Effects of 10-kHz Subthreshold Stimulation on Human Peripheral Nerve Activation.

OBJECTIVE: The mechanisms of action of high-frequency stimulation (HFS) are unknown. We investigated the possible mechanism of subthreshold superexcitability of HFS on the excitability of the peripheral nerve. MATERIALS AND METHODS: The ulnar nerve was stimulated at the wrist in six healthy participants with a single (control) stimulus, and the responses were compared with the responses to a continuous train of 5 seconds at frequencies of 500 Hz, 2.5 kHz, 5 kHz, and 10 kHz. Threshold intensity for compound muscle action potential (CMAP) was defined as intensity producing a 100-µV amplitude in ten sequential trials and "subthreshold" as 10% below the CMAP threshold. HFS threshold was defined as stimulation intensity eliciting visible tetanic contraction. RESULTS: Comparing the threshold of single pulse stimulation for eliciting CMAP vs threshold for HFS response and pooling data at different frequencies (500 Hz-10 kHz) revealed a significant difference (p = 0.00015). This difference was most obvious at 10 kHz, with a mean value for threshold reduction of 42.2%. CONCLUSIONS: HFS with a stimulation intensity below the threshold for a single pulse induces axonal superexcitability if applied in a train. It can activate the peripheral nerve and produce a tetanic muscle response. Subthreshold superexcitability may allow new insights into the mechanism of HFS.

Anesthesia and intraoperative neurophysiological spinal cord monitoring.

PURPOSE OF REVIEW: We will explain the basic principles of intraoperative neurophysiological monitoring (IONM) during spinal surgery. Thereafter we highlight the significant impact that general anesthesia can have on the efficacy of the IONM and provide an overview of the essential pharmacological and physiological factors that need to be optimized to enable IONM. Lastly, we stress the importance of teamwork between the anesthesiologist, the neurophysiologist, and the surgeon to improve clinical outcome after spinal surgery. RECENT FINDINGS: In recent years, the use of IONM has increased significantly. It has developed into a mature discipline, enabling neurosurgical procedures of ever-increasing complexity. It is thus of growing importance for the anesthesiologist to appreciate the interplay between IONM and anesthesia and to build up experience working in a team with the neurosurgeon and the neurophysiologist. SUMMARY: Safety measures, cooperation, careful choice of drugs, titration of drugs, and maintenance of physiological homeostasis are essential for effective IONM.

Dynamic Computational Model of the Human Spinal Cord Connectome.

Connectomes abound, but few for the human spinal cord. Using anatomical data in the literature, we constructed a draft connectivity map of the human spinal cord connectome, providing a template for the many calibrations of specialized behavior to be overlaid on it and the basis for an initial computational model. A thorough literature review gleaned cell types, connectivity, and connection strength indications. Where human data were not available, we selected species that have been studied. Cadaveric spinal cord measurements, cross-sectional histology images, and cytoarchitectural data regarding cell size and density served as the starting point for estimating numbers of neurons. Simulations were run using neural circuitry simulation software. The model contains the neural circuitry in all ten Rexed laminae with intralaminar, interlaminar, and intersegmental connections, as well as ascending and descending brain connections and estimated neuron counts for various cell types in every lamina of all 31 segments. We noted the presence of highly interconnected complex networks exhibiting several orders of recurrence. The model was used to perform a detailed study of spinal cord stimulation for analgesia. This model is a starting point for workers to develop and test hypotheses across an array of biomedical applications focused on the spinal cord. Each such model requires additional calibrations to constrain its output to verifiable predictions. Future work will include simulating additional segments and expanding the research uses of the model.

Practice guidelines for the supervising professional: intraoperative neurophysiological monitoring.

The American Society of Neurophysiological Monitoring (ASNM) was founded in 1989 as the American Society of Evoked Potential Monitoring. From the beginning, the Society has been made up of physicians, doctoral degree holders, Technologists, and all those interested in furthering the profession. The Society changed its name to the ASNM and held its first Annual Meeting in 1990. It remains the largest worldwide organization dedicated solely to the scientifically-based advancement of intraoperative neurophysiology. The primary goal of the ASNM is to assure the quality of patient care during procedures monitoring the nervous system. This goal is accomplished primarily through programs in education, advocacy of basic and clinical research, and publication of guidelines, among other endeavors. The ASNM is committed to the development of medically sound and clinically relevant guidelines for the performance of intraoperative neurophysiology. Guidelines are formulated based on exhaustive literature review, recruitment of expert opinion, and broad consensus among ASNM membership. Input is likewise sought from sister societies and related constituencies. Adherence to a literature-based, formalized process characterizes the construction of all ASNM guidelines. The guidelines covering the Professional Practice of intraoperative neurophysiological monitoring were initially published January 24th, 2013, and subsequently that document has undergone review and revision to accommodate broad inter- and intra-societal feedback. This current version of the ASNM Professional Practice Guideline was fully approved for publication according to ASNM bylaws on February 22nd, 2018, and thus overwrites and supersedes the initial guideline.

