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Arle, Jeffrey E., Nicolae Iftimia, Jay L. Shils, Longzhi Mei, and Kristen W. Carlson. "Dynamic Computational Model of the Human Spinal Cord Connectome." Neural Computation 31, no. 2 (February 2019): 388–416. http://dx.doi.org/10.1162/neco_a_01159.
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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.
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Shevtsova, Natalia A., Erik Z. Li, Shayna Singh, Kimberly J. Dougherty, and Ilya A. Rybak. "Ipsilateral and Contralateral Interactions in Spinal Locomotor Circuits Mediated by V1 Neurons: Insights from Computational Modeling." International Journal of Molecular Sciences 23, no. 10 (May 16, 2022): 5541. http://dx.doi.org/10.3390/ijms23105541.
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We describe and analyze a computational model of neural circuits in the mammalian spinal cord responsible for generating and shaping locomotor-like oscillations. The model represents interacting populations of spinal neurons, including the neurons that were genetically identified and characterized in a series of previous experimental studies. Here, we specifically focus on the ipsilaterally projecting V1 interneurons, their possible role in the spinal locomotor circuitry, and their involvement in the generation of locomotor oscillations. The proposed connections of these neurons and their involvement in different neuronal pathways in the spinal cord allow the model to reproduce the results of optogenetic manipulations of these neurons under different experimental conditions. We suggest the existence of two distinct populations of V1 interneurons mediating different ipsilateral and contralateral interactions within the spinal cord. The model proposes explanations for multiple experimental data concerning the effects of optogenetic silencing and activation of V1 interneurons on the frequency of locomotor oscillations in the intact cord and hemicord under different experimental conditions. Our simulations provide an important insight into the organization of locomotor circuitry in the mammalian spinal cord.
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Jérusalem, Antoine, Julián A. García-Grajales, Angel Merchán-Pérez, and José M. Peña. "A computational model coupling mechanics and electrophysiology in spinal cord injury." Biomechanics and Modeling in Mechanobiology 13, no. 4 (December 12, 2013): 883–96. http://dx.doi.org/10.1007/s10237-013-0543-7.
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Lempka, Scott F., Cameron C. McIntyre, Kevin L. Kilgore, and Andre G. Machado. "Computational Analysis of Kilohertz Frequency Spinal Cord Stimulation for Chronic Pain Management." Anesthesiology 122, no. 6 (June 1, 2015): 1362–76. http://dx.doi.org/10.1097/aln.0000000000000649.
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Abstract Background: Kilohertz frequency spinal cord stimulation (KHFSCS) is an emerging therapy for treating refractory neuropathic pain. Although KHFSCS has the potential to improve the lives of patients experiencing debilitating pain, its mechanisms of action are unknown and thus it is difficult to optimize its development. Therefore, the goal of this study was to use a computer model to investigate the direct effects of KHFSCS on specific neural elements of the spinal cord. Methods: This computer model consisted of two main components: (1) finite element models of the electric field generated by KHFSCS and (2) multicompartment cable models of axons in the spinal cord. Model analysis permitted systematic investigation into a number of variables (e.g., dorsal cerebrospinal fluid thickness, lead location, fiber collateralization, and fiber size) and their corresponding effects on excitation and conduction block thresholds during KHFSCS. Results: The results of this study suggest that direct excitation of large-diameter dorsal column or dorsal root fibers require high stimulation amplitudes that are at the upper end or outside of the range used in clinical KHFSCS (i.e., 0.5 to 5 mA). Conduction block was only possible within the clinical range for a thin dorsal cerebrospinal fluid layer. Conclusions: These results suggest that clinical KHFSCS may not function through direct activation or conduction block of dorsal column or dorsal root fibers. Although these results should be validated with further studies, the authors propose that additional concepts and/or alternative hypotheses should be considered when examining the pain relief mechanisms of KHFSCS.
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Endo, Toshiki, Yushi Fujii, Shin-ichiro Sugiyama, Rong Zhang, Shogo Ogita, Kenichi Funamoto, Ryuta Saito, and Teiji Tominaga. "Properties of convective delivery in spinal cord gray matter: laboratory investigation and computational simulations." Journal of Neurosurgery: Spine 24, no. 2 (February 2016): 359–66. http://dx.doi.org/10.3171/2015.5.spine141148.
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OBJECT Convection-enhanced delivery (CED) is a method for distributing small and large molecules locally into the interstitial space of the spinal cord. Delivering these molecules to the spinal cord is otherwise difficult due to the blood-spinal cord barrier. Previous research has proven the efficacy of CED for delivering molecules over long distances along the white matter tracts in the spinal cord. Conversely, the characteristics of CED for delivering molecules to the gray matter of the spinal cord remain unknown. The purpose of this study was to reveal regional distribution of macromolecules in the gray and white matter of the spinal cord with special attention to the differences between the gray and white matter. METHODS Sixteen rats (F344) underwent Evans blue dye CED to either the white matter (dorsal column, 8 rats) or the gray matter (ventral horn, 8 rats) of the spinal cord. The rates and total volumes of infusion were 0.2 μl/min and 2.0 μl, respectively. The infused volume of distribution was visualized and quantified histologically. Computational models of the rat spinal cord were also obtained to perform CED simulations in the white and gray matter. RESULTS The ratio of the volume of distribution to the volume of infusion in the gray matter of the spinal cord was 3.60 ± 0.69, which was comparable to that of the white matter (3.05 ± 0.88). When molecules were injected into the white matter, drugs remained in the white matter tract and rarely infused into the adjacent gray matter. Conversely, when drugs were injected into the gray matter, they infiltrated laterally into the white matter tract and traveled longitudinally and preferably along the white matter. In the infusion center, the areas were larger in the gray matter CED than in the white matter (Mann-Whitney U-test, p < 0.01). In computational simulations, the aforementioned characteristics of CED to the gray and white matter were reaffirmed. CONCLUSIONS In the spinal cord, the gray and white matter have distinct characteristics of drug distribution by CED. These differences between the gray and white matter should be taken into account when considering drug delivery to the spinal cord. Computational simulation is a useful tool for predicting drug distributions in the normal spinal cord.
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Pithapuram, Madhav Vinodh, and Mohan Raghavan. "Automatic rule-based generation of spinal cord connectome model for a neuro-musculoskeletal limb in-silico." IOP SciNotes 3, no. 1 (March 1, 2022): 014001. http://dx.doi.org/10.1088/2633-1357/ac585e.
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Abstract Studying spinal interactions with muscles has been of great importance for over a century. However, with surging spinal-related movement pathologies, the need for computational models to study spinal pathways is increasing. Although spinal cord connectome models have been developed, anatomically relevant spinal neuromotor models are rare. However, building and maintaining such models is time-consuming. In this study, the concept of the rule-based generation of a spinal connectome was introduced and lumbosacral connectome generation was demonstrated as an example. Furthermore, the rule-based autogenerated connectome models were synchronized with lower-limb musculoskeletal models to create an in-silico testbed. Using this setup, the role of the autogenic Ia-excitatory pathway in controlling the ankle angle was tested.
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Solanes, Carmen, Jose L. Durá, M. Ángeles Canós, Jose De Andrés, Luis Martí-Bonmatí, and Javier Saiz. "3D patient-specific spinal cord computational model for SCS management: potential clinical applications." Journal of Neural Engineering 18, no. 3 (March 16, 2021): 036017. http://dx.doi.org/10.1088/1741-2552/abe44f.
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Sarntinoranont, Malisa, Rupak K. Banerjee, Russell R. Lonser, and Paul F. Morrison. "A Computational Model of Direct Interstitial Infusion of Macromolecules into the Spinal Cord." Annals of Biomedical Engineering 31, no. 4 (April 2003): 448–61. http://dx.doi.org/10.1114/1.1558032.
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Sarntinoranont, Malisa, Xiaoming Chen, Jianbing Zhao, and Thomas H. Mareci. "Computational Model of Interstitial Transport in the Spinal Cord using Diffusion Tensor Imaging." Annals of Biomedical Engineering 34, no. 8 (July 11, 2006): 1304–21. http://dx.doi.org/10.1007/s10439-006-9135-3.
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Persson, Cecilia, Jon Summers, and Richard M. Hall. "The Effect of Cerebrospinal Fluid Thickness on Traumatic Spinal Cord Deformation." Journal of Applied Biomechanics 27, no. 4 (November 2011): 330–35. http://dx.doi.org/10.1123/jab.27.4.330.
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A spinal cord injury may lead to loss of motor and sensory function and even death. The biomechanics of the injury process have been found to be important to the neurological damage pattern, and some studies have found a protective effect of the cerebrospinal fluid (CSF). However, the effect of the CSF thickness on the cord deformation and, hence, the resulting injury has not been previously investigated. In this study, the effects of natural variability (in bovine) as well as the difference between bovine and human spinal canal dimensions on spinal cord deformation were studied using a previously validated computational model. Owing to the pronounced effect that the CSF thickness was found to have on the biomechanics of the cord deformation, it can be concluded that results from animal models may be affected by the disparities in the CSF layer thickness as well as by any difference in the biological responses they may have compared with those of humans.
