Headache in systemic lupus erythematosus: The LUNA registry cross-sectional study.

OBJECTIVES: This study investigated the clinically relevant factors for headaches in patients with systemic lupus erythematosus (SLE) using a registry from a Japanese multicenter cohort. METHODS: This cross-sectional study analysed the clinical information of patients with SLE who experienced headache episodes using the Migraine Disability Assessment (MIDAS) questionnaire. Significant findings in the comparisons between patients with headache (HA patients) and those without headache (non-HA patients) and in the comparisons depending on the grades of headache-induced disability in daily life based on the MIDAS scores were evaluated. Multivariate logistic regression analyses were performed to identify the relevant factors for headache. RESULTS: We analyzed 369 patients (median age, 45 years; female, 90.8%), including 113 HA patients who were significantly younger than non-HA patients (p < .005). HA patients had significantly higher frequencies of photosensitivity, rashes, and mucosal ulcers than non-HA patients (p < .05). Age and photosensitivity were significantly associated with headache (odds ratio (OR) 0.93, 95% confidence interval (CI) 0.95-0.99; OR 2.11, 95% CI 1.29-3.49, respectively). In the HA patients, hypocomplementemia was significantly associated with a disability of more than mild grade (OR 2.89, 95% CI 1.14-7.74), while rash was significantly observed in those presenting with moderate and severe disability. CONCLUSION: This study suggests that photosensitivity is a relevant manifestation of headache in patients with SLE. Persistent hypocomplementemia can contribute to headache-induced disability in daily life, whereas a rash may be a dominant manifestation in patients presenting with moderate/severe headache-induced disability.

[Rapid Screening System for Paralytic Shellfish Toxins in Bivalves by Oligonucleotide Lateral Flow Immunoassay].

The mouse bioassay (MBA) for paralytic shellfish toxins (PSTs) in bivalves has been used as an official method in Japan. It is necessary to develop an alternative method to animal experiments in PSTs assay because 3Rs (Replacement, Reduction, and Refinement) of animal experiments are required from the animal welfare point of view. Various methods such as HPLC-FL, receptor binding assay, LC-MS/MS and ELISA have been established to detect PSTs without performing animal experiments. The present study was undertaken to develop a screening method using oligonucleotide lateral flow immunoassay (OLFIA) for detecting PSTs in bivalves. The screening level was defined as positive at 2 MU/g of MBA that is the half regulation limit of PSTs monitoring in Japan. All 20 positive (equal to or more than 2 MU/g) samples judged from MBA showed a positive reaction in the OLFIA. No positive samples resulted in a false negative reaction. The OLFIA exhibited high accuracy at 2 MU/g of screening criteria. The authors demonstrated here that the OLFIA can be useful for rapid detection of PSTs in bivalves.

Computing Social Value Conversion in the Human Brain.

Social signals play powerful roles in shaping self-oriented reward valuation and decision making. These signals activate social and valuation/decision areas, but the core computation for their integration into the self-oriented decision machinery remains unclear. Here, we study how a fundamental social signal, social value (others' reward value), is converted into self-oriented decision making in the human brain. Using behavioral analysis, modeling, and neuroimaging, we show three-stage processing of social value conversion from the offer to the effective value and then to the final decision value. First, a value of others' bonus on offer, called offered value, was encoded uniquely in the right temporoparietal junction (rTPJ) and also in the left dorsolateral prefrontal cortex (ldlPFC), which is commonly activated by offered self-bonus value. The effective value, an intermediate value representing the effective influence of the offer on the decision, was represented in the right anterior insula (rAI), and the final decision value was encoded in the medial prefrontal cortex (mPFC). Second, using psychophysiological interaction and dynamic causal modeling analyses, we demonstrated three-stage feedforward processing from the rTPJ and ldPFC to the rAI and then from rAI to the mPFC. Further, we showed that these characteristics of social conversion underlie distinct sociobehavioral phenotypes. We demonstrate that the variability in the conversion underlies the difference between prosocial and selfish subjects, as seen from the differential strength of the rAI and ldlPFC coupling to the mPFC responses, respectively. Together, these findings identified fundamental neural computation processes for social value conversion underlying complex social decision making behaviors.SIGNIFICANCE STATEMENT In daily life, we make decisions based on self-interest, but also in consideration for others' status. These social influences modulate valuation and decision signals in the brain, suggesting a fundamental process called value conversion that translates social information into self-referenced decisions. However, little is known about the conversion process and its underlying brain mechanisms. We investigated value conversion using human fMRI with computational modeling and found three essential stages in a progressive brain circuit from social to empathic and decision areas. Interestingly, the brain mechanism of conversion differed between prosocial and individualistic subjects. These findings reveal how the brain processes and merges social information into the elemental flow of self-interested decision making.

