Selective GABA release as a mechanistic basis of high-frequency stimulation used for the treatment of neuropsychiatric diseases.

Electrical high-frequency stimulation (HFS) is applied in many brain areas to treat various clinical syndromes. The nearly identical constellation of stimulation parameters raises the question of a unique mechanism of action of this therapeutic option. The identification of a single HFS mechanism may help to optimize the HFS technology by targeting this single mechanism. Experimentally, only axonal membranes are targets of HFS, but not other membranes of neurons or glial cells. Within all HFS target regions, axons of excitatory glutamatergic and inhibitory GABAergic neurons are present and play roles in all clinical syndromes treated successfully with HFS. Therefore, glutamatergic or GABAergic fibres are likely candidates as mediators of a unique HFS mode of action. The selective involvement of another neuronal fibre type (e.g. monoaminergic, cholinergic, etc.) in the HFS mode of action is highly unlikely since the regional and syndromal dissimilarity of the clinical HFS applications precludes the assumption of such a fibre type as primary HFS site of action. Our recent experimental finding that HFS of human neocortical slices induces the action potential-mediated release of GABA, but not of glutamate, simplifies the possibilities to explain the HFS mode of action, as the explanation now may concentrate on GABAergic axons only. Thus, we are analysing, on the basis of the pathophysiological grounds of the various syndromes treated with deep brain stimulation, whether a selective GABA release is a collective explanation of the mode of action of HFS. We suggest that selective GABA release indeed may needfully and sufficiently explain efficacy and side effects of HFS.

On the estimation of the direction of information flow in networks of dynamical systems.

The inference of the interaction structure in networks of dynamical systems promises novel insights into the functioning or malfunctioning of systems in the neurosciences. This may improve the understanding of mechanisms underlying several diseases like tremor disorders and might eventually help to cure patients. Of particular interest is the estimation of the direction of information flow for which different methods have been suggested and have been applied to data from human tremor. Based on a simulated system motivated by the human tremor application we analyze the performance of three methods. The abilities and limitations of the individual techniques are compared and discussed. An application to essential tremor complements this investigation.

High functional connectivity of tremor related subthalamic neurons in Parkinson's disease.

OBJECTIVE: Tremor is a core symptom of Parkinson's disease (PD). The subthalamic nucleus (STN) seems to be crucial for tremor pathophysiology considering that deep brain stimulation (DBS) of the STN leads to an effective reduction of Parkinsonian tremor. Here, we investigate the functional connectivity between STN neurons in patients with Parkinsonian tremor. METHODS: STN activity was analyzed in 7 patients with Parkinsonian rest tremor who underwent stereotactic surgery for DBS. Spike activity was registered in different depths of the STN using an array of five microelectrodes. Interneuronal coherence within the STN was analyzed. RESULTS: Significant interneuronal coherence at the tremor frequency was detected in 78 out of 145 neurons. In contrast, interneuronal coherence in the beta band occurred only in 26 out of 145 neurons. Functional connectivity at the tremor frequency can be characterized by a slowly decaying exponential curve which describes coherence between STN neurons as a function of interneuronal distances between 0 and 4mm. CONCLUSIONS: Spatially distributed synchronization at the tremor frequency seems to be a key feature of STN pathophysiology in patients with Parkinsonian tremor. SIGNIFICANCE: The findings suggest a subthalamic tremor network which is widely extended and strongly coupled.

Time-variant estimation of directed influences during Parkinsonian tremor.

The inference of interaction structures in multidimensional time series is a major challenge not only in neuroscience but in many fields of research. To gather information about the connectivity in a network from measured data, several parametric as well as non-parametric approaches have been proposed and widely examined. Today a lot of interest is focused on the evolution of the network connectivity in time which might contain information about ongoing tasks in the brain or possible dynamic dysfunctions. Therefore an extension of the current approaches towards time-resolved analysis techniques is desired. We present a parametric approach for time variant analysis, test its performance for simulated data, and apply it to real-world data.

Tremor-correlated neuronal activity in the subthalamic nucleus of Parkinsonian patients.

Tremor in Parkinson's disease (PD) is generated by an oscillatory neuronal network consisting of cortex, basal ganglia and thalamus. The subthalamic nucleus (STN) which is part of the basal ganglia is of particular interest, since deep brain stimulation of the STN is an effective treatment for PD including Parkinsonian tremor. It is controversial if and how the STN contributes to tremor generation. In this study, we analyze neuronal STN activity in seven patients with Parkinsonian rest tremor who underwent stereotactic surgery for deep brain stimulation. Surface EMG was recorded from the wrist flexors and extensors. Simultaneously, neuronal spike activity was registered in different depths of the STN using an array of five microelectrodes. After spike-sorting, spectral coherence was analyzed between spike activity of STN neurons and tremor activity. Significant coherence at the tremor frequency was detected between EMG and neuronal STN activity in 76 out of 145 neurons (52.4%). In contrast, coherence in the beta band occurred only in 10 out of 145 neurons (6.9%). Tremor-coherent STN activity was widely distributed over the STN being more frequent in its dorsal parts (70.8-88.9%) than in its ventral parts (25.0-48.0%). Our results suggest that synchronous neuronal STN activity at the tremor frequency contributes to the pathogenesis of Parkinsonian tremor. The wide-spread spatial distribution of tremor-coherent spike activity argues for the recruitment of an extended network of subthalamic neurons for tremor generation.

Direct or indirect? Graphical models for neural oscillators.

