Subthalamic local field beta oscillations during ongoing deep brain stimulation in Parkinson's disease in hyperacute and chronic phases

In the past years, local field potential (LFP) signals recorded from the subthalamic nucleus (STN) in patients undergoing deep brain stimulation (DBS) for Parkinson's disease (PD) disclosed that DBS has a controversial effect on STN beta oscillations recorded 2-7 days after surgery for macroelectrode implantation. Nothing is known about these DBS-induced oscillatory changes 30 days after surgery. We recorded STN LFPs during ongoing DBS in 7 patients with PD, immediately (hyperacute phase) and 30 days (chronic phase) after surgery. STN LFP recordings showed stationary intranuclear STN beta LFP activity in hyperacute and chronic phases, confirming that beta peaks were also present in chronic recordings. Power spectra of nuclei with significant beta activity (54% of the sample) showed that it decreased significantly during DBS (p=0.021) under both recording conditions. The time course of beta activity showed more evident DBS-induced changes in the chronic than in the hyperacute phase (p=0.014). DBS-induced changes in STN beta LFPs in patients undergoing DBS in chronic phase provide useful information for developing a new neurosignal-controlled adaptive DBS system.     

Time and Frequency-Dependent Modulation of Local Field Potential Synchronization by Deep Brain Stimulation

High-frequency electrical stimulation of specific brain structures, known as deep brain stimulation (DBS), is an effective treatment for movement disorders, but mechanisms of action remain unclear. We examined the time-dependent effects of DBS applied to the entopeduncular nucleus (EP), the rat homolog of the internal globus pallidus, a target used for treatment of both dystonia and Parkinson’s disease (PD). We performed simultaneous multi-site local field potential (LFP) recordings in urethane-anesthetized rats to assess the effects of high-frequency (HF, 130 Hz; clinically effective), low-frequency (LF, 15 Hz; ineffective) and sham DBS delivered to EP. LFP activity was recorded from dorsal striatum (STR), ventroanterior thalamus (VA), primary motor cortex (M1), and the stimulation site in EP. Spontaneous and acute stimulation-induced LFP oscillation power and functional connectivity were assessed at baseline, and after 30, 60, and 90 minutes of stimulation. HF EP DBS produced widespread alterations in spontaneous and stimulus-induced LFP oscillations, with some effects similar across regions and others occurring in a region- and frequency band-specific manner. Many of these changes evolved over time. HF EP DBS produced an initial transient reduction in power in the low beta band in M1 and STR; however, phase synchronization between these regions in the low beta band was markedly suppressed at all time points. DBS also enhanced low gamma synchronization throughout the circuit. With sustained stimulation, there were significant reductions in low beta synchronization between M1-VA and STR-VA, and increases in power within regions in the faster frequency bands. HF DBS also suppressed the ability of acute EP stimulation to induce beta oscillations in all regions along the circuit. This dynamic pattern of synchronizing and desynchronizing effects of EP DBS suggests a complex modulation of activity along cortico-BG-thalamic circuits underlying the therapeutic effects of GPi DBS for conditions such as PD and dystonia.     

A population level computational model of the basal ganglia that generates parkinsonian local field potential activity

Recordings from the basal ganglia’s subthalamic nucleus are acquired via microelectrodes immediately prior to the application of Deep Brain Stimulation (DBS) treatment for Parkinson’s Disease (PD) to assist in the selection of the final point for the implantation of the DBS electrode. The acquired recordings reveal a persistent characteristic beta band peak in the power spectral density function of the Local Field Potential (LFP) signals. This peak is considered to lie at the core of the causality–effect relationships of the parkinsonian pathophysiology. Based on LFPs acquired from human subjects during DBS for PD, we constructed a computational model of the basal ganglia on the population level that generates LFPs to identify the critical pathophysiological alterations that lead to the expression of the beta band peak. To this end, we used experimental data reporting that the strengths of the synaptic connections are modified under dopamine depletion. The hypothesis that the altered dopaminergic modulation may affect both the amplitude and the time course of the postsynaptic potentials is validated by the model. The results suggest a pivotal role of both of these parameters to the pathophysiology of PD.     

