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.

Nociplastic pain: towards an understanding of prevalent pain conditions.

Nociplastic pain is the semantic term suggested by the international community of pain researchers to describe a third category of pain that is mechanistically distinct from nociceptive pain, which is caused by ongoing inflammation and damage of tissues, and neuropathic pain, which is caused by nerve damage. The mechanisms that underlie this type of pain are not entirely understood, but it is thought that augmented CNS pain and sensory processing and altered pain modulation play prominent roles. The symptoms observed in nociplastic pain include multifocal pain that is more widespread or intense, or both, than would be expected given the amount of identifiable tissue or nerve damage, as well as other CNS-derived symptoms, such as fatigue, sleep, memory, and mood problems. This type of pain can occur in isolation, as often occurs in conditions such as fibromyalgia or tension-type headache, or as part of a mixed-pain state in combination with ongoing nociceptive or neuropathic pain, as might occur in chronic low back pain. It is important to recognise this type of pain, since it will respond to different therapies than nociceptive pain, with a decreased responsiveness to peripherally directed therapies such as anti-inflammatory drugs and opioids, surgery, or injections.

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.

The E3 ligase synoviolin controls body weight and mitochondrial biogenesis through negative regulation of PGC-1ß.

Obesity is a major global public health problem, and understanding its pathogenesis is critical for identifying a cure. In this study, a gene knockout strategy was used in post-neonatal mice to delete synoviolin (Syvn)1/Hrd1/Der3, an ER-resident E3 ubiquitin ligase with known roles in homeostasis maintenance. Syvn1 deficiency resulted in weight loss and lower accumulation of white adipose tissue in otherwise wild-type animals as well as in genetically obese (ob/ob and db/db) and adipose tissue-specific knockout mice as compared to control animals. SYVN1 interacted with and ubiquitinated the thermogenic coactivator peroxisome proliferator-activated receptor coactivator (PGC)-1ß, and Syvn1 mutants showed upregulation of PGC-1ß target genes and increase in mitochondrion number, respiration, and basal energy expenditure in adipose tissue relative to control animals. Moreover, the selective SYVN1 inhibitor LS-102 abolished the negative regulation of PGC-1ß by SYVN1 and prevented weight gain in mice. Thus, SYVN1 is a novel post-translational regulator of PGC-1ß and a potential therapeutic target in obesity treatment.

The Endometriosis Fertility Index Is Useful for Predicting the Ability to Conceive without Assisted Reproductive Technology Treatment after Laparoscopic Surgery, Regardless of Endometriosis.

OBJECTIVE: The endometriosis fertility index (EFI) is a novel index for predicting pregnancy after surgery. We investigated the utility of the EFI for predicting the ability to conceive without assisted reproductive technology (ART) treatment after laparoscopic surgery. METHODS: From July 2011 through December 2012, we recruited 133 infertile patients who underwent laparoscopy, and the EFI was calculated. After surgery, 55 of 133 achieved pregnancy without ART treatment. We evaluated the factors that predicted a naturally successful pregnancy and compared them between the pregnant and non-pregnant subjects. RESULTS: On a univariate linear regression analysis, we found that a younger age, shorter duration of infertility, and higher EFI were positively associated with a successful pregnancy without ART after laparoscopic surgery (p < 0.05). According to 50th percentile EFI, the cutoff EFI predicting a successful pregnancy without ART was 7, the pregnancy rate in the high-EFI group (EFI; 8-10) was significantly higher than that in the low-EFI group (EFI ≤7; p < 0.05), but the duration to natural conception after surgery was similar between the 2 groups. CONCLUSION: The EFI possesses greater predictive power for a successful pregnancy with natural intercourse or intrauterine insemination in infertile patients, regardless of endometriosis, than the Revised-American Society of Reproductive Medicine classification.

Antipsychotics for delirium in the general hospital setting in consecutive 2453 inpatients: a prospective observational study.

