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Abstract Epidural spinal cord stimulation (SCS) is indicated for the treatment of intractable pain and is widely used in clinical practice. In previous basic research, the therapeutic effects of SCS have been demonstrated for epileptic seizure. However, the mechanism has not yet been elucidated. In this study, we investigated the therapeutic effect of SCS and the influence of epileptic seizure. First, SCS in the cervical spine was performed. The rats were divided into four groups: control group and treatment groups with SCS conducted at 2, 50, and 300 Hz frequency. Two days later, convulsions were induced by the intraperitoneal administration of kainic acid, followed by video monitoring to assess seizures. We also evaluated glial cells in the hippocampus by fluorescent immunostaining, electroencephalogram measurements, and inflammatory cytokines such as C–C motif chemokine ligand 2 (CCL2) by quantitative real-time polymerase chain reaction. Seizure frequency and the number of glial cells were significantly lower in the 300 Hz group than in the control group. SCS at 300 Hz decreased gene expression level of CCL2, which induces monocyte migration. SCS has anti-seizure effects by inhibiting CCL2-mediated cascades. The suppression of CCL2 and glial cells may be associated with the suppression of epileptic seizure.

The usefulness of transcranial motor evoked potentials (Tc-MEPs) in clipping surgery has been reported. However, numerous false positive and false negative cases were reported. We report the usefulness of a new protocol compared with direct cortical MEP (Dc-MEP). Materials were 351 patients who underwent aneurysmal clipping under simultaneous monitoring of Tc- and Dc-MEPs. A total of 337 patients without hemiparesis and 14 with hemiparesis were separately analyzed. Intraoperative changes of Tc-MEP thresholds were examined in the first 50 patients without hemiparesis. The stimulation strength of Tc-MEP was set at +20% of the stimulation threshold. As thresholds changed intraoperatively, thresholds were examined every 10 min and changed stimulation strength. Stimulation thresholds of Tc-MEP were significantly decreased after craniotomy and significantly increased after CSF aspiration. The recording ratios of Tc- and Dc-MEPs were 98.8% and 90.5%, respectively. Out of 304 patients without MEP change, 5 patients developed transient or mild hemiparesis with infarction of the territory of the perforating artery arising from the posterior communicating artery. Out of 31 patients whose MEP transiently disappeared, 3 patients developed transient or mild hemiparesis. The other two patients without MEP recovery manifested persistent hemiparesis. In 14 patients with preoperative hemiparesis, 3 patients whose healthy/affected ratio of Tc-MEP was large developed severe persistent hemiparesis. We clarified the intraoperative changes of Tc-MEP thresholds for the first time. A new protocol of Tc-MEP that followed thresholds and changed stimulation strength to +20% of thresholds is useful for stable monitoring. The usefulness of Tc-MEP is the same as that or better than that of Dc-MEP.

Background: Vagus nerve stimulation (VNS) exerts neuroprotective and anti-inflammatory effects in preclinical models of central nervous system disorders, including Parkinson's disease (PD). VNS setting applied for experimental models is limited into single-time or intermittent short-duration stimulation. We developed a VNS device which could deliver continuous stimulation for rats. To date, the effects of vagal afferent- or efferent-selective stimulation on PD using continuous electrical stimulation remains to be determined. Objective: To investigate the effects of continuous and selective stimulation of vagal afferent or efferent fiber on Parkinsonian rats. Methods: Rats were divided into 5 group: intact VNS, afferent VNS (left VNS in the presence of left caudal vagotomy), efferent VNS (left VNS in the presence of left rostral vagotomy), sham, vagotomy. Rats underwent the implantation of cuff-electrode on left vagus nerve and 6-hydroxydopamine administration into the left striatum simultaneously. Electrical stimulation was delivered just after 6-OHDA administration and continued for 14 days. In afferent VNS and efferent VNS group, the vagus nerve was dissected at distal or proximal portion of cuff-electrode to imitate the selective stimulation of afferent or efferent vagal fiber respectively. Results: Intact VNS and afferent VNS reduced the behavioral impairments in cylinder test and methamphetamine-induced rotation test, which were accompanied by reduced inflammatory glial cells in substantia nigra with the increased density of the rate limiting enzyme in locus coeruleus. In contrast, efferent VNS did not exert any therapeutic effects. Conclusion: Continuous VNS promoted neuroprotective and anti-inflammatory effect in experimental PD, highlighting the crucial role of the afferent vagal pathway in mediating these therapeutic outcomes.

“Paying it forward” is a behavior in which people help someone else because they were helped in the past. Although experimental evidence exists that indicates that real human beings often “pay-it-forward” even in the face of free-rider risks, the theoretical basis for the evolution of this behavior remains unclear. In this paper, we propose a game-theoretical model that explains how pay-it-forward behavior can evolve despite the temptation to free-ride. By assuming that human beings exhibit cognitive distortions, as predicted by prospect theory, and that free-riding is punished with a tiny probability, we demonstrate that pay-it-forward, alongside unconditional altruistic behavior, can evolve and effectively deter free-riding behavior.