Clinical characteristics of patients with myalgia as the initial manifestation of small and medium-sized vasculitis: a retrospective study.

Myalgia is a common symptom in small and medium-sized systemic vasculitis, sometimes occurring as the initial or only clinical manifestation of vasculitis. This study investigated the clinical features and diagnostic process in patients presenting with myalgia as the initial symptom of anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV) or polyarteritis nodosa (PAN). We included 93 patients diagnosed with AAV or PAN by retrospectively reviewing their clinical records at the initial diagnosis. Clinical findings and diagnostic methods were assessed in patients with myalgia. Of 93 patients, myalgia was observed in 21 (22.6%) patients, with diagnostic classifications of microscopic polyangiitis (MPA) in 12 (52.4%), granulomatosis with polyangiitis in 2 (9.5%), eosinophilic granulomatosis with polyangiitis in 2 (9.5%), and PAN in 5 (23.8%). Myalgia was present in the lower extremities of all patients; more than 80% of patients had pain in the calf muscle. In 10 patients with myalgia, including 7 with MPA and 3 with PAN, muscle biopsy was performed because myalgia was the main symptom and no other impaired organs were suitable for biopsy. Consequently, 8 patients had necrotizing vasculitis, leading to MPA or PAN diagnosis, although muscle pathology was not evaluated in patients without myalgia. Muscle magnetic resonance imaging was useful in determining the biopsy site. Myalgia, especially in the lower limbs, may be an initial clinical sign of vasculitis, particularly in MPA or PAN patients. Moreover, the histological evidence of muscular vasculitis can contribute to a definite diagnosis especially in patients presenting with myalgia as an early symptom of AAV or PAN.

Macrophage activation syndrome in adult dermatomyositis: a case-based review.

Macrophage activation syndrome (MAS) is a severe and life-threatening syndrome associated with autoimmune diseases, characterized by fever, hepatosplenomegaly, and pancytopenia. Dermatomyositis (DM) is one of the causes of MAS; however, its clinical characteristics in DM patients remain unclear. This study aimed to present a case of anti-melanoma differentiation-associated gene 5 (MDA5) antibody-positive DM complicated by MAS in a 29-year-old woman and to review the literatures including similar cases. Even though symptoms and cytopenia of our patient were refractory to combination therapy, including glucocorticoids, immunosuppressants, and plasma exchange, the administration of rituximab (RTX) resulted in rapid clinical improvement and glucocorticoid reduction. The literature review revealed 18 adult patients with DM associated MAS. Most patients developed MAS within 3 months from DM onset. A monotherapy of glucocorticoid was insufficient to control the disease, and the mortality of MAS in DM was higher than that of MAS in other rheumatic diseases, despite being treated by various means. RTX may be an effective treatment for patients with DM complicated by MAS who are refractory to conventional therapy. Anti-MDA5 antibody could influence the development of MAS; however, further investigations are needed to elucidate the association between myositis-specific antibody and MAS.

Cerebellar activation associated with model-based estimation of tool-use consequences.

BACKGROUND: Dexterous tool use is considered to be underpinned by model-based control relying on acquired internal models of tools. In particular, this is the case in situations where available sensory feedback regarding the consequences of tool use is restricted. In the present study, we conducted an fMRI study to identify cerebellar involvement in model-based estimation of tool-use consequences using tracking tasks with different levels of visual feedback. METHODS: Twenty healthy right-handed adults participated in this study. These participants tracked a moving target on a screen with a cursor controlled by a joystick using their right hand during fMRI scanning. For each trial, the level of visual feedback for cursor position was randomly selected from three task conditions, namely, Precise, Obscure, and No conditions. RESULTS: A conjunction analysis across all task conditions found extensive activation of the right cerebellum, covering the anterior lobe (lobule V) and inferior posterior lobe (lobule VIII). Also, contrasts among the three task conditions revealed additional significant activation of the left superior posterior lobe (Crus I) in the No compared to the Precise condition. Furthermore, a post hoc psychophysiological interaction analysis revealed conditional modulation of functional coupling between the right, but not the left, cerebellar region and right frontoparietal regions that are involved in self-body perception. CONCLUSIONS: Our data show that the left Crus I is the only region that was more active in a condition where no visual feedback for cursor position was available. This suggests that the left Crus I region plays a role in model-based estimation of tool-use consequences based on an acquired internal model of tools.