OBJECTIVE: Attention to risk of antipsychotics for older patients with delirium has been paid. A clinical question was whether risk of antipsychotics for older patients with delirium would exceed efficacy of those even in the general hospital setting. METHODS: A prospective observational study proceeded over a 1-year period at 33 general hospitals, where at least one psychiatrist worked full time. Subjects were patients who developed delirium during their admission due to acute somatic diseases or surgery, and who received antipsychotics for delirium. The primary outcome was rates and kinds of serious adverse events. RESULTS: Among 2834 patients who developed delirium, 2453 patients received antipsychotics, such as risperidone (34%), quetiapine (32%), and parenteral haloperidol (20%), for delirium. Out of 2453 patients, 22 serious adverse events (0.9%) were reported. Aspiration pneumonia was the most frequent (17 patients, 0.7%), followed by cardiovascular events (4 patients, 0.2%) and venous thromboembolism (1 patient, 0.0%). There was no patient with a fracture or intracranial injury due to a fall. No one died because of antipsychotic side effects. The mean Clinical Global Impressions-Improvement Scale score was 2.02 (SD 1.09). Delirium was resolved within 1 week in more than half of the patients (54%). CONCLUSIONS: In the general hospital setting under management including fine dosage adjustment and early detection of side effects, risk of antipsychotics for older patients with delirium might be low, in contrast to antipsychotics for dementia in the nursing home or outpatient settings. A point may be not how to avoid using antipsychotics but how to monitor their risk.

Effect of continuous positive airway pressure on regional cerebral blood flow during wakefulness in obstructive sleep apnea.

BACKGROUND: The alteration of regional cerebral blood flow (rCBF) during wakefulness after the treatment for obstructive sleep apnea syndrome (OSA) using continuous positive airway pressure (CPAP) has not been elucidated. The aim of this study was to investigate rCBF characteristics and the effects of nasal CPAP in OSA patients. METHODS: Fifteen severe OSA patients (apnea-hypopnea index, 62.7 ± 22.4/h), when awake, underwent Technetium-99m ethyl cysteinate dimer single photon emission computed tomography before and after CPAP treatment, and the findings were compared to those of nine healthy controls matched for age and sex. RESULTS: Compared to controls, patients with OSA before CPAP treatment showed a significantly lower rCBF in the frontal lobe. After the treatment, no difference in rCBF was observed between the good CPAP compliance group and the controls. In the former group, there was a positive correlation between the 3% oxygen desaturation index on diagnostic polysomnogram and the increase of rCBF after CPAP treatment in the frontal lobe. CONCLUSIONS: When awake, patients with severe OSA were shown to have reversible decreases in rCBF, especially in the frontal lobe, and an appropriate CPAP treatment was thought to improve rCBF in this area. Our results support the importance of appropriate CPAP treatment for severe OSA patients.

[Viewing 3D stereoscopic images in children and adults with and without strabismus: multicenter study in Japan].

PURPOSE: To investigate the ability of patients with strabismus and/or amblyopia to see 3D images. METHODS: A questionnaire survey conducted for children aged 6 to 19 years and adults aged 20 to 39 years on their experience of viewing 3D images (movies, motion attractions, television, games), asking whether they could see stereoscopically, with or without adverse effects. A retrospective investigation of ophthalmological examinations was followed. RESULTS: Of 507 cases, 342 had had the experience of veiwing 3D images. In 212 (62%) cases of strabismus and/or amblyopia, stereopsis was lacking in 17 to 18% of the subjects for movies, in 6 to 7% for attractions, in 32% in children and 50% in adults for television and 23% in children and 17% in adults for games. Adults complained of a higher rate of adverse effects, 65% for movies and 75% for games, as compared with 34% for movies and 26% for games in children(p < 0.01). The lack of stereopsis for games and movies was higher in the subgroup of Fly (-) and convergence insufficiency (p < 0.05). CONCLUSIONS: Since many patients with strabismus and/or amblyopia found some difficulty in stereoscopic viewing, precise examinations for stereopsis and convergence are needed to assess individual aptitude for 3D viewing.

An open-label long-term phase III extension trial to evaluate the safety and efficacy of pregabalin in Japanese patients with fibromyalgia.

OBJECTIVES: To assess the long-term safety and efficacy of pregabalin for the treatment of Japanese patients with fibromyalgia (FM). METHODS: This 53-week, open-label extension study was conducted at 20 study sites in Japan in patients with FM who had completed a preceding 16-week, placebo-controlled, double-blind trial. Patients received pregabalin, starting at 150 mg/day and increasing to a maintenance dose of 300 or 450 mg/day. The primary endpoint was safety, and secondary endpoints included measures of pain, sleep, and physical functioning. RESULTS: 106 patients entered the trial and received at least one dose of the study drug. The most common treatment-related adverse events were somnolence, dizziness, increased weight, and constipation. There were no treatment-related serious or severe adverse events. There were five (4.7%) discontinuations due to adverse events, of which three (2.8%) were considered related to the study drug. Most adverse events resolved over time and could be managed without dose reduction or treatment discontinuation. Improvements in secondary efficacy endpoints of pain, sleep, and physical functioning emerged early in the study and were maintained for the duration of treatment. CONCLUSIONS: These data indicate that the long-term treatment of Japanese FM patients with pregabalin may be both safe and effective.

