52 results on '"Saab CY"'
Search Results
2. Beyond pain privacy and pain meters: a new vision for pain biomarkers.
- Author
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Djordjevic C and Saab CY
- Abstract
To an individual, pain is unambiguously real. To a caregiver, assessing pain in others is a challenging process shrouded in doubt. To explain this challenge, many assume that pain "belongs" exclusively to the bearer of that experience and accept the dogma that pain is private. However, privacy also entails that it is not possible to identify, share, or communicate that experience with others. Obviously, this is not true and the consequences of pain privacy would be devastating for healthcare. Pain is indeed unique and subjective, but not necessarily private. Pain is in fact readily communicable, though perhaps not as effectively and reliably as caregivers would like. On the other hand, healthcare systems mandate objective metrics in pain diagnosis. Smiley face caricatures are a staple of clinical practice and a universal standard for reporting pain levels. These conditions create a double paradox: Assess a private experience that is inaccessible, and use numerical scales to measure subjective attributes. Navigating this stressful environment, medical professionals experience intellectual dissonance, patients are frustrated, and value-based care is undermined. Offering a way out, first, we refute the privacy and objectification of pain citing philosophical, behavioral, and neuroscientific arguments. We discuss Wittgensteinian views against privacy, explore the clear evolutionary advantage of communicating pain to others, and identify neural circuits in the mammalian brain that contribute to empathy. Second, we highlight the subjectivity of pain, embracing the complexity and uniqueness of an individual's pain. We also provide compelling evidence for brain mechanisms that actively shape the pain experience according to predictive coding principles. Third, we offer a vision for the development of biomarker technologies that assess pain fairly without engendering bias against the patient's narrative. Our recommendations are based on the overwhelming appreciation that "medicine by emoji" is inadequate for capturing the multidimensional nature of pain. Our view is that the most promising candidates for pain biomarkers consist of self-reports as ground truth augmented by physiological signatures of biological relevance to pain. Integration of subjective and objective multimodal features will be key for the development of comprehensive pain assessment models., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2024 Djordjevic and Saab.)
- Published
- 2024
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3. Machine learning algorithm for predicting seizure control after temporal lobe resection using peri-ictal electroencephalography.
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Sheikh SR, McKee ZA, Ghosn S, Jeong KS, Kattan M, Burgess RC, Jehi L, and Saab CY
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- Humans, Male, Female, Adult, Middle Aged, Epilepsy, Temporal Lobe surgery, Epilepsy, Temporal Lobe physiopathology, Drug Resistant Epilepsy surgery, Drug Resistant Epilepsy physiopathology, Young Adult, Algorithms, Treatment Outcome, Adolescent, Machine Learning, Electroencephalography methods, Seizures surgery, Seizures physiopathology, Seizures diagnosis, Temporal Lobe surgery, Temporal Lobe physiopathology
- Abstract
Brain resection is curative for a subset of patients with drug resistant epilepsy but up to half will fail to achieve sustained seizure freedom in the long term. There is a critical need for accurate prediction tools to identify patients likely to have recurrent postoperative seizures. Results from preclinical models and intracranial EEG in humans suggest that the window of time immediately before and after a seizure ("peri-ictal") represents a unique brain state with implications for clinical outcome prediction. Using a dataset of 294 patients who underwent temporal lobe resection for seizures, we show that machine learning classifiers can make accurate predictions of postoperative seizure outcome using 5 min of peri-ictal scalp EEG data that is part of universal presurgical evaluation (AUC 0.98, out-of-group testing accuracy > 90%). This is the first approach to seizure outcome prediction that employs a routine non-invasive preoperative study (scalp EEG) with accuracy range likely to translate into a clinical tool. Decision curve analysis (DCA) shows that compared to the prevalent clinical-variable based nomogram, use of the EEG-augmented approach could decrease the rate of unsuccessful brain resections by 20%., (© 2024. The Author(s).)
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- 2024
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4. Toward a brighter constellation: multiorgan neuroimaging of neural and vascular dynamics in the spinal cord and brain.
- Author
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Celinskis D, Black CJ, Murphy J, Barrios-Anderson A, Friedman NG, Shaner NC, Saab CY, Gomez-Ramirez M, Borton DA, and Moore CI
- Abstract
Significance: Pain comprises a complex interaction between motor action and somatosensation that is dependent on dynamic interactions between the brain and spinal cord. This makes understanding pain particularly challenging as it involves rich interactions between many circuits (e.g., neural and vascular) and signaling cascades throughout the body. As such, experimentation on a single region may lead to an incomplete and potentially incorrect understanding of crucial underlying mechanisms., Aim: We aimed to develop and validate tools to enable detailed and extended observation of neural and vascular activity in the brain and spinal cord. The first key set of innovations was targeted to developing novel imaging hardware that addresses the many challenges of multisite imaging. The second key set of innovations was targeted to enabling bioluminescent (BL) imaging, as this approach can address limitations of fluorescent microscopy including photobleaching, phototoxicity, and decreased resolution due to scattering of excitation signals., Approach: We designed 3D-printed brain and spinal cord implants to enable effective surgical implantations and optical access with wearable miniscopes or an open window (e.g., for one- or two-photon microscopy or optogenetic stimulation). We also tested the viability for BL imaging and developed a novel modified miniscope optimized for these signals (BLmini)., Results: We describe "universal" implants for acute and chronic simultaneous brain-spinal cord imaging and optical stimulation. We further describe successful imaging of BL signals in both foci and a new miniscope, the "BLmini," which has reduced weight, cost, and form-factor relative to standard wearable miniscopes., Conclusions: The combination of 3D-printed implants, advanced imaging tools, and bioluminescence imaging techniques offers a coalition of methods for understanding spinal cord-brain interactions. Our work has the potential for use in future research into neuropathic pain and other sensory disorders and motor behavior., (© 2024 The Authors.)
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- 2024
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5. Author Correction: Machine learning polysomnographically-derived electroencephalography biomarkers predictive of epworth sleepiness scale.
- Author
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Araujo M, Ghosn S, Wang L, Hariadi N, Wells S, Saab CY, and Mehra R
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- 2023
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6. Machine learning polysomnographically-derived electroencephalography biomarkers predictive of epworth sleepiness scale.
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Araujo M, Ghosn S, Wang L, Hariadi N, Wells S, Saab CY, and Mehra R
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- Humans, Reproducibility of Results, Electroencephalography adverse effects, Biomarkers, Sleepiness, Disorders of Excessive Somnolence etiology
- Abstract
Excessive daytime sleepiness (EDS) causes difficulty in concentrating and continuous fatigue during the day. In the clinical setting, the assessment and diagnosis of EDS rely mostly on subjective questionnaires and verbal reports, which compromises the reliability of clinical diagnosis and the ability to robustly discern candidacy for available therapies and track treatment response. In this study, we used a computational pipeline for the automated, rapid, high-throughput, and objective analysis of previously collected encephalography (EEG) data to identify surrogate biomarkers for EDS, thereby defining the quantitative EEG changes in individuals with high Epworth Sleepiness Scale (ESS) (n = 31), compared to a group of individuals with low ESS (n = 41) at the Cleveland Clinic. The epochs of EEG analyzed were extracted from a large overnight polysomnogram registry during the most proximate period of wakefulness. Signal processing of EEG showed significantly different EEG features in the low ESS group compared to high ESS, including enhanced power in the alpha and beta bands and attenuation in the delta and theta bands. Our machine learning (ML) algorithms trained on the binary classification of high vs. low ESS reached an accuracy of 80.2%, precision of 79.2%, recall of 73.8% and specificity of 85.3%. Moreover, we ruled out the effects of confounding clinical variables by evaluating the statistical contribution of these variables on our ML models. These results indicate that EEG data contain information in the form of rhythmic activity that could be leveraged for the quantitative assessment of EDS using ML., (© 2023. The Author(s).)
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- 2023
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7. Transient gamma events delineate somatosensory modality in S1.
- Author
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Black CJ, Saab CY, and Borton DA
- Abstract
Gamma band activity localized to the primary somatosensory cortex (S1) in humans and animals is implicated in the higher order neural processing of painful and tactile stimuli. However, it is unclear if gamma band activity differs between these distinct somatosensory modalities. Here, we coupled a novel behavioral approach with chronic extracellular electrophysiology to investigate differences in S1 gamma band activity elicited by noxious and innocuous hind paw stimulation in transgenic mice. Like prior studies, we found that trial-averaged gamma power in S1 increased following both noxious and innocuous stimuli. However, on individual trials, we noticed that evoked gamma band activity was not a continuous oscillatory signal but a series of transient spectral events. Upon further analysis we found that there was a significantly higher incidence of these gamma band events following noxious stimulation than innocuous stimulation. These findings suggest that somatosensory stimuli may be represented by specific features of gamma band activity at the single trial level, which may provide insight to mechanisms underlying acute pain.
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- 2023
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8. SARS-CoV-2 alters neural synchronies in the brain with more severe effects in younger individuals.
- Author
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Valsamis H, Baki SA, Leung J, Ghosn S, Lapin B, Chari G, Rasheed IY, Park J, Punia V, Masri G, Nair D, Kaniecki AM, Edhi M, and Saab CY
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- Adult, Humans, Aged, SARS-CoV-2, Retrospective Studies, Electroencephalography, Brain, COVID-19, Brain Diseases
- Abstract
Coronavirus disease secondary to infection by SARS-CoV-2 (COVID19 or C19) causes respiratory illness, as well as severe neurological symptoms that have not been fully characterized. In a previous study, we developed a computational pipeline for the automated, rapid, high-throughput and objective analysis of electroencephalography (EEG) rhythms. In this retrospective study, we used this pipeline to define the quantitative EEG changes in patients with a PCR-positive diagnosis of C19 (n = 31) in the intensive care unit (ICU) of Cleveland Clinic, compared to a group of age-matched PCR-negative (n = 38) control patients in the same ICU setting. Qualitative assessment of EEG by two independent teams of electroencephalographers confirmed prior reports with regards to the high prevalence of diffuse encephalopathy in C19 patients, although the diagnosis of encephalopathy was inconsistent between teams. Quantitative analysis of EEG showed distinct slowing of brain rhythms in C19 patients compared to control (enhanced delta power and attenuated alpha-beta power). Surprisingly, these C19-related changes in EEG power were more prominent in patients below age 70. Moreover, machine learning algorithms showed consistently higher accuracy in the binary classification of patients as C19 versus control using EEG power for subjects below age 70 compared to older ones, providing further evidence for the more severe impact of SARS-CoV-2 on brain rhythms in younger individuals irrespective of PCR diagnosis or symptomatology, and raising concerns over potential long-term effects of C19 on brain physiology in the adult population and the utility of EEG monitoring in C19 patients., (© 2023. The Author(s).)
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- 2023
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9. Pain phenotypes classified by machine learning using electroencephalography features.
