Search results
Found 9279 matches for
Changes in subcortical grey matter in rheumatoid arthritis
Introduction: Recently it has been demonstrated that chronic pain is associated with structural brain changes. So far there have been no morphometric studies on patients with rheumatoid arthritis (RA). Bekkelund et al. [1], used manual tracing methods, and observed larger brain atrophy in patients with long term RA, than in control subjects. Our previous studies demonstrated that there are no cortical changes in RA. We used FIRST, a shape-based morphometric method to compare shape of subcortical grey matter in RA patients versus healthy controls. Methods: We recruited 31 patients with severe rheumatoid arthritis, treated with non-biological disease-modifying antirheumatic drugs, and 25 age- and sex- matched healthy controls, free of any chronic pain complaint. High-resolution MP-RAGE images were acquired on a 3T Tim Trio scanner (Siemens, Erlangen). Data were analyzed using FIRST, a shape-based morphometry style analysis [2]. We used age and sex as regressors of no interest. In the patient group, only disease duration was entered into the model together with age and sex to investigate whether any of the structural changes were correlated with the duration of disease. Results: We observed a larger right caudate nucleus in the patient group. None of the structures was larger in the control group. There were no correlations between the disease duration and shape changes in any of the subcortical structures in the patient group. Discussion: The observed changes may reflect altered motor feedback related to pain in disability in RA, changes related to activity in the reward system (if we treat pain relief as a reward), finally increase of subcortical grey matter may be associated with alterations in dopaminergic transmission. Conclusions: We suggest that chronic pain in RA is associated with subcortical structural brain changes reflecting neuroplasticity related to chronic pain or motor changes. In the future, a follow-up study in early RA would help to improve our understanding of these changes.
Pain processing in rheumatoid arthritis patients successfully treated with anti-TNF medication
Introduction: Anti-TNF treatment blocks the action of proinflammatory cytokine, tumor necrosis factor, and reduces pain and disease activity in rheumatoid arthritis (RA). We were interested in changes in processing of evoked pain in RA patients after successful anti-TNF treatment. Methods: Ten patients with severe RA were scanned before the beginning of treatment and after 6 months of successful therapy. 22 healthy volunteers were recruited as a control group and were scanned only once. We used fMRI to investigate brain activation changes in response to joint pressure pain and thermal stimulation at a fixed temperature to elicit moderate pain. Results: At the baseline, the comparison of moderately painful pressure pain in patients vs. non-painful pressure stimulation in controls revealed more extensive activation in the anterior cingulate cortex, the brainstem and bilaterally in the thalamus and insula. As for the thermal stimulation, patients and controls rated it as moderately painful, however, there was less activation in the thalamus and insula in patients than in controls. Patients were scanned again after six months of the treatment and the same stimulation intensity was used as at the baseline. Joint pressure pain was rated significantly lower, whereas thermal pain ratings remained the same. In comparison to the control group imaging data, patients showed more activation in response to pressure stimulation in the cingulate cortex and brainstem; patients’ brain activation in response to thermal stimulation was not different from controls. Conclusions: We observed a normalization of pain processing after successful anti-TNF treatment. The study was funded by GlaxoSmithKline as a part of an ongoing academic collaboration.