Indirect reciprocity is one of the major mechanisms driving the evolution of cooperation in human societies. There are two types of indirect reciprocity: upstream and downstream reciprocity. Cooperation in downstream reciprocity follows the pattern ‘You helped someone, and I will help you’, while the direction of cooperation is reversed in upstream reciprocity, which follows the pattern ‘You helped me, and I will help someone else’. These two types of indirect reciprocity often occur in combination. However, upstream and downstream reciprocity have mostly been theoretically studied in isolation. In this study, we propose a new model that integrates both types of reciprocity. In particular, we apply the standard giving-game framework of indirect reciprocity and analyze the three-strategy model including reciprocal altruists, indiscriminate altruists, and free riders using evolutionary game theory. We show that the model allows reciprocal altruists and free riders to coexist stably in well-mixed populations. We also find that by accounting for inattention in the assessment rule, the stability of this mixed equilibrium can be strengthened to prevent the invasion of infamous indiscriminate altruists and can even be made globally stable.

Abstract Background Mesenchymal stromal cell (MSC) transplantation therapy is a promising therapy for stroke patients. In parallel, rehabilitation with physical exercise could ameliorate stroke-induced neurological impairment. In this study, we aimed to clarify whether combination therapy of intracerebral transplantation of human modified bone marrow-derived MSCs, SB623 cells, and voluntary exercise with running wheel (RW) could exert synergistic therapeutic effects on a rat model of ischemic stroke. Methods Wistar rats received right transient middle cerebral artery occlusion (MCAO). Voluntary exercise (Ex) groups were trained in a cage with RW from day 7 before MCAO. SB623 cells (4.0 × 105 cells/5 μl) were stereotactically injected into the right striatum at day 1 after MCAO. Behavioral tests were performed at day 1, 7, and 14 after MCAO using the modified Neurological Severity Score (mNSS) and cylinder test. Rats were euthanized at day 15 after MCAO for mRNA level evaluation of ischemic infarct area, endogenous neurogenesis, angiogenesis, and expression of brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF). The rats were randomly assigned to one of the four groups: vehicle, Ex, SB623, and SB623 + Ex groups. Results SB623 + Ex group achieved significant neurological recovery in mNSS compared to the vehicle group (p

Objectives To examine the national, 6-year trends in in-hospital clinical outcomes of patients with subarachnoid haemorrhage (SAH) who underwent clipping or coiling and the prognostic influence of temporal trends in the Comprehensive Stroke Center (CSC) capabilities on patient outcomes in Japan.Design Retrospective study.Setting Six hundred and thirty-one primary care institutions in Japan.Participants Forty-five thousand and eleven patients with SAH who were urgently hospitalised, identified using the J-ASPECT Diagnosis Procedure Combination database.Primary and secondary outcome measures Annual number of patients with SAH who remained untreated, or who received clipping or coiling, in-hospital mortality and poor functional outcomes (modified Rankin Scale: 3–6) at discharge. Each CSC was assessed using a validated scoring system (CSC score: 1–25 points).Results In the overall cohort, in-hospital mortality decreased (year for trend, OR (95% CI): 0.97 (0.96 to 0.99)), while the proportion of poor functional outcomes remained unchanged (1.00 (0.98 to 1.02)). The proportion of patients who underwent clipping gradually decreased from 46.6% to 38.5%, while that of those who received coiling and those left untreated gradually increased from 16.9% to 22.6% and 35.4% to 38%, respectively. In-hospital mortality of coiled (0.94 (0.89 to 0.98)) and untreated (0.93 (0.90 to 0.96)) patients decreased, whereas that of clipped patients remained stable. CSC score improvement was associated with increased use of coiling (per 1-point increase, 1.14 (1.08 to 1.20)) but not with short-term patient outcomes regardless of treatment modality.Conclusions The 6-year trends indicated lower in-hospital mortality for patients with SAH (attributable to better outcomes), increased use of coiling and multidisciplinary care for untreated patients. Further increasing CSC capabilities may improve overall outcomes, mainly by increasing the use of coiling. Additional studies are necessary to determine the effect of confounders such as aneurysm complexity on outcomes of clipped patients in the modern endovascular era.

Indirect reciprocity is one of the major mechanisms of the evolution of human cooperation. In indirect reciprocity, social norms with which individuals distinguish good people from bad people play essential roles. On the one hand, previous studies have suggested the various different norms which are evolutionarily stable against the invasion of free riders. However, these approaches could not reveal what norms would be selected in the process of evolution of cooperation because they are based on the premise that a single norm is shared in a society. On the other hand, recent studies have tackled the mechanisms of the coevolution of norms and cooperation. However, the norms which are necessary for emergence or sustenance of cooperation have not been revealed. Here, we show some indispensable norms for emergence and sustenance of cooperation using a norm knockout method which has been developed to analyze a function of each norm in the environment of coexistence of many norms. The results revealed that norms known as “shunning” and “image scoring” are indispensable in the emergence of cooperation but they are not required after a cooperative society is achieved. Furthermore, “simple standing” is a unique norm which is necessary to maintain cooperation. We call the former as a pioneer norm and the latter as a keystone norm. The results indicate importance to focus on the dynamics of evolution because the role of indispensable norms has been overlooked by the static analysis of evolutionarily stable norms.