[Determination of Nonvolatile Amines in Foods by HPLC Following Fluorescamine Derivatization].

A method was developed for the determination of nonvolatile amines, such as histamine, tyramine, putrescine, and cadaverine, in foods. These nonvolatile amines were extracted from a sample with 5% trichloroacetic acid, and the extract was purified using an InertSep MC-1 cartridge column. The four amines were derivatized with fluorescamine, determined by HPLC with a fluorescence detector, and confirmed by LC-MS/MS. The average recoveries (n=5) and the relative standard deviations from 11 foods (pacific saury, dried mackerel, canned mackerel in brine, canned tuna in oil, fish sauce, surimi, rice-koji miso, soy sauce, gouda cheese, red wine, and beer) spiked at 100 mg/kg were 81-100% and 0.4-3.1%, respectively.

Hue Selectivity in Human Visual Cortex Revealed by Functional Magnetic Resonance Imaging.

The variability of color-selective neurons in human visual cortex is considered more diverse than cone-opponent mechanisms. We addressed this issue by deriving histograms of hue-selective voxels measured using fMRI with a novel stimulation paradigm, where the stimulus hue changed continuously. Despite the large between-subject difference in hue-selective histograms, individual voxels exhibited selectivity for intermediate hues, such as purple, cyan, and orange, in addition to those along cone-opponent axes. In order to rule the possibility out that the selectivity for intermediate hues emerged through spatial summation of activities of neurons selectively responding to cone-opponent signals, we further tested hue-selective adaptations in intermediate directions of cone-opponent axes, by measuring responses to 4 diagonal hues during concurrent adaptation to 1 of the 4 hues. The selective and unidirectional reduction in response to the adapted hue lends supports to our argument that cortical neurons respond selectively to intermediate hues.

Neural basis of decision making guided by emotional outcomes.

Emotional events resulting from a choice influence an individual's subsequent decision making. Although the relationship between emotion and decision making has been widely discussed, previous studies have mainly investigated decision outcomes that can easily be mapped to reward and punishment, including monetary gain/loss, gustatory stimuli, and pain. These studies regard emotion as a modulator of decision making that can be made rationally in the absence of emotions. In our daily lives, however, we often encounter various emotional events that affect decisions by themselves, and mapping the events to a reward or punishment is often not straightforward. In this study, we investigated the neural substrates of how such emotional decision outcomes affect subsequent decision making. By using functional magnetic resonance imaging (fMRI), we measured brain activities of humans during a stochastic decision-making task in which various emotional pictures were presented as decision outcomes. We found that pleasant pictures differentially activated the midbrain, fusiform gyrus, and parahippocampal gyrus, whereas unpleasant pictures differentially activated the ventral striatum, compared with neutral pictures. We assumed that the emotional decision outcomes affect the subsequent decision by updating the value of the options, a process modeled by reinforcement learning models, and that the brain regions representing the prediction error that drives the reinforcement learning are involved in guiding subsequent decisions. We found that some regions of the striatum and the insula were separately correlated with the prediction error for either pleasant pictures or unpleasant pictures, whereas the precuneus was correlated with prediction errors for both pleasant and unpleasant pictures.

Functional signalers of changes in visual stimuli: cortical responses to increments and decrements in motion coherence.

How does our brain detect changes in a natural scene? While changes by increments of specific visual attributes, such as contrast or motion coherence, can be signaled by an increase in neuronal activity in early visual areas, like the primary visual cortex (V1) or the human middle temporal complex (hMT+), respectively, the mechanisms for signaling changes resulting from decrements in a stimulus attribute are largely unknown. We have discovered opposing patterns of cortical responses to changes in motion coherence: unlike areas hMT+, V3A and parieto-occipital complex (V6+) that respond to changes in the level of motion coherence monotonically, human areas V4 (hV4), V3B, and ventral occipital always respond positively to both transient increments and decrements. This pattern of responding always positively to stimulus changes can emerge in the presence of either coherence-selective neuron populations, or neurons that are not tuned to particular coherences but adapt to a particular coherence level in a stimulus-selective manner. Our findings provide evidence that these areas possess physiological properties suited for signaling increments and decrements in a stimulus and may form a part of cortical vigilance system for detecting salient changes in the environment.

Demonstration of tuning to stimulus orientation in the human visual cortex: a high-resolution fMRI study with a novel continuous and periodic stimulation paradigm.

