Mapping glymphatic solute transportation through the perivascular space of hippocampal arterioles with 14 Tesla MRI.

The perivascular space (PVS) plays a crucial role in facilitating the clearance of waste products and the exchange of cerebrospinal fluid and interstitial fluid in the central nervous system. While optical imaging methods identify the glymphatic transport of fluorescent tracers through PVS of surface-diving arteries, their limited depth penetration impedes the study of glymphatic dynamics in deep brain regions. In this study, we introduced a novel high-resolution dynamic contrast-enhanced MRI mapping approach based on single-vessel multi-gradient-echo methods. This technique allowed the differentiation of penetrating arterioles and venules from adjacent parenchymal tissue voxels and enabled the detection of Gd-enhanced signals coupled to PVS of penetrating arterioles in the deep cortex and hippocampus. By directly infusing Gd into the lateral ventricle, we eliminated delays in cerebrospinal fluid flow and focused on PVS Gd transport through PVS of hippocampal arterioles. The study revealed significant PVS-specific Gd signal enhancements, shedding light on glymphatic function in deep brain regions. These findings advance our understanding of brain-wide glymphatic dynamics and hold potential implications for neurological conditions characterized by impaired waste clearance, warranting further exploration of their clinical relevance and therapeutic applications.

No replication of direct neuronal activity-related (DIANA) fMRI in anesthetized mice.

Direct imaging of neuronal activity (DIANA) by functional magnetic resonance imaging (fMRI) could be a revolutionary approach for advancing systems neuroscience research. To independently replicate this observation, we performed fMRI experiments in anesthetized mice. The blood oxygenation level-dependent (BOLD) response to whisker stimulation was reliably detected in the primary barrel cortex before and after DIANA experiments; however, no DIANA-like fMRI peak was observed in individual animals' data with the 50 to 300 trials. Extensively averaged data involving 1050 trials in six mice showed a flat baseline and no detectable neuronal activity-like fMRI peak. However, spurious, nonreplicable peaks were found when using a small number of trials, and artifactual peaks were detected when some outlier-like trials were excluded. Further, no detectable DIANA peak was observed in the BOLD-responding thalamus from the selected trials with the neuronal activity-like reference function in the barrel cortex. Thus, we were unable to replicate the previously reported results without data preselection.

Alpha-180 spin-echo based line-scanning method for high resolution laminar-specific fMRI.

Laminar-specific functional magnetic resonance imaging (fMRI) has been widely used to study circuit-specific neuronal activity by mapping spatiotemporal fMRI response patterns across cortical layers. Hemodynamic responses reflect indirect neuronal activity given limit of spatial and temporal resolution. Previous gradient-echo based line-scanning fMRI (GELINE) method was proposed with high temporal (50 ms) and spatial (50 µm) resolution to better characterize the fMRI onset time across cortical layers by employing 2 saturation RF pulses. However, the imperfect RF saturation performance led to poor boundary definition of the reduced region of interest (ROI) and aliasing problems outside of the ROI. Here, we propose α (alpha)-180 spin-echo-based line-scanning fMRI (SELINE) method to resolve this issue by employing a refocusing 180° RF pulse perpendicular to the excitation slice. In contrast to GELINE signals peaked at the superficial layer, we detected varied peaks of laminar-specific BOLD signals across deeper cortical layers with the SELINE method, indicating the well-defined exclusion of the large drain-vein effect with the spin-echo sequence. Furthermore, we applied the SELINE method with 200 ms TR to sample the fast hemodynamic changes across cortical layers with a less draining vein effect. In summary, this SELINE method provides a novel acquisition scheme to identify microvascular-sensitive laminar-specific BOLD responses across cortical depth.

High-resolution awake mouse fMRI at 14 Tesla.

