Functional connectivity in autism spectrum disorder evaluated using rs-fMRI and DKI.

We evaluated functional connectivity (FC) in patients with adult autism spectrum disorder (ASD) using resting-state functional MRI (rs-fMRI) and diffusion kurtosis imaging (DKI). We acquired rs-fMRI data from 33 individuals with ASD and 33 healthy controls (HC) and DKI data from 18 individuals with ASD and 17 HC. ASD showed attenuated FC between the right frontal pole (FP) and the bilateral temporal fusiform cortex (TFusC) and enhanced FC between the right thalamus and the bilateral inferior division of lateral occipital cortex, and between the cerebellar vermis and the right occipital fusiform gyrus (OFusG) and the right lingual gyrus, compared with HC. ASD demonstrated increased axial kurtosis (AK) and mean kurtosis (MK) in white matter (WM) tracts, including the right anterior corona radiata (ACR), forceps minor (FM), and right superior longitudinal fasciculus (SLF). In ASD, there was also a significant negative correlation between MK and FC between the cerebellar vermis and the right OFusG in the corpus callosum, FM, right SLF and right ACR. Increased DKI metrics might represent neuroinflammation, increased complexity, or disrupted WM tissue integrity that alters long-distance connectivity. Nonetheless, protective or compensating adaptations of inflammation might lead to more abundant glial cells and cytokine activation effectively alleviating the degeneration of neurons, resulting in increased complexity. FC abnormality in ASD observed in rs-fMRI may be attributed to microstructural alterations of the commissural and long-range association tracts in WM as indicated by DKI.

Effects of long-term treatment with dietary theobromine on rat skeletal muscles.

BACKGROUND: Plastic changes of skeletal muscles, such as hypertrophy and atrophy, are dependent on physiological activities and regulated by a variety of signaling pathways, including cyclic adenosine monophosphate (cAMP) pathway. The cAMP inducing agents, such as the ß2-adrenergic agonist clenbuterol, are known to induce muscle hypertrophy, and has been reported to induce slow-to-fast transitions in rat soleus muscle. Theobromine, one of the active components of cacao, functions as an inhibitor of phosphodiesterase and increases cAMP. This study hypothesized that theobromine, like clenbuterol, can induce muscle hypertrophy and influence contractile properties. METHODS AND RESULTS: Male Wistar rats were fed a normal diet or a diet containing 0.05% theobromine for 20 weeks. Using biochemical, anatomical, and physiological techniques, effects of dietary theobromine on skeletal muscles (soleus, extensor digitorum longus, plantaris, and gastrocnemius) were examined. There were no significant differences in body weight, serum levels of proteins and lipids, muscle weights, dry/wet ratio of muscle weights, mitochondrial oxidation enzyme activity of muscles, isometric contractile properties of muscles, and muscle fatigue between control and theobromine-fed rats. Quantitative analysis of mRNA, however, revealed upregulation of myosin heavy chain 2x and myogenic differentiation 1, as previously reported in clenbuterol-treated muscles. CONCLUSION: The long-term theobromine (0.05%) diet in rats had no effect in inducing muscle hypertrophy and in changing contractile properties, although it had some similar effects of clenbuterol on muscle gene expression.

Blood lipid profile changes in type 2 diabetic rats after tail suspension and reloading.

PURPOSE: The effects of the tail suspension and reloading on the protein and lipid metabolism in muscle and blood in type 2 diabetes mellitus (T2DM) are unclear. This study evaluated the hypothesis that skeletal muscle catabolism is greater in T2DM than in non-diabetes mellitus (non-DM) rats and that the activity-dependent changes in the intramuscular lipid accumulation and blood lipid profile are poorer in T2DM than in non-DM rats. METHODS: T2DM and non-DM rats were suspended for two weeks followed by reloading for two weeks. The muscle and blood were then examined. RESULTS: In contrast to our hypothesis, there was no marked difference between the T2DM and non-DM groups in terms of the skeletal muscle catabolism and activity-dependent changes in intramuscular lipid accumulation. However, the blood lipid profile increased in the T2DM group compared to the non-DM group. One interesting finding in this study was the decrease in non-high-density lipoprotein (non-HDL) cholesterol levels after one week of reloading followed by a significant increase in the non-HDL cholesterol levels after two weeks of reloading in the T2DM group. CONCLUSION: These results suggest that a dramatic increase in activity after a period of inactivity may rapidly improve the blood lipid profile in T2DM rats.

