Background: Spinal cord injuries incite varying degrees of symptoms in patients, ranging from weakness and incoordination to paralysis. Common amongst spinal cord injury (SCI) patients, neuropathic pain (NP) is a debilitating medical condition. Unfortunately, there remain many clinical impediments in treating NP because there is a lack of understanding regarding the mechanisms behind SCI-induced NP (SCINP). Given that more than 450,000 people in the United States alone suffer from SCI, it is unsatisfactory that current treatments yield poor results in alleviating and treating NP. Summary: In this review, we briefly discussed the models of SCINP along with the mechanisms of NP progression. Further, current treatment modalities are herein explored for SCINP involving pharmacological interventions targeting glia cells and astrocytes. Key message: The studies presented in this review provide insight for new directions regarding SCINP alleviation. Given the severity and incapacitating effects of SCINP, it is imperative to study the pathways involved and find new therapeutic targets in coordination with stem cell research, and to develop a new gold-standard in SCINP treatment.

Background Spinal cord injury (SCI) leads to serious complications involving primary trauma and progressive loss due to inflammation, local ischemia, or infection. Despite a worldwide annual incidence of 15 to 40 cases per million, methylprednisolone is the only treatment available to alleviate neurologic dysfunction; therefore, research is currently focused on identifying novel targets by biochemical and molecular studies. Purpose Here, we investigated the expression of various molecular markers at the messenger ribonucleic acid (mRNA) and protein level at day 0 and day 30 post-SCI. Methods Enzyme-linked immunosorbent assay (ELISA) was performed to determine the expression of CASPASE-3 and heat shock protein-27 (HSP-27) in serum samples. Real-time polymerase chain reaction (RT-PCR) was performed to determine the level of mRNA expression of vascular endothelial growth factor receptor-1 (VEGFR-1), VEGFR-2, HSP-27, monocyte chemoattractant protein-1 (MCP-1), and CASPASE-3. Results HSP-27 expression at day 30, as compared with day 0, showed significant downregulation. In contrast, there was elevated expression of MCP-1. ELISA analysis showed no significant change in the expression of CASPASE-3 or HSP-27. Conclusion There may be possible opposing role of HSP-27 and MCP-1 governing SCI. Their association can be studied by designing in vitro studies.

BACKGROUND:Treatment of spinal cord injury (SCI) induced neuropathic pain (NP) proves to be extremely clinically challenging as the mechanism behind SCINP is poorly understood. Matrix metalloproteinase (MMP) is largely responsible for the early disruption of the blood spinal cord barrier. This system initiates macrophage infiltration and degradation of myelin, which plays a pivotal role in how NP occurs. In a recent study, we demonstrated that folic acid (FA) treatment to cSCI rats reduced NP and improved functional recovery by repressing MMP-2 expression. We hypothesize that MMP-2 expression is suppressed because FA actively methylates the DNA sequence that encodes for the MMP-2 protein. However, modulation of MMP-2 expression for alleviation of NP is only pertinent to the mid- to late-phase of injury. Therefore, we need to explore alternate therapeutic methods to target the early- to mid-phase of injury to wholly alleviate NP.PURPOSE:Furthering our previous findings on inhibiting MMP-2 expression by FA in mid- and late- phase following cSCI in rats, we hypothesized that FA will methylate and suppress MMP-9 expression during the early- phase, day 1, 3, 7 post cSCI and mid- phase (day 18 post cSCI), in comparison with MMP-2 expression during mid- and the late-phase of cSCI.METHODS:Adult male Sprague Dawley rats (250-270g) underwent cSCI, using a NYU impactor, with 12.5 gm/cm injury. The spinal cord-injured animals were treated intraperitoneally (i.p.) with a standardized dose of FA (80 μg/kg body weight) on day 1, 2, 3, prior to cSCI, followed by daily injection up to 14 or 17 days post-cSCI in different experiments. Animals were euthanized on day 1, 3, 7 post cSCI (early- phase), day 18 post cSCI (mid- phase), and day 42 post cSCI (late-phase) and the epicenter region of injured spinal cord were harvested for MMP-9 and MMP-2 expression analysis by Western blots technique.RESULTS:i) During early-phase on day 1, 3, and 7, the quantitation displayed no statistical significance in MMP-9 expression, between water- and FA- injected rats. ii) On day 18 post-cSCI, FA significantly modulates the expression of MMP-9 (p = 0.043) iii) Comparing results with MMP-2 expression and inhibition, FA significantly modulates the expression of MMP-2 on day 18 post cSCI (FA- and water-injected rats (p = 0.003). iv) In addition, FA significantly modulates the expression of MMP-2 on day 42 post-cSCI comparing FA- and water- injected rat groups (p = 0.034).CONCLUSION:We report that FA administration results in alleviating cSCI-induced NP by inhibiting MMP-9 in the proposed mid- phase of cSCI. However, FA administration resulted in MMP-2 decline during both mid- through late- phase following cSCI. Our study elucidates a new phase of cSCI, the mid-phase. We conclude that further investigation on discovering and quantifying the nature of the mid- phase of SCI injury is needed.

