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Somatosensory signals modulate activity throughout a widespread network in both of the brain hemispheres: the contralateral as well as the ipsilateral side of the brain relative to the stimulated limb. To analyze the ipsilateral somatosensory brain areas that are engaged during limb stimulation, we performed functional magnetic resonance imaging (fMRI) in 12 healthy subjects during electrical median nerve stimulation using both a block- and an event-related fMRI design. Data were analyzed through the use of model-dependent (SPM) and model-independent (ICA) approaches. Beyond the well-known positive blood oxygenation level-dependent (BOLD) responses, negative deflections of the BOLD response were found consistently in several ipsilateral brain areas, including the primary somatosensory cortex, the supplementary motor area, the insula, the dorsal part of the posterior cingulate cortex, and the contralateral cerebellum. Compared to their positive counterparts, the negative hemodynamic responses showed a different time course, with an onset time delay of 2.4 s and a peak delay of 0.7 s. This characteristic delay was observed in all investigated areas and verified by a second (purely tactile) event-related paradigm, suggesting a systematic difference for brain areas involved in the processing of somatosensory information. These findings may indicate that the physiological basis of these deactivations differs from that of the positive BOLD responses. Therefore, an altered model for the negative BOLD response may be beneficial to further model-dependent fMRI analyses.

Introduction: Tofacitinib is an oral JAK inhibitor indicated for the treatment of rheumatoid arthritis (RA). The efficacy and safety of tofacitinib have been shown in several randomized clinical trials. The study presented here aimed to assess the clinical tolerability and effectiveness of tofacitinib among RA patients in real life. Methods: Consecutive patients between January 2015 and April 2017 with RA who fulfilled the American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) 2010 criteria were included in a prospectively designed analysis of retrospective data. Patients were initiated on tofacitinib 5 mg bid. The primary objective was to analyze the safety of tofacitinib in a real-life cohort. Safety was assessed by the reasons to stop tofacitinib during follow up and changes of liver enzymes, hemoglobin, and creatinine. The secondary outcome was to analyze the frequency of and time to achieve low disease activity (LDA) and remission as defined by 28 joint count disease activity score (DAS28). Results: A total of 144 patients were treated with tofacitinib. A total of 84.9% of patients were pre-exposed to at least one biological agent. The average DAS28 at the initiation of tofacitinib was 4.43. A total of 50.0% of patients were positive for rheumatoid factor and 49.0% for ACPA. The mean follow up was 1.22 years (range 10d–3.7a) after initiation of tofacitinib treatment. A total of 94 (64.4%) patients remained on tofacitinib during follow-up. The average time to stop tofacitinib was 190.0 days. Reasons to stop tofacitinib were: insufficient response (n = 23), gastrointestinal symptoms (n = 18), infection (n = 5), myalgia (n = 2), remission (n = 2), headache (n = 2), cough, blue finger syndrome, intolerance, heartburn, psoriasis, and increased liver enzymes (all n = 1). Increased alanine amino transferase (ALAT) or aspartate amino transferase (ASAT) > 2× upper limit of normal (ULN) were detected in 3.3% and 4.4% of patients, respectively. Hemoglobin decrease of >10% was detected in 15.1% of the patients and decreased lymphocytes <500/μL in 3.4%. An increase of creatinine >20% was detected in 9.4% of patients. A total of 62.9% and 50.0% of the patients achieved low disease activity (LDA) or remission after a median of 319 and 645 days, respectively. These rates were significantly higher in patients naïve to biologic agents as compared to patients pre-exposed to biologics (LDA: naïve 100% 92 d, pre-exposed 57.0% 434 d, p ≤ 0.001; remission: naïve 86.7% 132 d, pre-exposed 44.1%, 692 d, p = 0.001). Conclusions: Tofacitinib is a safe and effective treatment option for patients with RA. Tofacitinib may induce high rates of LDA and remission in patients with active disease, even after the use of one or more biologics, though the rate appeared higher in patients naïve to biologics. Tofacitinib may be a valuable option in a treat-to-target approach. Our data demonstrate that Janus kinase (JAK) inhibitors are safe and efficacious in real life patients.

Habituation is a basic process of learning in which repeated exposure to a sensory stimulus leads to a decrease in the strength of neuronal activations and behavioral responses. In addition to increases in neuronal activity, sensory stimuli can also lead to decreases in neuronal activity. Until now, the effects of habituation on stimulus-induced neuronal deactivations have not been investigated. We performed functional magnetic resonance imaging in 30 healthy subjects during repetitive unilateral somatosensory stimulation and combined this analysis with a psychophysiological examination of changes in the perception threshold. Consistent with the literature, we found a time-dependent decrease of the positive blood oxygenation level-dependent (BOLD) response (indicative of habituation) in the primary somatosensory cortex (SI) contralateral to the stimulus. In contrast, the negative BOLD response (NBR) in the ipsilateral SI did not show a decrease in amplitude; instead, an increase in amplitude was found, i.e., a stronger NBR (increased response). The increased NBR was associated with an increased perception threshold of the nonstimulated hand. These findings suggest that habituation is not primarily characterized by a decrease in the neuronal response to repeated stimuli but rather a widespread change in the balance between excitatory and inhibitory effects that favors inhibitory effects.

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It is well known that the threshold for somatosensory perception may adapt to different inputs. Recent studies suggest the presence of a modulating effect of somatosensory inputs on the spinal dorsal horn. However, the effects of somatosensory inputs on cerebral processing and, in particular, on the functional and effective connectivity of the somatosensory brain network, are poorly understood. In this study, we investigated the longitudinal impact of somatosensory stimuli on the resting-state functional connectivity and effective connectivity of the somatosensory brain network. We performed resting-state functional magnetic resonance imaging (fMRI) in 12 healthy subjects before and after unilateral electrical median nerve stimulation. We combined this analysis with a psychophysiological examination of changes of the perception threshold. We found that the unilateral median nerve stimulation increased the perception thresholds bilaterally and increased the resting-state functional and effective connectivity between most cortical areas of the somatosensory network. The major finding, however, was a decreased resting-state functional connectivity between both secondary somatosensory cortices and the bilateral medial nuclear complex of the thalamus. This decreased connectivity was correlated with increased perception thresholds. These findings emphasize the importance of the medial thalamic nucleus for the perceptual awareness of somatosensory stimuli.

Radiocarbon dating is a cornerstone of climate and archaeological sciences. But the method is under threat as fossil fuel emissions negate a useful signal from atomic tests.