Perceptual uncertainty modulates auditory statistical learning: A magnetoencephalography study.

Statistical learning allows comprehension of structured information, such as that in language and music. The brain computes a sequence's transition probability and predicts future states to minimise sensory reaction and derive entropy (uncertainty) from sequential information. Neurophysiological studies have revealed that early event-related neural responses (P1 and N1) reflect statistical learning - when the brain encodes transition probability in stimulus sequences, it predicts an upcoming stimulus with a high transition probability and suppresses the early event-related responses to a stimulus with a high transition probability. This amplitude difference between high and low transition probabilities reflects statistical learning effects. However, how a sequence's transition probability ratio affects neural responses contributing to statistical learning effects remains unknown. This study investigated how transition-probability ratios or conditional entropy (uncertainty) in auditory sequences modulate the early event-related neuromagnetic responses of P1m and N1m. Sequence uncertainties were manipulated using three different transition-probability ratios: 90:10%, 80:20%, and 67:33% (conditional entropy: 0.47, 0.72, and 0.92 bits, respectively). Neuromagnetic responses were recorded when participants listened to sequential sounds with these three transition probabilities. Amplitude differences between lower and higher probabilities were larger in sequences with transition-probability ratios of 90:10% and smaller in sequences with those of 67:33%, compared to sequences with those of 80:20%. This suggests that the transition-probability ratio finely tunes P1m and N1m. Our study also showed larger amplitude differences between frequent- and rare-transition stimuli in P1m than in N1m. This indicates that information about transition-probability differences may be calculated in earlier cognitive processes.

Age-Dependent Echocardiographic and Pathologic Findings in a Rat Model with Duchenne Muscular Dystrophy Generated by CRISPR/Cas9 Genome Editing.

Duchenne muscular dystrophy (DMD) is X-linked recessive myopathy caused by mutations in the dystrophin gene. Although conventional treatments have improved their prognosis, inevitable progressive cardiomyopathy is still the leading cause of death in patients with DMD. To explore novel therapeutic options, a suitable animal model with heart involvement has been warranted.We have generated a rat model with an out-of-frame mutation in the dystrophin gene using CRISPR/Cas9 genome editing (DMD rats). The aim of this study was to evaluate their cardiac functions and pathologies to provide baseline data for future experiments developing treatment options for DMD.In comparison with age-matched wild rats, 6-month-old DMD rats showed no significant differences by echocardiographic evaluations. However, 10-month-old DMD rats showed significant deterioration in left ventricular (LV) fractional shortening (P = 0.024), and in tissue Doppler peak systolic velocity (Sa) at the LV lateral wall (P = 0.041) as well as at the right ventricular (RV) free-wall (P = 0.004). These functional findings were consistent with the fibrotic distributions by histological analysis.Although the cardiac phenotype was milder than anticipated, DMD rats showed similar distributions and progression of heart involvement to those of patients with DMD. This animal may be a useful model with which to develop effective drugs and to understand the underlying mechanisms of progressive heart failure in patients with DMD.

Pathological evaluation of rats carrying in-frame mutations in the dystrophin gene: a new model of Becker muscular dystrophy.

Dystrophin, encoded by the DMD gene on the X chromosome, stabilizes the sarcolemma by linking the actin cytoskeleton with the dystrophin-glycoprotein complex (DGC). In-frame mutations in DMD cause a milder form of X-linked muscular dystrophy, called Becker muscular dystrophy (BMD), characterized by the reduced expression of truncated dystrophin. So far, no animal model with in-frame mutations in Dmd has been established. As a result, the effect of in-frame mutations on the dystrophin expression profile and disease progression of BMD remains unclear. In this study, we established a novel rat model carrying in-frame Dmd gene mutations (IF rats) and evaluated the pathology. We found that IF rats exhibited reduced expression of truncated dystrophin in a proteasome-independent manner. This abnormal dystrophin expression caused dystrophic changes in muscle tissues but did not lead to functional deficiency. We also found that the expression of additional dystrophin named dpX, which forms the DGC in the sarcolemma, was associated with the appearance of truncated dystrophin. In conclusion, the outcomes of this study contribute to the further understanding of BMD pathology and help elucidate the efficiency of dystrophin recovery treatments in Duchenne muscular dystrophy, a more severe form of X-linked muscular dystrophy.

Usefulness of Carotid Arterial Strain Values for Evaluating the Arteriosclerosis.

