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Neuroimaging studies have shown that chronic pain is maladaptive and influences brain function and behavior by altering the flexible cerebral information flow. We utilized power spectral analysis to investigate the impact of classic trigeminal neuralgia (TN) on the oscillation dynamics of intrinsic brain activity in humans. The amplitude of low-frequency fluctuations (ALFF) and fractional ALFF (fALFF) were measured in 29 TN patients and 34 age- and sex-matched healthy controls (HCs) via resting-state functional MRI (R-fMRI). Two different frequency bands (slow-5: 0.01-0.027 Hz; slow-4: 0.027-0.073 Hz) were analyzed. Differences in blood oxygen level-dependent (BOLD) signal fluctuations and related resting-state functional connectivity (rsFC) between the TN patients and HCs were identified. The TN patients had reduced ALFF/fALFF in the posterior cingulate cortex (PCC), left insula, left dorsolateral prefrontal cortex (DLPFC), left putamen and bilateral temporal lobe, exclusively in the frequency of the slow-5 band. Whole brain rsFC analyses with these six different regions as seeds revealed two weaker circuits including the PCC-medial prefrontal cortex (mPFC) and DLPFC-hippocampus circuits, indicating abnormal interactions with the default mode network (DMN) in TN patients. The functional connectivity between the default-mode regions (mPFC and PCC) in the slow-5 band tracked pain intensity. Together, our results provide novel insights into how TN disturbs the cortical rhythms and functional interactions of the brain. These insights may have implications for the understanding and treatment of brain dysfunction in chronic pain patients, including TN patients.
Learn More >The aim of this study was to compare the effectiveness of a combined intervention of manual therapy and exercise (MET) versus usual care (UC), on disability, pain intensity and global perceived recovery, in patients with non-specific chronic neck pain (CNP).
Learn More >This study compares participants in RCTs (the MinT-trials) to participants in a related observational study with regards to their low back pain (LBP) symptom course.
Learn More >Migraine headache is an episodic phenomenon, and patients with episodic migraine have ictal (headache), peri-ictal (premonitory, aura, and postdrome), and interictal (asymptomatic) phases. We aimed to find the functional characteristics of migraine brain regardless of headache phase using dynamic functional connectivity analysis. We prospectively recruited 50 patients with migraine and 50 age- and sex-matched controls. All subjects underwent a resting-state functional MRI. Significant networks were defined in a data-driven fashion from the interictal (>48 hours apart from headache phases) patients and matched controls (interictal dataset) and tested to ictal or peri-ictal patients and controls (ictal/peri-ictal dataset). Both static and dynamic analyses were used for the between-group comparison. A false discovery rate correction was performed. As a result, the static analysis did not reveal a network which was significant in both interictal and ictal/peri-ictal datasets. Dynamic analysis revealed significant between-group differences in seven brain networks in the interictal dataset, among which a frontoparietal network (controls > patients, p=0.0467), two brainstem networks (patients > controls, p=0.0467 and <0.001), and a cerebellar network (controls > patients, p=0.0408 and <0.001 in two states) remained significant in the ictal/peri-ictal dataset. Using these networks, migraine was classified with a sensitivity of 0.70 and specificity of 0.76 in the ictal/peri-ictal dataset. In conclusion, the dynamic connectivity analysis revealed more functional networks related to migraine than the conventional static analysis, suggesting a substantial temporal fluctuation in functional characteristics. Our data also revealed migraine-related networks which show significant difference regardless of headache phases between patients and controls.
Learn More >The two-pore potassium channel, TRESK has been implicated in nociception and pain disorders. We have for the first time investigated TRESK function in human nociceptive neurons using induced pluripotent stem cell-based models. Nociceptors from migraine patients with the F139WfsX2 mutation show loss of functional TRESK at the membrane, with a corresponding significant increase in neuronal excitability. Furthermore, using CRISPR-Cas9 engineering to correct the F139WfsX2 mutation, we show a reversal of the heightened neuronal excitability, linking the phenotype to the mutation. In contrast we find no change in excitability in induced pluripotent stem cell derived nociceptors with the C110R mutation and preserved TRESK current; thereby confirming that only the frameshift mutation is associated with loss of function and a migraine relevant cellular phenotype. We then demonstrate the importance of TRESK to pain states by showing that the TRESK activator, cloxyquin, can reduce the spontaneous firing of nociceptors in an in vitro human pain model. Using the chronic nitroglycerine rodent migraine model, we demonstrate that mice lacking TRESK develop exaggerated nitroglycerine-induced mechanical and thermal hyperalgesia, and furthermore, show that cloxyquin conversely is able to prevent sensitization. Collectively, our findings provide evidence for a role of TRESK in migraine pathogenesis and its suitability as a therapeutic target.
