Publications by authors named "Karen-Amanda Irvine"

23 Publications

  • Page 1 of 1

Loss of diffuse noxious inhibitory control after traumatic brain injury in rats: A chronic issue.

Exp Neurol 2020 11 1;333:113428. Epub 2020 Aug 1.

Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University, School of Medicine, Stanford, CA 94305, USA; Anesthesiology Service, Veterans Affairs Palo Alto Health Care System, 3801 Miranda Ave (E4-220), Palo Alto, CA 94304, USA.

Chronic pain is one of the most challenging and debilitating symptoms to manage after traumatic brain injury (TBI), yet the underlying mechanisms remain elusive. The disruption of normal endogenous pain control mechanisms has been linked to several forms of chronic pain and may play a role in pain after TBI. We hypothesized therefore that dysfunctional descending noradrenergic and serotonergic pain control circuits may contribute to the loss of diffuse noxious inhibitory control (DNIC), a critical endogenous pain control mechanism, weeks to months after TBI. For these studies, the rat lateral fluid percussion model of mild TBI was used along with a DNIC paradigm involving a capsaicin-conditioning stimulus. We observed sustained failure of the DNIC response up to 180-days post injury. We confirmed, that descending α adrenoceptor-mediated noradrenergic signaling was critical for endogenous pain inhibition in uninjured rats. However, augmenting descending noradrenergic signaling using reboxetine, a selective noradrenaline reuptake inhibitor, failed to restore DNIC after TBI. Furthermore, blocking serotonin-mediated descending signaling using selective spinal serotonergic fiber depletion with 5, 7-dihydroxytryptamine was also unsuccessful at restoring endogenous pain modulation after TBI. Unexpectedly, increasing descending serotonergic signaling using the selective serotonin reuptake inhibitor escitalopram and the serotonin-norepinephrine reuptake inhibitor duloxetine restored the DNIC response in TBI rats at both 49- and 180- days post injury. Consistent with these observations, spinal serotonergic fiber depletion with 5, 7-dihydroxytryptamine eliminated the effects of escitalopram. Intact α adrenoceptor signaling, however, was not required for the serotonin-mediated restoration of DNIC after TBI. These results suggest that TBI causes maladaptation of descending nociceptive signaling mechanisms and changes in the function of both adrenergic and serotonergic circuits. Such changes could predispose those with TBI to chronic pain.
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http://dx.doi.org/10.1016/j.expneurol.2020.113428DOI Listing
November 2020

Mild Traumatic Brain Injury Causes Nociceptive Sensitization through Spinal Chemokine Upregulation.

Sci Rep 2019 12 20;9(1):19500. Epub 2019 Dec 20.

Department of Anesthesia, Perioperative and Pain Medicine, Stanford University, School of Medicine, Stanford, CA, 94305, USA.

High rates of acute and chronic pain are associated with traumatic brain injury (TBI), but mechanisms responsible for the association remain elusive. Recent data suggest dysregulated descending pain modulation circuitry could be involved. Based on these and other observations, we hypothesized that serotonin (5-HT)-dependent activation of spinal CXC Motif Chemokine Receptor 2 (CXCR2) may support TBI-related nociceptive sensitization in a mouse model of mild TBI (mTBI). We observed that systemic 5-HT depletion with p-chlorophenylalanine attenuated mechanical hypersensitivity seen after mTBI. Likewise, selective spinal 5-HT fiber depletion with 5,7-dihydroxytryptamine (5,7-DHT) reduced hypersensitivity after mTBI. Consistent with a role for spinal 5-HT serotonin receptors, intrathecal ondansetron administration after TBI dose-dependently attenuated nociceptive sensitization. Also, selective CXCR2 antagonist SCH527123 treatment attenuated mechanical hypersensitivity after mTBI. Furthermore, spinal CXCL1 and CXCL2 mRNA and protein levels were increased after mTBI as were GFAP and IBA-1 markers. Spinal 5,7-DHT application reduced both chemokine expression and glial activation. Our results suggest dual pathways for nociceptive sensitization after mTBI, direct 5-HT effect through 5-HT receptors and indirectly through upregulation of chemokine signaling. Designing novel clinical interventions against either the 5-HT mediated component or chemokine pathway may be beneficial in treating pain frequently seen in patients after mTBI.
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http://dx.doi.org/10.1038/s41598-019-55739-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6925232PMC
December 2019

Enhanced descending pain facilitation in acute traumatic brain injury.

Exp Neurol 2019 10 8;320:112976. Epub 2019 Jun 8.

Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University, School of Medicine, Stanford, CA 94305, USA; Anesthesiology Service, VA Palo Alto Health Care System, 3801 Miranda Ave (E4-220), Palo Alto, CA 94304, USA. Electronic address:

