Towards chronic deep brain stimulation in freely moving hemiparkinsonian rats: applicability and functionality of a fully implantable stimulation system.

Objective.This study aimed at investigating a novel fully implantable deep brain stimulation (DBS) system and its ability to modulate brain metabolism and behavior through subthalamic nucleus (STN) stimulation in a hemiparkinsonian rat model.Approach.Twelve male rats were unilaterally lesioned with 6-hydroxydopamine in the medial forebrain bundle and received a fully implantable DBS system aiming at the ipsilesional STN. Each rat underwent three cylinder tests to analyze front paw use: a PRE test before any surgical intervention, an OFF test after surgery but before stimulation onset and an ON test under DBS. To visualize brain glucose metabolism in the awake animal, two [18F]FDG scans were conducted in the OFF and ON condition. At least 4 weeks after surgery, an [18F]FDOPA scan was used to check for dopaminergic integrity.Main results.In general, STN DBS increased [18F]FDG uptake ipsilesionally and decreased it contralesionally. More specifically, bilateral orbitofrontal cortex, ipsilateral caudate putamen, sensorimotor cortex and nucleus accumbens showed significantly higher tracer uptake in ON compared to OFF condition. Contralateral cingulate and secondary motor cortex, caudate putamen, amygdala, hippocampus, retrosplenial granular cortex, superior colliculus, and parts of the cerebellum exhibited significantly higher [18F]FDG uptake in the OFF condition. On the behavioral level, stimulation was able improve use of the contralesional affected front paw suggesting an effective stimulation produced by the implanted system.Significance.The fully implantable stimulation system developed by us and presented here offers the output of arbitrary user-defined waveforms, patterns and stimulation settings and allows tracer accumulation in freely moving animals. It is therefore a suitable device for implementing behavioral PET studies. It contributes immensely to the possibilities to characterize and unveil the effects and mechanisms of DBS offering valuable clues for future improvements of this therapy.

Comparison of Bladder Inhibitory Effects of Patterned Spinal Nerve Stimulation With Conventional Neuromodulation in the Rat.

OBJECTIVES: The present study compared the effectiveness of patterned frequency of spinal nerve stimulation (SNS) with continuous, fixed-frequency nerve stimulation in an animal model of the bladder reflex contraction (BRC). MATERIALS AND METHODS: In anesthetized female rats, wire electrodes were placed under each of the L6 spinal nerve to produce bilateral SNS. A cannula was placed into the bladder via the urethra, and the urethra was ligated to ensure an isovolumetric bladder. RESULTS: Using motor threshold intensity, continuous stimulation at fixed frequencies of 4 Hz (n = 5) and 10 Hz (n = 7) decreased the frequency of BRC of 71 ± 24% (mean, SEM) and 85 ± 18% of controls, respectively (vs. no stimulation, n = 10, p < 0.05, two-way analysis of variance [ANOVA]). Fixed-frequency stimulation at 0.01, 0.1, 1, 40, and 100 Hz, did not demonstrate a trend change on BRC. When stimulation frequency is delivered with a 4-6 pulse/burst pattern every 1-100 sec, neuromodulation has demonstrated a trend toward effectiveness, with a four-pulse 40 Hz burst stimulation per second showing the most difference, reducing the BRC frequency of 74 ± 8% of control (n = 8, p < 0.05, two-way ANOVA). However, it is not more effective than continuous neuromodulation at a fixed frequency of 4 Hz or 10 Hz at BRC inhibition. CONCLUSIONS: Burst stimulations may inhibit bladder contractions; however, they are not more effective than continuous neuromodulation. Without further knowledge regarding mechanisms and potential benefit of burst stimulation on bladder control in patients with neuropathological conditions, applications should utilize continuous fixed 10 Hz stimulation for maximal clinical outcomes.

Effects on radiation oncology treatments involving various neuromodulation devices.

OBJECT: Where no society-based or manufacturer guidance on radiation limits to neuromodulation devices is available, this research provides the groundwork for neurosurgeons and radiation oncologists who rely on the computerized treatment plan clinically for cancer patients. The focus of the article is to characterize radiation parameters of attenuation and scatter when an incident therapeutic x-ray beam is directed upon them. At the time of this writing, manufacturers of Neuromodulation products do not recommend direct exposure of the device in the beam nor provide guidance for the maximum dose for these devices. METHODS: Ten neuromodulation models were chosen to represent the finite class of devices marketed by Medtronic before 2011. CT simulations permitted computer treatment modeling for dose distribution analysis as used routinely in radiation oncology for patients. Phantom case results were directly compared to actual clinical patient cases. Radiation detection measurements were then correlated to computational results. Where the x-ray beam passes through the device and is attenuated, dose reduction was identified with Varian Eclipse computer modeling for these posterior locations. RESULTS: Although the computer algorithm did not identify physical processes of side-scatter and back-scatter, these phenomena were proven by radiation measurement to occur. In general, the computer results underestimated the level of change seen by measurement. CONCLUSIONS: For these implantable neurostimulators, the spread in dose changes were found to be -6.2% to -12.5% by attenuation, +1.7% to +3.8% by side-scatter, and +1.1% to +3.1% by back-scatter at 6 MV. At 18 MV, these findings were observed to be -1.4% to -7.0% by attenuation, +1.8% to 5.7% by side-scatter, and 0.8% to 2.7% by back-scatter. No pattern for the behavior of these phenomena was deduced to be a direct consequence of device size.

