Comparison of the In Vitro and In Vivo Electrochemical Performance of Bionic Electrodes

The electrochemical performance of platinum electrodes was assessed in vitro and in vivo to determine the impact of electrode implantation and the relevance of in vitro testing in predicting in vivo behaviour. A significant change in electrochemical response was seen after electrode polarisation. As a result, initial in vitro measurements were poor predictors of subsequent measurements performed in vitro or in vivo. Charge storage capacity and charge density measurements from initial voltammetric measurements were not correlated with subsequent measurements. Electrode implantation also affected the electrochemical impedance. The typically reported impedance at 1 kHz was a very poor predictor of electrode performance. Lower frequencies were significantly more dependent on electrode properties, while higher frequencies were dependent on solution properties. Stronger correlations in impedance at low frequencies were seen between in vitro and in vivo measurements after electrode activation had occurred. Implanting the electrode increased the resistance of the electrochemical circuit, with bone having a higher resistivity than soft tissue. In contrast, protein fouling and fibrous tissue formation had a minimal impact on electrochemical response. In vivo electrochemical measurements also typically use a quasi-reference electrode, may operate in a 2-electrode system, and suffer from uncompensated resistance. The impact of these experimental conditions on electrochemical performance and the relevance of in vitro electrode assessment is discussed. Recommended in vitro testing protocols for assessing bionic electrodes are presented.

A Spatial Transcriptomics Study of the Brain-Electrode Interface in Rat Motor Cortex

The study of the foreign body reaction to implanted electrodes in the brain is an important area of research for the future development of neuroprostheses and experimental electrophysiology. After electrode implantation in the brain, microglial activation, reactive astrogliosis, and neuronal cell death create an environment immediately surrounding the electrode that is significantly altered from its homeostatic state. To uncover physiological changes potentially affecting device function and longevity, spatial transcriptomics was implemented in this preliminary study to identify changes in gene expression driven by electrode implantation. This RNA-sequencing technique (10x Genomics, Visium) uses spatially coded, RNA-binding oligonucleotides on a microscope slide to spatially identify each sequencing read. For these experiments, sections of rat motor cortex implanted with Michigan-style silicon electrodes were mounted on the Visium slide for processing. Each tissue section was labeled for neurons and astrocytes using immunohistochemistry to provide a spatial reference for mapping each sequencing read relative to the device tract. Results from rat motor cortex at 24 hours, 1 week, and 6 weeks post implantation showed up to 5811 differentially expressed genes between implanted and non-implanted tissue sections. Many of these genes are related to biological mechanisms previously reported in studies of the foreign body response to implanted electrodes, while others are novel to this study. These results will provide a foundation for future work to both improve and measure the effects of gene expression on the long-term stability of recordings from implanted electrodes in the brain. Ongoing work will expand on these initial observations as we gain a better understanding of the dynamic, molecular changes taking place in the brain in response to electrode implantation.

Electrically evoked and spontaneous neural activity in the subthalamic nucleus under general anesthesia

OBJECTIVE Deep brain stimulation (DBS) surgery is commonly performed with the patient awake to facilitate assessments of electrode positioning. However, awake neurosurgery can be a barrier to patients receiving DBS. Electrode implantation can be performed with the patient under general anesthesia (GA) using intraoperative imaging, although such techniques are not widely available. Electrophysiological features can also aid in the identification of target neural regions and provide functional evidence of electrode placement. Here we assess the presence and positional variation under GA of spontaneous beta and high-frequency oscillation (HFO) activity, and evoked resonant neural activity (ERNA), a novel evoked response localized to the subthalamic nucleus. METHODS ERNA, beta, and HFO were intraoperatively recorded from DBS leads comprising four individual electrodes immediately after bilateral awake implantation into the subthalamic nucleus of 21 patients with Parkinson’s disease (42 hemispheres) and after subsequent GA induction deep enough to perform pulse generator implantation. The main anesthetic agent was either propofol (10 patients) or sevoflurane (11 patients). RESULTS GA reduced the amplitude of ERNA, beta, and HFO activity (p < 0.001); however, ERNA amplitudes remained large in comparison to spontaneous local field potentials. Notably, a moderately strong correlation between awake ERNA amplitude and electrode distance to an “ideal” therapeutic target within dorsal STN was preserved under GA (awake: ρ = −0.73, adjusted p value [padj] < 0.001; GA: ρ = −0.69, padj < 0.001). In contrast, correlations were diminished under GA for beta (awake: ρ = −0.45, padj < 0.001; GA: ρ = −0.13, padj = 0.12) and HFO (awake: ρ = −0.69, padj < 0.001; GA: ρ = −0.33, padj < 0.001). The largest ERNA occurred at the same electrode (awake vs GA) for 35/42 hemispheres (83.3%) and corresponded closely to the electrode selected by the clinician for chronic therapy at 12 months (awake ERNA 77.5%, GA ERNA 82.5%). The largest beta amplitude occurred at the same electrode (awake vs GA) for only 17/42 (40.5%) hemispheres and 21/42 (50%) for HFO. The electrode measuring the largest awake beta and HFO amplitudes corresponded to the electrode selected by the clinician for chronic therapy at 12 months in 60% and 70% of hemispheres, respectively. However, this correspondence diminished substantially under GA (beta 20%, HFO 35%). CONCLUSIONS ERNA is a robust electrophysiological signal localized to the dorsal subthalamic nucleus subregion that is largely preserved under GA, indicating it could feasibly guide electrode implantation, either alone or in complementary use with existing methods.