Acute and persistent pain are recognized consequences of TBI that can enhance suffering and significantly impair rehabilitative efforts. Both experimental models and clinical studies suggest that TBI may result in an imbalance between descending pain facilitatory and inhibitory pathways. The aim of this study was to assess the role of enhanced descending serotonin-mediated pain facilitation in a rat TBI model using selective spinal serotonergic fiber depletion with 5, 7-dihydroxytryptamine (DHT). We observed significant hindpaw allodynia in TBI rats that was reduced after DHT but not vehicle treatment. Immunohistochemical studies demonstrated profound spinal serotonin depletion in DHT-treated rats. Furthermore, lumbar intrathecal administration of the 5-HT receptor antagonist ondansetron at 7 days post-injury (DPI), when hindpaw allodynia was maximal, also attenuated nociceptive sensitization. Additional immunohistochemical analyses of the lumbar spinal cord at 7 DPI revealed a robust bilateral microglial response in the superficial dorsal horns that was significantly reduced with DHT treatment. Furthermore, serotonin depletion also prevented the TBI-induced bilateral increase in c-Fos positive cells within the Rexed laminae I and II of the dorsal horns. These results indicate that in the weeks following TBI, pain may be responsive to 5-HT receptor antagonists or other measures which rebalance descending pain modulation.
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http://dx.doi.org/10.1016/j.expneurol.2019.112976DOI Listing
October 2019

Morphine Exacerbates Postfracture Nociceptive Sensitization, Functional Impairment, and Microglial Activation in Mice.

Anesthesiology 2019 02;130(2):292-308

From the Anesthesiology Service, Veterans Affairs Palo Alto Health Care System, Palo Alto, California, and Department of Anesthesiology, Stanford University School of Medicine, Stanford, California (W.-W.L., K.-A.I., P.S., X.-y.S., J.D.C.) Physical Medicine and Rehabilitation Service, Veterans Affairs Palo Alto Health Care System, Palo Alto, California (T.-Z.G., W.S.K.) Department of Anesthesiology, Perioperative & Pain Medicine, Stanford University School of Medicine, Stanford, California (V.L.T.).

Background: Emerging evidence suggests that opioid use immediately after surgery and trauma may worsen outcomes. In these studies, the authors aimed to determine whether morphine administered for a clinically relevant time period (7 days) in a tibia fracture orthopedic surgery model had adverse effects on postoperative recovery.

Methods: Mice were given morphine twice daily for 7 days after unilateral tibial fracture and intramedullary pin fixation to model orthopedic surgery and limb trauma. Mechanical allodynia, limb-specific weight bearing, gait changes, memory, and anxiety were measured after injury. In addition, spinal cord gene expression changes as well as glial activation were measured. Finally, the authors assessed the effects of a selective Toll-like receptor 4 antagonist, TAK-242, on nociceptive and functional changes after injury.

Results: Tibial fracture caused several weeks of mechanical nociceptive sensitization (F(1, 216) = 573.38, P < 0.001, fracture + vehicle vs. sham + vehicle, n = 10 per group), and this change was exacerbated by the perioperative administration of morphine (F(1, 216) = 71.61, P < 0.001, fracture + morphine vs. fracture + vehicle, n = 10 per group). In additional testing, injured limb weight bearing, gait, and object location memory were worse in morphine-treated fracture mice than in untreated fracture mice. Postfracture expression levels of several genes previously associated with opioid-induced hyperalgesia, including brain-derived neurotrophic factor and prodynorphin, were unchanged, but neuroinflammation involving Toll-like receptor 4 receptor-expressing microglia was observed (6.8 ± 1.5 [mean ± SD] cells per high-power field for fracture + vehicle vs. 12 ± 2.8 fracture + morphine, P < 0.001, n = 8 per /group). Treatment with a Toll-like receptor 4 antagonist TAK242 improved nociceptive sensitization for about 2 weeks in morphine-treated fracture mice (F(1, 198) = 73.36, P < 0.001, fracture + morphine + TAK242 vs. fracture + morphine, n = 10 per group).

Conclusions: Morphine treatment beginning at the time of injury impairs nociceptive recovery and other outcomes. Measures preventing glial activation through Toll-like receptor 4 signaling may reduce the adverse consequences of postoperative opioid administration.
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http://dx.doi.org/10.1097/ALN.0000000000002495DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6349476PMC
February 2019

Pharmacological Characters of Oliceridine, a μ-Opioid Receptor G-Protein-Biased Ligand in Mice.

Anesth Analg 2019 11;129(5):1414-1421

From the Department of Anesthesiology, Veterans Affairs Palo Alto Health Care System, Palo Alto, California.

Background: A major advancement in the field of analgesic pharmacology has been the development of G-protein-biased opioid agonists that display less respiratory depression than conventional drugs. It is uncertain, however, whether these new drugs cause less tolerance, hyperalgesia, and other maladaptations when administered repeatedly.

Methods: The archetypical µ-opioid receptor agonist morphine and, separately, the G-protein-biased µ-opioid receptor agonist oliceridine were administered to mice. These drugs were used in models of acute analgesia, analgesic tolerance, opioid-induced hyperalgesia, reward, and physical dependence. In addition, morphine and oliceridine were administered for 7 days after tibia fracture and pinning; mechanical allodynia and gait were followed for 3 weeks. Finally, the expression of toll-like receptor-4 and nacht domain-, leucine-rich repeat-, and pyrin domain-containing protein 3 (NALP3) and interleukin-1β mRNA were quantified in spinal tissue to measure surgical and drug effects on glia-related gene expression.

Results: We observed using the tail flick assay that oliceridine was a 4-fold more potent analgesic than morphine, but that oliceridine treatment caused less tolerance and opioid-induced hyperalgesia than morphine after 4 days of ascending-dose administration. Using similar analgesic doses, morphine caused reward behavior in the conditioned place preference assay while oliceridine did not. Physical dependence was, however, similar for the 2 drugs. Likewise, morphine appeared to more significantly impair the recovery of nociceptive sensitization and gait after tibial fracture and pinning than oliceridine. Furthermore, spinal cord toll-like receptor-4 levels 3 weeks after fracture were higher in fracture mice given morphine than those given oliceridine.

