Effects of STN DBS and auditory cueing on the performance of sequential movements and the occurrence of action tremor in Parkinson's disease.

BACKGROUND: Parkinson's disease (PD) patients show a higher ability to perform repetitive movements when they are cued by external stimuli, suggesting that rhythmic synchronization with an auditory timekeeper can be achieved in the absence of intact basal ganglia function. Deep brain stimulation (DBS) is another therapeutic method that improves movement performance in PD and may suppress or enhance action tremor. However, the combined effect of these therapies on action tremor has not been studied yet. In this pilot study, we thus test the effect of both DBS in the subthalamic nucleus (STN) and auditory cueing on movement performance and action tremor. METHODS: 7 PD patients treated with (bilateral) STN DBS were asked to move one hand or foot between two dots, separated by 30 cm as indicated on the table or the floor. The movement frequency was dictated by a metronome with a frequency in the range of 1.6 to 4.8 Hz. Each test was repeated three times for each extremity, with different stimulation settings applied during each repetition. The power spectral density patterns of recorded movements were studied. Tremor intermittency was taken into account by classifying each 2-second window of the recorded angular velocity signals as a tremor or non-tremor window. By determining the phase locking value it was tested whether movement or tremor was synchronized with the auditory cue. RESULTS: While action tremor presence or absence did not affect the level of synchronization of the movement signal with the auditory cue for the different metronome frequencies, the number of extremities showing action tremor was significantly reduced under external cueing conditions in combination with DBS. In this respect the cueing frequencies of 1.6 and 4.8 Hz showed similar effects, suggesting that the frequency of the cueing signal is not that critical. CONCLUSION: The combination of deep brain stimulation and auditory cueing, which both are proposed to involve the activation of cerebellar circuits, shows an enhanced action tremor reduction in Parkinson's disease.

Synchrony in Parkinson's disease: importance of intrinsic properties of the external globus pallidus.

The mechanisms for the emergence and transmission of synchronized oscillations in Parkinson's disease, which are potentially causal to motor deficits, remain debated. Aside from the motor cortex and the subthalamic nucleus, the external globus pallidus (GPe) has been shown to be essential for the maintenance of these oscillations and plays a major role in sculpting neural network activity in the basal ganglia (BG). While neural activity of the healthy GPe shows almost no correlations between pairs of neurons, prominent synchronization in the ß frequency band arises after dopamine depletion. Several studies have proposed that this shift is due to network interactions between the different BG nuclei, including the GPe. However, recent studies demonstrate an important role for the properties of neurons within the GPe. In this review, we will discuss these intrinsic GPe properties and review proposed mechanisms for activity decorrelation within the dopamine-intact GPe. Failure of the GPe to desynchronize correlated inputs can be a possible explanation for synchronization in the whole BG. Potential triggers of synchronization involve the enhancement of GPe-GPe inhibition and changes in ion channel function in GPe neurons.

Power spectral density analysis of physiological, rest and action tremor in Parkinson's disease patients treated with deep brain stimulation.

BACKGROUND: Observation of the signals recorded from the extremities of Parkinson's disease patients showing rest and/or action tremor reveal a distinct high power resonance peak in the frequency band corresponding to tremor. The aim of the study was to investigate, using quantitative measures, how clinically effective and less effective deep brain stimulation protocols redistribute movement power over the frequency bands associated with movement, pathological and physiological tremor, and whether normal physiological tremor may reappear during those periods that tremor is absent. METHODS: The power spectral density patterns of rest and action tremor were studied in 7 Parkinson's disease patients treated with (bilateral) deep brain stimulation of the subthalamic nucleus. Two tests were carried out: 1) the patient was sitting at rest; 2) the patient performed a hand or foot tapping movement. Each test was repeated four times for each extremity with different stimulation settings applied during each repetition. Tremor intermittency was taken into account by classifying each 3-second window of the recorded angular velocity signals as a tremor or non-tremor window. RESULTS: The distribution of power over the low frequency band (<3.5 Hz - voluntary movement), tremor band (3.5-7.5 Hz) and high frequency band (>7.5 Hz - normal physiological tremor) revealed that rest and action tremor show a similar power-frequency shift related to tremor absence and presence: when tremor is present most power is contained in the tremor frequency band; when tremor is absent lower frequencies dominate. Even under resting conditions a relatively large low frequency component became prominent, which seemed to compensate for tremor. Tremor absence did not result in the reappearance of normal physiological tremor. CONCLUSION: Parkinson's disease patients continuously balance between tremor and tremor suppression or compensation expressed by power shifts between the low frequency band and the tremor frequency band during rest and voluntary motor actions. This balance shows that the pathological tremor is either on or off, with the latter state not resembling that of a healthy subject. Deep brain stimulation can reverse the balance thereby either switching tremor on or off.