Intracranial approach for sub-second monitoring of neurotransmitters during DBS electrode implantation does not increase infection rate

Introduction: Currently, sub-second monitoring of neurotransmitter release in humans can only be performed during standard of care invasive procedures like DBS electrode implantation. The procedure requires acute insertion of a research probe and additional time in surgery, which may increase infection risk. We sought to determine the impact of our research procedure, particularly the extended time in surgery, on infection risk. Methods: We screened 607 DBS electrode implantation procedures performed at Wake Forest Baptist Medical Center between January 2011 through October 2020 using International Classification of Diseases (ICD) codes for infection. During this period, 116 cases included an IRB approved 30-minute research protocol, during the DBS electrode implantation surgery, to monitor sub-second neurotransmitter release. We used Fisher's Exact test (FET) to determine if there was a significant change in the infection rate following DBS electrode implantation procedures that included, versus those that did not include, the neurotransmitter monitoring research protocol. Results: Within 30-days following DBS electrode implantation, infection was observed in 7 (1.43%) out of 491 procedures that did not include the research procedure and 2 (1.72%) of the 116 procedures that did include the research procedure. Total infection rates (i.e., not constrained by 30-day time window) for all non-research cases was 28/491 (5.70%) and only 4/116 (3.45%) for research inclusive cases. Notably, all types of infection observed were typical of those expected for DBS electrode implantation. Conclusion: Total infection rates are not statistically different in patients who performed the research procedure (3.45% vs. 5.70%; p = 0.4872, FET) and not statistically different across research and non-research groups within 30-days following the research procedure (1.72% vs. 1.43%; p = 0.684, FET). Our results demonstrate that the research procedures used for sub-second monitoring of neurotransmitter release in humans can be performed without increasing the rate of infection.

Severity assessment of complex and repeated intracranial surgery in rats

Introduction Evidence-based grading of the impact of intracranial surgery on rat’s well-being is important for ethical and legal reasons. We assessed the severity of complex and repeated intracranial surgery in a 6-hydroxydopamine (6-OHDA) Parkinson’s rat model with subsequent intracranial electrode implantation, and in an intracranial tumor model with subsequent resection. Methods Stereotactic surgery was performed in adult male rats with the same general anesthesia and perioperative pain management. In the Parkinson’s model, Sprague Dawley (SD) rats received unilateral injection of 6-OHDA (n=11) or vehicle (n=7) into the medial forebrain bundle as first operation. After four weeks, neural electrodes were implanted in all rats as second operation. For tumor formation, BDIX/ UlmHanZtm (BDIX) rats (n=8) received frontocortical injection of BT4Ca cells as first operation, followed by tumor resection as second operation after one week. Multiple measures severity assessment was done two days before and four days after surgery in all rats, comprising clinical scoring, body weight and detailed behavioral screening. To include a condition with a known burden, rats with intracranial tumors were additionally assessed up to a predefined humane endpoint that has previously been classified as "moderate". Results After the first operation, only 6-OHDA injection resulted in transient elevated clinical scores, a mild long-lasting weight reduction and motor disturbances. After the second surgery, body weight was transiently reduced in all groups. All other parameters showed variable results. Principal Component Analysis showed a separation from the preoperative state driven by motor-related parameters after 6-OHDA injection, while separation after electrode implantation and more clearly after tumor resection was driven by pain-related parameters, although not reaching the level of the humane endpoint of our tumor model. Conclusion Overall, cranial surgery of different complexity only transiently and rather mildly affects rat’s well-being. Multiple measures assessment allows the differentiation of model-related motor disturbances in the Parkinson’s model from potentially pain-related conditions after tumor resection and electrode implantation.

