Predicting in vivo MRI Gradient-Field Induced Voltage Levels on Implanted Deep Brain Stimulation Systems Using Neural Networks.

INTRODUCTION: MRI gradient-fields may induce extrinsic voltage between electrodes and conductive neurostimulator enclosure of implanted deep brain stimulation (DBS) systems, and may cause unintended stimulation and/or malfunction. Electromagnetic (EM) simulations using detailed anatomical human models, therapy implant trajectories, and gradient coil models can be used to calculate clinically relevant induced voltage levels. Incorporating additional anatomical human models into the EM simulation library can help to achieve more clinically relevant and accurate induced voltage levels, however, adding new anatomical human models and developing implant trajectories is time-consuming, expensive and not always feasible. METHODS: MRI gradient-field induced voltage levels are simulated in six adult human anatomical models, along clinically relevant DBS implant trajectories to generate the dataset. Predictive artificial neural network (ANN) regression models are trained on the simulated dataset. Leave-one-out cross validation is performed to assess the performance of ANN regressors and quantify model prediction errors. RESULTS: More than 180,000 unique gradient-induced voltage levels are simulated. ANN algorithm with two fully connected layers is selected due to its superior generalizability compared to support vector machine and tree-based algorithms in this particular application. The ANN regression model is capable of producing thousands of gradient-induced voltage predictions in less than a second with mean-squared-error less than 200 mV. CONCLUSION: We have integrated machine learning (ML) with computational modeling and simulations and developed an accurate predictive model to determine MRI gradient-field induced voltage levels on implanted DBS systems.

The Dorsal Root Ganglion as a Therapeutic Target for Chronic Pain.

Chronic neuropathic pain is a widespread problem with negative personal and societal consequences. Despite considerable clinical neuroscience research, the goal of developing effective, reliable, and durable treatments has remained elusive. The critical role played by the dorsal root ganglion (DRG) in the induction and maintenance of chronic pain has been largely overlooked in these efforts, however. It may be that, by targeting this site, robust new options for pain management will be revealed. This review summarizes recent advances in the knowledge base for DRG-targeted treatments for neuropathic pain:• Pharmacological options including the chemical targeting of voltage-dependent calcium channels, transient receptor potential channels, neurotrophin production, potentiation of opioid transduction pathways, and excitatory glutamate receptors.• Ablation or modulation of the DRG via continuous thermal radiofrequency and pulsed radiofrequency treatments.• Implanted electrical neurostimulator technologies.• Interventions involving the modification of DRG cellular function at the genetic level by using viral vectors and gene silencing methods.

Inhibition of sphingosine 1-phosphate lyase for the treatment of rheumatoid arthritis: discovery of (E)-1-(4-((1R,2S,3R)-1,2,3,4-tetrahydroxybutyl)-1H-imidazol-2-yl)ethanone oxime (LX2931) and (1R,2S,3R)-1-(2-(isoxazol-3-yl)-1H-imidazol-4-yl)butane-1,2,3,4-tetraol (LX2932).

Sphingosine 1-phosphate lyase (S1PL) has been characterized as a novel target for the treatment of autoimmune disorders using genetic and pharmacological methods. Medicinal chemistry efforts targeting S1PL by direct in vivo evaluation of synthetic analogues of 2-acetyl-4(5)-(1(R),2(S),3(R),4-tetrahydroxybutyl)-imidazole (THI, 1) led to the discovery of 2 (LX2931) and 4 (LX2932). The immunological phenotypes observed in S1PL deficient mice were recapitulated by oral administration of 2 or 4. Oral dosing of 2 or 4 yielded a dose-dependent decrease in circulating lymphocyte numbers in multiple species and showed a therapeutic effect in rodent models of rheumatoid arthritis (RA). Phase I clinical trials indicated that 2, the first clinically studied inhibitor of S1PL, produced a dose-dependent and reversible reduction of circulating lymphocytes and was well tolerated at dose levels of up to 180 mg daily. Phase II evaluation of 2 in patients with active rheumatoid arthritis is currently underway.

Inhibition of sphingosine-1-phosphate lyase for the treatment of autoimmune disorders.

During nearly a decade of research dedicated to the study of sphingosine signaling pathways, we identified sphingosine-1-phosphate lyase (S1PL) as a drug target for the treatment of autoimmune disorders. S1PL catalyzes the irreversible decomposition of sphingosine-1-phosphate (S1P) by a retro-aldol fragmentation that yields hexadecanaldehyde and phosphoethanolamine. Genetic models demonstrated that mice expressing reduced S1PL activity had decreased numbers of circulating lymphocytes due to altered lymphocyte trafficking, which prevented disease development in multiple models of autoimmune disease. Mechanistic studies of lymphoid tissue following oral administration of 2-acetyl-4(5)-(1(R),2(S),3(R),4-tetrahydroxybutyl)-imidazole (THI) 3 showed a clear relationship between reduced lyase activity, elevated S1P levels, and lower levels of circulating lymphocytes. Our internal medicinal chemistry efforts discovered potent analogues of 3 bearing heterocycles as chemical equivalents of the pendant carbonyl present in the parent structure. Reduction of S1PL activity by oral administration of these analogues recapitulated the phenotype of mice with genetically reduced S1PL expression.

Epidurales cervicales: ¿Cómo, dónde, cuándo y por qué? La controversia continua / Cervical epidural injections: How, where, when and why? Still a controversial matter

Las inyecciones cervicales epidurales de esteroides se realizan comúnmente en pacientes con cuadros dolorosos en esa región, incluyendo patología discal degenerativa, síndrome post-laminectomía, dolores cervicales radiculares, etc. El mecanismo de acción aún no se conoce con claridad, pero se especula que los esteroides inyectados cerca del área afectada disminuyen el proceso inflamatorio responsable del dolor. El propósito de este procedimiento puede ser terapéutico o diagnóstico, y realizarse por vía interlaminar o transforaminal. En los últimos años, se han informado complicaciones severas con el uso de este tipo de inyecciones. En esta revisión discutiremos las bases anatómicas por las cuales una técnica puede preferirse a otra, así como los pro y contra de cada uno de estos procedimientos, con una breve visión general acerca de las mejores alternativas y sugerencias para evitar complicaciones catastróficas.

Epidurales cervicales: ¿Cómo, dónde, cuándo y por qué? La controversia continua / Cervical epidural injections: How, where, when and why? Still a controversial matter

Las inyecciones cervicales epidurales de esteroides se realizan comúnmente en pacientes con cuadros dolorosos en esa región, incluyendo patología discal degenerativa, síndrome post-laminectomía, dolores cervicales radiculares, etc. El mecanismo de acción aún no se conoce con claridad, pero se especula que los esteroides inyectados cerca del área afectada disminuyen el proceso inflamatorio responsable del dolor. El propósito de este procedimiento puede ser terapéutico o diagnóstico, y realizarse por vía interlaminar o transforaminal. En los últimos años, se han informado complicaciones severas con el uso de este tipo de inyecciones. En esta revisión discutiremos las bases anatómicas por las cuales una técnica puede preferirse a otra, así como los pro y contra de cada uno de estos procedimientos, con una breve visión general acerca de las mejores alternativas y sugerencias para evitar complicaciones catastróficas. (AU)