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Sarntinoranont, Malisa, Michael J. Iadarola, Russell R. Lonser, and Paul F. Morrison. "Direct interstitial infusion of NK1-targeted neurotoxin into the spinal cord: a computational model." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 285, no. 1 (July 2003): R243—R254. http://dx.doi.org/10.1152/ajpregu.00472.2002.
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Convection-enhanced delivery of substance P (SP) nocitoxins to the spinal cord interstitium is under consideration for the treatment of chronic pain. To characterize treatment protocols, a three-dimensional finite-element model of infusion into the human dorsal column was developed to predict the distribution of SP-diphtheria toxin fusion protein (SP-DT′) within normal and target tissue. The model incorporated anisotropic convective and diffusive transport through the interstitial space, hydrolysis by peptidases, and intracellular trafficking. For constant SP-DT′ infusion (0.1 μl/min), the distribution of cytotoxicity in NK1receptor-expressing neurons was predicted to reach an asymptotic limit at 6–8 h in the transverse direction at the level of the infusion cannula tip (∼60% ablation of target neurons in lamina I/II). Computations revealed that SP-DT′ treatment was favored by a stable SP analog (half-life ∼60 min), high infusate concentration (385 nM), and careful catheter placement (adjacent to target lamina I/II). Sensitivity of cytotoxic regions to NK1receptor density and white matter protease activity was also established. These data suggest that intraparenchymal infusions can be useful for treatment of localized chronic pain.
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Bilston, Lynne E., Marcus A. Stoodley, and David F. Fletcher. "The influence of the relative timing of arterial and subarachnoid space pulse waves on spinal perivascular cerebrospinal fluid flow as a possible factor in syrinx development." Journal of Neurosurgery 112, no. 4 (April 2010): 808–13. http://dx.doi.org/10.3171/2009.5.jns08945.
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Object The mechanisms of syringomyelia have long puzzled neurosurgeons and researchers alike due to difficulties in identifying the driving forces behind fluid flow into a syrinx, apparently against a pressure gradient between the spinal cord and the subarachnoid space (SAS). Recently, the synchronization between CSF flow and the cardiac cycle has been postulated to affect fluid flow in the spinal cord. This study aims to determine the effect of changes in the timing of SAS pressure on perivascular flow into the spinal cord. Methods This study uses a computational fluid dynamics model to investigate whether the relative timing of a spinal artery cardiovascular pulse wave and fluid pressure in the spinal SAS can influence CSF flow in the perivascular spaces. Results The results show that the mass flow rate of CSF through a model periarterial space is strongly influenced by the relative timing of the arterial pulse wave and the SAS pressure. Conclusions These findings suggest that factors that might alter the timing of the pulse wave or the fluid flow in the SAS could potentially affect fluid flow into a syrinx.
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Linge, Svein O., Kent-A. Mardal, Anders Helgeland, John D. Heiss, and Victor Haughton. "Effect of craniovertebral decompression on CSF dynamics in Chiari malformation Type I studied with computational fluid dynamics." Journal of Neurosurgery: Spine 21, no. 4 (October 2014): 559–64. http://dx.doi.org/10.3171/2014.6.spine13950.
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Object The effect of craniovertebral decompression surgery on CSF flow dynamics in patients with Chiari malformation Type I (CM-I) has been incompletely characterized. The authors used computational fluid dynamics to calculate the effect of decompression surgery on CSF flow dynamics in the posterior fossa and upper cervical spinal canal. Methods Oscillatory flow was simulated in idealized 3D models of the normal adult and the CM-I subarachnoid spaces (both previously described) and in 3 models of CM-I post–craniovertebral decompressions. The 3 postoperative models were created from the CM model by virtually modifying the CM model subarachnoid space to simulate surgical decompressions of different magnitudes. Velocities and pressures were computed with the Navier-Stokes equations in Star-CD for multiple cycles of CSF flow oscillating at 80 cycles/min. Pressure gradients and velocities were compared for 8 levels extending from the posterior fossa to the C3–4 level. Relative pressures and peak velocities were plotted by level from the posterior fossa to C3–4. The heterogeneity of flow velocity distribution around the spinal cord was compared between models. Results Peak systolic velocities were generally lower in the postoperative models than in the preoperative CM model. With the 2 larger surgical defects, peak systolic velocities were brought closer to normal model velocities (equal values at C-3 and C-4) than with the smallest surgical defect. For the smallest defect, peak velocities were decreased, but not to levels in the normal model. In the postoperative models, heterogeneity in flow velocity distribution around the spinal cord increased from normal model levels as the degree of decompression increased. Pressures in the 5 models differed in magnitude and in pattern. Pressure gradients along the spinal canal in the normal and CM models were nonlinear, with steeper gradients below C3–4 than above. The CM model had a steeper pressure gradient than the normal model above C3–4 and the same gradient below. The postoperative models had lower pressure gradients than the CM model above C2–3. The most conservative decompression had lower pressure gradients than the normal model above C2–3. The two larger decompression defects had CSF pressure gradients below those in the normal model above C2–3. These 2 models had a less steep gradient above C-3 and a steeper gradient below. Conclusions In computer simulations, craniovertebral surgical defects generally diminished CSF velocities and CSF pressures.
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Howell, Bryan, Shivanand P. Lad, and Warren M. Grill. "Evaluation of Intradural Stimulation Efficiency and Selectivity in a Computational Model of Spinal Cord Stimulation." PLoS ONE 9, no. 12 (December 23, 2014): e114938. http://dx.doi.org/10.1371/journal.pone.0114938.
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Ziraldo, Cordelia, Alexey Solovyev, Ana Allegretti, Shilpa Krishnan, M. Kristi Henzel, Gwendolyn A. Sowa, David Brienza, Gary An, Qi Mi, and Yoram Vodovotz. "A Computational, Tissue-Realistic Model of Pressure Ulcer Formation in Individuals with Spinal Cord Injury." PLOS Computational Biology 11, no. 6 (June 25, 2015): e1004309. http://dx.doi.org/10.1371/journal.pcbi.1004309.
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Ziraldo, C., A. Solovyev, A. Allegretti, S. Krishnan, M. K. Henzel, G. A. Sowa, D. Brienza, G. An, Q. Mi, and Y. Vodovotz. "A computational, tissue-realistic model of pressure ulcer formation in individuals with spinal cord injury." Journal of Critical Care 28, no. 1 (February 2013): e23. http://dx.doi.org/10.1016/j.jcrc.2012.10.061.
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Naveh, Ariel, Ofir Yesharim, and Ze’ev Bomzon. "EXTH-37. A NOVEL TRANSDUCER ARRAY LAYOUT FOR DELIVERING TUMOR TREATING FIELDS TO THE SPINE." Neuro-Oncology 21, Supplement_6 (November 2019): vi90. http://dx.doi.org/10.1093/neuonc/noz175.369.
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Abstract Tumor Treating Fields (TTFields) are an antimitotic technology utilising electric fields to disrupt mitosis in cancer cells. TTFields are currently approved by the FDA for the treatment of Glioblastoma Multiforme (GBM) and Malignant Pleural Mesothelioma (MPM). TTFields are delivered through 2 pairs of transducer arrays placed on the patient’s skin. Each pair delivers TTFields in a single direction, and the pairs are placed to provide perpendicular field. Preclinical studies show that 1V/cm is the clinical threshold for the treatment to be effective. Some types of cancers send metastases to the spinal cord and CSF, i.e. leptomeningeal disease. The purpose of this study was to find transducer array layouts that deliver TTFields to the spine at therapeutic intensities of above 1 V/cm. Computational simulations testing the delivery of TTFields to the spine were performed using the Sim4Life 4.0 (ZMT Zurich) computational platform, and the Duke 3.1 and Ella 3.0 (ITI’S, Zurich) realistic computational models of a male and female respectively. “Standard” layouts in which a pair of arrays are placed on the front and back of the patient and second pair on the lateral aspects of the patient failed to deliver TTFields at therapeutic intensities to the spinal cord. This is probably because the spinal cord is surrounded by the CSF and spine, which shunt the electric fields from reaching the spinal cord. However, field intensities above 1 V/cm were observed when delivering TTFields when both arrays were placed on the patients back, with a first array placed close to the neck, and second array placed towards the thighs. In this case, the spinal cord and surrounding CSF act as a conductive cable, directing the electric field along the spine. This novel layout opens the possibility for treating cancerous disease along the spine.
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Zander, Hans, Krzysztof E. Kowalski, Anthony F. DiMarco, and Scott F. Lempka. "A Computational Model of Upper Thoracic High‐Frequency Spinal Cord Stimulation to Optimize Inspiratory Muscle Activation." FASEB Journal 34, S1 (April 2020): 1. http://dx.doi.org/10.1096/fasebj.2020.34.s1.04201.