BackgroundSpinal cord stimulation (SCS) exerts neuroprotective effects in animal models of Parkinson’s disease (PD). Conventional stimulation techniques entail limited stimulation time and restricted movement of animals, warranting the need for optimizing the SCS regimen to address the progressive nature of the disease and to improve its clinical translation to PD patients.ObjectiveRecognizing the limitations of conventional stimulation, we now investigated the effects of continuous SCS in freely moving parkinsonian rats.MethodsWe developed a small device that could deliver continuous SCS. At the start of the experiment, thirty female Sprague-Dawley rats received the dopamine (DA)-depleting neurotoxin, 6-hydroxydopamine, into the right striatum. The SCS device was fixed below the shoulder area of the back of the animal, and a line from this device was passed under the skin to an electrode that was then implanted epidurally over the dorsal column. The rats were divided into three groups: control, 8-h stimulation, and 24-h stimulation, and behaviorally tested then euthanized for immunohistochemical analysis.ResultsThe 8- and 24-h stimulation groups displayed significant behavioral improvement compared to the control group. Both SCS-stimulated groups exhibited significantly preserved tyrosine hydroxylase (TH)-positive fibers and neurons in the striatum and substantia nigra pars compacta (SNc), respectively, compared to the control group. Notably, the 24-h stimulation group showed significantly pronounced preservation of the striatal TH-positive fibers compared to the 8-h stimulation group. Moreover, the 24-h group demonstrated significantly reduced number of microglia in the striatum and SNc and increased laminin-positive area of the cerebral cortex compared to the control group.ConclusionsThis study demonstrated the behavioral and histological benefits of continuous SCS in a time-dependent manner in freely moving PD animals, possibly mediated by anti-inflammatory and angiogenic mechanisms.

Abstract Reputation-based cooperation is often observed in modern society. People gain several types of information by assessing others. Among these, the most important information is the actions of people and those of their recipients. However, almost all studies assume that people consider all of the information they receive. This assumption is extreme, and people engaging in reputation-based cooperation may not pay attention to some information, i.e., they may display selective inattention. We demonstrate that subjects’ decision-making in relation to cooperative action depends on the content of the information they receive about their recipients. Our results show that subjects either consider or ignore information depending on the content of that information. When their recipients had cooperated previously, subjects cooperated without considering the information they received. When the recipients had played before with those who had bad reputations, subjects did not use that information, regardless of whether it was disclosed proactively. In other cases, subjects considered information on both the previous actions of recipients and those of the recipients’ own recipients. We found that subjects did not always use the information to make decisions, although they willingly received information about their recipients. This supports the proposition that selective inattention occurs in reputation-based cooperation.

Some cases of aneurysms originating from the fenestrated A1 segment of the anterior cerebral artery (ACA) have been reported, but the pitfalls of the surgical procedure have not been well determined. We herein report 2 cases of a saccular aneurysm arising from the fenestrated A1 segment. Case 1 was a 72-year-old man incidentally diagnosed with an unruptured left ACA aneurysm on magnetic resonance imaging (MRI). Cerebral angiography revealed a saccular aneurysm arising from the proximal end of the left A1 segment. He underwent surgical clipping via the left pterional approach. The aneurysm originated from the proximal bifurcation of the fenestrated left A1 segment. A fenestrated ring clip was applied to obliterate the aneurysmal neck and one small fenestrated trunk, preserving the other fenestrated trunk and perforators around the fenestration. Case 2 was a 73-year-old man incidentally diagnosed with an unruptured ACA aneurysm on MRI. Cerebral angiography revealed a saccular aneurysm arising from the proximal end of the fenestrated left A1 segment. He underwent surgical clipping via the interhemispheric approach. The aneurysm originated from the proximal bifurcation of the fenestrated left A1 segment. A fenestrated ring clip was applied to obliterate the aneurysmal neck and one hypoplastic fenestrated trunk, preserving the other fenestrated trunk and perforators around the aneurysm. Detailed intraoperative evaluations of the anatomical structure and hemodynamics around the fenestration are important. The intentional obliteration of a fenestrated trunk and application of fenestrated clips need to be considered in difficult cases in order to expose the aneurysmal neck.

