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To investigate the associations between signs of painful temporomandibular disorders (TMD) and number of tender points (TPs) and fibromyalgia in adolescents, as well as the relationship between TPs and pressure-pain threshold (PPT) in individuals presenting with local, regional, or widespread pain as a way to investigate the presence of central sensitization (CS).
Learn More >If touch is perceived as pleasant, it can counteract the experience of pain. However, its pain-inhibitory function might be disturbed in chronic pain and this could contribute to pain-related interference. We investigated the perception of pleasant touch and its brain correlates in chronic back pain patients (CBP) compared to subacute back pain patients (SABP) and healthy controls (HC) using soft brush strokes. CBP showed less positive evaluations of touch. We found the highest activation in somatosensory and insular cortices in CBP, ventral striatum (VS) in SABP, and the orbitofrontal cortex in HC. Brain responses were significantly positively correlated with pleasantness ratings in HC and SABP, but not CBP. Further, the insula responses in CBP were positively correlated with pain-related interference and the VS activation in SABP correlated negatively with affective distress. Brain and behavioral changes in the processing of touch and its pleasantness may be a marker of pain chronicity and raise questions about the therapeutic value of pleasant touch in pain prevention and treatment.
Learn More >Over 100 million people are challenged by the effects of chronic pain in the United States alone. This burden also impacts the U.S. economy; 600 billion dollars annually is spent on medical care, medications, and lost productivity in the workplace.1 Current opioid treatments cause adverse effects including nausea, constipation, tolerance, and addiction liability.2 Nociceptive sensitization is thought to perpetuate chronic pain, but too little is known about its mechanisms. Components of the pathways that sensitize the nociceptors after injury are likely to be valuable targets for novel medications for the relief or prevention of chronic pain. Utilizing the Drosophila melanogaster cell targeting and RNA interference toolkit, we are investigating the Bone Morphogenetic Protein (BMP) pathway and its role in ultraviolet light (UV) injury-induced nociceptive sensitization. BMPs are well known as secreted developmental morphogens that control development, but other functions are known.3 We have previously identified BMP signaling components used in nociceptors to modulate injury-induced allodynia, including Decapentaplegic (Dpp, orthologous to mammalian BMP 2/4), and its downstream signaling components.4 The morphogen Hedgehog has also been shown to be necessary for allodynia following injury.5 Here, we show that two membrane-embedded regulators of the Dpp and Hedgehog pathways, Dally and Dally-like, are necessary for injury-induced thermal allodynia, as the formation of sensitization was reduced when either component was suppressed. These BMP components are highly conserved and, because dysregulation of nociceptor sensitization underlies chronic pain, the homologs of Dally and Dally-like may represent novel therapeutic targets in humans challenged by chronic pain. Furthermore, because of their extracellular location, Dally and Dally-like represent attractive therapeutic drug targets because such drugs would not need to cross the plasma membrane.
Learn More >The box jellyfish Chironex fleckeri is extremely venomous, and envenoming causes tissue necrosis, extreme pain and death within minutes after severe exposure. Despite rapid and potent venom action, basic mechanistic insight is lacking. Here we perform molecular dissection of a jellyfish venom-induced cell death pathway by screening for host components required for venom exposure-induced cell death using genome-scale lenti-CRISPR mutagenesis. We identify the peripheral membrane protein ATP2B1, a calcium transporting ATPase, as one host factor required for venom cytotoxicity. Targeting ATP2B1 prevents venom action and confers long lasting protection. Informatics analysis of host genes required for venom cytotoxicity reveal pathways not previously implicated in cell death. We also discover a venom antidote that functions up to 15 minutes after exposure and suppresses tissue necrosis and pain in mice. These results highlight the power of whole genome CRISPR screening to investigate venom mechanisms of action and to rapidly identify new medicines.
Learn More >Structural and functional analyses of the human claustrum, a poorly understood telencephalic gray matter structure, are hampered by its sheet-like anatomical arrangement. Here, we first describe a functional magnetic resonance imaging (fMRI) method to reveal claustrum signal with no linear relationship with adjacent regions in human subjects. We applied this approach to resting state functional connectivity (RSFC) analysis of the claustrum at high resolution (1.5 mm isotropic voxels) using a 7T dataset (n = 20) and a separate 3T dataset for replication (n = 35). We then assessed claustrum activation during performance of a cognitive task, the multi-source interference task, at 3T (n = 33). Extensive functional connectivity was observed between claustrum and cortical regions associated with cognitive control, including anterior cingulate, prefrontal and parietal cortices. Cognitive task performance was associated with widespread activation and deactivation that overlapped with the cortical areas showing functional connectivity to the claustrum. Furthermore, during high cognitive conflict conditions of the task, the claustrum was significantly activated at the onset of the task, but not during the remainder of the difficult condition. Both of these findings suggest that the human claustrum can be functionally isolated with fMRI, and that it may play a role in cognitive control, and specifically task switching, independent of sensorimotor processing.