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Shils, Jay, Kris Carlson, Longzhi Mei, and Jeffrey Arle. "34. Mechanism of therapeutic benefit with dorsal column stimulation using a computational model of the spinal cord." Clinical Neurophysiology 125, no. 5 (May 2014): e23-e24. http://dx.doi.org/10.1016/j.clinph.2013.12.037.
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Zhang, Tianhe C., John J. Janik, Ryan V. Peters, Gang Chen, Ru-Rong Ji, and Warren M. Grill. "Spinal sensory projection neuron responses to spinal cord stimulation are mediated by circuits beyond gate control." Journal of Neurophysiology 114, no. 1 (July 2015): 284–300. http://dx.doi.org/10.1152/jn.00147.2015.
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Spinal cord stimulation (SCS) is a therapy used to treat intractable pain with a putative mechanism of action based on the Gate Control Theory. We hypothesized that sensory projection neuron responses to SCS would follow a single stereotyped response curve as a function of SCS frequency, as predicted by the Gate Control circuit. We recorded the responses of antidromically identified sensory projection neurons in the lumbar spinal cord during 1- to 150-Hz SCS in both healthy rats and neuropathic rats following chronic constriction injury (CCI). The relationship between SCS frequency and projection neuron activity predicted by the Gate Control circuit accounted for a subset of neuronal responses to SCS but could not account for the full range of observed responses. Heterogeneous responses were classifiable into three additional groups and were reproduced using computational models of spinal microcircuits representing other interactions between nociceptive and nonnociceptive sensory inputs. Intrathecal administration of bicuculline, a GABAA receptor antagonist, increased spontaneous and evoked activity in projection neurons, enhanced excitatory responses to SCS, and reduced inhibitory responses to SCS, suggesting that GABAA neurotransmission plays a broad role in regulating projection neuron activity. These in vivo and computational results challenge the Gate Control Theory as the only mechanism underlying SCS and refine our understanding of the effects of SCS on spinal sensory neurons within the framework of contemporary understanding of dorsal horn circuitry.
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Stein, Paul S. G. "Central pattern generators in the turtle spinal cord: selection among the forms of motor behaviors." Journal of Neurophysiology 119, no. 2 (February 1, 2018): 422–40. http://dx.doi.org/10.1152/jn.00602.2017.
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Neuronal networks in the turtle spinal cord have considerable computational complexity even in the absence of connections with supraspinal structures. These networks contain central pattern generators (CPGs) for each of several behaviors, including three forms of scratch, two forms of swim, and one form of flexion reflex. Each behavior is activated by a specific set of cutaneous or electrical stimuli. The process of selection among behaviors within the spinal cord has multisecond memories of specific motor patterns. Some spinal cord interneurons are partially shared among several CPGs, whereas other interneurons are active during only one type of behavior. Partial sharing is a proposed mechanism that contributes to the ability of the spinal cord to generate motor pattern blends with characteristics of multiple behaviors. Variations of motor patterns, termed deletions, assist in characterization of the organization of the pattern-generating components of CPGs. Single-neuron recordings during both normal and deletion motor patterns provide support for a CPG organizational structure with unit burst generators (UBGs) whose members serve a direction of a specific degree of freedom of the hindlimb, e.g., the hip-flexor UBG, the hip-extensor UBG, the knee-flexor UBG, the knee-extensor UBG, etc. The classic half-center hypothesis that includes all the hindlimb flexors in a single flexor half-center and all the hindlimb extensors in a single extensor half-center lacks the organizational complexity to account for the motor patterns produced by turtle spinal CPGs. Thus the turtle spinal cord is a valuable model system for studies of mechanisms responsible for selection and generation of motor behaviors. NEW & NOTEWORTHY The concept of the central pattern generator (CPG) is a major tenet in motor neuroethology that has influenced the design and interpretations of experiments for over a half century. This review concentrates on the turtle spinal cord and describes studies from the 1970s to the present responsible for key developments in understanding the CPG mechanisms responsible for the selection and production of coordinated motor patterns during turtle hindlimb motor behaviors.
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Bui, Tuan V., and Robert M. Brownstone. "Sensory-evoked perturbations of locomotor activity by sparse sensory input: a computational study." Journal of Neurophysiology 113, no. 7 (April 2015): 2824–39. http://dx.doi.org/10.1152/jn.00866.2014.
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Sensory inputs from muscle, cutaneous, and joint afferents project to the spinal cord, where they are able to affect ongoing locomotor activity. Activation of sensory input can initiate or prolong bouts of locomotor activity depending on the identity of the sensory afferent activated and the timing of the activation within the locomotor cycle. However, the mechanisms by which afferent activity modifies locomotor rhythm and the distribution of sensory afferents to the spinal locomotor networks have not been determined. Considering the many sources of sensory inputs to the spinal cord, determining this distribution would provide insights into how sensory inputs are integrated to adjust ongoing locomotor activity. We asked whether a sparsely distributed set of sensory inputs could modify ongoing locomotor activity. To address this question, several computational models of locomotor central pattern generators (CPGs) that were mechanistically diverse and generated locomotor-like rhythmic activity were developed. We show that sensory inputs restricted to a small subset of the network neurons can perturb locomotor activity in the same manner as seen experimentally. Furthermore, we show that an architecture with sparse sensory input improves the capacity to gate sensory information by selectively modulating sensory channels. These data demonstrate that sensory input to rhythm-generating networks need not be extensively distributed.
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Gadomski, Benjamin C., Bradley J. Hindman, Mitchell I. Page, Franklin Dexter, and Christian M. Puttlitz. "Intubation Biomechanics: Clinical Implications of Computational Modeling of Intervertebral Motion and Spinal Cord Strain during Tracheal Intubation in an Intact Cervical Spine." Anesthesiology 135, no. 6 (November 9, 2021): 1055–65. http://dx.doi.org/10.1097/aln.0000000000004024.
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Background In a closed claims study, most patients experiencing cervical spinal cord injury had stable cervical spines. This raises two questions. First, in the presence of an intact (stable) cervical spine, are there tracheal intubation conditions in which cervical intervertebral motions exceed physiologically normal maximum values? Second, with an intact spine, are there tracheal intubation conditions in which potentially injurious cervical cord strains can occur? Methods This study utilized a computational model of the cervical spine and cord to predict intervertebral motions (rotation, translation) and cord strains (stretch, compression). Routine (Macintosh) intubation force conditions were defined by a specific application location (mid-C3 vertebral body), magnitude (48.8 N), and direction (70 degrees). A total of 48 intubation conditions were modeled: all combinations of 4 force locations (cephalad and caudad of routine), 4 magnitudes (50 to 200% of routine), and 3 directions (50, 70, and 90 degrees). Modeled maximum intervertebral motions were compared to motions reported in previous clinical studies of the range of voluntary cervical motion. Modeled peak cord strains were compared to potential strain injury thresholds. Results Modeled maximum intervertebral motions occurred with maximum force magnitude (97.6 N) and did not differ from physiologically normal maximum motion values. Peak tensile cord strains (stretch) did not exceed the potential injury threshold (0.14) in any of the 48 force conditions. Peak compressive strains exceeded the potential injury threshold (–0.20) in 3 of 48 conditions, all with maximum force magnitude applied in a nonroutine location. Conclusions With an intact cervical spine, even with application of twice the routine value of force magnitude, intervertebral motions during intubation did not exceed physiologically normal maximum values. However, under nonroutine high-force conditions, compressive strains exceeded potentially injurious values. In patients whose cords have less than normal tolerance to acute strain, compressive strains occurring with routine intubation forces may reach potentially injurious values. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New
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Ausborn, Jessica, Natalia A. Shevtsova, and Simon M. Danner. "Computational Modeling of Spinal Locomotor Circuitry in the Age of Molecular Genetics." International Journal of Molecular Sciences 22, no. 13 (June 25, 2021): 6835. http://dx.doi.org/10.3390/ijms22136835.
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Neuronal circuits in the spinal cord are essential for the control of locomotion. They integrate supraspinal commands and afferent feedback signals to produce coordinated rhythmic muscle activations necessary for stable locomotion. For several decades, computational modeling has complemented experimental studies by providing a mechanistic rationale for experimental observations and by deriving experimentally testable predictions. This symbiotic relationship between experimental and computational approaches has resulted in numerous fundamental insights. With recent advances in molecular and genetic methods, it has become possible to manipulate specific constituent elements of the spinal circuitry and relate them to locomotor behavior. This has led to computational modeling studies investigating mechanisms at the level of genetically defined neuronal populations and their interactions. We review literature on the spinal locomotor circuitry from a computational perspective. By reviewing examples leading up to and in the age of molecular genetics, we demonstrate the importance of computational modeling and its interactions with experiments. Moving forward, neuromechanical models with neuronal circuitry modeled at the level of genetically defined neuronal populations will be required to further unravel the mechanisms by which neuronal interactions lead to locomotor behavior.