Fast repetitive stretch suppresses denervation-induced muscle fibrosis.

BACKGROUND: We aimed to examine the influence of different speeds of stretching on denervation-induced skeletal muscle fibrosis. METHODS: Stretching was passively applied to rat plantaris muscle denervated by sciatic nerve excision in three different cycles of 0.5, 3, or 12 cycles/min, for 20 min/d for 2 weeks. RESULTS: Gene analysis results showed greater expression of fibrosis-related factors with fast stretching compared with non-stretched muscle. Laser Doppler blood flow analysis indicated reduced intramuscular blood flow during stretching. Histological analysis demonstrated fibrotic area decreases in 12 cycles/min stretched muscle compared with non-stretched muscle. CONCLUSIONS: Slower stretching induced greater mRNA expression of collagen and fibroblasts and greater decrement of blood flow. Histologically, faster stretching suppressed fibrosis. These results suggest that fast repetitive stretching of denervated muscle might suppress processes of muscle fibrosis.

Music Intervention Reduces Persistent Fibromyalgia Pain and Alters Functional Connectivity Between the Insula and Default Mode Network.

OBJECTIVE: The aims of the present study were to examine the effects of short-term music interventions among patients with fibromyalgia (FM) and to clarify the alterations in functional connectivity and persistent pain. DESIGN: Pilot study. SETTING: All participants were evaluated at Juntendo University from November 2017 to January 2019. SUBJECTS: We enrolled female patients who had been clinically diagnosed with FM (N = 23). METHODS: All participants listened to Mozart's Duo for Violin and Viola No. 1, K. 423, in a quiet room for 17 minutes. We compared the degree of pain using resting-state functional magnetic resonance imaging and the numeric rating scale before and after listening to music. RESULTS: Pain scores were significantly reduced after listening to music. Further, we observed there was a significant difference in connectivity between the right insular cortex (IC) and posterior cingulate cortex (PCC)/precuneus (PCu) before and after listening to music. We also found that the difference between the right IC-PCu connectivity and the difference in pain scores were significantly correlated. CONCLUSIONS: We found that a short period of music intervention reduced chronic pain and altered functional IC-default mode network connectivity. Furthermore, music potentially normalized the neural network via IC-default mode network connectivity, yielding temporary pain relief in patients with FM. Further longitudinal studies with larger sample sizes are required to confirm these results.

Mechanistic insights from sequential combination therapy with a sodium glucose co-transporter-2 inhibitor and a dipeptidyl peptidase-4 inhibitor: Results from the CANARIS Trial using canagliflozin and teneligliptin.

AIM: To elucidate the mechanisms involved in the sequential use of SGLT2 and DPP4 inhibitors (SGLT2i and DPP-4i). METHODS: Twenty-six type-2 diabetes mellitus patients were recruited into a stepped regimen of 100 mg of canagliflozin daily from day 1, supplemented with 20 mg of teneligliptin daily from day 4. Glucose (Glu), insulin and glucagon were measured at fasting and after ingesting a mixed meal on days 1, 4 and 6. RESULTS: Canagliflozin decreased fasting plasma glucose to an extent inversely proportional to the change in the glucagon-to-insulin (G/I) ratio. This correlation at fasting was maintained when adding teneligliptin, while the change in the area under the curve of Glu (GluAUC) correlated closely with that in the G/I ratio at fasting and 60 min with canagliflozin. Moreover, these correlations persisted at 60 and 120 min postprandially, but not at fasting on day 6 when teneligliptin was added. CONCLUSION: The result suggested that the dominant mechanism responsible for the glucose metabolism reflected in the G/I ratio was attributable to SGLT2i and that its active mechanism persisted, despite adding a DPP-4i.

Functional Connectivity of the Caudate in Schizophrenia Evaluated with Simultaneous Resting-State Functional MRI and Electroencephalography Recordings.