The Japanese version of the modified ACR preliminary diagnostic criteria for fibromyalgia and the fibromyalgia symptom scale: reliability and validity.

PURPOSE: The aim of this study is to investigate the reliability and validity of the Japanese version of the modified American College of Rheumatology (ACR) Preliminary Diagnostic Criteria for Fibromyalgia (mACR 2010-J) and the Fibromyalgia Symptom Scale (mFS-J). METHODS: According to the ACR 1990 classification criteria, patients with chronic pain were divided into the fibromyalgia group and nonfibromyalgia group (rheumatoid arthritis and osteoarthritis). Patients in both groups were assessed using mACR 2010-J and mFS-J. RESULTS: 294 of 462 (64 %) patients in the fibromyalgia group met mACR 2010-J, whereas 4 % (9/231) of the nonfibromyalgia group did, with sensitivity of 64 %, specificity of 96 %, positive predictive value of 97 %, negative predictive value of 56 %, and positive likelihood ratio of 16.3. Mean total scores on mFS-J significantly differentiated the fibromyalgia from the nonfibromyalgia group. According to the value of the Youden index, the best cutoff score for the mFS-J was 9/10. CONCLUSION: Our findings indicate that mACR 2010-J as a positive test and mFS-J as a quantification scale might be suitable for assessing fibromyalgia among Japanese chronic pain populations.

Acceptability of transdermal antipsychotic patches by patients who refuse oral medication and their effectiveness in preventing recurrence of delirium: a retrospective observational study.

Injectable antipsychotics had been used for patients who refuse oral medications in delirium practice. The objectives were to investigate acceptability of transdermal antipsychotic patches by patients who refuse oral medications and their effectiveness in preventing recurrence of delirium. In this retrospective observational study, data were collected between October 2019 and December 2021. The sample was represented by patients hospitalized because of acute diseases or elective surgery who had delirium on the night before the consultation and had refused oral therapy after consultation. Delirium has been diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. Instead, a transdermal patch of blonanserin, a second-generation antipsychotic drug, was tried. The primary outcome was the rate of patients who accepted it. The secondary outcome was recurrence rates of delirium. As much as 95.1% of patients who refused oral medications (98/103 patients) accepted to receive the transdermal patch. Of these, 24 patients developed delirium again, whereas all five patients who refused it developed delirium again [24.5% (24/98) vs. 100% (5/5); P = 0.0014]. The present findings suggest that transdermal antipsychotic patches are more likely to be accepted by patients who refuse oral medications. Prospective studies are needed.

Paradox of schizophrenia genetics: is a paradigm shift occurring?

BACKGROUND: Genetic research of schizophrenia (SCZ) based on the nuclear genome model (NGM) has been one of the most active areas in psychiatry for the past two decades. Although this effort is ongoing, the current situation of the molecular genetics of SCZ seems disappointing or rather perplexing. Furthermore, a prominent discrepancy between persistence of the disease at a relatively high prevalence and a low reproductive fitness of patients creates a paradox. Heterozygote advantage works to sustain the frequency of a putative susceptibility gene in the mitochondrial genome model (MGM) but not in the NGM. METHODS: We deduced a criterion that every nuclear susceptibility gene for SCZ should fulfill for the persistence of the disease under general assumptions of the multifactorial threshold model. SCZ-associated variants listed in the top 45 in the SZGene Database (the version of the 23rd December, 2011) were selected, and the distribution of the genes that could meet or do not meet the criterion was surveyed. RESULTS: 19 SCZ-associated variants that do not meet the criterion are located outside the regions where the SCZ-associated variants that could meet the criterion are located. Since a SCZ-associated variant that does not meet the criterion cannot be a susceptibility gene, but instead must be a protective gene, it should be linked to a susceptibility gene in the NGM, which is contrary to these results. On the other hand, every protective gene on any chromosome can be associated with SCZ in the MGM. Based on the MGM we propose a new hypothesis that assumes brain-specific antioxidant defenses in which trans-synaptic activations of dopamine- and N-methyl-d-aspartate-receptors are involved. Most of the ten predictions of this hypothesis seem to accord with the major epidemiological facts and the results of association studies to date. CONCLUSION: The central paradox of SCZ genetics and the results of association studies to date argue against the NGM, and in its place the MGM is emerging as a viable option to account for genomic and pathophysiological research findings involving SCZ.

