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There is substantial interest in the potential for traumatic brain injury to result in progressive neurological deterioration. While blood biomarkers such as glial fibrillary acid protein and neurofilament light have been widely explored in characterising acute traumatic brain injury, their use in the chronic phase is limited. Given increasing evidence that these proteins may be markers of ongoing neurodegeneration in a range of diseases, we examined their relationship to imaging changes and functional outcome in the months to years following traumatic brain injury. Two-hundred and three patients were recruited in two separate cohorts; six months post-injury (n=165); and >5 years post-injury (n=38; 12 of whom also provided data ∼8 months post-TBI). Subjects underwent blood biomarker sampling (n=199) and magnetic resonance imaging (n=172; including diffusion tensor imaging). Data from patient cohorts were compared to 59 healthy volunteers and 21 non-brain injury trauma controls. Mean diffusivity and fractional anisotropy were calculated in cortical grey matter, deep grey matter and whole brain white matter. Accelerated brain ageing was calculated at a whole brain level as the predicted age difference defined using T1-weighted images, and at a voxel-based level as the annualised Jacobian determinants in white matter and grey matter, referenced to a population of 652 healthy control subjects. Serum neurofilament light concentrations were elevated in the early chronic phase. While GFAP values were within the normal range at ∼8 months, many patients showed a secondary and temporally distinct elevations up to >5 years after injury. Biomarker elevation at six months was significantly related to metrics of microstructural injury on diffusion tensor imaging. Biomarker levels at ∼8 months predicted white matter volume loss at >5 years, and annualised brain volume loss between ∼8 months and 5 years. Patients who worsened functionally between ∼8 months and >5 years showed higher than predicted brain age and elevated neurofilament light levels. Glial fibrillary acid protein and neurofilament light levels can remain elevated months to years after traumatic brain injury, and show distinct temporal profiles. These elevations correlate closely with microstructural injury in both grey and white matter on contemporaneous quantitative diffusion tensor imaging. Neurofilament light elevations at ∼8 months may predict ongoing white matter and brain volume loss over >5 years of follow up. If confirmed, these findings suggest that blood biomarker levels at late time points could be used to identify traumatic brain injury survivors who are at high risk of progressive neurological damage.
Learn More >Activation of astrocytes has a profound effect on brain plasticity and is critical for the pathophysiology of several neurological disorders including neuropathic pain. Here, we show that metabotropic glutamate receptor 5 (mGluR5), which reemerges in astrocytes in a restricted time frame, is essential for these functions. Although mGluR5 is absent in healthy adult astrocytes, it transiently reemerges in astrocytes of the somatosensory cortex (S1). During a limited spatiotemporal time frame, astrocytic mGluR5 drives Ca2+ signals; upregulates multiple synaptogenic molecules such as Thrombospondin-1, Glypican-4, and Hevin; causes excess excitatory synaptogenesis; and produces persistent alteration of S1 neuronal activity, leading to mechanical allodynia. All of these events were abolished by the astrocyte-specific deletion of mGluR5. Astrocytes dynamically control synaptic plasticity by turning on and off a single molecule, mGluR5, which defines subsequent persistent brain functions, especially under pathological conditions.
Learn More >ITCH is an E3 ubiquitin ligase associated with some inflammatory diseases, but its role in osteoarthritis (OA) remains to be explored. Here, we investigated the effects of ITCH in OA-induced chondrocyte damage and its potential mechanisms. Here, we found that ITCH was downregulated, while JAG1 was upregulated in OA tissues compared to normal cartilaginous tissues. And primary human chondrocytes were induced by LPS to simulate OA condition. Overexpressing ITCH or silencing JAG1 promoted proliferation, and restrained apoptosis, inflammation and extracellular matrix (ECM) degradation in LPS-stimulated chondrocytes. Mechanistically, ITCH bound to JAG1 protein through the WW-PPXY motif and degraded it via K48 ubiquitination. JAG1 overexpression reversed the protective effect of ITCH on LPS-induced chondrocyte damage. ITCH prevented LPS-caused Notch1 signaling activation by suppressing JAG1. Furthermore, GSI (a Notch specific inhibitor) abrogated the effects of ITCH knockdown on chondrocyte injury. Additionally, a mouse OA model was established by destabilization of the medial meniscus operation, and H&E and Safranin O-fast green staining was used to evaluate articular cartilage damage. And ITCH overexpression alleviated OA-induced articular cartilage damage in vivo. In conclusion, ITCH mitigated LPS-induced chondrocyte injury and OA-induced articular cartilage damage through attenuating Notch1 pathway activation by degrading JAG1 via ubiquitination, which provides a novel strategy for the treatment of OA.