Conclusions: Aside from reduced respiratory depression, G-protein-biased agonists such as oliceridine may reduce opioid maladaptations and enhance the quality of surgical recovery.
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http://dx.doi.org/10.1213/ANE.0000000000003662DOI Listing
November 2019

Nociceptive and Cognitive Changes in a Murine Model of Polytrauma.

J Pain 2018 12 30;19(12):1392-1405. Epub 2018 Jun 30.

Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University School of Medicine, Stanford, California; Anesthesiology Service, Veterans Affairs Palo Alto Health Care System, Palo Alto, California.

Polytrauma commonly involves concussion (mild traumatic brain injury [mTBI]) and peripheral trauma including limb fractures. Interactions between mTBI and peripheral injuries are poorly understood, both leading to chronic pain and neurobehavioral impairments. To elucidate these interactions, a murine polytrauma model was developed. mTBI alone resulted in similar increased mechanical allodynia in male and female mice. Female fracture and polytrauma groups displayed greater increases in hind paw tactile hypersensitivity for weeks after injury than did the respective male groups. Capsaicin-evoked spontaneous pain behaviors were greater in fracture and polytrauma female mice compared with male mice. The mTBI and polytrauma male mice displayed significant deficits in spatial working memory. All fracture, mTBI, or polytrauma groups had deficits in object recognition memory. Only male mTBI or polytrauma mice showed greater agitation and increased risk-taking behavior in open field testing as well as zero maze tests. Additionally, impaired diffuse noxious inhibitory control was observed in all mTBI and polytrauma mice. The model presented offers clinically relevant features useful for studying persistent pain as well as cognitive and other behavioral changes after TBI including polytrauma. A better understanding of nervous system dysfunction after TBI and polytrauma might help prevent or reduce persistent pain and disability in these patients. PERSPECTIVE: The polytrauma model presented has relevant features of chronic pain and neurobehavioral impairments useful for studying mechanisms involved in their development. This model may have special value in understanding altered descending pain modulation after TBI and polytrauma.
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http://dx.doi.org/10.1016/j.jpain.2018.06.004DOI Listing
December 2018

Traumatic Brain Injury Disrupts Pain Signaling in the Brainstem and Spinal Cord.

J Neurotrauma 2018 07 30;35(13):1495-1509. Epub 2018 Apr 30.

1 Department of Anesthesiology, Veterans Affairs Palo Alto Health Care System , Palo Alto, California.

Chronic pain is a common consequence of traumatic brain injury (TBI) that can increase the suffering of a patient and pose a significant challenge to rehabilitative efforts. Unfortunately, the mechanisms linking TBI to pain are poorly understood, and specific treatments for TBI-related pain are still lacking. Our laboratory has shown that TBI causes pain sensitization in areas distant to the site of primary injury, and that changes in spinal gene expression may underlie this sensitization. The aim of this study was to examine the roles that pain modulatory pathways descending from the brainstem play in pain after TBI. Deficiencies in one type of descending inhibition, diffuse noxious inhibitory control (DNIC), have been suggested to be responsible for the development of chronic pain by allowing excess and uncontrolled afferent nociceptive inputs. Here we expand our knowledge of pain after TBI in two ways: (1) by outlining the neuropathology in pain-related centers of the brain and spinal cord involved in DNIC using the rat lateral fluid percussion (LFP) model of TBI, and (2) by evaluating the effects of a potent histone acetyl transferase inhibitor, anacardic acid (AA), on LFP-induced pain behaviors and neuropathology when administered for several days after TBI. The results revealed that TBI induces transient mechanical allodynia and a chronic persistent loss of DNIC. Further, while short-term AA treatment can block acute nociceptive sensitization and some early neuropathological changes, this treatment neither prevented the loss of DNIC nor did it alter long-term neuropathological changes in the brain or spinal cord.
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http://dx.doi.org/10.1089/neu.2017.5411DOI Listing
July 2018

Effects of Veliparib on Microglial Activation and Functional Outcomes after Traumatic Brain Injury in the Rat and Pig.

J Neurotrauma 2018 Apr 12;35(7):918-929. Epub 2018 Mar 12.

Department of Neurology University of California San Francisco, and San Francisco Veterans Affairs Medical Center; San Francisco, California.

The inflammation response induced by brain trauma can impair recovery. This response requires several hours to develop fully and thus provides a clinically relevant therapeutic window of opportunity. Poly(ADP-ribose) polymerase inhibitors suppress inflammatory responses, including brain microglial activation. We evaluated delayed treatment with veliparib, a poly(ADP-ribose) polymerase inhibitor, currently in clinical trials as a cancer therapeutic, in rats and pigs subjected to controlled cortical impact (CCI). In rats, CCI induced a robust inflammatory response at the lesion margins, scattered cell death in the dentate gyrus, and a delayed, progressive loss of corpus callosum axons. Pre-determined measures of cognitive and motor function showed evidence of attentional deficits that resolved after three weeks and motor deficits that recovered only partially over eight weeks. Veliparib was administered beginning 2 or 24 h after CCI and continued for up to 12 days. Veliparib suppressed CCI-induced microglial activation at doses of 3 mg/kg or higher and reduced reactive astrocytosis and cell death in the dentate gyrus, but had no significant effect on delayed axonal loss or functional recovery. In pigs, CCI similarly induced a perilesional microglial activation that was attenuated by veliparib. CCI in the pig did not, however, induce detectable persisting cognitive or motor impairment. Our results showed veliparib suppression of CCI-induced microglial activation with a delay-to-treatment interval of at least 24 h in both rats and pigs, but with no associated functional improvement. The lack of improvement in long-term recovery underscores the complexities in translating anti-inflammatory effects to clinically relevant outcomes.
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http://dx.doi.org/10.1089/neu.2017.5044DOI Listing
April 2018

Chronic Pain After Traumatic Brain Injury: Pathophysiology and Pain Mechanisms.

