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The perioperative risk of sporadic hemangioblastomas (HBs) and von Hippel-Lindau disease (VHL)-associated hemangioblastomas (VHL-associated HBs) remains unclear due to the rare prevalence of HB. Therefore, this study aimed to clarify risk factors for better surgical management of patients with HBs.A retrospective analysis of surgically treated HB patients registered in the Diagnosis Procedure Combination database of Japan, between 2010 and 2015, was performed. Age, sex, sporadic HBs or VHL-associated HBs, medical history, tumor location, hospital case load, postoperative complications, and Barthel index (BI) deterioration were assessed. We also evaluated the outcomes and factors of perioperative BI deterioration.In total, 676 patients with 609 intracranial lesions, 64 spinal lesions, and 3 with both types were eligible. Among them, 618 and 58 patients had sporadic HBs and VHL-associated HBs, respectively. The rates of perioperative BI deterioration were 12.5% and 12.2% for sporadic HBs and VHL-associated HBs, respectively. Perioperative mortality was 1.8% and 0% for sporadic HBs and VHL-associated HBs, respectively. Male sex, old age, high hospital case load, and medical history of diabetes mellitus were significantly associated with perioperative BI deterioration in all cases and sporadic HBs. Only medical history of diabetes mellitus was a significant risk factor for perioperative BI deterioration in VHL-associated HBs.No differences in perioperative BI deterioration rates between sporadic HBs and VHL-associated HBs were found. However, different risk factors for perioperative BI deterioration were identified. Consideration of these risk factors is recommended in all patients undergoing surgery for HB.

Fear memory has an important role in survival, but excess fear memory could be cause to fear-related disorders such as post traumatic disorder (PTSD). People who undergo a fearful event do not always develop PTSD, suggesting that there are vulnerable factors to develop the disorder. It is believed that sex, in particular female, is one of the factors as it is known that the prevalence rate of PTSD is higher in women than in men. However, the biological mechanisms underlying the sex differences in their prevalence rate remain unclear. Because previous studies reported that patients with fear-related disorders show an impairment of fear extinction, investigation of sex differences in fear extinction may be useful for understanding the greater vulnerability of women to fear-related disorders. Although number of papers investigating sex differences in fear extinction, these reports have increased recently. This review introduces fear extinction, sex differences in fear extinction is low, and the molecular mechanisms of sex differences in fear extinction. In the molecular mechanisms, we focused brain-derived neurotrophic factor (BDNF)-tropomyosin-related kinase B (TrkB) receptor signal which has been investigated by independent research groups.

Endocannabinoids are involved in various physiological functions, including synaptic plasticity and memory, and some psychiatric disorders, such as posttraumatic stress disorder (PTSD), through the activation of cannabinoid (CB) receptors. Patients with PTSD often show excessive fear memory and impairment of fear extinction (FE). It has been reported that the stability of acquired fear memory is altered through multiple memory stages, such as consolidation and reconsolidation. FE also affects the stability of fear memory. Each stage of fear memory formation and FE are regulated by different molecular mechanisms, including the CB system. However, to the best of our knowledge, no review summarizes the role of the CB system during each stage of fear memory formation and FE. In this review, we summarize the roles of endocannabinoids in fear memory formation and FE. Moreover, based on the summary, we propose a new hypothesis for the role of endocannabinoids in fear regulation, and discuss treatment for PTSD using CB system-related drugs.

This study aimed to determine the prevalence and risk factors for brain white matter changes in normal young and middle-aged participants who underwent Brain Dock (brain screening). We analyzed 5,000 consecutive healthy participants from the Brain Dock registry between August to December 2018. Age, sex, body mass index (BMI), medical history, deep subcortical white matter high intensity (DSWMH), periventricular high intensity (PVH), and enlargement of perivascular space (EPVS) were investigated in relation to age. The prevalence of DSWMH, PVH, and EPVS were 35.3%, 14.0%, and 17.8%, respectively. Multivariate logistic regression analyses for brain white matter changes were conducted. The significant risk factors in participants aged < 50 years were: age (OR:1.09, 95% CI:1.07-1.12), the female sex (1.29, 1.03-1.60), BMI obesity (1.86, 1.12-3.08), and hypertension (1.67, 1.18-2.35) for DSWMH; age (1.08, 1.04-1.13) and the female sex (1.56, 1.03-2.36) for PVH; and age (1.07, 1.05–1.10) and the female sex (0.77, 0.60-1.00) for EPVS. In conclusion, age was consistently identified as a significant risk factor in young and middle-aged participants. Some risk factors for brain white matter changes were identified even in young and middle-aged participants in this study. Further longitudinal studies should be done in the future.

There are no scoring methods for optimal treatment of patients with aneurysmal subarachnoid hemorrhage (aSAH). We developed a scoring model to predict clinical outcomes according to aSAH risk factors using data from the Japan Stroke Data Bank (JSDB). Of 5344 patients initially registered in the JSDB, 3547 met the inclusion criteria. Patients had been diagnosed with aSAH and treated with surgical clipping or endovascular coiling between 1998 and 2013. We performed multivariate logistic regression for poor outcomes at discharge, indicated by a modified Rankin Scale (mRS) score >2, and in-hospital mortality for both treatment methods. Based on each risk factor, we developed a scoring model assessing its validity using another dataset of our institution. In the surgical clipping group, scoring criteria for aSAH were age >72 years, history of more than once stroke, World Federation of Neurological Societies (WFNS) grades II–V, aneurysmal size >15 mm, and vertebrobasilar artery (VBA) aneurysm location. In the endovascular coiling group, scoring criteria were age >80 years, history of stroke, WFNS grades III–V, computed tomography (CT) Fisher group 4, and aneurysmal location in the middle cerebral artery (MCA) and anterior cerebral artery (ACA). The rates of poor outcome of mRS score >2 in an isolated dataset using these scoring criteria were significantly correlated with our model’s scores, so this scoring model was validated. This scoring model can help in the more objective treatment selection in patients with aSAH.