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Nakayama, Takayuki, and Hidenori Kimura. "Trajectory tracking control of robot arm by using computational models of spinal cord and cerebellum." Systems and Computers in Japan 35, no. 11 (2004): 1–13. http://dx.doi.org/10.1002/scj.10646.
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De Los Santos, Jennifer, Smadar Arvatz, Oshrit Zeevi, Shay levi, Zeev Bomzon, and Tal Marciano. "INNV-05. TUMOR TREATING FIELDS (TTFIELDS) TREATMENT PLANNING FOR A PATIENT WITH ASTROCYTOMA IN THE SPINAL CORD." Neuro-Oncology 22, Supplement_2 (November 2020): ii117. http://dx.doi.org/10.1093/neuonc/noaa215.489.
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Abstract BACKGROUND The use of Tumor Treating Fields (TTFields) following resection and chemoradiation has increased survival in patients with Glioblastoma. Randomized data provide strong rationale for planning TTFields transducer array placement to maximize TTFields dose at the tumor in a patient-specific manner. Here we present a case demonstrating the use of numerical simulations for patient-specific TTFields treatment planning for a spinal tumor. METHODS Treatment planning was performed for a 48 year old patient following T10-L1 laminectomy, gross total resection, and postoperative chemoradiation for an anaplastic astrocytoma of the spinal cord. An MRI at 3 weeks following chemoradiation showed tumor recurrence. Based on the post-chemoradiation MRI, a patient-specific model was created. The model was created by modifying a realistic computational phantom of a healthy female. To mimic the laminectomy, the lamina in T10-L1 was removed, and the region assigned electric conductivity similar to that of muscle. A virtual mass was introduced into the spinal cord. Virtual transducer arrays were placed on the model at multiple positions, and delivery of TTFields simulated. The dose delivered by different transducer array layouts was calculated, and the layouts that yielded maximal dose to the tumor and spine identified. RESULTS Transducer array layouts, in which the arrays were placed on the back of the patient with one array above the tumor and one array below the tumor, yielded the highest doses at the tumor site. Such layouts yielded TTFields doses of over 3.4mW/cm3 which is well above the threshold dose of 1.1 mW/cm3 reported previously [Ballo et al Red Jour 2019]. CONCLUSIONS These data represent the first ever study on utilizing numerical simulations in order to plan treatment for a spinal tumor in a patient-specific manner. This is an important milestone in the developing a framework for TTFields dosimetry and treatment planning.
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Hillen, Brian K., Devin L. Jindrich, James J. Abbas, Gary T. Yamaguchi, and Ranu Jung. "Effects of spinal cord injury-induced changes in muscle activation on foot drag in a computational rat ankle model." Journal of Neurophysiology 113, no. 7 (April 2015): 2666–75. http://dx.doi.org/10.1152/jn.00507.2014.
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Spinal cord injury (SCI) can lead to changes in muscle activation patterns and atrophy of affected muscles. Moderate levels of SCI are typically associated with foot drag during the swing phase of locomotion. Foot drag is often used to assess locomotor recovery, but the causes remain unclear. We hypothesized that foot drag results from inappropriate muscle coordination preventing flexion at the stance-to-swing transition. To test this hypothesis and to assess the relative contributions of neural and muscular changes on foot drag, we developed a two-dimensional, one degree of freedom ankle musculoskeletal model with gastrocnemius and tibialis anterior muscles. Anatomical data collected from sham-injured and incomplete SCI (iSCI) female Long-Evans rats as well as physiological data from the literature were used to implement an open-loop muscle dynamics model. Muscle insertion point motion was calculated with imposed ankle trajectories from kinematic analysis of treadmill walking in sham-injured and iSCI animals. Relative gastrocnemius deactivation and tibialis anterior activation onset times were varied within physiologically relevant ranges based on simplified locomotor electromyogram profiles. No-atrophy and moderate muscle atrophy as well as normal and injured muscle activation profiles were also simulated. Positive moments coinciding with the transition from stance to swing phase were defined as foot swing and negative moments as foot drag. Whereas decreases in activation delay caused by delayed gastrocnemius deactivation promote foot drag, all other changes associated with iSCI facilitate foot swing. Our results suggest that even small changes in the ability to precisely deactivate the gastrocnemius could result in foot drag after iSCI.
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Shuaib, Ali, Ali K. Bourisly, and Eman Alazmi. "Fluence as a Function of Weight: A Photobiomodulation Therapy (PBMT) Spinal Cord Injury (SCI) Rat Model—A Computational Study." IEEE Photonics Journal 12, no. 6 (December 2020): 1–8. http://dx.doi.org/10.1109/jphot.2020.3033476.
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Crodelle, Jennifer, and Pedro D. Maia. "A Computational Model for Pain Processing in the Dorsal Horn Following Axonal Damage to Receptor Fibers." Brain Sciences 11, no. 4 (April 16, 2021): 505. http://dx.doi.org/10.3390/brainsci11040505.
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Computational modeling of the neural activity in the human spinal cord may help elucidate the underlying mechanisms involved in the complex processing of painful stimuli. In this study, we use a biologically-plausible model of the dorsal horn circuitry as a platform to simulate pain processing under healthy and pathological conditions. Specifically, we distort signals in the receptor fibers akin to what is observed in axonal damage and monitor the corresponding changes in five quantitative markers associated with the pain response. Axonal damage may lead to spike-train delays, evoked potentials, an increase in the refractoriness of the system, and intermittent blockage of spikes. We demonstrate how such effects applied to mechanoreceptor and nociceptor fibers in the pain processing circuit can give rise to dramatically distinct responses at the network/population level. The computational modeling of damaged neuronal assemblies may help unravel the myriad of responses observed in painful neuropathies and improve diagnostics and treatment protocols.
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Le Franc, Yann, and Gwendal Le Masson. "Multiple Firing Patterns in Deep Dorsal Horn Neurons of the Spinal Cord: Computational Analysis of Mechanisms and Functional Implications." Journal of Neurophysiology 104, no. 4 (October 2010): 1978–96. http://dx.doi.org/10.1152/jn.00919.2009.
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Deep dorsal horn relay neurons (dDHNs) of the spinal cord are known to exhibit multiple firing patterns under the control of local metabotropic neuromodulation: tonic firing, plateau potential, and spontaneous oscillations. This work investigates the role of interactions between voltage-gated channels and the occurrence of different firing patterns and then correlates these two phenomena with their functional role in sensory information processing. We designed a conductance-based model using the NEURON software package, which successfully reproduced the classical features of plateau in dDHNs, including a wind-up of the neuronal response after repetitive stimulation. This modeling approach allowed us to systematically test the impact of conductance interactions on the firing patterns. We found that the expression of multiple firing patterns can be reproduced by changes in the balance between two currents (L-type calcium and potassium inward rectifier conductances). By investigating a possible generalization of the firing state switch, we found that the switch can also occur by varying the balance of any hyperpolarizing and depolarizing conductances. This result extends the control of the firing switch to neuromodulators or to network effects such as synaptic inhibition. We observed that the switch between the different firing patterns occurs as a continuous function in the model, revealing a particular intermediate state called the accelerating mode. To characterize the functional effect of a firing switch on information transfer, we used correlation analysis between a model of peripheral nociceptive afference and the dDHN model. The simulation results indicate that the accelerating mode was the optimal firing state for information transfer.
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Silva, Afonso J. C., Ricardo J. Alves de Sousa, Fábio A. O. Fernandes, Mariusz Ptak, and Marco P. L. Parente. "Development of a Finite Element Model of the Cervical Spine and Validation of a Functional Spinal Unit." Applied Sciences 12, no. 21 (November 7, 2022): 11295. http://dx.doi.org/10.3390/app122111295.
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The cervical spine is a common site of injury in the vertebral column, with severe injuries often associated with damage to the spinal cord. Several studies have been performed to better understand the mechanisms of such situations and develop ways to treat or even prevent them. Among the most advantageous and most widely used methods are computational models, as they offer unique features such as providing information on strains and stresses that would otherwise be difficult to obtain. Therefore, the main objective of this work is to help better understand the mechanics of the neck by creating a new finite element model of the human cervical spine that accurately represents most of its components. The initial geometry of the cervical spine was obtained using the computer tomography scans of a 46-year-old female. The complete model was then sectioned, and a functional spinal unit consisting of the C6–C7 segment was simulated to initiate the validation process. The reduced model was validated against experimental data obtained from in vitro tests that evaluated the range of motion of various cervical segments in terms of flexion–extension, axial rotation, and lateral bending.
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Kinzel, A., O. Yesharim, A. Naveh, and Z. Bomzon. "P11.18 Tumor treating fields (TTFields) treatment of spinal cord metastases." Neuro-Oncology 21, Supplement_3 (August 2019): iii46. http://dx.doi.org/10.1093/neuonc/noz126.164.