Modeling the vagus nerve system with the Unified Modeling Language.

Traditionally, the means of describing anatomical and physiological structures of the autonomic nervous system is natural language, drawings and images as represented in the scientific literature. In behavioral studies of this system, mathematical and electrical models and computer simulation tools are in use. In this article, we propose the use of the Unified Modeling Language to describe and specify the anatomical and physiological structures and indicate how these can be enriched to capture the behavioral view as well. Using the metamodel facilities of the language, we propose a domain specific language that captures the domain concepts, their relationships and constraints. Application of the language is demonstrated by modeling the vagus nerve in part.

Phase-dependent effects of stimuli locked to oscillatory activity in cultured cortical networks.

The archetypal activity pattern in cultures of dissociated neurons is spontaneous network-wide bursting. Bursts may interfere with controlled activation of synaptic plasticity, but can be suppressed by the application of stimuli at a sufficient rate. We sinusoidally modulated (4 Hz) the pulse rate of random background stimulation (RBS) and found that cultures were more active, burst less frequently, and expressed oscillatory activity. Next, we studied the effect of phase-locked tetani (four pulses, 200 s(-1)) on network activity. Tetani were applied to one electrode at the peak or trough of mRBS stimulation. We found that when tetani were applied at the peak of modulated RBS (mRBS), a significant potentiation of poststimulus histograms (PSTHs) occurred. Conversely, tetani applied at the trough resulted in a small but insignificant depression of PSTHs. In addition to PSTHs, electrode-specific firing rate profiles within spontaneous bursts before and after mRBS were analyzed. Here, significant changes in firing rate profiles were found only for stimulation at the peak of mRBS. Our study shows that rhythmic activity in culture is possible, and that the network responds differentially to strong stimuli depending on the phase at which they are delivered. This suggests that plasticity mechanisms may be differentially accessible in an oscillatory state.

The effect of learning on bursting.

We have studied the effect that learning a new stimulus-response (SR) relationship had within a neuronal network cultured on a multielectrode array. For training, we applied repetitive focal electrical stimulation delivered at a low rate (<1/s). Stimulation was withdrawn when a desired SR success ratio was achieved. It has been shown elsewhere, and we verified that this training algorithm, named conditional repetitive stimulation (CRS), can be used to strengthen an initially weak SR. So far, it remained unclear what the role of the rest of the network during learning was. We therefore studied the effect of CRS on spontaneously occurring network bursts. To this end, we made profiles of the firing rates within network bursts. We have earlier shown that these profiles change shape on a time base of several hours during spontaneous development. We show here that profiles of summed activity, called burst profiles, changed shape at an increased rate during CRS. This suggests that the whole network was involved in making the changes necessary to incorporate the desired SR relationship. However, a local (path-specific) component to learning was also found by analyzing profiles of single-electrode-activity phase profiles. Phase profiles that were not part of the SR relationship changed far less during CRS than the phase profiles of the electrodes that were part of the SR relationship. Finally, the manner in which phase profiles changed shape varied and could not be linked to the SR relationship.

Single pulse and pulse train modulation of cutaneous electrical stimulation: a comparison of methods.

SUMMARY: : Changing the amplitude of single rectangular pulse stimuli (SP) has the disadvantage of recruiting tactile and nociceptive fibers in a changing, unknown proportion. Keeping the amplitude constant, but applying a varying number of pulses in a train is another way of stimulus variation, keeping the proportion constant. So, pulse trains (PT) with a variable number of pulses but fixed amplitude might be more suitable to study nonperipheral aspects of processing of stimuli. In this study, we compared the effects of PT and SP stimulation on subjective Numeric Rating Scale scores of perceived stimulus strength and evoked potentials (EP). A total of 41 healthy subjects were electrically stimulated at the left forearm or left middle fingertip using SP and PT stimuli. Numeric Rating Scale scores and EPs were averaged from 105 randomized stimuli at 5 stimulus amplitudes or number of pulses for each subject. The relationships between stimulus amplitudes or number of pulses, EP components and Numeric Rating Scale scores differed depending on the stimulation method and stimulus location. Although the repeatedly reported Numeric Rating Scale-EP (N150-P200) correlation was reproduced for SP at the fingertip, no significant correlation was found for SP stimulation at the forearm. For PT this correlation was found for both stimulus locations. These findings demonstrate that SP and PT involve different ways of processing. The two methods result in different Numeric Rating Scale scores and EP components. Furthermore, PT stimulation is less dependent on stimulus location.