Spinal cord injury (SCI) and associated neuropathic pain are among the most complex medical conditions to treat and thus therapies that are consistently effective across patient populations do not exist. The development of more effective therapies is hampered by the animal models widely used in SCI research. Currently, spinal cord research to advance the discovery and development of novel therapies primarily relies on rodent models that pose significant translational limitations due to differences in size and physiology to humans. Swine, in contrast, compare more favorably to humans with respect to spine and spinal cord anatomy and vasculature, injury-induced immune response, and functional assessments of pain. Additionally, specific breeds of swine such as the Wisconsin Miniature SwineTM (WMSTM) possess thoracic spine that is more similar to the human spine in terms of length, vertebral body size, and overall shape, when compared to a conventional breed of swine. In the current pilot study, we examine the ex vivo distribution of infusate in the WMSTM spinal cord to demonstrate the reproducibility of infusions and thus the suitability of WMSTM for the development of novel SCI therapy delivery platforms such as convection enhanced delivery. Infusions of bromophenol blue dye were performed in 3 cadaver spines through the superior intervertebral space via a needle at 4 locations (C6, T2, T10 and L2). Thirty minutes later a laminectomy was performed to remove the spinal cord and measure the distance travelled by dye. Spinal cord location of the dye injection had a significant (P < 0.005) effect on the diffusion distance of the dye. The reproducibility of infusion data allowed for determination of differences even when using a small number of spines. This pilot study indicates the feasibility of using WMSTM as a platform for developing delivery devices. *Correspondence to: Dhanansayan (Dhanu) Shanmuganayagam, Ph.D., Director, Biomedical & Genomic Research (BGR) Group, Assistant Professor of Physiology, Immunology and Nutrition, Department of Animal Sciences, University of Wisconsin, Madison, 1675 Observatory Drive, Rm 666, Madison, WI 53706, USA, Tel: 1-(608) 890-1332, Fax: 1-(608) 262-5157, E-mail: dshanmug@wisc.edu

Background: Closed-loop neurostimulation is a novel alternative therapy for medically intractable focal epilepsy for patients who are not candidates for surgical resection of a seizure focus. Electrodes for this system can be implanted either within the brain parenchyma or in the subdural space. The electrodes then serve the dual role of detecting seizures and delivering an electrical signal aimed at aborting seizure activity. The Responsive Neurostimulation (RNS®) system (Neuropace, Mountain View, CA, USA) is an FDA-approved implantable device designed for this purpose. Objective: One of the challenges of the brain machine interface devices is the potential for implanted neurostimulator devices to induce progressive gliosis, apart from that associated with the minimal trauma at implantation. Gliosis has the potential to alter impedances over time, thereby affecting the clinical efficacy of these devices, and also poses a challenge to the prospects of in vivo repositioning of depth electrodes. We present a clinical case with 3-year follow-up and pathology. Methods: Single-case, retrospective review within a randomized trial with specific minimum follow-up and impedance measurements. Results: Impedance changes in the surface electrode over time were observed. Surgical pathological findings revealed significant gliosis in the leptomeninges of the cortices. Conclusion: We report, for the first time, long-term impedance recordings from a surface electrode associated with pathologic findings of gliosis at the Neuropace device-tissue interface in a patient who was enrolled in the multicenter RNS System Pivotal Clinical Investigation. Further study is required to elucidate the temporal relationship of pathological findings over time. Impedance changes were more complex than can be explained by a progressive or transient pathological mechanism. Further effort is required to elucidate the relationship between impedance change and seizure event capture.