AIM: We investigated the clinical usefulness of carotid arterial strain and the strain rate for evaluating the progression of arteriosclerosis measured using a two-dimensional speckle-tracking method in carotid ultrasonography. METHODS: We enrolled 259 participants (age: 64±12 years; men: 149; women: 110) in this retrospective analysis. The circumferential strain and the strain rate were measured in bilateral common carotid arteries, and the lowest values were used for the analyses. To assess the characteristics of strain and the strain rate, we investigated the associations between the strain values and gender, age, body mass index (BMI), blood pressure (BP), and the presence of hypertension, diabetes mellitus, and hyperlipidemia. We also examined the explanatory factors for the strain values using clinical parameters along with the intima-media thickness (IMT), the ankle brachial index (ABI), and the cardio-ankle vascular index (CAVI) as possible candidates. Finally, we investigated whether the strain values might be an independent predictor for vascular diseases using multivariate logistic regression analyses. RESULTS: The carotid circumferential strain and the strain rate were significantly correlated with age, IMT, and the CAVI, but not with the BMI, BP, or ABI. Strain and the strain rates were lower in participants with hypertension or cerebrovascular disease and were selected as significant predictive factors for the presence of cerebrovascular diseases, together with diabetes and the CAVI. CONCLUSIONS: Strain and the strain rate of carotid arteries, which could represent local arterial stiffness, might be associated with atherosclerosis and could possibly be used to predict cerebrovascular disease.

Evaluation of right ventricle by speckle tracking and conventional echocardiography in rats with right ventricular heart failure.

Speckle tracking echocardiography (STE) has been reported to be a promising technique for evaluating right ventricular (RV) function in the clinical setting. On the other hand, the usefulness of STE for RV evaluation in small animal models has not been clarified, although the rat model is among the most commonly used animal models to develop novel effective treatments against pulmonary hypertension and RV heart failure (HF).We validated the use of STE and conventional echocardiographic variables for evaluating RV functions in a rat model by comparing the echocardiographic values of RVHF rats (n = 12) induced by monocrotaline injection with those of control rats (n = 12).Most conventional echocardiographic variables demonstrated that RVHF rats have significant RV dysfunction. The area under the curve (AUC) values to distinguish RV dysfunction in RVHF rats from normal RV function in control rats using fractional area change (FAC), tricuspid annular plane systolic excursion (TAPSE), RV myocardial performance index (MPI), peak tissue Doppler tricuspid annular velocities at systole (Sa), and at early diastole (Ea) were 0.71, 0.98, 0.79, 0.92, and 0.91, respectively. However, using STE analysis for RV evaluation, limited reproducibility was observed (variability 19-37 %, ICC 0.74-0.88) and the only circumferential strain showed significantly lower absolute values (P = 0.039, AUC = 0.76).To evaluate RV function in rat models, circumferential strain may be useful, however, the reproducibility and diagnostic utility were limited. Conventional echocardiographic variables such as TAPSE, tissue Doppler Sa, and Ea have superior diagnostic utility.

Speckle tracking global strain rate E/E' predicts LV filling pressure more accurately than traditional tissue Doppler E/E'.

BACKGROUND: The ratio of early diastolic transmitral flow velocity (E) to tissue Doppler (TD) mitral annular early diastolic velocity (E/E'(VEL-TD)) has been widely used for the noninvasive assessment of LV diastolic filling pressures. However, it has been reported that E/E'(VEL-TD) is not accurate particularly when being applied to patients with advanced heart failure. METHODS: Fifty-six ICU patients with decompensated heart failure underwent simultaneous echocardiography and PCWP measurements. Patients with elevated PCWP (n = 41) were compared with patients normal PCWP (n = 15) as well as age-matched healthy controls (n = 32). In the apical 4-chamber view, the ratio of E to speckle tracking (ST) mitral annular velocity (E/E'(VEL-ST)) and early diastolic global LV longitudinal strain rate (E/E'(SR-ST)) were evaluated as new surrogate markers of elevated PCWP. RESULTS: Correlations with PCWP were observed for speckle tracking derived E/E'(VEL-ST) (r = 0.40,P = 0.002) and E/E'(SR-ST) (r = 0.56, P < 0.001), although the traditional E/E'(VEL-TD) did not show a significant correlation (r = 0.23, P = 0.082). Compared with controls, patients with elevated PCWP had significant increases in all variables. The best cutoff values and diagnostic accuracies for identifying elevated PCWP were E/E'(VEL-TD) >12 (Sensitivity/Specificity/area under the ROC curve: 0.58/0.90/0.78), E/E'(VEL-ST) > 14 (0.60/0.85/0.80), and E/E'(SR-ST) > 93 (0.80/0.88/0.89). CONCLUSION: Speckle tracking derived E/E'(SR-ST) may be a robust surrogate marker of elevated LV filling pressure. In ICU patients, E/E'(SR-ST) showed better correlation with PCWP and higher diagnostic accuracy than the tissue Doppler approach.