Theoretical Effect of DBS on Axonal Fibers of Passage: Firing Rates, Entropy, and Information Content.

BACKGROUND: Deep brain stimulation (DBS) has effects on axons that originate and terminate outside the DBS target area. OBJECTIVE: We hypothesized that DBS generates action potentials (APs) in both directions in "axons of passage," altering their information content and that of all downstream cells and circuits, and sought to quantify the change in fiber information content. METHODS: We incorporated DBS parameters (fiber firing frequency and refractory time, and AP initiation location along the fiber and propagation velocity) in a filtering function determining the AP frequency reaching the postsynaptic cell. Using neural circuitry simulation software, we investigated the ability of the filtering function to predict the firing frequency of APs reaching neurons targeted by axons of passage. We calculated their entropy with and without DBS, and with the electrode applied at various distances from the cell body. RESULTS: The predictability of the filtering function exceeded 98%. Entropy calculations showed that the entropy ratio "without DBS" to "with DBS" was always >1.0, thus DBS reduces fiber entropy. CONCLUSIONS: (1) The results imply that DBS effects are due to entropy reduction within fibers, i.e., a reduction in their information. (2) Where fibers of passage do not terminate in target regions, DBS may have side effects on nontargeted circuitry.

High-Frequency Stimulation of Dorsal Column Axons: Potential Underlying Mechanism of Paresthesia-Free Neuropathic Pain Relief.

OBJECTIVE: Spinal cord stimulation (SCS) treats neuropathic pain through retrograde stimulation of dorsal column axons and their inhibitory effects on wide dynamic range (WDR) neurons. Typical SCS uses frequencies from 50-100 Hz. Newer stimulation paradigms use high-frequency stimulation (HFS) up to 10 kHz and produce pain relief but without paresthesia. Our hypothesis is that HFS preferentially blocks larger diameter axons (12-15 µm) based on dynamics of ion channel gates and the electric potential gradient seen along the axon, resulting in inhibition of WDR cells without paresthesia. METHODS: We input field potential values from a finite element model of SCS into an active axon model with ion channel subcomponents for fiber diameters 1-20 µm and simulated dynamics on a 0.001 msec time scale. RESULTS: Assuming some degree of wave rectification seen at the axon, action potential (AP) blockade occurs as hypothesized, preferentially in larger over smaller diameters with blockade in most medium and large diameters occurring between 4.5 and 10 kHz. Simulations show both ion channel gate and virtual anode dynamics are necessary. CONCLUSION: At clinical HFS frequencies and pulse widths, HFS preferentially blocks larger-diameter fibers and concomitantly recruits medium and smaller fibers. These effects are a result of interaction between ion gate dynamics and the "activating function" (AF) deriving from current distribution over the axon. The larger fibers that cause paresthesia in low-frequency simulation are blocked, while medium and smaller fibers are recruited, leading to paresthesia-free neuropathic pain relief by inhibiting WDR cells.

The rationale driving the evolution of deep brain stimulation to constant-current devices.

OBJECTIVE: Deep brain stimulation (DBS) is an effective therapy for the treatment of a number of movement and neuropsychiatric disorders. The effectiveness of DBS is dependent on the density and location of stimulation in a given brain area. Adjustments are made to optimize clinical benefits and minimize side effects. Until recently, clinicians would adjust DBS settings using a voltage mode, where the delivered voltage remained constant. More recently, a constant-current mode has become available where the programmer sets the current and the stimulator automatically adjusts the voltage as impedance changes. METHODS: We held an expert consensus meeting to evaluate the current state of the literature and field on constant-current mode versus voltage mode in clinical brain-related applications. RESULTS/CONCLUSIONS: There has been little reporting of the use of constant-current DBS devices in movement and neuropsychiatric disorders. However, as impedance varies considerably between patients and over time, it makes sense that all new devices will likely use constant current.