Background/Aims: Spine and spinal cord pathologies and associated neuropathic pain are among the most complex medical disorders to treat. While rodent models are widely used in spine and spinal cord research and have provided valuable insight into pathophysiological mechanisms, these models offer limited translatability. Thus, studies in rodent models have not led to the development of clinically effective therapies. More recently, swine has become a favored model for spine research because of the high congruency of the species to humans with respect to spine and spinal cord anatomy, vasculature, and immune responses. However, conventional breeds of swine commonly used in these studies present practical and translational hurdles due to their rapid growth toward weights well above those of humans. Methods: In the current study, we evaluated the suitability of a human-sized breed of swine developed at the University of Wisconsin-Madison, the Wisconsin Miniature SwineTM (WMSTM), in the context of thoracic spine morphometry for use in research to overcome limitations of conventional swine breeds. The morphometry of thoracic vertebrae (T1–T15) of 5–6 months-old WMS was analyzed and compared to published values of human and conventional swine spines. Results: The key finding of this study is that WMS spine more closely models the human spine for many of the measured vertebrae parameters, while being similar to conventional swine in respect to the other parameters. Conclusion: WMS provides an improvement over conventional swine for use in translational spinal cord injury studies, particularly long-term ones, because of its slower rate of growth and its maximum growth being limited to human weight and size.

Background: The molecular underpinnings of spinal cord injury (SCI) associated with neuropathic pain (NP) are unknown. Recent studies have demonstrated that matrix metalloproteinases ( MMPs) such as MMP2 play a critical role in inducing NP following SCI. Promoter methylation of MMPs is known to suppress their transcription and reduce NP. In this context, it has been shown in rodents that folic acid (FA), an FDA approved dietary supplement and key methyl donor in the central nervous system (CNS), increases axonal regeneration and repair of injured CNS in part via methylation. Purpose: Based on above observations, in this study, we test whether FA could decrease MMP2 expression and thereby decrease SCI-induced NP. Methods: Sprague-Dawley male rats weighing 250-270 g received contusion spinal cord injuries (cSCIs) with a custom spinal cord impactor device that drops a 10 g weight from a height of 12.5 mm. The injured rats received either i.p. injections of FA (80 mu g/kg) or water (control) 3 days prior and 17 days post-cSCI (mid phase) or for 3 days pre-cSCI and 14 days post-cSCI ending on the 42nd day of cSCI (late phase). The functional neurological deficits due to cSCI were then assessed by Basso, Beattie, and Bresnahan (BBB) scores either on post-impaction days 0 through 18 post-cSCI (mid phase) or on days 0, 2, 7, 14, 21, 28, 35, and 42 (late phase). Baseline measurements were taken the day before starting treatments. Thermal hyperalgesia (TH) testing for pain was performed on 4 days pre-cSCI (baseline data) and on days 18, 21, 28, 35, and 42 post-cSCI. Following TH testing, animals were euthanized and spinal cords harvested for MMP-2 expression analysis. Result: The FA-treated groups showed higher BBB scores during mid phase (day 18) and in late phase (day 42) of injury compared to controls, suggesting enhanced functional recovery. There is a transient decline in TH in animals from the FA-treated group compared to controls when tested on days 18, 21, 28, and 35, indicative of a decrease in NP. However, when tested 25 days after stopping FA administration on day 42 of cSCI, no significant difference in TH was observed between FA-treated and control animals. Western blot analysis of the injured spinal cord from FA-treated animals showed significant decline in MMP2 expression compared to spinal cord samples from water-treated controls. Conclusion: Together, these data suggest that FA could alleviate NP and improve functional recovery post-SCI, possibly by reducing the expression of MMP2. Further studies will open up a novel and easy natural therapy, ideal for clinical translation with minimal side effects, for managing SCI-induced NP. Such studies might also throw light on a possible epigenetic mechanism in FA- induced recovery after SCI. (C) 2017 S. Karger AG, Basel.