- Author
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Levitt J, Edhi MM, Thorpe RV, Leung JW, Michishita M, Koyama S, Yoshikawa S, Scarfo KA, Carayannopoulos AG, Gu W, Srivastava KH, Clark BA, Esteller R, Borton DA, Jones SR, and Saab CY
- Subjects
- Adult, Aged, Aged, 80 and over, Brain Waves, Female, Humans, Lumbosacral Region physiopathology, Male, Middle Aged, Pain physiopathology, Radiculopathy complications, Radiculopathy diagnosis, Radiculopathy physiopathology, Signal Processing, Computer-Assisted, Spinal Diseases complications, Electroencephalography, Machine Learning, Pain classification, Pain diagnosis, Spinal Diseases diagnosis, Spinal Diseases physiopathology
- Abstract
Pain is a multidimensional experience mediated by distributed neural networks in the brain. To study this phenomenon, EEGs were collected from 20 subjects with chronic lumbar radiculopathy, 20 age and gender matched healthy subjects, and 17 subjects with chronic lumbar pain scheduled to receive an implanted spinal cord stimulator. Analysis of power spectral density, coherence, and phase-amplitude coupling using conventional statistics showed that there were no significant differences between the radiculopathy and control groups after correcting for multiple comparisons. However, analysis of transient spectral events showed that there were differences between these two groups in terms of the number, power, and frequency-span of events in a low gamma band. Finally, we trained a binary support vector machine to classify radiculopathy versus healthy subjects, as well as a 3-way classifier for subjects in the 3 groups. Both classifiers performed significantly better than chance, indicating that EEG features contain relevant information pertaining to sensory states, and may be used to help distinguish between pain states when other clinical signs are inconclusive., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Published
- 2020
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10. Time-dynamic pulse modulation of spinal cord stimulation reduces mechanical hypersensitivity and spontaneous pain in rats.
- Author
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Edhi MM, Heijmans L, Vanent KN, Bloye K, Baanante A, Jeong KS, Leung J, Zhu C, Esteller R, and Saab CY
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- Animals, Electrodes, Implanted, Hyperalgesia physiopathology, Male, Neuralgia physiopathology, Pain Measurement, Pain Threshold physiology, Peripheral Nerve Injuries physiopathology, Rats, Rats, Sprague-Dawley, Sciatic Nerve pathology, Sciatic Nerve surgery, Spinal Cord pathology, Stereotaxic Techniques, Time Factors, Hyperalgesia therapy, Neuralgia therapy, Pain Management methods, Peripheral Nerve Injuries therapy, Spinal Cord Stimulation methods
- Abstract
Enhancing the efficacy of spinal cord stimulation (SCS) is needed to alleviate the burden of chronic pain and dependence on opioids. Present SCS therapies are characterized by the delivery of constant stimulation in the form of trains of tonic pulses (TPs). We tested the hypothesis that modulated SCS using novel time-dynamic pulses (TDPs) leads to improved analgesia and compared the effects of SCS using conventional TPs and a collection of TDPs in a rat model of neuropathic pain according to a longitudinal, double-blind, and crossover design. We tested the effects of the following SCS patterns on paw withdrawal threshold and resting state EEG theta power as a biomarker of spontaneous pain: Tonic (conventional), amplitude modulation, pulse width modulation, sinusoidal rate modulation, and stochastic rate modulation. Results demonstrated that under the parameter settings tested in this study, all tested patterns except pulse width modulation, significantly reversed mechanical hypersensitivity, with stochastic rate modulation achieving the highest efficacy, followed by the sinusoidal rate modulation. The anti-nociceptive effects of sinusoidal rate modulation on EEG outlasted SCS duration on the behavioral and EEG levels. These results suggest that TDP modulation may improve clinical outcomes by reducing pain intensity and possibly improving the sensory experience.
- Published
- 2020
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11. Automated and rapid self-report of nociception in transgenic mice.
- Author
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Black CJ, Allawala AB, Bloye K, Vanent KN, Edhi MM, Saab CY, and Borton DA
- Subjects
- Afferent Pathways, Animals, Behavior, Animal, Female, Male, Mice, Mice, Transgenic, Optogenetics, Reflex, Nociception, Pain Measurement methods
- Abstract
There are currently no rapid, operant pain behaviors in rodents that use a self-report to directly engage higher-order brain circuitry. We have developed a pain detection assay consisting of a lick behavior in response to optogenetic activation of predominantly nociceptive peripheral afferent nerve fibers in head-restrained transgenic mice expressing ChR2 in TRPV1 containing neurons. TRPV1-ChR2-EYFP mice (n = 5) were trained to provide lick reports to the detection of light-evoked nociceptive stimulation to the hind paw. Using simultaneous video recording, we demonstrate that the learned lick behavior may prove more pertinent in investigating brain driven pain processes than the reflex behavior. Within sessions, the response bias of transgenic mice changed with respect to lick behavior but not reflex behavior. Furthermore, response similarity between the lick and reflex behaviors diverged near perceptual threshold. Our nociceptive lick-report detection assay will enable a host of investigations into the millisecond, single cell, neural dynamics underlying pain processing in the central nervous system of awake behaving animals.
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- 2020
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12. Discovery and validation of biomarkers to aid the development of safe and effective pain therapeutics: challenges and opportunities.
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Davis KD, Aghaeepour N, Ahn AH, Angst MS, Borsook D, Brenton A, Burczynski ME, Crean C, Edwards R, Gaudilliere B, Hergenroeder GW, Iadarola MJ, Iyengar S, Jiang Y, Kong JT, Mackey S, Saab CY, Sang CN, Scholz J, Segerdahl M, Tracey I, Veasley C, Wang J, Wager TD, Wasan AD, and Pelleymounter MA
- Subjects
- Analgesics, Opioid adverse effects, Biomarkers blood, Chronic Pain genetics, Chronic Pain therapy, Education methods, Education trends, Humans, Neuroimaging methods, Opioid Epidemic prevention & control, Opioid Epidemic trends, Opioid-Related Disorders blood, Opioid-Related Disorders diagnostic imaging, Opioid-Related Disorders genetics, Opioid-Related Disorders therapy, Treatment Outcome, United States, Chronic Pain blood, Chronic Pain diagnostic imaging, National Institutes of Health (U.S.) trends, Pain Management methods, Pain Management trends
- Abstract
Pain medication plays an important role in the treatment of acute and chronic pain conditions, but some drugs, opioids in particular, have been overprescribed or prescribed without adequate safeguards, leading to an alarming rise in medication-related overdose deaths. The NIH Helping to End Addiction Long-term (HEAL) Initiative is a trans-agency effort to provide scientific solutions to stem the opioid crisis. One component of the initiative is to support biomarker discovery and rigorous validation in collaboration with industry leaders to accelerate high-quality clinical research into neurotherapeutics and pain. The use of objective biomarkers and clinical trial end points throughout the drug discovery and development process is crucial to help define pathophysiological subsets of pain, evaluate target engagement of new drugs and predict the analgesic efficacy of new drugs. In 2018, the NIH-led Discovery and Validation of Biomarkers to Develop Non-Addictive Therapeutics for Pain workshop convened scientific leaders from academia, industry, government and patient advocacy groups to discuss progress, challenges, gaps and ideas to facilitate the development of biomarkers and end points for pain. The outcomes of this workshop are outlined in this Consensus Statement.
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- 2020
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13. What does a pain 'biomarker' mean and can a machine be taught to measure pain?
- Author
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Levitt J and Saab CY
- Subjects
- Biomarkers, Electroencephalography, Pain physiopathology, Terminology as Topic, Machine Learning, Pain diagnosis, Pain Measurement
- Abstract
Artificial intelligence allows machines to predict human faculties such as image and voice recognition. Can machines be taught to measure pain? We argue that the two fundamental requirements for a device with 'pain biomarker' capabilities are hardware and software. We discuss the merits and limitations of electroencephalography (EEG) as the hardware component of a putative embodiment of the device, and advances in the application of machine learning approaches to EEG for predicting pain., (Copyright © 2018 Elsevier B.V. All rights reserved.)
- Published
- 2019
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14. An Electroencephalography Bioassay for Preclinical Testing of Analgesic Efficacy.
- Author
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Koyama S, LeBlanc BW, Smith KA, Roach C, Levitt J, Edhi MM, Michishita M, Komatsu T, Mashita O, Tanikawa A, Yoshikawa S, and Saab CY
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- Animals, Behavior, Animal drug effects, Drug Evaluation, Preclinical, Male, Nociception drug effects, Pain Threshold drug effects, Rats, Rats, Sprague-Dawley, Somatosensory Cortex drug effects, Somatosensory Cortex physiology, Analgesics pharmacology, Biological Assay, Electroencephalography
- Abstract
We present a multimodal method combining quantitative electroencephalography (EEG), behavior and pharmacology for pre-clinical screening of analgesic efficacy in vivo. The method consists of an objective and non-invasive approach for realtime assessment of spontaneous nociceptive states based on EEG recordings of theta power over primary somatosensory cortex in awake rats. Three drugs were chosen: (1) pregabalin, a CNS-acting calcium channel inhibitor; (2) EMA 401, a PNS-acting angiotensin II type 2 receptor inhibitor; and (3) minocycline, a CNS-acting glial inhibitor. Optimal doses were determined based on pharmacokinetic studies and/or published data. The effects of these drugs at single or multiple doses were tested on the attenuation of theta power and paw withdrawal latency (PWL) in a rat model of neuropathic pain. We report mostly parallel trends in the reversal of theta power and PWL in response to administration of pregabalin and EMA 401, but not minocycline. We also note divergent trends at non-optimal doses and following prolonged drug administration, suggesting that EEG theta power can be used to detect false positive and false negative outcomes of the withdrawal reflex behavior, and yielding novel insights into the analgesic effects of these drugs on spontaneous nociceptive states in rats.
- Published
- 2018
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15. Automated detection of electroencephalography artifacts in human, rodent and canine subjects using machine learning.
- Author
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Levitt J, Nitenson A, Koyama S, Heijmans L, Curry J, Ross JT, Kamerling S, and Saab CY
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- Animals, Dogs, Humans, ROC Curve, Rats, Rats, Sprague-Dawley, Artifacts, Brain Waves physiology, Electroencephalography, Machine Learning, Signal Processing, Computer-Assisted
- Abstract
Background: Electroencephalography (EEG) invariably contains extra-cranial artifacts that are commonly dealt with based on qualitative and subjective criteria. Failure to account for EEG artifacts compromises data interpretation., New Method: We have developed a quantitative and automated support vector machine (SVM)-based algorithm to accurately classify artifactual EEG epochs in awake rodent, canine and humans subjects. An embodiment of this method also enables the determination of 'eyes open/closed' states in human subjects., Results: The levels of SVM accuracy for artifact classification in humans, Sprague Dawley rats and beagle dogs were 94.17%, 83.68%, and 85.37%, respectively, whereas 'eyes open/closed' states in humans were labeled with 88.60% accuracy. Each of these results was significantly higher than chance., Comparison With Existing Methods: Other existing methods, like those dependent on Independent Component Analysis, have not been tested in non-human subjects, and require full EEG montages, instead of only single channels, as this method does., Conclusions: We conclude that our EEG artifact detection algorithm provides a valid and practical solution to a common problem in the quantitative analysis and assessment of EEG in pre-clinical research settings across evolutionary spectra., (Copyright © 2018 Elsevier B.V. All rights reserved.)