Modeling effects of scar on patterns of dorsal column stimulation.

OBJECTIVE: The purpose of this study was to examine how scar formation may affect electrical current distribution in the spinal cord when using paddle leads placed in the epidural space during treatment with spinal cord stimulation. MATERIALS AND METHODS: A finite element model of the spinal cord was used to examine changes in stimulation using a guarded cathode configuration with and without scar. Additionally, two potential "compensatory" programming patterns were examined in order to understand how the three-dimensional electrical field may be affected by scar. Direct comparisons with prior studies in the literature and use of known anatomy of dorsal column fiber distributions also enabled a computational estimate of the number of fibers likely reaching threshold with each stimulus pattern. RESULTS: Notable potential and current distribution changes were found related to the modeled scar. Compensatory stimulation patterns (both in spatial and in amplitude dimensions) affect the fiber activation patterns in complex ways that may not be easily predetermined by a programming specialist. CONCLUSIONS: This study is one of the first to examine the effects of scar tissue on dorsal column stimulation and the only one using a detailed computational approach toward that end. It appears that different thickness and location of scar between electrode contacts and the dura may likely lead to a significant number and location of complex changes in the activated fibers. It is likely that a more complete assessment of scarring and its effect on the electrical environment of any given paddle lead would allow more accurate and predictable reprogramming of patients with commercially available systems in place.

Mechanism of dorsal column stimulation to treat neuropathic but not nociceptive pain: analysis with a computational model.

OBJECTIVE: Stimulation of axons within the dorsal columns of the human spinal cord has become a widely used therapy to treat refractory neuropathic pain. The mechanisms have yet to be fully elucidated and may even be contrary to standard "gate control theory." Our hypothesis is that a computational model provides a plausible description of the mechanism by which dorsal column stimulation (DCS) inhibits wide dynamic range (WDR) cell output in a neuropathic model but not in a nociceptive pain model. MATERIALS AND METHODS: We created a computational model of the human spinal cord involving approximately 360,000 individual neurons and dendritic processing of some 60 million synapses--the most elaborate dynamic computational model of the human spinal cord to date. Neuropathic and nociceptive "pain" signals were created by activating topographically isolated regions of excitatory interneurons and high-threshold nociceptive fiber inputs, driving analogous regions of WDR neurons. Dorsal column fiber activity was then added at clinically relevant levels (e.g., Aß firing rate between 0 and 110 Hz by using a 210-µsec pulse width, 50-150 Hz frequency, at 1-3 V amplitude). RESULTS: Analysis of the nociceptive pain, neuropathic pain, and modulated circuits shows that, in contradiction to gate control theory, 1) nociceptive and neuropathic pain signaling must be distinct, and 2) DCS neuromodulation predominantly affects the neuropathic signal only, inhibiting centrally sensitized pathological neuron groups and ultimately the WDR pain transmission cells. CONCLUSION: We offer a different set of necessary premises than gate control theory to explain neuropathic pain inhibition and the relative lack of nociceptive pain inhibition by using retrograde DCS. Hypotheses regarding not only the pain relief mechanisms of DCS were made but also regarding the circuitry of pain itself, both nociceptive and neuropathic. These hypotheses and further use of the model may lead to novel stimulation paradigms.

Efficient extraction of data from intra-operative evoked potentials: 1.-Theory and simulations.

Quickly and efficiently extracting evoked potential information from noise is critical to the clinical practice of intraoperative neurophysiologic monitoring (IONM). Currently this is primarily done using trained professionals to interpret averaged waveforms. The purpose of this paper is to evaluate and compare multiple means of electronically extracting simple to understand evoked potential characteristics with minimum averaging. A number of evoked potential models are studied and their performance evaluated as a function of the signal to noise level in simulations. Methods: which extract the least number of parameters from the data are least sensitive to the effects of noise and are easiest to interpret. The simplest model uses the baseline evoked potential and the correlation receiver to provide an amplitude measure. Amplitude measures extracted using the correlation receiver show superior performance to those based on peak to peak amplitude measures. In addition, measures of change in latency or shape of the evoked potential can be extracted using the derivative of the baseline evoked response or other methods. This methodology allows real-time access to amplitude measures that can be understood by the entire OR staff as they are small, dimensionless numbers of order unity which are simple to interpret. The IONM team can then adjust averaging and other parameters to allow for visual interpretation of waveforms as appropriate.

