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Successful behavior requires selection and preferred processing of relevant sensory information. The cortical representation of relevant sensory information has been related to neuronal oscillations in the gamma frequency band. Pain is of invariably high behavioral relevance and, thus, nociceptive stimuli receive preferred processing. Here, by using magnetoencephalography, we show that selective nociceptive stimuli induce gamma oscillations between 60 and 95 Hz in primary somatosensory cortex. Amplitudes of pain-induced gamma oscillations vary with objective stimulus intensity and subjective pain intensity. However, around pain threshold, perceived stimuli yielded stronger gamma oscillations than unperceived stimuli of equal stimulus intensity. These results show that pain induces gamma oscillations in primary somatosensory cortex that are particularly related to the subjective perception of pain. Our findings support the hypothesis that gamma oscillations are related to the internal representation of behaviorally relevant stimuli that should receive preferred processing.

Isolated REM Sleep Behavior Disorder (iRBD) is considered a prodrome of Parkinson’s disease (PD). We investigate whether the potentially disease-modifying compound acetyl- DL -leucine (ADLL; 5 g/d) has an effect on prodromal PD progression in 2 iRBD-patients. Outcome parameters are RBD-severity sum-score (RBD-SS-3), dopamine-transporter single-photon emission computerized tomography (DAT-SPECT) and metabolic “Parkinson-Disease-related-Pattern (PDRP)”-z-score in 18 F-fluorodeoxyglucose positron emission tomography (FDG-PET). After 3 weeks ADLL-treatment, the RBD-SS-3 drops markedly in both patients and remains reduced for >18 months of ADLL-treatment. In patient 1 (female), the DAT-SPECT putaminal binding ratio (PBR) decreases in the 5 years pretreatment from normal (1.88) to pathological (1.22) and the patient’s FDG-PET-PDRP-z-score rises from 1.72 to 3.28 (pathological). After 22 months of ADLL-treatment, the DAT-SPECT-PBR increases to 1.67 and the FDG-PET-PDRP-z-score stabilizes at 3.18. Similar results are seen in patient 2 (male): his DAT-SPECT-PBR rises from a pretreatment value of 1.42 to 1.72 (close to normal) and the FDG-PET-PDRP-z-score decreases from 1.02 to 0.30 after 18 months of ADLL-treatment. These results support exploration of whether ADLL may have disease-modifying properties in prodromal PD. Clinical trials with N-acetyl-L-leucine showed beneficial effects in lysosomal diseases. Here, the authors investigate a disease modifying effect of acetyl-DL-leucine in 2 patients with REM sleep behavior disorder, a prodrome of Parkinson’s disease, and report improvements in neurological symptoms and imaging biomarkers.

Transfer entropy (TE) provides a generalized and model-free framework to study Wiener-Granger causality between brain regions. Because of its nonparametric character, TE can infer directed information flow also from nonlinear systems. Despite its increasing number of applications in neuroscience, not much is known regarding the influence of common electrophysiological preprocessing on its estimation. We test the influence of filtering and downsampling on a recently proposed nearest neighborhood based TE estimator. Different filter settings and downsampling factors were tested in a simulation framework using a model with a linear coupling function and two nonlinear models with sigmoid and logistic coupling functions. For nonlinear coupling and progressively lower low-pass filter cut-off frequencies up to 72% false negative direct connections and up to 26% false positive connections were identified. In contrast, for the linear model, a monotonic increase was only observed for missed indirect connections (up to 86%). High-pass filtering (1 Hz, 2 Hz) had no impact on TE estimation. After low-pass filtering interaction delays were significantly underestimated. Downsampling the data by a factor greater than the assumed interaction delay erased most of the transmitted information and thus led to a very high percentage (67-100%) of false negative direct connections. Low-pass filtering increases the number of missed connections depending on the filters cut-off frequency. Downsampling should only be done if the sampling factor is smaller than the smallest assumed interaction delay of the analyzed network.