- Published
- 2018
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16. Sub-paresthesia spinal cord stimulation reverses thermal hyperalgesia and modulates low frequency EEG in a rat model of neuropathic pain.
- Author
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Koyama S, Xia J, Leblanc BW, Gu JW, and Saab CY
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- Animals, Double-Blind Method, Electroencephalography, Humans, Hyperalgesia physiopathology, Neuralgia diagnostic imaging, Neuralgia physiopathology, Pain Management, Pain Measurement, Paresthesia physiopathology, Paresthesia therapy, Rats, Spinal Cord diagnostic imaging, Hyperalgesia therapy, Neuralgia therapy, Spinal Cord physiopathology, Spinal Cord Stimulation methods
- Abstract
Paresthesia, a common feature of epidural spinal cord stimulation (SCS) for pain management, presents a challenge to the double-blind study design. Although sub-paresthesia SCS has been shown to be effective in alleviating pain, empirical criteria for sub-paresthesia SCS have not been established and its basic mechanisms of action at supraspinal levels are unknown. We tested our hypothesis that sub-paresthesia SCS attenuates behavioral signs of neuropathic pain in a rat model, and modulates pain-related theta (4-8 Hz) power of the electroencephalogram (EEG), a previously validated correlate of spontaneous pain in rodent models. Results show that sub-paresthesia SCS attenuates thermal hyperalgesia and power amplitude in the 3-4 Hz range, consistent with clinical data showing significant yet modest analgesic effects of sub-paresthesia SCS in humans. Therefore, we present evidence for anti-nociceptive effects of sub-paresthesia SCS in a rat model of neuropathic pain and further validate EEG theta power as a reliable 'biosignature' of spontaneous pain.
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- 2018
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17. Thalamic Bursts Down-regulate Cortical Theta and Nociceptive Behavior.
- Author
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LeBlanc BW, Cross B, Smith KA, Roach C, Xia J, Chao YC, Levitt J, Koyama S, Moore CI, and Saab CY
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- Action Potentials physiology, Animals, Behavior, Animal physiology, Humans, Hyperalgesia physiopathology, Mice, Neurons pathology, Neurons physiology, Cerebral Cortex physiopathology, Pain physiopathology, Somatosensory Cortex physiopathology, Thalamus physiopathology
- Abstract
We tested the relation between pain behavior, theta (4-8 Hz) oscillations in somatosensory cortex and burst firing in thalamic neurons in vivo. Optically-induced thalamic bursts attenuated cortical theta and mechanical allodynia. It is proposed that thalamic bursts are an adaptive response to pain that de-synchronizes cortical theta and decreases sensory salience.
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- 2017
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18. Electroencephalographic frontal synchrony and caudal asynchrony during painful hand immersion in cold water.
- Author
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Levitt J, Choo HJ, Smith KA, LeBlanc BW, and Saab CY
- Subjects
- Adult, Brain physiology, Brain Waves, Cold Temperature, Electroencephalography, Hand, Humans, Young Adult, Cortical Synchronization, Frontal Lobe physiology, Pain physiopathology, Pain Perception physiology
- Abstract
Recent studies in our laboratory showed that cortical theta oscillations correlate with pain in rodent models. In this study, we sought to validate our pre-clinical data using EEG recordings in humans during immersion of the hand in ice cold water, a moderately noxious stimulus. Power spectral analysis shows that an increase in pain score is associated with an increase in power amplitude within a frequency range of 6-7Hz at the frontal (Fz) electrode. These results are consistent with our previous pre-clinical animal studies and the clinical literature. We also report a novel reduction in power at the caudal (O1) electrode within a broader 3-30Hz rand and decreased coherence between Fz and C3, C4 electrodes within the theta (4-8Hz) and low beta (13-21Hz) bands, while coherence (an indirect measure of functional connectivity) between Fz and O1 increased within the theta and alpha (8-12Hz) bands. We argue that pain is associated with EEG frontal synchrony and caudal asynchrony, leading to the disruption of cortico-cortical connectivity., (Copyright © 2016 Elsevier Inc. All rights reserved.)
- Published
- 2017
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19. Thalamic Bursts and the Epic Pain Model.
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Saab CY and Barrett LF
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- 2017
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20. Electroencephalographic signatures of pain and analgesia in rats.
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LeBlanc BW, Bowary PM, Chao YC, Lii TR, and Saab CY
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- Animals, Cerebral Cortex drug effects, Disease Models, Animal, Electroencephalography, Freund's Adjuvant toxicity, Functional Laterality, Hyperalgesia drug therapy, Hyperalgesia etiology, Male, Neuralgia chemically induced, Pain Measurement, Rats, Rats, Sprague-Dawley, Wakefulness, Anesthetics, Inhalation therapeutic use, Brain Waves drug effects, Cerebral Cortex physiopathology, Isoflurane therapeutic use, Neuralgia drug therapy, Neuralgia physiopathology
- Abstract
Pain modulates rhythmic neuronal activity recorded by Electroencephalography (EEG) in humans. Our laboratory previously showed that rat models of acute and neuropathic pain manifest increased power in primary somatosensory cortex (S1) recorded by electrocorticography (ECoG). In this study, we hypothesized that pain increases EEG power and corticocortical coherence in different rat models of pain, whereas treatments with clinically effective analgesics reverse these changes. Our results show increased cortical power over S1 and prefrontal cortex (PFC) in awake, freely behaving rat models of acute, inflammatory and neuropathic pain. Coherence between PFC and S1 is increased at a late, but not early, time point during the development of neuropathic pain. Electroencephalography power is not affected by ibuprofen in the acute pain model. However, pregabalin and mexiletine reverse the changes in power and S1-PFC coherence in the inflammatory and neuropathic pain models. These data suggest that quantitative EEG might be a valuable predictor of pain and analgesia in rodents.
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- 2016
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21. T-type calcium channel blocker Z944 restores cortical synchrony and thalamocortical connectivity in a rat model of neuropathic pain.
- Author
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LeBlanc BW, Lii TR, Huang JJ, Chao YC, Bowary PM, Cross BS, Lee MS, Vera-Portocarrero LP, and Saab CY
- Subjects
- Action Potentials drug effects, Action Potentials physiology, Animals, Calcium Channels, T-Type, Cerebral Cortex physiopathology, Disease Models, Animal, Male, Neural Pathways drug effects, Neural Pathways physiopathology, Piperidines, Rats, Rats, Sprague-Dawley, Thalamus physiopathology, Acetamides pharmacology, Benzamides pharmacology, Calcium Channel Blockers pharmacology, Cerebral Cortex drug effects, Neuralgia physiopathology, Thalamus drug effects
- Abstract
Oscillations are fundamental to communication between neuronal ensembles. We previously reported that pain in awake rats enhances synchrony in primary somatosensory cortex (S1) and attenuates coherence between S1 and ventral posterolateral (VPL) thalamus. Here, we asked whether similar changes occur in anesthetized rats and whether pain modulates phase-amplitude coupling between VPL and S1. We also hypothesized that the suppression of burst firing in VPL using Z944, a novel T-type calcium channel blocker, restores S1 synchrony and thalamocortical connectivity. Local field potentials were recorded from S1 and VPL in anesthetized rats 7 days after sciatic chronic constriction injury (CCI). In rats with CCI, low-frequency (4-12 Hz) synchrony in S1 was enhanced, whereas VPL-S1 coherence and theta-gamma phase-amplitude coupling were attenuated. Moreover, Granger causality showed decreased informational flow from VPL to S1. Systemic or intrathalamic delivery of Z944 to rats with CCI normalized these changes. Systemic Z944 also reversed thermal hyperalgesia and conditioned place preference. These data suggest that pain-induced cortical synchrony and thalamocortical disconnectivity are directly related to burst firing in VPL.
- Published
- 2016
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22. Cortical theta is increased while thalamocortical coherence is decreased in rat models of acute and chronic pain.
- Author
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LeBlanc BW, Lii TR, Silverman AE, Alleyne RT, and Saab CY
- Subjects
- Acute Pain physiopathology, Analysis of Variance, Animals, Capsaicin pharmacology, Chronic Pain physiopathology, Disease Models, Animal, Electrodes, Implanted, Electroencephalography, Hyperalgesia pathology, Hyperalgesia physiopathology, Male, Rats, Rats, Sprague-Dawley, Time Factors, Acute Pain pathology, Cerebral Cortex physiopathology, Chronic Pain pathology, Neural Pathways physiology, Thalamus physiopathology, Theta Rhythm physiology
- Abstract
Thalamocortical oscillations are critical for sensory perception. Although pain is known to disrupt synchrony in thalamocortical oscillations, evidence in the literature is controversial. Thalamocortical coherence has been reported to be increased in patients with neurogenic pain but decreased in a rat model of central pain. Moreover, theta (4 to 8 Hz) oscillations in primary somatosensory (S1) cortex are speculated to predict pain in humans. To date, the link between pain and network oscillations in animal models has been understudied. Thus, we tested the hypothesis that pain disrupts thalamocortical coherence and S1 theta power in two rat models of pain. We recorded electrocorticography (ECoG) waveforms over S1 and local field potentials (LFP) within ventral posterolateral thalamus in freely behaving rats under spontaneous (stimulus-independent) pain conditions. Rats received intradermal capsaicin injection (Cap) in the hindpaw, followed hours later by chronic constriction injury (CCI) of the sciatic nerve lasting several days. Our results show that pain decreases coherence between LFP and ECoG waveforms in the 2- to 30-Hz range, and increases ECoG power in the theta range. These changes are short-lasting after Cap and longer-lasting after CCI. These data might be particularly relevant to preclinical correlates of spontaneous pain-like behavior, with potential implications to clinical biomarkers of ongoing pain., (Copyright © 2014 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.)
- Published
- 2014
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23. Pain-related changes in the brain: diagnostic and therapeutic potentials.
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Saab CY
- Subjects
- Animals, Brain drug effects, Chronic Pain diagnosis, Chronic Pain drug therapy, Disease Models, Animal, Gyrus Cinguli metabolism, Gyrus Cinguli physiology, Humans, Ion Channels metabolism, Ion Channels physiology, Models, Neurological, Neural Pathways physiopathology, Neuronal Plasticity physiology, Neurons physiology, Periaqueductal Gray metabolism, Thalamus metabolism, Thalamus physiology, Brain physiopathology, Chronic Pain physiopathology, Diagnostic Techniques, Neurological, Molecular Targeted Therapy methods
- Abstract
Emerging evidence suggests that chronic pain is a disease that can alter brain function. Imaging studies have demonstrated structural remapping and functional reorganization of brain circuits under various pain conditions. In parallel, preclinical models have demonstrated that chronic pain causes long-term neuroplasticity. For example, thalamo-cortical oscillations are dysregulated and neurons in the sensory thalamus undergo ectopic firing linked to misexpression of membrane ion channels. In theory, physiological changes at the single-unit, multi-unit, and circuitry levels can be used as predictors of pain, and possibly to guide targeted neuromodulation of specific brain regions for therapeutic purposes. Therefore, multidisciplinary research into the mechanisms of pain-related phenomena in the brain may offer insights into novel approaches for the diagnosis, monitoring, and management of persistent pain., (Copyright © 2012 Elsevier Ltd. All rights reserved.)