Structural brain changes in patients with rheumatoid arthritis
Introduction: Recent studies demonstrated that chronic pain leads to possible structural brain changes in diseases such as lower back pain, migraine and fibromyalgia. We used two automated methods to investigate whether morphometric changes occur in patients with rheumatoid arthritis (RA). Methods: We recruited 28 patients with severe RA, and 25 age- and sex-matched healthy controls. High-resolution MP-RAGE images were acquired on a 3T scanner Tim Trio (Siemens, Erlangen). Data were analyzed using FSL_VBM, a voxel-based morphometry style analysis and FreeSurfer, a surface-based morphometry. To investigate the effect of disease duration, a model with disease duration as a regressor of interest was used in the patients group. Results: There were no local structural grey-matter differences between patients and controls in the FSL_VBM. The FreeSurfer analysis however revealed decrease in grey-matter thickness in both parahippocampal gyri. Moreover, RA patients had significantly smaller brains compared to controls, estimated using intracranial volume (ICV). In the patient group, disease duration, when controlled for age, significantly correlated with ICV (r = 0.44 p = 0.019) and there was a trend for ASF (r = −0.36 p = 0.055). Furthermore, in the patients group the disease duration regressor negatively correlated with grey matter density in the thalamus. Conclusions: These results suggest that there are global brain differences associated with RA. However, it is not clear whether these changes represent an accelerated rate of atrophy as observed in fibromyalgia, the effect of systemic inflammation and vasculopathy similar to lupus erythrematosus or rathe
Cerebral processing of pain in rheumatoid arthritis patients treated with antiTNF-alpha
Aim of Investigation: To examine the mechanisms involved in chronic pain and its relief using functional magnetic resonance imaging (fMRI). We were interested in how evoked clinical joint pain processing in rheumatoid arthritis (RA) patients changes after anti-TNF-alpha treatment. Anti-TNF treatment blocks the action of TNF-alpha, a key factor in joint inflammation, suppressing disease activity in severe RA reducing both joint pain and inflammation. Methods: Twenty-one patients with severe RA and due to begin anti-TNF treatment have so far been recruited to the study with full informed consent. We used fMRI to investigate changes in brain activation in response to joint pressure pain and thermal stimulation at a fixed temperature to elicit moderate pain over the course of treatment (i) before the treatment, (ii) 1 month, (iii) 8 months after treatment began. Clinical, psychological and psychophysical data was collected at each time point. Results: Up to now, 10 patients have responded positively to treatment and completed all 3 time points (TP). Clinical and psychobehavioural results Between TP-1 and TP-2 there was a significant decrease in pain ratings, on 11-point numerical rating scale for both pressure (5.1 vs. 3.3 p=0.002) and heat (6.2 vs. 5.1 p=0.004), as well as for daily pain (5.9 vs. 4.3 p=0.004). The difference between the TP-1 and TP-3 was even more significant: for pressure pain ( and daily pain but not more sp for heat pain. There was a significant reduction in disease activity score in 28 joints (DAS 28) and blood inflammatory markers. There was no significant difference in the depression and catastrophising scores for TP-1 vs. TP-2, but they both significantly decreased at TP-3 vs. TP-1. Imaging results: We observed a robust activation in response to both types of painful stimuli. In the pressure pain condition there was a decrease in activation, at TP-2 vs. TP-1 in the left primary sensorimotor cortex, secondary sensory cortex bilaterally and right insula. For TP-3 vs. TP-1 there was a decrease of activation bilaterally in insula and somatosensory cortex. For heat stimulation, there was a bilateral decrease in activation in cingulate, thalamus and striatum for the TP-2 vs. TP-1 but not for the TP-3 vs. TP-1, reflecting perhaps modulation of nociceptive processing as patients recover. Conclusions: We observed a notable reduction in disease activity after 1 month of treatment in clinical, psychological and fMRI data. The observed imaging changes correlated with a reduced noxious input and decreased perceived pain intensity. Acknowledgments: The study was funded by GlaxoSmithKline as a part of an ongoing academic collaboration.
Changes in brain activation related to pain relief in rheumatoid arthritis patients following the anti-TNF treatment
Background and aims: Functional magnetic resonance imaging (fMRI) offers comprehensive information on brain function. The objective fMRI data can be correlated with behavioural and clinical measures to help dissect a subjective pain experience into its components. In this study we compared changes of experimental and clinical pain processing in rheumatoid arthritis (RA) before and after treatment with etanercept or infliximab; agents that block the action of proinflammatory cytokine, tumor necrosis factor (anti-TNF). Methods: We recruited 10 patients with active rheumatoid arthritis (RA) due to begin the anti-TNF treatment and 10 age and sex matched healthy volunteers. We used fMRI to investigate changes in brain activation patterns in response to clinically-relevant stimuli (joint squeeze and experimental heat pain stimulation) pre- and post-treatment. We collected also clinical and psychophysical information from each patient. Results: We observed robust activation in response to both clinical and experimental pain in all major pain processing areas. Preliminary analysis suggests that fMRI is able to detect differences in experimental pain processing between patients and healthy subjects, as well as differences between clinical and experimental pain in RA patients alone. We found significant (p<0.05) decreases in pain ratings for both kinds of stimuli, clinical markers of inflammation, disease activity score (DAS 28) and significant changes in fMRI signal in insula cortex post anti-TNF treatment. Conclusions: Our findings suggest that fMRI is a sensitive measure of pain experience and has the potential to become a useful tool in understanding pathophysiology of chronic pain as well as measuring treatment effects.
Harmonising data collection from osteoarthritis studies to enable stratification: recommendations on core data collection from an Arthritis Research UK clinical studies group.
