自己効力感の神経基盤と動機づけにおける役割

学位の種別: 課程博士審査委員会委員 : （主査）東京大学教授 長谷川 壽一, 東京大学教授 丹野 義彦, 東京大学准教授 四本 裕子, 東京大学准教授 本吉 勇, 東京大学准教授 柳原 大University of Tokyo(東京大学

Therapeutic potential of DNA methyltransferase inhibitors with immune checkpoint inhibitor therapy in breast cancer

Immune checkpoint inhibitor (ICI) therapy has changed the landscape of cancer treatment, particularly for high-mutation burden cancers. However, ICI therapy has thus far demonstrated limited efficacy in breast cancers, where tumor mutation rates are intermediate. Nonetheless, because of limited but positive signals in early trials, combinations of therapies to enhance anti-tumor immunity, and thus response to ICIs in breast cancer, are actively being sought. Our laboratory recently found that guadecitabine, a next-generation DNA methyltransferase inhibitor (DMTi), potentiated cytotoxic CD8+ T cell responses in breast cancer, which appeared to occur by the following mechanisms: (1) DMTi treatment hypomethylated and up-regulated both baseline and IFN-γ-induced MHC-I expression, thereby enhancing antigen presentation capacity, (2) DMTi treatment increased Cxcr3 ligands/chemokines (i.e., Cxcl9, Cxcl10, and Cxcl11) expression and recruited cytotoxic CD8+ T cells into the tumors and (3) DMTi treatment activated NFκB signaling, presumably through the expression of endogenous retroviral (ERV) sequences in tumor cells, initiating an innate response observed in other solid tumor types [Luo et al., Nat Commun 9(1):248]. Most importantly, DMTi treatment primed breast cancer and improved responses to anti-PD-L1 therapy

Regional gray matter volume in the posterior precuneus is associated with general self-efficacy

Motivation in doing a task is influenced not only by the expected outcome of the task, but also by the belief that one has in successfully executing the task. Over time, individuals accumulate experiences that contribute to a general belief in one’s overall ability to successfully perform tasks, which is called general self-efficacy (GSE). We investigated the relationship between regional gray matter volume and individual differences in GSE. Brain anatomy was analyzed using magnetic resonance images obtained from 64 healthy right-handed participants who had completed Sherer’s GSE scale. After controlling for other factors related to motivation, age, sex, and total gray matter volume of each subject, results showed that regional gray matter volume in the posterior part of the precuneus significantly and positively correlated with GSE score. These results suggest that one’s accumulated experiences of success and failure, which contribute to GSE, also influence the anatomical characteristics of the precuneus

Rational design of DNA sequence-specific zinc fingers

AbstractWe developed a rational scheme for designing DNA binding proteins. The scheme was applied for a zinc finger protein and the designed sequences were experimentally characterized with high DNA sequence specificity. Starting with the backbone of a known finger structure, we initially calculated amino acid sequences compatible with the expected structure and the secondary structures of the designed fingers were then experimentally confirmed. The DNA-binding function was added to the designed finger by reconsidering a section of the amino acid sequence and computationally selecting amino acids to have the lowest protein–DNA interaction energy for the target DNA sequences. Among the designed proteins, one had a gap between the lowest and second lowest protein–DNA interaction energies that was sufficient to give DNA sequence-specificity

Social equality in the number of choice options is represented in the ventromedial prefrontal cortex

A distinct aspect of the sense of fairness in humans is that we care not only about equality in material rewards but also about equality in non-material values. One such value is the opportunity to choose freely among many options, often regarded as a fundamental right to economic freedom. In modern developed societies, equal opportunities in work, living, and lifestyle are enforced by anti-discrimination laws. Despite the widespread endorsement of equal opportunity, no studies have explored how people assign value to it. We used functional magnetic resonance imaging to identify the neural substrates for subjective valuation of equality in choice opportunity. Participants performed a two-person choice task in which the number of choices available was varied across trials independently of choice outcomes. By using this procedure, we manipulated the degree of equality in choice opportunity between players and dissociated it from the value of reward outcomes and their equality. We found that activation in the ventromedial prefrontal cortex tracked the degree to which the number of options between the two players was equal. In contrast, activation in the ventral striatum tracked the number of options available to participants themselves but not the equality between players. Our results demonstrate that the vmPFC, a key brain region previously implicated in the processing of social values, is also involved in valuation of equality in choice opportunity between individuals. These findings may provide valuable insight into the human ability to value equal opportunity, a characteristic long emphasized in politics, economics, and philosophy