High-resolution awake mouse fMRI remains challenging despite extensive efforts to address motion-induced artifacts and stress. This study introduces an implantable radiofrequency (RF) surface coil design that minimizes image distortion caused by the air/tissue interface of mouse brains while simultaneously serving as a headpost for fixation during scanning. Using a 14T scanner, high-resolution fMRI enabled brain-wide functional mapping of visual and vibrissa stimulation at 100×100×200µm resolution with a 2s per frame sampling rate. Besides activated ascending visual and vibrissa pathways, robust BOLD responses were detected in the anterior cingulate cortex upon visual stimulation and spread through the ventral retrosplenial area (VRA) with vibrissa air-puff stimulation, demonstrating higher-order sensory processing in association cortices of awake mice. In particular, the rapid hemodynamic responses in VRA upon vibrissa stimulation showed a strong correlation with the hippocampus, thalamus, and prefrontal cortical areas. Cross-correlation analysis with designated VRA responses revealed early positive BOLD signals at the contralateral barrel cortex (BC) occurring 2 seconds prior to the air-puff in awake mice with repetitive stimulation, which was not detectable with the randomized stimulation paradigm. This early BC activation indicated learned anticipation through the vibrissa system and association cortices in awake mice under continuous training of repetitive air-puff stimulation. This work establishes a high-resolution awake mouse fMRI platform, enabling brain-wide functional mapping of sensory signal processing in higher association cortical areas.

No Replication of Direct Neuronal Activity-related (DIANA) fMRI in Anesthetized Mice.

Toi et al. (Science, 378, 160-168, 2022) reported direct imaging of neuronal activity (DIANA) by fMRI in anesthetized mice at 9.4 T, which could be a revolutionary approach for advancing systems neuroscience research. There have been no independent replications of this observation to date. We performed fMRI experiments in anesthetized mice at an ultrahigh field of 15.2 T using the identical protocol as in their paper. The BOLD response to whisker stimulation was reliably detected in the primary barrel cortex before and after DIANA experiments; however, no direct neuronal activity-like fMRI peak was observed in individual animals' data with the 50-300 trials used in the DIANA publication. Extensively averaged data involving 1,050 trials in 6 mice (1,050×54 = 56,700 stimulus events) and having a temporal signal-to-noise ratio of 7,370, showed a flat baseline and no detectable neuronal activity-like fMRI peak. Thus we were unable to replicate the previously reported results using the same methods, despite a much higher number of trials, a much higher temporal signal-to-noise ratio, and a much higher magnetic field strength. We were able to demonstrate spurious, non-replicable peaks when using a small number of trials. It was only when performing the inappropriate approach of excluding outliers not conforming to the expected temporal characteristics of the response did we see a clear signal change; however, these signals were not observed when such a outlier elimination approach was not used.

A consensus protocol for functional connectivity analysis in the rat brain.

Task-free functional connectivity in animal models provides an experimental framework to examine connectivity phenomena under controlled conditions and allows for comparisons with data modalities collected under invasive or terminal procedures. Currently, animal acquisitions are performed with varying protocols and analyses that hamper result comparison and integration. Here we introduce StandardRat, a consensus rat functional magnetic resonance imaging acquisition protocol tested across 20 centers. To develop this protocol with optimized acquisition and processing parameters, we initially aggregated 65 functional imaging datasets acquired from rats across 46 centers. We developed a reproducible pipeline for analyzing rat data acquired with diverse protocols and determined experimental and processing parameters associated with the robust detection of functional connectivity across centers. We show that the standardized protocol enhances biologically plausible functional connectivity patterns relative to previous acquisitions. The protocol and processing pipeline described here is openly shared with the neuroimaging community to promote interoperability and cooperation toward tackling the most important challenges in neuroscience.

Identifying the distinct spectral dynamics of laminar-specific interhemispheric connectivity with bilateral line-scanning fMRI.