Impaired self-awareness of cognitive deficits (ISAcog) has rarely been investigated in Parkinson's disease (PD). ISAcog is associated with poorer long-term outcome in other diseases. This study examines ISAcog in PD with and without mild cognitive impairment (PD-MCI), compared to healthy controls, and its clinical-behavioral and neuroimaging correlates. We examined 63 PD patients and 30 age- and education-matched healthy controls. Cognitive state was examined following the Movement Disorder Society Level II criteria. ISAcog was determined by subtracting -scores (based on controls' scores) of objective tests and subjective questionnaires. Neural correlates were assessed by structural magnetic resonance imaging (MRI) and 2-[fluorine-18]fluoro-2-deoxy-d-glucose-positron emission tomography (FDG-PET) in 47 patients (43 with MRI) and 11 controls. We analyzed whole-brain glucose metabolism and cortical thickness in regions where FDG-uptake correlated with ISAcog. PD-MCI patients ( = 23) showed significantly more ISAcog than controls and patients without MCI ( = 40). When all patients who underwent FDG-PET were examined, metabolism in the bilateral superior medial frontal gyrus, anterior and midcingulate cortex negatively correlated with ISAcog (FWE-corrected p < 0.001). In PD-MCI, ISAcog was related to decreased metabolism in the right superior temporal lobe and insula ( = 13; FWE-corrected = 0.023) as well as the midcingulate cortex (FWE-corrected = 0.002). Cortical thickness was not associated with ISAcog in these regions. No significant correlations were found between ISAcog and glucose metabolism in controls and patients without MCI. Similar to Alzheimer's disease, the cingulate cortex seems to be relevant in ISAcog in PD. In PD-MCI patients, ISAcog might result from a disrupted network that regulates awareness of cognition and error processes.

Background Postural instability greatly reduces quality of life in people with Parkinson’s disease (PD). Early and objective detection of postural impairments is crucial to facilitate interventions. Our aim was to use a convolutional neural network (CNN) to differentiate people with early to mid-stage PD from healthy age-matched individuals based on spectrogram images obtained from their body sway. We hypothesized the time–frequency content of body sway to be predictive of PD, even when impairments are not yet clinically apparent. Methods 18 people with idiopathic PD and 15 healthy controls (HC) participated in the study. We tracked participants’ center of pressure (COP) using a Wii Balance Board and their full-body motion using a Microsoft Kinect, out of which we calculated the trajectory of their center of mass (COM). We used 30 s-snippets of motion data from which we acquired wavelet-based time–frequency spectrograms that were fed into a custom-built CNN as labeled images. We used binary classification to have the network differentiate between individuals with PD and controls ( n  = 15, respectively). Results Classification performance was best when the medio-lateral motion of the COM was considered. Here, our network reached a predictive accuracy, sensitivity, specificity, precision and F1-score of 100%, respectively, with a receiver operating characteristic area under the curve of 1.0. Moreover, an explainable AI approach revealed high frequencies in the postural sway data to be most distinct between both groups. Conclusion Heeding our small and heterogeneous sample, our findings suggest a CNN classifier based on cost-effective and conveniently obtainable posturographic data to be a promising approach to detect postural impairments in early to mid-stage PD and to gain novel insight into the subtle characteristics of impairments at this stage of the disease.

Bimanual motor control declines during ageing, affecting the ability of older adults to maintain independence. An important underlying factor is cortical atrophy, particularly affecting frontal and parietal areas in older adults. As these regions and their interplay are highly involved in bimanual motor preparation, we investigated age-related connectivity changes between prefrontal and premotor areas of young and older adults during the preparatory phase of complex bimanual movements using high-density electroencephalography. Generative modelling showed that excitatory inter-hemispheric prefrontal to premotor coupling in older adults predicted age-group affiliation and was associated with poor motor-performance. In contrast, excitatory intra-hemispheric prefrontal to premotor coupling enabled older adults to maintain motor-performance at the cost of lower movement speed. Our results disentangle the complex interplay in the prefrontal-premotor network during movement preparation underlying reduced bimanual control and the well-known speed-accuracy trade-off seen in older adults. [Display omitted]

The vagus nerve constitutes a key link between the autonomic and the central nervous system. Previous studies provide evidence for the impact of vagal activity on distinct cognitive processes including functions related to social cognition. Recent studies in animals and humans show that vagus nerve stimulation is associated with enhanced reward-seeking and dopamine-release in the brain. Social interaction recruits similar brain circuits to reward processing. We hypothesize that vagus nerve stimulation (VNS) boosts rewarding aspects of social behavior and compare the impact of transcutaneous VNS (tVNS) and sham stimulation on social interaction in 19 epilepsy patients in a double-blind pseudo-randomized study with cross-over design. Using a well-established paradigm, i.e., the prisoner’s dilemma, we investigate effects of stimulation on cooperative behavior, as well as interactions of stimulation effects with patient characteristics. A repeated-measures ANOVA and a linear mixed-effects model provide converging evidence that tVNS boosts cooperation. Post-hoc correlations reveal that this effect varies as a function of neuroticism, a personality trait linked to the dopaminergic system. Behavioral modeling indicates that tVNS induces a behavioral starting bias towards cooperation, which is independent of the decision process. This study provides evidence for the causal influence of vagus nerve activity on social interaction.

