Optimization of Radiofrequency Needle Placement in Percutaneous Cordotomy Using Electromyography in the Deeply Sedated Patient.

BACKGROUND AND OBJECTIVES: Cordotomy, the selective disconnection of the nociceptive fibers in the spinothalamic tract, is used to provide pain palliation to oncological patients suffering from intractable cancer-related pain. Cordotomies are commonly performed using a cervical (C1-2) percutaneous approach under imaging guidance and require patients' cooperation to functionally localize the spinothalamic tract. This can be challenging in patients suffering from extreme pain. It has recently been demonstrated that intraoperative neurophysiology monitoring by electromyography may aid in safe lesion positioning. The aim of this study was to evaluate the role of compound muscle action potential (CMAP) in deeply sedated patients undergoing percutaneous cervical cordotomy (PCC). METHODS: A retrospective analysis was conducted of all patients who underwent percutaneous cordotomy while deeply sedated between January 2019 and November 2022 in 2 academic centers. The operative report, neuromonitoring logs, and clinical medical records were evaluated. RESULTS: Eleven patients underwent PCC under deep sedation. In all patients, the final motor assessment prior to ablation was done using the electrophysiological criterion alone. The median threshold for evoking CMAP activity at the lesion site was 0.9 V ranging between 0.5 and 1.5 V (average 1 V ± 0.34 V SD). An immediate, substantial decrease in pain was observed in 9 patients. The median pain scores (Numeric Rating Scale) decreased from 10 preoperatively (range 8-10) to a median 0 (range 0-10) immediately after surgery. None of our patients developed motor deficits. CONCLUSION: CMAP-guided PCC may be feasible in deeply sedated patients without added risk to postoperative motor function. This technique should be considered in a group of patients who are not able to undergo awake PCC.

Human sensorimotor organoids derived from healthy and amyotrophic lateral sclerosis stem cells form neuromuscular junctions.

Human induced pluripotent stem cells (iPSC) hold promise for modeling diseases in individual human genetic backgrounds and thus for developing precision medicine. Here, we generate sensorimotor organoids containing physiologically functional neuromuscular junctions (NMJs) and apply the model to different subgroups of amyotrophic lateral sclerosis (ALS). Using a range of molecular, genomic, and physiological techniques, we identify and characterize motor neurons and skeletal muscle, along with sensory neurons, astrocytes, microglia, and vasculature. Organoid cultures derived from multiple human iPSC lines generated from individuals with ALS and isogenic lines edited to harbor familial ALS mutations show impairment at the level of the NMJ, as detected by both contraction and immunocytochemical measurements. The physiological resolution of the human NMJ synapse, combined with the generation of major cellular cohorts exerting autonomous and non-cell autonomous effects in motor and sensory diseases, may prove valuable to understand the pathophysiological mechanisms of ALS.

A high-content platform for physiological profiling and unbiased classification of individual neurons.

High-throughput physiological assays lose single-cell resolution, precluding subtype-specific analyses of activation mechanism and drug effects. We demonstrate APPOINT (automated physiological phenotyping of individual neuronal types), a physiological assay platform combining calcium imaging, robotic liquid handling, and automated analysis to generate physiological activation profiles of single neurons at large scale. Using unbiased techniques, we quantify responses to sequential stimuli, enabling subgroup identification by physiology and probing of distinct mechanisms of neuronal activation within subgroups. Using APPOINT, we quantify primary sensory neuron activation by metabotropic receptor agonists and identify potential contributors to pain signaling. We expand the role of neuroimmune interactions by showing that human serum directly activates sensory neurons, elucidating a new potential pain mechanism. Finally, we apply APPOINT to develop a high-throughput, all-optical approach for quantification of activation threshold and pharmacologically validate contributions of ion channel families to optical activation.

Delayed variations in the diagnostic accuracy of intraoperative neuromonitoring in the resection of intramedullary spinal cord tumors.

OBJECTIVE: The use of intraoperative neuromonitoring (IONM) has become an imperative adjunct to the resection of intramedullary spinal cord tumors (IMSCTs). While the diagnostic utility of IONM during the immediate postoperative period has been previously studied, its long-term diagnostic accuracy has seldom been thoroughly assessed. The aim of this study was to evaluate long-term variations in the diagnostic accuracy of transcranial motor evoked potentials (tcMEPs), somatosensory evoked potentials (SSEPs), and D-wave recordings during IMSCT excision. METHODS: The authors performed a retrospective evaluation of imaging studies, patient charts, operative reports, and IONM recordings of patients who were operated on for gross-total or subtotal resection of IMSCTs at a single institution between 2012 and 2018. Variations in the specificity, sensitivity, positive predictive value (PPV), and negative predictive value (NPV) for postoperative functional outcome (McCormick Scale) were analyzed at postoperative day 1 (POD1), 6 weeks postoperatively (PO-6 weeks), and at the latest follow-up. RESULTS: Overall, 28 patients were included. The mean length of follow-up was 19 ± 23.4 months. Persistent motor attenuations occurred in 71.4% of the cohort. MEP was the most sensitive modality (78.6%, 87.5%, and 85.7% sensitivity at POD1, PO-6 weeks, and last follow-up, respectively). The specificity of the D-wave was the most consistent over time (100%, 83.35%, and 90% specificity at the aforementioned time points). The PPV of motor recordings decreased over time (58% vs 33% and 100% vs 0 for tcMEP and D-wave at POD1 and last follow-up, respectively), while their NPV consistently increased (67% vs 89% and 70% vs 100% for tcMEP and D-wave at POD1 and last follow-up, respectively). CONCLUSIONS: The diagnostic accuracy of IONM in the resection of IMSCTs varies during the postoperative period. The decrease in the PPV of motor recordings over time suggests that this method is more predictive of short-term rather than long-term neurological deficits. The increasing NPV of motor recordings indicates a higher diagnostic accuracy in the identification of patients who preserve neurological function, albeit with an increased proportion of false-negative alarms for the immediate postoperative period. These variations should be considered in the surgical decision-making process when weighing the risk of resection-associated neurological injury against the implications of incomplete tumor resection.