Despite extensive efforts to identify interhemispheric functional connectivity (FC) with resting-state (rs-) fMRI, correlated low-frequency rs-fMRI signal fluctuation across homotopic cortices originates from multiple sources. It remains challenging to differentiate circuit-specific FC from global regulation. Here, we developed a bilateral line-scanning fMRI method to detect laminar-specific rs-fMRI signals from homologous forepaw somatosensory cortices with high spatial and temporal resolution in rat brains. Based on spectral coherence analysis, two distinct bilateral fluctuation spectral features were identified: ultra-slow fluctuation (<0.04 Hz) across all cortical laminae versus Layer (L) 2/3-specific evoked BOLD at 0.05 Hz based on 4 s on/16 s off block design and resting-state fluctuations at 0.08-0.1 Hz. Based on the measurements of evoked BOLD signal at corpus callosum (CC), this L2/3-specific 0.05 Hz signal is likely associated with neuronal circuit-specific activity driven by the callosal projection, which dampened ultra-slow oscillation less than 0.04 Hz. Also, the rs-fMRI power variability clustering analysis showed that the appearance of L2/3-specific 0.08-0.1 Hz signal fluctuation is independent of the ultra-slow oscillation across different trials. Thus, distinct laminar-specific bilateral FC patterns at different frequency ranges can be identified by the bilateral line-scanning fMRI method.

Mapping the bioimaging marker of Alzheimer's disease based on pupillary light response-driven brain-wide fMRI in awake mice.

Pupil dynamics has emerged as a critical non-invasive indicator of brain state changes. In particular, pupillary-light-responses (PLR) in Alzheimer's disease (AD) patients may be used as biomarkers of brain degeneration. To characterize AD-specific PLR and its underlying neuromodulatory sources, we combined high-resolution awake mouse fMRI with real-time pupillometry to map brain-wide event-related correlation patterns based on illumination-driven pupil constriction ( P c ) and post-illumination pupil dilation recovery (amplitude, P d , and time, T ). The P c -driven differential analysis revealed altered visual signal processing coupled with reduced thalamocortical activation in AD mice compared with the wild-type normal mice. In contrast, the post-illumination pupil dilation recovery-based fMRI highlighted multiple brain areas related to AD brain degeneration, including the cingulate cortex, hippocampus, septal area of the basal forebrain, medial raphe nucleus, and pontine reticular nuclei (PRN). Also, brain-wide functional connectivity analysis highlighted the most significant changes in PRN of AD mice, which serves as the major subcortical relay nuclei underlying oculomotor function. This work combined non-invasive pupil-fMRI measurements in preclinical models to identify pupillary biomarkers based on neuromodulatory dysfunction coupled with AD brain degeneration.

Correction: Assessment of single-vessel cerebral blood velocity by phase contrast fMRI.

[This corrects the article DOI: 10.1371/journal.pbio.3000923.].

Laminar-specific functional connectivity mapping with multi-slice line-scanning fMRI.

Despite extensive studies detecting laminar functional magnetic resonance imaging (fMRI) signals to illustrate the canonical microcircuit, the spatiotemporal characteristics of laminar-specific information flow across cortical regions remain to be fully investigated in both evoked and resting conditions at different brain states. Here, we developed a multislice line-scanning fMRI (MS-LS) method to detect laminar fMRI signals in adjacent cortical regions with high spatial (50 µm) and temporal resolution (100 ms) in anesthetized rats. Across different trials, we detected either laminar-specific positive or negative blood-oxygen-level-dependent (BOLD) responses in the surrounding cortical region adjacent to the most activated cortex under the evoked condition. Specifically, in contrast to typical Layer (L) 4 correlation across different regions due to the thalamocortical projections for trials with positive BOLD, a strong correlation pattern specific in L2/3 was detected for trials with negative BOLD in adjacent regions, which indicated brain state-dependent laminar-fMRI responses based on corticocortical interaction. Also, in resting-state (rs-) fMRI study, robust lag time differences in L2/3, 4, and 5 across multiple cortices represented the low-frequency rs-fMRI signal propagation from caudal to rostral slices. In summary, our study provided a unique laminar fMRI mapping scheme to better characterize trial-specific intra- and inter-laminar functional connectivity in evoked and resting-state MS-LS.

Focal fMRI signal enhancement with implantable inductively coupled detectors.

Despite extensive efforts to increase the signal-to-noise ratio (SNR) of fMRI images for brain-wide mapping, technical advances of focal brain signal enhancement are lacking, in particular, for animal brain imaging. Emerging studies have combined fMRI with fiber optic-based optogenetics to decipher circuit-specific neuromodulation from meso to macroscales. High-resolution fMRI is needed to integrate hemodynamic responses into cross-scale functional dynamics, but the SNR remains a limiting factor given the complex implantation setup of animal brains. Here, we developed a multimodal fMRI imaging platform with an implanted inductive coil detector. This detector boosts the tSNR of MRI images, showing a 2-3-fold sensitivity gain over conventional coil configuration. In contrast to the cryoprobe or array coils with limited spaces for implanted brain interface, this setup offers a unique advantage to study brain circuit connectivity with optogenetic stimulation and can be further extended to other multimodal fMRI mapping schemes.