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Abstract BACKGROUND Tumor Treating Fields (TTFields) is an anti-mitotic cancer treatment approved for the treatment of Glioblastoma multiforme (GBM) and is currently also investigated in a phase III trial in 1–10 brain metastases from non-small cell lung cancer (METIS). Apart from spread to the brain, some cancer types, such as breast cancer, lung cancer, and melanoma, may lead to metastatic spread to the spinal cord. Previous studies have shown that reported transducer array layouts for the treatment of abdominal/pelvic tumors (e.g. pancreatic cancer), with one pair of arrays positioned on the anterior and posterior of the patient, and the second pair of arrays placed on each side of the thorax, yield therapeutically insufficient field intensities of <1 V/cm in the spinal cord. This finding probably results from the anatomical structure of the spine, consisting of the cerebrospinal fluid as a highly conductive layer, encased by a resistive bone structure that shunts the current delivered across the body by the arrays away from the spine. This simulation-based study aimed at resolving this challenge by identifying novel array layouts on the body that effectively deliver TTFields to the spine. MATERIAL AND METHODS For the simulations of the TTFields delivery to the spine, a human male 34 years old realistic computational model (DUKE v3.1 by ITI’S, Zurich) and the ZMT’s Sim4Life v4.0 electro-quasi-static solver was utilized. TTFields were simulated by imposing an alternating current with a current density of 200 mA/disk and a frequency of 150 kHz on the outer surfaces of the disks of each pair of arrays. RESULTS For one of the tested array layouts, a high electric field was shown to be induced within the spinal cord and surrounding CSF: Our calculations of mean field intensity within the spine and nerves from vertebrae T8-T9 at the top to L3-L4 at the bottom added up to 1.77 V/cm. This layout consisted of the placement of a pair of arrays on the back of the patient, with one array positioned above the section in the spine to which treatment would be delivered, and the other array positioned below the target section. Notably, the resulting electric field is directed along the spine in this setting (ie, vertically). CONCLUSION Our results demonstrate that treatment of the whole spinal cord and nerves in a single direction can be achieved by placing a pair of transducer arrays on the patient’s back: one array on the neck, and one at the bottom of the spine. For the development of an active treatment in the perpendicular direction, further studies need to be conducted.
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York, Gareth, Hugh Osborne, Piyanee Sriya, Sarah Astill, Marc de Kamps, and Samit Chakrabarty. "The effect of limb position on a static knee extension task can be explained with a simple spinal cord circuit model." Journal of Neurophysiology 127, no. 1 (January 1, 2022): 173–87. http://dx.doi.org/10.1152/jn.00208.2021.
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The role of sensory feedback in motor control when limbs are held in a fixed position is disputed. We performed a novel experiment involving fixed position tasks based on two common clinical tests. We identified patterns of muscle activity during the tasks that changed with different leg positions and then inferred how sensory feedback might influence the observations. We developed a computational model that required three distinct inputs to reproduce the activity patterns observed experimentally. The model provides a neural explanation for how the activity patterns can be changed by sensory feedback.
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de Los Santos, Jennifer, Smadar Arvatz, Oshrit Zeevi, Shay Levi, Noa Urman, Ariel Naveh, and Tal Marciano. "RBIO-01. DEVELOPING THE FRAMEWORK FOR TUMOR TREATING FIELDS (TTFIELDS) TREATMENT PLANNING FOR A PATIENT WITH ASTROCYTOMA IN THE SPINAL CORD." Neuro-Oncology 23, Supplement_6 (November 2, 2021): vi191. http://dx.doi.org/10.1093/neuonc/noab196.758.
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Abstract The use of Tumor Treating Fields (TTFields) following resection and chemoradiation has increased survival in patients with Glioblastoma. Patient-specific planning for TTFields transducer array placement has been demonstrated to maximize TTFields dose at the tumor: providing higher TTFields intensity (≥ 1.0 V/cm) and power density (≥ 1.1 mW/cm3) which are associated with improved overall survival. Treatment planning was performed for a 48 year old patient following T10-L1 laminectomy, gross total resection, and postoperative chemoradiation for an anaplastic astrocytoma of the spinal cord. An MRI at 3 weeks following chemoradiation showed tumor recurrence. Based on the post-chemoradiation MRI, a patient-specific model was created. The model was created by modifying a realistic computational phantom of a healthy female. To mimic the laminectomy, the lamina in T10-L1 was removed, and the region assigned electric conductivity similar to that of muscle. A virtual mass was introduced into the spinal cord. Virtual transducer arrays were placed on the model at multiple positions, and delivery of TTFields simulated. The dose delivered by different transducer array layouts was calculated, and the layouts that yielded maximal dose to the tumor and spine identified. Transducer array layouts, in which the arrays were placed on the back of the patient with one array above the tumor and one array below the tumor, yielded the highest doses at the tumor site. Such layouts yielded TTFields doses of over 3.4mW/cm3 which is well above the threshold dose of 1.1 mW/cm3 reported previously [Ballo et al. Red Jour 2019]. The framework developed for TTFields dosimetry and treatment planning for this spinal tumor will have the potential to increase dose delivery to the tumor bed while optimizing placement that may enhance comfort and encourage device usage.
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Santos, Jennifer De Los, Smadar Arvatz, Oshrit Zeevi, Shay Levi, Noa Urman, Melissa Shackelford, Ariel Naveh, and Tal Marciano. "Abstract 3447: Tumor treating fields (TTFields) treatment planning for a patient with astrocytoma in the spinal cord." Cancer Research 82, no. 12_Supplement (June 15, 2022): 3447. http://dx.doi.org/10.1158/1538-7445.am2022-3447.
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Abstract Objectives: The use of TTFields following resection and chemoradiation has increased survival in patients with Glioblastoma (Stupp, et al. JAMA. 2015;314:2535-2543). Randomized data provide a strong rationale for the treatment of high grade gliomas using TTFields with individualized array placement that maximizes the dose at the tumor in a patient-specific manner: providing higher TTFields intensity (≥1.0 V/cm) and power density (≥1.1 mW/cm3) which are associated with improved overall survival (Ballo, et al. Int J Radiat Oncol Biol Phys. 2019;104:1106-11). Here for the first time, we present a case demonstrating the use of numerical simulations for patient-specific TTFields treatment planning for a spinal tumor. Methods: Treatment planning was performed for a 48 year old patient following T10-L1 laminectomy, gross total resection, and postoperative chemoradiation for an anaplastic astrocytoma of the spinal cord. An MRI at 3 weeks following chemoradiation showed tumor recurrence. Based on the post-chemoradiation MRI, a patient-specific model was created. The model was created by modifying a realistic computational phantom of a healthy female. To mimic the laminectomy, the lamina in T10-L1 was removed and the region was assigned an electric conductivity similar to that of muscle. A virtual mass was introduced into the spinal cord. Virtual transducer arrays were placed on the model at multiple positions, and delivery of TTFields simulated. The dose delivered by different transducer array layouts was calculated, and the layouts that yielded maximal dose to the tumor and spine identified. Results: Combinations of the best layouts targeting the tumor (all above 2.5 mW/cm3) and the best layouts targeting the spinal cord were investigated. Transducer array layouts where the arrays were placed on the back of the patient with one above the tumor and one below yielded the highest doses at the tumor site. Such layouts yielded TTFields doses of over 2.5mW/cm3, which is well above the threshold dose of 1.1 mW/cm3. Three such layouts were presented as possibilities for a recommended treatment plan. As patient usage, or time on treatment, is correlated with improved patient outcomes, an interactive process was followed to adjust the treatment so that it incorporates both increased therapeutic dose to the tumor and increased overall patient usage and comfort. Conclusions: These data represent the first ever study on utilizing numerical simulations to plan treatment for a spinal tumor in a patient-specific manner. This is an important milestone in the development of a framework for TTFields dosimetry and treatment planning. This framework will have the potential to increase dose delivery to the tumor bed while optimizing placement that may enhance comfort and encourage device usage. Citation Format: Jennifer De Los Santos, Smadar Arvatz, Oshrit Zeevi, Shay Levi, Noa Urman, Melissa Shackelford, Ariel Naveh, Tal Marciano. Tumor treating fields (TTFields) treatment planning for a patient with astrocytoma in the spinal cord [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3447.
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Maza, Rodrigo M., María Asunción Barreda-Manso, David Reigada, Ágata Silván, Teresa Muñoz-Galdeano, Altea Soto, Ángela del Águila, and Manuel Nieto-Díaz. "MicroRNA-138-5p Targets Pro-Apoptotic Factors and Favors Neural Cell Survival: Analysis in the Injured Spinal Cord." Biomedicines 10, no. 7 (June 30, 2022): 1559. http://dx.doi.org/10.3390/biomedicines10071559.