Urine catecholamine levels are not influenced by electroconvulsive therapy in depression or schizophrenia over the long term.

AIM: Change in catecholamine seems to be associated with not only effects of electroconvulsive therapy (ECT), but also adverse events associated with ECT. Our aim in this study was to investigate whether or not ECT influences the concentration of catecholamine over the long term. Patients with a major depressive episode or schizophrenia, diagnosed according to DSM-IV criteria, who were newly admitted to Juntendo University Hospital to receive ECT, were recruited. METHODS: Urine was collected during the 24 h before the first ECT treatment, during the 24 h after the first ECT treatment, during the 24 h after the final ECT treatment and during the 24 h 1 week after the final ECT treatment. Heart rate, the Hamilton Rating Scale for Depression and the Positive and Negative Syndrome Scale were assessed before and after ECT. RESULTS: Twenty-four patients were included in the final sample, which consisted of 14 patients with major depressive episodes and 10 patients with schizophrenia. Abnormal electrocardiograms were indicated in four patients with depression during the ECT operation but all recovered naturally. There were no significant differences in the levels of dopamine, adrenaline or noradrenaline the day before the first ECT, a day after the first ECT, a day after the final ECT and a week after the final ECT. CONCLUSION: These results suggest that ECT does not alter urine catecholamine levels after ECT over the long term. Further studies will be required to confirm these findings in a larger sample of patients.

The Japanese version of the 2010 American College of Rheumatology Preliminary Diagnostic Criteria for Fibromyalgia and the Fibromyalgia Symptom Scale: reliability and validity.

The aim of this study was to investigate the reliability and the validity of the Japanese version of the 2010 American College of Rheumatology Preliminary Diagnostic Criteria for Fibromyalgia (ACR 2010-J), and its quantification scale, the Fibromyalgia Symptom Scale (FS-J). In this study, we divided patients with chronic pain without psychiatric disorders other than depression into two groups according to the 1990 ACR Diagnostic Criteria for Fibromyalgia, a fibromyalgia group and a non-fibromyalgia group (rheumatoid arthritis, osteoarthritis, and gout). Patients in both groups were assessed using the ACR 2010-J and FS-J. Seventy-seven of 94 (82%) patients in the fibromyalgia group met the ACR 2010-J, whereas 9% (4/43) of the non-fibromyalgia group did so, with a sensitivity of 82%, specificity of 91%, positive predictive value of 95%, negative predictive value of 70%, and positive likelihood ratio of 8.8. Mean total scores on the FS-J significantly differentiated the fibromyalgia from the non-fibromyalgia group. The scale had high inter-rater reliability and high internal consistency. With a cutoff score of 10, the positive likelihood ratio was 10.1. Our findings indicate that the ACR 2010-J and FS-J have high reliability and validity, and are useful for assessing fibromyalgia in Japanese populations with chronic pain. As regards the positive likelihood ratio, that of the FS-J might be suitable as a positive test.

Association Between Step Count Measured With a Smartphone App (Pain-Note) and Pain Level in Patients With Chronic Pain: Observational Study.

BACKGROUND: Chronic pain is the leading cause of disability, affecting between 20% and 50% of the global population. The key recommended treatment is physical activity, which can be measured in daily life using a pedometer. However, poor adherence to pedometer use can result in incorrect measurements. Furthermore, only a few studies have investigated a possible curvilinear association between physical activity and chronic pain. OBJECTIVE: In this study, we developed the Pain-Note smartphone app to collect real-world data on step count, using the smartphone's built-in pedometer. The aims of our research are (1) to evaluate the association between daily step count and pain level among patients with chronic pain and (2) determine if the association between daily step count and pain level was curvilinear. METHODS: We conducted a cross-sectional study based on step count data collected with the app and on the results of questionnaires, which measured the duration and intensity of pain, the widespread pain index, the symptom severity score, and the insomnia severity scale, including 7 questions for symptoms of depression. We analyzed the association between step count and pain level as a nonlinear relationship using a restricted cubic spline model. A prespecified subgroup analysis was also conducted based on fibromyalgia criteria. RESULTS: Between June 1, 2018, and June 11, 2020, a total of 6138 records were identified, of which 1273 were analyzed. The mean age of the participants was 38.7 years, 81.9% (1043/1273) were female, and chronic pain was present for more than 5 years in 43.2% (550/1273) of participants. Participants in the third and fourth quartiles for step count (more than 3045 and 5668 steps a day, respectively) showed a significant positive association between higher step count and lower numerical pain rating scale (mean difference -0.43, 95% CI -0.78 to -0.08, P=.02; -0.45; 95% CI -0.8 to -0.1, P=.01, respectively) than those in the first quartile (less than or equal to 1199 steps a day). The restricted cubic spline model for the association between step count and pain scale displayed a steep decline followed by a moderate decrease as the step count increased; the inflection point was 5000 steps. However, this association was not observed among participants who met the fibromyalgia criteria (491/1273), who showed a steep positive increase below 2000 steps. Data were collected between June 1, 2018, and June 11, 2020, and were analyzed on November 18, 2021. CONCLUSIONS: Step count measured with the Pain-Note app showed a nonlinear association with pain level. Although participants with and without fibromyalgia showed a negative correlation between step count and pain level, participants who meet the criteria for fibromyalgia may present a different relationship between walking and pain perception compared to those in the general chronic pain population.