Assessment of single-vessel cerebral blood velocity by phase contrast fMRI.

Current approaches to high-field functional MRI (fMRI) provide 2 means to map hemodynamics at the level of single vessels in the brain. One is through changes in deoxyhemoglobin in venules, i.e., blood oxygenation level-dependent (BOLD) fMRI, while the second is through changes in arteriole diameter, i.e., cerebral blood volume (CBV) fMRI. Here, we introduce cerebral blood flow-related velocity-based fMRI, denoted CBFv-fMRI, which uses high-resolution phase contrast (PC) MRI to form velocity measurements of flow. We use CBFv-fMRI in measure changes in blood velocity in single penetrating microvessels across rat parietal cortex. In contrast to the venule-dominated BOLD and arteriole-dominated CBV fMRI signals, CBFv-fMRI is comparable from both arterioles and venules. A single fMRI platform is used to map changes in blood pO2 (BOLD), volume (CBV), and velocity (CBFv). This combined high-resolution single-vessel fMRI mapping scheme enables vessel-specific hemodynamic mapping in animal models of normal and diseased states and further has translational potential to map vascular dementia in diseased or injured human brains with ultra-high-field fMRI.

Effectiveness of simulation-based interprofessional education for medical and nursing students in South Korea: a pre-post survey.

BACKGROUND: Effective collaboration and communication among health care team members are critical for providing safe medical care. Interprofessional education aims to instruct healthcare students how to learn with, from, and about healthcare professionals from different occupations to encourage effective collaboration to provide safe and high-quality patient care. The purpose of this study is to confirm the effectiveness of Interprofessional education by comparing students' attitudes toward interprofessional learning before and after simulation-based interprofessional education, the perception of teamwork and collaboration between physicians and nurses, and the self-reported competency differences among students in interprofessional practice. METHODS: The survey responses from 37 5th-year medical students and 38 4th-year nursing students who participated in an interprofessional education program were analyzed. The Attitude Towards Teamwork in Training Undergoing Designed Educational Simulation scale, the Jefferson Scale of Attitudes Toward Physician-Nurse Collaboration, and the Interprofessional Education Collaborative competency scale were used for this study. The demographic distribution of the study participants was obtained, and the perception differences before and after participation in interprofessional education between medical and nursing students were analyzed. RESULTS: After interprofessional education, student awareness of interprofessional learning and self-competency in interprofessional practice improved. Total scores for the Jefferson Scale of Attitudes Toward Physician-Nurse Collaboration did not change significantly among medical students but increased significantly among nursing students. Additionally, there was no significant change in the perception of the role of other professions among either medical or nursing students. CONCLUSIONS: We observed an effect of interprofessional education on cultivating self-confidence and recognizing the importance of interprofessional collaboration between medical professions. It can be inferred that exposure to collaboration situations through Interprofessional education leads to a positive perception of interprofessional learning. However, even after their interprofessional education experience, existing perceptions of the role of other professional groups in the collaboration situation did not change, which shows the limitations of a one-time short-term program. This suggests that efforts should be made to ensure continuous exposure to social interaction experiences with other professions.

Real-Time fMRI Brain Mapping in Animals.

Dynamic fMRI responses vary largely according to the physiological conditions of animals either under anesthesia or in awake states. We developed a real-time fMRI platform to guide experimenters to monitor fMRI responses instantaneously during acquisition, which can be used to modify the physiology of animals to achieve desired hemodynamic responses in animal brains. The real-time fMRI set-up is based on a 14.1T preclinical MRI system, enabling the real-time mapping of dynamic fMRI responses in the primary forepaw somatosensory cortex (FP-S1) of anesthetized rats. Instead of a retrospective analysis to investigate confounding sources leading to the variability of fMRI signals, the real-time fMRI platform provides a more effective scheme to identify dynamic fMRI responses using customized macro-functions and a common neuroimage analysis software in the MRI system. Also, it provides immediate troubleshooting feasibility and a real-time biofeedback stimulation paradigm for brain functional studies in animals.

