Objective. Effective rehabilitation for upper limb paralysis in patients with intracerebral hemorrhage mediated by hemiplegia has not yet been established. We evaluated the effectiveness of upper limb functional training using a wearable-type exoskeleton driven by bio-electric signals using upper limb motor function scores and tractography of the corticospinal tract (CST). Approach. Nine patients with putamen and seven with thalamus hemorrhage were trained using the hybrid assistive limb (HAL) of the wearable exoskeleton. Among the participants, 12 individuals were patients with severe hemiplegic, indicated by a Fugl–Meyer assessment (FMA) score of 10. We also investigated the relationship between improvement in upper limb function and changes in mean diffusivity, axial diffusivity, radial diffusivity (RD), or fractional anisotropy (FA) in the CST. Main results. Following HAL training, upper limb function scores increased in all patients. We observed a clinically significant improvement in nine patients, with a mean effect size of 26 ± 12.7. HAL training was effective in improving upper limb function in patients with an FA ratio (the affected/unaffected side) ⩾0.86 in the CST. Patients with clinically significant improvements had a mean 16 ± 15% increase in FA ratio in the CST. Patients with greater improvement in upper-limb function tended to have lower RD values in the CST, and the effect size of the RD value and FMA was demonstrated to be negatively correlated ( rs = −0.54). An increase in FA ratio and a decrease in RD values in the CST of the cerebral peduncle are significant findings that suggest improvements in upper limb function. Significance. These findings highlight the effectiveness of HAL training in improving upper-limb dysfunction in patients with subacute cerebral hemorrhage. Improvement of upper limb function by assistive actuation with the wearable exoskeleton based on bio-electric signals may be caused by the promotion of the restoration of white matter integrity of the CST.

OBJECTIVE Meningiomas are predominantly benign, but some cases exhibit recurrent growth after surgery and undergo malignant transformation to WHO grade 2 or grade 3. Despite progress in genetic analyses, advancements in metabolomic analysis remain less established. Herein, the authors investigated metabolic activity differences between WHO grade 1 meningiomas and WHO grade 2 or 3 meningiomas by noninvasively using proton magnetic resonance spectroscopy (1H-MRS), aiming to preoperatively estimate malignancy. They also reviewed the literature to elucidate this aspect of meningioma research. METHODS At Ryukyu University Hospital, the authors focused on 93 patients diagnosed with meningioma between 2011 and 2021. The inclusion criteria encompassed prior surgery, pathological diagnoses of meningioma, and preoperative 1H-MRS. Group I included 71 patients with WHO grade 1 meningioma and group II included 22 patients, comprising 19 and 3 with WHO grade 2 and 3 meningioma, respectively. The authors retrospectively conducted a comparative analysis of patient backgrounds and tumor metabolites. RESULTS Group I and II did not differ significantly in terms of patient demographic characteristics (age and sex). Group II demonstrated a significantly lower extent of tumor resection (p < 0.01), higher MIB-1 labeling index (LI) (p < 0.05), higher incidence of prior irradiation (p < 0.001), and increased rate of tumor recurrence (p = 0.005) compared to group I. According to 1H-MRS, all metabolites, except lactate, displayed significantly higher median creatine (Cr) ratios in group II than group I: glutamine/Cr was 8.46, glutamate/Cr was 9.49, lipid/Cr was 11.36, and choline/Cr was 2.77. According to the receiver operating characteristic (ROC) analysis, glutamine had the largest area under the curve of 0.765 among 10 metabolites, and the cutoff value for distinguishing between group I and II was 5.76. CONCLUSIONS In cases pathologically graded as WHO grade 2 or 3 meningiomas, metabolic products such as glutamine, glutamate, lipids, and choline increased significantly. These changes were correlated with elevation of the MIB-1 LI. In group II, the mean MIB-1 LI was 8.58, significantly higher than in group I, suggesting a strong association with pathological malignancy. Therefore, 1H-MRS may help to noninvasively predict tumor metabolic activity and tumor recurrence. Furthermore, the authors concluded from the ROC analysis that glutamine may be a potential indicator of future growth of meningioma and benefits of early surgery.