Processes such as trauma, neurodegenerative disorders, inflammation, and infection may result in spinal cord injury (SCI) and associated neuropathic pain (NP).NP can be difficult to treat and presents an opportunity for advancing research on several issues related to pain, explicitly relating to transcriptional, epigenetic and post-transcriptional research [1].Effective treatment for relief of NPis currently limited; however, direct delivery of either cellular or biologically active therapeutics into the spinal cord may offer an opportunity for treatment of NP.Distinct role of matrix metalloproteinase MMP9 and MMP2 reported recently in causing NP following spinal nerve ligation in a rodent model [2].MMP-9 induces NP through interleukin-1β cleavage and microglia activation at early phase of injury and MMP2 maintains NP through interleukin-1β cleavage and astrocyte activation at later phase of injury.Intrathecal injections of tissue inhibitors TIMP-Abstract: The incidence of traumatic spinal cord injury (SCI) in the United States is around 12,500 new cases per year with a total prevalence of roughly 276,000 patients.Neuropathic pain (NP) is present in 70% of patients suffering from SCI and is a significant concern.Most research focuses on small animal models with small spinal cords (SC) where simple diffusion of a pharmaceutical or biologic treatment can have a substantial effect.However, promising molecular, gene and cell therapies for treating SCI and NP often fail to demonstrate efficacy in the much larger human SC where simple diffusion is not strong enough to bring the therapy into a significant portion of the transverse spinal cord.Additionally, there is a need to visualize, target and control delivery in humans to specific gray matter SC tracts to generate the desired treatment while avoiding undesired side effects.The development of these promising therapies, however, significantly hampered by the lack of a platform for targeted delivery of therapeutics and lack of a relevant large animal model.To address hurdles in delivering agents across the blood/SC barrier, we propose to utilize a CED injection technique that delivers therapeutic agents into neural tissue using a positive pressure gradient that expands the interstitial space and increases fluid penetrance; we have successfully employed CED to overcome limitations of drug delivery in the brain.From clinical perspective, evidence makes it clear that miRNAs may manipulate cell state and molecular processes in order to enhance functional recovery following SCI and alleviate NP.This review contains the extensive history of the use of modeling CED in the spinal cord and understanding the role of siRNA, miRNA, TIMP therapies and limitations if any.This knowledge can serve as a foundation in the development of minimally invasive CED platforms for the delivery of therapeutics into targeted regions of the SC for the attenuation and repair of SCI induced NP.

Background: Neuropathic pain (NP) is a debilitating condition that may result from spinal cord injury (SCI). Nearly 75% of all SCIs result in NP affecting 17,000 new individuals in the United States every year, and an estimated 7-10% of people worldwide. It is caused by damaged or dysfunctional nerve fibers sending aberrant signals to pain centers in the central nervous system causing severe pain that affects daily life and routine. The mechanisms underlying NP are not fully understood, making treatment difficult. Identification of specific molecular pathways that are involved in pain syndromes and finding effective treatments has become a major priority in current SCI research. Yoga has therapeutic applications that may prove beneficial in treating subjects suffering chronically from SCI-induced NP, chronic back and associated pain if necessary experimental data are generated. Summary: This review aims to discuss the implications of various mechanistic approaches of yoga which can be tested by new study designs around various nociceptive molecules including matrix metalloproteinases, cation-dependent chloride transporter (NKCC1), etc. in SCI-induced NP patients. Key Messages: Yogic practices could be used in managing SCI-induced NP pain by regulating the action of various mechanisms and its associated molecules. Modern prescriptive treatment strategies combined with alternative approaches like yoga should be used in rehabilitation centers and clinics in order to ameliorate chronic NP. We recommend practical considerations of careful yoga practice as part of an integrative medicine approach for NP associated with SCI.