Intraoperative neurophysiologic methods for spinal cord stimulator placement under general anesthesia.

OBJECTIVES: To demonstrate that spinal cord stimulators (SCSs) may be placed safely and accurately under general anesthesia (GA) and that the proposed evaluation method activates structures predominantly in the dorsal columns. MATERIALS AND METHODS: Data were retrospectively analyzed from 172 electrodes implanted with spinal cord SCSs at the Lahey Clinic between September 2008 and July 2011. All patients had their SCS placed under GA. Electromyography was recorded from upper or lower limb muscle groups related to the placement of the stimulator electrode. Lateralization was performed based on electromyographic responses and electrode pairs stimulated. In a select group of patients, standard neurophysiologic tests, paired pulse, and collision studies were performed to demonstrate that the pain stimuli were activating the dorsal columns. RESULTS: One hundred fifty-five patients had standard thoracic or cervical SCS placement. Preoperatively this cohort of patients had a visual analog score (VAS) of 7.51 ± 1.93, while postoperatively the VAS was 3.63 ± 2.43 (a reduction of 52.11%). Based on the electromyographic recording technique, the electrodes were repositioned intraoperatively in 15.9% of patients. The recovery time (initial approximately 70 msec and complete approximately 150-300 msec) in both the paired-pulse tests and the collision studies showed that the stimulation used to elicit the compound muscle action potentials came from antidromic activation of the dorsal columns and not from the corticospinal tract. CONCLUSION: GA SCS is safe and appears to be at least as accurate and efficacious as using the awake SCS placement technique based on a 50% improvement in the VAS. In addition, the technique presented herein demonstrates that the test stimuli activate the same fiber tracts as that of the therapeutic stimulation.

Neurophysiology during movement disorder surgery.

During stereotactic procedures for treating medically refractory movement disorders, intraoperative neurophysiology shifts its focus from simply monitoring the effects of surgery to an integral part of the surgical procedure. The small size, poor visualization, and physiologic nature of these deep brain targets compel the surgeon to rely on some form of physiologic for confirmation of proper anatomic targeting. Even given the newer reliance on imaging and asleep deep brain stimulator electrode placement, it is still a physiologic target and thus some form of intraoperative physiology is necessary. This chapter reviews the neurophysiologic monitoring method of microelectrode recording that is commonly employed during these neurosurgical procedures today.

Safety issues during surgical monitoring.

While intra-operative neuro-physiologic assessment and monitoring improve the safety of patients, its use may also introduce new risks of injuries. This chapter looks at the electric safety of equipment and the potential hazards during the set-up of the monitoring. The physical and functional physiologic effects of electric shocks and stimulation currents, standards for safety limits, and conditions for tissue damage are described from basic physical principles. Considered are the electrode-tissue interface in relation to electrode dimensions and stimulation parameters as applied in various modalities of evoked sensory and motor potentials as to-date used in intra-operative monitoring, mapping of neuro-physiologic functions. A background is given on circumstances for electric tissue heating and heat drainage, thermal toxicity, protection against thermal injuries and side effects of unintended activation of neural and cardiac tissues, adverse effects of physiologic amplifiers from transcranial stimulation (TES) and excitotoxicity of direct cortical stimulation. Addressed are safety issues of TES and measures for prevention. Safety issues include bite and movement-induced injuries, seizures, and after discharges, interaction with implanted devices as cardiac pacemaker and deep brain stimulators. Further discussed are safety issues of equipment leakage currents, protection against electric shocks, and maintenance.

Intraoperative Neuromonitoring.

Intraoperative neuromonitoring encompasses a variety of different modalities in which different neuropathways are monitored either continuously or at defined time points throughout a neurosurgical procedure. Surgical morbidity can be mitigated with careful patient selection and thoughtful implementation of the appropriate neuromonitoring modalities through the identification of eloquent areas or early detection of iatrogenic pathway disruption. Modalities covered in this article include somatosensory and motor evoked potentials, electromyography, electroencephalography, brainstem auditory evoked responses, and direct cortical stimulation.

Motor Evoked Potential Recordings During Segmented Deep Brain Stimulation-A Feasibility Study.

