Translational model of cortical premotor-motor networks

Deciphering the physiological patterns of motor network connectivity is a prerequisite to elucidate aberrant oscillatory transformations and elaborate robust translational models of movement disorders. In the proposed translational approach, we studied the connectivity between premotor (PMC) and primary motor cortex (M1) by recording high-density electroencephalography in humans and between caudal (CFA) and rostral forelimb (RFA) areas by recording multi-site extracellular activity in mice to obtain spectral power, functional and effective connectivity. We identified a significantly higher spectral power in β- and γ-bands in M1compared to PMC and similarly in mice CFA layers (L) 2/3 and 5 compared to RFA. We found a strong functional β-band connectivity between PMC and M1 in humans and between CFA L6 and RFA L5 in mice. We observed that in both humans and mice the direction of information flow mediated by β- and γ-band oscillations was predominantly from PMC toward M1 and from RFA to CFA, respectively. Combining spectral power, functional and effective connectivity, we revealed clear similarities between human PMC-M1 connections and mice RFA-CFA network. We propose that reciprocal connectivity of mice RFA-CFA circuitry presents a suitable model for analysis of motor control and physiological PMC-M1 functioning or pathological transformations within this network

Identifying seizure onset zone and epileptic networks with the dynamic imaging of coherent sources [Abstract]

Purpose: In the presurgical evaluation of children with refractory focalepilepsy the main difficulty is to locate the exact point of seizure onset.The aim of this study was to characterize the areas of seizure onset as wellas the epileptic network involved in seizure propagation usingDynamicimaging of coherent sources (DICS)of ictal EEGs. Method: DICS is an inverse solution in the frequency domain whichdescribes neuronal networks and coherence of oscillatory brain activityby applying a spatial filter (Gross et al. PNAS 2001; 98:694–699). In 15children with refractory focal epilepsy, typical seizures were selectedfrom the EEGs recorded during the presurgical evaluation. For every sei-zure, two data sets of 10 s duration were extracted: one EEG segmentcontained the seizure onset and the other segment included the middlepart of the seizure. For both segments, the frequency range was definedand analyzed with DICS. The brain area with the strongest power in thecorresponding frequency range was defined as a reference region and itscoherence with the entire brain was computed using DICS. The result ofthe reference region was compared with the electroclinical localizationof seizure onset as well as with the postoperative resection site to deter-mine concordance. Results: For the beginning of the seizure, a good concordance betweenresults of the DICS localization and postoperative outcome was achievedin all 15 patients. The analysis of seizure propagation revealed an epilep-tic network which resembled reverberation of epileptic activity betweendifferent brain areas. Conclusion: DICS may be a useful tool to define the seizure onset zoneand study epileptic networks

Movement-related beta and gamma synchronization of the supplementary and primary motor cortex measured in epilepsy patients during longterm video EEG monitoring with subdural electrodes [Abstract]

Introduction: Exploration of sensorimotor integration processes during movement regulation is crucial to understand the pathophysiology of movement disorders and the effect of neuromodulation therapy. In Parkinson’s disease, dysfunction of supplementary motor cortex (SMA) has a primary role in evoking typical symptoms. In this study we detected post-movement beta (PMBS) and gamma synchronization of the SMA and primary motor cortex with electrocorticography (ECoG) in patients with epilepsy. PMBS is an electrophysiological indicator of sensorimotor integration, its parameters alter differently in several movement disorders. Methods: ECoG in 3 patients with epilepsy was recorded during invasive preoperative long-term video EEG monitoring through subdural strip and grid electrodes placed on the SMA and lobulus paracentralis and the representation field of the hand area in the primary motor cortex. Patients were requested in the interictal period to repeat short flexions of each thumb thirty times voluntarily; the trials were averaged with respect to the offset of the brisk movements. Time-frequency analysis of power was performed with multitaper method. Results: Post-movement synchronization could be detected mainly in the gamma frequency band above SMA and in the beta band above primary motor cortex. Latencies of post-movement synchronization varied in the SMA and primary motor cortex. Conclusions: Activity of the SMA in the two hemispheres cannot be detected with electroencephalography or magnetoencephalography. In our study we showed the first time that post-movement synchronization appears mainly in the gamma band in the SMA. Evaluation of the latencies supports the hypothesis that post-movement synchronization indicates a motor network activity

Low and high beta band activity in the primary sensorimotor cortex is diminished by ipsilateral subthalamic stimulation in Parkinsonian patients [Abstract]