OBJECTIVE: Treatment of OA by stratifying for commonly used and novel therapies will likely improve the range of effective therapy options and their rational deployment in this undertreated, chronic disease. In order to develop appropriate datasets for conducting post hoc analyses to inform approaches to stratification for OA, our aim was to develop recommendations on the minimum data that should be recorded at baseline in all future OA interventional and observational studies. METHODS: An Arthritis Research UK study group comprised of 32 experts used a Delphi-style approach supported by a literature review of systematic reviews to come to a consensus on core data collection for OA studies. RESULTS: Thirty-five systematic reviews were used as the basis for the consensus group discussion. For studies with a primary structural endpoint, core domains for collection were defined as BMI, age, gender, racial origin, comorbidities, baseline OA pain, pain in other joints and occupation. In addition to the items generalizable to all anatomical sites, joint-specific domains included radiographic measures, surgical history and anatomical factors, including alignment. To demonstrate clinical relevance for symptom studies, the collection of mental health score, self-efficacy and depression scales were advised in addition to the above. CONCLUSIONS: Currently it is not possible to stratify patients with OA into therapeutic groups. A list of core and optional data to be collected in all OA interventional and observational studies was developed, providing a basis for future analyses to identify predictors of progression or response to treatment.
Recommendations for the conduct of efficacy trials of treatment devices for osteoarthritis: a report from a working group of the Arthritis Research UK Osteoarthritis and Crystal Diseases Clinical Studies Group.
OBJECTIVE: There are unique challenges to designing and carrying out high-quality trials testing therapeutic devices in OA and other rheumatic diseases. Such challenges include determining the mechanisms of action of the device and the appropriate sham. Design of device trials is more challenging than that of placebo-controlled drug trials. Our aim was to develop recommendations for designing device trials. METHODS: An Arthritis Research UK study group comprised of 30 rheumatologists, physiotherapists, podiatrists, engineers, orthopaedists, trialists and patients, including many who have carried out device trials, met and (using a Delphi-styled approach) came to consensus on recommendations for device trials. RESULTS: Challenges unique to device trials include defining the mechanism of action of the device and, therefore, the appropriate sham that provides a placebo effect without duplicating the action of the active device. Should there be no clear-cut mechanism of action, a three-arm trial including a no-treatment arm and one with presumed sham action was recommended. For individualized devices, generalizable indications and standardization of the devices are needed so that treatments can be generalized. CONCLUSION: A consensus set of recommendations for device trials was developed, providing a basis for improved trial design, and hopefully improvement in the number of effective therapeutic devices for rheumatic diseases.
IgA production requires B cell interaction with subepithelial dendritic cells in Peyer's patches.
Immunoglobulin A (IgA) induction primarily occurs in intestinal Peyer's patches (PPs). However, the cellular interactions necessary for IgA class switching are poorly defined. Here we show that in mice, activated B cells use the chemokine receptor CCR6 to access the subepithelial dome (SED) of PPs. There, B cells undergo prolonged interactions with SED dendritic cells (DCs). PP IgA class switching requires innate lymphoid cells, which promote lymphotoxin-β receptor (LTβR)-dependent maintenance of DCs. PP DCs augment IgA production by integrin αvβ8-mediated activation of transforming growth factor-β (TGFβ). In mice where B cells cannot access the SED, IgA responses against oral antigen and gut commensals are impaired. These studies establish the PP SED as a niche supporting DC-B cell interactions needed for TGFβ activation and induction of mucosal IgA responses.
Feasibility of Diffusion Tensor and Morphologic Imaging of Peripheral Nerves at Ultra-High Field Strength.
OBJECTIVES: The aim of this study was to describe the development of morphologic and diffusion tensor imaging sequences of peripheral nerves at 7 T, using carpal tunnel syndrome (CTS) as a model system of focal nerve injury. MATERIALS AND METHODS: Morphologic images were acquired at 7 T using a balanced steady-state free precession sequence. Diffusion tensor imaging was performed using single-shot echo-planar imaging and readout-segmented echo-planar imaging sequences. Different acquisition and postprocessing methods were compared to describe the optimal analysis pipeline. Magnetic resonance imaging parameters including cross-sectional areas, signal intensity, fractional anisotropy (FA), as well as mean, axial, and radial diffusivity were compared between patients with CTS (n = 8) and healthy controls (n = 6) using analyses of covariance corrected for age (significance set at P < 0.05). Pearson correlations with Bonferroni correction were used to determine association of magnetic resonance imaging parameters with clinical measures (significance set at P < 0.01). RESULTS: The 7 T acquisitions with high in-plane resolution (0.2 × 0.2mm) afforded detailed morphologic resolution of peripheral nerve fascicles. For diffusion tensor imaging, single-shot echo-planar imaging was more efficient than readout-segmented echo-planar imaging in terms of signal-to-noise ratio per unit scan time. Distortion artifacts were pronounced, but could be corrected during postprocessing. Registration of FA maps to the morphologic images was successful. The developed imaging and analysis pipeline identified lower median nerve FA (pisiform bone, 0.37 [SD 0.10]) and higher radial diffusivity (1.08 [0.20]) in patients with CTS compared with healthy controls (0.53 [0.06] and 0.78 [0.11], respectively, P < 0.047). Fractional anisotropy and radial diffusivity strongly correlated with patients' symptoms (r = -0.866 and 0.866, respectively, P = 0.005). CONCLUSIONS: Our data demonstrate the feasibility of morphologic and diffusion peripheral nerve imaging at 7 T. Fractional anisotropy and radial diffusivity were found to be correlates of symptom severity.