An 83-year-old Japanese man was admitted with dysarthria and right hemiparesis. He had had a large intracranial aneurysm on the left internal carotid artery 5 years before admission and had been followed up under conservative treatment. On admission, diffusion-weighted imaging revealed a hyperintense signal on the left anterior choroidal artery territory. Time-of-flight magnetic resonance angiography demonstrated poor visibility of the middle and anterior cerebral arteries and the inferior giant aneurysm, suggesting distal emboli from aneurysm thrombosis or a reduction of blood outflow due to aneurysm thrombosis. Arterial spin labeling (ASL) signal increased in the giant aneurysm, suggesting blood stagnation within the aneurysmal sac, and decreased in the left hemisphere. We diagnosed cerebral infarction due to aneurysm thrombosis, and started antithrombotic therapy. On day 2, he suddenly died of subarachnoid hemorrhage due to rupturing of the giant aneurysm. When thrombosis occurs in a giant aneurysm, increasing ASL signal within the aneurysm and decreasing ASL signal with poor visibility on magnetic resonance angiography in the same arterial territory may indicate the danger of impending rupture of the giant aneurysm.

Background/Aims: Bone marrow stromal cells (BMSCs) transplantation is an important strategy for the treatment of ischemic stroke. Currently, there are no effective methods to guide BMSCs toward the targeted site. In this study, we investigated the effect of electrical stimulation on BMSCs migration in an ischemic model of rats. Methods: Adult male Wistar rats weighing 200 to 250 g received right middle cerebral artery occlusion (MCAO) for 90 minutes. BMSCs (2.5×105 cells/ 4 µl PBS) were stereotaxically injected into the left corpus callosum at 1 day after MCAO. After BMSCs injection, a plate electrode with a diameter of 3 mm connected to an implantable electrical stimulator was placed on the right frontal epidural space and a counter electrode was placed in the extra-cranial space. Electrical stimulation at preset current (100 µA) and frequency (100 Hz) was performed for two weeks. Behavioral tests were performed at 1, 4, 8, and 15 days after MCAO using the modified Neurological Severity Score (mNSS) and cylinder test. Rats were euthanized at 15 days after MCAO for evaluation of infarction area and the migration distance and area of BMSCs found in the brain tissue. After evaluating cell migration, we proceeded to explore the mechanisms guiding these observations. MCAO rats without BMSCs transplantation were stimulated with same current and frequency. At 1 and 2 weeks after MCAO, rats were euthanized to evaluate stromal cell-derived factor 1 alpha (SDF-1α) level of brain tissues in the bilateral cortex and striatum. Results: Behavioral tests at 4, 8, and 15 days after MCAO revealed that stimulation group displayed significant amelioration in mNSS and cylinder test compared to control group (p

Background: The major surgical treatment for Parkinson’s disease (PD) is deep brain stimulation (DBS), but a less invasive treatment is desired. Vagus nerve stimulation (VNS) is a relatively safe treatment without cerebral invasiveness. In this study, we developed a wireless controllable electrical stimulator to examine the efficacy of VNS on PD model rats. Methods: Adult female Sprague-Dawley rats underwent placement of a cuff-type electrode and stimulator on the vagus nerve. Following which, 6-hydroxydopamine (6-OHDA) was administered into the left striatum to prepare a PD model. VNS was started immediately after 6-OHDA administration and continued for 14 days. We evaluated the therapeutic effects of VNS with behavioral and immunohistochemical outcome assays under different stimulation intensity (0.1, 0.25, 0.5 and 1 mA). Results: VNS with 0.25–0.5 mA intensity remarkably improved behavioral impairment, preserved dopamine neurons, reduced inflammatory glial cells, and increased noradrenergic neurons. On the other hand, VNS with 0.1 mA and 1 mA intensity did not display significant therapeutic efficacy. Conclusions: VNS with 0.25–0.5 mA intensity has anti-inflammatory and neuroprotective effects on PD model rats induced by 6-OHDA administration. In addition, we were able to confirm the practicality and effectiveness of the new experimental device.

Subplate (SP) neurons are among the earliest-born neurons in the cerebral cortex and heterogeneous in terms of gene expression. SP neurons consist mainly of projection neurons, which begin to extend their axons to specific target areas very early during development. However, the relationships between axon projection and gene expression patterns of the SP neurons, and their remnant layer 6b (L6b) neurons, are largely unknown. In this study, we analyzed the corticocortical projections of L6b/SP neurons in the mouse cortex and searched for a marker gene expressed in L6b/SP neurons that have ipsilateral inter-areal projections. Retrograde tracing experiments demonstrated that L6b/SP neurons in the primary somatosensory cortex (S1) projected to the primary motor cortex (M1) within the same cortical hemisphere at postnatal day (PD) 2 but did not show any callosal projection. This unilateral projection pattern persisted into adulthood. Our microarray analysis identified the gene encoding a β subunit of voltage-gated potassium channel (Kcnab1) as being expressed in L6b/SP. Double labeling with retrograde tracing and in situ hybridization demonstrated that Kcnab1 was expressed in the unilaterally-projecting neurons in L6b/SP. Embryonic expression was specifically detected in the SP as early as embryonic day (E) 14.5, shortly after the emergence of SP. Double immunostaining experiments revealed different degrees of co-expression of the protein product Kvβ1 with L6b/SP markers Ctgf (88%), Cplx3 (79%), and Nurr1 (58%), suggesting molecular subdivision of unilaterally-projecting L6b/SP neurons. In addition to expression in L6b/SP, scattered expression of Kcnab1 was observed during postnatal stages without layer specificity. Among splicing variants with three alternative first exons, the variant 1.1 explained all the cortical expression mentioned in this study. Together, our data suggest that L6b/SP neurons have corticocortical projections and Kcnab1 expression defines a subpopulation of L6b/SP neurons with a unilateral inter-areal projection.