Neuropathic pain (NP) is common among spinal cord injury (SCI) patients, and there remain clinical difficulties in treating NP due to the lack of understanding of underlying mechanisms. Extracellular proteins, such as matrix metalloproteinase and β-catenin, have been shown to be activated in the spinal cord regions following an injury, and may play a key role in contributing to NP states. While these extracellular proteins have been used as therapeutic targets in the spinal cord, there has also been evidence of up-regulation in the hypothalamus following a SCI. We hypothesize that the hypothalamus is involved in regulating NP following a SCI, and hence should be researched further to determine if it is a viable target for future therapeutic treatments.

Neuropathic pain (NP) affects approximately 4 million people in the United States with spinal cord injury (SCI) being a common cause. Matrix metalloproteinases (MMPs) play an integral role in mediating inflammatory responses, cellular signaling, cell migration, extracellular matrix degradation and tissue remodeling and repair. As such, they are major components in the pathogenesis of secondary injury within the central nervous system. Other gene regulatory pathways, specifically MAPK/extracellular signaling-regulated kinase (ERK) and Wnt/β-catenin, are also believed to participate in secondary injury likely intersect. The study aims to examine the MMP-2 signaling pathway associated with ERK and Wnt/β-catenin activity during contusion SCI (cSCI)-induced NP in a rat model. This is an experimental study investigating the implication of MMP-2 in SCI-induced NP and its association with the cellular and molecular changes in the interactions between extracellular signaling kinase and β-catenin. Adult Sprague-Dawley rats received cSCI injury by NYU impactor by dropping 10 g weight from a height of 12.5 mm. Locomotor functional recovery of injured rats was measured on post cSCI day 1, and weekly thereafter for 6 weeks using Basso, Beattie and Bresnahan scores. Thermal hyperalgesia (TH) testing was performed on days 21, 28, 35 and 42 post cSCI. The expression and/or activity of MMP-2, β-catenin and ERK were studied following harvest of spinal cord tissues between 3 and 6 weeks post cSCI. All experiments were funded by the department of Neurological Surgery at the University of Wisconsin, School of Medicine and Public Health having no conflict of interest. MMP-2 and β-catenin expression were elevated and gradually increased from days 21 to 42 compared to sham-operated rats and injured rats that did not exhibit TH. The expression of phosphorylated ERK (phospho-ERK) increased on day 21 but returned to baseline levels on day 42 whereas total ERK levels remained relatively unchanged and constant. Chronic NP is associated with changes in the expression of MMP-2, β-catenin and ERK. Our data suggest that the transient upregulation of phospho-ERK is involved in the initial upregulation of both β-catenin and MMP-2 following cSCI-induced NP states.

Neuropathic pain, especially that resulting from spinal cord injury, is a tremendous clinical challenge. A myriad of biological changes have been implicated in producing these pain states including cellular interactions, extracellular proteins, ion channel expression, and epigenetic influences. Physiological consequences of these changes are varied and include functional deficits and pain responses. Developing therapies that effectively address the cause of these symptoms require a deeper knowledge of alterations in the molecular pathways. Matrix metalloproteinases and tissue inhibitors of metalloproteinases are two promising therapeutic targets. Matrix metalloproteinases interact with and influence many of the studied pain pathways. Gene expression of ion channels and inflammatory mediators clearly contributes to neuropathic pain. Localized and time dependent targeting of these proteins could alleviate and even prevent neuropathic pain from developing. Current therapeutic options for neuropathic pain are limited primarily to analgesics targeting the opioid pathway. Therapies directed at molecular targets are highly desirable and in early stages of development. These include transplantation of exogenously engineered cell populations and targeted gene manipulation. This review describes specific molecular targets amenable to therapeutic intervention using currently available delivery systems.

