Successful social interaction depends on not only the ability to identify with others but also the ability to distinguish between aspects of self and others 1–4. Although there is considerable ...knowledge of a shared neural substrate between self-action and others' action 5, it remains unknown where and how in the brain the action of others is uniquely represented. Exploring such agent-specific neural codes is important because one's action and intention can differ between individuals 1. Moreover, the assignment of social agency breaks down in a range of mental disorders 6–8. Here, using two monkeys monitoring each other's action for adaptive behavioral planning, we show that the medial frontal cortex (MFC) contains a group of neurons that selectively encode others' action. These neurons, observed in both dominant and submissive monkeys, were significantly more prevalent in the dorsomedial convexity region of the MFC including the pre-supplementary motor area than in the cingulate sulcus region of the MFC including the rostral cingulate motor area. Further tests revealed that the difference in neuronal activity was not due to gaze direction or muscular activity. We suggest that the MFC is involved in self-other differentiation in the domain of motor action and provides a fundamental neural signal for social learning.
► Monkeys can utilize others' action information for planning their own action ► MFC contains neurons selectively encoding actions of a social partner ► Partner-selective neurons are more prevalent in MFC convexity than in MFC sulcus ► Monkey MFC is involved in self-other differentiation in the domain of motor action
Ischemic neuronal death causes serious lifelong neurological deficits; however, there is no proven effective treatment that can prevent neuronal death after the ischemia. We investigated the ...feasibility of mRNA therapeutics for preventing the neuronal death in a rat model of transient global ischemia (TGI). By intraventricular administration of mRNA encoding brain-derived neurotrophic factor (BDNF) using a polymer-based carrier, polyplex nanomicelle, the mRNA significantly increased the survival rate of hippocampal neurons after TGI, with a rapid rise of BDNF in the hippocampus. Interestingly, mRNA administration on Day 2 after TGI provided significantly better survival rate than the administration immediately after TGI. Eventually, dosing twice on Day 2 and 5 exerted long-term therapeutic effects, which were confirmed by a Y-maze behavioral test demonstrating improved spatial memory compared with untreated rats on Day 20. Immunohistochemical analysis showed that astrocytes were chief targets of the BDNF mRNA-loaded nanomicelles, suggesting that the augmented BDNF secretion from astrocytes creates a supportive microenvironment for the neurons to tolerate changes caused by ischemic stresses, and terminate the process of progressive neuronal death after the ischemic attack. Overall, the unique mechanism of action of mRNA therapeutics provide a promising approach for preventing ischemic neuronal death.
Although much learning occurs through direct experience of errors, humans and other animals can learn from the errors of other individuals. The medial frontal cortex (MFC) processes self-generated ...errors, but the neuronal architecture and mechanisms underlying the monitoring of others' errors are poorly understood. Exploring such mechanisms is important, as they underlie observational learning and allow adaptive behavior in uncertain social environments. Using two paired monkeys that monitored each other's action for their own action selection, we identified a group of neurons in the MFC that exhibited a substantial activity increase that was associated with another's errors. Nearly half of these neurons showed activity changes consistent with general reward-omission signals, whereas the remaining neurons specifically responded to another's erroneous actions. These findings indicate that the MFC contains a dedicated circuit for monitoring others' mistakes during social interactions.
Certain driver mutations and pathological diagnoses are associated with the anatomical site of meningioma, based on which the meninges have different embryological origins. We hypothesized that ...mutations and pathological diagnoses of meningiomas are associated with different embryological origins. We comprehensively evaluated associations among tumor location, pathological diagnosis (histological type), and genetic alterations including AKT1, KLF4, SMO, POLR2A, and NF2 mutations and 22q deletion in 269 meningioma cases. Based on the embryological origin of meninges, the tumor locations were as follows: neural crest, paraxial mesodermal, and dorsal mesodermal origins. Tumors originating from the dura of certain embryologic origin displayed a significantly different pathological diagnoses and genetic abnormality ratio. For instance, driver genetic mutations with AKT1, KLF4, SMO, and POLR2A, were significantly associated with the paraxial mesodermal origin (p = 1.7 × 10
). However, meningiomas with NF2-associated mutations were significantly associated with neural crest origin (p = 3.9 × 10
). On analysis of recurrence, no difference was observed in embryological origin. However, POLR2A mutation was a risk factor for the tumor recurrence (p = 1.7 × 10
, Hazard Ratio 4.08, 95% Confidence Interval 1.28-13.0). Assessment of the embryological origin of the meninges may provide novel insights into the pathomechanism of meningiomas.