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The central nervous system microRNA miR-138-5p has attracted much attention in cancer research because it inhibits pro-apoptotic genes including CASP3. We hypothesize that miR-138-5p downregulation after SCI leads to overexpression of pro-apoptotic genes, sensitizing neural cells to noxious stimuli. This study aimed to identify miR-138-5p targets among pro-apoptotic genes overexpressed following SCI and to confirm that miR-138-5p modulates cell death in neural cells. Gene expression and histological analyses revealed that the drop in miR-138-5p expression after SCI is due to the massive loss of neurons and oligodendrocytes and its downregulation in neurons. Computational analyses identified 176 potential targets of miR-138-5p becoming dysregulated after SCI, including apoptotic proteins CASP-3 and CASP-7, and BAK. Reporter, RT-qPCR, and immunoblot assays in neural cell cultures confirmed that miR-138-5p targets their 3′UTRs, reduces their expression and the enzymatic activity of CASP-3 and CASP-7, and protects cells from apoptotic stimuli. Subsequent RT-qPCR and histological analyses in a rat model of SCI revealed that miR-138-5p downregulation correlates with the overexpression of its pro-apoptotic targets. Our results suggest that the downregulation of miR-138-5p after SCI may have deleterious effects on neural cells, particularly on spinal neurons.
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Burkhart, Michael C., David M. Brandman, Brian Franco, Leigh R. Hochberg, and Matthew T. Harrison. "The Discriminative Kalman Filter for Bayesian Filtering with Nonlinear and Nongaussian Observation Models." Neural Computation 32, no. 5 (May 2020): 969–1017. http://dx.doi.org/10.1162/neco_a_01275.
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The Kalman filter provides a simple and efficient algorithm to compute the posterior distribution for state-space models where both the latent state and measurement models are linear and gaussian. Extensions to the Kalman filter, including the extended and unscented Kalman filters, incorporate linearizations for models where the observation model [Formula: see text] is nonlinear. We argue that in many cases, a model for [Formula: see text] proves both easier to learn and more accurate for latent state estimation. Approximating [Formula: see text] as gaussian leads to a new filtering algorithm, the discriminative Kalman filter (DKF), which can perform well even when [Formula: see text] is highly nonlinear and/or nongaussian. The approximation, motivated by the Bernstein–von Mises theorem, improves as the dimensionality of the observations increases. The DKF has computational complexity similar to the Kalman filter, allowing it in some cases to perform much faster than particle filters with similar precision, while better accounting for nonlinear and nongaussian observation models than Kalman-based extensions. When the observation model must be learned from training data prior to filtering, off-the-shelf nonlinear and nonparametric regression techniques can provide a gaussian model for [Formula: see text] that cleanly integrates with the DKF. As part of the BrainGate2 clinical trial, we successfully implemented gaussian process regression with the DKF framework in a brain-computer interface to provide real-time, closed-loop cursor control to a person with a complete spinal cord injury. In this letter, we explore the theory underlying the DKF, exhibit some illustrative examples, and outline potential extensions.
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Petrella, Jeffrey R., Wenrui Hao, Adithi Rao, and P. Murali Doraiswamy. "Computational Causal Modeling of the Dynamic Biomarker Cascade in Alzheimer’s Disease." Computational and Mathematical Methods in Medicine 2019 (February 3, 2019): 1–8. http://dx.doi.org/10.1155/2019/6216530.
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Background. Alzheimer’s disease (AD) is a major public health concern, and there is an urgent need to better understand its complex biology and develop effective therapies. AD progression can be tracked in patients through validated imaging and spinal fluid biomarkers of pathology and neuronal loss. We still, however, lack a coherent quantitative model that explains how these biomarkers interact and evolve over time. Such a model could potentially help identify the major drivers of disease in individual patients and simulate response to therapy prior to entry in clinical trials. A current theory of AD biomarker progression, known as the dynamic biomarker cascade model, hypothesizes AD biomarkers evolve in a sequential but temporally overlapping manner. A computational model incorporating assumptions about the underlying biology of this theory and its variations would be useful to test and refine its accuracy with longitudinal biomarker data from clinical trials. Methods. We implemented a causal model to simulate time-dependent biomarker data under the descriptive assumptions of the dynamic biomarker cascade theory. We modeled pathologic biomarkers (beta-amyloid and tau), neuronal loss biomarkers, and cognitive impairment as nonlinear first-order ordinary differential equations (ODEs) to include amyloid-dependent and nondependent neurodegenerative cascades. We tested the feasibility of the model by adjusting its parameters to simulate three specific natural history scenarios in early-onset autosomal dominant AD and late-onset AD and determine whether computed biomarker trajectories agreed with current assumptions of AD biomarker progression. We also simulated the effects of antiamyloid therapy in late-onset AD. Results. The computational model of early-onset AD demonstrated the initial appearance of amyloid, followed by biomarkers of tau and neurodegeneration and the onset of cognitive decline based on cognitive reserve, as predicted by the prior literature. Similarly, the late-onset AD computational models demonstrated the first appearance of amyloid or nonamyloid-related tauopathy, depending on the magnitude of comorbid pathology, and also closely matched the biomarker cascades predicted by the prior literature. Forward simulation of antiamyloid therapy in symptomatic late-onset AD failed to demonstrate any slowing in progression of cognitive decline, consistent with prior failed clinical trials in symptomatic patients. Conclusions. We have developed and computationally implemented a mathematical causal model of the dynamic biomarker cascade theory in AD. We demonstrate the feasibility of this model by simulating biomarker evolution and cognitive decline in early- and late-onset natural history scenarios, as well as in a treatment scenario targeted at core AD pathology. Models resulting from this causal approach can be further developed and refined using patient data from longitudinal biomarker studies and may in the future play a key role in personalizing approaches to treatment.
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Fregly, Benjamin J. "A Conceptual Blueprint for Making Neuromusculoskeletal Models Clinically Useful." Applied Sciences 11, no. 5 (February 25, 2021): 2037. http://dx.doi.org/10.3390/app11052037.
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The ultimate goal of most neuromusculoskeletal modeling research is to improve the treatment of movement impairments. However, even though neuromusculoskeletal models have become more realistic anatomically, physiologically, and neurologically over the past 25 years, they have yet to make a positive impact on the design of clinical treatments for movement impairments. Such impairments are caused by common conditions such as stroke, osteoarthritis, Parkinson’s disease, spinal cord injury, cerebral palsy, limb amputation, and even cancer. The lack of clinical impact is somewhat surprising given that comparable computational technology has transformed the design of airplanes, automobiles, and other commercial products over the same time period. This paper provides the author’s personal perspective for how neuromusculoskeletal models can become clinically useful. First, the paper motivates the potential value of neuromusculoskeletal models for clinical treatment design. Next, it highlights five challenges to achieving clinical utility and provides suggestions for how to overcome them. After that, it describes clinical, technical, collaboration, and practical needs that must be addressed for neuromusculoskeletal models to fulfill their clinical potential, along with recommendations for meeting them. Finally, it discusses how more complex modeling and experimental methods could enhance neuromusculoskeletal model fidelity, personalization, and utilization. The author hopes that these ideas will provide a conceptual blueprint that will help the neuromusculoskeletal modeling research community work toward clinical utility.
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BRANDOLINI, NICOLA, LUCA CRISTOFOLINI, and MARCO VICECONTI. "EXPERIMENTAL METHODS FOR THE BIOMECHANICAL INVESTIGATION OF THE HUMAN SPINE: A REVIEW." Journal of Mechanics in Medicine and Biology 14, no. 01 (February 2014): 1430002. http://dx.doi.org/10.1142/s0219519414300026.
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In vitro mechanical testing of spinal specimens is extremely important to better understand the biomechanics of the healthy and diseased spine, fracture, and to test/optimize surgical treatment. While spinal testing has extensively been carried out in the past four decades, testing methods are quite diverse. This paper aims to provide a critical overview of the in vitro methods for mechanical testing the human spine at different scales. Specimens of different type are used, according to the aim of the study: spine segments (two or more adjacent vertebrae) are used both to investigate the spine kinematics, and the mechanical properties of the spine components (vertebrae, ligaments, discs); single vertebrae (whole vertebra, isolated vertebral body, or vertebral body without endplates) are used to investigate the structural properties of the vertebra itself; core specimens are extracted to test the mechanical properties of the trabecular bone at the tissue-level; mechanical properties of spine soft tissue (discs, ligaments, spinal cord) are measured on isolated elements, or on tissue specimens. Identification of consistent reference frames is still a debated issue. Testing conditions feature different pre-conditioning and loading rates, depending on the simulated action. Tissue specimen preservation is a very critical issue, affecting test results. Animal models are often used as a surrogate. However, because of different structure and anatomy, extreme caution is required when extrapolating to the human spine. In vitro loading conditions should be based on reliable in vivo data. Because of the high complexity of the spine, such information (either through instrumented implants or through numerical modeling) is currently unsatisfactory. Because of the increasing ability of computational models in predicting biomechanical properties of musculoskeletal structures, a synergy is possible (and desirable) between in vitro experiments and numerical modeling. Future perspectives in spine testing include integration of mechanical and structural properties at different dimensional scales (from the whole-body-level down to the tissue-level) so that organ-level models (which are used to predict the most relevant phenomena such as fracture) include information from all dimensional scales.