Cells in the animal early visual cortex are sensitive to contour orientations and form repeated structures known as orientation columns. At the behavioral level, there exist 2 well-known global biases in orientation perception (oblique effect and radial bias) in both animals and humans. However, their neural bases are still under debate. To unveil how these behavioral biases are achieved in the early visual cortex, we conducted high-resolution functional magnetic resonance imaging experiments with a novel continuous and periodic stimulation paradigm. By inserting resting recovery periods between successive stimulation periods and introducing a pair of orthogonal stimulation conditions that differed by 90° continuously, we focused on analyzing a blood oxygenation level-dependent response modulated by the change in stimulus orientation and reliably extracted orientation preferences of single voxels. We found that there are more voxels preferring horizontal and vertical orientations, a physiological substrate underlying the oblique effect, and that these over-representations of horizontal and vertical orientations are prevalent in the cortical regions near the horizontal- and vertical-meridian representations, a phenomenon related to the radial bias. Behaviorally, we also confirmed that there exists perceptual superiority for horizontal and vertical orientations around horizontal and vertical meridians, respectively. Our results, thus, refined the neural mechanisms of these 2 global biases in orientation perception.

Polyarteritis nodosa with central nervous system involvement mimicking relapsing-remitting multiple sclerosis.

We report a patient with polyarteritis nodosa (PN) who showed frequent episodes of acute-onset central nervous system (CNS) involvement mimicking relapsing-remitting multiple sclerosis (MS) for 22 years. Long-term use of oral prednisolone successfully avoided recurrence of neurological symptoms. PN can sometimes affect the CNS, and is an important item in the differential diagnosis of neurological manifestations with lesion dissemination in time and space, as seen in MS.

Developing intuition: neural correlates of cognitive-skill learning in caudate nucleus.

The superior capability of cognitive experts largely depends on automatic, quick information processing, which is often referred to as intuition. Intuition develops following extensive long-term training. There are many cognitive models on intuition development, but its neural basis is not known. Here we trained novices for 15 weeks to learn a simple board game and measured their brain activities in early and end phases of the training while they quickly generated the best next-move to a given board pattern. We found that the activation in the head of caudate nucleus developed over the course of training, in parallel to the development of the capability to quickly generate the best next-move, and the magnitude of the caudate activity was correlated with the subject's performance. In contrast, cortical activations, which already appeared in the early phase of training, did not further change. Thus, neural activation in the caudate head, but not those in cortical areas, tracked the development of capability to quickly generate the best next-move, indicating that circuitries including the caudate head may automate cognitive computations.

Clinical characteristics and treatment of elderly onset adult-onset Still's disease.

Adult-onset Still's disease (AOSD)-a systemic inflammatory disease-often occurs at a young age. Recently, elderly onset patient proportion has been increasing; however, data are limited. To evaluate the characteristics of elderly patients with AOSD in a multicenter cohort, we retrospectively analyzed 62 patients with AOSD at five hospitals during April 2008-December 2020. Patients were divided into two groups according to age at disease onset: younger-onset (≤ 64 years) and elderly onset (≥ 65 years). Clinical symptoms, complications, laboratory findings, treatment, and outcomes were compared. Twenty-six (41.9%) patients developed AOSD at age ≥ 65 years. The elderly onset group had a lower frequency of sore throat (53.8% vs. 86.1%), higher frequency of pleuritis (46.2% vs. 16.7%), and higher complication rates of disseminated intravascular coagulation (30.8% vs. 8.3%) and macrophage activation syndrome (19.2% vs. 2.8%) than the younger onset group. Cytomegalovirus infections were frequent in elderly onset patients (38.5% vs. 13.9%) but decreased with early glucocorticoid dose reduction and increased immunosuppressant and tocilizumab use. Elderly AOSD is not uncommon; these patients have different characteristics than younger-onset patients. Devising a way to control disease activity quickly while managing infections may be an important goal in elderly AOSD.

Opposing effects of contextual surround in human early visual cortex revealed by functional magnetic resonance imaging with continuously modulated visual stimuli.

Spatial context in vision has profound effects on neural responses and perception. Recent animal studies suggest that the effect of surround on a central stimulus can dramatically change its character depending on the contrast of the center stimulus, but such a drastic change has not been demonstrated in the human visual cortex. To examine the dependency of the surround effect on the contrast of the center stimulus, we conducted an functional magnetic resonance imaging experiment by using a low or a high contrast in the center region while the surround contrast was sinusoidally modulated between the two contrasts. We found that the blood oxygen level-dependent response in human V1 corresponding to the center region was differentially modulated by the surround contrast, depending crucially on the center contrast: whereas a suppressive effect was observed in conditions in which the center contrast was high, a facilitative effect was seen in conditions where the center contrast was low.