Chronic primary musculoskeletal pain: a new concept of nonstructural regional pain.

The concept that a regional musculoskeletal pain may occur in the absence of identifiable tissue abnormality may be puzzling. Previously these regional complaints were generally categorized as myofascial pain syndromes, or prior to the formalization of the nociplastic pain concept, as musculoskeletal pain with a neuropathic component, and treatments were anatomically focussed. Chronic primary musculoskeletal pain is now identified under the chronic primary pain stem category with the mechanistic descriptor of nociplastic pain. It is possible that many patients previously diagnosed with myofascial pain do in fact suffer from chronic primary musculoskeletal pain, requiring a paradigm shift in management towards more centrally directed treatment strategies. Many questions remain, including validation of the proposed examination techniques, prevalence, ideal treatment, and uptake and acceptance by the healthcare community. This new classification should be welcomed as an explanation for regional pain conditions that previously responded poorly to physically focussed treatments.

A case of erythema multiforme associated with primary Epstein-Barr virus infection.

We present a case of primary Epstein-Barr virus (EBV) infection with erythema multiforme. A 1-year-old Japanese boy presented with skin eruptions, including typical target lesions and a low-grade fever. Just before the skin biopsy, 95 copies/µg DNA of EBV genome was detected in peripheral blood mononuclear cells, which subsequently increased to 6,834 copies/µg DNA. Skin tissue collected from the skin lesion showed the typical pathologic findings of erythema multiforme. EBV-encoded small nuclear RNA signals were not detected in the skin tissue by in situ hybridization.

A prospective naturalistic multicentre study of intravenous medications in behavioural emergencies: haloperidol versus flunitrazepam.

A prospective naturalistic multicentre study for deep sedation was conducted in intensive care with continuous electrocardiogram (ECG) monitoring. Clinical purpose was enough sedation, which made uncooperative and disrupted patients receive brain computed tomography (CT), magnetic resonance imaging (MRI), or fluid therapy, with minimum drug doses. A first infusion was either haloperidol (HAL group) or flunitrazepam (FNP group). If enough sedation was not achieved, a second infusion, which was the opposite drug to the first infusion, was given. The proportion requiring a second infusion was higher in the HAL group than in the FNP group (82% vs. 36%, P<0.0001). The mean reduction of the Excited Component for Positive and Negative syndrome scale at 15 min was greater for the FNP first group (FNP+HAL group) than the HAL first group (HAL+FNP group) (68% [S.D. 17] vs. 54% [S.D. 31], P=0.02). The mean dose of flunitrazepam in the HAL+FNP group was significantly lower than that in the FNP+HAL-group (1.3 mg vs. 3.5 mg, P=0.0003). Thus, in terms of monotherapy and speed of action, flunitrazepam has advantages over haloperidol as a first infusion for deep sedation. Regarding drug dosages, haloperidol has an advantage over flunitrazepam as a first infusion in safety.

Utility and sufficiency of psychiatric inpatient units in general hospitals: a cross-sectional study in Tokyo.

In order to investigate the utility and sufficiency of psychiatric beds in general hospitals (GHP beds), a cross-sectional study was performed in general hospitals all over Tokyo. Reasons for admission were acute-phase treatment (43%), medical comorbidity (15%), electroconvulsive therapy (13%), differential diagnosis (12%), and others (17%). The number of patients who could not be admitted to GHP beds despite appropriate reasons for admission was estimated to be greater than that of inpatients without indispensable reasons for admission to GHP beds on the day of the survey. GHP beds played the expected roles, and were in short supply.