Pain Med 2018 07;19(7):1315-1333

Veterans Affairs Palo Alto Health Care System, Anesthesiology Service, Palo Alto, California.

Background: Traumatic brain injury refers to a broad range of neurological, cognitive, and emotional factors that result from the application of an external force to the head. Individuals recovering from traumatic brain injury will frequently experience acute and chronic pain.

Objective: The objective of this paper is to discuss the pathophysiological changes resulting from traumatic brain injury and how these may be involved in the development and persistence of pain after injury.

Methods: We based our review on articles retrieved from the MEDLINE database of references and abstracts on life sciences and biomedical topics (1966 to present) using the search engine PubMed (United States National Library of Medicine). The published literature focused on traumatic brain injury and pain.

Conclusions: This review presents evidence that pain is common after traumatic brain injury. However, while there are many potential mechanisms explaining this problem such as neuroinflammation, excitotoxicity, and axonal degeneration, we have no clear understanding of which of them contribute in individual patients. The authors highlight the priorities for research that will expand our knowledge and that may lead to the rational design of therapies that both reduce pain and provide optimal overall outcomes after traumatic brain injury.
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http://dx.doi.org/10.1093/pm/pnx153DOI Listing
July 2018

TBI-induced nociceptive sensitization is regulated by histone acetylation.

IBRO Rep 2017 Jun 23;2:14-23. Epub 2016 Dec 23.

Department of Anesthesiology, Veterans Affairs Palo Alto Health Care System, Palo Alto, CA, 3801 Miranda Ave, 94304, USA.

Chronic pain after traumatic brain injury (TBI) is very common, but the mechanisms linking TBI to pain and the pain-related interactions of TBI with peripheral injuries are poorly understood. In these studies we pursued the hypothesis that TBI pain sensitization is associated with histone acetylation in the rat lateral fluid percussion model. Some animals received hindpaw incisions in addition to TBI to mimic polytrauma. Neuropathological analysis of brain tissue from sham and TBI animals revealed evidence of bleeding, breakdown of the blood brain barrier, in the cortex, hippocampus, thalamus and other structures related to pain signal processing. Mechanical allodynia was measured in these animals for up to eight weeks post-injury. Inhibitors of histone acetyltransferase (HAT) and histone deacetylase (HDAC) were used to probe the role of histone acetylation in such pain processing. We followed serum markers including glial fibrillary acidic protein (GFAP), neuron-specific enolase 2 (NSE) myelin basic protein (MBP) and S100β to gauge TBI injury severity. Our results showed that TBI caused mechanical allodynia in the hindpaws of the rats lasting several weeks. Hindpaws contralateral to TBI showed more rapid and profound sensitization than ipsilateral hindpaws. The inhibition of HAT using curcumin 50 mg/kg s.c reduced mechanical sensitization while the HDAC inhibitor suberoylanilide hydroxamic acid 50 mg/kg i.p. prolonged sensitization in the TBI rats. Immunohistochemical analyses of spinal cord tissue localized changes in the level of acetylation of the H3K9 histone mark to dorsal horn neurons. Taken together, these findings demonstrate that TBI induces sustained nociceptive sensitization, and changes in spinal neuronal histone proteins may play an important role.
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http://dx.doi.org/10.1016/j.ibror.2016.12.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6084866PMC
June 2017

AMPA Receptor Phosphorylation and Synaptic Colocalization on Motor Neurons Drive Maladaptive Plasticity below Complete Spinal Cord Injury.

eNeuro 2015 Sep-Oct;2(5). Epub 2015 Nov 16.

Department of Neurological Surgery, Brain and Spinal Injury Center, University of California San Francisco , San Francisco, California 94110 ; San Francisco Veterans Affairs Medical Center , San Francisco, California 94121.