- Published
- 2012
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24. A channelopathy contributes to cerebellar dysfunction in a model of multiple sclerosis.
- Author
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Shields SD, Cheng X, Gasser A, Saab CY, Tyrrell L, Eastman EM, Iwata M, Zwinger PJ, Black JA, Dib-Hajj SD, and Waxman SG
- Subjects
- Aniline Compounds therapeutic use, Animals, Cerebellar Diseases genetics, Cerebellum cytology, Cerebellum metabolism, Cerebellum pathology, Channelopathies genetics, Disease Models, Animal, Encephalomyelitis, Autoimmune, Experimental drug therapy, Furans therapeutic use, Mice, Mice, Transgenic, Multiple Sclerosis genetics, NAV1.8 Voltage-Gated Sodium Channel, Purkinje Cells pathology, Purkinje Cells physiology, Sodium Channel Blockers therapeutic use, Sodium Channels biosynthesis, Sodium Channels genetics, Sodium Channels metabolism, Up-Regulation genetics, Cerebellar Diseases physiopathology, Channelopathies physiopathology, Encephalomyelitis, Autoimmune, Experimental physiopathology, Multiple Sclerosis physiopathology
- Abstract
Objective: Cerebellar dysfunction in multiple sclerosis (MS) contributes significantly to disability, is relatively refractory to symptomatic therapy, and often progresses despite treatment with disease-modifying agents. We previously observed that sodium channel Nav1.8, whose expression is normally restricted to the peripheral nervous system, is present in cerebellar Purkinje neurons in a mouse model of MS (experimental autoimmune encephalomyelitis [EAE]) and in humans with MS. Here, we tested the hypothesis that upregulation of Nav1.8 in cerebellum in MS and EAE has functional consequences contributing to symptom burden., Methods: Electrophysiology and behavioral assessment were performed in a new transgenic mouse model overexpressing Nav1.8 in Purkinje neurons. We also measured EAE symptom progression in mice lacking Nav1.8 compared to wild-type littermates. Finally, we administered the Nav1.8-selective blocker A803467 in the context of previously established EAE to determine reversibility of MS-like deficits., Results: We report that, in the context of an otherwise healthy nervous system, ectopic expression of Nav1.8 in Purkinje neurons alters their electrophysiological properties, and disrupts coordinated motor behaviors. Additionally, we show that Nav1.8 expression contributes to symptom development in EAE. Finally, we demonstrate that abnormal patterns of Purkinje neuron firing and MS-like deficits in EAE can be partially reversed by pharmacotherapy using a Nav1.8-selective blocker., Interpretation: Our results add to the evidence that a channelopathy contributes to cerebellar dysfunction in MS. Our data suggest that Nav1.8-specific blockers, when available for humans, merit study in MS., (Copyright © 2012 American Neurological Association.)
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- 2012
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25. High-frequency stimulation in the ventral posterolateral thalamus reverses electrophysiologic changes and hyperalgesia in a rat model of peripheral neuropathic pain.
- Author
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Iwata M, LeBlanc BW, Kadasi LM, Zerah ML, Cosgrove RG, and Saab CY
- Subjects
- Action Potentials physiology, Animals, Chronic Pain physiopathology, Chronic Pain therapy, Disease Models, Animal, Evoked Potentials physiology, Male, Neuronal Plasticity physiology, Nociceptors physiology, Rats, Rats, Sprague-Dawley, Deep Brain Stimulation methods, Hyperalgesia physiopathology, Hyperalgesia therapy, Neuralgia physiopathology, Neuralgia therapy, Ventral Thalamic Nuclei physiology
- Abstract
Chronic neuropathic pain is associated with long-term changes at multiple levels of the neuroaxis, including in the brain, where electrical stimulation has been used to manage severe pain conditions. However, the clinical outcome of deep brain stimulation is often mixed, and the mechanisms are poorly understood. By means of electrophysiologic methods, we sought to characterize the changes in neuronal activity in the ventral posterolateral nucleus of the thalamus (VPL) in a rat model of peripheral neuropathic pain, and to reverse these changes with low-voltage, high-frequency stimulation (HFS) in the VPL. Extracellular single-unit neuronal activity was recorded in naive rats and in those with sciatic chronic constriction injury (CCI). Seven days after CCI, brush- and pinch-evoked firing, as well as spontaneous firing and afterdischarge, were significantly increased compared to naive rats. Spontaneous rhythmic oscillation in neuronal firing was also observed in rats with CCI. HFS decreased neuronal firing rates in rats with CCI up to ~50% except for spontaneous activity, whereas low-frequency stimulation had no effect. Compared to naive rats, burst firing properties (burst events, percentage of spikes in burst, and mean interburst time) were altered in rats with CCI, whereas these changes were reversed to near normal after HFS. Thermal hyperalgesia in rats with CCI was significantly attenuated by HFS. Therefore, this study demonstrates that electrical stimulation within the VPL can effectively modulate some nociceptive phenomena associated with peripheral neuropathic pain., (Copyright © 2011 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.)
- Published
- 2011
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26. Minocycline injection in the ventral posterolateral thalamus reverses microglial reactivity and thermal hyperalgesia secondary to sciatic neuropathy.
- Author
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LeBlanc BW, Zerah ML, Kadasi LM, Chai N, and Saab CY
- Subjects
- Animals, Antibodies, Monoclonal biosynthesis, Antibodies, Monoclonal genetics, Gene Expression Regulation, Glial Fibrillary Acidic Protein biosynthesis, Glial Fibrillary Acidic Protein genetics, Hot Temperature adverse effects, Hyperalgesia drug therapy, Hyperalgesia etiology, Male, Microglia pathology, Minocycline administration & dosage, Minocycline therapeutic use, Nerve Tissue Proteins biosynthesis, Nerve Tissue Proteins genetics, Neuralgia drug therapy, Neuralgia etiology, Neuronal Plasticity physiology, Rats, Rats, Sprague-Dawley, Ventral Thalamic Nuclei physiopathology, p38 Mitogen-Activated Protein Kinases metabolism, Hyperalgesia physiopathology, Microglia drug effects, Minocycline pharmacology, Neuralgia physiopathology, Neuronal Plasticity drug effects, Sciatic Nerve injuries, Ventral Thalamic Nuclei drug effects
- Abstract
We hypothesized that microglia in the ventral posterolateral (VPL) nucleus of the thalamus are reactive following peripheral nerve injury, and that inhibition of microglia by minocycline injection in the VPL attenuates thermal hyperalgesia. Our results show increased expression of OX-42 co-localized with phosphorylated p38MAPK (P-p38) in the VPL seven days after chronic constriction injury (CCI) of the sciatic nerve. However, astrocytic GFAP expression in the VPL is unchanged 7 and 14 days after CCI. Microinjection of minocycline into the VPL contralateral to CCI reverses thermal hyperalgesia, whereas vehicle injection has no effect on paw withdrawal latency. Minocycline abrogates the increased expression of OX-42 in the VPL after CCI. Therefore, peripheral nerve injury favors a hyperactive microglial phenotype in the VPL, suggesting remote neuroimmune signaling from the damaged nerve to the brain, concomitant with neuropathic behavior that is reversed by local intervention in the VPL to inhibit microglia., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)
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- 2011
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27. A cyclic peptide targeted against PSD-95 blocks central sensitization and attenuates thermal hyperalgesia.
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LeBlanc BW, Iwata M, Mallon AP, Rupasinghe CN, Goebel DJ, Marshall J, Spaller MR, and Saab CY
- Subjects
- Action Potentials drug effects, Animals, Disks Large Homolog 4 Protein, Hot Temperature, Humans, Hyperalgesia physiopathology, Injections, Spinal, Ligands, Long-Term Potentiation drug effects, Lumbosacral Region, Nerve Fibers, Unmyelinated drug effects, Nerve Fibers, Unmyelinated physiology, PDZ Domains, Pain physiopathology, Pain prevention & control, Peripheral Nervous System Diseases physiopathology, Peripheral Nervous System Diseases prevention & control, Phosphorylation, Protein Binding, Rats, Rats, Sprague-Dawley, Sciatic Nerve physiopathology, Spinal Cord physiopathology, p38 Mitogen-Activated Protein Kinases metabolism, Analgesics pharmacology, Hyperalgesia prevention & control, Intracellular Signaling Peptides and Proteins metabolism, Membrane Proteins metabolism, Peptides, Cyclic pharmacology, Spinal Cord drug effects
- Abstract
Post-synaptic density protein PSD-95 is emerging as a valid target for modulating nociception in animal studies. Based on the key role of PSD-95 in neuronal plasticity and the maintenance of pain behavior, we predicted that CN2097, a peptide-based macrocycle of nine residues that binds to the PSD-95 Discs large, Zona occludens 1 (PDZ) domains of PSD-95, would interfere with physiologic phenomena in the spinal cord related to central sensitization. Furthermore, we tested whether spinal intrathecal injection of CN2097 attenuates thermal hyperalgesia in a rat model of sciatic neuropathy. Results demonstrate that spinal CN2097 reverses hyperexcitability of wide dynamic range (WDR) neurons in the dorsal horn of neuropathic rats and decreases their evoked responses to peripheral stimuli (brush, low caliber von Frey and pressure), whereas CN5125 ("negative control") has no effect. CN2097 also blocks C-fiber long-term potentiation (LTP) in the dorsal horn, which is linked to neuronal plasticity and central sensitization. At a molecular level, CN2097 attenuates the increase in phosphorylated p38 MAPK, a key intracellular signaling pathway in neuropathic pain. Moreover, spinal injection of CN2097 blocks thermal hyperalgesia in neuropathic rats. We conclude that CN2097 is a small molecule peptide with putative anti-nociceptive effects that modulates physiologic phenomena related to central sensitization under conditions of chronic pain., ((c) 2010 IBRO. Published by Elsevier Ltd. All rights reserved.)
- Published
- 2010
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28. Transient increase in cytokines and nerve growth factor in the rat dorsal root ganglia after nerve lesion and peripheral inflammation.