Treatment of acute carbon monoxide poisoning with induced hypothermia.

OBJECTIVE: The effect of induced hypothermia on severe acute carbon monoxide (CO) poisoning remains to be addressed further. We investigated the effect of induced hypothermia on severe acute CO poisoning. METHODS: Retrospective chart review was conducted for patients who diagnosed as severe acute CO poisoning in emergency department and underwent induced hypothermia from May 2013 to May 2014. Hospital courses with critical medication and major laboratory results were investigated through the chart review. RESULTS: Among total 227 patients with acute CO poisoning during the period of study, patients with severe acute CO poisoning were 15. All patients underwent induced hypothermia with a temperature goal 33°C. Initial and follow-up levels of S100B protein after induced hypothermia were 0.47 µg/L (interquartile range, 0.11 to 0.71) and 0.10 µg/L (interquartile range, 0.06 to 0.37), respectively (P = 0.01). The mean Glasgow Coma Scales at emergency department admission was 6.87 ± 3.36. Except 1 patient who expired after cardiopulmonary resuscitation, Glasgow Coma Scales at 30-day of hospital discharge were 15 in 10 patients (71.4%), 14 in 1 patient (7.1%), 13 in 1 patient (7.1%), and 6 in 2 patients (14.2%). Seven patients (46.7%) developed delayed neurologic sequelae. Four patients showed mild types of delayed neurologic sequelae and 3 showed moderate to severe types of delayed neurologic sequelae. CONCLUSION: Most of patients underwent induced hypothermia had a good recovery from severe acute CO poisoning. Therefore, induced hypothermia may be considered as a possible treatment in severe acute CO poisoning.

The Poisoning Information Database Covers a Large Proportion of Real Poisoning Cases in Korea.

The poisoning information database (PIDB) provides clinical toxicological information on commonly encountered toxic substances in Korea. The aim of this study was to estimate the coverage rate of the PIDB by comparing the database with the distribution of toxic substances that real poisoning patients presented to 20 emergency departments. Development of the PIDB started in 2007, and the number of toxic substances increased annually from 50 to 470 substances in 2014. We retrospectively reviewed the medical records of patients with toxic exposure who visited 20 emergency departments in Korea from January to December 2013. Identified toxic substances were classified as prescription drug, agricultural chemical, household product, animal or plant, herbal drug, or other. We calculated the coverage rate of the PIDB for both the number of poisoning cases and the kinds of toxic substances. A total of 10,887 cases of intoxication among 8,145 patients was collected. The 470 substances registered in the PIDB covered 89.3% of 8,891 identified cases related to poisoning, while the same substances only covered 45.3% of the 671 kinds of identified toxic substances. According to category, 211 prescription drugs, 58 agricultural chemicals, 28 household products, and 32 animals or plants were not covered by the PIDB. This study suggested that the PIDB covered a large proportion of real poisoning cases in Korea. However, the database should be continuously extended to provide information for even rare toxic substances.

Prognostication of cardiac arrest survivors using low apparent diffusion coefficient cluster volume.