BACKGROUND: Aberrant functional connectivity (FC) is increasingly implicated in the clinical phenomenology of schizophrenia. This study focused on the FC of the cortico-striatal network, which is thought to be disrupted in schizophrenia and to contribute to its clinical manifestations. METHODS: We used simultaneous resting-state functional magnetic resonance imaging (rsfMRI) and electroencephalography (EEG) recordings to investigate FC in patients with schizophrenia. The study included 20 patients with schizophrenia and 20 healthy controls (HCs). Simultaneously recorded rsfMRI and EEG data were collected with an MR-compatible amplifier, and rsfMRI data were analyzed with the CONN toolbox to calculate FC. The study focused on the caudate, which was defined as the seed. We also performed between-group comparisons of standardized low-resolution electromagnetic tomography intracortical lagged coherence for each EEG frequency band. RESULTS: Compared to HCs, patients with schizophrenia showed enhanced FC between the caudate nucleus and the posterior cingulate cortex, temporal, and occipital regions on rsfMRI. It is thus possible that HCs have negative FC between these regions, whereas patients with schizophrenia have non-negative FC. The EEG results showed no significant differences in oscillations or in FC between the groups in any frequency band in any region. CONCLUSIONS: Increased FC in the caudate may represent aberrant between-network FC resulting from the disruption of segregation between networks.

White matter alterations in adult with autism spectrum disorder evaluated using diffusion kurtosis imaging.

PURPOSE: Autism spectrum disorder (ASD) is related to impairment in various white matter (WM) pathways. Utility of the recently developed two-compartment model of diffusion kurtosis imaging (DKI) to analyse axial diffusivity of WM is restricted by several limitations. The present study aims to validate the utility of model-free DKI in the evaluation of WM alterations in ASD and analyse the potential relationship between DKI-evident WM alterations and personality scales. METHODS: Overall, 15 participants with ASD and 15 neurotypical (NT) controls were scanned on a 3 T magnetic resonance (MR) scanner, and scores for autism quotient (AQ), systemising quotient (SQ) and empathising quotient (EQ) were obtained for both groups. Multishell diffusion-weighted MR data were acquired using two b-values (1000 and 2000 s/mm2). Differences in mean kurtosis (MK), radial kurtosis (RK) and axial kurtosis (AK) between the groups were evaluated using tract-based spatial statistics (TBSS). Finally, the relationships between the kurtosis indices and personality quotients were examined. RESULTS: The ASD group demonstrated significantly lower AK in the body and splenium of corpus callosum than the NT group; however, no other significant differences were identified. Negative correlations were found between AK and AQ or SQ, predominantly in WM areas related to social-emotional processing such as uncinate fasciculus, inferior fronto-occipital fasciculus, and inferior and superior longitudinal fasciculi. CONCLUSIONS: Model-free DKI and its indices may represent a novel, objective method for detecting the disease severity and WM alterations in patients with ASD.

The parietal opercular auditory-sensorimotor network in musicians: A resting-state fMRI study.

Auditory-sensorimotor coupling is critical for musical performance, during which auditory and somatosensory feedback signals are used to ensure desired outputs. Previous studies reported opercular activation in subjects performing or listening to music. A functional connectivity analysis suggested the parietal operculum (PO) as a connector hub that links auditory, somatosensory, and motor cortical areas. We therefore examined whether this PO network differs between musicians and non-musicians. We analyzed resting-state PO functional connectivity with Heschl's gyrus (HG), the planum temporale (PT), the precentral gyrus (preCG), and the postcentral gyrus (postCG) in 35 musicians and 35 non-musicians. In musicians, the left PO exhibited increased functional connectivity with the ipsilateral HG, PT, preCG, and postCG, whereas the right PO exhibited enhanced functional connectivity with the contralateral HG, preCG, and postCG and the ipsilateral postCG. Direct functional connectivity between an auditory area (the HG or PT) and a sensorimotor area (the preCG or postCG) did not significantly differ between the groups. The PO's functional connectivity with auditory and sensorimotor areas is enhanced in musicians relative to non-musicians. We propose that the PO network facilitates musical performance by mediating multimodal integration for modulating auditory-sensorimotor control.