Introduction:Endoscopic transsphenoidal surgery can be performed by two surgeons, including an endoscopist (PE/2S), and by a single surgeon with an endoscope-holder system (PE/1S + H). We analyzed the surgical outcome, and outcome predictors in acromegaly patients in endoscopic transsphenoidal surgery using floor standing pneumatic endoscope-holder system. Methods:Endoscopic transsphenoidal surgery was performed with PE/1S+H (n = 51) and PE/2S (n = 20). Postoperative remission was evaluated by the 2010 consensus criteria for acromegaly. We compared the surgical results of PE/2S style and PE/1S+H style, and investigated the factors associated with favorable surgical outcomes. Results:There was no difference in clinical background between the PE/2S and the PE/1S + H groups. The remission rates for PE/2S and PE/1S+H were 65.0% and 82.4%, respectively, with no significant difference (p = 0.128). In consecutive 71 cases, statistically useful predictors of remission were low preoperative growth hormone (GH) level (<12 ng/mL), low Knosp grade (0-2), and low revised Knosp grade (0-3A). In the conventional Knosp grade 0-2 and 3/4, the sensitivity was 0.76 and the specificity was 0.81. In the revised Knosp grade 0-3A and 3B/4, the sensitivity was 0.96 and the specificity was 0.44. Conclusion:The outcome of GH-producing pituitary neuroendocrine tumors surgically removed by PE/1S+H could be almost equivalent to that by PE/2S. Preoperative low GH level and Knosp grades, including revised Knosp grades, are useful preoperative predictors for surgical remission of acromegaly.

Purpose Pineal parenchymal tumors of intermediate differentiation (PPTIDs), which were recognized in the 2007 World Health Organization (WHO) classification, are rare, accounting for less than 1% of all central nervous system tumors. This rarity and novelty complicate the diagnosis and treatments of PPTID. We therefore aimed to evaluate the clinicopathological significance of this tumor. Methods At 11 institutions participating in the Kyushu Neuro-Oncology Study Group, data for patients diagnosed with PPTID were collected. Central pathology review and KBTBD4 mutation analysis were applied to attain the diagnostically accurate cohort. Results PPTID was officially diagnosed in 28 patients: 11 (39%) with WHO grade 2 and 17 (61%) with WHO grade 3 tumors. Median age was 49 years, and the male:female ratio was 1:2.1. Surgery was attempted in all 28 patients, and gross total resection (GTR) was achieved in 46% (13/28). Adjuvant radiotherapy and chemotherapy were administered to, respectively, 82% (23/28) and 46% (13/28). The 5-year progression-free survival (PFS) and overall survival rates were 64.9% and 70.4% respectively. Female sex (p = 0.018) and GTR (p < 0.01) were found to be independent prognostic factors for PFS and female sex (p = 0.019) was that for OS. Initial and second recurrences were most often leptomeningeal (67% and 100% respectively). 80% (20/25) of patients harbored a KBTBD4 mutation. Conclusions Female sex and GTR were independent prognostic factors in our patients with PPTID. Leptomeningeal recurrence was observed to be particularly characteristic of this tumor. The rate of KBTBD4 mutation observed in our cohort was acceptable and this could prove the accuracy of our PPTID cohort.

BACKGROUND:Radiotherapy is an important treatment option for central nervous system malignancies. However, cranial radiation induces hippocampal dysfunction and white matter injury; this leads to cognitive dysfunction, and results in a reduced quality of life in patients. Excitatory glutamate signaling through N-methyl-d-aspartate receptors (NMDARs) plays a central role both in hippocampal neurogenesis and in the myelination of oligodendrocytes in the cerebrum.METHODS:We provide a method for quantifying neurogenesis in human subjects in live brain during cancer therapy. Neuroimaging using originally created behavioral tasks was employed to examine human hippocampal memory pathway in patients with brain disorders.RESULTS:Treatment with memantine, a non-competitive NMDAR antagonist, reversed impairment in hippocampal pattern separation networks as detected by functional magnetic resonance imaging. Hyperbaric preconditioning of the patients just before radiotherapy with memantine mostly reversed white matter injury as detected by whole brain analysis with Tract-Based Spatial Statics. Neuromodulation combined with the administration of hyperbaric oxygen therapy and memantine during radiotherapy facilitated the restoration of hippocampal function and white matter integrity, and improved higher cognitive function in patients receiving cranial radiation.CONCLUSIONS:The method described herein, for diagnosis of hippocampal dysfunction, and therapeutic intervention can be utilized to restore some of the cognitive decline experienced by patients who have received cranial radiation. The underlying mechanism of restoration is the production of new neurons, which enhances functionality in pattern separation networks in the hippocampi, resulting in an increase in cognitive score, and restoration of microstructural integrity of white matter tracts revealed by Tract-Based Spatial Statics Analysis.