The objective of the study was to clarify the prevalence of and factors associated with changes in patients' outcomes between discharge and 3 months after the onset of aneurysmal subarachnoid hemorrhage (aSAH). Additionally, the World Federation of Neurosurgical Societies (WFNS) and modified WFNS (mWFNS) scales were compared.The data of curatively treated patients with aSAH, collected prospectively in the mWFNS scale study between January 2010 and December 2012, were analyzed retrospectively. The improvement or decline in the modified Rankin Scale (mRS) scores between discharge and 3 months after onset was determined. A multivariable logistic regression analysis was performed to identify factors, such as age and WFNS and mWFNS grades, associated with changes in the outcome.The mRS scores improved in 28.3% and declined in 2.5% of the patients. WFNS and mWFNS grades Ⅱ-V on admission were significantly associated with improved mRS scores at 3 months after onset. Older age (age: 65-74 years vs. age65 years, odds ratio: 6.59, 95% confidence interval: 1.28-34.01; age ≥75 years vs. age65 years, odds ratio: 17.67, 95% confidence interval: 2.11-148.26) and WFNS grade III were significantly associated with a decline in mRS scores at 3 months after onset.The optimal timing for postdischarge assessment of outcomes may be at 3 months after onset, especially in older patients with aSAH. The mWFNS scale is presumed to more accurately assess the outcomes of patients with aSAH than the WFNS scale, as demonstrated in this study.

There is currently no precise guide for the treatment and management of elderly patients with aneurysmal subarachnoid hemorrhage (aSAH). Thus, the aim of this study was to clarify the factors of poor outcome and mortality in elderly patients with aSAH.In the modified World Federation of Neurosurgical Societies (mWFNS) scale study, 1124 patients were divided into 2 groups, elderly (age ≥65 years) and non-elderly (age65 years), with aSAH investigated between October 2010 and March 2013 in Japan. The odds ratio (OR) and 95% confidence interval (CI) of each risk factor was calculated through multivariate logistic regression analysis for poor outcomes, as indicated by the modified Rankin Scale (mRS) score ≥3 and mortality at 3 months after onset in each group.Both groups demonstrated that the mWFNS scale was significant as a grade order risk factor for poor outcomes and mortality associated with disease. In the elderly group, risk factors for poor outcomes at 3 months after onset were older age (OR 1.10, 95% CI 1.06-1.14), male sex (OR 2.03, 95% CI 1.10-3.73), and severe cerebral vasospasm category (OR 10.13, 95% CI 4.30-23.87). Risk factors for mortality at 3 months after onset were older age (OR 1.06, 95% CI 1.01-1.11) and severe vasospasm category (OR 2.17, 95% CI 1.00-4.72).The mWFNS scale is a useful prognostic predictor for both non-elderly and elderly patients with aSAH. Elderly male patients with aSAH presenting with severe vasospasm should be managed more carefully.

As the global population ages, the incidence of traumatic brain injury (TBI) is increasing. Whereas mild TBI can impair the cognitive function of older adults, the cause and background of mild TBI-induced cognitive impairment remain unclear, and the evaluation of risk factors for cognitive impairment after mild TBI remains open for consideration, especially in the aging population. This study aimed to evaluate the risks associated with cognitive impairment following mild TBI.Between January 2006 and December 2018, a total of 2209 patients with TBI required hospitalization in Shimane Prefectural Central Hospital. Mild TBI was defined as a Japan Coma Scale ≤10 at admission. Patients' cognitive function was measured with the Hasegawa Dementia Rating Scale-Revised or Mini-Mental State Examination at least twice during the patients' hospital stays. The odds ratio (OR) and 95% confidence interval (CI) of each considered risk factor was calculated with multivariable logistic regression analysis after univariate analysis.Among 1674 patients with mild TBI, 172 patients underwent cognitive function examinations, of whom 145 (84.3%) were found to have cognitive impairment at discharge. Significant risk factors for cognitive impairment included age (P = 0.008) and hypertension (P = 0.013) in univariate analysis; and age (OR, 1.04: 95% CI, 1.01-1.07) and hypertension (OR, 5.81: 95% CI, 1.22-27.68) by multivariable analysis.Older patients with hypertension displayed a significantly higher risk for cognitive impairment after even mild TBI. These patients warrant careful management after even mild TBI.