Where do neurologists look when viewing brain CT images? An eye-tracking study involving stroke cases.

The aim of this study was to investigate where neurologists look when they view brain computed tomography (CT) images and to evaluate how they deploy their visual attention by comparing their gaze distribution with saliency maps. Brain CT images showing cerebrovascular accidents were presented to 12 neurologists and 12 control subjects. The subjects' ocular fixation positions were recorded using an eye-tracking device (Eyelink 1000). Heat maps were created based on the eye-fixation patterns of each group and compared between the two groups. The heat maps revealed that the areas on which control subjects frequently fixated often coincided with areas identified as outstanding in saliency maps, while the areas on which neurologists frequently fixated often did not. Dwell time in regions of interest (ROI) was likewise compared between the two groups, revealing that, although dwell time on large lesions was not different between the two groups, dwell time in clinically important areas with low salience was longer in neurologists than in controls. Therefore it appears that neurologists intentionally scan clinically important areas when reading brain CT images showing cerebrovascular accidents. Both neurologists and control subjects used the "bottom-up salience" form of visual attention, although the neurologists more effectively used the "top-down instruction" form.

Retrotransposon-mediated Fgf5(go-Utr) mutant mice with long pelage hair.

We found 6 spontaneous mutant mice with long pelage hair in our ICR breeding colony. The abnormal trait was restricted to long hair in these mice, which we named moja. They were fertile and showed the same growth and behavior as wild-type mice. To investigate the manner of the genetic inheritance of the moja allele, offspring were bred by mating the moja mice; all offspring had long pelage hair. Furthermore, we performed a reciprocal cross between moja mice and wild-type ICR mice with normal hair. All offspring exhibited normal hair suggesting an autosomal recessive inheritance of the trait. The moja/moja hair phenotype was maintained in skin grafted onto nude mice, suggesting that circulating or diffusible humoral factors regulating the hair cycle are not involved in the abnormal trait. The phenotype of moja/moja mice is similar to that of Fgf5-deficient mice. Therefore, we examined the expression of Fgf5 by RT-PCR in moja/moja mice. As expected, no Fgf5 expression was found in moja/moja mouse skin. PCR and DNA sequence analyses were performed to investigate the structure of the Fgf5 gene. We found a deletion of a 9.3-kb region in the Fgf5 gene including exon 3 and its 5' and 3' flanking sequences. Interestingly, the genomic deletion site showed insertion of a 498-bp early transposon element long terminal repeat. Taken together, these results suggest that the long hair mutation of moja/moja mice is caused by disruption of Fgf5 mediated by insertion of a retrotransposon.

Thrombocytopenia is more severe in patients with advanced chronic hepatitis C than B with the same grade of liver stiffness and splenomegaly.

BACKGROUND AND AIM: The mechanism responsible for thrombocytopenia in chronic liver diseases (CLD) is not yet fully understood. The prevalence of thrombocytopenia has been reported to be higher in patients with hepatitis C virus-related hepatocellular carcinoma (CLD-C) than in those with hepatitis B virus-related hepatocellular carcinoma (CDC-B). We have examined the potential difference in thrombocytopenia between patients with CLD-B and those with CLD-C in terms of liver fibrosis adjustment and splenomegaly. METHODS: The study cohort consisted of 102 patients with CLD-B and 143 patients with CLD-C were enrolled. Liver stiffness, which is reported to be well correlated with the degree of liver fibrosis, was measured by transient elastography. RESULTS: The analysis of covariance with liver stiffness as a covariate revealed that the platelet count was lower in CLD-C patients than in CLD-B patients. Following stratification for liver stiffness, thrombocytopenia was found to be more severe in CLD-C patients than CLD-B patients with advanced liver stiffness, whereas the degree of splenomegaly was not significantly different. The plasma thrombopoietin level was not different between CLD-B and CLD-C patients with advanced liver stiffness, and the immature platelet number was lower in CLD-C patients despite thrombocytopenia being more severe in these patients. CONCLUSIONS: CLD-C patients with advanced liver stiffness presented with more severe levels of thrombocytopenia than CLD-B patients even with the same grade of splenomegaly. Impaired platelet production rather than enhanced platelet destruction may underlie the mechanism responsible for thrombocytopenia in patients with CLD.

