The posterior parietal cortex (PPC) features close anatomical and functional relationships with the prefrontal cortex. However, the necessity of the PPC in executive functions has been questioned. ...The present study used the stop-signal task to examine response inhibition, an executive function that inhibits prepotent response tendency. The brain activity and resting-state functional connectivity were measured to analyze a parcellation-based network that was aimed at identifying a candidate PPC region essential for response inhibition in humans. The intraparietal sulcus (IPS) was activated during response inhibition and connected with the inferior frontal cortex and the presupplementary motor area, the two frontal regions known to be necessary for response inhibition. Next, transcranial magnetic stimulation (TMS) was used to test the essential role of the IPS region for response inhibition. TMS over the IPS region prolonged the stop-signal reaction time (SSRT), the standard behavioral index used to evaluate stopping performance, when stimulation was applied 30-0 ms before stopping. On the contrary, stimulation over the temporoparietal junction region, an area activated during response inhibition but lacking connectivity with the two frontal regions, did not show changes in SSRT. These results indicate that the IPS identified using the parcellation-based network plays an essential role in executive functions.
Based on the previous neuropsychological studies reporting no impairment in executive functions after lesions in the posterior parietal cortex (PPC), the necessity of PPC in executive functions has been questioned. Here, contrary to the long-lasting view, by using recently developed analysis in functional MRI ("parcellation-based network analysis"), we identified the intraparietal sulcus (IPS) region in the PPC as essential for response inhibition: one executive function to stop actions that are inaccurate in a given context. The necessity of IPS for response inhibition was further tested by an interventional technique of transcranial magnetic stimulation. Stimulation to the IPS disrupted the performance of stopping. Our findings suggest that the IPS plays essential roles in executive functions.
Despite their critical roles in autonomic functions, individual hypothalamic nuclei have not been extensively investigated in humans using functional magnetic resonance imaging, partly due to the ...difficulty in resolving individual nuclei contained in the small structure of the hypothalamus. Areal parcellation analyses enable discrimination of individual hypothalamic nuclei but require a higher spatial resolution, which necessitates long scanning time or large amounts of data to compensate for the low signal-to-noise ratio in 3T or 1.5T scanners. In this study, we present analytic procedures to estimate likely locations of individual nuclei in the standard 2-mm resolution based on our higher resolution dataset. The spatial profiles of functional connectivity with the cerebral cortex for each nucleus in the medial hypothalamus were calculated using our higher resolution dataset. Voxels in the hypothalamus in standard resolution images from the Human Connectome Project (HCP) database that predominantly shared connectivity profiles with the same nucleus were subsequently identified. Voxels representing individual nuclei, as identified with the analytic procedures, were reproducible across 20 HCP datasets of 20 subjects each. Furthermore, the identified voxels were spatially separate. These results suggest that these analytic procedures are capable of refining voxels that represent individual hypothalamic nuclei in standard resolution. Our results highlight the potential utility of these procedures in various settings such as patient studies, where lengthy scans are infeasible.
The glymphatic system is a glial-based perivascular network that promotes brain metabolic waste clearance. Reduced glymphatic flow has been observed in rat models of type 2 diabetes and hypertension, ...indicating the role of vascular risk factors in the glymphatic system. However, little is known about how vascular risk factors affect the human glymphatic system. The present study aims to assess the relationships between metabolic syndrome (MetS), a cluster of vascular risk factors, and the glymphatic system function using diffusion magnetic resonance imaging (MRI)-based measures of water diffusivity in the glymphatic compartments, including the brain interstitial space and perivascular spaces around the deep medullary vein. We hypothesized that vascular risk factors are associated with glymphatic dysfunction, leading to cognitive impairment in older adults.
This cross-sectional study assessed 61 older adults (age range, 65–82 years) who had participated in the Bunkyo Health Study, including 15 healthy controls (mean age, 70.87 ± 4.90 years) and 46 individuals with MetS (mean age, 71.76 ± 4.61 years). Fractional volume of extracellular-free water (FW) and an index of diffusion tensor imaging along the perivascular space (DTI-ALPS) were used as indirect indicators of water diffusivity in the interstitial extracellular and perivenous spaces of white matter, respectively.
