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

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

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.

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.

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.

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.

Carbon monoxide-induced cardiomyopathy.

BACKGROUND: Previous reports demonstrated mechanisms of cardiac toxicity in acute carbon monoxide (CO) poisoning. Still, none established CO-induced cardiomyopathy (CMP) as a clinical entity. The aim of this study is to investigate CO-induced CMP in patients with acute CO poisoning in terms of its epidemiology, clinical characteristics, and prognosis. METHODS AND RESULTS: A retrospective study was conducted on consecutive patients who were diagnosed with acute CO poisoning at the emergency department of Ajou University Hospital during the period of 62 month. Six hundred and twenty-six patients were diagnosed with acute CO poisoning. During the initial echocardiography, 19 patients were abnormal: (1) global hypokinesia/akinesia (n=7), (2) regional wall hypokinesia/akinesia [n=12; takotsubo type (n=6), reverse takotsubo type (n=2), non-specific type (n=4)]. The ejection fraction (EF) was 36.3±13.5% (from 15% to 55%) and less than 45% for 14 patients. In the follow-up echocardiography performed within 12 days after the initial performance, most patients were found to have cardiac wall motion abnormalities, and their EF had returned to normal (ie, EF ≥50%). CONCLUSIONS: CO-induced CMP was identified in 3.04% (n=19) of all patients (n=626). It might not be too critical in acute clinical courses of acute CO poisoning because the prognosis seems favorable. Considering the common factors between CO-induced CMP and takotsubo CMP, myocardial stunning subject to a catecholamine surge most likely plays a central role in the development of CO-induced CMP.

Evaluation of exhaled nitric oxide in acute paraquat poisoning: a pilot study.

BACKGROUND: Fractional exhaled nitric oxide (FENO) is nitric oxide (NO) in the lower airway measured by oral exhalation. FENO can be a useful non-invasive marker for asthma. Paraquat-mediated lung injury can be reflective of an ROS-induced lung injury. We aimed to verify if FENO is a clinical parameter of ROS formation and responsiveness to medical therapies in acute paraquat intoxication. MATERIAL AND METHODS: We recruited 12 patients admitted with acute paraquat poisoning. A portable and noninvasive device called NIOX MINO™ (Aerocrine AB, Solna, Sweden) was used to measure FENO. Measurements were made at the time of hospital admission and at 24, 48, 72, 96, and 120 h after paraquat ingestion. RESULTS: Six out of the total 12 recruited patients had general conditions (e.g. oral pain) that made it difficult for them to exhale with adequate force. Mean plasma paraquat level was 1.4 ± 2.5 g/mL. We found no direct correlation between the paraquat levels (both ingestion amount and plasma concentration) and FENO (initial, maximal, and minimal values). All the measured FENO values were no greater than 20 ppb for the 2 patients who died. FENO did not vary more than 20% from the baseline. Compared to the above findings, FENO measurements were found to be greater than 20 ppb for the patients who survived. FENO tends to reach its peak value at between 50 h and 80 h. CONCLUSIONS: FENO did not predict mortality, and there was no increase of FENO in patients with severe paraquat intoxication.

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.

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.

Injuries associated with the 580 km university student grand voluntary road march: focus on foot injuries.

College student volunteers (n = 142) completed a 580 km road march for 21 consecutive days. Each volunteer carried a backpack that weighed 14.1 ± 1.4 kg on the average. We investigated the incidence and location of blisters associated with the road march using a foot map along with other injuries. Overall, 95.1% of the subjects (135 of 142) sustained one or more injuries. All injured subjects had foot blisters, and 18% had other foot injuries. The most common locations of blister development were the right 5th toe (61%) and the left 5th toe (57%). The little toes seem to have been subjected to the greatest friction and shearing forces. March-related injuries, excluding foot injuries, were ankle pain (12.7%), knee pain (12.7%) and Achilles tendon pain (7.7%). Six subjects (4.2%) needed extra medical treatment for more than 2 weeks prior to returning to their daily lives after completion of the march due to associated injuries. The present study observed a very high incidence rate of injuries (95.1%) associated with the 580 km university students grand road march. These injuries posed an obstacle against completion of the road march and against returning to daily life. Active preventive interventions such as physical therapy and customized reinforced shoes and education program are recommended for reducing incidence rate and severity of injuries.

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.

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.

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.

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.

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.

Acute oral poisoning due to chloracetanilide herbicides.

Chloracetanilide herbicides (alachlor, butachlor, metachlor) are used widely. Although there are much data about chronic low dose exposure to chloracetanilide in humans and animals, there are few data about acute chloracetanilide poisoning in humans. This study investigated the clinical feature of patients following acute oral exposure to chloracetanilide. We retrospectively reviewed the data on the patients who were admitted to two university hospitals from January 2006 to December 2010. Thirty-five patients were enrolled. Among them, 28, 5, and 2 cases of acute alachlor, metachlor, butachlor poisoning were included. The mean age was 49.8 ± 15.4 yr. The poison severity score (PSS) was 17 (48.6%), 10 (28.6%), 5 (14.3%), 2 (5.7%), and 1 (2.9%) patients with a PSS of 0, 1, 2, 3, and 4, respectively. The age was higher for the symptomatic patients (1-4 PSS) than that for the asymptomatic patients (0 PSS) (43.6 ± 15.2 vs 55.7 ± 13.5). The arterial blood HCO3⁻ was lower in the symptomatic patients (1-4 PSS) than that in the asymptomatic patients (0 PSS). Three patients were a comatous. One patient died 24 hr after the exposure. In conclusion, although chloracetanilide poisoning is usually of low toxicity, elder patients with central nervous system symptoms should be closely monitored and cared after oral exposure.