The subthalamic nucleus. Part I: development, cytology, topography and connections.

This monograph (Part I of two volumes) on the subthalamic nucleus (STN) accentuates the gap between experimental animal and human information concerning subthalamic development, cytology, topography and connections. The light and electron microscopical cytology focuses on the open nucleus concept and the neuronal types present in the STN. The cytochemistry encompasses enzymes, NO, glial fibrillary acidic protein (GFAP), calcium binding proteins, and receptors (dopamine, cannabinoid, opioid, glutamate, gamma-aminobutyric acid (GABA), serotonin, cholinergic, and calcium channels). The ontogeny of the subthalamic cell cord is also reviewed. The topography concerns the rat, cat, baboon and human STN. The descriptions of the connections are also given from a historical point of view. Recent tracer studies on the rat nigro-subthalamic connection revealed contralateral projections. Part II of the two volumes (volume 199) on the subthalamic nucleus (STN) starts with a systemic model of the basal ganglia to evaluate the position of the STN in the direct, indirect and hyperdirect pathways. A summary of in vitro studies is given, describing STN spontaneous activity as well as responses to depolarizing and hyperpolarizing inputs and high-frequency stimulation. STN bursting activity and the underlying ionic mechanisms are investigated. Deep brain stimulation used for symptomatic treatment of Parkinson's disease is discussed in terms of the elements that are influenced and its hypothesized mechanisms. This part of the monograph explores the pedunculopontine-subthalamic connections and summarizes attempts to mimic neurotransmitter actions of the pedunculopontine nucleus in cell cultures and high-frequency stimulation on cultured dissociated rat subthalamic neurons. STN cell models--single- and multi-compartment models and system-level models are discussed in relation to subthalamic function and dysfunction. Parts I and II are compared.

The subthalamic nucleus part II: modelling and simulation of activity.

Part I of The Subthalamic Nucleus (volume 198) (STN) accentuates the gap between experimental animal and human information concerning subthalamic development, cytology, topography and connections.The light and electron microscopical cytology focuses on the open nucleus concept and the neuronal types present in the STN. The cytochemistry encompasses enzymes, NO, glial fibrillary acidic protein (GFAP), calcium binding proteins, and receptors (dopamine, cannabinoid, opioid, glutamate, gamma-aminobutyric acid (GABA), serotonin, cholinergic, and calcium channels). The ontogeny of the subthalamic cell cord is also reviewed. The topography concerns the rat, cat, baboon and human STN. The descriptions of the connections are also given from a historical point of view. Recent tracer studies on the rat nigro-subthalamic connection revealed contralateral projections. This monograph (Part II of the two volumes) on the subthalamic nucleus (STN) starts with a systemic model of the basal ganglia to evaluate the position of the STN in the direct, indirect and hyperdirect pathways. A summary of in vitro studies is given, describing STN spontaneous activity as well as responses to depolarizing and hyperpolarizing inputs and high-frequency stimulation. STN bursting activity and the underlying ionic mechanisms are investigated. Deep brain stimulation used for symptomatic treatment of Parkinson's disease is discussed in terms of the elements that are influenced and its hypothesized mechanisms. This part of the monograph explores the pedunculopontine-subthalamic connections and summarizes attempts to mimic neurotransmitter actions of the pedunculopontine nucleus in cell cultures and high-frequency stimulation on cultured dissociated rat subthalamic neurons. STN cell models - single- and multi-compartment models and system-level models are discussed in relation to subthalamic function and dysfunction. Parts I and II are compared.

Analysis of cultured neuronal networks using intraburst firing characteristics.

It is an open question whether neuronal networks, cultured on multielectrode arrays, retain any capability to usefully process information (learning and memory). A necessary prerequisite for learning is that stimulation can induce lasting changes in the network. To observe these changes, one needs a method to describe the network in sufficient detail, while stable in normal circumstances. We analyzed the spontaneous bursting activity that is encountered in dissociated cultures of rat neocortical cells. Burst profiles (BPs) were made by estimating the instantaneous array-wide firing frequency. The shape of the BPs was found to be stable on a time scale of hours. Spatiotemporal detail is provided by analyzing the instantaneous firing frequency per electrode. The resulting phase profiles (PPs) were estimated by aligning BPs to their peak spiking rate over a period of 15 min. The PPs reveal a stable spatiotemporal pattern of activity during bursts over a period of several hours, making them useful for plasticity and learning studies. We also show that PPs can be used to estimate conditional firing probabilities. Doing so, yields an approach in which network bursting behavior and functional connectivity can be studied.

