Tomáš Sieger

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

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.

Subthalamic Nucleus Stimulation Affects Incentive Salience Attribution in Parkinson's Disease

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 Parkinsons 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.

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

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.

The Subthalamic Microlesion Story in Parkinson's Disease: Electrode Insertion-Related Motor Improvement with Relative Cortico-Subcortical Hypoactivation in fMRI

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 55.9± (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.

Horizontal and vertical eye movement metrics: What is important?

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.

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

Significance The involvement of the subthalamic nucleus (STN) in affective processing has been suggested with the appearance of neuropsychiatric side effects of deep brain stimulation in Parkinson’s disease (PD), but direct evidence has been lacking. In our study, we recorded single-neuron activity from the STN during affective picture presentation to PD patients intraoperatively. We discovered two spatially distinct populations of “affective” neurons responding to the emotional dimensions of the stimuli: valence (pleasantness-unpleasantness) and arousal (intensity). As previously believed, neural circuits underlying these two affective dimensions are functionally segregated. Here we observed separated emotional processing even at the single neuron level. These results extend our knowledge regarding the emotional role of the STN and the neural basis of emotions. 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.

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

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.

Sex, Food and Threat: Startling Changes after Subthalamic Stimulation in Parkinson's Disease

BACKGROUND Changes in motivational processing may play a role in weight gain and other non-motor side effects in Parkinsons 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.

Abnormal activity in the precuneus during time perception in Parkinson’s disease: An fMRI study

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). 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 (≥14.1s) and short (≤11.9s) 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.

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

Background Falls are a common complication of advancing Parkinsons 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.