Changes in outcome after discharge of patients with aneurysmal subarachnoid hemorrhage (aSAH) have not been examined in detail in recent aging society. This study aimed to clarify the prevalence and factors of changes in outcome in these patients based on a registry database in Japan. Overall, 1,111 radically treated patients with aSAH in the acute stage were selected between January 2010 and December 2012 for inclusion in the modified World Federation of Neurosurgical Societies (mWFNS) scale study. The modified Rankin Scale (mRS) score at discharge and 3 months after onset, prevalence of improvement and decline between these two periods, and their factors were evaluated by age groups through multivariate logistic regression analysis. The rates of improvement and decline were 28.4% and 2.4%, respectively. Factors that improved the mRS score were WFNS and mWFNS scale grade Ⅳ versus (vs.) Ⅰ (odds ratio: 0.47, 95% confidence interval: 0.31–0.71), grade Ⅴ vs. Ⅰ (0.49, 0.31–0.76), and cerebral vasospasm category 4 vs. 1 (0.43, 0.25–0.77). Factors that decreased the mRS score were pre-elderly (65–74 years) vs. non-elderly (

The prevalence of post-traumatic stress disorder (PTSD) is higher in women than in men. Among both humans and mice, females exhibit higher resistance to fear extinction than males, suggesting that differences between sexes in fear-extinction processes are involved in the pathophysiology of such fear-related diseases. Sex differences in molecular mechanisms underlying fear memory and extinction are unclear. The cannabinoid (CB) system is well known to be involved in fear memory and extinction, but this involvement is based mainly on experiments using male rodents. It is not known whether there are sex differences in the role of the CB system in fear memory and extinction. To explore this possibility, we investigated the effects of pharmacological manipulations of the CB system on the retrieval and extinction of contextual fear memory in male and female mice. WIN55,212-2, a CB receptor (CBR) agonist, augmented the retrieval of fear memory in both sexes, but SR141716 (a CB1R antagonist) did not affect it in either sex. An enhancement of 2-arachidonylglycerol (2-AG, one of the two major endocannabinoids) via JZL184 (an inhibitor of the 2-AG hydrolase monoacylglycerol lipase [MAGL]), augmented the retrieval of fear memory through the activation of CB1R but not CB2R in female mice. In contrast, the enhancement of N-arachidonylethanolamine (AEA, the other major endocannabinoid) via URB597, an inhibitor of an AEA hydrolase (fatty acid amide hydrolase-1) did not show any effects on the retrieval of fear memory in either sex. WIN55,212-2, SR141716, and JZL184 inhibited fear extinction irrespective of sex. URB enhanced fear extinction in females that were in diestrus phase at the first extinction session, but not in males. These results suggest that although the role of CB1R in the retrieval and extinction of contextual fear memory is common among males and females, the effects of an increase in endocannabinoid levels on the retrieval or extinction of contextual fear memory differ between the sexes.

The prevalence of post-traumatic stress disorder (PTSD) is higher in women than in men. Among both humans and mice, females exhibit higher resistance to fear extinction than males, suggesting that differences between sexes in processes of fear extinction are involved in the pathophysiology of such fear-related diseases. Sex differences in molecular mechanisms for fear memory and extinction are unclear. The cannabinoid (CB) system is well known to be involved in fear memory and extinction, but this involvement is based mainly on experiments using male rodents. It has been unclear whether there are sex differences in the role of the CB system in fear memory and extinction. To explore the possibility of such differences, we investigated the effects of pharmacological manipulations of the CB system on the retrieval and extinction of contextual fear memory in male and female mice. WIN55,212-2, a CB receptor (CBR) agonist, augmented the retrieval of fear memory in both sexes, but SR141716 (a CB1R antagonist) did not affect it in either sex. An enhancement of 2-arachidonylglycerol (2-AG, one of the two major endocannabinoids) via JZL184 [an inhibitor of the 2-AG hydrolase monoacylglycerol lipase (MAGL)], augmented the retrieval of fear memory through the activation of CB1R but not CB2R in female mice. In contrast, the enhancement of N-arachidonylethanolamine (AEA, the other major endocannabinoid) via URB597, an inhibitor of an AEA hydrolase (fatty acid amide hydrolase-1) did not show any effects on the retrieval or extinction of fear memory in either sex. WIN55,212-2, SR141716, and JZL184 inhibited fear extinction irrespective of sex. These results suggest that although the role of CB1R in the retrieval and extinction of contextual fear memory is common among males and females, the effects of an increase in the 2-AG level on the retrieval of contextual fear memory differ between the sexes.

Background Pial arteriovenous fistulas (PAVFs) are rare, accounting for 1.6%–4.7% of all intracranial vascular malformations. Often diagnosed in childhood, about 30% are associated with hereditary hemorrhagic telangiectasia. A case of PAVF diagnosed soon after birth and given cerebrovascular therapy 4 months after birth is reported. Case Description The patient presented with heart failure immediately after birth. Ultrasonography of the head showed abnormal blood flow in the brain. On digital subtraction angiography performed 4 months after birth, a PAVF with a dural feeder shunt and a giant varix at the posterior temporal part was confirmed. After transarterial embolization (TAE), shunt blood flow disappeared. New shunt flow from the right posterior cerebral artery into the varix was confirmed by magnetic resonance imaging 3 months after the operation. A second TAE procedure using a liquid embolic material was performed and confirmed the complete disappearance of the shunt. Conclusions This report describes a case of infant PAVF with heart failure, a giant varix, hydrocephalus, and intraventricular hemorrhage treated by TAE using platinum coils and liquid embolic material.

Various guidelines regarding surgical site infection (SSI) have recently been established. However, perioperative management of the wound and use of antibiotics have never been standardized completely in departments of neurosurgery in Japan. This survey investigated current perioperative management and administration of surgical antibiotic prophylaxis (SAP) and compared with guidelines intended to reduce SSI associated with neurosurgery in Japan. Questionnaires were distributed to members of the conference on Neurosurgical Techniques and Tools and the Japan Society of Aesthetic Neurosurgery via internet. The questionnaires asked about methods of perioperative management. A total of 255 members returned answers to the questionnaires. The questionnaires revealed that partial or no removal of the hair and hair shampooing at the day before surgery were performed in 96.1% and 88.1% of each institute following the World Health Organization (WHO) guidelines. Use of SAP at just before, during, and after surgery were 65.0%, 86.2%, and 63.0%, respectively. The postoperative period of use of intravenous SAP prolonged beyond 24 h in 80.0% against the recommendation of WHO. Perioperative management of wounds and use of SAP varies in institutes in Japan and some procedures were far different from the WHO guidelines. Japanese neurosurgeons should notice the prolonged SAP and comply with the WHO guidelines.