Evidence has accumulated that higher consumption of high-fat diets (HFDs) during the juvenile/adolescent period induces altered hippocampal function and morphology; however, the mechanism behind this phenomenon remains elusive. Using high-resolution structural imaging combined with molecular and functional interrogation, a murine model of obesity treated with HFDs for 12 weeks after weaning mice was shown to change in the glutamate-mediated intracellular calcium signaling and activity, including further selective reduction of gray matter volume in the hippocampus associated with memory recall disturbance. Dysregulation of intracellular calcium concentrations was restored by a non-competitive α-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR) antagonist, followed by normalization of hippocampal volume and memory recall ability, indicating that AMPARs may serve as an attractive therapeutic target for obesity-associated cognitive decline.

We report the case of a 14-year-old girl with petrous bone cholesteatoma resected through a combined approach from the middle cranial fossa and mastoid process. A favorable outcome can be achieved when applying the transmastoid approach to a cholesteatoma by incorporating the middle fossa approach to preserve inner ear function. We emphasize the utility of integrated three-dimensional image reconstruction as a surgical strategy to determine beneficial routes for facial and inner ear function and accomplishment of radical resection. Visualization by an integrated image of irregular tumor infiltration within the petrous bone facilitates information sharing for better cooperation between surgeons in otolaryngeal and neurosurgical fields.

Introduction Hippocampal dentate gyrus related to pattern separation has attracted attention as an area for neurogenesis. However, the associations between the pattern separation and the volumes of hippocampal subfields in humans remain unknown. Methods 58 young adults were examined the memory task (pattern separation, pattern completion) and the hippocampal volumes. Subjects were asked to determine whether the visual image is a new stimulus, or a similar but different stimulus (pattern separation), or the same stimulus (pattern completion), compared to preceding stimuli, and response time and correct response were measured. The volumes of the whole brain, hippocampus 6 subfields and perihippocampus 5 subfields, were measured using FreeSurfer 6.0. Results Negative associations between the pattern separation task and the volumes of whole brain areas were found in bilateral cerebellar cortex, fourth ventricle, left hippocampus, left thalamus, left ventral diencephalon, and brainstem. Simple linear regression analysis revealed a significant association with the left hippocampal-amygdaloid transition area only, while no significant associations were found in any of the subfield volumes when adjusted with covariates. Conclusions The principle "bigger is better"-an idea that the larger the volume the better the function-could not be applied to the relation between the pattern separation ability and the dentate gyrus.

We report four cases of high-grade astrocytoma with a BRAF V600E mutation, ATRX inactivation, and CDKN2A/B homozygous deletion. Children to young adults aged 3–46 presented with a well demarcated contrast-enhancing mass in the supratentorial area. Pathological examination revealed packed growth of short spindle to round polygonal cells including some pleomorphic cells. The tumors had less ability to infiltrate into the adjacent brain parenchyma and presented a circumscribed growth pattern. Mitosis was readily found, accompanied by focal necrosis and/or microvascular proliferation. Tumors were histologically similar in part to pleomorphic xanthoastrocytoma (PXA) or anaplastic PXA, but did not fit criteria for either neoplasm. A BRAF V600E mutation and homozygous deletion of CDKN2A/B were observed, which is similar to the genetic features of PXA or epithelioid glioblastoma, but the additional loss of ATRX nuclear immunoreactivity and absence of TERT promoter mutation were unusual findings, indicating a novel genetic profile. Despite their malignant histological features, all patients had a favorable clinical course and remained alive for 6 months to 28 years under standard medical treatment for malignant glioma. In summary, high grade astrocytomas with BRAF V600E, ATRX, and CDKN2A/B alternations had unique clinicopathological features and may be a novel subset of high grade glioma.

The factors that lead to the improvement of gait function in patients with diseases of the central nervous system (CNS) who use a hybrid assistive limb (HAL) are not yet fully understood. The purpose of the present study was to analyze these factors to determine the prognosis of the patients' gait function. Patients whose CNS disease was within 180 days since onset were designated as the subacute-phase patients, and patients whose disease onset had occurred more than 180 days previously were designated as chronic-phase patients. Fifteen subacute-phase patients and 15 chronic-phase patients were given HAL training. The study analyzed how post-training walking independence in these patients was affected by the following factors: age, disease, lesion area, lower limb function, balance, period until the start of training, number of training sessions, additional rehabilitation, higher-order cognitive dysfunction, HAL model, and the use of a non-weight-bearing walking-aid. In subacute-phase patients, walking independence was related to lower limb function (r(s) = 0.35). In chronic-phase patients, there was a statistically significant correlation between post-training walking independence and balance (r(s) = 0.78). In addition, in patients with a severe motor dysfunction that was accompanied by inattention and global cognitive dysfunction, little improvement occurred, even with double-leg model training, because they had difficulty wearing the device. The results demonstrated that the factors that improved walking independence post HAL training differed between patients with subacute-and chronic-stage CNS diseases. The findings may serve as valuable information for future HAL training of patients with CNS diseases.