To study relationship between friction and plastic deformation modes of single crystals, wear patterns were analyzed for BaSO4, an orthorhombic crystal having various cleavage faces and slip systems. Upon scanning a sapphire stylus along the b-axis at (0 0 1) face, formation of triangular deformation patterns extending outside the wear track were observed with optical microscopy. Atomic force microscopic analysis revealed that the triangular areas were elevated, and the two sides were formed by {2 1 0} cleavage steps, starting within the track, and continued by {1 1 0} slip steps outside the track. Upon scanning with heavier normal loads, lots of {0 1 1} slip steps were formed inside the triangles, presumably due to horizontal compression given by the stylus to the triangular areas isolated from the rest of the surface. Mechanism of the wear pattern formation was proposed. When the stylus was scanned along the a-axis, the wear tracks were segmented into short strips by {1 0 1} slips. Under heavier normal loads, the segment structures were partly destroyed by the stylus, presumably by (0 0 1) slip and cleavage, producing debris on both sides of the track. The changes in deformation patterns under heavier normal loads caused steeper increase in friction curves measured in the two directions. Different deformation modes were activated depending upon the scan directions, normal loads and locations relative to the stylus.

Theoretical and empirical studies have generally weighed the effect of peer punishment and pool punishment for sanctioning free riders separately. However, these sanctioning mechanisms often pose a puzzling tradeoff between efficiency and stability in detecting and punishing free riders. Here, we combine the key aspects of these qualitatively different mechanisms in terms of evolutionary game theory. Based on the dilemmatic donation game, we introduce a strategy of commitment to both cooperation and peer punishment. To make the commitment credible, we assume that those willing to commit have to make a certain deposit. The deposit will be refunded as long as the committers faithfully cooperate in the donation game and punish free riders and non-committers. It turns out that the deposit-based commitment offers both the efficiency of peer punishment and the stability of pool punishment and that the replicator dynamics lead to transitions of different systems: pool punishment to commitment to peer punishment.

Several reports have shown that long-term potentiation (LTP) per se effectively enhances neurogenesis in the hippocampus of intact animals. If LTP can enhance neurogenesis in chronic hypoperfusion, this approach could potentially become a new therapeutic strategy for the restoration of cognitive function and for prevention from deterioration of mild cognitive impairment (MCI). Using an in vivo LTP model of rats, we examined whether LTP per se can enhance neurogenesis in hypoperfusion rats that underwent permanent bilateral common carotid artery occlusion (permanent 2-vessel occlusion, P2VO). High frequency stimulation (HFS) in the subacute phase after P2VO enhanced hippocampal cell proliferation and neurogenesis. However, most enhanced cell proliferation and neurogenesis was seen in the hypoperfusion rats that received HFS and for which LTP could finally be induced. In contrast, the same effect was not seen in the LTP induction in the chronic phase. The present findings, which reveal that most enhanced neurogenesis was seen in hypoperfusion rats for which LTP could be finally induced, could explain the ability of LTP-like activities such as learning paradigms and environmental stimuli to increase the rate of neurogenesis in the hippocampus even under hypoperfusion conditions. Moreover, the present findings, which reveal that LTP induction in the chronic phase after P2VO could not effectively enhance neurogenesis in the hypoperfusion rats, could indicate that patients with MCI and even middle-aged healthy control individuals should start LTP-like activities as early as possible and continue with these activities to prevent age-related deterioration of hippocampal function.

Indirect reciprocity is one of the basic mechanisms to sustain mutual cooperation, by which beneficial acts are returned, not by the recipient, but by third parties. This mechanism relies on the ability of individuals to know the past actions of others, and to assess those actions. There are many different systems of assessing others, which can be interpreted as rudimentary social norms (i.e., views on what is “good” or “bad”). In this paper, impacts of different adaptive architectures, i.e., ways for individuals to adapt to environments, on indirect reciprocity are investigated. We examine two representative architectures: one based on replicator dynamics and the other on genetic algorithm. Different from the replicator dynamics, the genetic algorithm requires describing the mixture of all possible norms in the norm space under consideration. Therefore, we also propose an analytic method to study norm ecosystems in which all possible second order social norms potentially exist and compete. The analysis reveals that the different adaptive architectures show different paths to the evolution of cooperation. Especially we find that so called Stern-Judging, one of the best studied norms in the literature, exhibits distinct behaviors in both architectures. On one hand, in the replicator dynamics, Stern-Judging remains alive and gets a majority steadily when the population reaches a cooperative state. On the other hand, in the genetic algorithm, it gets a majority only temporarily and becomes extinct in the end.