Objective: We analyzed how change of the low and high beta power in the primary sensorimotor cortex relates to different levels of subthalamic stimulation; we hypothesized that it is a suitable biomarker for a closed-loop system. Background: Beta power in the motor system is shown to indicate the kinetic state in Parkinson’s disease. Method: We recruited 20 Parkinsonian patients. Bradykinesia of the most affected hand was measured first with Kinesia motion sensor system (Great Lakes NeuroTechnologies) in medication withdrawal; and four levels of contralateral stimulation (0: OFF, 1-3: decreasing symptoms to ON state) was individually selected. We performed 64-channel electroencephalography (EEG) measurement during a resting state with the four levels of stimulation settings mentioned above. We stimulated the usually used contacts during the whole study, and the ipsilateral stimulation remained ON and unchanged. The 2 minutes long EEG segments were cleaned from DBS artifacts by in-house algorithms. We performed line-noise removal; eye blinks and muscle artifacts were eliminated using ICA analyses. We calculated spectral power at the low (13-20Hz) and high (21-30Hz) beta frequency bands at the sensorimotor cortical region both sides using a beamformer algorithm called the Dynamic Imaging of Coherent Sources. We used repeated measures ANOVA to compare power values in the different locations and stimulation conditions in the two frequency bands. The Medical Research Council in Hungary provided ethical approval. (080958/2015/OTIG). Results: Resting state low- and high-frequency beta power in the primary sensorimotor cortex gradually decreased with the elevation of the ipsilateral stimulation level. In the continuously stimulated contralateral hemisphere, beta power remained at the baseline level. The beta power values measured in the two hemispheres were significantly different in stimulation levels 0-2 but not in level 3 (p < 0.05) both in the low- and high-frequency bands. Conclusion: The change of beta power in the primary sensorimotor cortex during STN-DBS is strictly ipsilateral, and depends on the level of stimulation. Beta power in the sensorimotor cortex could be a potential biomarker for closed-loop DBS. The support of Medtronic Inc. for this project is gratefully acknowledged

Effects of ON and OFF subthalamic nucleus-DBS on prefrontal cortex activation during a cognitive task: an fNIRS study

Subthalamic nucleus (STN) deep brain stimulation (DBS) therapy is an effective treatment for the appendicular motor symptoms of Parkinson’s disease (PD). The STN contains multiple segregated circuits subserving motor, cognitive and mood functions through distinct connectivity to cortical regions. Therefore, we examined prefrontal cortical (PFC) effects of “ON” and “OFF” STN-DBS on executive function (Go/NoGo) using functional near-infrared spectroscopy (fNIRS). Methods Out of 8 PD STN-DBS patients, we present here preliminary analysis of a male (62y) PD patient with bilateral STN-DBS (unipolar, 180Hz, 3.5V). The patient was tested after 12h withdrawal of dopamine medications in both an “OFF” and “ON” DBS session separated by 30min. The subject performed a computerised GoNoGo task with 3 alternating Go/NoGo blocks of 30s duration (20 trials/block) interspersed with 30s rest. Reaction time (RT) and accuracy (omission-Om and commission-Cm errors) results were the average of the 3 Go/NoGo blocks. During performance of the Go/NoGo blocks, changes in oxygenated (O2Hb) and deoxygenated (HHb) haemoglobin concentrations were measured by a fNIRS system (Oxymon MkIII, Artinis Medical Systems) covering the bilateral PFC regions. Results/Discussion Clinical motor performance (UPDRSIII) improved from OFF (31) to ON (20). RT during Go and NoGo was ∼40ms faster in OFF (460 and 364ms) than ON (516 and 407ms). Furthermore, the NoGo condition increased misses (Om) in ON (7%) than OFF (0%); while false alarms (Cm) were similarly increased in ON (27%) and OFF (30%). The Go and NoGo conditions increased bilateral PFC activation (i.e., increase in O2Hb and decrease in HHb). However, there was a general decrease in PFC activation in OFF relative to ON, and this was more obvious in Go than NoGo (see Fig. 1) Conclusion These preliminary results indicate that STN-DBS modulates neurovascular responses in the bilateral PFC that are associated with response inhibition

Dynamic networks differentiate the language ability of children with cochlear implants