- Author
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Saab CY, Shamaa F, El Sabban ME, Safieh-Garabedian B, Jabbur SJ, and Saadé NE
- Subjects
- Animals, Cytokines physiology, Female, Ganglia, Spinal immunology, Hyperalgesia immunology, Hyperalgesia metabolism, Hyperalgesia pathology, Inflammation immunology, Inflammation metabolism, Nerve Growth Factor physiology, Peripheral Nervous System Diseases immunology, Peripheral Nervous System Diseases metabolism, Peripheral Nervous System Diseases pathology, Rats, Rats, Sprague-Dawley, Sciatic Neuropathy immunology, Sciatic Neuropathy metabolism, Time Factors, Cytokines biosynthesis, Ganglia, Spinal metabolism, Ganglia, Spinal pathology, Nerve Growth Factor biosynthesis, Sciatic Neuropathy pathology
- Abstract
Inflammatory response occurs, in general, at the peripheral site of injury or irritation and in the corresponding spinal dorsal horn segments. In this study, we show transient increases in the protein concentrations of interleukins 1beta, 6, 8 and NGF in lumbar DRGs within hours after sciatic mononeuropathy in the rat. Comparable increases, with variation in temporal patterns, were observed after skin inflammation induced by intraplantar injection of endotoxin or complete Freund's adjuvant. The non-matching temporal profiles of cytokines and NGF increases and those of behavioral hypersensitivity, particularly peak values, suggest that the roles of these proteins are not necessarily pro-nociceptive in the DRGs at the chronic phase of neuropathy.
- Published
- 2009
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29. Remote neuroimmune signaling: a long-range mechanism of nociceptive network plasticity.
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Saab CY and Hains BC
- Subjects
- Animals, Central Nervous System cytology, Gliosis immunology, Gliosis physiopathology, Humans, Lymphocyte Activation immunology, Microglia immunology, Neuronal Plasticity physiology, Signal Transduction physiology, Central Nervous System physiology, Nerve Net physiology, Neuroimmunomodulation physiology, Nociceptors physiology, Pain physiopathology
- Abstract
Chronic pain secondary to neuronal injury is actively and continuously modulated at multiple locations along the sensory neuraxis. Here, we describe how nociceptive neurons of the spinal cord and thalamus process and communicate nociceptive information in terms of precisely calibrated firing patterns. We then discuss how several cell types with immunogenic properties (e.g. blood cells and glia) cause system-wide interference in nociceptive processing through novel signaling schema, thus contributing to nociceptive network plasticity and chronic pain.
- Published
- 2009
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30. Alarm or curse? The pain of neuroinflammation.
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Saab CY, Waxman SG, and Hains BC
- Subjects
- Animals, Humans, Inflammation Mediators metabolism, Inflammation Mediators physiology, Microglia metabolism, Models, Biological, Neuralgia etiology, Neuralgia metabolism, Neutrophils metabolism, Peripheral Nerve Injuries, Peripheral Nerves physiopathology, Signal Transduction physiology, Spinal Cord Injuries complications, Spinal Cord Injuries physiopathology, Microglia physiology, Neuralgia physiopathology, Neutrophils physiology
- Abstract
The nociceptive nervous system and the immune system serve to defend and alarm the host of imminent or actual damage. However, persistent or recurring exposure of neurons to activated immune cells is associated with an increase in painful behavior following experimental neuropathic injuries. Our understanding of the functional consequences of immune cell-neuron interaction is still incomplete. The purpose of this review is to focus on a seriously detrimental consequence of chronic activation of these two systems, by discussing the contributions of microglia and polymorphonuclear neutrophils to neuropathic pain following experimental spinal cord injury or peripheral nerve injury. Identification of molecules mediating pro-nociceptive signaling between immune cells and neurons, as well as the distinction between neuroprotective versus neuroexcitatory effects of activated immune cells, may be useful in the development of pharmacotherapy for the management of chronic pain and restoration of the beneficial alarm function of pain.
- Published
- 2008
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31. Activated polymorphonuclear cells promote injury and excitability of dorsal root ganglia neurons.
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Shaw SK, Owolabi SA, Bagley J, Morin N, Cheng E, LeBlanc BW, Kim M, Harty P, Waxman SG, and Saab CY
- Subjects
- Anesthetics, Local pharmacology, Animals, Annexin A5 metabolism, Calcium metabolism, Cell Count, Cells, Cultured, Coculture Techniques methods, Dose-Response Relationship, Radiation, Electric Stimulation methods, Glial Fibrillary Acidic Protein metabolism, Lidocaine pharmacology, Male, Membrane Potentials drug effects, Membrane Potentials physiology, Membrane Potentials radiation effects, Neurons drug effects, Neutrophils drug effects, Patch-Clamp Techniques methods, Phosphopyruvate Hydratase metabolism, Rats, Rats, Sprague-Dawley, Reactive Oxygen Species metabolism, Tumor Necrosis Factor-alpha pharmacology, Ganglia, Spinal cytology, Neurons physiology, Neutrophils physiology
- Abstract
Therapies aimed at depleting or blocking the migration of polymorphonuclear leukocytes (PMN or neutrophils) are partially successful in the treatment of neuroinflammatory conditions and in attenuating pain following peripheral nerve injury or subcutaneous inflammation. However, the functional effects of PMN on peripheral sensory neurons such as dorsal root ganglia (DRG) neurons are largely unknown. We hypothesized that PMN are detrimental to neuronal viability in culture and increase neuronal activity and excitability. We demonstrate that isolated peripheral PMN are initially in a relatively resting state but undergo internal oxidative burst and activation by an unknown mechanism within 10 min of co-culture with dissociated DRG cells. Co-culture for 24 h decreases neuronal count at a threshold<0.4:1 PMN:DRG cell ratio and increases the number of injured and apoptotic neurons. Within 3 min of PMN addition, fluorometric calcium imaging reveals intracellular calcium transients in small size (<25 microm diam) and large size (>25 microm diam) neurons, as well as in capsaicin-sensitive neurons. Furthermore, small size isolectin B4-labeled neurons undergo hyperexcitability manifested as decreased current threshold and increased firing frequency. Although co-culture of PMN and DRG cells does not perfectly model neuroinflammatory conditions in vivo, these findings suggest that activated PMN can potentially aggravate neuronal injury and cause functional changes to peripheral sensory neurons. Distinguishing the beneficial from the detrimental effects of PMN on neurons may aid in the development of more effective drug therapies for neurological disorders involving neuroinflammation, including painful neuropathies.
- Published
- 2008
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32. Neutrophils invade lumbar dorsal root ganglia after chronic constriction injury of the sciatic nerve.
- Author
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Morin N, Owolabi SA, Harty MW, Papa EF, Tracy TF Jr, Shaw SK, Kim M, and Saab CY
- Subjects
- Animals, Chemokine CCL2 genetics, Chemokine CCL2 metabolism, Constriction, Functional Laterality, Gene Expression Regulation physiology, Lumbosacral Region, Male, Pain Measurement methods, RNA, Messenger metabolism, Rats, Reverse Transcriptase Polymerase Chain Reaction, Time Factors, Ganglia, Spinal pathology, Neutrophils physiology, Sciatic Neuropathy pathology, Sciatic Neuropathy physiopathology
- Abstract
To test whether neutrophils (PMN) target lumbar dorsal root ganglia (DRG) following axonal injury leading to neuropathic pain, we visualized PMN infiltration in DRG tissue sections and estimated PMN count by flow cytometry following sciatic chronic constriction injury (CCI). Seven days after CCI, results show PMN within DRG where their count increased by three fold ipsilateral to injury compared to contralateral or sham, concomitant with peak neuropathic pain behavior. Superoxide burst in PMN isolated from rats d7 after CCI was elevated by 170% +/-18 compared to naïve and MCP-1 mRNA expression in DRG increased by 8.9+/-2.9 fold, but that of MIP-2, CINC-1, and RANTES did not change. We conclude that CCI causes PMN invasion of the DRG whereby the functional implication of their close proximity to neuronal axon and soma remains unknown.
- Published
- 2007
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33. Long-term protection of central axons with phenytoin in monophasic and chronic-relapsing EAE.
- Author
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Black JA, Liu S, Hains BC, Saab CY, and Waxman SG
- Subjects
- Action Potentials physiology, Administration, Oral, Animals, Cell Count methods, Cervical Vertebrae, Chronic Disease, Encephalomyelitis, Autoimmune, Experimental pathology, Encephalomyelitis, Autoimmune, Experimental physiopathology, Immunohistochemistry methods, Injections, Subcutaneous, Mice, Mice, Inbred C57BL, Myelin Proteins, Myelin-Associated Glycoprotein administration & dosage, Myelin-Oligodendrocyte Glycoprotein, Neural Conduction, Recurrence, Spinal Cord pathology, Spinal Cord physiopathology, Treatment Outcome, Axons drug effects, Encephalomyelitis, Autoimmune, Experimental drug therapy, Phenytoin administration & dosage, Sodium Channel Blockers administration & dosage, Spinal Cord drug effects
- Abstract
Axonal degeneration is a major contributor to non-remitting deficits in multiple sclerosis, and there is thus considerable current interest in the development of strategies that might prevent axonal loss in neuroinflammatory disease. Dysregulation of sodium ion homeostasis has been implicated in mechanisms leading to axonal degeneration, and several studies have shown that blockade of sodium channels can ameliorate axon damage following anoxic, traumatic and nitric oxide-induced CNS injury. Two sodium channel blockers, phenytoin and flecainide, have been reported to protect axons in experimental autoimmune encephalomyelitis (EAE) for 30 days, but long-term protective effects have not been studied. We demonstrate here that oral administration of phenytoin provides long-term (up to 180 days) protection for spinal cord corticospinal tract (CST) and dorsal column (DC) axons in both monophasic (C57/BL6 mice) and chronic-relapsing (Biozzi mice) murine EAE. Untreated C57/BL6 mice exhibit a 40-50% loss of CST and DF axons at 90 and 180 days post-EAE induction via myelin-oligodendrocyte glycoprotein (MOG) injection. In contrast, only 4% of DF axons are lost at 90 days, and only 8% are lost at 180 days in phenytoin-treated C57/BL6 mice with EAE; only 21-29% of CST axons are lost at 90 and 180 days in phenytoin-treated C57/BL6 mice with EAE. Attenuation of dorsal column compound action potentials was ameliorated and clinical status was also significantly enhanced with phenytoin treatment at 90 and 180 days in this model. In addition, inflammatory cell infiltration into the dorsal columns was reduced in phenytoin-treated mice with EAE compared with untreated mice with EAE. Similar results were obtained in Biozzi mice with chronic-relapsing EAE followed for 120 days post-injection. These observations demonstrate that phenytoin provides long-term protection of CNS axons and improves clinical status in both monophasic and chronic-relapsing models of neuroinflammation.
- Published
- 2006
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34. Microglia: a newly discovered role in visceral hypersensitivity?