New approaches to eliminating common-noise artifacts in recordings from intracortical microelectrode arrays: inter-electrode correlation and virtual referencing.

Intracortical microelectrode arrays record multi-unit extracellular activity for neurophysiology studies and for brain-machine interface applications. The common first step is neural spike-detection; a process complicated by common-noise signals from motion artifacts, electromyographic activity, and electric field pickup, especially in awake/behaving subjects. Often common-noise spikes are very similar to neural spikes in their magnitude, spectral, and temporal features. Provided sufficient spacing exists between electrodes of the array, a local neural spike is rarely recorded on multiple electrodes simultaneously. This is not true for distant common-noise sources. Two new techniques compatible with standard spike-detection schemes are introduced and evaluated. The first method, virtual referencing (VR), takes the average recording from all functional electrodes in the array (represents the signal from a virtual-electrode at the array's center) and subtracts it from the test electrode signal. The second method, inter-electrode correlation (IEC), computes a correlation coefficient between threshold exceeding candidate spike segments on the test electrode and concurrent segments from remaining electrodes. When sufficient correlation is detected, the candidate spike is rejected as originating from a distant common-noise source. The performance of these algorithms was compared with standard thresholding and differential referencing approaches using neural recordings from un-anaesthetized rats. By evaluating characteristics of mean-spike waveforms generated by each method under different levels of common-noise, it was found that IEC consistently offered the most robust means of neural spike-detection. Furthermore, IEC's rejection of supra-threshold events not likely originating from local neurons significantly reduces data handling for downstream spike sorting and processing operations.

Collagenase-aided intracortical microelectrode array insertion: effects on insertion force and recording performance.

Intracortical microelectrodes puncture the intact pia mater membrane during insertion, a process that can cause brain dimpling and trauma. To ensure that the device is able to withstand forces during implantation without buckling, the selection of acceptable implant materials and geometries is limited to rigid designs with large cross-sectional areas. Such designs likely increase insertion trauma and potentially exacerbate the chronic tissue response. In this paper, a technique that may relax the mechanical requirements of implanted microelectrodes through enzymatic (collagenase mediated) manipulation of the pia mater is quantified experimentally. Measurements of the insertion force profiles were obtained with a load cell during computer controlled (10 microm/s) insertion of microwire arrays into the cortex of rats. It was observed that collagenase application reduced the peak insertion force experienced by the microwire arrays by almost 40% on average (4.04 +/-2.03 mN versus 2.36 +/-1.17 mN; control versus treated sites). Peak insertion force magnitudes were highly dependent on implant location with anterior sites registering lower peaks than more posterior sites. Chronic neural recording performance (up to one month) did not appear to be adversely affected by the collagenase treatment, suggesting the overall safety of the technique. Our data suggest that controlled application of collagenase is a useful method in enabling implantation of thinner microelectrodes, potentially facilitating reduced insertion trauma and lower immune response. Furthermore, due to dependence of insertion force on anatomical location, the intended target region should be considered in implant design.

Automated reduction of non-neuronal signals from intra-cortical microwire array recordings by use of correlation technique.

Implanted intra-cortical micro-electrode arrays record multi-unit extracellular spike activity that is used in deciphering the neural basis for adaptation, learning, plasticity and as command signal for brain-machine interfaces (BMI). Detection of spike activity is the first step in successful implementation of all the aforementioned applications. However, with awake and behaving animals, micro-electrode arrays typically also record non-neuronal signals induced by the animal's movement, feeding and grooming actions. The spectral and temporal nature of these artifacts is similar to neural spikes, which complicates accurate detection. The distal source and higher strength of non-neuronal signals result in their near simultaneous registration on most electrodes, while neural spiking event is rarely recorded on more than one electrode of an array. This difference is utilized in identifying non-neuronal content from acquired data by performing a correlation analysis. The efficacy of the method is evaluated by comparing outcomes from algorithms that use absolute threshold and Principal Component Analysis (PCA) as a means of identifying neural spikes with the same methods incorporating correlation analysis.

Collagenase-aided insertion of intracortical microelectrode arrays: evaluation of insertion force and chronic recording performance.

Typically intracortical electrodes are required to puncture the intact pia mater during insertion which in the process can lead to brain dimpling and trauma. Furthermore, there is interest in the development of more flexible substrates to reduce relative micromotion after implantation, but such device have difficulty penetrating the pia without buckling. In this paper a strategy for reducing the mechanical integrity of the pia's collagen network by treatment with collagenase is evaluated experimentally. Measurements of the insertion force were carried out with a load cell during computer controlled slow (10 microm/sec) electrode insertion into the cortex of rats. It is shown that controlled application of collagenase reduces the peak insertion force experienced by the microwire arrays around 30% on average. In addition, chronic neural recordings (up to 1 month) suggest that there is no appreciable difference in the signal quality as recorded from the collagenase treated and the control sites. The results suggest the technique is useful for reducing insertion forces without compromising neural recording capabilities.