INTRODUCTION: We developed a new neuroprognostication method for cardiac arrest (CA) using the relative volume of the most dominant cluster of low apparent diffusion coefficient (ADC) voxels and tested its performance in a multicenter setting. METHODS: Adult (>15 years) out-of-hospital CA patients from three different facilities who underwent an MRI 12h after resuscitation were retrospectively analyzed. Patients with unknown long-term prognosis or poor baseline neurologic function were excluded. Average ADCs (mean and median), LADCV (relative volume of low-ADC voxels) and DC-LADCV (relative volume of most dominant cluster of low-ADC voxels) were extracted using different thresholds between 400 and 800 × 10(-6) mm(2) s(-1) at 10 × 10(-6) mm(2) s(-1) intervals. Area under the receiver operating characteristic curve (AUROC) and sensitivity for poor outcome (6-month cerebral performance category score >2) while maintaining 100% specificity were measured. RESULTS: 110 patients were analyzed. Average ADCs showed fair performance with an AUROC of 0.822 (95% confidence interval [CI], 0.744-0.900) for the mean and 0.799 (95% CI, 0.716-0.882) for the median. LADCV showed better performance with a higher AUROC (maximum, 0.925) in an ADC threshold range of 400 to 690 × 10(-6) mm(2) s(-1). DC-LADCV showed the best performance with a higher AUROC (maximum, 0.955) compared with LADCV in an ADC threshold range of 600 to 680 × 10(-6) mm(2) s(-1). DC-LADCV had a high sensitivity for poor outcomes (>80%) in a wide threshold range from 400 to 580 × 10(-6) mm(2) s(-1) with a maximum of 89.2%. CONCLUSIONS: Quantitative analysis using DC-LADCV showed impressive performance in determining the prognosis of out-of-hospital CA patients in a multicenter setting.

Various Echocardiographic Patterns of Left Ventricular Systolic Dysfunction Induced by Carbon Monoxide Intoxication.

Carbon monoxide (CO) intoxication could cause significant cardiac injury. Although cardiac dysfunction after CO intoxication can be presented, the echocardiographic findings after CO intoxication are poorly defined. The purpose of this study was to evaluate the clinical patterns of left ventricular (LV) systolic dysfunction using echocardiography. A total of 132 CO-intoxicated patients were enrolled. Clinical, demographic and laboratory data and echocardiographic findings were analyzed. The LV dysfunction group (29 patients) showed higher lactate level (5.8 ± 3.3 vs. 4.1 ± 3.5 mmol/L, p = 0.024) and lower base excess (BE) (-8.2 ± 6.0 vs. -4.8 ± 4.7 mEq/L, p = 0.001) compared with normal LV function group. Among the LV dysfunction group, three different echocardiographic patterns were presented. Regional wall motion abnormality was presented in 14 patients. Apical ballooning, typical finding of stress-induced cardiomyopathy, was presented in eight patients. Global hypokinesia of LV was presented in seven patients. Laboratory findings indicating the severity of CO intoxication, such as lactate level, pH value, BE and aspartate aminotransferase, showed statistical significance according to the patterns of LV dysfunction (p = 0.033, 0.022, 0.02 and 0.006, respectively). Our results demonstrate that CO intoxication could induce various patterns of LV dysfunction. The patterns of LV dysfunction might affect subsequent clinical outcomes.

Clinical insights for early detection of acute transverse myelitis in the emergency department.

OBJECTIVE: Acute transverse myelitis (ATM) is characterized by motor weakness, sensory changes, and autonomic dysfunction. However, diagnosis of ATM is based on early-stage clinical features only (and clarification of the cause of disease), which are difficult for emergency department (ED) physicians owing to low incidence rates. We performed retrospective analysis of ATM in order to provide clinical insights for early detection. METHODS: Medical records of patients, who were finally diagnosed with ATM from January 2005 to February 2013, were investigated. Data, including demographics, clinical findings, and radiographic findings, were reviewed. RESULTS: Forty-six patients were included in the present study, with a mean age of 43.4 years. Sensory changes were identified in 45 patients (97.8%), motor weakness in 33 patients (71.7%), and autonomic dysfunction in 35 patients (76.1%). Thirty patients (65.2%) showed high signal intensity in T2-weighted magnetic resonance imaging (MRI), with lesions most frequently found in the thoracic level of the spinal cord (56.7%). There were discrepancies between sensory changes and levels of MRI lesions. Thirty-five patients (76.1%) were diagnosed with idiopathic ATM. Initial diagnostic impressions in the ED were herniated intervertebral disc (38.7%), stroke (19.4%), Guillain-Barré syndrome (12.9%), cauda equina syndrome (9.7%), ATM (9.7%), and others (9.7%). CONCLUSION: When a patient presents with motor weakness, sensory changes, or autonomic dysfunction, ATM should be initially considered as a differential diagnosis, unless the ED physician's impression after initial evaluation is clear.