Processing of infant-directed speech by adults.

Adults typically address infants in a special speech mode called infant-directed speech (IDS). IDS is characterized by a special prosody (i.e., higher pitched, slower and hyperarticulated) and a special lexicon ("baby talk"). Here we investigated which areas of the adult brain are involved in processing IDS, which aspects of IDS (prosodic or lexical) are processed, to what extent the experience of being a parent affects the way adults process IDS, and the effects of gender and personality on IDS processing. Using functional magnetic resonance imaging, we found that mothers with preverbal infants showed enhanced activation in the auditory dorsal pathway of the language areas, regardless of whether they listened to the prosodic or lexical component of IDS. We also found that extroverted mothers showed higher cortical activation in speech-related motor areas than did mothers with lower extroverted personality scores. Increased cortical activation levels were not found for fathers, non-parents, or mothers with older children.

A temporal frequency-dependent functional architecture in human V1 revealed by high-resolution fMRI.

Although cortical neurons with similar functional properties often cluster together in a columnar organization, only ocular dominance columns, the columnar structure representing segregated anatomical input (from one of the two eyes), have been found in human primary visual cortex (V1). It has yet to be shown whether other columnar organizations that arise only from differential responses to stimulus properties also exist in human V1. Using high-resolution functional magnetic resonance imaging, we have found such a functional architecture containing domains that respond preferentially to either low or high temporal frequency.

Neuroplastic Reorganization Induced by Sensory Augmentation for Self-Localization During Locomotion.

Sensory skills can be augmented through training and technological support. This process is underpinned by neural plasticity in the brain. We previously demonstrated that auditory-based sensory augmentation can be used to assist self-localization during locomotion. However, the neural mechanisms underlying this phenomenon remain unclear. Here, by using functional magnetic resonance imaging, we aimed to identify the neuroplastic reorganization induced by sensory augmentation training for self-localization during locomotion. We compared activation in response to auditory cues for self-localization before, the day after, and 1 month after 8 days of sensory augmentation training in a simulated driving environment. Self-localization accuracy improved after sensory augmentation training, compared with the control (normal driving) condition; importantly, sensory augmentation training resulted in auditory responses not only in temporal auditory areas but also in higher-order somatosensory areas extending to the supramarginal gyrus and the parietal operculum. This sensory reorganization had disappeared by 1 month after the end of the training. These results suggest that the use of auditory cues for self-localization during locomotion relies on multimodality in higher-order somatosensory areas, despite substantial evidence that information for self-localization during driving is estimated from visual cues on the proximal part of the road. Our findings imply that the involvement of higher-order somatosensory, rather than visual, areas is crucial for acquiring augmented sensory skills for self-localization during locomotion.

The implication of interferon-γ-producing immunocompetent cells for evaluating disease activity and severity in adult-onset Still's disease.

OBJECTIVE: To investigate the relationship between interferon-γ (IFN-γ), IFN-γ-producing immunocompetent cells, their related cytokines, and the clinical features in adult-onset Still's disease (AOSD). METHODS: Twenty-five patients with AOSD before initiating treatment (acute AOSD), 9 patients after remission (remission AOSD), and 12 healthy controls (HC) were included. Circulating IFN-γ-producing CD4+ and CD8+ cells, natural killer (NK) cells, and IFN-γ production in NK cells were evaluated by flow cytometry. Serum levels of IFN-γ, interleukin (IL)-6, IL-12, IL-15, and IL-18 were also measured. The obtained results were statistically analyzed with clinical findings. RESULTS: Serum levels of IFN-γ, IL-6, IL-12, IL-18, intracellular expression of IFN-γ in CD4+, CD8+, and NK cells were significantly higher in acute AOSD than in HC. The proportion of NK cells was significantly lower in acute AOSD than in HC. Serum levels of IFN-γ and IFN-γ expression in CD4+ cells were significantly correlated with serum ferritin levels. The proportion of NK cells had a significant inverse correlation with serum IFN-γ levels. A lower proportion of NK cells was significantly noted in patients refractory to initial immunosuppressive treatment. In remission AOSD, serum levels of IL-6, IL-12, and IL-18 were significantly higher than in HC. CONCLUSION: Increased serum levels of IFN-γ, increased expression of IFN-γ in CD4+ cells, and decreased NK cell proportion correlate with disease activity in AOSD. Moreover, a lower proportion of NK cells may be useful for predicting a refractory clinical course. Meanwhile, increased serum levels of IL-6, IL-12, and IL-18 may persist after clinical remission.