Spatial clustering analysis in neuroanatomy: applications of different approaches to motor nerve fiber distribution.

Spatial organization of the nerve fibers in the peripheral nerves may be important for the studies of axonal regeneration, the degenerative nerve diseases and the construction of interfaces with peripheral nerves, such as nerve prostheses. Functional topography of motor axons related to the gastrocnemius muscle was revealed in the ventral spinal roots by retrograde tracing. Gastrocnemius muscles of adult rats were injected with the tracer Fluoro-Gold. After 3 days of survival the animals were sacrificed and their ventral roots were harvested, sectioned, and imaged on a fluorescence microscope. Maps of the traced fibers were automatically analyzed using a novel approach, local spatial clustering statistics, that tested for occurrences of clusters of motor fibers and visualized them. Thresholds indicating the presence of clustering at various scales of observation were computed based on series of Monte Carlo simulations of random spatial point patterns. Clusters were visualized by kernel interpolation. The approach was tested on simulated data and subsequently applied to the motor fiber maps in the ventral roots. Results revealed clustering of the motor fibers innervating the gastrocnemius muscle at the level of the L6 ventral spinal root. The analysis was validated using Voronoi tessellation and nearest neighbor analysis.

Automatic morphometry of synaptic boutons of cultured cells using granulometric analysis of digital images.

Numbers, linear density, and surface area of synaptic boutons can be important parameters in studies on synaptic plasticity in cultured neurons. We present a method for automatic identification and morphometry of boutons based on filtering of digital images using granulometric analysis. Cultures of cortical neurons (DIV8 and DIV21) were fixed and marked with fluorescently labeled antibodies for synapsin I (a marker for synaptic boutons) and MAP-2 (a marker for dendrites). Images were acquired on a confocal microscope and automatically processed. Granulometry, a morphological operator sensitive to the geometry and size of objects, was used to construct a filter passing fuzzy fluorescent grains of a certain size. Next, the filter was overlaid with the original image (masking) and the positive pixels were identified by an integral intensity threshold (thresholding). Disjoint grains, representing individual boutons, were reconstructed from the connected pixels above the threshold, numbered and their area was measured. In total, 1498 boutons with a mean diameter of 1.63 +/- 0.49 microm (S.D.) were measured. Comparisons with manual counts showed that the proposed method was capable of identifying boutons in a systematic manner at the light microscopic level and was a viable alternative to manual bouton counting.

Three-dimensional topography of the motor endplates of the rat gastrocnemius muscle.

Spatial distribution of motor endplates affects the shape of the electrical activity recorded from muscle. In order to provide information for realistic models of action potential propagation within muscles, we assembled three-dimensional maps of the motor endplates of the rat medial gastrocnemius (MGM) and lateral gastrocnemius (MGL) muscles. The maps were assembled from histological cross sections stained for acetylcholinesterase activity. Within MGL, the motor endplates formed three columns along its longitudinal axis. Within MGM, the motor endplates were arranged in a leaf-like body that shifted obliquely from proximal to distal. As inferred from the proximo-distal distribution of the cross-sectional projection area, the majority of the motor endplates were concentrated in the middle of MGL and in the distal third of MGM. Regions of maximal motor endplate concentration are considered most suitable for injections of neuroactive substances, such as neuronal tracers. The assembled maps of the gastrocnemius muscles can be used as guides for such injections within the motor endplate zones.

Adhesion and proliferation of human Schwann cells on adhesive coatings.

Attachment to and proliferation on the substrate are deemed important considerations when Schwann cells (SCs) are to be seeded in synthetic nerve grafts. Attachment is a prerequisite for the SCs to survive and fast proliferation will yield large numbers of SCs in a short time, which appears promising for stimulation of peripheral nerve regeneration. The aim of the present study was to compare the adhesion and proliferation of human Schwann cells (HSCs) on different substrates. The following were selected for their suitability as an internal coating of synthetic nerve grafts; the extracellular matrix proteins fibronectin, laminin and collagen type I and the poly-electrolytes poly(d-lysine) (PDL) and poly(ethylene-imine) (PEI). On all coatings, attachment of HSCs was satisfactory and comparable, indicating that this factor is not a major consideration in choosing a suitable coating. Proliferation was best on fibronectin, laminin and PDL, and worst on collagen type I and PEI. Since nerve regeneration is enhanced by laminin and/or fibronectin, these are preferred as coatings for synthetic nerve grafts seeded with SCs.

Adhesion and growth of human Schwann cells on trimethylene carbonate (co)polymers.