Learn More >Trigeminal neuralgia (TN) commonly results in pain behaviors and cognitive impairment. Convincing evidence suggests that TWIK-related spinal cord K+ (TRESK) exerts antinociceptive and neuroprotective effects. However, its possible potentials in TN remain unclear. TN model was established in rats by generating an infraorbital nerve chronic constriction injury (ION-CCI), and rats received intrathecal injections of TRESK overexpressing lentivirus (LV-TRESK) and siRNA expression vector targeted against TRESK (si-TRESK) into the trigeminal ganglions. Mechanical allodynia was evaluated by mechanical withdrawal threshold (MWT). Cognitive capacity was tested using Morris water maze (MWM). The TRESK expression was determined by quantitative real-time PCR (qRT-PCR) and western blotting. Results showed that the mRNA and protein levels of TRESK were significantly downregulated in trigeminal ganglions in injured rats. Intrathecal treatment with TRESK reduced mechanical allodynia and relieved learning and memory deficits in TN rats, while si-TRESK injection caused neuropathic pain and cognitive deficits. In summary, the present study concluded that TRESK ameliorated pain-associated behaviors and cognitive deficits, which was useful as an alternative approach in management of TN.
Learn More >The ACCURATE randomized, controlled trial compared outcomes of dorsal root ganglion (DRG) stimulation versus tonic spinal cord stimulation (SCS) in 152 subjects with chronic lower extremity pain due to complex regional pain syndrome (CRPS) type I or II. This ACCURATE sub-study was designed to evaluate whether therapy habituation occurs with DRG stimulation as compared to SCS through 12-months. A modified intention-to-treat analysis was performed to assess percentage pain relief (PPR) and responder rates at follow-up visits (end-of-trial, 1, 3, 6, 9, 12-months post-permanent implant) for all subjects that completed trial stimulation (DRG:N=73, SCS_N=72). For both groups, mean PPR was significantly greater at end-of-trial (DRG:82.2%, SCS:77.0%) than all other follow-ups. Following permanent DRG system implantation, none of the time points were significantly different from one another in PPR (range:69.3-73.9%). For the SCS group, PPR at 9-months (58.3%) and 12-months (57.9%) was significantly less than at 1-month (66.9%). The responder rate also decreased for the SCS group from 1-month (68.1%) to 12-months (61.1%). After stratifying by diagnosis, it was found that only the CRPS-I population had diminishing pain relief with SCS. DRG stimulation resulted in more stable pain relief through 12-months, while tonic SCS demonstrated therapy habituation at 9- and 12-months. Trial Registration: The ACCURATE study was registered at ClinicalTrials.gov with Identifier NCT01923285. Perspective: This article reports on an ACCURATE sub-study, which found that long-term therapy habituation occurred at 12-months with SCS, but not DRG stimulation, in patients with CRPS. The underlying mechanisms of action for these results remain unclear, although several lines of inquiry are proposed.
Learn More >The Hospital Anxiety and Depression Scale (HADS) is a scale originally developed for the assessment of anxiety and depression in hospitalized patients. Despite its wide diffusion, the HADS factorial structure has displayed inconsistent results, leaving doubts about its use in chronic musculoskeletal pain. The purpose of this study was to thoroughly assess the factorial structure of the HADS in patients with chronic pain and to give guidance for a potential refinement. Data from 2522 patients with chronic pain from the Amsterdam Pain (AMS-PAIN) cohort were analyzed through: (1) exploratory bifactor analysis based on a Schmid-Leiman orthogonalization, (2) confirmatory factor analysis comparing a unidimensional model, the original correlated factors model and a bifactor model, (3) item response theory (IRT) analysis based on the graded response model. The results of the confirmatory factor analysis and of the IRT analysis were then cross – validated in an independent sample of patients with chronic pain (n = 8604). Both exploratory and confirmatory analyses revealed the presence of a strong general emotional distress factor, suggesting that the HADS can be used as a unidimensional scale. The IRT analysis led to the exclusion of three items and to the recoding of one item. The refined 11-item HADS scale was successfully cross-validated and confirmed as a unidimensional, locally independent, monotonic and reliable scale. Perspective: An 11-item shorter version of the HADS could be used to measure emotional distress in patients with chronic musculoskeletal pain. Given its unidimensionality, the use of its total score seems appropriate.
Learn More >A descriptive analysis of secondary data.
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