- Author
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Saab CY, Wang J, Gu C, Garner KN, and Al-Chaer ED
- Abstract
Given the growing body of evidence for a role of glia in pain modulation, it is plausible that the exaggerated visceral pain in chronic conditions might be regulated by glial activation. In this study, we have investigated a possible role for microglia in rats with chronic visceral hypersensitivity and previously documented altered neuronal function. Experiments were performed on adult male Sprague-Dawley rats pre-treated with neonatal colon irritation (CI) and on control rats. Effects of fractalkine (FKN, a chemokine involved in neuron-to-microglia signaling) and of minocycline (an inhibitor of microglia) on visceral sensitivity were examined. Visceral sensitivity was assessed by recording the electromyographic (EMG) responses to graded colorectal distension (CRD) in mildly sedated rats. Responses to CRD were recorded before and after injection of FKN, minocycline or vehicle. Somatic thermal hyperalgesia was measured by latency of paw withdrawal to radiant heat. The pattern and intensity of microglial distribution at L6-S2 in the spinal cord was also compared in rats with CI and controls by fluorescence microscopy using OX-42. Results show that: (1) FKN significantly facilitated EMG responses to noxious CRD by >52% in control rats. FKN also induced thermal hyperalgesia in control rats, consistent with previous reports; (2) minocycline significantly inhibited EMG responses to noxious CRD by >70% in rats with CI compared to controls 60 min after injection. The anti-nociceptive effect of minocycline lasted for 180 min in rats with CI, reaching peak values 60 min after injection. Our results show that FKN enhances visceral and somatic nociception, whereas minocycline inhibits visceral hypersensitivity in chronically sensitized rats, which indicates a role for microglia in visceral hypersensitivity.
- Published
- 2006
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35. Fractalkine and minocycline alter neuronal activity in the spinal cord dorsal horn.
- Author
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Owolabi SA and Saab CY
- Subjects
- Action Potentials drug effects, Animals, Chemokine CX3CL1, Chemokines, CX3C antagonists & inhibitors, Ligation, Male, Membrane Proteins antagonists & inhibitors, Pain chemically induced, Posterior Horn Cells physiology, Rats, Rats, Sprague-Dawley, Spinal Nerves surgery, Chemokines, CX3C pharmacology, Membrane Proteins pharmacology, Minocycline pharmacology, Posterior Horn Cells drug effects
- Abstract
Fractalkine (FKN) evokes nociceptive behavior in nai ve rats, whereas minocycline attenuates pain acutely after neuronal injury. We show that, in nai ve rats, FKN causes hyperresponsiveness of lumbar wide dynamic range neurons to brush, pressure and pinch applied to the hindpaw. One day after spinal nerve ligation (SNL), minocycline attenuates after-discharge and responses to brush and pressure. In contrast, minocycline does not alter evoked neuronal responses 10 days after SNL or sciatic constriction, but increases spontaneous discharge. We speculate that microglia rapidly alter sensory neuronal activity in nai ve and neuropathic rats acutely, but not chronically, after injury.
- Published
- 2006
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36. Alterations in burst firing of thalamic VPL neurons and reversal by Na(v)1.3 antisense after spinal cord injury.
- Author
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Hains BC, Saab CY, and Waxman SG
- Subjects
- Adaptation, Physiological, Animals, DNA, Antisense genetics, Gene Silencing, Male, NAV1.3 Voltage-Gated Sodium Channel, Nerve Tissue Proteins genetics, Neuronal Plasticity, Rats, Rats, Sprague-Dawley, Sodium Channels genetics, Action Potentials, Biological Clocks, Nerve Tissue Proteins metabolism, Neurons, Sodium Channels metabolism, Spinal Cord Injuries physiopathology, Ventral Thalamic Nuclei physiopathology
- Abstract
We recently showed that spinal cord contusion injury (SCI) at the thoracic level induces pain-related behaviors and increased spontaneous discharges, hyperresponsiveness to innocuous and noxious peripheral stimuli, and enlarged receptive fields in neurons in the ventral posterolateral (VPL) nucleus of the thalamus. These changes are linked to the abnormal expression of Na(v)1.3, a rapidly repriming voltage-gated sodium channel. In this study, we examined the burst firing properties of VPL neurons after SCI. Adult male Sprague-Dawley rats underwent contusion SCI at the T9 level. Four weeks later, when Na(v)1.3 protein was upregulated within VPL neurons, extracellular unit recordings were made from VPL neurons in intact animals, those with SCI, and in SCI animals after receiving lumbar intrathecal injections of Na(v)1.3 antisense or mismatch oligodeoxynucleotides for 4 days. After SCI, VPL neurons with identifiable peripheral receptive fields showed rhythmic oscillatory burst firing with changes in discrete burst properties, and alternated among single-spike, burst, silent, and spindle wave firing modes. Na(v)1.3 antisense, but not mismatch, partially reversed alterations in burst firing after SCI. These results demonstrate several newly characterized changes in spontaneous burst firing properties of VPL neurons after SCI and suggest that abnormal expression of Na(v)1.3 contributes to these phenomena.
- Published
- 2006
- Full Text
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37. Changes in electrophysiological properties and sodium channel Nav1.3 expression in thalamic neurons after spinal cord injury.
- Author
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Hains BC, Saab CY, and Waxman SG
- Subjects
- Action Potentials physiology, Animals, Behavior, Animal, Evoked Potentials physiology, Immunohistochemistry methods, Lateral Thalamic Nuclei metabolism, Male, NAV1.3 Voltage-Gated Sodium Channel, Nerve Tissue Proteins analysis, Oligonucleotides, Antisense genetics, Rats, Rats, Sprague-Dawley, Sodium Channels analysis, Spinal Cord Injuries genetics, Spinal Cord Injuries metabolism, Thoracic Vertebrae, Up-Regulation, Ventral Thalamic Nuclei metabolism, Nerve Tissue Proteins metabolism, Neurons metabolism, Sodium Channels metabolism, Spinal Cord Injuries physiopathology, Thalamus metabolism
- Abstract
Spinal cord contusion injury (SCI) is known to induce pain-related behaviour, as well as hyperresponsiveness in lumbar dorsal horn nociceptive neurons associated with the aberrant expression of Na(v)1.3, a rapidly repriming voltage-gated sodium channel. Many of these second-order dorsal horn neurons project to third-order neurons in the ventrobasal complex of the thalamus. In this study we hypothesized that, following SCI, neurons in the thalamus undergo electrophysiological changes linked to aberrant expression of Na(v)1.3. Adult male Sprague-Dawley rats underwent contusion SCI at the T9 thoracic level. Four weeks post-SCI, Na(v)1.3 protein was upregulated within thalamic neurons in ventroposterior lateral (VPL) and ventroposterior medial nuclei, where extracellular unit recordings revealed increased spontaneous discharge, afterdischarge, hyperresponsiveness to innocuous and noxious peripheral stimuli, and expansion of peripheral receptive fields. Altered electrophysiological properties of VPL neurons persisted after interruption of ascending spinal barrage by spinal cord transection above the level of the injury. Lumbar intrathecal administration of specific antisense oligodeoxynucleotides generated against Na(v)1.3 caused a significant reduction in Na(v)1.3 expression in thalamic neurons and reversed electrophysiological alterations. These results show, for the first time, a change in sodium channel expression within neurons in the thalamus after injury to the spinal cord, and suggest that these changes contribute to altered processing of somatosensory information after SCI.
- Published
- 2005
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38. Abnormal Purkinje cell activity in vivo in experimental allergic encephalomyelitis.
- Author
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Saab CY, Craner MJ, Kataoka Y, and Waxman SG
- Subjects
- Action Potentials physiology, Afferent Pathways immunology, Afferent Pathways metabolism, Afferent Pathways physiopathology, Animals, Cell Shape physiology, Cerebellar Cortex immunology, Cerebellar Cortex metabolism, Disease Models, Animal, Encephalomyelitis, Autoimmune, Experimental immunology, Encephalomyelitis, Autoimmune, Experimental metabolism, Mice, Multiple Sclerosis immunology, Multiple Sclerosis metabolism, NAV1.8 Voltage-Gated Sodium Channel, Purkinje Cells immunology, RNA, Messenger metabolism, Sodium metabolism, Sodium Channels genetics, Synaptic Transmission physiology, Up-Regulation physiology, Cerebellar Cortex physiopathology, Encephalomyelitis, Autoimmune, Experimental physiopathology, Multiple Sclerosis physiopathology, Purkinje Cells metabolism, Sodium Channels metabolism
- Abstract
Cerebellar deficits in multiple sclerosis (MS) tend to persist and can produce significant disability. Although the pathophysiological basis for these deficits is not clear, it was recently reported that the expression of the sensory neuron-specific sodium channel Nav1.8 (which is not normally expressed within the cerebellum) is aberrantly upregulated within Purkinje cells in experimental allergic encephalomyelitis (EAE) and in human MS. The expression of Nav1.8 in cultured Purkinje cells has been shown to alter the activity pattern of these cells in vitro by decreasing the number of spikes per conglomerate action potential and by contributing to the production of sustained, pacemaker-like activity upon depolarization, suggesting the hypothesis that, in pathophysiological situations where Nav1.8 is upregulated within Purkinje cells, the pattern of activity in these cells will be altered. In the present study, we examined this hypothesis in vivo in mice with EAE. Our results demonstrate a reduction in the number of secondary spikes per complex spike and irregularity in the temporal organization of secondary spikes in Purkinje cells from mice with EAE in which Nav1.8 is upregulated. We also observed abnormal bursting activity in Purkinje cells from mice with EAE, which was not observed in control animals. These results demonstrate functional changes in Purkinje cells in vivo within their native cerebellar environment in EAE, a model of MS, and support the hypothesis that misexpression of Nav1.8 can contribute to cerebellar deficits in neuroinflammatory disorders by altering the pattern of electrical activity within the cerebellum.
- Published
- 2004
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39. Potentiation of sural nerve Abeta action potential after neurogenic inflammation.
- Author
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Saab CY and Waxman SG
- Subjects
- Action Potentials drug effects, Animals, Capsaicin toxicity, Male, Rats, Rats, Sprague-Dawley, Sciatic Nerve drug effects, Sciatic Nerve physiology, Sural Nerve drug effects, Action Potentials physiology, Amyloid beta-Peptides physiology, Neurogenic Inflammation metabolism, Neurogenic Inflammation physiopathology, Sural Nerve physiology
- Abstract
Inflammatory mediators modulate voltage-gated sodium channels through protein kinase-mediated pathways. However, it is not clear whether neurogenic inflammation may also alter the properties of distantly located channels along axon shafts supplying the inflamed dermatome. In this study, localized inflammation was induced via intradermal injection of capsaicin within the receptive field of the sural nerve, and compound action potentials (CAP) evoked by sural nerve stimulation were recorded from the sciatic nerve proximally. The area measured under the A beta CAP increased significantly within 5 min after capsaicin injection. Distal injection of lidocaine at the ankle division of the sural nerve prior to capsaicin injection reversed this increase. In addition, application of a lipophilic protein kinase inhibitor H7 (100 microM) through a perfusion chamber placed on the sciatic nerve also reversed this increase. Our results suggest that during neurogenic inflammation, action potential activity is increased, triggering activation of protein kinases that may rapidly alter membrane conductance to potentiate action potential propagation along peripheral nerves.
- Published
- 2004
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40. Sodium channel blockade with phenytoin protects spinal cord axons, enhances axonal conduction, and improves functional motor recovery after contusion SCI.