Cell therapy for Parkinson’s disease (PD) began in 1979 with the transplantation of fetal rat dopamine-containing neurons that improved motor abnormalities in the PD rat model with good survival of grafts and axonal outgrowth. Thirty years have passed since the 2 clinical trials using cell transplantation for PD patients were first reported. Recently, cell therapy is expected to develop as a realistic treatment option for PD patients owing to the advancement of biotechnology represented by pluripotent stem cells. Medication using levodopa, surgery including deep brain stimulation, and rehabilitation have all been established as current therapeutic strategies. Strong therapeutic effects have been demonstrated by these treatment methods, but they have been unable to stop the progression of the disease. Fortunately, cell therapy might be a key for true neurorestoration. This review article describes the historical development of cell therapy for PD, the current status of cell therapy, and the future direction of this treatment method.

Cerebral venous thrombosis as a manifestation of paraneoplastic angitis and otitis media, revealing non-Hodgkin B-cell lymphoma (NHBL), is extremely rare. A 57-year-old woman presented with headache, auditory disturbance and recalcitrant otitis media. Magnetic resonance imaging showed brain edema in the temporal lobe and transverse sinus thrombosis. External drainage under antibiotic treatment was repeated based on a diagnosis of invasive otitis media and mastoiditis associated with infectious sinus thrombosis, but the condition deteriorated progressively. Open surgery for otitis media was performed 6 years after the initial symptoms and after a tumorous lesion had been detected in the middle ear. Pathological findings revealed NHBL. We report a rare case of NHBL presenting as otitis media and mastoiditis associated with sinus thrombosis, and a literature review.

Dural arteriovenous fistula (AVF) presenting with subdural hematoma is relatively rare. We report a case of dural AVF presenting as acute subdural hematoma (ASDH) and provide a review of the literature. A 56-year-old man presented with disturbance of consciousness. Computed tomography demonstrated a right ASDH and a small right occipital subcortical hematoma. Cerebral angiography showed a dural AVF on the occipital convexity draining into the cortical veins. Emergent endovascular embolization was immediately performed and the shunt flow disappeared. Hematoma removal and external decompression were safely conducted. Combined therapy successfully recovered the patient's consciousness level. This rare case of dural AVF presenting with ASDH was treated with combined treatments of endovascular and open surgery.

Traumatic acute subdural hematoma (ASDH) is generally addressed by craniotomy under general anesthesia. We report a patient whose traumatic ASDH was treated under local anesthesia by one-burr-hole endoscopic surgery. This 87-year-old woman had undergone coil embolization for a ruptured right middle-cerebral artery aneurysm and placement of a ventriculoperitoneal shunt for normal pressure hydrocephalus 5 years earlier. Upon admission, she manifested consciousness disturbance after suffering head trauma and right hemiplegia. Her Glasgow Coma Scale score was 8 (E2V2M4). Computed tomography (CT) demonstrated a thick, left-frontotemporal ASDH. Due to her advanced age and poor condition, we performed endoscopic surgery rather than craniotomy to evacuate the ASDH. Under local anesthesia, we made a burr hole in her left forehead and increased its size to 15 mm in diameter. After introducing a transparent sheath into the hematoma cavity with a rigid endoscope, the clot was evacuated with a suction tube. The arterial bleeding point was electrically coagulated. A postoperative CT scan confirmed the reduction of the hematoma. There was neither brain compression nor brain swelling. Her consciousness disturbance and right hemiplegia improved immediately. Endoscopic surgery may represent a viable method to address traumatic intracranial hematomas in some patients.

Social dilemmas are among the most puzzling issues in the biological and social sciences. Extensive theoretical efforts have been made in various realms such as economics, biology, mathematics, and even physics to figure out solution mechanisms to the dilemma in recent decades. Although punishment is thought to be a key mechanism, evolutionary game theory has revealed that the simplest form of punishment called peer punishment is useless to solve the dilemma, since peer punishment itself is costly. In the literature, more complex types of punishment, such as pool punishment or institutional punishment, have been exploited as effective mechanisms. So far, mechanisms that enable peer punishment to function as a solution to the social dilemma remain unclear. In this paper, we propose a theoretical way for peer punishment to work as a solution mechanism for the dilemma by incorporating prospect theory into evolutionary game theory. Prospect theory models human beings as agents that estimate small probabilities and loss of profit as greater than they actually are; thus, those agents feel that punishments are more frequent and harsher than they really are. We show that this kind of cognitive distortion makes players decide to cooperate to avoid being punished and that the cooperative state achieved by this mechanism is globally stable as well as evolutionarily stable in a wide range of parameter values.

Epilepsy is a chronic neurological disorder, which presents with various forms of seizures. Traditional treatments, including medication using antiepileptic drugs, remain the treatment of choice for epilepsy. Recent development in surgical techniques and approaches has improved treatment outcomes. However, several epileptic patients still suffer from intractable seizures despite the advent of the multimodality of therapies. In this article, we initially provide an overview of clinical presentation of epilepsy then describe clinically relevant animal models of epilepsy. Subsequently, we discuss the concepts of regenerative medicine including cell therapy, neuroprotective agents, and electrical stimulation, which are reviewed within the context of our data.