The simplified 5-factor modified frailty index (mFI-5) is a useful indicator of outcome for patients undergoing surgeries and considered as an important risk factor in elderly patients. However, its usefulness has not been validated based on age groups. We aimed to investigate the risk factors including the mFI-5 across age groups for complications and worse outcomes in meningioma surgery using data obtained from the nationwide database in Japan. We extracted data from the nationwide registry database in Japan between 2010 and 2015. Age (< 65, 65–74, and ≥ 75 years), sex, Barthel Index (BI), mFI-5 scores, and complications were evaluated. Multivariate logistic regression analyses identified risk factors across all age groups for worsening BI scores and complications after surgery. In 8,138 included cases, an mFI-5 score ≥ 2 items was a significant risk factor for worsening BI scores in patients aged < 65 years (odds ratio: 2.00; 95% confidence interval: 1.31-3.06), but not in patients aged 65-74 years and those aged ≥ 75 years. Similar results were noted for complications in patients aged < 65 years (2.40; 1.67–3.44), but not in patients aged 65-74 years and those aged ≥ 75 years. In conclusion, the mFI-5 scores can predict the risk of worsening outcome and complications in non-elderly patients aged < 65 years rather than in elderly patients aged ≥ 65 years. In meningioma surgeries, care must be taken when making decisions using the mFI-5 scores based on the patients’ age.Trial RegistrationName: Study on treatment method, age group, complications, and outcome of meningiomas and hemangioblastomas using DPC, URL: http://www.umin.ac.jp/ctr/index-j.htmID: UMIN000038486, No.: R000043856

Object: This study aimed to assess the relationships between trend of mortality rate from subarachnoid hemorrhage (SAH) and blood pressure and smoking prevalence among about 700,000 residents of Shimane prefecture, Japan. Methods: A retrospective review was performed to identify the age-adjusted mortality rate from SAH calculated using the standard population of Japan in 2010 and changes in population of Shimane prefecture used the date based on government statistics during 1999 through 2017. Blood pressure dates were extracted from Ministry of Health, Labour and Welfare during 2008 through 2015, and smoking prevalence from Cancer Registry and Statistics. Cancer Information Service, National Cancer Center, Japan every 3 years since 2001. Result: Age-adjusted mortality rate from SAH in Shimane prefecture tended to decline by 3.6% between 1999 through 2017 regardless of gender, as 14.86 (95%CI:14.65-15.07) per 100,000 person-year in 1999 to 7.96 (95%CI:7.81-8.11) in 2017. The Population of Shimane prefecture, where one of the most aging region in Japan, was decreased by 10.4% since 764,291 in 1999 to 684,668 in 2017. Blood pressure was invariable during 2008 through 2015, while smoking prevalence decreased since 2001 to 2016, as 25.0% to 18.0%. Conclusion: Age-adjusted mortality rate from SAH in Shimane prefecture have declined since 1999 to 2017, regardless of decrease of population and advancement of aging region. The factor of decline might be not only development of treatment and management, but decrease of incidence of SAH in Japan accompanied by improvement of smoking prevalence or lifestyle habitation.

Central nervous system tuberculosis is a devastating complication of systemic tuberculosis. Intradural extramedullary (IDEM) tuberculoma at the foramen magnum is rare, and mimics en plaque meningioma. We report the case of a 53-year-old woman who presented with dysesthesia of the tongue and lower cranial nerve (CN) palsy, with onset 4 months prior to admission. The neurologic examination revealed left upper-limb weakness and hypoesthesia on the sole and dorsum of the left foot. Other physical examinations revealed no features of tubercular infection. Laboratory investigations likewise showed no signs of infection or inflammation. Magnetic resonance imaging of the brain showed an IDEM mass originating from the left intradural surface at the foramen magnum extending to the C2 segment and compressing the brainstem and upper cervical cord. The mass was isointense/hypointense on T1- and T2-weighted images and homogeneously-enhanced on postcontrast images. The lesion also exhibited the dural-tail sign and was preoperatively diagnosed as en plaque meningioma. The patient underwent surgery via the left transcondylar fossa approach with partial laminectomy of the atlas. Intraoperatively, the mass exhibited a dural origin and encased the vertebral artery and lower CNs, with strong adhesions. While the histopathological study of the mass was strongly suggestive of tuberculoma with multifocal granulomas, caseous necrosis, and Langerhans giant cells, extensive diagnostic studies failed to detect Mycobacterium tuberculosis itself. Although the patient had recurrence with multisystem involvement, she responded well to antitubercular treatment. IDEM tuberculoma of the foramen magnum may present as en plaque meningioma. Histopathology is required for a definitive diagnosis. Prompt surgical resection and decompression with adequate antitubercular treatment yield better neurological outcomes.