Accuracy of high-frequency oscillations recorded intraoperatively for classification of epileptogenic regions

To see whether acute intraoperative recordings using stereo EEG (SEEG) electrodes can replace prolonged interictal intracranial EEG (iEEG) recording, making the process more efficient and safer, 10 min of iEEG were recorded following electrode implantation in 16 anesthetized patients, and 1–2 days later during non-rapid eye movement (REM) sleep. Ripples on oscillations (RonO, 80–250 Hz), ripples on spikes (RonS), sharp-spikes, fast RonO (fRonO, 250–600 Hz), and fast RonS (fRonS) were semi-automatically detected. HFO power and frequency were compared between the conditions using a generalized linear mixed-effects model. HFO rates were compared using a two-way repeated measures ANOVA with anesthesia type and SOZ as factors. A receiver-operating characteristic (ROC) curve analysis quantified seizure onset zone (SOZ) classification accuracy, and the scalar product was used to assess spatial reliability. Resection of contacts with the highest rate of events was compared with outcome. During sleep, all HFOs, except fRonO, were larger in amplitude compared to intraoperatively (p < 0.01). HFO frequency was also affected (p < 0.01). Anesthesia selection affected HFO and sharp-spike rates. In both conditions combined, sharp-spikes and all HFO subtypes were increased in the SOZ (p < 0.01). However, the increases were larger during the sleep recordings (p < 0.05). The area under the ROC curves for SOZ classification were significantly smaller for intraoperative sharp-spikes, fRonO, and fRonS rates (p < 0.05). HFOs and spikes were only significantly spatially reliable for a subset of the patients (p < 0.05). A failure to resect fRonO areas in the sleep recordings trended the most sensitive and accurate for predicting failure. In summary, HFO morphology is altered by anesthesia. Intraoperative SEEG recordings exhibit increased rates of HFOs in the SOZ, but their spatial distribution can differ from sleep recordings. Recording these biomarkers during non-REM sleep offers a more accurate delineation of the SOZ and possibly the epileptogenic zone.

Deep Brain Stimulation of the Pallidofugal Pathways to Rescue Severe Life-Threatening Dyskinesias after STN-DBS Lead Implantation

We present a patient with severe life-threatening dyskinesias due to a persistent microlesion effect after STN-DBS electrode implantation. The pallidofugal pathways were identified using patient-specific tractography, and steering the current toward this white matter structure resulted in complete resolution of the severe dyskinesias.

Remote targeted electrical stimulation

The ability to generate electric fields in deep tissues remotely, without surgically implanting electrodes, could transform diagnoses and treatments of nervous system disorders. Here, we show that focal electrostimulation effects can be elicited remotely by combining two noninvasive forms of energies---magnetic and focused ultrasonic fields. The approach, based in the Lorentz equation and referred to as Lstim, electrically stimulates specified tissue targets with the precision of deep brain or spinal cord stimulation, but does not require electrode implantation. Lstim potentiated the responses of human nerves, enhancing the neuromodulatory effects of ultrasound by 74% on average. The effects showed a double dissociation---a significant and substantial increase in nociceptive responses, yet a significant reduction in tactile responses. In line with the Lorentz equation, Lstim was only observed when nerves were oriented perpendicularly to the magnetic and ultrasonic fields. A sham condition showed no effects. Both the ultrasonic and the induced electric fields were well below the respective safety indices, and no detrimental effects were detected. Lstim uniquely integrates noninvasiveness, sharp focus, and the efficacy of electrical stimulation. The approach has the potential to provide a noninvasive tool to dissect brain function in humans and to diagnose the neural circuits involved in nervous system disorders. Moreover, this effect should be taken into account when ultrasound is applied inside MRI.

Altered Regional Homogeneity and Functional Connectivity during Microlesion Period after Deep Brain Stimulation in Parkinson’s Disease

Background. Patients with Parkinson’s disease (PD) undergoing deep brain electrode implantation experience a temporary improvement in motor symptoms before the electrical stimulation begins. We usually call this the microlesion effect (MLE), but the mechanism behind it is not clear. Purpose. This study aimed to assess the alterations in brain functions at the regional and whole-brain levels, using regional homogeneity (ReHo) and functional connectivity (FC), during the postoperative microlesion period after deep brain stimulation (DBS) in PD patients. Method. Resting-state functional MRI data were collected from 27 PD patients before and after the first day of DBS and 12 healthy controls (HCs) in this study. The ReHo in combination with FC analysis was used to investigate the alterations of regional brain activity in all the subjects. Results. There were increased ReHo in the basal ganglia-thalamocortical circuit (left supplementary motor area and bilateral paracentral lobule), whereas decreased ReHo in the default mode network (DMN) (left angular gyrus, bilateral precuneus), prefrontal cortex (bilateral middle frontal gyrus), and the cerebello-thalamocortical (CTC) circuit (Cerebellum_crus2/1_L) after DBS. In addition, we also found abnormal FC in the lingual gyrus, cerebellum, and DMN. Conclusion. Microlesion of the thalamus caused by electrode implantation can alter the activity of the basal ganglia-thalamocortical circuit, prefrontal cortex, DMN, and CTC circuit and induce abnormal FC in the lingual gyrus, cerebellum, prefrontal cortex, and DMN among PD patients. The findings of this study contribute to the understanding of the mechanism of MLE.