The number of diabetes mellitus (DM) patients is increasing, and stroke is deeply associated with DM. Recently, neuroprotective effects of glucagon-like peptide-1 (GLP-1) are reported. In this study, we explored whether liraglutide, a GLP-1 analogue exerts therapeutic effects on a rat stroke model. Wistar rats received occlusion of the middle cerebral artery for 90 min. At one hour after reperfusion, liraglutide or saline was administered intraperitoneally. Modified Bederson’s test was performed at 1 and 24 h and, subsequently, rats were euthanized for histological investigation. Peripheral blood was obtained for measurement of blood glucose level and evaluation of oxidative stress. Brain tissues were collected to evaluate the level of vascular endothelial growth factor (VEGF). The behavioral scores of liraglutide-treated rats were significantly better than those of control rats. Infarct volumes of liraglutide-treated rats at were reduced, compared with those of control rats. The level of derivatives of reactive oxygen metabolite was lower in liraglutide-treated rats. VEGF level of liraglutide-treated rats in the cortex, but not in the striatum significantly increased, compared to that of control rats. In conclusion, this is the first study to demonstrate neuroprotective effects of liraglutide on cerebral ischemia through anti-oxidative effects and VEGF upregulation.

Prediction of rupture status in cerebral aneurysms remains challenging for clinicians, and the important rupture indicator (wall shear stress, WSS) is controversially discussed. Recent studies report that flow instabilities appear to play an influential role in the evolution and rupture of aneurysms and it is strongly correlated with both geometries and inlet flow rate waveforms. However, how frequency harmonics in inlet flow rate waveforms influence the flow instabilities and hence WSS fluctuations in cerebral aneurysms are still unclear. In this study, we used a computational fluid dynamic (CFD) model of anatomically realistic cerebral aneurysms combining with Fourier series and power spectral density (PSD) analysis to investigate the association between inflow waveform's harmonic frequencies and flow fluctuations in terminal cerebral aneurysms. Our simulated results demonstrated that there exists a harmonic frequency dependency in inlet flow rate waveforms inherently associated with flow instabilities in cerebral aneurysms: low-frequency harmonics play a crucial role in causing significant WSS fluctuations. This is partly explained by that the low-frequency harmonics govern a primary local adverse pressure gradient at late systole during flow deceleration, which induces flow instabilities while giving it sufficient time to develop into flow instabilities whereas high-frequency harmonics do not but decay rapidly. This implies that flow fluctuations in cerebral aneurysms may be of some robustness, dependent mainly on the primary harmonic frequency initiated by heart contraction but against unpredictable high-frequency perturbations in the inflow waveforms.

Although positive incentives for cooperators and/or negative incentives for free-riders in social dilemmas play an important role in maintaining cooperation, there is still the outstanding issue of who should pay the cost of incentives. The second-order free-rider problem, in which players who do not provide the incentives dominate in a game, is a well-known academic challenge. In order to meet this challenge, we devise and analyze a meta-incentive game that integrates positive incentives (rewards) and negative incentives (punishments) with second-order incentives, which are incentives for other players' incentives. The critical assumption of our model is that players who tend to provide incentives to other players for their cooperative or non-cooperative behavior also tend to provide incentives to their incentive behaviors. In this paper, we solve the replicator dynamics for a simple version of the game and analytically categorize the game types into four groups. We find that the second-order free-rider problem is completely resolved without any third-order or higher (meta) incentive under the assumption. To do so, a second-order costly incentive, which is given individually (peer-to-peer) after playing donation games, is needed. The paper concludes that (1) second-order incentives for first-order reward are necessary for cooperative regimes, (2) a system without first-order rewards cannot maintain a cooperative regime, (3) a system with first-order rewards and no incentives for rewards is the worst because it never reaches cooperation, and (4) a system with rewards for incentives is more likely to be a cooperative regime than a system with punishments for incentives when the cost-effect ratio of incentives is sufficiently large. This solution is general and strong in the sense that the game does not need any centralized institution or proactive system for incentives.