After adjusting for age, sex, years of education, total Fazekas scale, Pittsburgh sleep quality index (PSQI) score, and intracranial volume (ICV), a significantly (P = 0.030; Cohen's d = 1.01) higher FW was observed in individuals with MetS than in the healthy controls. Furthermore, individuals with MetS had a significantly (P = 0.031; Cohen's d = 0.86) lower ALPS index than the healthy controls, with age, sex, years of education, total Fazekas scale, PSQI score, ICV, fractional anisotropy, and mean diffusivity included as confounding factors. Higher FW was significantly associated with lower ALPS index (r = −0.37; P = 0.004). Multiple linear regression (MLR) with backward elimination analyses showed that higher diastolic blood pressure (BP; standardized β = 0.33, P = 0.005) was independently associated with higher FW, whereas higher fasting plasma glucose levels (standardized β = −0.63, P = 0.002) or higher Brinkman index of cigarette consumption cumulative amount (standardized β = −0.27, P = 0.022) were associated with lower ALPS index. The lower ALPS index (standardized β, 0.28; P = 0.040) was associated with poorer global cognitive performance, which was determined using the Japanese version of the Montreal Cognitive Assessment (MOCA-J) scores. Finally, partial correlation analyses showed a significant correlation between higher FW and lower MOCA-J scores (r = −0.35; P = 0.025) and between higher FW and higher diastolic BP (r = 0.32, P = 0.044).
The present study shows the changes in diffusion MRI-based measures reflected by the higher FW and lower ALPS index in older adults with MetS, possibly due to the adverse effect of vascular risk factors on the glymphatic system. Our findings also indicate the associations between the diffusion MRI-based measures and elevated diastolic BP, hyperglycemia, smoking habit, and poorer cognitive performance. However, owing to the limitations of this study, the results should be cautiously interpreted.
•Vascular risk factors are known to adversely affect the glymphatic flow.•Diffusion MRI metrics changes suggest glymphatic dysfunction in metabolic syndrome.•Diastolic blood pressure positively linked to white matter interstitial free water.•Hyperglycemia and smoking habit reduced diffusivity along the perivascular space.•Diffusion MRI metrics alterations were associated with poorer cognitive performance.
Objective
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FFluciclovine (
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FFACBC) has demonstrated diagnostic efficacy for cancers of the brain where
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Ffludeoxyglucose has limitations. We conducted a phase IIa study of
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...FFACBC to assess its accumulation pattern and safety in patients with malignant glioma.
Methods
Five patients with glioma scheduled for brain tumor resection received
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FFACBC. Brain positron emission tomography (PET) was performed following intravenous administration of
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FFACBC, and subsequently, preoperative gadolinium contrast-enhanced T1-weighted (CE-T1W) magnetic resonance imaging (MRI) was performed for surgery. Specimens for histopathological evaluation were collected during surgery, and their location was precisely determined on CE-T1W MRI and
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FFACBC PET/CT images. In addition, tumor extent defined on the MRI and PET/CT images was compared. To determine time–activity curves for
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FFACBC uptake in brain tumor and normal tissues, regions of interest were set in the brain tumor, contralateral normal tissue and the cerebellum, and their standardized uptake values (SUV) were calculated. The safety of
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FFACBC was assessed based on subjective symptoms and objective findings, electrocardiograms, vital signs, laboratory results, and the incidence of adverse events.
Results
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FFACBC accumulated in the malignant gliomas of all patients. CE-T1W MRI detected gliomas in all patients, but
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FFACBC PET/CT generally delineated wider regions of tumor extent than CE-T1W MRI. Two of the histopathologically confirmed tumors were located in regions that were defined using
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FFACBC PET/CT, but not using CE-T1W MRI. Two patients experienced three mild adverse events: one complained of a dull headache and later a mild headache, and the other showed general malaise. These symptoms resolved spontaneously without treatment. Only the mild headache could not be ruled out from having a causal relationship with
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FFACBC. Favorable
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ratios regarding
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FFACBC uptake between tumors and normal control tissues were demonstrated in this trial.
Conclusions
It is suggested that
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FFACBC PET/CT has the ability to delineate glioma spread that is undetectable using CE-T1W MRI.
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FFACBC is safe in patients with malignant glioma.
This study was registered in the Japan Pharmaceutical Information Center Clinical Trials Information, which is one of the World Health Organization registries (registration number: JapicCTI-111387).
The interaction of human leukocyte antigen (HLA) with specific drugs is associated with delayed-type hypersensitivity reactions, which cause severe cutaneous toxicity. Such interactions induce ...structural alterations in HLA complexes via several different mechanisms such as the hapten theory, p-i concept, and altered peptide repertoire model, leading to the activation of cytotoxic T cells. To date, comprehensive detection of such structural alterations in preclinical studies has been difficult. Here, we evaluated structural alterations in HLA complexes focusing on the interaction between the HLA-B*57 : 01 allele and abacavir (an anti-human immunodeficiency virus drug), representing a model of abacavir hypersensitivity syndrome induced by changes in the peptide repertoire on the HLA molecule. We employed a phage display method using a commercially available antibody library to screen specific phage antibodies able to recognize HLA-B*57 : 01. The affinity of selected phage antibodies increased because of structural alterations in HLA-B*57 : 01 following exposure to abacavir, indicating that specific phage antibodies can identify drug-mediated structural changes in HLA complexes. We also identified an unreported structural change in HLA-B*57 : 01 using the phage display method, whereby abacavir increased the expression of peptide-deficient HLA-B*57 : 01 on the cell surface. These results suggest that phage display technology is a useful method for detecting structural changes in HLA complexes. This technology represents a potential novel strategy for predicting HLA-associated hypersensitivity reactions by drugs in pre-clinical studies.