Univariate and bivariate time series analysis techniques have enabled new insights into neural processes. However, these techniques are not feasible to distinguish direct and indirect interrelations in multivariate systems. To this aim multivariate times series techniques are presented and investigated by means of simulated as well as physiological time series. Pitfalls and limitations of these techniques are discussed.

Testing for directed influences among neural signals using partial directed coherence.

One major challenge in neuroscience is the identification of interrelations between signals reflecting neural activity. When applying multivariate time series analysis techniques to neural signals, detection of directed relationships, which can be described in terms of Granger-causality, is of particular interest. Partial directed coherence has been introduced for a frequency domain analysis of linear Granger-causality based on modeling the underlying dynamics by vector autoregressive processes. We discuss the statistical properties of estimates for partial directed coherence and propose a significance level for testing for nonzero partial directed coherence at a given frequency. The performance of this test is illustrated by means of linear and non-linear model systems and in an application to electroencephalography and electromyography data recorded from a patient suffering from essential tremor.

Deep brain stimulation of the nucleus ventralis intermedius for Holmes (rubral) tremor and associated dystonia caused by upper brainstem lesions. Report of two cases.

Holmes tremor is caused by structural lesions in the perirubral area of the midbrain. Patients often present with associated symptoms such as dystonia and paresis, which are usually refractory to medical therapy. Here, the authors describe two patients in whom both tremor and associated dystonia improved markedly following unilateral stimulation of the thalamic nucleus ventralis intermedius.

Single-unit analysis of substantia nigra pars reticulata neurons in freely behaving rats with genetic absence epilepsy.

PURPOSE: The substantia nigra pars reticulata (SNpr) is assumed to be involved in the control of several kinds of epileptic seizures, an assumption based mostly on neuropharmacologic evidence. However, only very few neurophysiological recordings from the basal ganglia support neuropharmacologic data. We investigated the electrophysiologic activity of SNpr neurons in rats with genetic absence epilepsy. METHODS: Electrocorticography (ECoG) and multi-unit recordings using permanently implanted tetrodes were obtained in freely behaving rats. After spike sorting, auto- and cross-correlation analysis was used to detect oscillatory neuronal activities and synchronizations. RESULTS: During interictal periods, neither oscillation nor synchronization could be observed in the firing patterns of SNpr neurons. At the beginning of the absence seizure, the firing rate increased significantly. The SNpr neurons started firing in bursts of action potentials. Bursts were highly correlated to the spike-and-wave discharges (SWDs) in the ECoG, mainly after the spike component of the cortical spike-and-wave complex. Moreover, pairs of SNpr neurons tended to fire synchronously. Before the end of the seizure, the firing rate decreased progressively, and the burst-firing pattern ended at or before the end of the SWDs. Once the SWDs had stopped, the SNpr neurons resumed their basal firing pattern as before the seizure onset. CONCLUSIONS: These results provide electrophysiologic evidence that firing patterns and synchronization of SNpr neurons are in phase with the occurrence of SWDs. The findings support the concept that nigral control mechanisms are involved in modulating the propagation of an ongoing generalized seizure.

[Clinical symptomatology, diagnostics, and treatment in patients with tuberculous meningoencephalitis]. / Tuberkulöse Meningoenzephalitis: klinisches Bild, Diagnostik und Behandlung.

BACKGROUND: Tuberculous meningoencephalitis (TBM) is still associated with a high mortality. The relative rareness of TBM in Western European countries and the accompanying heterogeneous and unspecific clinical symptoms often result in a delayed diagnosis. PATIENTS AND METHODS: We present six HIV-negative patients (age 37-72 years) with a laboratory-confirmed or clinically probable diagnosis of TBM. The diagnosis could be confirmed in three patients by culture of the cerebrospinal fluid (CSF), in one patient by positive tracheal aspirate culture. In the cases with probable TBM, the diagnosis was confirmed by the combination of clinical symptoms, CSF analysis, and magnetic resonance imaging (MRI). DISCUSSION: The diagnostic and therapeutic problems in TBM are discussed. Moreover, the neurologic complications are presented which developed in all patients during the clinical course despite immediate antituberculous therapy.

Effects of attention and precision of exerted force on beta range EEG-EMG synchronization during a maintained motor contraction task.

OBJECTIVE: The present study was aimed at investigating the effect of attention and precision level of exerted force on beta range EEG-EMG synchronization. METHODS: We simultaneously recorded cortical electrical activity (EEG) in a bipolar manner from the contralateral sensorimotor areas and surface electromyographic (EMG) activity from the flexor digitorum superficialis muscle in 10 healthy subjects during a maintained motor contraction task at 8% of the maximal voluntary contraction (MVC) force level. The coherence between oscillatory processes in the EEG and EMG was calculated. Three different conditions were investigated: (i) performing the task with high precision (HP); (ii) performing the task with high precision and simultaneously performing a mental arithmetic task (HPAT), i.e. attention was divided between the motor task and the mental arithmetic task; and (iii) performing the task with low precision (LP). RESULTS: We have found that the amount of beta range EEG-EMG synchronization decreases below the 95% confidence level when attention is divided between the motor task and the mental arithmetic task. The results also show that the frequency of beta range synchronization is higher with a higher level of precision but still lies within the beta frequency range (15-30 Hz). CONCLUSIONS: The data indicate that beta range synchronization represents a state of the cortico-muscular network when attention is directed towards the motor task. The frequency of synchronization of this network is associated with, and possibly encodes, precision in force production.