Clinical spinal cord injury (SCI) is accompanied by comorbid peripheral injury in 47% of patients. Human and animal modeling data have shown that painful peripheral injuries undermine long-term recovery of locomotion through unknown mechanisms. Peripheral nociceptive stimuli induce maladaptive synaptic plasticity in dorsal horn sensory systems through AMPA receptor (AMPAR) phosphorylation and trafficking to synapses. Here we test whether ventral horn motor neurons in rats demonstrate similar experience-dependent maladaptive plasticity below a complete SCI in vivo. Quantitative biochemistry demonstrated that intermittent nociceptive stimulation (INS) rapidly and selectively increases AMPAR subunit GluA1 serine 831 phosphorylation and localization to synapses in the injured spinal cord, while reducing synaptic GluA2. These changes predict motor dysfunction in the absence of cell death signaling, suggesting an opportunity for therapeutic reversal. Automated confocal time-course analysis of lumbar ventral horn motor neurons confirmed a time-dependent increase in synaptic GluA1 with concurrent decrease in synaptic GluA2. Optical fractionation of neuronal plasma membranes revealed GluA2 removal from extrasynaptic sites on motor neurons early after INS followed by removal from synapses 2 h later. As GluA2-lacking AMPARs are canonical calcium-permeable AMPARs (CP-AMPARs), their stimulus- and time-dependent insertion provides a therapeutic target for limiting calcium-dependent dynamic maladaptive plasticity after SCI. Confirming this, a selective CP-AMPAR antagonist protected against INS-induced maladaptive spinal plasticity, restoring adaptive motor responses on a sensorimotor spinal training task. These findings highlight the critical involvement of AMPARs in experience-dependent spinal cord plasticity after injury and provide a pharmacologically targetable synaptic mechanism by which early postinjury experience shapes motor plasticity.
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http://dx.doi.org/10.1523/ENEURO.0091-15.2015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4677690PMC
September 2016

Topological data analysis for discovery in preclinical spinal cord injury and traumatic brain injury.

Nat Commun 2015 Oct 14;6:8581. Epub 2015 Oct 14.

Department of Neurosurgery, Brain and Spinal Injury Center, University of California, San Francisco, 1001 Potrero Avenue, Building 1, Room 101, San Francisco, California 94143, USA.

Data-driven discovery in complex neurological disorders has potential to extract meaningful syndromic knowledge from large, heterogeneous data sets to enhance potential for precision medicine. Here we describe the application of topological data analysis (TDA) for data-driven discovery in preclinical traumatic brain injury (TBI) and spinal cord injury (SCI) data sets mined from the Visualized Syndromic Information and Outcomes for Neurotrauma-SCI (VISION-SCI) repository. Through direct visualization of inter-related histopathological, functional and health outcomes, TDA detected novel patterns across the syndromic network, uncovering interactions between SCI and co-occurring TBI, as well as detrimental drug effects in unpublished multicentre preclinical drug trial data in SCI. TDA also revealed that perioperative hypertension predicted long-term recovery better than any tested drug after thoracic SCI in rats. TDA-based data-driven discovery has great potential application for decision-support for basic research and clinical problems such as outcome assessment, neurocritical care, treatment planning and rapid, precision-diagnosis.
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http://dx.doi.org/10.1038/ncomms9581DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4634208PMC
October 2015

Corticospinal sprouting differs according to spinal injury location and cortical origin in macaque monkeys.

J Neurosci 2014 Sep;34(37):12267-79

Department of Comparative Medicine, Stanford University School of Medicine, Stanford, California 94305-5342.

The primate corticospinal tract (CST), the major descending pathway mediating voluntary hand movements, comprises nine or more functional subdivisions. The role of subcomponents other than that from primary motor cortex, however, is not well understood. We have previously shown that following a cervical dorsal rhizotomy (Darian-Smith et al., 2013), CST projections originating from primary somatosensory (S1) and motor (M1) cortex responded quite differently to injury. Terminal projections from the S1 (areas 3b/1/2) shrank to <60% of the contralateral side, while M1 CST projections remained robust or expanded (>110%). Here, we asked what happens when a central lesion is added to the equation, to better simulate clinical injury. Monkeys (n = 6) received either a unilateral (1) dorsal root lesion (DRL), (2) or a combined DRL/dorsal column lesion (DRL/DCL), or (3) a DRL/DCL where the DCL was made 4 months following the initial DRL. Electrophysiological recordings were made in S1 4 months postlesion in the first two groups, and 6 weeks after the DCL in the third lesion group, to identify the reorganized region of D1-D3 (thumb, index finger, and middle finger) representation. Anterograde tracers were then injected bilaterally to assess spinal terminal labeling. Remarkably, in all DRL/DCL animals, terminal projections from the S1 and M1 extended bilaterally and caudally well beyond terminal territories in normal animals or following a DRL. These data were highly significant. Extensive sprouting from the S1 CST has not been reported previously, and these data raise important questions about S1 CST involvement in recovery following spinal injury.
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http://dx.doi.org/10.1523/JNEUROSCI.1593-14.2014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4160766PMC
September 2014

Development of a database for translational spinal cord injury research.

J Neurotrauma 2014 Nov 31;31(21):1789-99. Epub 2014 Jul 31.

1 Brain and Spinal Injury Center, Department of Neurological Surgery, University of California San Francisco , San Francisco, California.

Efforts to understand spinal cord injury (SCI) and other complex neurotrauma disorders at the pre-clinical level have shown progress in recent years. However, successful translation of basic research into clinical practice has been slow, partly because of the large, heterogeneous data sets involved. In this sense, translational neurological research represents a "big data" problem. In an effort to expedite translation of pre-clinical knowledge into standards of patient care for SCI, we describe the development of a novel database for translational neurotrauma research known as Visualized Syndromic Information and Outcomes for Neurotrauma-SCI (VISION-SCI). We present demographics, descriptive statistics, and translational syndromic outcomes derived from our ongoing efforts to build a multi-center, multi-species pre-clinical database for SCI models. We leveraged archived surgical records, postoperative care logs, behavioral outcome measures, and histopathology from approximately 3000 mice, rats, and monkeys from pre-clinical SCI studies published between 1993 and 2013. The majority of animals in the database have measures collected for health monitoring, such as weight loss/gain, heart rate, blood pressure, postoperative monitoring of bladder function and drug/fluid administration, behavioral outcome measures of locomotion, and tissue sparing postmortem. Attempts to align these variables with currently accepted common data elements highlighted the need for more translational outcomes to be identified as clinical endpoints for therapeutic testing. Last, we use syndromic analysis to identify conserved biological mechanisms of recovery after cervical SCI between rats and monkeys that will allow for more-efficient testing of therapeutics that will need to be translated toward future clinical trials.
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http://dx.doi.org/10.1089/neu.2014.3399DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4186058PMC
November 2014

The Irvine, Beatties, and Bresnahan (IBB) Forelimb Recovery Scale: An Assessment of Reliability and Validity.