BACKGROUND:Neuropathic pain (NP) is a common occurrence following spinal cord injury (SCI). Identification of specific molecular pathways that are involved in pain syndromes has become a major priority in current SCI research. We have investigated the role of a cation-dependent chloride transporter, Cl-regulatory protein Na(+)-K(+)-Cl(-) 1 (NKCC1), phosphorylation profile of NKCC1 and its specific involvement in neuropathic pain following contusion SCI (cSCI) using a rat model. Administration of the NKCC1 inhibitor bumetanide (BU) increases the mean hindpaw withdrawal latency time (WLT), thermal hyperalgesia (TH) following cSCI. These results demonstrate implication of NKCC1 co-transporter and BUin SCI-induced neuropathic pain. The with-no-lysine (K)-1 (WNK1) kinase has been shown to be an important regulator of NKCC1 phosphorylation in many systems, including nocioception. Mutations in a neuronal-specific exon of WNK1 (HSN2) was identified in patients that have hereditary sensory neuropathy type II (HSANII) also implicates WNK1 in nocioception, such that these patients have loss of perception to pain, touch and heat. In our ongoing research we proposed two studies utilizing our contusion SCI (cSCI) NP model of rat.PURPOSE:Study 1 aimed at NKCC1 expression and activity is up-regulated following cSCI in the early edema and chronic neuropathic pain phases. Study 2 aimed at identifying the expression profile of alternatively spliced WNK1 isoforms in animals exhibiting thermal hyperalgesia (TH) following cSCI.METHODS:Adult male Sprague Dawley rats (275-300 g) following laminectomy received cSCI at T9 with the NYU impactor-device II by dropping 10 g weight from the height of 12.5 mm. Control rats obtained laminectomy but no impaction. Following injury, functional recovery was assessed by BBB locomotor scores on day 1, 7, 14, 21, 35, and 42 and development of thermal hyperalgesia on day 21, 28, 35, and 42 day of injury by monitoring hind paw withdraw latency time (WLT) in seconds compared with the baseline data before injury.RESULTS:Increased NKCC1 may explain observed increase in magnetic resonance imaging (MRI) T2, exhibiting NKCC1 localization in neurons. This data supports NKCC1's role in the pathogenesis of acute and chronic phases of injury, namely spinal cord edema and chronic phase neuropathic pain. NKCC1 dependent chloride influx requires the phosphorylation at specific residues. Probing for the HSN2 exon of WNK1 reveals two key findings: i) the HSN2 exon is found in alternatively spliced neuronal isoforms found at 250 kDa and 230 kDa; ii) the 250 kDa isoform is found only in tissue that is injured.CONCLUSIONS:This data implicates the NKCC1/WNK1/WNK1HSN2 involvement in post-injury response that contributes to the development of neuropathic pain. Targeting this system may have therapeutic benefit.

BACKGROUND CONTEXT: NKCC1 regulates neuronal homeostasis of chloride ions and mediates GABAergic activities in nociceptive processing. WNK1 is an upstream regulator of NKCC1 and acts via SPAK (STE20/SPS1-related proline/alanine-rich kinase) and oxidative stress-responsive kinase 1. NKCC1 activity has been shown to be important in edema formation and nociception following spinal cord injury (SCI).PURPOSE: To determine the role of NKCC1 and WNK1 in spinal cord tissues in the acute and chronic phases following contusional SCI.STUDY DESIGN: An experimental study investigating the phosphorylation profile of an important Cl-regulatory protein Na+-K+-Cl- cotransporter 1 (NKCC1) and its regulatory-kinase WNK1 (kinase with-no-lysine).METHODS: Sprague-Dawley rats underwent a contusive SCI at T9. The epicenter spinal cord tissues were harvested at Days 1, 3, and 7 for acute phase of injury or Days 35 and 42 in the chronic phase of injury. Western blot was used to compare phosphorylated levels of both NKCC1 and WNK1 in injured tissues compared with those of sham.RESULTS: A sustained increase in phosphorylation of NKCC1 and WNK1 was detected in the lesion epicenter in spinal cord during both acute and chronic phases following SCI.CONCLUSIONS: These results suggest that persistent activation of NKCC1 and WNK1 may play an important role in SCI. (C) 2014 Elsevier Inc. All rights reserved.