Estimating Extracellular Spike Waveforms from CA1 Pyramidal Cells with Multichannel Electrodes

Extracellular (EC) recordings of action potentials from the intact brain are embedded in background voltage fluctuations known as the “local field potential” (LFP). In order to use EC spike recordings for studying biophysical properties of neurons, the spike waveforms must be separated from the LFP. Linear low-pass and high-pass filters are usually insufficient to separate spike waveforms from LFP, because they have overlapping frequency bands. Broad-band recordings of LFP and spikes were obtained with a 16-channel laminar electrode array (silicone probe). We developed an algorithm whereby local LFP signals from spike-containing channel were modeled using locally weighted polynomial regression analysis of adjoining channels without spikes. The modeled LFP signal was subtracted from the recording to estimate the embedded spike waveforms. We tested the method both on defined spike waveforms added to LFP recordings, and on in vivo-recorded extracellular spikes from hippocampal CA1 pyramidal cells in anaesthetized mice. We show that the algorithm can correctly extract the spike waveforms embedded in the LFP. In contrast, traditional high-pass filters failed to recover correct spike shapes, albeit produceing smaller standard errors. We found that high-pass RC or 2-pole Butterworth filters with cut-off frequencies below 12.5 Hz, are required to retrieve waveforms comparable to our method. The method was also compared to spike-triggered averages of the broad-band signal, and yielded waveforms with smaller standard errors and less distortion before and after the spike.     

Brain-stem auditory evoked potentials (BAEPs) from basal surface of temporal lobe recorded from chronic subdural electrodes

BAEPs were recorded from the basal surface of the temporal lobe by subdural electrodes chronically implanted in 6 patients who were evaluated for surgical management of intractable partial seizures. Near-field recordings were obtained by recording between the subdural electrode closet and most distant to the brain-stem. Far-field recordings were obtained by recording between the subdural electrodes and an indifferent electrode over the spinal process of the seventh cervical vertebrae. The recordings were compared with standard ear-vertex recordings.After ipsilateral ear stimulation, the subdural electrode closet to the brain-stem recorded large amplitude waves I and II, followed by less well-defined waves of longer latencies. Recordings to contralateral stimulation showed no clearly defined waves I and II and a large amplitude wave Vn. Waves III, IV, V, Vn and VI were of opposite polarity after ipsi- and contralateral stimulation. These findings indicate that waves I and II are generated ipsilaterally to the stimulation side, whereas wave Vn has a contralateral origin. Wave Vn may be generated in the brachium of the inferior colliculus, as suggested from latency and from dipole configuration studies. This conclusion is consistent with the classical anatomical observations that the supracollicular auditory pathways are predominantly crossed.     

Microelectrode Guided Implantation of Electrodes into the Subthalamic Nucleus of Rats for Long-term Deep Brain Stimulation

Deep brain stimulation (DBS) is a widely used and effective therapy for several neurologic disorders, such as idiopathic Parkinson’s disease, dystonia or tremor. DBS is based on the delivery of electrical stimuli to specific deep anatomic structures of the central nervous system. However, the mechanisms underlying the effect of DBS remain enigmatic. This has led to an interest in investigating the impact of DBS in animal models, especially in rats. As DBS is a long-term therapy, research should be focused on molecular-genetic changes of neural circuits that occur several weeks after DBS. Long-term DBS in rats is challenging because the rats move around in their cage, which causes problems in keeping in place the wire leading from the head of the animal to the stimulator. Furthermore, target structures for stimulation in the rat brain are small and therefore electrodes cannot easily be placed at the required position. Thus, a set-up for long-lasting stimulation of rats using platinum/iridium electrodes with an impedance of about 1 MΩ was developed for this study. An electrode with these specifications allows for not only adequate stimulation but also recording of deep brain structures to identify the target area for DBS. In our set-up, an electrode with a plug for the wire was embedded in dental cement with four anchoring screws secured onto the skull. The wire from the plug to the stimulator was protected by a stainless-steel spring. A swivel was connected to the circuit to prevent the wire from becoming tangled. Overall, this stimulation set-up offers a high degree of free mobility for the rat and enables the head plug, as well as the wire connection between the plug and the stimulator, to retain long-lasting strength.     

