New insights into the impact of neuro-inflammation in rheumatoid arthritis.

Rheumatoid arthritis (RA) is considered to be, in many respects, an archetypal autoimmune disease that causes activation of pro-inflammatory pathways resulting in joint and systemic inflammation. RA remains a major clinical problem with the development of several new therapies targeted at cytokine inhibition in recent years. In RA, biologic therapies targeted at inhibition of tumor necrosis factor alpha (TNFα) have been shown to reduce joint inflammation, limit erosive change, reduce disability and improve quality of life. The cytokine TNFα has a central role in systemic RA inflammation and has also been shown to have pro-inflammatory effects in the brain. Emerging data suggests there is an important bidirectional communication between the brain and immune system in inflammatory conditions like RA. Recent work has shown how TNF inhibitor therapy in people with RA is protective for Alzheimer's disease. Functional MRI studies to measure brain activation in people with RA to stimulus by finger joint compression, have also shown that those who responded to TNF inhibition showed a significantly greater activation volume in thalamic, limbic, and associative areas of the brain than non-responders. Infections are the main risk of therapies with biologic drugs and infections have been shown to be related to disease flares in RA. Recent basic science data has also emerged suggesting that bacterial components including lipopolysaccharide induce pain by directly activating sensory neurons that modulate inflammation, a previously unsuspected role for the nervous system in host-pathogen interactions. In this review, we discuss the current evidence for neuro-inflammation as an important factor that impacts on disease persistence and pain in RA

Insula-specific responses induced by dental pain: a proton magnetic resonance spectroscopy study

OBJECTIVES: To evaluate whether induced dental pain leads to quantitative changes in brain metabolites within the left insular cortex after stimulation of the right maxillary canine and to examine whether these metabolic changes and the subjective pain intensity perception correlate. METHODS: Ten male volunteers were included in the pain group and compared with a control group of 10 other healthy volunteers. The pain group received a total of 87-92 electrically induced pain stimuli over 15 min to the right maxillary canine tooth. Contemporaneously, they evaluated the subjective pain intensity of every stimulus using an analogue scale. Neurotransmitter changes within the left insular cortex were evaluated by MR spectroscopy. RESULTS: Significant metabolic changes in glutamine (+55.1%), glutamine/glutamate (+16.4%) and myo-inositol (-9.7%) were documented during pain stimulation. Furthermore, there was a significant negative correlation between the subjective pain intensity perception and the metabolic levels of Glx, Gln, glutamate and N-acetyl aspartate. CONCLUSION: The insular cortex is a metabolically active region in the processing of acute dental pain. Induced dental pain leads to quantitative changes in brain metabolites within the left insular cortex resulting in significant alterations in metabolites. Negative correlation between subjective pain intensity rating and specific metabolites could be observed

In vivo functional neurochemistry of human cortical cholinergic function during visuospatial attention

Cortical acetylcholine is involved in key cognitive processes such as visuospatial attention. Dysfunction in the cholinergic system has been described in a number of neuropsychiatric disorders. Levels of brain acetylcholine can be pharmacologically manipulated, but it is not possible to directly measure it in vivo in humans. However, key parts of its biochemical cascade in neural tissue, such as choline, can be measured using magnetic resonance spectroscopy (MRS). There is evidence that levels of choline may be an indirect but proportional measure of acetylcholine availability in brain tissue. In this study, we measured relative choline levels in the parietal cortex using functional (event-related) MRS (fMRS) during performance of a visuospatial attention task, with a modelling approach verified using simulated data. We describe a task-driven interaction effect on choline concentration, specifically driven by contralateral attention shifts. Our results suggest that choline MRS has the potential to serve as a proxy of brain acetylcholine function in humans

Frontal GABA Levels Change during Working Memory

Functional neuroimaging metrics are thought to reflect changes in neurotransmitter flux, but changes in neurotransmitter levels have not been demonstrated in humans during a cognitive task, and the relationship between neurotransmitter dynamics and hemodynamic activity during cognition has not yet been established. We evaluate the concentration of the major inhibitory (GABA) and excitatory (glutamate + glutamine: Glx) neurotransmitters and the cerebral perfusion at rest and during a prolonged delayed match-to-sample working memory task. Resting GABA levels in the dorsolateral prefrontal cortex correlated positively with the resting perfusion and inversely with the change in perfusion during the task. Further, only GABA increased significantly during the first working memory run and then decreased continuously across subsequent task runs. The decrease of GABA over time was paralleled by a trend towards decreased reaction times and higher task accuracy. These results demonstrate a link between neurotransmitter dynamics and hemodynamic activity during working memory, indicating that functional neuroimaging metrics depend on the balance of excitation and inhibition required for cognitive processing