BACKGROUND:Cerebral hemangioblastomas are benign tumors with abundant blood flow that occur mainly in the posterior fossa. Tumor removal en bloc is important in surgical treatment because of the risk of bleeding; however, it is actually rather difficult in practice. Therefore, we propose a surgical strategy for visualizing hypervascular tumors of the posterior fossa utilizing indocyanine green (ICG). CASE DESCRIPTION:Case 1 involved a 48-year-old male with a history of von Hippel-Lindau (VHL) disease. Magnetic resonance imaging (MRI) revealed a solid tumor measuring 3.0 cm in diameter in the right cerebellopontine angle. We performed surgery because the tumor was pressing against the brainstem. Surgery was performed via the posterior subtemporal transtentorial approach in order to visualize the feeding artery and draining vein intraoperatively. The vessels were confirmed by ICG and the tumor was removed en bloc. Case 2 involved a 30-year-old woman. Signs of increased intracranial pressure were noted, and an MRI revealed a solid tumor 3.5 cm in diameter in the left cerebellar hemisphere. Surgery was performed via the midline suboccipital approach. Similarly, we confirmed the vessels using ICG and the tumor was removed en bloc. CONCLUSIONS:For hypervascular tumors of the posterior fossa, preoperative image assessment is important. Furthermore, the use of ICG during surgery is advantageous for surgical strategies where the feeding arteries and draining veins exist superficially in the operative field and are therefore easier to remove en bloc.

Pediatric high‐grade gliomas are rare and occasionally hard to classify. These tumors often feature a well‐demarcated histology and are expected to have a better outcome than ordinary diffuse high‐grade gliomas in adults. We herein report a case of circumscribed high‐grade glioma that showed a distinct molecular profile and followed an excellent course for 26 years. The patient, a 3‐year‐old boy at onset, presented with a contrast‐enhancing mass in the right temporal lobe and underwent resection. Histologically, the tumor mainly consisted of compact bundles of GFAP‐positive spindle cells. With its malignant features including brisk mitotic activity and pseudopallisading necrosis, a diagnosis of high‐grade astrocytoma was made and adjuvant chemoradiotherapy was administered. After a disease‐free period of two decades, the tumor recurred locally. The resected tumor was histologically identical to the primary tumor and additionally contained pleomorphic cells, but lacked eosinophilic granular bodies and reticulin networks. The primary and recurrent tumors both harbored the BRAF V600E mutation, and the recurrent tumor was immunonegative for ATRX. Combined BRAF and ATRX mutations are rare in gliomas, with only a pediatric case of glioblastoma being reported in the literature. However, our case cannot be regarded as glioblastoma because of its well‐demarcated histology and excellent course. The distinction of either a diffuse or localized nature in gliomas is important, particularly in children, for predicting prognoses and selecting adjuvant therapies that consequently affect life‐long health care. The present case provides novel insights into pediatric high‐grade astrocytomas.

The Linear-Quadratic (LQ) model is commonly used for evaluating fractionation schedules in clinical practice of radiation oncology, but it is sometimes reported that the biologically effective dose (BED) based on the LQ model is not adequate to hypofractionated radiation therapy like stereotactic irradiation(STI). The purpose of this study was to evaluate the relationship between the BED based on the LQ model and tumor control following high dose per fraction in vivo. Human glioblastoma with mutant-type p53 was subcutaneously transplanted into nude mice and irradiated with X rays (150 kV, 20 mA, 0.5 mm Al and 0.1 mm Cu filters). Doses equivalent to 12 Gy/ fraction (fx) were calculated according to the LQ model using the alpha/beta ratio 10Gy for the tumor. Twice daily irradiation schedules were utilized to reduce the effect of treatment time differences, and also used once daily irradiation for 8 fx to confirm this. Intervals of each irradiation were more than 10 hours. The irradiation started at the day calculated tumor volume exceeded 200mm3. Tumor sizes were measured every three days by calipers to evaluate the tumor growth delay (TGD). Tumors removed from mice after reaching five times as large as the original volume were fixed in formalin and embedded paraffin. The changes of necrosis, vascular endothelial damages, and other morphological changes were estimated by hematoxylin and eosin staining. CD133, CD44, Ki67 and GFAP expression were evaluated immunohistochemically. Mean TGD of the unirradiated control, 12 Gy/1 fx, 15.06 Gy/2 fx, 18.16 Gy/4 fx and 20.96 Gy/8 fx were 5.69, 22.64, 37.26, 36.81 and 28.96 days respectively. Mean TGD of each irradiated groups was significant longer than the control and 15.06 Gy/2 fx, 18.16 Gy/4 fx and 20.96 Gy/8 fx groups showed statistically longer than the control, but no significant differences were shown among the irradiated groups (P>0.05). Mean TDG2 of twice a day irradiation was 45.00 days, and a little longer than once a day irradiation. However, there are no differences between these comparisons (P>0.05). In the control group, some atypical cells that have oval or irregular nucleus were observed, but it was relatively uniform compared with irradiated groups. In the irradiated group, irregular multinucleated giant cells were found in a particular area. There were some differences between control and irradiated groups, but no significant changes were found among the irradiated groups. No significant changes were noted in CD133, CD44, Ki67, and GFAP expressions. TGD, immunohistochemically and morphological changes were suggested that the BED based on the LQ model might be applicable to hypofractionated radiation therapy until 12 Gy.