A Multimodal,SU-8 - Platinum - Polyimide Microelectrode Array for Chronic In Vivo Neurophysiology

Utilization of polymers as insulator and bulk materials of microelectrode arrays (MEAs) makes the realization of flexible, biocompatible sensors possible, which are suitable for various neurophysiological experiments such as in vivo detection of local field potential changes on the surface of the neocortex or unit activities within the brain tissue. In this paper the microfabrication of a novel, all-flexible, polymer-based MEA is presented. The device consists of a three dimensional sensor configuration with an implantable depth electrode array and brain surface electrodes, allowing the recording of electrocorticographic (ECoG) signals with laminar ones, simultaneously. In vivo recordings were performed in anesthetized rat brain to test the functionality of the device under both acute and chronic conditions. The ECoG electrodes recorded slow-wave thalamocortical oscillations, while the implanted component provided high quality depth recordings. The implants remained viable for detecting action potentials of individual neurons for at least 15 weeks.     

Spatial coherence and stationarity of local field potentials in an isolated whole hippocampal preparation <Emphasis Type="Italic">in vitro</Emphasis>

Local field potential (LFP) multielectrode recordings of spontaneous rhythms in an isolated whole hippocampal preparation are characterized with respect to their spatial variability within the hippocampus, and their frequency properties. Using simulated data, we categorize potential relationships between frequency variation over time in LFP recordings and spatial variability between electrodes. We then use data recorded from the intact preparation to distinguish between our theoretical categories. We find that the LFP recordings have a close to spatially invariant frequency distribution (not phase) across the hippocampus, and differ in frequency only in a component that may be seen as physiological noise. From these facts, we conclude that the isolated hippocampal LFP recordings represent a single signal and may be regarded as a unitary circuitry. We additionally examine phase differences across our recording sites. We use our characterization of the hippocampal isolate’s properties to predict its spatial coherence in response to high frequency stimulation. We find that there is a finely tuned inverse relationship between temporal variability in the hippocampal isolate’s LFP recordings and their spatial coherence.     

Frequency Dependence of Signal Power and Spatial Reach of the Local Field Potential

Despite its century-old use, the interpretation of local field potentials (LFPs), the low-frequency part of electrical signals recorded in the brain, is still debated. In cortex the LFP appears to mainly stem from transmembrane neuronal currents following synaptic input, and obvious questions regarding the ‘locality’ of the LFP are: What is the size of the signal-generating region, i.e., the spatial reach, around a recording contact? How far does the LFP signal extend outside a synaptically activated neuronal population? And how do the answers depend on the temporal frequency of the LFP signal? Experimental inquiries have given conflicting results, and we here pursue a modeling approach based on a well-established biophysical forward-modeling scheme incorporating detailed reconstructed neuronal morphologies in precise calculations of population LFPs including thousands of neurons. The two key factors determining the frequency dependence of LFP are the spatial decay of the single-neuron LFP contribution and the conversion of synaptic input correlations into correlations between single-neuron LFP contributions. Both factors are seen to give low-pass filtering of the LFP signal power. For uncorrelated input only the first factor is relevant, and here a modest reduction (<50%) in the spatial reach is observed for higher frequencies (>100 Hz) compared to the near-DC () value of about . Much larger frequency-dependent effects are seen when populations of pyramidal neurons receive correlated and spatially asymmetric inputs: the low-frequency () LFP power can here be an order of magnitude or more larger than at 60 Hz. Moreover, the low-frequency LFP components have larger spatial reach and extend further outside the active population than high-frequency components. Further, the spatial LFP profiles for such populations typically span the full vertical extent of the dendrites of neurons in the population. Our numerical findings are backed up by an intuitive simplified model for the generation of population LFP.     