Decreasing adrenergic or sympathetic hyperactivity after severe traumatic brain injury using propranolol and clonidine (DASH After TBI Study): study protocol for a randomized controlled trial

BACKGROUND: Severe TBI, defined as a Glasgow Coma Scale ≤ 8, increases intracranial pressure and activates the sympathetic nervous system. Sympathetic hyperactivity after TBI manifests as catecholamine excess, hypertension, abnormal heart rate variability, and agitation, and is associated with poor neuropsychological outcome. Propranolol and clonidine are centrally acting drugs that may decrease sympathetic outflow, brain edema, and agitation. However, there is no prospective randomized evidence available demonstrating the feasibility, outcome benefits, and safety for adrenergic blockade after TBI. METHODS/DESIGN: The DASH after TBI study is an actively accruing, single-center, randomized, double-blinded, placebo-controlled, two-arm trial, where one group receives centrally acting sympatholytic drugs, propranolol (1 mg intravenously every 6 h for 7 days) and clonidine (0.1 mg per tube every 12 h for 7 days), and the other group, double placebo, within 48 h of severe TBI. The study uses a weighted adaptive minimization randomization with categories of age and Marshall head CT classification. Feasibility will be assessed by ability to provide a neuroradiology read for randomization, by treatment contamination, and by treatment compliance. The primary endpoint is reduction in plasma norepinephrine level as measured on day 8. Secondary endpoints include comprehensive plasma and urine catecholamine levels, heart rate variability, arrhythmia occurrence, infections, agitation measures using the Richmond Agitation-Sedation Scale and Agitated Behavior scale, medication use (anti-hypertensive, sedative, analgesic, and antipsychotic), coma-free days, ventilator-free days, length of stay, and mortality. Neuropsychological outcomes will be measured at hospital discharge and at 3 and 12 months. The domains tested will include global executive function, memory, processing speed, visual-spatial, and behavior. Other assessments include the Extended Glasgow Outcome Scale and Quality of Life after Brain Injury scale. Safety parameters evaluated will include cardiac complications. DISCUSSION: The DASH After TBI Study is the first randomized, double-blinded, placebo-controlled trial powered to determine feasibility and investigate safety and outcomes associated with adrenergic blockade in patients with severe TBI. If the study results in positive trends, this could provide pilot evidence for a larger multicenter randomized clinical trial. If there is no effect of therapy, this trial would still provide a robust prospective description of sympathetic hyperactivity after TBI. TRIAL REGISTRATION: ClinicalTrials.gov NCT0132204

Transforaminal endoscopic surgery in professional baseball players

Transforaminal endoscopic discectomy has been established as the least minimally invasive spine surgical procedure because it avoids the surgical morbidity from surgical dissection and denervation of normal anatomy responsible for the functional stability of the spine. There have been few reports on endoscopic spine surgery for professional athletes who are dependent on the preservation of vital anatomy to maintain the highest level of function. This report is on five Japanese professional baseball players who underwent transforaminal endoscopic foraminoplasty-discectomy with pulsed radiofrequency thermal annuloplasty under the local anesthesia. There were no adverse surgical events nor complications. Three athletes suffered from discogenic back pain, one from symptomatic herniated nucleus pulposus (HNP), and another player from sciatica due to foraminal stenosis. Three players decided to undergo surgery at the beginning of the off-season. Therefore, they returned to professional play at the beginning of the following season. The remaining two players underwent surgery just before the beginning of the next season. They all returned to play sooner than with traditional open decompression. Two players returned to play about one month after the start of the season. All five players quickly returned to their sport within three months despite the rigors required of their sport to maintain high proficiency and were able to complete the season

Phaseâ amplitude coupling between interictal highâ frequency activity and slow waves in epilepsy surgery