Postural instability marks a prevalent symptom of Parkinson’s disease (PD). It often manifests in increased body sway, which is commonly assessed by tracking the Center of Pressure (CoP). Yet, in terms of postural control the body’s Centre of Mass (CoM) is what is regulated in a gravitational field, and not the CoP. To find potential biomarkers of subclinical alterations of early-stage PD regarding postural control, we determined CoP and CoM in response to unpredictable visual perturbations. We investigated three different cohorts: (i) 18 patients with early to mid-stage PD, (ii) a group of 15 age-matched controls (CT) and (iii) a group of 12 young healthy adults (YG). Participants stood on a force plate to track their CoP, while movement of their entire body was recorded with a video-based motion tracking system to monitor their CoM. A moving room paradigm was applied through a head-mounted virtual reality headset. The stimulus consisted of a virtual tunnel that stretched in the anterior-posterior direction. The tunnel either remained static or moved back and forth in an unpredictable fashion. We found differences in mean velocities of CoP and CoM between the groups under both conditions with higher velocities of CoP and CoM for PD and CT when compared to YG. Visual perturbation increased mean CoP velocity in all groups, but only had a slight effect on mean CoM velocity. While being significantly lower for the young adults, the net-effect of visual perturbation on mean CoP velocity was similar between patients with PD and age-matched controls. There was no effect of the perturbation on mean CoM velocity for any of the groups. Our simultaneous assessment of CoP and CoM revealed that postural control is reflected differently in CoM and CoP. As motion of the CoM remained mostly unaffected, all groups successfully counteracted the perturbation and maintained their balance. Higher CoP velocity for PD and CT revealed increased corrective motion needed to achieve this successful behavior, which however was similar in both groups. This suggests increased effort, expressed in CoP velocity, to be an effect of age rather than disease in earlier stages of PD.

Despite advances in symptomatic treatment options the pathomechanism of idiopathic Parkinson’s disease (PD) remains poorly understood. Animal studies from recent years suggest pathological information processing in the basal ganglia network to be responsible for major movement deficits observed in patients, which, according to the information lesion hypothesis, might also explain the mechanism of action of deep brain stimulation (DBS). Using novel measures from information theory we characterize the information content, storage and transfer of intraoperatively recorded local field potentials (LFP) from the subthalamic area of n ​= ​19 PD patients undergoing surgery for implantation of electrodes for deep brain stimulation. In agreement with recent animal studies we demonstrate a significant positive correlation of subthalamic information content and movement deficits (ρ ​> ​0.48). Analysis of information storage reveals a larger processing memory in the zona incerta (ZI) than in the subthalamic nucleus (STN). We discuss possible implications for the efficiency of high frequency DBS. Further, we estimate the information transfer between forearm muscles and ZI/STN. Here, we show that the bidirectional information flow with respect to the STN is larger compared to the ZI. In contrast to the STN, however, the bidirectional information flow in the ZI is modulated, namely increased, by movement. The results of our study may help to understand the mechanism of action of deep brain stimulation and further explain recent studies claiming efficiency of ZI stimulation for certain motor symptoms.

ObjectiveTo examine 36-month effects of bilateral subthalamic nucleus deep brain stimulation (STN-DBS) on non-motor symptoms (NMS) compared with standard-of-care medical treatment (MED) in Parkinson’s disease (PD).MethodsHere we report the 36-month follow-up of a prospective, observational, controlled, international multicentre study of the NILS cohort. Assessments included NMSScale (NMSS), PDQuestionnaire-8 (PDQ-8), Scales for Outcomes in PD (SCOPA)-motor examination, -activities of daily living, and -complications, and levodopa equivalent daily dose (LEDD). Propensity score matching resulted in a pseudo-randomised sub-cohort balancing baseline demographic and clinical characteristics between the STN-DBS and MED groups. Within-group longitudinal outcome changes were analysed using Wilcoxon signed-rank and between-group differences of change scores with Mann-Whitney U test. Strength of clinical responses was quantified with Cohen’s effect size. In addition, bivariate correlations of change scores were explored.ResultsPropensity score matching applied on the cohort of 151 patients (STN-DBS n=67, MED n=84) resulted in a well-balanced sub-cohort including 38 patients per group. After 36 months, STN-DBS significantly improved NMSS, PDQ-8, SCOPA-motor examination and -complications and reduced LEDD. Significant between-group differences, all favouring STN-DBS, were found for NMSS, SCOPA-motor complications, LEDD (large effects), motor examination and PDQ-8 (moderate effects). Furthermore, significant differences were found for the sleep/fatigue, urinary (large effects) and miscellaneous NMSS domains (moderate effects). NMSS total and PDQ-8 change scores correlated significantly.ConclusionsThis study provides Class IIb evidence for beneficial effects of STN-DBS on NMS at 36-month follow-up which also correlated with quality of life improvements. This highlights the importance of NMS for DBS outcomes assessments.