Adolescence is a vulnerable period for developing anxiety-related mental disorders such as post-traumatic stress disorder (PTSD), which requires a long-term course of therapy when a traumatic event has been experienced during childhood. However, the biological mechanism underlying these age-dependent characteristics remains unclear. In the present study, we used early adolescent, late adolescent and adult (4-, 8-, and 15-week old) male mice to examine age differences in fear memory, fear extinction, and spontaneous recovery of fear. We also measured the activation of extracellular signal-regulated kinase (ERK) 2 in the dorsal hippocampus (dHip) and the basolateral amygdala (BLA) following a spontaneous recovery test. Our major findings were as follows: (1) early adolescent and adult mice did not recover the fear response; only late adolescent mice recovered the fear response. (2) The ERK2 in the dHip was more activated after the spontaneous recovery test in late adolescent mice than in adult mice, and the ERK2 in the BLA was more activated after the spontaneous recovery test in adult mice than in late adolescent mice. These results suggest that there exists a unique period in which spontaneous recovery occurs and that these late adolescent behavioral signatures may be related to alteration in the ERK2 phosphorylation in the dHip and BLA.

Concurrent multiple tumors developing in the spinal cord are rare, except for in genetic disorders, such as neurofibromatosis and von Hippel-Lindau disease. Furthermore, concurrent tumors arising in the same spinal level with discrete histopathology are much rarer. We report two such cases. Case 1: A 53-year-old man presented with intracranial hemorrhage that manifested as disturbed consciousness and right hemiparesis. Magnetic resonance (MR) angiography demonstrated severe stenosis of the terminal portion of the bilateral internal carotid arteries, implying Moyamoya disease. Cranial MR images showed a hematoma in the left basal ganglia perforating into the lateral ventricle, which was incidentally detected as a spinal tumor compressing the cervical cord at the C2 level. After conservative management for cerebral hemorrhage, the patient underwent total removal of the spinal tumor. Surgical findings showed that the tumor consisted of extra- and intradural components. Histopathological findings showed that the extra- and intradural components were schwannoma and meningioma, respectively. Case 2: A 70-year-old man presented with progressive left hemiparesis and numbness in both lower extremities. Craniocervical MR images demonstrated a paraspinal tumor compressing the spinal cord at C2 level. Surgical findings disclosed that the tumor consisted of major extradural- and minor intradural components. Histopathological study showed that these components had discrete histological findings: extradural lesion was schwannoma and intradural lesion was meningioma. Concurrent tumors with discrete histopathology should be considered in tumors with extra- and intradural components, particularly, when they are located in the high cervical spine.

Tropomyosin-related kinase B receptor (TrkB) is one of the new candidate receptors for drugs targeting psychiatric and neurodegenerative disorders. Recently, 7,8-dihydroxyflavone (7,8-DHF) has been identified as a selective TrkB agonist that crosses the blood-brain barrier after oral or intraperitoneal administration, and it enhances cued fear extinction in male rodents. However, its effects on females remain unclear. Preclinical research including both sexes is important for the development of treatment, particularly, for stress-related disorders such as post-traumatic stress disorder because such disorders are more prevalent in women. Therefore, we investigated the effects of 7,8-DHF on cued and contextual fear extinction in both male and female mice. Here we demonstrated that the administration of 7,8-DHF before each extinction session attenuated cued fear extinction in females; conversely, it enhanced cued fear extinction in males. However, administration of 7,8-DHF immediately after each extinction session did not affect cued fear extinction in either sex. Moreover, in contextual fear extinction, administration of 7,8-DHF before each extinction session did not affect fear extinction in either sex. Thus, 7,8-DHF showed sex-dependent opposite effects on cued fear extinction in mice when administered before but not immediately after each extinction session. Our results could contribute to the development of pharmacotherapy involving 7,8-DHF, particularly for stress-related disorders.

The characteristics of cerebral aneurysms in Japan differ from other countries in the higher incidence of unruptured cerebral aneurysm detected by brain check-up screening, higher rupture rate of unruptured cerebral aneurysm, higher incidence of subarachnoid hemorrhage, and superior outcome after subarachnoid hemorrhage based on meta-analysis. Head shape, genetic features, environmental factors, demographics, and medical system in Japan are also different from other countries. Unruptured cerebral aneurysms are 2.8 times more likely to rupture in Japanese than western aneurysms, resulting in the highest incidence of subarachnoid hemorrhage in the world. The exact and specific mechanisms of de novo, growth, and rupture of cerebral aneurysms have not been elucidated. Investigations will contribute to the understanding of cerebral aneurysms and subarachnoid hemorrhage worldwide. Some features of cerebral aneurysm in Japan are discussed for possible research guidance in the elucidation of the predominance of subarachnoid hemorrhage in Japan.

The etiology and background factors which cause decreases in the size of ruptured intracranial aneurysms remain unclear.To clarify the age- and sex-related differences in aneurysmal subarachnoid hemorrhage (SAH) based on a 35-year-old hospital database and demographic data.A database of patients admitted to our hospital with aneurysmal SAH from 1983 to 2017 was split into 5-year intervals and analyzed. Demographic data of the general population were also analyzed for reference.Altogether, 1,523 aneurysmal SAH events were enrolled in the analysis. Age (p0.001), proportion of elderly patients ≥ 65 years old (p0.001), female sex (p=0.005), very small aneurysms less than 5 mm (p0.001), and the yearly-averaged number of fatal events showed increasing trends. The proportion of aneurysm size of 10 mm or more (p = 0.011) and the yearly-averaged population of Shimane prefecture (p0.001) showed declining trends. In the subgroup analyses, the proportion of very small aneurysms was found to increase significantly in the non-elderly male and elderly female subgroups. The proportion of large aneurysms (10 mm or more) decreased in the non-elderly subgroup (p0.05). As for the elderly subgroups, the yearly-averaged number of events did not show a significant tendency, although the yearly-averaged population of Shimane prefecture showed an increasing trend.We found an increasing trend in the prevalence of very small aneurysms in elderly females. Recent aging may contribute to this trend. The number of aneurysmal SAH events was confirmed to not increase, despite the increased aging population of Shimane prefecture.