Gold nanograin microelectrodes for neuroelectronic interfaces

Neuroelectronic interfaces are imperative in investigating neural tissues as electrical signals are the main information carriers in the nervous system and metal microelectrodes have been widely used for recording and stimulation of nerve cells. For high performance microelectrodes, low tissue-electrode interfacial impedance and high charge injection limits are essential and nanoscale surface engineering has been utilized to meet the requirements for microelectrodes. We report a single-cell sized microelectrode, which has unique gold nanograin structures, using a simple electrochemical deposition method. The fabricated microelectrode had a sunflower shape with 1–5 (m of micropetals along the circumference of the microelectrode and 500 nm nanograins at the center. The nanograin electrodes had 69-fold decrease of impedance and 10-fold increase in electrical stimulation capability compared to unmodified flat gold microelectrodes. The recording and stimulation performance of nanograin electrodes was tested using dissociated rat hippocampal neuronal cultures. Noise levels were extremely low (2.89 μV_rms) resulting in high signal-to-noise ratio for low-amplitude action potentials (18.6–315 μV). Small biphasic current pulses (20–60 μA) could evoke action potentials from neurons nearby electrodes. This new nanostructured neural electrode may be applicable for the development of cell-based biosensors or clinical neural prosthetic devices.     

Problems of recordings of nervous activity with glass microelectrodes in the CNS of insects

1. Extracellular single unit recordings with glass microelectrodes in the central nervous system of insects display action potentials of variable amplitude, polarity and time course. This phenomenon is due to capacitive influences at the electrode in contact with the tissue. This is demonstrated by an electrical model circuit simulating extracellular recording conditions. 2. Extracellularly recorded potentials often are very similar to intracellularly recorded ones. Criteria for the decision whether the electrode is intracellularly or not are discussed. 3. Action potentials and slow potentials were recorded simultaneously in the acoustic neuropiles of Locusta. Since slow potentials may not only be distorted by capacitive properties of both the tissue and the electrode, but also are influenced by the anatomical organization of the nervous tissue, their interpretation is ambiguous.     

Voltage Biasing, Cyclic Voltammetry, & Electrical Impedance Spectroscopy for Neural Interfaces

Electrical impedance spectroscopy (EIS) and cyclic voltammetry (CV) measure properties of the electrode-tissue interface without additional invasive procedures, and can be used to monitor electrode performance over the long term. EIS measures electrical impedance at multiple frequencies, and increases in impedance indicate increased glial scar formation around the device, while cyclic voltammetry measures the charge carrying capacity of the electrode, and indicates how charge is transferred at different voltage levels. As implanted electrodes age, EIS and CV data change, and electrode sites that previously recorded spiking neurons often exhibit significantly lower efficacy for neural recording. The application of a brief voltage pulse to implanted electrode arrays, known as rejuvenation, can bring back spiking activity on otherwise silent electrode sites for a period of time. Rejuvenation alters EIS and CV, and can be monitored by these complementary methods. Typically, EIS is measured daily as an indication of the tissue response at the electrode site. If spikes are absent in a channel that previously had spikes, then CV is used to determine the charge carrying capacity of the electrode site, and rejuvenation can be applied to improve the interface efficacy. CV and EIS are then repeated to check the changes at the electrode-tissue interface, and neural recordings are collected. The overall goal of rejuvenation is to extend the functional lifetime of implanted arrays.     

A Wireless EEG Recording Method for Rat Use inside the Water Maze

With the continued miniaturisation of portable embedded systems, wireless EEG recording techniques are becoming increasingly prevalent in animal behavioural research. However, in spite of their versatility and portability, they have seldom been used inside water-maze tasks designed for rats. As such, a novel 3D printed implant and waterproof connector is presented, which can facilitate wireless water-maze EEG recordings in freely-moving rats, using a commercial wireless recording system (W32; Multichannel Systems). As well as waterproofing the wireless system, battery, and electrode connector, the implant serves to reduce movement-related artefacts by redistributing movement-related forces away from the electrode connector. This implant/connector was able to successfully record high-quality LFP in the hippocampo-striatal brain regions of rats as they undertook a procedural-learning variant of the double-H water-maze task. Notably, there were no significant performance deficits through its use when compared with a control group across a number of metrics including number of errors and speed of task completion. Taken together, this method can expand the range of measurements that are currently possible in this diverse area of behavioural neuroscience, whilst paving the way for integration with more complex behaviours.     