Front Neurol 2014 7;5:116. Epub 2014 Jul 7.

Brain and Spinal Cord Injury Center, Department of Neurological Surgery, University of California San Francisco , San Francisco, CA , USA.

The IBB scale is a recently developed forelimb scale for the assessment of fine control of the forelimb and digits after cervical spinal cord injury [SCI; (1)]. The present paper describes the assessment of inter-rater reliability and face, concurrent and construct validity of this scale following SCI. It demonstrates that the IBB is a reliable and valid scale that is sensitive to severity of SCI and to recovery over time. In addition, the IBB correlates with other outcome measures and is highly predictive of biological measures of tissue pathology. Multivariate analysis using principal component analysis (PCA) demonstrates that the IBB is highly predictive of the syndromic outcome after SCI (2), and is among the best predictors of bio-behavioral function, based on strong construct validity. Altogether, the data suggest that the IBB, especially in concert with other measures, is a reliable and valid tool for assessing neurological deficits in fine motor control of the distal forelimb, and represents a powerful addition to multivariate outcome batteries aimed at documenting recovery of function after cervical SCI in rats.
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http://dx.doi.org/10.3389/fneur.2014.00116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4083223PMC
July 2014

Derivation of multivariate syndromic outcome metrics for consistent testing across multiple models of cervical spinal cord injury in rats.

PLoS One 2013 27;8(3):e59712. Epub 2013 Mar 27.

Brain and Spinal Injury Center (BASIC), Department of Neurological Surgery, University of California San Francisco, San Francisco, California, United States of America.

Spinal cord injury (SCI) and other neurological disorders involve complex biological and functional changes. Well-characterized preclinical models provide a powerful tool for understanding mechanisms of disease; however managing information produced by experimental models represents a significant challenge for translating findings across research projects and presents a substantial hurdle for translation of novel therapies to humans. In the present work we demonstrate a novel 'syndromic' information-processing approach for capitalizing on heterogeneous data from diverse preclinical models of SCI to discover translational outcomes for therapeutic testing. We first built a large, detailed repository of preclinical outcome data from 10 years of basic research on cervical SCI in rats, and then applied multivariate pattern detection techniques to extract features that are conserved across different injury models. We then applied this translational knowledge to derive a data-driven multivariate metric that provides a common 'ruler' for comparisons of outcomes across different types of injury (NYU/MASCIS weight drop injuries, Infinite Horizons (IH) injuries, and hemisection injuries). The findings revealed that each individual endpoint provides a different view of the SCI syndrome, and that considering any single outcome measure in isolation provides a misleading, incomplete view of the SCI syndrome. This limitation was overcome by taking a novel multivariate integrative approach for leveraging complex data from preclinical models of neurological disease to identify therapies that target multiple outcomes. We suggest that applying this syndromic approach provides a roadmap for translating therapies for SCI and other complex neurological diseases.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0059712PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3609747PMC
September 2013

A novel method for assessing proximal and distal forelimb function in the rat: the Irvine, Beatties and Bresnahan (IBB) forelimb scale.

J Vis Exp 2010 Dec 16(46). Epub 2010 Dec 16.

Department of Neurological Surgery, University of California, San Francisco, USA.

Several experimental models of cervical spinal cord injury (SCI) have been developed recently to assess the consequences of damage to this level of the spinal cord (Pearse et al., 2005, Gensel et al., 2006, Anderson et al., 2009), as the majority of human SCI occur here (Young, 2010; www.sci-info-pages.com). Behavioral deficits include loss of forelimb function due to damage to the white matter affecting both descending motor and ascending sensory systems, and to the gray matter containing the segmental circuitry for processing sensory input and motor output for the forelimb. Additionally, a key priority for human patients with cervical SCI is restoration of hand/arm function (Anderson, 2004). Thus, outcome measures that assess both proximal and distal forelimb function are needed. Although there are several behavioral assays that are sensitive to different aspects of forelimb recovery in experimental models of cervical SCI (Girgis et al., 2007, Gensel et al., 2006, Ballerman et al., 2001, Metz and Whishaw, 2000, Bertelli and Mira, 1993, Montoya et al., 1991, Whishaw and Pellis, 1990), few techniques provide detailed information on the recovery of fine motor control and digit movement. The current measurement technique, the Irvine, Beatties and Bresnahan forelimb scale (IBB), can detect recovery of both proximal and distal forelimb function including digit movements during a naturally occurring behavior that does not require extensive training or deprivation to enhance motivation. The IBB was generated by observing recovery after a unilateral C6 SCI, and involves video recording of animals eating two differently shaped cereals (spherical and doughnut) of a consistent size. These videos were then used to assess features of forelimb use, such as joint position, object support, digit movement and grasping technique. The IBB, like other forelimb behavioral tasks, shows a consistent pattern of recovery that is sensitive to injury severity. Furthermore, the IBB scale could be used to assess recovery following other types of injury that impact normal forelimb function.
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http://dx.doi.org/10.3791/2246DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3159659PMC
December 2010

Forelimb locomotor assessment scale (FLAS): novel assessment of forelimb dysfunction after cervical spinal cord injury.