Learn More >Pain is a major symptom of bone metastases from advanced cancer and represents a clinical challenge to treat effectively. Basic neurobiology in preclinical animal models implicates enhanced sensory processing in the central nervous system, acting through -methyl-D-aspartate (NMDA) glutamate receptors, as an important mechanism underpinning persistent pain. The non-receptor tyrosine kinase Src is thought to act as a hub for regulating NMDA receptor activity and the orally available Src inhibitor saracatinib has shown promise as a potential analgesic in recent animal studies. Here we tested the efficacy of saracatinib as a novel analgesic in an exploratory phase II randomized controlled trial on cancer patients with painful bone metastases. Twelve patients completed the study, with 6 receiving saracatinib 125 mg/day for 28 days and 6 receiving placebo. Pharmacokinetic measurements confirmed appropriate plasma levels of drug in the saracatinib-treated group and Src inhibition was achieved clinically by a significant reduction in the bone resorption biomarker serum cross-linked C-terminal telopeptide of type I collagen. Differences between the saracatinib and placebo groups self-reported pain scores, measured using the short form of the Brief Pain Inventory, were not clinically significant after 4 weeks of treatment. There was also no change in consumption of maintenance analgesia in the saracatinib-treated group and no improvement in Quality-of-Life scores. The data were insufficient to demonstrate saracatinib has efficacy as analgesic, although it may have a role as an anti-bone resorptive agent.
Learn More >Fibromyalgia syndrome (FMS) is a chronic pain syndrome. Neuroimaging studies provided evidence of altered gray matter volume (GMV) in FMS but, similarly, in chronic pain of other origin as well. Therefore, the purpose of this study was to evaluate the disease specificity of GMV alterations in FMS by direct comparison. Structural MRI data of the brain were acquired in 25 females with FMS and two different control groups: 21 healthy subjects and 23 patients with osteoarthritis. Regional GMVs were compared by voxel-based morphometry and additional ROI-analyses. In conclusion we did not identify significant GMV alterations in either FMS or OA patients compared to healthy controls when adopting a conservative statistical approach with multiple comparison correction. However, even under a more liberal approach no FMS-specific GMV changes were found because both pain groups presented increased gray matter volumes in the precentral gyrus and decreased GMV in the angular gyrus/middle occipital gyrus and middle temporal gyrus in comparison to healthy controls. Since no differences between both pain groups could be detected cortical GMV changes in FMS should not be interpreted as FMS-specific but might rather reflect changes in chronic pain in general. This previously held notion is confirmed in this study by direct comparison with a control group consisting of another pain disorder. This article is protected by copyright. All rights reserved.
Learn More >Educating medical trainees across the continuum is essential to a multifaceted strategy for addressing the opioid epidemic.
Learn More >To evaluate previous results from a questionnaire-based study, we studied objective neuropathy measures to determine sex differences in the prevalence of neuropathy and neuropathic pain in longstanding type 1 diabetes. Despite better neuropathy measures in females compared to males, we confirmed a trend towards higher neuropathic pain in females.
Learn More >10Hz repetitive transcranial magnetic stimulation (10Hz-rTMS) to the left dorsolateral prefrontal cortex (L-DLPFC) produces analgesia, probably by activating the pain modulation system. A newer rTMS paradigm, called theta burst stimulation (TBS), has been developed. Unlike 10Hz-rTMS, prolonged continuous TBS (pcTBS) mimics endogenous theta rhythms, which can improve induction of synaptic long-term potentiation. Therefore, this study investigated whether pcTBS to the L-DLPFC reduced pain sensitivity more efficiently compared with 10Hz-rTMS, the analgesic effects lasted beyond the stimulation period, and the reduced pain sensitivity was associated with increased efficacy of conditioned pain modulation (CPM) and/or intra-cortical excitability. Sixteen subjects participated in a randomized cross-over study with pcTBS and 10Hz-rTMS. Pain thresholds to heat (HPT), cold (CPT), pressure (PPT), intra-cortical excitability assessment, and CPM with mechanical and heat supra-pain threshold test stimuli and the cold pressor test as conditioning were collected before (Baseline), 3 (Day3) and 4 days (Day4) after 3-day session of rTMS. HPTs and PPTs increased with 10Hz-rTMS and pcTBS at Day3 and Day4 compared with Baseline (P=0.007). Based on pooled data from pcTBS and 10Hz-rTMS, the increased PPTs correlated with increased efficacy of CPM at Day3 (P=0.008), while no correlations were found at Day4 or with the intra-cortical excitability. PERSPECTIVE: Preliminary results of this comparative study did not show stronger pain sensitivity reduction by pcTBS compared with 10Hz-rTMS to the L-DPFC. Both protocols maintained increased pain thresholds up to 24-hours after the last session, which were partially associated with modulation of CPM efficacy but not with the intra-cortical excitability changes.
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