Vascular malformations of the female and male genitalia: type and distribution patterns revealed by magnetic resonance imaging

Background Vascular malformations of the genitalia often go undetected in clinical examination. These vascular malformations can cause a variety of clinical symptoms such as swelling, pain and bleeding. Aim To characterize the distribution patterns of genital vascular malformations using magnetic resonance imaging (MRI) and to correlate these patterns with clinical findings in order to guide diagnostic decisions. Methods A retrospective analysis of MRIs of the pelvis and legs in 370 patients with vascular malformation was performed to determine the involvement of the internal and external genitalia. Results In 71 patients (19%), genital involvement could be identified by MRI. Of these, 11.3% (8 of 71) presented with internal involvement, 36.6% (26 of 71) with external involvement and 52.1% (37 of 71) with both internal and external involvement. Over half (57.1%) of the 49 patients with visible external genital signs detected during a clinical examination had additional internal genital involvement. Conclusions Genital involvement is a common finding in patients with vascular malformation of the legs and/or pelvis. Based on our data, we recommend MRI of the legs and pelvic region in patients with externally visible signs of a vascular malformation of the external genitalia in order to exclude additional internal involvement

MR imaging of venous malformations: sciatic nerve infiltration patterns and involved muscle groups

The aim of this retrospective cross-sectional study was to provide an MRI-based examination framework of venous malformations (VMs) infiltrating the sciatic nerve and determine the frequency of nerve infiltration patterns and muscle involvement in correlation to the patients' quality of life. Pelvic and lower limb MR images of 378 patients with vascular malformations were examined retrospectively. Pain levels and restriction of motion were evaluated with a questionnaire. Cross-sectional areas of affected nerves were compared at standardized anatomical landmarks. Intraneural infiltration patterns and involvement of muscles surrounding the sciatic nerve were documented. Sciatic nerve infiltration occurred in 23/299 patients (7.7%) with VM. In all cases (23/23; 100%), gluteal or hamstring muscles surrounding the nerve were affected by the VM. Infiltrated nerves were enlarged and showed signal alterations (T2-hyperintensity) compared to the unaffected side. Enlarged nerve cross-sectional areas were associated with elevated pain levels. Three nerve infiltration patterns were observed: subepineurial (12/23; 52.2%), subparaneurial (6/23; 26.1%) and combined (5/23; 21.7%) infiltration. This study provides a clinically relevant assessment for sciatic nerve infiltration patterns and muscle involvement of VMs, while suggesting that VMs in gluteal and hamstring muscles require closer investigation of the sciatic nerve by the radiologist

Classification of first-episode psychosis using cortical thickness: a large multicenter MRI study

Machine learning classifications of first-episode psychosis (FEP) using neuroimaging have predominantly analyzed brain volumes. Some studies examined cortical thickness, but most of them have used parcellation approaches with data from single sites, which limits claims of generalizability. To address these limitations, we conducted a large-scale, multi-site analysis of cortical thickness comparing parcellations and vertex-wise approaches. By leveraging the multi-site nature of the study, we further investigated how different demographical and site-dependent variables affected predictions. Finally, we assessed relationships between predictions and clinical variables. 428 subjects (147 females, mean age 27.14) with FEP and 448 (230 females, mean age 27.06) healthy controls were enrolled in 8 centers by the ClassiFEP group. All subjects underwent a structural MRI and were clinically assessed. Cortical thickness parcellation (68 areas) and full cortical maps (20,484 vertices) were extracted. Linear Support Vector Machine was used for classification within a repeated nested cross-validation framework. Vertex-wise thickness maps outperformed parcellation-based methods with a balanced accuracy of 66.2% and an Area Under the Curve of 72%. By stratifying our sample for MRI scanner, we increased generalizability across sites. Temporal brain areas resulted as the most influential in the classification. The predictive decision scores significantly correlated with age at onset, duration of treatment, and positive symptoms. In conclusion, although far from the threshold of clinical relevance, temporal cortical thickness proved to classify between FEP subjects and healthy individuals. The assessment of site-dependent variables permitted an increase in the across-site generalizability, thus attempting to address an important machine learning limitation