ObjectiveWe hypothesized that the modulation index (MI), a summary measure of the strength of phaseâ amplitude coupling between highâ frequency activity (>150 Hz) and the phase of slow waves (3â 4 Hz), would serve as a useful interictal biomarker for epilepsy presurgical evaluation.MethodsWe investigated 123 patients who underwent focal cortical resection following extraoperative electrocorticography recording and had at least 1 year of postoperative followâ up. We examined whether consideration of MI would improve the prediction of postoperative seizure outcome. MI was measured at each intracranial electrode site during interictal slowâ wave sleep. We compared the accuracy of prediction of patients achieving International League Against Epilepsy class 1 outcome between the full multivariate logistic regression model incorporating MI in addition to conventional clinical, seizure onset zone (SOZ), and neuroimaging variables, and the reduced logistic regression model incorporating all variables other than MI.ResultsNinety patients had class 1 outcome at the time of most recent followâ up (mean followâ up = 5.7 years). The full model had a noteworthy outcome predictive ability, as reflected by regression model fit R2 of 0.409 and area under the curve (AUC) of receiver operating characteristic plot of 0.838. Incomplete resection of SOZ (P < 0.001), larger number of antiepileptic drugs at the time of surgery (P = 0.007), and larger MI in nonresected tissues relative to that in resected tissue (P = 0.020) were independently associated with a reduced probability of class 1 outcome. The reduced model had a lower predictive ability as reflected by R2 of 0.266 and AUC of 0.767. Anatomical variability in MI existed among nonepileptic electrode sites, defined as those unaffected by magnetic resonance imaging lesion, SOZ, or interictal spike discharges. With MI adjusted for anatomical variability, the full model yielded the outcome predictive ability of R2 of 0.422, AUC of 0.844, and sensitivity/specificity of 0.86/0.76.SignificanceMI during interictal recording may provide useful information for the prediction of postoperative seizure outcome.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/146440/1/epi14544_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/146440/2/epi14544.pd

TE-LUL for lumbar central canal stenosis

Full-endoscopic spinal surgery was first developed for the lumbar herniated nucleus pulposus. Mainly, there are two types in the full-endoscopic lumbar surgery : i.e., transforaminal (TF) and interlaminar approach. The surgery can be done under the local anesthesia for the TF approach ; therefore, we need to further develop the TF approach to variety of the spinal disorders. Recently, the TF full-endoscopic surgery has been applied for the spinal canal stenosis. First, transforaminal full-endoscopic lumbar foraminoplasty for the foraminal stenosis ; then, transforaminal lumbar lateral recess decompression for the lateral recess stenosis has been developed. Finally, we have developed the surgical technique to decompress the central stenosis via TF approach under the local anesthesia. Prior to initiate the clinical case, we have attempted the lumbar undercutting laminectomy using a fresh cadaveric spine. After we technically confirmed that the transforaminal full-endoscopic lumbar undercutting laminectomy (TE-LUL) is possible, we applied the technique to the patient whose lung capacity did not allow general anesthesia. The 72 years old female patient with central canal stenosis could be improved her left leg pain and muscle weakness after TE-LUL under the local anesthesia. In this paper, we introduce the surgical technique of the TE-LUL and discuss of the efficacy of the TE-LUL

Motivated with joy or anxiety: does approach-avoidance goal framing elicit differential reward-network activation in the brain?

Psychological research on human motivation repeatedly observed that approach goals (i.e., goals to attain success) increase task enjoyment and intrinsic motivation more strongly than avoidance goals (i.e., goals to avoid failure). The present study sought to address how the reward network in the brain-including the striatum and ventromedial prefrontal cortex-is involved when individuals engage in the same task with a focus on approach or avoidance goals. Participants reported stronger positive emotions when they focused on approach goals, but stronger anxiety and disappointment when they focused on avoidance goals. The fMRI analyses revealed that the reward network in the brain showed similar levels of activity to cues predictive of approach and avoidance goals. In contrast, the two goal states were associated with different patterns of activity in the visual cortex, hippocampus, and cerebellum during success and failure outcomes. Representation similarity analysis further revealed shared and different representations within the striatum and vmPFC between the approach and avoidance goal states, suggesting both the similarity and uniqueness of the mechanisms behind the two goal states. In addition, the distinct patterns of activation in the striatum were associated with distinct subjective experiences participants reported between the approach and the avoidance conditions. These results suggest the importance of examining the pattern of striatal activity in understanding the mechanisms behind different motivational states in humans