Seeding of artificial nerve grafts with Schwann cells is a promising strategy for bridging large nerve defects. The aim of the present study was to evaluate the adhesion and growth of human Schwann cells (HSCs) on 1,3-trimethylene carbonate (TMC) and epsilon-caprolactone copolymers, with the final goal of using these materials in the development of an artificial nerve graft. The adhesion, proliferation, and morphology of HSCs on copolymers containing 10 and 82 mol % of TMC and on the parent homopolymers were investigated. HSCs adhered faster and in greater numbers on the copolymer with 82 mol % of TMC and on the TMC homopolymer compared with the other (co)polymers. On all polymer films, cell adhesion was lower than on gelatin (positive control). Despite differences in cell adhesion, cells displayed exponential growth on all tested surfaces, with similar growth rates. Cell numbers doubled approximately every 3 days on all substrates. When the polymer films were coated with fibronectin, no significant differences in cell adhesion and proliferation were observed between coated polymer surfaces and gelatin. The results indicate that all tested materials support the adhesion and proliferation of HSCs and can in principle be used for the preparation of flexible and slowly degrading nerve guides.

Geometry-based finite-element modeling of the electrical contact between a cultured neuron and a microelectrode.

The electrical contact between a substrate embedded microelectrode and a cultured neuron depends on the geometry of the neuron-electrode interface. Interpretation and improvement of these contacts requires proper modeling of all coupling mechanisms. In literature, it is common practice to model the neuron-electrode contact using lumped circuits in which large simplifications are made in the representation of the interface geometry. In this paper, the finite-element method is used to model the neuron-electrode interface, which permits numerical solutions for a variety of interface geometries. The simulation results offer detailed spatial and temporal information about the combined electrical behavior of extracellular volume, electrode-electrolyte interface and neuronal membrane.

Repair of ventral root avulsion using autologous nerve grafts in cats.

This study focuses on the capacity of motor axons to elongate from the spinal cord through an autologous nerve graft into a spinal nerve. Applying a ventral surgical approach, C7 ventral roots were avulsed from the cord in 12 cats. Autologous saphenous nerve grafts were implanted into the cord at the ventral root outlet site and coaptated to the spinal nerve. Outgrowth of axons was studied at survival times 7, 14, 30, 60 and 120 days, respectively. The results showed horseradish peroxidase positive motoneurons in the C7 ventral horn after retrograde labeling, as well as neurofilament and acetylcholinesterase positive axons in the entire trajectory from spinal cord to spinal nerve. Neurotization of the C7 spinal nerve started between 14 and 30 days after graft implantation. In addition electrophysiology provided evidence that outgrowing axons had re-established functional contact with the spinodeltoid muscle at 120 days after implantation.

Anatomy of the arcus tendineus fasciae pelvis in females.

Because of its proximity to the urethra, the anterior part of the arcus tendineus fasciae pelvis (ATFP) may be used in urethrosuspension procedures for urinary stress incontinence. In this study, 10 embalmed female cadaver hemipelves were dissected and their gross anatomy described. In females, the ATFP is a condensation of the endopelvic fascia. The anterior attachment of the ATFP is to the caudal inner surface of the body of the pubic bone at a site averaging 4 mm lateral to the pubic symphysis and covering an average area of 53 mm(2). Posteriorly, it attaches to the medial surface of the ischial spine. In nine of the 10 hemipelves the first anterior centimeters of the ATFP have a clear lateral fixation either to the lateral part of the levator ani muscle (n = 1), to the fascia covering the obturator internus muscle (n = 7), or to the obturator membrane (n = 1). Medially from the ATFP derives a 2-3-cm long flat fibrous attachment to the posterolateral aspect of the urethra. In eight unembalmed cadavers, the ATFP gave way at a pulling force of 8.2 kg (range = 3.5-11.5 kg). The ATFP resists caudal movement of the proximal anterior vaginal wall and the urethra in the upright posture and, therefore, may be suitable for urethrosuspension procedures.

Repair of ventral root avulsions of the brachial plexus: a review.

Traumatic root avulsions of the brachial plexus constitute a devastating lesion resulting in loss of function of the upper limb and carry a large emotional and socioeconomic impact. In this literature survey, the different factors involved in root avulsion are discussed in combination with various surgical techniques for repair of experimental ventral root avulsion. Until now repair of root avulsions did not generate unequivocal proof of recovery of limb function, particularly of the hand. More experimental studies are needed to assess the efficacy of several repair techniques, the optimal timing for surgery, and the complications associated with spinal cord manipulation.