Effect of hindlimb unloading and reloading on the soleus and plantaris muscles in diabetic rats.

[Purpose] This study aimed to induce disuse muscle atrophy in Goto-Kakizaki rats, a type 2 diabetes model, to investigate the effects of reloading on the soleus and plantaris muscles. [Materials and Methods] Wistar and Goto-Kakizaki (GK) rats were divided into 6 groups: Wistar Control (WC), GK Control (GC), Wistar Tail suspension (WS), GK Tail suspension (GS), and Wistar Reload (WR), GK Reload (GR). [Results] Investigation of myofiber cross-sectional area in Goto-Kakizaki rat soleus muscles indicated that the GS group showed significantly lower values than the GC and GR groups. No significant differences were observed between the GC and GR groups. However, investigation of plantaris muscles in Goto-Kakizaki rats indicated that the GS and GR groups showed a significant decrease compared to the GC group. No significant differences were found between the GS and GR groups. [Conclusion] Investigation of muscle weight/body weight ratios and myofiber cross-sectional area in tail suspension groups confirmed the induction of muscular atrophy. The differences in the degree of atrophy and recovery in terms of myofiber cross-sectional area observed in Goto-Kakizaki rat plantaris muscles may be influenced by the myofiber type and diabetes.

Effect of moderate exercise intensities on the cortical activity in young adults.

[Purpose] To examine the influence of different exercise intensities on cortical activity. [Participants and Methods] Twenty-six healthy adults aged 20-30 years performed exercise at three intensities on a bicycle ergometer as follows: (a) 15-minute exercise at 40% peak oxygen uptake, (b) same as (a) but at 60% peak oxygen uptake, and (c) 15 minutes of rest. The cognitive function of the participants was measured before and after exercise by the Paced Auditory Serial Addition Test (PASAT) under these three conditions. The cerebral blood flow in the left prefrontal and temporal cortices was measured using near-infrared spectroscopy during the PASAT. [Results] The PASAT score was significantly higher after exercise under condition (b) than before exercise (41.4 ± 9.1 vs. 47.7 ± 8.3). The cerebral blood flow in the prefrontal cortex under condition (b) was significantly increased compared to that under condition (c), as determined by the Tukey method (0.019 ± 0.030 vs. -0.008 ± 0.044). Significant differences were not observed in the cerebral blood flow in the temporal cortex under these three conditions. [Conclusion] Cortical activation of the frontal lobe increased after high-intensity aerobic exercise with no change in the cortical activity of the temporal lobe.

Simultaneous resting-state functional MRI and electroencephalography recordings of functional connectivity in patients with schizophrenia.

AIM: It remains unclear how functional connectivity (FC) may be related to specific cognitive domains in neuropsychiatric disorders. Here we used simultaneous resting-state functional magnetic resonance imaging (rsfMRI) and electroencephalography (EEG) recording in patients with schizophrenia, to evaluate FC within and outside the default mode network (DMN). METHODS: Our study population included 14 patients with schizophrenia and 15 healthy control participants. From all participants, we acquired rsfMRI data, and simultaneously recorded EEG data using an MR-compatible amplifier. We analyzed the rsfMRI-EEG data, and used the CONN toolbox to calculate the FC between regions of interest. We also performed between-group comparisons of standardized low-resolution electromagnetic tomography-based intracortical lagged coherence for each EEG frequency band. RESULTS: FC within the DMN, as measured by rsfMRI and EEG, did not significantly differ between groups. Analysis of rsfMRI data showed that FC between the right posterior inferior temporal gyrus and medial prefrontal cortex was stronger among patients with schizophrenia compared to control participants. CONCLUSION: Analysis of FC within the DMN using rsfMRI and EEG data revealed no significant differences between patients with schizophrenia and control participants. However, rsfMRI data revealed over-modulated FC between the medial prefrontal cortex and right posterior inferior temporal gyrus in patients with schizophrenia compared to control participants, suggesting that the patients had altered FC, with higher correlations across nodes within and outside of the DMN. Further studies using simultaneous rsfMRI and EEG are required to determine whether altered FC within the DMN is associated with schizophrenia.