A new look at painful diabetic neuropathy.
The prevalence of diabetes mellitus and its chronic complications continue to increase alarmingly. Consequently, the massive expenditure on diabetic distal symmetrical polyneuropathy (DSPN) and its sequelae, will also likely rise. Up to 50% of patients with diabetes develop DSPN, and about 20% develop neuropathic pain (painful-DSPN). Painful-DSPN can cast a huge burden on sufferers' lives with increased rates of unemployment, mental health disorders and physical co-morbidities. Unfortunately, due to limited understanding of the mechanisms leading to painful-DSPN, current treatments remain inadequate. Recent studies examining the pathophysiology of painful-DSPN have identified maladaptive alterations at the level of both the peripheral and central nervous systems. Additionally, genetic studies have suggested that patients with variants of voltage gated sodium channels may be more at risk of developing neuropathic pain in the presence of a disease trigger such as diabetes. We review the recent advances in genetics, skin biopsy immunohistochemistry and neuro-imaging, which have the potential to further our understanding of the condition, and identify targets for new mechanism based therapies.
Reaffirming the link between chronic phantom limb pain and maintained missing hand representation.
Phantom limb pain (PLP) is commonly considered to be a result of maladaptive brain plasticity. This model proposes that PLP is mainly caused by reorganisation in the primary somatosensory cortex, presumably characterised by functional degradation of the missing hand representation and remapping of other body part representations. In the current study, we replicate our previous results by showing that chronic PLP correlates with maintained representation of the missing hand in the primary sensorimotor missing hand cortex. We asked unilateral upper-limb amputees to move their phantom hand, lips or other body parts and measured the associated neural responses using functional magnetic resonance imaging (fMRI). We confirm that amputees suffering from worse chronic PLP have stronger activity in the primary sensorimotor missing hand cortex while performing phantom hand movements. We find no evidence of lip representation remapping into the missing hand territory, as assessed by measuring activity in the primary sensorimotor missing hand cortex during lip movements. We further show that the correlation between chronic PLP and maintained representation of the missing hand cannot be explained by the experience of chronic non-painful phantom sensations or compensatory usage of the residual arm or an artificial arm (prosthesis). Together, our results reaffirm a likely relationship between persistent peripheral inputs pertaining to the missing hand representation and chronic PLP. Our findings emphasise a need to further study the role of peripheral inputs from the residual nerves to better understand the mechanisms underlying chronic PLP.
General anaesthesia as fragmentation of selfhood: insights from electroencephalography and neuroimaging.
Selfhood is linked to brain processes that enable the experience of a person as a distinct entity, capable of agency. This framework naturally incorporates a continuum of both non-conscious and conscious self-related information processing, and includes a hierarchy of components, such as awareness of existence (core self), embodied self (sentience), executive self (agency/volition), and various other higher-order cognitive processes. Consciousness relates to, but is not congruent, with selfhood; understanding the processes required for selfhood can explain the partial consciousness seen in anaesthesia. Functional-brain-imaging and electroencephalographic studies in sleep and general anaesthesia have shown differential effects of anaesthetic drugs on various specific self-related functional brain networks. In particular, drug-induced selective impairment of anterior insula function suggests there might be a crucial difference between anaesthesia and natural sleep when it comes to the salience network. With increasing concentrations of anaesthetics, it is not uncommon for patients to become depersonalised (i.e. to lose sentience and agency), but retain many higher-order functions and a disembodied self-awareness, until quite high concentrations are reached. In this respect, general anaesthesia differs significantly from physiological sleep, where it appears that loss of agency and sentience parallels, or lags behind, the decrease in self-awareness. Interestingly, connectivity within the posterior brain regions is maintained even to quite high concentrations of anaesthetics, potentially representing a pathognomonic marker of the core self that possibly is involved in maintaining a reduced energy state of homeostasis.