Enlarged gold-tipped silicon microprobe arrays and signal compensation for multi-site electroretinogram recordings in the isolated carp retina

In order to record multi-site electroretinogram (ERG) responses in isolated carp retinae, we utilized three-dimensional (3D), extracellular, 3.5-μm-diameter silicon (Si) probe arrays fabricated by the selective vapor-liquid-solid (VLS) growth method. Neural recordings with the Si microprobe exhibit low signal-to-noise (S/N) ratios of recorded responses due to the high-electrical-impedance characteristics of the small recording area at the probe tip. To increase the S/N ratio, we designed and fabricated enlarged gold (Au) tipped Si microprobes (10-μm-diameter Au tip and 3.5-μm-diameter probe body). In addition, we demonstrated that the signal attenuation and phase delay of ERG responses recorded via the Si probe can be compensated by the inverse filtering method. We conclude that the reduction of probe impedance and the compensation of recorded signals are useful approaches to obtain distortion-free recording of neural signals with high-impedance microelectrodes.     

Intrinsic dendritic filtering gives low-pass power spectra of local field potentials

The local field potential (LFP) is among the most important experimental measures when probing neural population activity, but a proper understanding of the link between the underlying neural activity and the LFP signal is still missing. Here we investigate this link by mathematical modeling of contributions to the LFP from a single layer-5 pyramidal neuron and a single layer-4 stellate neuron receiving synaptic input. An intrinsic dendritic low-pass filtering effect of the LFP signal, previously demonstrated for extracellular signatures of action potentials, is seen to strongly affect the LFP power spectra, even for frequencies as low as 10 Hz for the example pyramidal neuron. Further, the LFP signal is found to depend sensitively on both the recording position and the position of the synaptic input: the LFP power spectra recorded close to the active synapse are typically found to be less low-pass filtered than spectra recorded further away. Some recording positions display striking band-pass characteristics of the LFP. The frequency dependence of the properties of the current dipole moment set up by the synaptic input current is found to qualitatively account for several salient features of the observed LFP. Two approximate schemes for calculating the LFP, the dipole approximation and the two-monopole approximation, are tested and found to be potentially useful for translating results from large-scale neural network models into predictions for results from electroencephalographic (EEG) or electrocorticographic (ECoG) recordings.     

Intracranial recording from the brain-stem and the trigeminal nerve following upper lip stimulation

Short latency evoked potentials following stimulation of the upper lip were recorded intracranially during neurosurgical procedures in 14 patients. In 10 patients, a suboccipital craniectomy provided direct access to the trigeminal root and the pons at the root entry zone. Direct recordings from the trigeminal root were characterized by a large triphasic potential at 2.4–2.7 msec. The latency of this potential increased as a result of moving the recording electrode proximally towards the brain-stem. The same potential could be recorded from the brain-stem surface at a latency suggesting an intra-axial presynaptic origin. A second component, N4.7, was recorded from over the most rostral aspect of the brain-stem in 3 patients and from the tentorium free edge in 4 patients. This potential of smaller amplitude did not show significant difference in latency or polarity at various electrode locations, suggesting a deep diencephalic origin remote from the recording electrode.     

Use of micromachined probes for the recording of cardiac electrograms in isolated heart tissues

Micromachined probes, with iridium (Ir) microelectrodes on silicon shanks, were evaluated to assess their suitability for cardiac electrogram recording. The electrochemical activation (anodic oxidation) procedure for the circular Ir microelectrode was investigated using the square wave potential according to the electrode size, number of cycles, and cathodic-anodic potential level of the square wave. Increase in the charge storage capacity was pronounced either in smaller electrodes or with higher potential level of the square wave. The electrode impedance reduced in a similar manner with increasing number of cycle irrespective of the electrode size. With either lower potential level (-0.70/+0.60 V) or smaller number of cycle (200 cycles) than those for the activation of stimulating electrode, the likelihood of overactivation of the recording microelectrode can be minimized. These anodic IrOx film (AIROF) microelectrodes were used for the recording of extracellular electrograms in two different ex vivo cardiac tissue preparations. A single-shank microprobe was applied to the left ventricle of a mouse heart. Both the spontaneous and paced transmural responses propagating between epicardium and endocardium were obtained. Longitudinal cardiac wavefronts propagating along the rabbit papillary muscle were also recorded with a unique multiple-shank design. The measured mean amplitude and the propagation velocity of the extracellular voltage were 12.2 +/- 1.8 mV and 58.9 +/- 2.2 cm/s, respectively (n = 27). These microprobes with precisely defined electrode spacing make a useful tool for the spatial and temporal mapping of electrical properties in isolated heart tissues ex vivo.     