Learn More >Pain transmission at the spinal cord is modulated by noradrenaline (NA)-mediated actions that arise from supraspinal areas. We studied the locus coeruleus (LC) to evaluate the expression of the cathecolamine-synthetizing enzyme tyrosine hydroxylase (TH) and search for local oxidative stress and possible consequences in descending pain modulation in a model of hydrocephalus, a disease characterized by enlargement of the cerebral ventricular system usually due to the obstruction of cerebrospinal fluid flow. Four weeks after kaolin injection into the cisterna magna, immunodetection of the catecholamine-synthetizing enzymes TH and dopamine-β-hydroxylase (DBH) was performed in the LC and spinal cord. Colocalization of the oxidative stress marker 8-OHdG (8-hydroxyguanosine; 8-OHdG), with TH in the LC was performed. Formalin was injected in the hindpaw both for behavioral nociceptive evaluation and the immunodetection of Fos expression in the spinal cord. Hydrocephalic rats presented with a higher expression of TH at the LC, of TH and DBH at the spinal dorsal horn along with decreased nociceptive behavioral responses in the second (inflammatory) phase of the formalin test, and formalin-evoked Fos expression at the spinal dorsal horn. The expression of 8-OHdG was increased in the LC neurons, with higher co-localization in TH-immunoreactive neurons. Collectively, the results indicate increased noradrenergic expression at the LC during hydrocephalus. The strong oxidative stress damage at the LC neurons may lead to local neuroprotective-mediated increases in NA levels. The increased expression of catecholamine-synthetizing enzymes along with the decreased nociception-induced neuronal activation of dorsal horn neurons and behavioral pain signs may indicate that hydrocephalus is associated with alterations in descending pain modulation.
Learn More >Classic trigeminal neuralgia (CTN) is a neuropathic pain disorder displaying spontaneously stabbing or electric shock-like paroxysms in the face. Previous research suggests structural and functional abnormalities in brain regions related to sensory and cognitive-affective dimensions of pain contribute to the pathophysiology of CTN. However, few studies to date have investigated how changes in whole-brain functional networks and white matter connectivity are related to CTN. We performed an independent component analysis to examine abnormalities in resting state functional connectivity of large-scale networks in 48 patients with CTN compared to 46 matched healthy participants. Then, diffusion tensor tractography was performed to test whether these alterations of functional connectivity in intrinsic networks were associated with impairment of the white matter tracts connecting them. Distinct patterns of functional connectivity were detected within default mode network (DMN), somatosensory network (SMN), and salience network (SN) in the CTN group when compared with healthy controls. Furthermore, abnormality of SN was negatively correlated with pain severity. In support of aberrant functional connectivity within SN, structural disintegration was observed in the white matter tract from left anterior insula (aIns) to left anterior cingulate cortex (ACC) in CTN. These results suggest that altered structural and functional connectivity between aIns and ACC may underpin the aberrant SN in patients with CTN and provide an alternative target for clinical interventions. PERSPECTIVE: This article presents distinctive abnormalities of functional and structural connectivity from aIns to ACC in the patients with CTN, which is associated with pain ratings. This measure could potentially provide an alternative target for clinicians to alleviate this type of intermittent and refractory pain.
Learn More >Emerging research indicates that physical activity can ameliorate chronic pain, but the underlying mechanisms are still largely obscure. In particular, little is known on the mechanisms behind exercise-induced analgesia in the setting of inflammatory pain. In our previous studies on systemic inflammation in mice using lipopolysaccharide (LPS) administration, we characterized satellite glial cells (SGCs) and neurons in dorsal root ganglia (DRG). We found that a week post-LPS injection, the sensitivity to mechanical stimulation was lowered, SGCs were activated and coupling among SGCs increased 3 to 4.5-fold. In the present work, we examined the effects of exercise (free wheel running) on tactile sensitivity and on pathological changes in mouse DRG in the LPS model. We found that exercise prevented tactile hypersensitivity, and also reversed thecellular changes in the DRG induced by LPS that were listed above. We propose that the analgesic effect of exercise is at least partly mediated by reversing the pathological changes in SGCs.