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Laschowski, Brock, Naser Mehrabi, and John McPhee. "Inverse Dynamics Modeling of Paralympic Wheelchair Curling." Journal of Applied Biomechanics 33, no. 4 (August 2017): 294–99. http://dx.doi.org/10.1123/jab.2016-0143.
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Paralympic wheelchair curling is an adapted version of Olympic curling played by individuals with spinal cord injuries, cerebral palsy, multiple sclerosis, and lower extremity amputations. To the best of the authors’ knowledge, there has been no experimental or computational research published regarding the biomechanics of wheelchair curling. Accordingly, the objective of the present research was to quantify the angular joint kinematics and dynamics of a Paralympic wheelchair curler throughout the delivery. The angular joint kinematics of the upper extremity were experimentally measured using an inertial measurement unit system; the translational kinematics of the curling stone were additionally evaluated with optical motion capture. The experimental kinematics were mathematically optimized to satisfy the kinematic constraints of a subject-specific multibody biomechanical model. The optimized kinematics were subsequently used to compute the resultant joint moments via inverse dynamics analysis. The main biomechanical demands throughout the delivery (ie, in terms of both kinematic and dynamic variables) were about the hip and shoulder joints, followed sequentially by the elbow and wrist. The implications of these findings are discussed in relation to wheelchair curling delivery technique, musculoskeletal modeling, and forward dynamic simulations.
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Chen, Xingjuan, Degang Liu, Donghui Zhou, Yubing Si, David Xu, Christopher W. Stamatkin, Mona K. Ghozayel, et al. "Small-molecule CaVα1⋅CaVβ antagonist suppresses neuronal voltage-gated calcium-channel trafficking." Proceedings of the National Academy of Sciences 115, no. 45 (October 24, 2018): E10566—E10575. http://dx.doi.org/10.1073/pnas.1813157115.
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Extracellular calcium flow through neuronal voltage-gated CaV2.2 calcium channels converts action potential-encoded information to the release of pronociceptive neurotransmitters in the dorsal horn of the spinal cord, culminating in excitation of the postsynaptic central nociceptive neurons. The CaV2.2 channel is composed of a pore-forming α1subunit (CaVα1) that is engaged in protein–protein interactions with auxiliary α2/δ and β subunits. The high-affinity CaV2.2α1⋅CaVβ3protein–protein interaction is essential for proper trafficking of CaV2.2 channels to the plasma membrane. Here, structure-based computational screening led to small molecules that disrupt the CaV2.2α1⋅CaVβ3protein–protein interaction. The binding mode of these compounds reveals that three substituents closely mimic the side chains of hot-spot residues located on the α-helix of CaV2.2α1. Site-directed mutagenesis confirmed the critical nature of a salt-bridge interaction between the compounds and CaVβ3Arg-307. In cells, compounds decreased trafficking of CaV2.2 channels to the plasma membrane and modulated the functions of the channel. In a rodent neuropathic pain model, the compounds suppressed pain responses. Small-molecule α-helical mimetics targeting ion channel protein–protein interactions may represent a strategy for developing nonopioid analgesia and for treatment of other neurological disorders associated with calcium-channel trafficking.
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Solovyev, Alexey, Qi Mi, Yi-Ting Tzen, David Brienza, and Yoram Vodovotz. "Hybrid Equation/Agent-Based Model of Ischemia-Induced Hyperemia and Pressure Ulcer Formation Predicts Greater Propensity to Ulcerate in Subjects with Spinal Cord Injury." PLoS Computational Biology 9, no. 5 (May 16, 2013): e1003070. http://dx.doi.org/10.1371/journal.pcbi.1003070.
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Grassmann, Greta, Mattia Miotto, Lorenzo Di Rienzo, Federico Salaris, Beatrice Silvestri, Elsa Zacco, Alessandro Rosa, Gian Gaetano Tartaglia, Giancarlo Ruocco, and Edoardo Milanetti. "A Computational Approach to Investigate TDP-43 RNA-Recognition Motif 2 C-Terminal Fragments Aggregation in Amyotrophic Lateral Sclerosis." Biomolecules 11, no. 12 (December 19, 2021): 1905. http://dx.doi.org/10.3390/biom11121905.
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Many of the molecular mechanisms underlying the pathological aggregation of proteins observed in neurodegenerative diseases are still not fully understood. Among the aggregate-associated diseases, Amyotrophic Lateral Sclerosis (ALS) is of relevant importance. In fact, although understanding the processes that cause the disease is still an open challenge, its relationship with protein aggregation is widely known. In particular, human TDP-43, an RNA/DNA binding protein, is a major component of the pathological cytoplasmic inclusions observed in ALS patients. Indeed, the deposition of the phosphorylated full-length TDP-43 in spinal cord cells has been widely studied. Moreover, it has also been shown that the brain cortex presents an accumulation of phosphorylated C-terminal fragments (CTFs). Even if it is debated whether the aggregation of CTFs represents a primary cause of ALS, it is a hallmark of TDP-43 related neurodegeneration in the brain. Here, we investigate the CTFs aggregation process, providing a computational model of interaction based on the evaluation of shape complementarity at the molecular interfaces. To this end, extensive Molecular Dynamics (MD) simulations were conducted for different types of protein fragments, with the aim of exploring the equilibrium conformations. Adopting a newly developed approach based on Zernike polynomials, able to find complementary regions in the molecular surface, we sampled a large set of solvent-exposed portions of CTFs structures as obtained from MD simulations. Our analysis proposes and assesses a set of possible association mechanisms between the CTFs, which could drive the aggregation process of the CTFs. To further evaluate the structural details of such associations, we perform molecular docking and additional MD simulations to propose possible complexes and assess their stability, focusing on complexes whose interacting regions are both characterized by a high shape complementarity and involve β3 and β5 strands at their interfaces.
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Huss, Mikael, Anders Lansner, Peter Wallén, Abdeljabbar El Manira, Sten Grillner, and Jeanette H. Kotaleski. "Roles of Ionic Currents in Lamprey CPG Neurons: A Modeling Study." Journal of Neurophysiology 97, no. 4 (April 2007): 2696–711. http://dx.doi.org/10.1152/jn.00528.2006.
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The spinal network underlying locomotion in the lamprey consists of a core network of glutamatergic and glycinergic interneurons, previously studied experimentally and through mathematical modeling. We present a new and more detailed computational model of lamprey locomotor network neurons, based primarily on detailed electrophysiological measurements and incorporating new experimental findings. The model uses a Hodgkin–Huxley-like formalism and consists of 86 membrane compartments containing 12 types of ion currents. One of the goals was to introduce a fast, transient potassium current (Kt) and two sodium-dependent potassium currents, one faster (KNaF) and one slower (KNaS), in the model. Not only has the model lent support to the interpretation of experimental results but it has also provided predictions for further experimental analysis of single-network neurons. For example, Kt was shown to be one critical factor for controlling action potential duration. In addition, the model has proved helpful in investigating the possible influence of the slow afterhyperpolarization on repetitive firing during ongoing activation. In particular, the balance between the simulated slow sodium-dependent and calcium-dependent potassium currents has been explored, as well as the possible involvement of dendritic conductances.
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Cortés, Camilo, Ana de los Reyes-Guzmán, Davide Scorza, Álvaro Bertelsen, Eduardo Carrasco, Ángel Gil-Agudo, Oscar Ruiz-Salguero, and Julián Flórez. "Inverse Kinematics for Upper Limb Compound Movement Estimation in Exoskeleton-Assisted Rehabilitation." BioMed Research International 2016 (2016): 1–14. http://dx.doi.org/10.1155/2016/2581924.
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Robot-Assisted Rehabilitation (RAR) is relevant for treating patients affected by nervous system injuries (e.g., stroke and spinal cord injury). The accurate estimation of the joint angles of the patient limbs in RAR is critical to assess the patient improvement. The economical prevalent method to estimate the patient posture in Exoskeleton-based RAR is to approximate the limb joint angles with the ones of the Exoskeleton. This approximation is rough since their kinematic structures differ. Motion capture systems (MOCAPs) can improve the estimations, at the expenses of a considerable overload of the therapy setup. Alternatively, the Extended Inverse Kinematics Posture Estimation (EIKPE) computational method models the limb and Exoskeleton as differing parallel kinematic chains. EIKPE has been tested with single DOF movements of the wrist and elbow joints. This paper presents the assessment of EIKPE with elbow-shoulder compound movements (i.e., object prehension). Ground-truth for estimation assessment is obtained from an optical MOCAP (not intended for the treatment stage). The assessment shows EIKPE rendering a good numerical approximation of the actual posture during the compound movement execution, especially for the shoulder joint angles. This work opens the horizon for clinical studies with patient groups, Exoskeleton models, and movements types.