Sub-second dopamine detection in human striatum

Fast-scan cyclic voltammetry at carbon fiber microelectrodes allows rapid (sub-second) measurements of dopamine release in behaving animals. Herein, we report the modification of existing technology and demonstrate the feasibility of making sub-second measurements of dopamine release in the caudate nucleus of a human subject during brain surgery. First, we describe the modification of our electrodes that allow for measurements to be made in a human brain. Next, we demonstrate in vitro and in vivo, that our modified electrodes can measure stimulated dopamine release in a rat brain equivalently to previously determined rodent electrodes. Finally, we demonstrate acute measurements of dopamine release in the caudate of a human patient during DBS electrode implantation surgery. The data generated are highly amenable for future work investigating the relationship between dopamine levels and important decision variables in human decision-making tasks.     

Microelectrode Neuronal Activity of the Internal Globus Pallidus in Dystonia Correlates with Postoperative Neuromodulation Effects and Placement of the Stimulation Electrode

BackgroundDeep brain stimulation (DBS) is emerging as a viable treatment option for selected patients with dystonia. Intraoperative extracellular microelectrode recordings (MER) are considered as the standard electrophysiological method for the precise positioning of the DBS electrode into the target brain structure. Accurate targeting of the permanent stimulation electrode into the Globus Pallidus internus (GPi) is key to positive long-term effects. The suitability of the location is peroperatively assessed by microelectrodes that register single-unit neuronal activity. The aim of this article is to analyse electrophysiological recordings of patient's neuronal activity with a focus on the identification of markers relevant to the patient's clinical state.MethodsIn this study, 13 patients chronically treated with double-sided DBS GPi were examined with a microrecording. The signal (24 kHz) processing, included bandpass filtering (0.5–5 kHz), automated detection of artefacts and feature extraction. Pre-processed signals were analysed by means of statistical learning.ResultsThe results show that the GPi was distinguished from its vicinity with p < 0.001 and 3 machine learning models AUCs had an accuracy of higher than 0.87. The observed biomarker, Hjort mobility, additionally correlated with the long-term neuromodulation effect (rho = −0.4; p < 0.05). Furthermore, we revealed a change of neural activity associated with the active distal DBS contact localization along the medio-lateral direction.ConclusionThis paper demonstrates the quantitative relationship between electrophysiological findings and the clinical effects of pallidal stimulation in dystonia and suggested objectification predictors of the effectiveness of this therapy.     

Independent Components of Neural Activity Carry Information on Individual Populations

Local field potential (LFP), the low-frequency part of the potential recorded extracellularly in the brain, reflects neural activity at the population level. The interpretation of LFP is complicated because it can mix activity from remote cells, on the order of millimeters from the electrode. To understand better the relation between the recordings and the local activity of cells we used a large-scale network thalamocortical model to compute simultaneous LFP, transmembrane currents, and spiking activity. We used this model to study the information contained in independent components obtained from the reconstructed Current Source Density (CSD), which smooths transmembrane currents, decomposed further with Independent Component Analysis (ICA). We found that the three most robust components matched well the activity of two dominating cell populations: superior pyramidal cells in layer 2/3 (rhythmic spiking) and tufted pyramids from layer 5 (intrinsically bursting). The pyramidal population from layer 2/3 could not be well described as a product of spatial profile and temporal activation, but by a sum of two such products which we recovered in two of the ICA components in our analysis, which correspond to the two first principal components of PCA decomposition of layer 2/3 population activity. At low noise one more cell population could be discerned but it is unlikely that it could be recovered in experiment given typical noise ranges.