Epileptogenic zones (EZs), where epileptic seizures cease after resection, are localized by assessing the seizure-onset zone using ictal electroencephalography (EEG). Owing to the difficulty in ...capturing unpredictable seizures, biomarkers capable of identifying EZs from interictal EEG are anticipated. Recent studies using intracranial EEG have identified several potential candidate biomarkers for epileptogenicity. High-frequency oscillation (HFO) was initially expected to be a robust biomarker of abnormal excitatory activity in the ictogenic region. However, HFO-guided resection failed to improve seizure prognosis. Meanwhile, the regularity of low-gamma oscillations (30-80 Hz) indicates inhibitory interneurons' hypersynchronization, which could be used to localize the EZ. Besides resting-state EEG assessments, evoked potentials elicited by single-pulse electrical stimulation, such as corticocortical evoked potentials (CCEP), became valuable tools for assessing epileptogenic regions. CCEP responses recorded in the cortex remote from the stimulation site indicate functional connectivity, revealing increased internal connectivity within the ictogenic region and elevated inhibitory input from the non-involved regions to the ictogenic region. Conversely, large responses close to the stimulation site reflect local excitability, manifesting as an increased N1 amplitude and overriding HFO. Further research is required to establish whether these novel electrophysiological methods, either individually or in combination, can function as robust biomarkers of epileptogenicity and hold promise for improving seizure prognosis.
Tumor recurrence is a leading cause of cancer mortality. Therapies for recurrent disease may fail, at least in part, because the genomic alterations driving the growth of recurrences are distinct ...from those in the initial tumor. To explore this hypothesis, we sequenced the exornes of 23 initial low-grade gliomas and recurrent tumors resected from the same patients. In 43% of cases, at least half of the mutations in the initial tumor were undetected at recurrence, including driver mutations in TP53, ATRX, SMARCA4, and BRAF; this suggests that recurrent tumors are often seeded by cells derived from the initial tumor at a very early stage of their evolution. Notably, tumors from 6 of 10 patients treated with the chemotherapeutic drug temozolomide (TMZ) followed an alternative evolutionary path to high-grade glioma. At recurrence, these tumors were hypermutated and harbored driver mutations in the RB (retinoblastoma) and Akt-mTOR (mammalian target of rapamycin) pathways that bore the signature of TMZ-induced mutagenesis.
The c.14576G>A variant in ring finger protein 213 (RNF213) was recently identified as a susceptibility gene variant for moyamoya disease (MMD). The occurrence of c.14576G>A variant was evaluated in ...patients with intracranial major artery stenosis/occlusion (ICASO) without signs of MMD (non-MMD ICASO), as well as in patients with MMD and other cerebrovascular diseases as controls.
This single-hospital-based case-control study was completed in 7 months (from October 2011-April 2012) at Department of Neurosurgery, The University of Tokyo Hospital. The occurrence of c.14576G>A variant was analyzed in 41 patients with non-MMD ICASO, in 48 with MMD, in 21 with cervical disease, in 61 with cerebral aneurysm, and in 25 normal subjects.
Nine of 41 patients (21.9%) with non-MMD ICASO and 41 of 48 (85.4%) with MMD had the c.14576G>A variant. One of 61 patients (1.6%) with cerebral aneurysm and no patients with cervical disease or normal subjects had the variant. Comparison of each phenotype group with the normal subjects showed that presence of c.14576G>A variant had significant associations with MMD (odds ratio OR, 292.8; 95% confidence interval CI, 15.4-5153.0; P<0.0001) and with non-MMD ICASO (OR, 14.9; 95% CI, 0.82-268.4; P=0.01), but no association with either cerebral aneurysm (OR, 1.2; 95% CI, 0.04-32.0; P=1.00) or cervical disease (OR, 1.1; 95% CI, 0.02-62.3; P=1.00).
The present study indicates that a particular subset of Japanese patients with non-MMD ICASO has a genetic variant associated with MMD. Therefore, we propose the existence of a new entity of ICASO caused by the c.14576G>A variant in RNF213.
To assess the clinicopathological features and prognostic factors of pediatric intracranial ependymomas and to explore the current diagnostic practice, we analyzed clinical data from the Brain Tumor ...Registry of Japan (BTRJ). Data of fifty children under 18 years of age diagnosed with intracranial ependymoma were extracted from the BTRJ database. Cases were reviewed for overall survival (OS) and progression-free survival (PFS), with attention to gender, preoperative Karnofsky performance status score, location of the tumor, the extent of resection, World Health Organization (WHO) histopathological grading, and adjuvant therapy. The median age at diagnosis was 6.1 years, ranging from 7 months to 17.6 years. Based on the WHO histopathological grading, 27 patients were classified under grade 2 (54%) and 23 patients were classified under grade 3 (46%). Gross total resection (GTR) was achieved in 30 patients (60%). The median follow-up time was 65 months. Five-year PFS and OS were 47.2 ± 7.3% and 73.3 ± 6.7%, respectively. GTR was associated with longer OS (P = 0.02). The histopathological grading was not an independent prognostic factor for the OS. Mitosis and microvascular proliferation were higher among patients with grade 3 than in those with grade 2, which aided in deciding the WHO grade. This nationwide study revealed the characteristics and outcomes of patients with childhood ependymomas. GTR was the factor most consistently associated with improved survival. In contrast, the histopathological grading in this cohort was not a significant prognostic factor. More reproducible and practical criteria for the diagnosis of intracranial ependymomas should be further pursued in future studies.
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