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.

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.

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.

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.

Motor cortex stimulation in patients with Parkinson disease: 12-month follow-up in 4 patients.

OBJECT: Since the initial 1991 report by Tsubokawa et al., stimulation of the M1 region of cortex has been used to treat chronic pain conditions and a variety of movement disorders. METHODS: A Medline search of the literature published between 1991 and the beginning of 2007 revealed 459 cases in which motor cortex stimulation (MCS) was used. Of these, 72 were related to a movement disorder. More recently, up to 16 patients specifically with Parkinson disease were treated with MCS, and a variety of results were reported. In this report the authors describe 4 patients who were treated with extradural MCS. RESULTS: Although there were benefits seen within the first 6 months in Unified Parkinson's Disease Rating Scale Part III scores (decreased by 60%), tremor was only modestly managed with MCS in this group, and most benefits seen initially were lost by the end of 12 months. CONCLUSIONS: Although there have been some positive findings using MCS for Parkinson disease, a larger study may be needed to better determine if it should be pursued as an alternative surgical treatment to DBS.

Neuromonitoring for Spinal Cord Stimulation Lead Placement Under General Anesthesia.

Spinal cord stimulation (SCS) is a common therapeutic technique for treating medically refractory neuropathic back and other limb pain syndromes. SCS has historically been performed using a sedative anesthetic technique where the patient is awakened at various times during a surgical procedure to evaluate the location of the stimulator lead. This technique has potential complications, and thus other methods that allow the use of a general anesthetic have been developed. There are two primary methods for placing leads under general anesthesia, based on 1) compound muscle action potentials and 2) collisions between somatosensory evoked potentials. Both techniques are discussed, and the literature on SCS lead placement under general anesthesia using intraoperative neurophysiological mapping is comprehensively reviewed.

Neurosurgical decision-making with IOM: DBS surgery.

Intraoperative monitoring (IOM) adds new information to intraoperative surgical decision-making. When presented clearly and accurately, it can help guide decision processes during the procedure, but can be a detriment overall if the information is inaccurate or misleading. Troubleshooting abilities and vigilance of the IOM staff play a large role in bolstering the level of trust a surgeon develops in IOM. Additionally, a surgeon may impart his own interpretation and experience with this new information that can undermine or enhance its impact on the case. In this article, we explore these issues with IOM in general and as they relate to the special context of DBS for movement disorders.

Immediate and sustained relief of levodopa-induced dyskinesias after dorsal relocation of a deep brain stimulation lead. Case report.

The authors demonstrate that high-frequency electrical stimulation dorsal to the subthalamic nucleus (STN) can directly suppress levodopa-induced dyskinesias. This 63-year-old woman with idiopathic Parkinson disease underwent surgery for placement of bilateral subthalamic deep brain stimulation (DBS) electrodes to control progressive rigidity, motor fluctuations, and levodopa-induced dyskinesias. The model 3389 DBS leads were implanted with microelectrode guidance. Magnetic resonance imaging confirmed proper placement of the leads. Postoperatively the patient exhibited improvement in all of her parkinsonian symptoms; however, her right leg dyskinesias had not improved. Based on their previous experiences treating levodopa-induced dyskinesias with subthalamic stimulation through the more dorsally located contacts of the model 3387 lead, the authors withdrew the implanted 3389 lead 3 mm. Following relocation of the lead they were able to suppress the right leg dyskinesias by using the most dorsal contacts. The patient's dopaminergic medication intake increased slightly. These findings indicate that electrical stimulation dorsal to the STN can directly suppress levodopa-induced dyskinesias independent of dopaminergic medication changes. The 3389 lead may provide inadequate coverage of the subthalamic region for some patients.