Exp Neurol 2009 Nov 3;220(1):23-33. Epub 2009 Sep 3.

Reeve-Irvine Research Center, University of California at Irvine School of Medicine, Irvine, 1113 Hewitt Hall, Irvine, CA 92697-1385, USA.

We describe here a novel forelimb locomotor assessment scale (FLAS) that assesses forelimb use during locomotion in rats injured at the cervical level. A quantitative scale was developed that measures movements of shoulder, elbow, and wrist joints, forepaw position and digit placement, forelimb-hindlimb coordination, compensatory behaviors adopted while walking, and balance. Female Sprague-Dawley rats received graded cervical contusions ranging from 200 to 230 ("mild," n=11) and 250-290 kdyn ("moderate," n=13) between C5 and C8. Rats were videotaped post-injury as they walked along an alley to determine deficits and recovery of forelimb function. Recovery of shoulder and elbow joint movement occurred rapidly (within 1-7 days post-injury), whereas recovery of wrist joint movement was slower and more variable. Most rats in all groups displayed persistent deficits in forepaw and digit movement, but developed compensatory behaviors to allow functional forward locomotion within 1-2 weeks post-injury. Recovery of forelimb function as measured by the FLAS reached a plateau by 3 weeks post-injury in all groups. Rats with mild contusions displayed greater locomotor recovery than rats with moderate contusions, but exhibited persistent deficits compared to sham controls. Reliability was tested by having seven raters (three internal, four external) from different laboratories, independently and blindly score videos of all rats. The multivariate correlation between all raters, all animals, and all time points ranged from r(2)=0.88-0.96 (p<0.0001), indicating a high inter-rater reliability. Thus, the FLAS is a simple, inexpensive, sensitive, and reliable measure of forelimb function during locomotion following cervical SCI.
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http://dx.doi.org/10.1016/j.expneurol.2009.08.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2771771PMC
November 2009

Dysregulation of the Wnt pathway inhibits timely myelination and remyelination in the mammalian CNS.

Genes Dev 2009 Jul 10;23(13):1571-85. Epub 2009 Jun 10.

Institute for Regeneration Medicine, Howard Hughes Medical Institute, University of California at San Francisco, San Francisco, California 94143, USA.

The progressive loss of CNS myelin in patients with multiple sclerosis (MS) has been proposed to result from the combined effects of damage to oligodendrocytes and failure of remyelination. A common feature of demyelinated lesions is the presence of oligodendrocyte precursors (OLPs) blocked at a premyelinating stage. However, the mechanistic basis for inhibition of myelin repair is incompletely understood. To identify novel regulators of OLP differentiation, potentially dysregulated during repair, we performed a genome-wide screen of 1040 transcription factor-encoding genes expressed in remyelinating rodent lesions. We report that approximately 50 transcription factor-encoding genes show dynamic expression during repair and that expression of the Wnt pathway mediator Tcf4 (aka Tcf7l2) within OLPs is specific to lesioned-but not normal-adult white matter. We report that beta-catenin signaling is active during oligodendrocyte development and remyelination in vivo. Moreover, we observed similar regulation of Tcf4 in the developing human CNS and lesions of MS. Data mining revealed elevated levels of Wnt pathway mRNA transcripts and proteins within MS lesions, indicating activation of the pathway in this pathological context. We show that dysregulation of Wnt-beta-catenin signaling in OLPs results in profound delay of both developmental myelination and remyelination, based on (1) conditional activation of beta-catenin in the oligodendrocyte lineage in vivo and (2) findings from APC(Min) mice, which lack one functional copy of the endogenous Wnt pathway inhibitor APC. Together, our findings indicate that dysregulated Wnt-beta-catenin signaling inhibits myelination/remyelination in the mammalian CNS. Evidence of Wnt pathway activity in human MS lesions suggests that its dysregulation might contribute to inefficient myelin repair in human neurological disorders.
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http://dx.doi.org/10.1101/gad.1806309DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2704469PMC
July 2009

Transplanted oligodendrocyte precursor cells reduce neurodegeneration in a model of glaucoma.

Invest Ophthalmol Vis Sci 2009 Sep 8;50(9):4244-53. Epub 2009 Apr 8.

Centre for Brain Repair and National Institute for Health Research)Biomedical Research Centre, University of Cambridge, Cambridge, United Kingdom.

Purpose: Glaucoma is a common neurodegenerative disease for which current therapies are often insufficient; thus, new neuroprotective strategies are an important goal. Stem cells are attracting increasing attention as mediators of neuroprotection, often conferred via the trophic support of injured neurons. The purpose of our investigation was to determine whether oligodendrocyte precursor cells (OPCs), a type of neural stem cell, can protect retinal ganglion cells (RGCs) from glaucomatous damage in vivo.