The cerebellum is a crucial structure for cognitive function as well as motor control. Benign brain tumors such as schwannomas, meningiomas, and epidermoids tend to occur in the cerebellopontine angle cisterns and may cause compression of the posterior lateral cerebellum near the superior posterior fissure, where the eloquent area for cognitive function was recently identified. The present study examined cognitive impairment in patients with benign cerebellar tumors before and after surgical intervention in order to clarify the functional implications of this region in humans. Patients with cerebellar tumors showed deficits in psychomotor speed and working memory compared with healthy controls. Moreover, these impairments were more pronounced in patients with right cerebellar tumors. Functional magnetic resonance imaging during performance of a lure task also demonstrated that cerebellar tumors affected pattern separation or the ability to distinguish similar experiences of episodic memory or events with discrete, non-overlapping representations, which is one of the important cognitive functions related to the hippocampus. The present findings indicate that compression of the human posterior lateral cerebellum affects hippocampal memory function.

Endoplasmic reticulum (ER) stress is profoundly involved in dysfunction of β-cells under high-fat diet and hyperglycemia. Our recent study in mice showed that γ-oryzanol, a unique component of brown rice, acts as a chemical chaperone in the hypothalamus and improves feeding behavior and diet-induced dysmetabolism. However, the entire mechanism whereby γ-oryzanol improves glucose metabolism throughout the body still remains unclear. In this context, we tested whether γ-oryzanol reduces ER stress and improves function and survival of pancreatic β-cells using murine β-cell line MIN6. In MIN6 cells with augmented ER stress by tunicamycin, γ-oryzanol decreased exaggerated expression of ER stress-related genes and phosphorylation of eukaryotic initiation factor-2α, resulting in restoration of glucose-stimulated insulin secretion and prevention of apoptosis. In islets from high-fat diet-fed diabetic mice, oral administration of γ-oryzanol improved glucose-stimulated insulin secretion on following reduction of exaggerated ER stress and apoptosis. Furthermore, we examined the impact of γ-oryzanol on low-dose streptozotocin-induced diabetic mice, where exaggerated ER stress and resultant apoptosis in β-cells were observed. Also in this model, γ-oryzanol attenuated mRNA level of genes involved in ER stress and apoptotic signaling in islets, leading to amelioration of glucose dysmetabolism. Taken together, our findings demonstrate that γ-oryzanol directly ameliorates ER stress-induced β-cell dysfunction and subsequent apoptosis, highlighting usefulness of γ-oryzanol for the treatment of diabetes mellitus.

Recent epidemiological studies have demonstrated that coffee drinking is associated with reduced mortality of cardiovascular disease. However, its precise mechanisms remain to be clarified. In this study, we examined whether single ingestion of caffeine contained in a cup of coffee improves microvascular function in healthy subjects. A double-blind, placebo-controlled, crossover study was performed in 27 healthy volunteers. A cup of either caffeinated or decaffeinated coffee was drunk by the subjects, and reactive hyperemia of finger blood flow was assessed by laser Doppler flowmetry. In an interval of more than 2 days, the same experimental protocol was repeated with another coffee in a crossover manner. Caffeinated coffee intake slightly but significantly elevated blood pressure and decreased finger blood flow as compared with decaffeinated coffee intake. There was no significant difference in heart rate between caffeinated and decaffeinated coffee intake. Importantly, caffeinated coffee intake significantly enhanced post-occlusive reactive hyperemia of finger blood flow, an index of microvascular endothelial function, compared with decaffeinated coffee intake. These results provide the first evidence that caffeine contained in a cup of coffee enhances microvascular function in healthy individuals.