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Montaño, Carlos Julio, and Tarcisio Passos Ribeiro de Campos. "RADIOACTIVE CEMENT OF PMMA AND HAP-Sm-153, Ho-166, OR RE-188 FOR BONE METASTASIS TREATMENT." Acta Ortopédica Brasileira 27, no. 1 (February 2019): 64–68. http://dx.doi.org/10.1590/1413-785220192701190288.
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ABSTRACT Polymethylmetacrylte (PMMA) is used in the fields of dentistry and biomedicine as a constituent of bone cements. Hydroxyapatite (HAp) is a bioceramic produced naturally in the bones. PMMA and HAp are fundamental constituents in the preparation of bone cements. Bisphosphonates have also been used as radiopharmaceutical in dental implants and nuclear medicine, or as palliative systemic treatment for pain reduction in bone metastasis. Vertebroplasty and kyphoplasty are bone cement-based techniques used in orthopedics, being minimally invasive procedures with low risks of infections, applied in osteoporosis and high-impact fractures. Recently, Núcleo de Radiações Ionizantes da Universidade Federal de Minas Gerais proposed a synthetic composite of M-HAp with a metallic nuclide M. After irradiation, M-HAp was added to PMMA, compounding a radioactive bone cement that can recover bone body stabilization, pasting microfractures and recomposing the anatomy and functionality of the affected parts by the compression of bone metastases, with possible pain reduction through quick radiation-induced decompression. Computational dosimetric models, and the synthesis and characterization of bioceramics that incorporate Re-188, Ho-166, or Sm-153 have demonstrated the benefits of these biometrics as promising alternative therapies, mainly from their ability to maintain the ionization in the bone structure, thereby sparing the spinal cord. This article presents a review on this topic. Level of Evidence V, Expert Opinion.
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Di Russo, Andrea, Dimitar Stanev, Stéphane Armand, and Auke Ijspeert. "Sensory modulation of gait characteristics in human locomotion: A neuromusculoskeletal modeling study." PLOS Computational Biology 17, no. 5 (May 19, 2021): e1008594. http://dx.doi.org/10.1371/journal.pcbi.1008594.
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The central nervous system of humans and other animals modulates spinal cord activity to achieve several locomotion behaviors. Previous neuromechanical models investigated the modulation of human gait changing selected parameters belonging to CPGs (Central Pattern Generators) feedforward oscillatory structures or to feedback reflex circuits. CPG-based models could replicate slow and fast walking by changing only the oscillation’s properties. On the other hand, reflex-based models could achieve different behaviors through optimizations of large dimensional parameter spaces. However, they could not effectively identify individual key reflex parameters responsible for gait characteristics’ modulation. This study investigates which reflex parameters modulate the gait characteristics through neuromechanical simulations. A recently developed reflex-based model is used to perform optimizations with different target behaviors on speed, step length, and step duration to analyze the correlation between reflex parameters and their influence on these gait characteristics. We identified nine key parameters that may affect the target speed ranging from slow to fast walking (0.48 and 1.71 m/s) as well as a large range of step lengths (0.43 and 0.88 m) and step duration (0.51, 0.98 s). The findings show that specific reflexes during stance significantly affect step length regulation, mainly given by positive force feedback of the ankle plantarflexors’ group. On the other hand, stretch reflexes active during swing of iliopsoas and gluteus maximus regulate all the gait characteristics under analysis. Additionally, the results show that the hamstrings’ group’s stretch reflex during the landing phase is responsible for modulating the step length and step duration. Additional validation studies in simulations demonstrated that the modulation of identified reflexes is sufficient to regulate the investigated gait characteristics. Thus, this study provides an overview of possible reflexes involved in modulating speed, step length, and step duration of human gaits.
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Khammad, Vasilii, Jose Javier Otero, Yolanda Cabello Izquierdo, Francisco Garagorry Guerra, Aline P. Becker, Nataliy Kharchenko, and Gadzhimurad Zapirov. "Application of machine learning algorithms for the diagnosis of primary brain tumors." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): 2533. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.2533.
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2533 Background: Primary lesions of the CNS refer to a heterogeneous group of benign or malignant tumors arising in different parts of the brain and spinal cord. According to the 2016 CNS WHO classification, the accurate diagnosis of primary brain tumors requires a layered approach of histologic, anatomic and molecular features to generate an integrated diagnosis with clinical and prognostic significance. However, in the US and worldwide, scarce resources are available to perform all the required tests routinely, so methods that improve pre-test probabilities and decrease false positive results have significant clinical and financial impact. Aims: 1) validate new diagnostic workflows with implementation of modern machine learning/artificial intelligence approaches; 2) design a reliable and interactive computational platform for primary CNS tumor diagnosis. Methods: To achieve these goals we have developed a population model in Rstudio, “La Tabla”, based on the articles from open resources of MEDLINE database and the latest version of WHO classification of CNS tumors. The data of “La Tabla” is comprised of more than 100,000 adult and pediatric cases, including rare brain tumor diagnoses, such as Gangliocytoma, Diffuse Midline Glioma and etc. Results: Boruta package and weights function in R have been used to distinguish the most important features for diagnosis prediction. To visualize correlation between these features (age, ki67 level, tumor location, presence of myxoid areas, calcifications, necrosis and etc.) and all diagnoses in two-dimensional space, we used a t-SNE algorithm. Models trained with decision tree algorithms (randomForest, XGBoost and C5.0) showed high overall accuracy in predicting diagnoses of “La Tabla” (95%, 94% and 92%) and 300 patients at OSUCCC-James (93%, 74% and 87%) in the absence of IHC and molecular data. Neural networks provided by keras and nnet packages predicted diagnoses using just clinical and histological findings with 94% and 88% accuracy on “La Tabla” and James patient databases respectively. Currently, we are building “Shiny” applications with R to deliver easily operated platform for pathologists and physicians. Conclusions: In conclusion, we managed to generate models that are able to diagnose primary brain lesions using basic clinical data (age, gender, tumor location), ki67 levels and distinct features of histological architecture. Most of the models distinguish brain tumors and associated molecular status with high accuracy and will serve as a reliable tool for second opinion in clinical neuro-oncology.
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Noorsal, Emilia, Saharul Arof, Saiful Zaimy Yahaya, Zakaria Hussain, Daniel Kho, and Yusnita Mohd Ali. "Design of an FPGA-Based Fuzzy Feedback Controller for Closed-Loop FES in Knee Joint Model." Micromachines 12, no. 8 (August 16, 2021): 968. http://dx.doi.org/10.3390/mi12080968.
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Functional electrical stimulation (FES) device has been widely used by spinal cord injury (SCI) patients in their rehab exercises to restore motor function to their paralysed muscles. The major challenge of muscle contraction induced by FES is early muscle fatigue due to the open-loop stimulation strategy. To reduce the early muscle fatigue phenomenon, a closed-loop FES system is proposed to track the angle of the limb’s movement and provide an accurate amount of charge according to the desired reference angle. Among the existing feedback controllers, fuzzy logic controller (FLC) has been found to exhibit good control performance in handling complex non-linear systems without developing any complex mathematical model. Recently, there has been considerable interest in the implementation of FLC in hardware embedded systems. Therefore, in this paper, a digital fuzzy feedback controller (FFC) embedded in a field-programmable gate array (FPGA) board was proposed. The digital FFC mainly consists of an analog-to-digital converter (ADC) Data Acquisition and FLC sub-modules. The FFC was designed to monitor and control the progress of knee extension movement by regulating the stimulus pulse width duration to meet the target angle. The knee is expected to extend to a maximum reference angle setting (70°, 40° or 30°) from its normal position of 0° once the stimulus charge is applied to the muscle by the FES device. Initially, the FLC was modelled using MATLAB Simulink. Then, the FLC was hardcoded into digital logic using hardware description language (HDL) Verilog codes. Thereafter, the performance of the digital FLC was tested with a knee extension model using the HDL co-simulation technique in MATLAB Simulink. Finally, for real-time verification, the designed digital FFC was downloaded to the Intel FPGA (DE2-115) board. The digital FFC utilized only 4% of the total FPGA (Cyclone IV E) logic elements (LEs) and required 238 µs to regulate stimulus pulse width data, including 3 µs for the FLC computation. The high processing speed of the digital FFC enables the stimulus pulse width duration to be updated every stimulation cycle. Furthermore, the implemented digital FFC has demonstrated good control performance in accurately controlling the stimulus pulse width duration to reach the desired reference angle with very small overshoot (1.4°) and steady-state error (0.4°). These promising results are very useful for a real-world closed-loop FES application.