Methods: Intraocular pressure was chronically increased by trabecular laser treatment delivered unilaterally to adult rat eyes. OPCs were isolated in vitro and then transplanted intravitreally either before, or concurrent with, injury induction. Survival, migration, differentiation, and integration of grafted cells were assessed by immunohistochemistry. RGC survival was assessed by optic nerve axon quantification.

Results: Transplanted OPCs were found to survive within the eye for at least 12 weeks and to localize close to the RGCs. Moreover, OPCs significantly enhanced the survival of RGCs in the glaucomatous eye, but only when concomitantly activated by inflammation. Axonal loss relative to the untreated fellow eye was 28.34% +/- 11.51% in eyes that received activated OPCs, compared with 60.34% +/- 8.28% in control eyes (mean +/- SEM; P = 0.05). Amelioration of RGC death was not attributable to inflammation but relied on an interaction between inflammatory cells and OPCs. Engrafted cells also displayed multipotentiality in vivo.

Conclusions: The impressive neuroprotection conferred by OPCs in this model suggests stem cell-based therapies should be explored further as a potential treatment for glaucoma.
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http://dx.doi.org/10.1167/iovs.08-3239DOI Listing
September 2009

An experimental model of secondary progressive multiple sclerosis that shows regional variation in gliosis, remyelination, axonal and neuronal loss.

J Neuroimmunol 2008 Sep 30;201-202:200-11. Epub 2008 Jul 30.

Cambridge Centre for Brain Repair, University of Cambridge, ED Adrian Building, Forvie Site, Robinson Way, Cambridge, CB2 2PY. UK.

Multiple sclerosis (MS) represents a considerable challenge to experimentally model due to its twin pathologies of inflammatory demyelination and neurodegeneration along with its multifocal and multiphasic nature. Experimental autoimmune encephalomyelitis (EAE) in Biozzi ABH mice has previously been shown to reproduce many clinical features also found in secondary progressive MS. In this study we sought to characterise the pathology of chronic EAE in ABH mice. In addition to marked gliosis, we report substantial demyelination, remyelination and axonal and neuronal loss. Together with the clinical pattern, our findings identify chronic EAE as an excellent model of secondary progressive multiple sclerosis.
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http://dx.doi.org/10.1016/j.jneuroim.2008.05.034DOI Listing
September 2008

Environmental signals regulate lineage choice and temporal maturation of neural stem cells from human embryonic stem cells.

Brain 2007 May;130(Pt 5):1263-75

Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK.

Human embryonic stem cells (hESCs) are a potential source of defined tissue for cell-based therapies in regenerative neurology. In order for this potential to be realized, there is a need for the evaluation of the behaviour of human embryonic stem cell-derived neural stem cells (hES-NSCs) both in the normal and the injured CNS. Using normal tissue and two experimental models, we examined the response of clinically compatible hES-NSCs to physiological and pathological signals. We demonstrate that the phenotypic potential of a multipotent population of hES-NSCs is influenced by these cues both in vitro and in vivo. hES-NSCs display a temporal profile of neurogenic and gliogenic differentiation, with the generation of mature neurons and glia over 4 weeks in vitro, and 20 weeks in the uninjured rodent brain. However, transplantation into the pathological CNS accelerates maturation and polarizes hES-NSC differentiation potential. This study highlights the role of environmental signals in determining both lineage commitment and temporal maturation of human neural stem cells. Controlled manipulation of environmental signals appropriate to the pathological specificity of the targeted disease will be necessary in the design of therapeutic stem cell-based strategies.
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http://dx.doi.org/10.1093/brain/awm070DOI Listing
May 2007

A different regional response by mouse oligodendrocyte progenitor cells (OPCs) to high-dose X-irradiation has consequences for repopulating OPC-depleted normal tissue.

Eur J Neurosci 2007 Jan;25(2):417-24

MS Society Cambridge Centre for Myelin Repair and the Department of Veterinary Medicine, Madingley Road, Cambridge CB3 0ES, UK.

This study was designed to investigate whether the residual, dysfunctional oligodendrocyte progenitor cells (OPCs) observed following X-irradiation of the mouse spinal cord [D. M. Chari et al. (2003) Exp. Neurol., 198, 145-153], the presence of which prevented the endogenous repopulation of these areas from normal tissue, reflects a general response of OPCs in the mouse central nervous system (CNS) to X-irradiation. The brains of adult mice were exposed to 40 Gy of X-irradiation and the effect of X-irradiation on the OPCs was assessed up to 4 weeks post-irradiation using anti-NG2 antibodies. X-irradiation resulted in almost complete depletion of OPCs within the telencephalon (cortex, corpus callosum and hippocampus) by 7 days post-irradiation, which was followed by progressive repopulation of OPCs from non-irradiated areas of the cortex. By contrast, within the lower brain centres (the diencephalon and mesencephalon) OPC loss occurred much more slowly so that 26% of the OPCs still remained 4 weeks after X-irradiation. The consequence of this heterogeneous response to X-irradiation was that whereas transplanted and endogenous OPCs rapidly established themselves in the OPC-depleted telencephalon this did not occur in the areas where there was incomplete depletion of endogenous OPCs. Our findings confirm not only the requirement for almost complete OPC depletion in order to establish transplanted OPCs in normal tissue but also highlight a heterogeneity of progenitor populations in different areas of the mouse CNS.
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http://dx.doi.org/10.1111/j.1460-9568.2007.05313.xDOI Listing
January 2007