Learn More >Poor access to care is a top patient-oriented research priority for youth with chronic pain in Canada, and the COVID-19 pandemic has exacerbated these concerns. Our patient-oriented project team engaged with marginalized and racialized youth with chronic pain (Black youth with sickle cell disease, Indigenous youth and youth with complex medical needs) and their families to ensure that best practice recommendations for virtual care are inclusive and equitable. Input provided through virtual round-table discussions improved recommendations for leveraging, implementing and selecting best platforms for virtual care for youth with chronic pain and identified new gaps for future research, practice and policy change.
Learn More >Chronic neuropathic pain (CNP) can result from surgery or traumatic injury, but also from peripheral neuropathies caused by diseases, viral infections, or toxic treatments. Opioids, although very effective for acute pain, do not prevent the development of CNP, and are considered as insufficient treatment. Therefore, there is high need for effective and safe non-opioid options to treat, prevent and eventually reverse CNP. A more effective approach to alleviating CNP would constitute a treatment that acts concurrently on various mechanisms involved in relieving pain symptoms and preventing or reversing chronification by enhancing both neuroprotection and neuroregeneration. We have identified and characterized GRT-X (N-[(3-fluorophenyl)-methyl]-1-(2-methoxyethyl)-4-methyl-2-oxo-(7-trifluoromethyl)-1H-quinoline-3-caboxylic acid amide), a novel drug which is able to activate both voltage-gated potassium channels of the Kv7 family and the mitochondrial translocator protein 18 kDa (TSPO). The dual mode-of-action (MoA) of GRT-X was indicated in in vitro studies and in vivo in a rat model of diabetic neuropathy. In this model, mechanical hyperalgesia was dose-dependently inhibited. After severe crush lesion of cervical spinal nerves in rats, GRT-X promoted survival, speeded up regrowth of sensory and motor neurons, and accelerated recovery of behavioral and neuronal responses to heat, cold, mechanical and electrical stimuli. These properties may reduce the likelihood of chronification of acute pain, and even potentially relieve established CNP. The absence of a conditioned place preference in rats suggests lack of abuse potential. In conclusion, GRT-X offers a promising preclinical profile with a novel dual MoA.
Learn More >Fibromyalgia (FM) is a common and disabling disorder characterized by chronic widespread pain, fatigue, and dyscognition. Previous studies have shown strong positive correlations between pain, fatigue, and dyscognition. However, bidirectional relationships, particularly with dyscognition modeled as a predictor, have rarely been established. The purpose of this study was to examine the bidirectional, predictive nature of the relationships between these FM symptoms. Pain, fatigue, and dyscognition were measured via the Brief Pain Inventory, Multidimensional Fatigue Inventory, and Multiple Ability Self-Report Questionnaire at baseline and a 2-year follow-up in a large sample of 450 well-characterized female patients with FM. Relationships between FM symptoms were evaluated using a cross-lagged, longitudinal model. Dyscognition, pain, and fatigue were positively correlated at both baseline and follow-up (s .13 -.53, s<.01). Dyscognition at baseline was predictive of dyscognition (=.76, β=.75, <.001), pain, (=.01, β=.09, =.033) and fatigue (=.05, β=.08, =.050) at follow-up. Pain at baseline was predictive of pain (=.59, β=.59, <.001), dyscognition (=.88, β=.07, =.022), and fatigue (=.85, β=.11, =.004) at follow-up. Fatigue at baseline was only associated with fatigue (=.61, β=.60, <.001) at follow-up. Dyscognition is predictive of future pain and fatigue in patients with FM. Continued work should examine dyscognition as a clinical predictor of future severity of core symptoms such as pain and fatigue.
Learn More >Our original patient-oriented research project identified the top 10 priorities for pediatric chronic pain research and care in Canada from the perspective of people with lived experience (patients), their family members and healthcare professionals through a modified James Lind Alliance Priority Setting Partnership. We undertook subsequent knowledge translation activities with youth, families, healthcare professionals, decision makers and researchers to (1) generate awareness and interest in the top 10 priorities and our partnership process, (2) facilitate collaborative dialogue and open innovation and (3) integrate and adopt the top 10 priorities into stakeholder activities. This paper describes our knowledge translation activities, outcomes and impact.
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