- Author
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Hains BC, Saab CY, Lo AC, and Waxman SG
- Subjects
- Animals, Anticonvulsants pharmacology, Axons physiology, Behavior, Animal drug effects, Disease Models, Animal, Electrophysiology, Male, Motor Activity drug effects, Neural Conduction drug effects, Rats, Rats, Sprague-Dawley, Recovery of Function drug effects, Sodium Channels metabolism, Spinal Cord pathology, Spinal Cord physiopathology, Spinal Cord Injuries pathology, Spinal Cord Injuries physiopathology, Wounds, Nonpenetrating, Axons drug effects, Phenytoin pharmacology, Sodium Channel Blockers pharmacology, Sodium Channels drug effects, Spinal Cord drug effects, Spinal Cord Injuries drug therapy
- Abstract
Accumulation of intracellular sodium through voltage-gated sodium channels (VGSCs) is an important event in the cascade leading to anatomic degeneration of spinal cord axons and poor functional outcome following traumatic spinal cord injury (SCI). In this study, we hypothesized that phenytoin, a sodium channel blocker, would result in protection of axons with concomitant improvement of functional recovery after SCI. Adult male Sprague-Dawley rats underwent T9 contusion SCI after being fed normal chow or chow containing phenytoin; serum levels of phenytoin were within therapeutic range at the time of injury. At various timepoints after injury, quantitative assessment of lesion volumes, axonal degeneration, axonal conduction, and functional locomotor recovery were performed. When compared to controls, phenytoin-treated animals demonstrated reductions in the degree of destruction of gray and white matter surrounding the lesion epicenter, sparing of axons within the dorsal corticospinal tract (dCST) and dorsal column (DC) system rostral to the lesion site, and within the dorsolateral funiculus (DLF) caudal to the lesion site, and enhanced axonal conduction across the lesion site. Improved performance in measures of skilled locomotor function was observed in phenytoin-treated animals. Based on these results, we conclude that phenytoin provides neuroprotection and improves functional outcome after experimental SCI, and that it merits further examination as a potential treatment strategy in human SCI.
- Published
- 2004
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41. Thalamic modulation of visceral nociceptive processing in adult rats with neonatal colon irritation.
- Author
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Saab CY, Park YC, and Al-Chaer ED
- Subjects
- Anesthetics, Local administration & dosage, Anesthetics, Local pharmacology, Animals, Catheterization, Electrophysiology, Lidocaine administration & dosage, Lidocaine pharmacology, Male, Mechanoreceptors physiology, Microinjections, Neuronal Plasticity physiology, Physical Stimulation, Posterior Horn Cells physiology, Rats, Rats, Sprague-Dawley, Rectum physiology, Spinal Cord physiology, Animals, Newborn physiology, Colitis physiopathology, Pain physiopathology, Thalamus physiology
- Abstract
Visceral pain originates from visceral organs in response to a noxious stimulus which, if prolonged, may lead to chronic changes in the neural network mediating visceral nociception. For instance, colon inflammation enhances the responses of neurons in the thalamus to colorectal distension (CRD), whereas lesion in the dorsal column (DC) reverses this neuronal sensitization, suggesting that the thalamus and the DC play major roles in chronic visceral pain. In this study, we used adult rats sensitized with neonatal painful colon irritation to reveal the contribution of the thalamus and the DC to neuronal hyperexcitability in a model of chronic visceral pain. We recorded the responses of lumbosacral neurons to CRD in control rats and in rats with colon irritation following stimulation or inactivation of the thalamus, and after DC lesion. Our results show that, first, neuronal responses to CRD decreased following thalamic stimulation in control rats, whereas, in rats with colon irritation, responses either decreased or increased; second, DC lesion attenuated or enhanced these effects in the positively or in the negatively modulated group of neurons, respectively; third, lidocaine injection in the thalamus reduced the responses to CRD in some of the neurons recorded in rats with colon irritation, but had no effect on those in control rats. Therefore, it is reasonable to speculate that plasticity in rats with colon irritation that may underlie chronic pain is sustained by feedback loops ascending in the DC and engaging the thalamus., (Copyright 2004 Elsevier B.V.)
- Published
- 2004
- Full Text
- View/download PDF
42. Altered sodium channel expression in second-order spinal sensory neurons contributes to pain after peripheral nerve injury.
- Author
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Hains BC, Saab CY, Klein JP, Craner MJ, and Waxman SG
- Subjects
- Animals, Behavior, Animal drug effects, Behavior, Animal physiology, Disease Models, Animal, Hyperalgesia etiology, Hyperalgesia metabolism, Immunohistochemistry, In Situ Hybridization, Ligation, Male, NAV1.3 Voltage-Gated Sodium Channel, Nerve Tissue Proteins antagonists & inhibitors, Nerve Tissue Proteins genetics, Neurons, Afferent drug effects, Oligonucleotides, Antisense pharmacology, Pain etiology, Pain Measurement drug effects, Posterior Horn Cells drug effects, Posterior Horn Cells metabolism, RNA, Messenger metabolism, Rats, Rats, Sprague-Dawley, Reverse Transcriptase Polymerase Chain Reaction, Sciatic Neuropathy complications, Sciatic Neuropathy metabolism, Sodium Channels genetics, Spinal Cord drug effects, Up-Regulation, Nerve Tissue Proteins metabolism, Neurons, Afferent metabolism, Pain physiopathology, Sciatic Neuropathy physiopathology, Sodium Channels metabolism, Spinal Cord metabolism
- Abstract
Peripheral nerve injury is known to upregulate the rapidly repriming Na(v)1.3 sodium channel within first-order spinal sensory neurons. In this study, we hypothesized that (1) after peripheral nerve injury, second-order dorsal horn neurons abnormally express Na(v)1.3, which (2) contributes to the responsiveness of these dorsal horn neurons and to pain-related behaviors. To test these hypotheses, adult rats underwent chronic constriction injury (CCI) of the sciatic nerve. Ten days after CCI, allodynia and hyperalgesia were evident. In situ hybridization, quantitative reverse transcription-PCR, and immunocytochemical analysis revealed upregulation of Na(v)1.3 in dorsal horn nociceptive neurons but not in astrocytes or microglia, and unit recordings demonstrated hyperresponsiveness of dorsal horn sensory neurons. Intrathecal antisense oligodeoxynucleotides targeting Na(v)1.3 decreased the expression of Na(v)1.3 mRNA and protein, reduced the hyperresponsiveness of dorsal horn neurons, and attenuated pain-related behaviors after CCI, all of which returned after cessation of antisense delivery. These results demonstrate for the first time that sodium channel expression is altered within higher-order spinal sensory neurons after peripheral nerve injury and suggest a link between misexpression of the Na(v)1.3 sodium channel and central mechanisms that contribute to neuropathic pain after peripheral nerve injury.
- Published
- 2004
- Full Text
- View/download PDF
43. Phenytoin protects spinal cord axons and preserves axonal conduction and neurological function in a model of neuroinflammation in vivo.
- Author
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Lo AC, Saab CY, Black JA, and Waxman SG
- Subjects
- Animals, Disease Models, Animal, Encephalomyelitis, Autoimmune, Experimental pathology, Male, Mice, Mice, Inbred C57BL, Phenytoin therapeutic use, Axonal Transport drug effects, Encephalomyelitis, Autoimmune, Experimental physiopathology, Encephalomyelitis, Autoimmune, Experimental prevention & control, Neural Conduction drug effects, Phenytoin pharmacology, Spinal Cord drug effects, Spinal Cord pathology
- Abstract
Axonal degeneration within the spinal cord contributes substantially to neurological disability in multiple sclerosis (MS). Thus neuroprotective therapies that preserve axons, so that they maintain their integrity and continue to function, might be expected to result in improved neurological outcome. Sodium channels are known to provide a route for sodium influx that can drive calcium influx, via reverse operation of the Na+/Ca2+ exchanger, after injury to axons within the CNS, and sodium channel blockers have been shown to protect CNS axons from degeneration after experimental anoxic, traumatic, and nitric oxide (NO)-induced injury. In this study, we asked whether phenytoin, which is known to block sodium channels, can protect spinal cord axons from degeneration in mice with experimental allergic encephalomyelitis (EAE), which display substantial axonal degeneration and clinical paralysis. We demonstrate that the loss of dorsal corticospinal tract (63%) and dorsal column (cuneate fasciculus; 43%) axons in EAE is significantly ameliorated (corticospinal tract: 28%; cuneate fasciculus: 17%) by treatment with phenytoin. Spinal cord compound action potentials (CAP) were significantly attenuated in untreated EAE, whereas spinal cords from phenytoin-treated EAE had robust CAPs, similar to those from phenytoin-treated control mice. Clinical scores in phenytoin-treated EAE at 28 days were significantly improved (1.5, i.e., minor righting reflex abnormalities) compared with untreated EAE (3.8, i.e., near-complete hindlimb paralysis). Our results demonstrate that phenytoin has a protective effect in vivo on spinal cord axons, preventing their degeneration, maintaining their ability to conduct action potentials, and improving clinical status in a model of neuroinflammation.
- Published
- 2003
- Full Text
- View/download PDF
44. Upregulation of sodium channel Nav1.3 and functional involvement in neuronal hyperexcitability associated with central neuropathic pain after spinal cord injury.
- Author
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Hains BC, Klein JP, Saab CY, Craner MJ, Black JA, and Waxman SG
- Subjects
- Animals, Behavior, Animal drug effects, Cell Count, Disease Models, Animal, Electrophysiology, Immunohistochemistry, In Situ Hybridization, Male, NAV1.3 Voltage-Gated Sodium Channel, Nerve Tissue Proteins genetics, Neuralgia complications, Neurons drug effects, Neurons pathology, Nociceptors pathology, Nociceptors physiopathology, Oligodeoxyribonucleotides, Antisense metabolism, Oligodeoxyribonucleotides, Antisense pharmacology, Pain Measurement, Posterior Horn Cells drug effects, Posterior Horn Cells pathology, Rats, Rats, Sprague-Dawley, Reverse Transcriptase Polymerase Chain Reaction, Sodium Channels genetics, Spinal Cord Injuries complications, Up-Regulation drug effects, Up-Regulation physiology, Nerve Tissue Proteins metabolism, Neuralgia physiopathology, Neurons metabolism, Posterior Horn Cells physiopathology, Sodium Channels metabolism, Spinal Cord Injuries physiopathology
- Abstract
Spinal cord injury (SCI) can result in hyperexcitability of dorsal horn neurons and central neuropathic pain. We hypothesized that these phenomena are consequences, in part, of dysregulated expression of voltage-gated sodium channels. Because the rapidly repriming TTX-sensitive sodium channel Nav1.3 has been implicated in peripheral neuropathic pain, we investigated its role in central neuropathic pain after SCI. In this study, adult male Sprague Dawley rats underwent T9 spinal contusion injury. Four weeks after injury when extracellular recordings demonstrated hyperexcitability of L3-L5 dorsal horn multireceptive nociceptive neurons, and when pain-related behaviors were evident, quantitative RT-PCR, in situ hybridization, and immunocytochemistry revealed an upregulation of Nav1.3 in dorsal horn nociceptive neurons. Intrathecal administration of antisense oligodeoxynucleotides (ODNs) targeting Nav1.3 resulted in decreased expression of Nav1.3 mRNA and protein, reduced hyperexcitability of multireceptive dorsal horn neurons, and attenuated mechanical allodynia and thermal hyperalgesia after SCI. Expression of Nav1.3 protein and hyperexcitability in dorsal horn neurons as well as pain-related behaviors returned after cessation of antisense delivery. Responses to normally noxious stimuli and motor function were unchanged in SCI animals administered Nav1.3 antisense, and administration of mismatch ODNs had no effect. These results demonstrate for the first time that Nav1.3 is upregulated in second-order dorsal horn sensory neurons after nervous system injury, showing that SCI can trigger changes in sodium channel expression, and suggest a functional link between Nav1.3 expression and neuronal hyperexcitability associated with central neuropathic pain.