Dynamic mapping using an electrified ultrasonic aspirator in lipomyelomeningocele and spinal cord detethering surgery-a feasibility study.

BACKGROUND: Intraoperative neurophysiologic monitoring (IONM) is an established technique and adjunct of brain and spinal lesion resection surgery. In spina bifida syndrome surgery, mapping of the surgical wound is a common and accepted method in determining the position and functionality of nerve roots of the cauda equina (CE), especially when the anatomy is not straightforward and roots are splayed across or entangled within the lesion. Here, we describe a novel technique of continuous CE mapping using an electrified cavitron ultrasonic aspirator (eCUSA) in children with lipomyelomeningocele (LMMC) lesions. METHODS: We assessed a method of dynamic CE mapping using an eCUSA as a stimulation probe. Twenty children (0.5-18 years) were included in this study, diagnosed with occult spina bifida LMMC in which the eCUSA stimulator was applied. IONM data and 2-weeks post-operative data were collected. RESULTS: LMMC lesions were located in the lumbar, sacral, and lumbosacral spine. eCUSA stimulation at 0.3-3.0 mA intensities elicited positive lower extremity muscle responses in 12 of the 20 patients included in the study. These responses allowed the surgeon real-time identification of the nerve roots tangent at the LMMC-cauda equina structure and intensive removal of the fat tissue in the area non-responding to the eCUSA stimulation. CONCLUSION: Continuous eCUSA-based stimulation of the cauda equina during LMMC resection is a feasible mapping technique with potential added value improving safety of untethering. Future studies evaluating extension of untethering, as well as the rates of retethering and long-term neurological and urological outcomes, are warranted.

Intraoperative Neurophysiology for Optimization of Percutaneous Spinothalamic Cordotomy for Intractable Cancer Pain.

BACKGROUND: Percutaneous ablation of the cervical spinothalamic tract (STT) remains a therapeutic remedy for intractable cancer pain. However, it is accompanied by the risk of collateral damage to essential spinal cord circuitry, including the corticospinal tract (CST). Recent studies describe threshold-based mapping of the CST with the objective of motor bundle preservation during intramedullary spinal cord and supratentorial surgery. OBJECTIVE: To assess the possibility that application of spinal cord mapping using intraoperative neuromonitoring in percutaneous cordotomy procedures may aid in minimizing iatrogenic motor tract injury. METHODS: We retrospectively reviewed the files of 11 patients who underwent percutaneous cervical cordotomy for intractable oncological pain. We performed quantitative electromyogram (EMG) recordings to stimulation of the ablation needle prior to the STT-ablative stage. We compared evoked motor and sensory electrical thresholds, and the electrical span between them as a reliable method to confirm safe electrode location inside the STT. RESULTS: Quantified EMG data were collected in 11 patients suffering from intractable cancer pain. The threshold range for evoking motor activity was 0.3 to 1.2 V. Stimulation artifacts were detected from trapezius muscles even at the lowest stimulation intensity, while thenar muscles were found to be maximally sensitive and specific. The minimal stimulation intensity difference between the motor and the sensory threshold, set as "Δ-threshold," was 0.26 V, with no new motor deficit at 3 days or 1 month postoperatively. CONCLUSION: Selective STT ablation is an effective procedure for treating intractable pain. It can be aided by quantitative evoked EMG recordings, with tailored parameters and thresholds.

Dissecting the Causal Mechanism of X-Linked Dystonia-Parkinsonism by Integrating Genome and Transcriptome Assembly.

X-linked Dystonia-Parkinsonism (XDP) is a Mendelian neurodegenerative disease that is endemic to the Philippines and is associated with a founder haplotype. We integrated multiple genome and transcriptome assembly technologies to narrow the causal mutation to the TAF1 locus, which included a SINE-VNTR-Alu (SVA) retrotransposition into intron 32 of the gene. Transcriptome analyses identified decreased expression of the canonical cTAF1 transcript among XDP probands, and de novo assembly across multiple pluripotent stem-cell-derived neuronal lineages discovered aberrant TAF1 transcription that involved alternative splicing and intron retention (IR) in proximity to the SVA that was anti-correlated with overall TAF1 expression. CRISPR/Cas9 excision of the SVA rescued this XDP-specific transcriptional signature and normalized TAF1 expression in probands. These data suggest an SVA-mediated aberrant transcriptional mechanism associated with XDP and may provide a roadmap for layered technologies and integrated assembly-based analyses for other unsolved Mendelian disorders.

Auxiliary subunits of the CKAMP family differentially modulate AMPA receptor properties.

AMPA receptor (AMPAR) function is modulated by auxiliary subunits. Here, we report on three AMPAR interacting proteins-namely CKAMP39, CKAMP52 and CKAMP59-that, together with the previously characterized CKAMP44, constitute a novel family of auxiliary subunits distinct from other families of AMPAR interacting proteins. The new members of the CKAMP family display distinct regional and developmental expression profiles in the mouse brain. Notably, despite their structural similarities they exert diverse modulation on AMPAR gating by influencing deactivation, desensitization and recovery from desensitization, as well as glutamate and cyclothiazide potency to AMPARs. This study indicates that AMPAR function is very precisely controlled by the cell-type specific expression of the CKAMP family members.