BACKGROUND CONTEXT:Ongoing research to understand the mechanism behind pain is heavily dependent on animal testing. However, unlike humans, animal subjects cannot directly communicate with researchers to express the degree of pain they are experiencing. Therefore, measuring the presence of pain in animal studies is based on behavioral tests. The use of arbitrary values for determining the presence of pain in animal studies is an oversimplification of a complex and cortically dependent process.PURPOSE:The purpose of the present study was to identify a statistically supported latency time indicator that can be used as an accurate index for hyperalgesia to thermal stimuli in Sprague-Dawley rats subjected to T9 contusive spinal cord injury (SCI).STUDY DESIGN:A statistical analysis of latency of withdrawal from stimulus-mediated spinal reflex in 979 Sprague-Dawley rats that had been subjected to a T9 contusive SCI was performed.METHODS:This is a retrospective review of a large research database derived from a series of studies performed evaluating thermal hyperalgesia in rats after SCI. Sprague-Dawley rats underwent a T9 contusive SCI and were tested for withdrawal latency from a heat stimulus. Assessment was done preinjury and on Postinjury Days 21, 28, 35, and 42 of the chronic phase of injury via a plantar withdrawal test.RESULTS:The baseline test results of the 979 rats showed a significant resemblance to the normal distribution. The observed change in withdrawal showed mean latency drops of 0.42 second (standard error of the mean [SEM], 0.18; p=.026), 0.57 second (SEM, 0.19; p=.004), 0.63 second (SEM, 0.19; p=.002), and 0.69 second (SEM, 0.19; p=.0003). The standard deviation from the mean at all four postsurgical assessments was between 2.8 and 2.9 seconds.CONCLUSIONS:Interpretation of withdrawal latency times as a marker for thermal hyperalgesia must be based on an appreciation for the normal distribution of pain scores. Recognizing that withdrawal latency is normally distributed both before and after injury allows for rational assignment of animals to groups designated as hyperalgesic and nonhyperalgesic. Two point nine seconds faster than the mean latency time is a statistically reliable indicator of thermal hyperalgesia in Sprague-Dawley rats subjected to contusive SCI. Repeated testing of animals to establish the presence or absence of thermal hyperalgesia beyond 21 days is not necessary in the absence of intervention.