BACKGROUND: Segmented deep brain stimulation (DBS) leads, which are capable of steering current in the direction of any 1 of 3 segments, can result in a wider therapeutic window by directing current away from unintended structures, particularly, the corticospinal tract (CST). It is unclear whether the use of motor evoked potentials (MEPs) is feasible during DBS surgery via stimulation of individual contacts/segments in order to quantify CST activation thresholds and optimal contacts/segments intraoperatively. OBJECTIVE: To assess the feasibility of using MEP to identify CST thresholds for ring and individual segments of the DBS lead under general anesthesia. METHODS: MEP testing was performed during pulse generator implantation under general anesthesia on subjects who underwent DBS lead implantation into the subthalamic nucleus (STN). Stimulation of each ring and segmented contacts of the directional DBS lead was performed until CST threshold was reached. Stereotactic coordinates and thresholds for each contact/segment were recorded along with the initially activated muscle group. RESULTS: A total of 34 hemispheres were included for analysis. MEP thresholds were recorded from 268 total contacts/segments. For segmented contacts (2 and 3, respectively), the mean highest CST thresholds were 2.33 and 2.62 mA, while the mean lowest CST thresholds were 1.7 and 1.89 mA, suggesting differential thresholds in relation to CST. First dorsal interosseous and abductor pollicis brevis (34% each) were the most commonly activated muscle groups. CONCLUSION: MEP threshold recording from segmented DBS leads is feasible. MEP recordings can identify segments with highest CST thresholds and may identify segment orientation in relation to CST.

Subthalamic Peak Beta Ratio Is Asymmetric in Glucocerebrosidase Mutation Carriers With Parkinson's Disease: A Pilot Study.

Introduction: Up to 27% of individuals undergoing subthalamic nucleus deep brain stimulation (STN-DBS) have a genetic form of Parkinson's disease (PD). Glucocerebrosidase (GBA) mutation carriers, compared to sporadic PD, present with a more aggressive disease, less asymmetry, and fare worse on cognitive outcomes with STN-DBS. Evaluating STN intra-operative local field potentials provide the opportunity to assess and compare symmetry between GBA and non-GBA mutation carriers with PD; thus, providing insight into genotype and STN physiology, and eligibility for and programming of STN-DBS. The purpose of this pilot study was to test differences in left and right STN resting state beta power in non-GBA and GBA mutation carriers with PD. Materials and Methods: STN (left and right) resting state local field potentials were recorded intraoperatively from 4 GBA and 5 non-GBA patients with PD while off medication. Peak beta power expressed as a ratio to total beta power (peak beta ratio) was compared between STN hemispheres and groups while co-varying for age, age of disease onset, and disease severity. Results: Peak beta ratio was significantly different between the left and the right STN for the GBA group (p < 0.01) but not the non-GBA group (p = 0.56) after co-varying for age, age of disease onset, and disease severity. Discussion: Peak beta ratio in GBA mutation carriers was more asymmetric compared with non-mutation carriers and this corresponded with the degree of clinical asymmetry as measured by rating scales. This finding suggests that GBA mutation carriers have a physiologic signature that is distinct from that found in sporadic PD.

Analysis of Movement-Related Beta Oscillations in the Off-Medication State During Subthalamic Nucleus Deep Brain Stimulation Surgery.

PURPOSE: Local field potential recordings from deep brain stimulation (DBS) leads provide insight into the pathophysiology of Parkinson disease (PD). We recorded local field potential activity from DBS leads within the subthalamic nucleus in patients with PD undergoing DBS surgery to identify reproducible pathophysiological signatures of the disease. METHODS: Local field potentials were recorded in 11 hemispheres from patients with PD undergoing subthalamic nucleus-DBS. Bipolar recordings were performed off medication for 2 minutes at rest and another 2 minutes with continuous repetitive opening-closing of the contralateral hand. Spectral analysis and bicoherence were performed and compared between the two testing conditions. RESULTS: In all hemispheres, predominance of the beta band frequency (13-30 Hz) was observed at rest and during movement. Beta peak energy was significantly (P < 0.05) increased during movement compared with rest in 6 of 10 hemispheres. Significant beta bicoherence was observed at rest and during movement in 5 of 10 hemispheres. The most robust local field potential recordings were observed at the DBS contact(s) independently chosen for programming in 9 of the 10 hemispheres. CONCLUSIONS: In patients with PD, beta activity that increases with repetitive movement may be a signature of the "off" medication state. These findings provide new data on beta oscillatory activity during the Parkinsonian "off" state that may help further define the local field potential signatures of PD.