Myogenic cell response to muscle contraction with short electrical stimulation.

[Purpose] The present study aimed to determine the effects of short muscle strength exercise on hepatocyte growth factor expression and satellite cell activation. [Subjects] The study included 72 2-12-week-old male Sprague-Dawley rats. [Methods] The rat plantaris muscle was contracted with a 5-min electrical stimulation of the sciatic nerve, and then, the mRNA expressions of hepatocyte growth factor and myogenic regulatory factors in the plantaris muscle were determined, and the phosphorylation of the hepatocyte growth factor receptor (c-Met) was examined. [Results] The mRNA expressions of hepatocyte growth factor and myogenic regulatory factors increased after a short muscle contraction compared to that un-contraction. Immunofluorescence analysis showed the expression of hepatocyte growth factor protein and the possibility that downstream biological changes occurred in the hepatocyte growth factor-bound c-Met. [Conclusion] Our results demonstrated that activation of satellite cells induced hepatocyte growth factor expression during muscle contraction with a short 5-min electrical stimulation, which simulates short muscle strength exercise in physical therapy. The present study provides evidence for the use of short muscle strength exercise in physical therapy.

Influence of exercise intensity on atrophied quadriceps muscle in the rat.

[Purpose] The aim of this study was to determine the effect of resistance training on atrophied skeletal muscle in rats based on evidence derived from physical therapy. [Subjects and Methods] Rats were forced to undergo squats as resistance training for 3 weeks after atrophying the rectus femoris muscle by hindlimb suspension for 2 weeks. The intensity of resistance training was adjusted to 50% and 70% of the maximum lifted weight, i.e., 50% of the one-repetition maximum and 70% of the one-repetition maximum, respectively. [Results] Three weeks of training did not alter the one-repetition maximum, and muscle fibers were injured while measuring the one-repetition maximum and reloading. The decrease in cross-sectional area in the rectus femoris muscle induced by unloading for 2 weeks was significantly recovered after training at 70% of the one-repetition maximum. The levels of muscle RING-finger protein-1 mRNA expression were significantly lower in muscles trained at 70% of the one-repetition maximum than in untrained muscles. [Conclusion] These results suggest that high-intensity resistance training can promote atrophic muscle recovery, which provides a scientific basis for therapeutic exercise methods for treatment of atrophic muscle in physical therapy.

Classification of schizophrenia patients and healthy controls using p100 event-related potentials for visual processing.

The study of event-related potentials (ERPs) is capable of elucidating the abnormalities in brain network dynamics relevant to the information-processing deficits in schizophrenia patients. In contrast to P50 and P300 ERPs, however, the results of P100 ERP studies in schizophrenia patients are less consistent. We have previously reported that P100 amplitudes did not differ significantly between patients with schizophrenia and healthy subjects. This result raised a question as to whether P100 ERPs carry information on brain network dynamics in schizophrenia patients that is distinct from normal controls. To answer this question, in this study we performed discrimination analysis on the P100 data. The rate of correct classification of patients and controls was high (80-90% depending on stimulus categories), indicating that patients have spatial patterns of P100 amplitudes that are distinguishable from those in healthy subjects. To further explore this possibility, we performed principal component analysis on the P100 data. For the patients, the first principal component represented global activity, the second component represented the reciprocal anterior-posterior activation, and the third component represented the hemispheric reciprocity in activity. The first and second components were similar to those of the control group; however, the third component in control subjects showed activation of the center versus anterior and posterior regions. This result is consistent with the notion of abnormalities in hemispheric asymmetries during the processing of sensory information in schizophrenia. In conclusion, this ERP study demonstrated that P100 amplitudes have information that can successfully classify patients and controls.

[Analysis of factors affecting the duration of treatment with sorafenib in patients with hepatocellular carcinoma].