ObjectiveIntra-arterial stem cell transplantation exerts neuroprotective effects for ischemic stroke. However, the optimal therapeutic time window and mechanisms have not been completely understood. In this study, we investigated the relationship between the timing of intra-arterial transplantation of allogeneic mesenchymal stem cells (MSCs) in ischemic stroke model in rats and its efficacy in acute phase.MethodsAdult male Wistar rats weighing 200 to 250 g received right middle cerebral artery occlusion (MCAO) for 90 minutes. MSCs (1 × 10(6) cells/ 1 ml PBS) were intra-arterially injected at either 1, 6, 24, or 48 hours (1, 6, 24, 48 h group) after MCAO. PBS (1 ml) was intra-arterially injected to control rats at 1 hour after MCAO. Behavioral test was performed immediately after reperfusion, and at 3, 7 days after MCAO using the Modified Neurological Severity Score (mNSS). Rats were euthanized at 7 days after MCAO for evaluation of infarct volumes and the migration of MSCs. In order to explore potential mechanisms of action, the upregulation of neurotrophic factor and chemotactic cytokine (bFGF, SDF-1α) induced by cell transplantation was examined in another cohort of rats that received intra-arterial transplantation at 24 hours after recanalization then euthanized at 7 days after MCAO for protein assays.ResultsBehavioral test at 3 and 7 days after transplantation revealed that stroke rats in 24h group displayed the most robust significant improvements in mNSS compared to stroke rats in all other groups (p'sConclusionsThese results suggest that intra-arterial allogeneic transplantation of MSCs provides post-stroke functional recovery and reduction of infarct volumes in ischemic stroke model of rats. The upregulation of bFGF and SDF-1α likely played a key mechanistic role in enabling MSC to afford functional effects in stroke. MSC transplantation at 24 hours after recanalization appears to be the optimal timing for ischemic stroke model, which should guide the design of clinical trials of cell transplantation for stroke patients.

Despite recent advances in reputation technologies, it is not clear how reputation systems can affect human cooperation in social networks. Although it is known that two of the major mechanisms in the evolution of cooperation are spatial selection and reputation-based reciprocity, theoretical study of the interplay between both mechanisms remains almost uncharted. Here, we present a new individual-based model for the evolution of reciprocal cooperation between reputation and networks. We comparatively analyze four of the leading moral assessment rules—shunning, image scoring, stern judging, and simple standing—and base the model on the giving game in regular networks for Cooperators, Defectors, and Discriminators. Discriminators rely on a proper moral assessment rule. By using individual-based models, we show that the four assessment rules are differently characterized in terms of how cooperation evolves, depending on the benefit-to-cost ratio, the network-node degree, and the observation and error conditions. Our findings show that the most tolerant rule—simple standing—is the most robust among the four assessment rules in promoting cooperation in regular networks.

This paper presents a grouser developed for the wheels of lunar exploration rovers to measure sinkage. The wheels, which are intended to traverse loose soil such as lunar regolith, contain grousers that transfer thrust to the wheels and thus to the body of the rover. The interaction between the wheel (with grousers) and the loose soil can be described using a kinematic model. When traversing loose soil, the wheel sinks into the soil, which necessitates knowledge of the entrance angle needed in order to avoid this problem. If the entrance angle is known, the sinkage can be measured in real time before adverse conditions occur. Because of the importance and usefulness of detecting the entrance angle of the wheel, we herein propose a grouser with an embedded tactile sensor. A strain gauge on the surface of the grousers serves as the tactile sensor. In order to confirm the precision of the proposed grouser, we have performed tests on a rigid surface and loose soil surfaces.

In clinical practice, deep brain stimulation (DBS) is effective for treatment of motor symptoms in Parkinson's disease (PD). However, the mechanisms have not been understood completely. There are some reports that electrical stimulation exerts neuroprotective effects on the central nervous system diseases including cerebral ischemia, head trauma, epilepsy and PD, although there are a few reports on neuroprotective effects of spinal cord stimulation (SCS). We investigated the neuroprotective effects of high cervical SCS on PD model of rats. Adult female Sprague-Dawley rats received hour-long SCS (2, 50 or 200 Hz) with an epidural electrode at C1-2 level for 16 consecutive days. At 2 days after initial SCS, 6-hydroxydopamine (6-OHDA) was injected into the right striatum of rats. Behavioral evaluations of PD symptoms were employed, including cylinder test and amphetamine-induced rotation test performed at 1 and 2 weeks after 6-OHDA injection. Animals were subsequently euthanized for immunohistochemical investigations. In order to explore neurotrophic and growth factor upregulation induced by SCS, another cohort of rats that received 50 Hz SCS was euthanized at 1 and 2 weeks after lesion for protein assays. Behavioral tests revealed that the number of amphetamine-induced rotations decreased in SCS groups. Immunohistochemically, tyrosine hydroxylase (TH)-positive fibers in the striatum were significantly preserved in SCS groups. TH-positive neurons in the substantia nigra pars compacta were significantly preserved in 50 Hz SCS group. The level of vascular endothelial growth factor (VEGF) was upregulated by SCS at 1 week after the lesion. These results suggest that high cervical SCS exerts neuroprotection in PD model of rats, at least partially by upregulation of VEGF. SCS is supposed to suppress or delay PD progression and might become a less invasive option for PD patients, although further preclinical and clinical investigations are needed to confirm the effectiveness and safety.

Coronary artery fistulas, including coronary pulmonary fistulas, are usually discovered accidently among the adult population when undergoing invasive coronary angiographies. We report here a 58-year-old woman with dual fistulas originating from the left anterior descending coronary artery and right coronary sinus to the main pulmonary artery, demonstrating noninvasively with multidetector-computed tomography (MDCT) and transthoracic echocardiography (TTE).