Karen-Amanda Irvine

VA Palo Alto Health Care System · Anesthesia

Traumatic brain injury (TBI) patients frequently experience chronic pain that can enhance their suffering and significantly impair rehabilitative efforts. Clinical studies suggest that damage to the periaqueductal gray matter (PAG) following TBI, a principal center involved in endogenous pain control, may underlie the development of chronic pain. W...

Inhibition of actin remodeling in nerves modulates action potential propagation and therefore could be used to treat acute pain. N-001 is a novel protein analgesic engineered from several C. Botulinum toxins. N-001 targets sensory neurons through ganglioside GT1b binding and ADP-ribosylates G-actin reducing actin remodeling. The activity and effica...

Traumatic brain injury (TBI) can cause acute and chronic pain along with motor, cognitive and emotional problems. Although the mechanisms are poorly understood, previous studies suggest disruptions in endogenous pain modulation may be involved. Voluntary exercise after a TBI has been shown to reduce some consequences of injury including cognitive i...

Background: Individuals recovering from mild traumatic brain injury (mTBI) have increased rates of acute and chronic pain. However, the mechanism through which mTBI triggers heightened pain responses and the link between mTBI and postsurgical pain remain elusive. Recent data suggest that dysregulated serotonergic pain-modulating circuits could be...

Traumatic brain injury (TBI) is a significant public health concern, with the majority of injuries being mild. Many TBI victims experience chronic pain. Unfortunately, the mechanisms underlying pain after TBI are poorly understood. Here we examined the contribution of spinal monoamine signaling to dysfunctional descending pain modulation after TBI....

Disruption of endogenous pain control mechanisms including descending pain inhibition has been linked to several forms of pain including chronic pain after traumatic brain injury (TBI). The locus coeruleus (LC) is the principal noradrenergic (NA) nucleus participating in descending pain inhibition. We therefore hypothesized that selectively stimula...

Blast exposure can injure brain by multiple mechanisms, and injury attributable to direct effects of the blast wave itself have been difficult to distinguish from that caused by rapid head displacement and other secondary processes. To resolve this issue, we used a rat model of blast exposure in which head movement was either strictly prevented or...

Blast exposure can injure brain by multiple mechanisms, and injury attributable to direct effects of the blast wave itself have been difficult to distinguish from that caused by rapid head displacement and other secondary processes. To resolve this issue, we used a rat model of blast exposure in which head movement was either strictly prevented or...

Traumatic spinal cord injury (SCI) produces a complex syndrome that is expressed across multiple endpoints ranging from molecular and cellular changes to functional behavioral deficits. Effective therapeutic strategies for CNS injury are therefore likely to manifest multi-factorial effects across a broad range of biological and functional outcome m...

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 dysfuncti...

Traumatic spinal cord injury (SCI) produces a complex syndrome that is expressed across multiple endpoints ranging from molecular and cellular changes to functional behavioral deficits. Effective therapeutic strategies for CNS injury are therefore likely to manifest multi-factorial effects across a broad range of biological and functional outcome m...

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...

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 desc...

What we already know about this topic: WHAT THIS ARTICLE TELLS US THAT IS NEW: 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...

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...

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 result...

Chronic pain is a common consequence of traumatic brain injury (TBI) that can increase a patient's suffering 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 lab has shown that TBI causes pain sensit...

The inflammation response induced by brain trauma can impair recovery. This response requires several hours to fully develop, and thus provides a clinically relevant therapeutic window of opportunity. Poly(ADP-ribose) polymerase inhibitors suppress inflammatory responses, including brain microglial activation. Here we evaluated delayed treatment wi...

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 pathophysiol...

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...

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 thro...

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 inj...

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),...

Abstract 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 neurologica...

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...

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 p...

Decision rules for PC retention and interpretation in complete dataset including cervical hemisection and hemicontusions. A, PCA performed on the full dataset (N = 159, 24 outcome variables) revealed 5 PCs that met the liberal ‘Kaiser rule’ criterion of eigenvalue >1. B, Conservative, scree plot criterion suggests retaining 3 PCs for interpretation...

Effects of injury severity on PC1-3 after correcting for tissue displacement. Analysis of covariance (ANCOVA) indicated that tissue displacement was a significant covariate, for PC1 p<.05. However, correcting for tissue displacement did not alter the statistical significance of injury effects (compare to Fig. 4E–G). This suggests that differences a...

Decision rules for PC retention and interpretation after NYU/MASCIS injury. A, PCA performed on sham controls and graded cervical hemicontusion injury performed with the NYU/MASCIS weight drop (N = 52, 24 outcome variables) revealed 5 PCs that met the liberal ‘Kaiser rule’ criterion of eigenvalue >1. B, Conservative scree plot criterion suggests re...

Decision rules for PC retention and interpretation after IH injury. A, PCA performed on cervical hemicontusion injuries with the IH device and sham controls (N = 100, 24 outcome variables) revealed 5 PCs that met the liberal ‘Kaiser rule’ criterion of eigenvalue >1. B, Conservative, scree plot criterion suggests retaining 3 PCs for interpretation....

Cross-validation exercises using equalized n across groups and application of sparse PCA. A, Results from an iterative subsampling procedure used to homogenize group sizes (n = 9/injury condition) prior to PCA through 10 randomized subsampling iterations. PC pattern matching statistics comparing subsampled PC loading patterns to the loading pattern...

Multiple views of the multivariate syndromic space characterized by PC1-3. Each subject is represented as a unique point within the syndrome space. Note that each PC axis is orthogonal to the other axes, indicating that differences in the syndrome features characterized by PC1 are independent from differences along the PC2 and PC3. (AVI)

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 fore...

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...

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...

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 w...

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 fo...

The adult bone marrow contains a population of multipotent mesenchymal stromal cells (MSCs), defined by plastic adherence, expression of stromal cell surface markers, and differentiation into mesenchymal lineages. There has been much interest in the possible therapeutic use of MSCs in the treatment of demyelinating diseases of the central nervous s...

In multiple sclerosis, demyelination of the CNS axons is associated with axonal injury and degeneration, which is now accepted as the major cause of neurological disability in the disease. Although the kinetics and the extent of axonal damage have been described in detail, the mechanisms by which it occurs are as yet unclear; one suggestion is fail...

The relative merits of endogenous and exogenous oligodendrocyte progenitor cells (OPCs) for remyelination are compared in terms of their ability to repopulate OPC-depleted tissue and generate remyelinating oligodendrocytes. Exogenous neonatal OPCs can repopulate OPC-depleted tissue 5-10 times faster than endogenous cells and as a result are capable...

The development of reliable, valid, and quantifiable measurement of neurological function is important for the testing and translation of strategies aimed at improving function after CNS injury or disease. Tests of neurological function in spinal cord and brain injury range from descriptive locomotor measures to high speed kinematics. In this secti...

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...

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 respons...

Axon loss is recognised as a significant contributor to the progression of the disability associated with multiple sclerosis. Although evidence of axon damage is found in areas of chronic demyelination it is more frequently seen in association with acute demyelination. This study compares the incidence of axon degeneration associated with the areas...