The current status of treatment with sorafenib, and factors affecting the duration of treatment in patients started on sorafenib for hepatocellular carcinoma from July 2009 until April 2011 in the Department of Gastroenterology at Kobe City Medical Center General Hospital, were examined. Of 21 patients, 12 were able to continue the administration of sorafenib for more than one month, but 9 had to be discontinued within one month due to disease progression, worsening of general condition, and severe adverse reactions. In the group that was discontinued early, the rate of discontinuation due to side effects such as general fatigue, diarrhea, and hepatic encephalopathy was higher than in the long-term treatment group. On the other hand, hand-foot syndrome developed only in one case in both groups. The median value of PIVKA- II at the start of treatment in the long-term and early discontinued treatment groups were 672.5 and 14, 203 mAU/mL, respectively, and the values in the long-term group were significantly lower than those in the early-discontinued group (p < 0.05). From these results, the values of PIVKA-II at the start of sorafenib were considered to be factors affecting the continuation of sorafenib treatment. In addition, the dosing period was considered to be extended to focus on measures to take against the side effects of sorafenib within the early phase. Therefore, it was considered that these factors improved the effect of treatment with sorafenib in patients with hepatocellular carcinoma.

Corrigendum: Mirror neuron activity during audiovisual appreciation of opera performance.

[This corrects the article DOI: 10.3389/fpsyg.2020.563031.].

Development of Connective Tissue Area Increases by Initial Impact With High-Intensity Exercise After Reloading in Rat Soleus Muscle.

OBJECTIVE: The aim of the study is to clarify whether high-intensity exercise in atrophied skeletal muscle after reloading (1) increases the injury and promotes the development of the muscle connective tissue area in the soleus muscle and (2) delays muscle strength recovery. DESIGN: Rats had their hindlimbs suspended for 14 days followed by hindlimb reloading and squat exercise of 30% or 70%-one-repetition maximum exercise until 14 days of reloading. The influences of reloading and exercise in muscles were examined by histological and immunofluorescence analyses based on the exercise load. RESULTS: Seventy percent-one-repetition maximum exercise increased the extramyofiber area more than the control group and the central nuclear fiber number than the other groups after 7 days of reloading. Seventy percent-one-repetition maximum exercise resulted in a larger muscle connective tissue area than the control and reload groups after 14 days of reloading. Myogenin and M2-type macrophages after 7 days of reloading increased by reloading but were not increased by the exercise load. CONCLUSIONS: Seventy percent-one-repetition maximum exercise to atrophied muscle increased injury early in postreloading and increased the muscle connective tissue area after 14 days of reloading, but evidence that it delays muscle strength recovery was lacking. Therefore, muscle connective tissue area induced by high-intensity exercise after reloading seems to be associated with initial exercise damage but not with repetition over 14 days.

Distorted neurocomputation by a small number of extra-large spines in psychiatric disorders.

Human genetics strongly support the involvement of synaptopathy in psychiatric disorders. However, trans-scale causality linking synapse pathology to behavioral changes is lacking. To address this question, we examined the effects of synaptic inputs on dendrites, cells, and behaviors of mice with knockdown of SETD1A and DISC1, which are validated animal models of schizophrenia. Both models exhibited an overrepresentation of extra-large (XL) synapses, which evoked supralinear dendritic and somatic integration, resulting in increased neuronal firing. The probability of XL spines correlated negatively with working memory, and the optical prevention of XL spine generation restored working memory impairment. Furthermore, XL synapses were more abundant in the postmortem brains of patients with schizophrenia than in those of matched controls. Our findings suggest that working memory performance, a pivotal aspect of psychiatric symptoms, is shaped by distorted dendritic and somatic integration via XL spines.

[Safety of pemetrexed mono-therapy in elderly patients with non-small cell lung cancer].

Safety of pemetrexed mono-therapy in elderly patients with non-small-cell lung cancer was examined between May 2009 and April 2010 at Kobe City Medical Center General Hospital . The numbers of non-elderly and elderly(over 70 years old)patients were 14 and 19, respectively. Rates of neutropenia over Grade 3 were 14. 3% in the non-elderly group, and 36. 8% in the elderly group(p=0. 297). However, febrile neutropenia was only seen in one case in each group(p=0. 606), and no treatment-related death was observed. Although the rates of rash appearance were 28. 6% and 36. 8%(p=0. 347)for the non-elderly and the elderly, respectively, most rashes were relieved by steroids. From these results, pemetrexed mono-therapy is considered one of the applicable regimens for elderly patients.