A more accurate lung nodule detection algorithm is needed. We developed a modified three-dimensional (3D) U-net deep-learning model for the automated detection of lung nodules on chest CT images. The ...purpose of this study was to evaluate the accuracy of the developed modified 3D U-net deep-learning model.
In this Health Insurance Portability and Accountability Act-compliant, Institutional Review Board-approved retrospective study, the 3D U-net based deep-learning model was trained using the Lung Image Database Consortium and Image Database Resource Initiative dataset. For internal model validation, we used 89 chest CT scans that were not used for model training. For external model validation, we used 450 chest CT scans taken at an urban university hospital in Japan. Each case included at least one nodule of >5 mm identified by an experienced radiologist. We evaluated model accuracy using the competition performance metric (CPM) (average sensitivity at 1/8, 1/4, 1/2, 1, 2, 4, and 8 false-positives per scan). The 95% confidence interval (CI) was computed by bootstrapping 1000 times.
In the internal validation, the CPM was 94.7% (95% CI: 89.1%–98.6%). In the external validation, the CPM was 83.3% (95% CI: 79.4%–86.1%).
The modified 3D U-net deep-learning model showed high performance in both internal and external validation.
Stopping an inappropriate response requires the involvement of the prefrontal-subthalamic hyperdirect pathway. However, how the prefrontal-striatal indirect pathway contributes to stopping is poorly ...understood. In this study, transcranial ultrasound stimulation is used to perform interventions in a task-related region in the striatum. Functional magnetic resonance imaging (MRI) reveals activation in the right anterior part of the putamen during response inhibition, and ultrasound stimulation to the anterior putamen, as well as the subthalamic nucleus, results in significant impairments in stopping performance. Diffusion imaging further reveals prominent structural connections between the anterior putamen and the right anterior part of the inferior frontal cortex (IFC), and ultrasound stimulation to the anterior IFC also shows significant impaired stopping performance. These results demonstrate that the right anterior putamen and right anterior IFC causally contribute to stopping and suggest that the anterior IFC-anterior putamen circuit in the indirect pathway serves as an essential route for stopping.
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•The human subthalamic nucleus and striatum are stimulated by ultrasound•The right anterior putamen in the striatum shows a causal contribution to stopping•The right anterior IFC is a cortical counterpart of the anterior putamen•The anterior IFC-anterior putamen circuit works as an essential route for stopping
Nakajima et al. find that ultrasound stimulation to the right anterior putamen and the right anterior inferior frontal cortex (aIFC), a cortical counterpart of the anterior putamen, elicits impaired stopping performance. The aIFC-anterior putamen circuit in the indirect pathway serves as an essential route for stopping.
•Abacavir-induced severe skin hypersensitivity could be reproduced in mice.•PD1 knockout facilitated Abacavir-induced CD8 T cell activation.•CD4 T cell depletion could promote sufficient DC ...maturation.•PD1 knockout and CD4 T cell depletion could lead to CD8 T cells proliferation.
Based on recent genome-wide association studies, abacavir-induced hypersensitivity is highly associated with human leukocyte antigen (HLA)-B*57:01 allele. However, the underlying mechanism of this occurrence is unclear. To investigate the underlying mechanism, we developed HLA-B*57:01 transgenic mice and found that application of abacavir could cause CD8 T cell activation with elevation in PD1 expression; however, severe skin hypersensitivity was not observed. To eliminate the immunosuppressive effect of PD1, HLA-B*57:01 transgenic/PD1 knockout (01Tg/PD1) mice were generated by mating HLA-B*57:01 transgenic mice and PD1 knockout mice. Thereafter, 01Tg/PD1 mice were treated with abacavir. Similar to the above results, severe skin hypersensitivity was not observed. Therefore, we treated 01Tg/PD1 mice with an anti-CD4 antibody to deplete CD4 T cells, followed by abacavir topically and orally. Severe abacavir-induced skin hypersensitivity was observed in 01Tg/PD1 mice after depletion of CD4 T cells, in addition to significant CD8 T cell activation and dendritic cell maturation. Taken together, we succeeded in reproducing severe skin hypersensitivity in a mouse model. And we found that through the combined depletion of PD1 and CD4 T cells, CD8 T cells could be activated and could proceed to clonal proliferation, which is promoted by mature dendritic cells, thereby eventually inducing severe skin hypersensitivity.
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