The effect of electromagnetic field emitted by a mobile phone on the inhibitory control of saccades.

OBJECTIVE: To investigate whether exposure to a pulsed high-frequency electromagnetic field (pulsed EMF) emitted by a mobile phone has short-term effects on the inhibitory control of saccades. METHODS: A double-blind, counterbalanced crossover study design was employed. We assessed the performance of 10 normal subjects on antisaccade (AS) and cued saccade (CUED) tasks as well as two types of overlap saccade (OL1, OL2) task before and after 30 min of exposure to EMF emitted by a mobile phone or sham exposure. RESULTS: After EMF or sham exposure, we observed a slight but significant shortening of latency in the CUED and OL2 tasks. AS amplitude decreased as well as the saccade velocities in the AS, CUED, and OL1 tasks after exposure. These changes occurred regardless of whether exposure was real or sham. The frequencies of pro-saccades in the AS task, saccades to cue in the CUED task, and prematurely initiated saccades in the overlap (OL2) task did not change significantly after real or sham EMF exposure. CONCLUSIONS: Thirty minutes of mobile phone exposure has no significant short-term effect on the inhibitory control of saccades. SIGNIFICANCE: The cortical processing responsible for saccade inhibition is not affected by exposure to EMF emitted by a mobile phone.

Antigen-specific IL-23/17 pathway activation by murine semi-mature DC-like cells.

We analyzed the phenotype and function of bone marrow-derived dendritic cells (DCs) induced in vitro without using any serum during the late stage of cultivation. These 'serum-free' DCs (SF-DCs) possessed the ability to induce T cell proliferation as well as antibody responses, indicating that they were functional DCs. Surprisingly, the SF-DCs akin to semi-mature DCs in terms of both phenotypic and functional characteristics. The SF-DCs did not produce IL-12 but produced large amounts of IL-23 following lipopolysaccharide stimulation. The antigen-specific production of IL-17 by CD4(+) T cells co-cultured with OVA-loaded SF-DCs was significantly higher than that with OVA-loaded conventional DCs. These results suggest that SF-DCs tend to produce IL-23 and can consequently induce the IL-17 producing CD4(+) T cells. The semi-mature DC-like cells reported here will be useful vehicles for DC immunization and might contribute to studies on the possible involvement of semi-mature DCs in Th17 cell differentiation.

Effects of short-term W-CDMA mobile phone base station exposure on women with or without mobile phone related symptoms.

To investigate possible health effects of mobile phone use, we conducted a double-blind, cross-over provocation study to confirm whether subjects with mobile phone related symptoms (MPRS) are more susceptible than control subjects to the effect of electromagnetic fields (EMF) emitted from base stations. We sent questionnaires to 5,000 women and obtained 2,472 valid responses from possible candidates; from these, we recruited 11 subjects with MPRS and 43 controls. There were four EMF exposure conditions, each of which lasted 30 min: continuous, intermittent, and sham exposure with and without noise. Subjects were exposed to EMF of 2.14 GHz, 10 V/m (W-CDMA), in a shielded room to simulate whole-body exposure to EMF from base stations, although the exposure strength we used was higher than that commonly received from base stations. We measured several psychological and cognitive parameters pre- and post-exposure, and monitored autonomic functions. Subjects were asked to report on their perception of EMF and level of discomfort during the experiment. The MPRS group did not differ from the controls in their ability to detect exposure to EMF; nevertheless they consistently experienced more discomfort, regardless of whether or not they were actually exposed to EMF, and despite the lack of significant changes in their autonomic functions. Thus, the two groups did not differ in their responses to real or sham EMF exposure according to any psychological, cognitive or autonomic assessment. In conclusion, we found no evidence of any causal link between hypersensitivity symptoms and exposure to EMF from base stations.

Effects of thirty-minute mobile phone exposure on saccades.