There is a rapidly growing demand for female animals in preclinical animal, and thus it is necessary to determine animals' estrous cycle stages from vaginal smear cytology. However, the determination of estrous stages requires extensive training, takes a long time, and is costly; moreover, the results obtained by human examiners may not be consistent. Here, we report a machine learning model trained with 2,096 microscopic images that we named the "Stage Estimator of estrous Cycle of RodEnt using an Image-recognition Technique (SECREIT)." With the test dataset (736 images), SECREIT achieved area under the receiver-operating-characteristic curve of 0.962 or more for each estrous stage. A test using 100 images showed that SECREIT provided correct classification that was similar to that provided by two human examiners (SECREIT: 91%, Human 1: 91%, Human 2: 79%) in 11 s. The SECREIT can be a first step toward accelerating the research using female rodents.

Fear conditioning and extinction is a useful tool for understanding the pathogenesis of fear-related disorders including post-traumatic stress disorder (PTSD) and for developing treatments for them. To investigate the role of sub-brain regions or molecular mechanisms in fear conditioning and extinction, neuroscientists have been employing an optogenetic or in vivo recording technique, in which placement of an optical fiber or an electrode into the brain region of a free-moving mouse is essential. These methods require isolation rearing (at least one week) from the brain surgery to the behavioral test. Although such short-term adult rearing has been shown not to influence fear memory and extinction in males, the effect in females remains unclear. In the present study, we investigated the effect on fear memory and fear extinction of adult isolation rearing during the one week before contextual fear conditioning in both male and female mice. This short-term adult isolation rearing increased fear responses in the contextual fear memory test in females but not in males. On the other hand, the rearing showed no effect on fear responses during fear extinction or the recall test in either sex. In summary, adult short-term isolation rearing enhanced only fear memory, and only in females.

Onset of fear-related disorders such as post-traumatic stress disorder is enhanced from adolescence until adulthood. However, the biological mechanisms underlying this vulnerability remain unclear. Therefore, we investigated contextual fear memory and extinction in 4-, 6-, 8-, 10-, and 15-week-old female mice. We also measured phosphorylation of ERK2 in the medial prefrontal cortex (mPFC) and the dorsal hippocampus following fear conditioning or extinction in 6- and 15-week-old mice. We found that 10- and 15-week-old mice showed stronger fear memory and more resistance to fear extinction than 6-week-old mice. Moreover, 15-week-old mice showed lower ERK2 phosphorylation levels following fear extinction in the mPFC than those 6 weeks old. Our results suggest that female mice acquire strong fear memory and resistance to fear extinction throughout adulthood, which may be related to alteration in ERK2 activation in the mPFC.

Fear extinction is a major task in our understanding of the biological mechanisms of exposure therapy, one of the most used treatments for stress-related disorders. It was recently reported that an extinction of 5 consecutive days prevents spontaneous recovery of fear memory. Memory age and the timing of fear extinction influence the effect of fear extinction. In this study, we used contextual fear extinction in adult male mice to examine whether memory age influences an extinction of 5 consecutive days and whether consecutiveness is necessary to prevent spontaneous recovery. Our results showed that, although fear memory was not affected by the passage of time, the old fear memory (28 days after fear conditioning) was more sensitive to fear extinction than the young fear memory (7 days after fear conditioning). Additionally, we demonstrated that consecutiveness of extinction sessions is not necessary to prevent spontaneous recovery. Instead, fear extinction sessions at spaced intervals were found to be more effective than consecutive extinction sessions for young fear memory. Our results suggest that taking memory age and the interval of fear extinction sessions into consideration would help to optimize exposure therapy.

Background Tethered cord syndrome is a well-known complication after myelomeningocele (MMC) repair in childhood. However, late complications in adults with a repaired MMC are not well understood. In particular, the influence of a degenerative spinal deformity on a sustained tethered cord is still unclear. Case Description A 63-year-old man with a repaired MMC exhibited a progressive gait disturbance and numbness in both lower limbs. Magnetic resonance imaging demonstrated that the tethered spinal cord was compressed by severe canal stenosis along the entire lumbar spine. After a multi-level lumbar decompression surgery, the patient recovered to baseline neurologic status. Conclusion In adults with a repaired MMC, lumbar canal stenosis should be investigated as a possible cause of late neurologic decline. Clinical manifestations may be complicated by the coexistence of both the original and subsequent neurologic disorders. Because these additional disorders result from compressive myelopathy, early surgical decompression is indicated to avoid irreversible spinal cord dysfunction.

Social interaction is known to alter behavior and emotional responses to various events. It has been reported that when fear-conditioned animals are put in a fear extinction paradigm with non-fearful conspecifics (pair-exposure), freezing behavior decreases compared to a solitary situation. However, it remains unclear whether pair-exposure during fear extinction is persistently effective in reducing the freezing response. In this study, we examined whether the effect of pair-exposure could be persistently effective on cued and contextual fear extinction. The reduction of the fear compared to the solitary condition was transiently observed only in the cued fear extinction with no difference in the subsequent recall session. We also found that the correlation between corticosterone levels and freezing behavior during extinction was disrupted in the pair-exposure situation. These results suggest that pair-exposure reduces freezing behavior in cued fear extinction, although this fear response reduction is not persistent. The pair-exposure changed an association between corticosterone levels and freezing behavior during extinction.