Background: Cochlear implantation (CI) in prelingually deafened children has been shown to be an effective intervention for developing language and reading skill. However, there is a substantial proportion of the children receiving CI who struggle with language and reading. The current study–one of the first to implement electrical source imaging in CI population was designed to identify the neural underpinnings in two groups of CI children with good and poor language and reading skill. Methods: Data using high density electroencephalography (EEG) under a resting state condition was obtained from 75 children, 50 with CIs having good (HL) or poor language skills (LL) and 25 normal hearing (NH) children. We identified coherent sources using dynamic imaging of coherent sources (DICS) and their effective connectivity computing time-frequency causality estimation based on temporal partial directed coherence (TPDC) in the two CI groups compared to a cohort of age and gender matched NH children. Findings: Sources with higher coherence amplitude were observed in three frequency bands (alpha, beta and gamma) for the CI groups when compared to normal hearing children. The two groups of CI children with good (HL) and poor (LL) language ability exhibited not only different cortical and subcortical source profiles but also distinct effective connectivity between them. Additionally, a support vector machine (SVM) algorithm using these sources and their connectivity patterns for each CI group across the three frequency bands was able to predict the language and reading scores with high accuracy. Interpretation: Increased coherence in the CI groups suggest overall that the oscillatory activity in some brain areas become more strongly coupled compared to the NH group. Moreover, the different sources and their connectivity patterns and their association to language and reading skill in both groups, suggest a compensatory adaptation that either facilitated or impeded language and reading development. The neural differences in the two groups of CI children may reflect potential biomarkers for predicting outcome success in CI children

Gene-environment interaction elicits dystonia-like features and impaired translational regulation in a DYT-TOR1A mouse model

DYT-TOR1A dystonia is the most common monogenic dystonia characterized by involuntary muscle contractions and lack of therapeutic options. Despite some insights into its etiology, the disease's pathophysiology remains unclear. The reduced penetrance of about 30% suggests that extragenetic factors are needed to develop a dystonic phenotype. In order to systematically investigate this hypothesis, we induced a sciatic nerve crush injury in a genetically predisposed DYT-TOR1A mouse model (DYT1KI) to evoke a dystonic phenotype. Subsequently, we employed a multi-omic approach to uncover novel pathophysiological pathways that might be responsible for this condition. Using an unbiased deep-learning-based characterization of the dystonic phenotype showed that nerve-injured DYT1KI animals exhibited significantly more dystonia-like movements (DLM) compared to naive DYT1KI animals. This finding was noticeable as early as two weeks following the surgical procedure. Furthermore, nerve-injured DYT1KI mice displayed significantly more DLM than nerve-injured wildtype (wt) animals starting at 6 weeks post injury. In the cerebellum of nerve-injured wt mice, multi-omic analysis pointed towards regulation in translation related processes. These observations were not made in the cerebellum of nerve-injured DYT1KI mice; instead, they were localized to the cortex and striatum. Our findings indicate a failed translational compensatory mechanisms in the cerebellum of phenotypic DYT1KI mice that exhibit DLM, while translation dysregulations in the cortex and striatum likely promotes the dystonic phenotype

Cross-modal plasticity in children with cochlear implant: converging evidence from EEG and functional near-infrared spectroscopy

Over the first years of life, the brain undergoes substantial organization in response to environmental stimulation. In a silent world, it may promote vision by (i) recruiting resources from the auditory cortex and (ii) making the visual cortex more efficient. It is unclear when such changes occur and how adaptive they are, questions that children with cochlear implants can help address. Here, we examined 7–18 years old children: 50 had cochlear implants, with delayed or age-appropriate language abilities, and 25 had typical hearing and language. High-density electroencephalography and functional near-infrared spectroscopy were used to evaluate cortical responses to a low-level visual task. Evidence for a ‘weaker visual cortex response’ and ‘less synchronized or less inhibitory activity of auditory association areas’ in the implanted children with language delays suggests that cross-modal reorganization can be maladaptive and does not necessarily strengthen the dominant visual sense

Structure of the lipoprotein lipase-GPIHBP1 complex that mediates plasma triglyceride hydrolysis

The intravascular processing of triglyceride-rich lipoproteins by the lipoprotein lipase (LPL)–GPIHBP1 complex is crucial for clearing triglycerides from the bloodstream and for the delivery of lipid nutrients to vital tissues. A deficiency of either LPL or GPIHBP1 impairs triglyceride processing, resulting in severe hypertriglyceridemia (chylomicronemia). Despite intensive investigation by biochemists worldwide, the structures for LPL and GPIHBP1 have remained elusive. Inspired by the recent discovery that GPIHBP1 stabilizes LPL structure and activity, we crystallized the LPL–GPIHBP1 complex and solved its structure. The structure provides insights into the ability of GPIHBP1 to preserve LPL structure and activity and also reveals how inherited defects in these proteins impair triglyceride hydrolysis and cause chylomicronemia