Background: Convection enhanced delivery (CED) is a technique using infusion convection currents to deliver therapeutic agents into targeted regions of the brain.Recently, CED is gaining significant acceptance for use in gene therapy of Parkinson's disease (PD) employing direct infusion into the brain.CED offers advantages in that it targets local areas of the brain, bypasses the blood-brain barrier (BBB), minimizes systemic toxicity of the therapeutics, and allows for delivery of larger molecules that diffusion driven methods cannot achieve.Investigating infusion characteristics such as backflow and morphology is important in developing standard and effective protocols in order to successfully deliver treatments into the brain.Optimizing clinical infusion protocols may reduce backflow, improve final infusion cloud morphology, and maximize infusate penetrance into targeted tissue.Purpose: The purpose of the current study was to compare metrics during ramped-rate and continuous-rate infusions using two different catheters in order to optimize current infusion protocols.Occasionally, the infusate refluxes proximally up the catheter tip, known as backflow, and minimizing this can potentially reduce undesirable effects in the clinical setting.Traditionally, infusions are performed at a constant rate throughout the entire duration, and backflow is minimized only by slow infusion rates, which increases the time required to deliver the desired amount of infusate.In this study, we investigate the effects of ramping and various infusion rates on backflow and infusion cloud morphology.The independent parameters in the study are: ramping, maximum infusion rate, time between rate changes, and increments of rate changes.Methods: Backflow was measured using two methods: i) at the point of pressure stabilization within the catheter, and ii) maximum backflow as shown by video data.Infusion cloud morphology was evaluated based on the height-to-width ratio of each infusion cloud at the end of each experiment.Results were tabulated and statistically analyzed to identify any significant differences between protocols.Results: The experimental results show that CED rampedrate infusion protocols result in smaller backflow distances and more spherical cloud morphologies compared to continuous-rate infusion protocols ending at the same maximum infusion rate.Our results also suggest internal-line pressure measurements can approximate the time-point at which backflow ceases. Conclusion:Our findings indicate that ramping CED infusion protocols can potentially minimize backflow and produce more spherical infusion clouds.However, further research is required to determine the strength of this correlation, especially in relation to maximum infusion rates.

This purpose of this paper is to review the recent history of the use of agarose gels. Although originally confined to electrophoresis work, agarose gels have proven themselves useful to a number of disciplines in the modern world, which includes brain infusion studies for research involving the treatment of various neurological conditions, such as Parkinson's Disease. In reviewing the relevant research leading up to the modern day, this paper attempts to track agarose gels through their stages of accuracy verification, highlighting why they are useful to the neurosurgery discipline and characterizing the nature of their use. Agarose gels do have significant limitations, which are also discussed, but they have substantial potential as a modifiable medium or as a basis of comparison for even more accurate models in the future.

Background Convection enhanced delivery (CED) is emerging as a promising infusion toolto facilitate delivery of therapeutic agents into the brain via mechanically controlled pumps. Infusion protocols and catheter design have an important impact on delivery. CED is a valid alternative for systemic administration of agents in clinical trials for cell and gene therapies. Where gel and ex vivo models are not sufficient in modeling the disease, in vivo models allow researchers to better understand the underlying mechanisms of neuron degeneration, which is helpful in finding novel approaches to control the process or reverse the progression. Determining the risks, benefits, and efficacy of new gene therapies introduced via CED will pave a way to enter human clinical trial. Purpose The objective of this study is to compare volume distribution (Vd)/ volume infused (Vi) ratios and backflow measurements following CED infusions in ex vivo versus in vivo non-human primate brain tissue, based on infusion protocols developed in vitro. Methods In ex vivo infusions, the first brain received 2 infusions using a balloon catheter at rates of 1 μL/min and 2 μL/min for 30 minutes. The second and third brains received infusions using a valve-tip (VT) catheter at 1 μL/min for 30 minutes. The fourth brain received a total of 45 μL infused at a rate of 1 μL/min for 15 minutes followed by 2 μL/min for 15 minutes. Imaging was performed (SPGR FA34) every 3 minutes. In the in vivo group, 4 subjects received a total of 8 infusions of 50 μL. Subjects 1 and 2 received infusions at 1.0 μL/min using a VT catheter in the left hemisphere and a smart-flow (SF) catheter in the right hemisphere. Subjects 3 and 4 each received 1 infusion in the left and right hemisphere at 1.0 μL/min. Results MRI calculations of Vd/Vi did not significantly differ from those obtained on post-mortem pathology. The mean measured Vd/Vi of in vivo (5.23 + /-1.67) compared to ex vivo (2.17 + /-1.39) demonstrated a significantly larger Vd/Vi for in vivo by 2.4 times (p = 0.0017). Conclusion We detected higher ratios in the in vivo subjects than in ex vivo. This difference could be explained by the extra cellular space volume fraction. Studies evaluating backflow and morphology use in vivo tissue as a medium are recommended. Further investigation is warranted to evaluate the role blood pressure and heart rate may play in human CED clinical trials.