Prepulse inhibition (PPI) of the acoustic startle response is one of the few and major paradigms for investigating sensorimotor gating systems in humans and rodents in a similar fashion. PPI deficits are observed not only in patients with schizophrenia, but also in patients with anxiety disorders. Previous studies have shown that PPI in rats can be enhanced by auditory fear conditioning. In this study, we evaluated the effects of contextual fear conditioning (FC) for six times a day and fear extinction (FE) for seven days on PPI in mice. C57BL/6J mice (male, 8-12 weeks) were divided into three groups; no-FC (control), FC and FC + FE. We measured PPI at the following three time points, (1) baseline before FC, (2) after FC, and (3) after FE. The results showed that PPI was increased after FC. Moreover, the enhanced PPI following FC was observed even after FE with decreased freezing behaviors. These results suggested contextual fear conditioning could enhance acoustic PPI, and that contextual fear extinction could decrease freezing behaviors, but not acoustic PPI.

Cognitive restructuring is a fundamental method within cognitive behavioural therapy of changing dysfunctional beliefs into flexible beliefs and learning to react appropriately to the reality of an anxiety-causing situation. To clarify the neural mechanisms of cognitive restructuring, we designed a unique task that replicated psychotherapy during a brain scan. The brain activities of healthy male participants were analysed using functional magnetic resonance imaging. During the brain scan, participants underwent Socratic questioning aimed at cognitive restructuring regarding the necessity of handwashing after using the restroom. The behavioural result indicated that the Socratic questioning effectively decreased the participants' degree of belief (DOB) that they must wash their hands. Alterations in the DOB showed a positive correlation with activity in the left posterior parietal cortex (PPC) while the subject thought about and rated own belief. The involvement of the left PPC not only in planning and decision-making but also in conceptualization may play a pivotal role in cognitive restructuring.

Stress-related disorders, such as post-traumatic stress disorder (PTSD) and panic disorders, are disproportionately prevalent in females. However, the biological mechanism underlying these sex differences in the prevalence rate remains unclear. In the present study, we examined sex differences in fear memory, fear extinction, and spontaneous recovery of fear. We investigated the presence of sex differences in recent and remote fear memory in mice using contextual fear conditioning, as well as sex differences in spontaneous recovery of fear memory using a consecutive fear extinction paradigm. We examined the number of fear extinction days required to prevent spontaneous recovery of fear in either sex. We investigated whether ovariectomy affected fear extinction and spontaneous recovery. We also measured the activation of extracellular signal-regulated kinase (ERK) 1 and 2 in the dorsal hippocampus and the medial prefrontal cortex following fear extinction sessions. In our results, we found no sex difference in recent or remote fear memory. However, females required more fear extinction sessions compared to males to prevent spontaneous recovery. Within-extinction freezing also differed between males and females. Moreover, females required more extinction sessions than males to increase ERK2 phosphorylation in the dorsal hippocampus. Our data suggest that contextual fear extinction was unstable in females compared to males and that such sex differences may be related to the ERK2 phosphorylation in the hippocampus.

Array of vortex rings in circular synthetic jets was investigated experimentally by instantaneous velocity measurements using a hot-wire anemometer. The ensemble averaged velocities were derived by referencing the oscillatory flow in a circular orifice. The contours of the ensemble averaged velocity showed that the elliptical shaped high-velocity regions were generated per a cycle of the oscillatory flow. These high-velocity regions were caused by vortex rings, consequently their travelling and disappearance in the downstream indicated the convection and collapse of the vortex rings. The structures of vortex array were examined for seven dimensionless strokes of the oscillatory flow range of L/d = 0.712-7.10, where the stroke L was the length of the fluid ejected in an oscillatory cycle and d is the diameter of the orifice. It was found that vortex rings with nearly equal intervals along the jet axis travelled downstream, and collapsed in a further downstream location. In the process of vortex collapse, no direct interactions with the neighbouring vortices were observed. For the dimensionless strokes larger than 3.6, it was observed the vortex ring accompanied weak and small trailing vortex rings. It was also found that dimensionless convection velocities of vortex ring were independent of the stroke, but the spatial intervals of vortex rings increased as the stroke was increased. As the stroke was increased, the location of the vortex collapse moved downstream. The correlation between the location of the vortex collapse and the starting point of jet width growth was good. The effect of the stroke on the jet evolution was attributed to the change in the location of the vortex collapse.