- Published
- 2003
45. GTP gamma S increases Nav1.8 current in small-diameter dorsal root ganglia neurons.
- Author
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Saab CY, Cummins TR, and Waxman SG
- Subjects
- Action Potentials drug effects, Action Potentials physiology, Animals, Ganglia, Spinal physiology, Male, NAV1.8 Voltage-Gated Sodium Channel, Neurons physiology, Rats, Rats, Sprague-Dawley, Ganglia, Spinal drug effects, Guanosine 5'-O-(3-Thiotriphosphate) pharmacology, Nerve Tissue Proteins physiology, Neurons drug effects, Sodium Channels physiology
- Abstract
Tetrodotoxin-resistant (TTX-R) sodium current in small-size dorsal root ganglia (DRG) neurons is upregulated by prostaglandin E(2) and serotonin through a protein kinase A (PKA)/protein kinase (PKC) pathway, suggesting G protein modulation of one or more TTX-R channels in these neurons. Recently, GTP(gammaS), a hydrolysis-resistant analogue of GTP, was shown to increase the persistent current produced by the TTX-R Na(v)1.9. In this study, we investigated the modulation of another TTX-R channel, Na(v)1.8, by GTP(gammaS) in small-diameter DRG neurons from rats using whole-cell voltage clamp recordings. Because it has been suggested that fluoride, often used in intracellular recording solutions, may bind to trace amounts of aluminum and activate G proteins, we recorded Na(v)1.8 currents with and without intracellular fluoride, and with the addition of deferoxamine, an aluminum chelator, to prevent fluoride-aluminum binding. Our results show that GTP(gammaS) (100 micro M) caused a significant increase in Na(v)1.8 current (67%) with a chloride-based intracellular solution. Although the inclusion of fluoride instead of chloride in the pipette solution increased the Na(v)1.8 current by 177%, GTP(gammaS) further increased Na(v)1.8 current by 67% under these conditions. While the effect of GTP(gammaS) was prevented by pretreatment with H7 (100 micro M), a non-selective PKA/PKC inhibitor, the fluoride-induced increase in Na(v)1.8 current was not sensitive to H7 (100 micro M), or to inclusion of deferoxamine (1 mM) in the intracellular solution. We conclude that G protein activation by GTP(gammaS) increases Na(v)1.8 current through a PKA/PKC mechanism and that addition of fluoride to the pipette solution further enhances the current, but is not a confounding variable in the study of Na(v)1.8 channel modulation by G proteins independent of a PKA/PKC pathway or binding to aluminum.
- Published
- 2003
- Full Text
- View/download PDF
46. The cerebellum: organization, functions and its role in nociception.
- Author
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Saab CY and Willis WD
- Subjects
- Animals, Brain Mapping, Electrophysiology, Humans, Magnetic Resonance Imaging, Motor Activity, Sensation, Vision, Ocular, Cerebellum anatomy & histology, Cerebellum cytology, Cerebellum physiology, Neural Pathways physiology, Pain physiopathology
- Abstract
Our vision of the cerebellum has been gradually transformed throughout the last century from a 'little brain' to a 'neuronal machine' capable of multitasks, all arguably based on a principle computational model. We review here the main functions of the cerebellum in light of its organization and connectivity. In addition to providing a clear and extensive review of the cerebellar literature, we emphasize the role of the cerebellum in nociception, which is novel to the neurophysiology of pain. However, it is premature to conclude that the cerebellum influences sensory experience in the absence of clinical data.
- Published
- 2003
- Full Text
- View/download PDF
47. Molecular determinant of Na(v)1.8 sodium channel resistance to the venom from the scorpion Leiurus quinquestriatus hebraeus.
- Author
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Saab CY, Cummins TR, Dib-Hajj SD, and Waxman SG
- Subjects
- Action Potentials drug effects, Action Potentials genetics, Action Potentials immunology, Animals, Cells, Cultured, Chimera, Ganglia, Spinal drug effects, Ganglia, Spinal immunology, Immunity, Innate physiology, Molecular Structure, NAV1.8 Voltage-Gated Sodium Channel, Neurons drug effects, Neurons immunology, Neuropeptides genetics, Neuropeptides immunology, Patch-Clamp Techniques, Rats, Scorpion Venoms genetics, Scorpion Venoms immunology, Sodium Channels genetics, Sodium Channels immunology, Neuropeptides drug effects, Scorpion Venoms pharmacology, Sodium Channels drug effects
- Abstract
The scorpion venom from Leiurus quinquestriatus (LQTX) alters the kinetics of tetrodotoxin (TTX)-sensitive channels such as the skeletal muscle sodium channel Na(v)1.4. In this study, we tested the effects of LQTX on the TTX-resistant sodium current generated by Na(v)1.8 channels in sensory neurons. Na(v)1.8 current was found to be resistant to LQTX, whereas LQTX slowed inactivation of the current generated by Na(v)1.4 and induced a persistent current. LQTX has been shown to bind the S3-S4 linker of domain four (D4S3-S4) of rat brain Na(v)1.2 sodium channels. Sequence analysis shows that the D4S3-S4 linker is longer in Na(v)1.8 than in Na(v)1.4 by four amino acids: Serine; Leucine; Glutamic acid; and Aspargine (SLEN). Na(v)1.4-SLEN, a chimera construct carrying SLEN at the analogous position in the D4S3-S4 linker, was also found to be resistant to LQTX. Therefore, we conclude that the tetrapeptide SLEN at the D4S3-S4 linker region is sufficient to make Na(v)1.8 resistant to LQTX.
- Published
- 2002
- Full Text
- View/download PDF
48. Cerebellar stimulation modulates the intensity of a visceral nociceptive reflex in the rat.
- Author
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Saab CY and Willis WD
- Subjects
- Animals, Bicuculline pharmacology, Brain Mapping, Cerebellar Cortex physiology, Colon innervation, Colon physiology, Electric Stimulation, Electromyography, GABA Agonists pharmacology, Homocysteine pharmacology, Male, Muscle, Skeletal innervation, Muscle, Skeletal physiology, Neural Pathways physiology, Physical Stimulation, Rats, Rats, Sprague-Dawley, Rectum innervation, Rectum physiology, Stereotaxic Techniques, Cerebellum physiology, Homocysteine analogs & derivatives, Nociceptors physiology, Pain physiopathology, Reflex physiology
- Abstract
The cerebellum modulates different nociceptive phenomena and influences visceral functions. This study shows cerebellar modulation of an abdominal reflex elicited by a visceral noxious stimulus (colorectal distension, CRD). The intensity of the reflex was measured by electromyographic (EMG) recording from the rectus abdominus muscle, and the cerebellar cortex (vermis, lobule VIII), the fastigial nucleus, or the dentate nucleus was stimulated using D, L-homocysteic acid (0.1 M, 1 micro l). To release the fastigial nucleus from inhibition by the Purkinje cells, bicuculline (GABA(A) receptor antagonist, 100 micro M, 1 micro l) was used. Stimulation of the cerebellar cortex enhanced, whereas stimulation or disinhibition of the fastigial nucleus decreased, the responses to CRD measured by EMG. Stimulation of the dentate nucleus did not have an obvious effect on the intensity of the reflex. These results are in agreement with the hypothesis that the cerebellum modulates visceral nociceptive functions, whereby the cerebellar cortex and the fastigial nucleus, respectively, play a pro-nociceptive and an anti-nociceptive role.
- Published
- 2002
- Full Text
- View/download PDF
49. Stimulation in the rat fastigial nucleus enhances the responses of neurons in the dorsal column nuclei to innocuous stimuli.
- Author
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Saab CY, Garcia-Nicas E, and Willis WD
- Subjects
- Action Potentials physiology, Animals, Homocysteine pharmacology, Male, Physical Stimulation, Rats, Rats, Sprague-Dawley, Vibration, Cerebellar Nuclei cytology, Cerebellar Nuclei physiology, Homocysteine analogs & derivatives, Neurons, Afferent physiology, Touch physiology
- Abstract
The cerebellum was recently proposed to play a role in cognition and sensation in addition to motor phenomena. We have shown that the cerebellum is involved in the processing of sensory nociceptive information. In this study, the activity of neurons in the dorsal column nuclei (DCN) was tested following stimulation in the rat fastigial nucleus. The results showed an enhancement of the extracellularly recorded responses of DCN neurons to somatic non-noxious stimuli following injection of D,L-homocysteic acid (0.1 M, 1 microl) into the area of the fastigial nucleus. We conclude that the cerebellum influences the processing of non-noxious somatosensory information at the level of the DCN, an important relay and a center for the processing of fine tactile and vibratory information. This observation is not yet supported by clinical data.
- Published
- 2002
- Full Text
- View/download PDF
50. Nociceptive visceral stimulation modulates the activity of cerebellar Purkinje cells.
- Author
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Saab CY and Willis WD
- Subjects
- Afferent Pathways physiology, Animals, Biological Clocks physiology, Catheterization adverse effects, Foot innervation, Foot physiology, Mechanoreceptors physiology, Physical Stimulation methods, Posterior Horn Cells physiology, Rats, Rats, Sprague-Dawley, Reaction Time physiology, Rectum innervation, Rectum physiopathology, Action Potentials physiology, Nociceptors physiology, Pain physiopathology, Purkinje Cells physiology, Visceral Afferents physiology
- Abstract
The cerebellum is a system with various input and output functions that influence motor, sensory, cognitive, and other processes. In a previous study, we showed that cerebellar cortical stimulation increases spinal neuronal responses to visceral noxious stimulation by colorectal distension (CRD). However, the neuronal network underlying the cerebellar modulation of nociceptive phenomena is largely unknown. Purkinje cells of the cerebellar cortex receive ascending and descending inputs and exert a major inhibitory control over neurons in the underlying cerebellar nuclei that constitute the cerebellar output. Therefore, in this study, we tested the effect of CRD and other somatic stimuli on the firing rate of Purkinje cells using in vivo extracellular recording techniques. The results suggest that Purkinje cells respond to nociceptive visceral and somatic stimulation in the form of early and delayed changes in activity. Based on these and previous findings, we propose a negative feedback circuitry involving the cerebellum for the modulation of peripheral nociceptive events.
- Published
- 2001
- Full Text
- View/download PDF
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