A method for correcting breathing-induced field fluctuations in T2*-weighted spinal cord imaging using a respiratory trace.
PURPOSE: Spinal cord MRI at ultrahigh field is hampered by time-varying magnetic fields associated with the breathing cycle, giving rise to ghosting artifacts in multi-shot acquisitions. Here, we suggest a correction approach based on linking the signal from a respiratory bellows to field changes inside the spinal cord. The information is used to correct the data at the image reconstruction level. METHODS: The correction was demonstrated in the context of multi-shot T2*-weighted imaging of the cervical spinal cord at 7T. A respiratory trace was acquired during a high-resolution multi-echo gradient-echo sequence, used for structural imaging and quantitative T2* mapping, and a multi-shot EPI time series, as would be suitable for fMRI. The coupling between the trace and the breathing-induced fields was determined by a short calibration scan in each individual. Images were reconstructed with and without trace-based correction. RESULTS: In the multi-echo acquisition, breathing-induced fields caused severe ghosting in images with long TE, which led to a systematic underestimation of T2* in the spinal cord. The trace-based correction reduced the ghosting and increased the estimated T2* values. Breathing-related ghosting was also observed in the multi-shot EPI images. The correction largely removed the ghosting, thereby improving the temporal signal-to-noise ratio of the time series. CONCLUSIONS: Trace-based retrospective correction of breathing-induced field variations can reduce ghosting and improve quantitative metrics in multi-shot structural and functional T2*-weighted imaging of the spinal cord. The method is straightforward to implement and does not rely on sequence modifications or additional hardware beyond a respiratory bellows.
Structural and Functional Abnormalities of the Primary Somatosensory Cortex in Diabetic Peripheral Neuropathy: A Multimodal MRI Study.
Diabetic distal symmetrical peripheral polyneuropathy (DSP) results in decreased somatosensory cortical gray matter volume, indicating that the disease process may produce morphological changes in the brains of those affected. However, no study has examined whether changes in brain volume alter the functional organization of the somatosensory cortex and how this relates to the various painful DSP clinical phenotypes. In this case-controlled, multimodal brain MRI study of 44 carefully phenotyped subjects, we found significant anatomical and functional changes in the somatosensory cortex. Subjects with painful DSP insensate have the lowest somatosensory cortical thickness, with expansion of the area representing pain in the lower limb to include face and lip regions. Furthermore, there was a significant relationship between anatomical and functional changes within the somatosensory cortex and severity of the peripheral neuropathy. These data suggest a dynamic plasticity of the brain in DSP driven by the neuropathic process. It demonstrates, for the first time in our knowledge, a pathophysiological relationship between a clinically painful DSP phenotype and alterations in the somatosensory cortex.
Strategy-dependent modulation of cortical pain circuits for the attenuation of pain.
The effectiveness of cognitive strategies to attenuate pain has been reported in various behavioural studies, however the underlying neuronal mechanisms are only now beginning to be understood. Using a 7 T fMRI, we investigated three different pain attenuation strategies in 20 healthy subjects via: (a) non-imaginal distraction by counting backwards in steps of seven; (b) imaginal distraction by imagining a safe place; and (c) reinterpretation of the pain valence (reappraisal). Although we found considerable variability in the performances, all strategies exhibited a significant relief of pain compared to an unmodulated pain condition. Our finding argues against a subject's potential predisposition for a certain attenuation approach, as some of the subjects performed well on all attenuation tasks yet others performed low on all attenuation tasks. We further investigated the variability of performance within-subjects and explored the cortical regions that contribute to successful single attempts of pain attenuation at trial level. For each of the three tasks, we found a different pattern of brain activity that reflects the performance of pain attenuation. The more successful trials are related to reduced activity of different parts of the insular cortex. Behavioural data suggest that distraction is the preferable cognitive strategy to modulate pain perception. For three different cognitive strategies we revealed brain regions that are suggested to reliably modulate the perception of pain. The findings could be of utmost benefit for future attempts to integrate neuroscientific techniques into the treatment of pain. Further studies are necessary to investigate whether the present results are transferable to patients as an essential part of the multimodal therapy for chronic pain. These patients may also benefit from additional neurofeedback techniques by combining the strategies with the cortical feedback in order to modulate pain-related brain activity.