OBJECTIVE: To investigate whether exposure to pulsed high-frequency electromagnetic field (pulsed EMF) emitted by a mobile phone has short-term effects on saccade performances. METHODS: A double blind, counterbalanced crossover design was employed. In 10 normal subjects, we studied the performance of visually guided saccade (VGS), gap saccade (GAP), and memory guided saccade (MGS) tasks before and after exposure to EMF emitted by a mobile phone for thirty minutes or sham exposure. We also implemented a hand reaction time (RT) task in response to a visual signal. RESULTS: With the exception of VGS and MGS latencies, the parameters of VGS, GAP and MGS tasks were unchanged before and after real or sham EMF exposure. In addition, the latencies of VGS and MGS did not change differently after real and sham exposure. The hand RT shortened with the repetition of trials, but again this trend was of similar magnitude for real and sham exposures. CONCLUSIONS: Thirty minutes of mobile phone exposure has no significant short-term effect on saccade performances. SIGNIFICANCE: This is the first study to investigate saccade performance in relation to mobile phone exposure. No significant effect of mobile phone use was demonstrated on the performance of various saccade tasks, suggesting that the cortical processing for saccades and attention is not affected by exposure to EMF emitted by a mobile phone.

Median nerve somatosensory evoked potentials and their high-frequency oscillations in amyotrophic lateral sclerosis.

OBJECTIVE: To investigate sensory cortical changes in amyotrophic lateral sclerosis (ALS), we studied somatosensory evoked potentials (SEPs) and their high-frequency oscillation potentials. METHODS: Subjects were 15 healthy volunteers and 26 ALS patients. Median nerve SEPs were recorded and several peaks of oscillations were obtained by digitally filtering raw SEPs. The patients were sorted into three groups according to the level of weakness of abductor pollicis brevis muscle (APB): mild, moderate and severe. The latencies and amplitudes of main and oscillation components of SEP were compared among normal subjects and the three patient groups. RESULTS: The early cortical response was enlarged in the moderate weakness group, while it was attenuated in the severe weakness group. No differences were noted in the size ratios of oscillations to the main SEP component between the patients and normal subjects. The central sensory conduction time (CCT) and N20 duration were prolonged in spite of normal other latencies. CONCLUSIONS: The median nerve SEP amplitude changes are associated with motor disturbances in ALS. The cortical potential enhancement of SEPs with moderate weakness in ALS may reflect some compensatory function of the sensory cortex for motor disturbances. SIGNIFICANCE: The sensory cortical compensation for motor disturbances is shown in ALS, which must be important information for rehabilitation.

[A case of anti-MuSK antibody-positive myasthenia gravis with dropped head as the initial presenting symptom].

A 53-year-old woman was admitted to our hospital because of dropped head. Neurological examination showed no abnormality except for weakness of the neck extensor muscles. Her symptoms worsened in the evening, requiring her to support her head by placing her hand against her chin. Edrophonium and repetitive stimulation tests gave negative results, and anti-acetylcholine receptor antibodies were not detected. She had no thymoma. However, she was found to have a high serum titer of anti-MuSK antibody (37.3 nM). She was diagnosed as having myasthenia gravis (MG) and treatment with pyridostigmine was started. However, this had to be withdrawn because of fasciculation as an adverse effect. She was therefore treated with prednisolone, and this resulted in marked improvement. The initial presenting symptom in this case was dropped head, and there were none of the results of laboratory or electrophysiological examinations that are usually typical of MG. MG was eventually diagnosed by measurement of anti-MuSK antibody. The present case suggests that a patient presenting with dropped head without any obvious cause needs to be studied for the presence of anti-MuSK antibody.

Effects of thirty-minute mobile phone use on visuo-motor reaction time.

OBJECTIVE: To investigate whether exposure to pulsed high-frequency electromagnetic field (pulsed EMF) emitted by a mobile phone has short-term effects on the visuo-motor choice reaction time (RT) and movement time (MT). METHODS: A double blind, counterbalanced crossover design was employed. In 16 normal subjects, we studied the performance of a visuo-motor precued choice reaction time task (PCRT) before and after exposure to EMF emitted by a mobile phone for 30 minutes or sham exposure. RESULTS: The RTs and MTs under different conditions of precue information were not affected by exposure to pulsed EMF emitted by a mobile phone or by sham phone use. CONCLUSIONS: Thirty minutes of mobile phone use has no significant short-term effect on the cortical visuo-motor processing as studied by the present PCRT task. SIGNIFICANCE: This is the first study to investigate visuo-motor behavior in relation to mobile phone exposure. No significant effect of mobile phone use was demonstrated on the performance of the visuo-motor reaction time task.