DNA methylation is one of the essential factors in the control of gene expression. Folic acid, methionine and choline (methyl donors)--all nutrients related to one-carbon metabolism--are known as important mediators of DNA methylation. A previous study has shown that long-term administration of a diet lacking in methyl donors caused global DNA hypermethylation in the brain (Pogribny et al., 2008). However, no study has investigated the effects of a diet lacking in methyl donors during the developmental period on emotional behaviors such as fear and anxiety-like behavior in association with gene expressions in the brain. In addition, it has not been elucidated whether a diet supplemented with methyl donors later in life can reverse these changes. Therefore, we examined the effects of methyl donor deficiency during the developmental period on fear memory acquisition/extinction and anxiety-like behavior, and the relevant gene expressions in the hippocampus in juvenile (6-wk) and adult (12-wk) mice. We found that juvenile mice fed a methyl-donor-deficient diet had impaired fear memory acquisition along with decreases in the gene expressions of Dnmt3a and Dnmt3b. In addition, reduced anxiety-like behavior with decreased gene expressions of Grin2b and Gabar2 was observed in both the methyl-donor-deficient group and the body-weight-matched food-restriction group. After being fed a diet supplemented with methyl donors ad libitum, adult mice reversed the alteration of gene expression of Dnmt3a, Dnmt3b, Grin2b and Gabar2, but anxiety-like behavior became elevated. In addition, impaired fear-memory formation was observed in the adult mice fed the methyl-donor-deficient diet during the developmental period. Our study suggested that developmental alterations in the one-carbon metabolic pathway in the brain could have effects on emotional behavior and memory formation that last into adulthood.

Perinatal exposure to bisphenol A (BPA), an endocrine-disrupting chemical, affects the central nervous system, including effects on emotional responses and neurotransmitter release. In this study, we investigated the effects of BPA (250 ng/kg/day, from gestational day 10 to postnatal day 20) on fear memory and serotonin (5-HT) metabolites in the brain using contextual fear conditioning (FC) and high-performance liquid chromatography (HPLC), respectively, in adult and juvenile mice of both sexes. Furthermore, we studied the effects of BPA on the gene expression of 5-HT metabolite-related enzymes and 5-HT receptors using quantitative real-time RT PCR in the brains of juvenile females. BPA enhanced fear memory and increased serotonin metabolite (5-HIAA) levels and 5-HIAA/5-HT in the hippocampus, the striatum, the midbrain, the pons, and the medulla oblongata of juvenile female mice. In contrast, alterations in those areas were much smaller in adult females and in both juvenile and adult males. Furthermore, BPA induced increases in the expression levels of Tph2, Slc6a4, and Maoa mRNA in the hippocampus of juvenile females, indicating that BPA induces hyper 5-HT turnover in the hippocampus. Our results suggest that perinatal exposure to a low dose of BPA enhances fear memory and the 5-HTergic system in juvenile mice.

Recently, Monfils et al. [9] and Clem and Huganir [3] have shown that an isolated retrieval trial before the extinction sessions (retrieval-extinction) in mice and rats prevented the renewal and spontaneous recovery of the original fear memory by inhibiting reconsolidation in a hippocampus-independent manner. In contrast, Chan et al. [2], using the same paradigm, reported that retrieval extinction in rats augmented the renewal and reinstatement of extinguished fear. However, it remains unclear whether or not retrieval extinction in a hippocampus-independent paradigm erases the original fear memory by inhibiting reconsolidation. We therefore conducted three experiments to investigate whether or not retrieval extinction erases the original fear memory by inhibiting reconsolidation in mice. Our major findings were as follows. (1) Retrieval-extinction in mice did not suppress spontaneous recovery and fear renewal in a hippocampus-independent paradigm. (2) Fear renewal was observed when retrieval-strong extinction in a hippocampus-independent paradigm was performed. (3) Retrieval extinction in a hippocampus-dependent paradigm did not erase the original fear memory. These results suggested that fear extinction after retrieval in mice does not inhibit reconsolidation of previously consolidated fear memory in either a hippocampus-independent or -dependent paradigm.

Based on NMDA hypofunction hypothesis for negative symptoms and cognitive deficits in schizophrenia, MK-801-induced animal models of schizophrenia may help us understand the different effects between typical and atypical antipsychotics. On the other hand, the mitogen-activated protein kinase (MAPK) signaling pathways may participate in antipsychotic actions. The aim of this study was to investigate the effects of aripiprazole on MK-801-induced prepulse inhibition (PPI) disruption and MAPK phosphorylation in mice. To clarify the effects of aripiprazole on MK-801-induced PPI disruption, we measured PPI of 51 ddY male mice after aripiprazole was administered 15 min prior to the injection of MK-801, and measured activation of cytosol and nuclear MAPK phosphorylation by western blotting. Aripiprazole (4.0 mg/kg) significantly reversed the MK-801 (0.15 mg/kg)-induced PPI deficits. Pretreatment of aripiprazole (40 mg/kg) had a tendency to suppress MK-801 (1.0 mg/kg)-induced pMEK/MEK (Ser218/222) activation. In addition, aripiprazole treatment showed a significant decrease of pERK/ERK. Our data suggested that aripiprazole may reverse MK-801-induced PPI deficits through regulation of MAPK phosphorylation in the same way as the atypical antipsychotic drug, clozapine.

To examine whether exposure to bisphenol A (BPA) at low levels affect brain function, monoamine concentrations in hippocampus, striatum and brain stem, were investigated in neonatal male rats injected intracranially with BPA at 0-10microgkg(-1). Significant increases of serotonin (5-HT) in hippocampus, 5-HIAA and 5-HIAA/5-HT in brain stem, dopamine (DA) and DOPAC in striatum were observed at 28d after the injection on postnatal day 2. At 7d after the injection, increases in 5-HT and norepinephrine (NE) and decreases in DOPAC and 5-HIAA were observed in hippocampus. To investigate the degradation of BPA in brain, we also measured BPA concentrations of whole neonatal rat brain. Free BPA disappeared from brain tissues within 5h, even when the highest dose (1000microgkg(-1)) was injected. The present results suggest that BPA exposure at lower doses than environmentally relevant levels may have a great impact on monoamine levels in neonatal brain over 28d after its disappearance.