755-63. Epub 2011 Sep 7.

Dept. of Neurology and Center of Clinical Neuroscience, Charles University in Prague, 1st Faculty of Medicine and General University Hospital, Prague, Czech Republic.

Objective: 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).

Methods: Eleven WC patients (10F, 1M, mean age 41.5 ± (SD)7.2 years) 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.

Results: 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). No significant inter-group differences were found for simple movements.

Conclusions: Although WC patients' complex movements during fMRI were never associated with dystonic cramp, they exhibited an abnormally low cortical activity. This phenomenon was not observed in simple movements and was unrelated to the character of handwriting or to visual feedback.

Significance: Our results support the dualistic behavior in the sensorimotor system in WC.
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http://dx.doi.org/10.1016/j.clinph.2011.08.002DOI Listing
April 2012

Subthalamic nucleus stimulation affects incentive salience attribution in Parkinson's disease.

Mov Disord 2011 Oct 20;26(12):2260-6. Epub 2011 Jul 20.

Department of Neurology and Center of Clinical Neuroscience, Charles University in Prague, 1st Faculty of Medicine and General University Hospital, Prague, Czech Republic.

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. In the STN DBS ON condition, the PD patients attributed lower valence scores to the aversive pictures compared with the OFF condition (P < .01) and compared with controls (P < .01). The difference between the OFF condition and controls was less pronounced (P < .05). Furthermore, postoperative weight gain correlated with arousal ratings from the food pictures in the STN DBS ON condition (P < .05 compensated for OFF condition). Our results suggest that STN DBS increases activation of the aversive motivational system so that more relevance is attributed to aversive fearful stimuli. In addition, STN DBS-related sensitivity to food reward stimuli cues might drive DBS-treated patients to higher food intake and subsequent weight gain.
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http://dx.doi.org/10.1002/mds.23880DOI Listing
October 2011