Risk factors for massive transfusion in obstetrical hemorrhage and consideration of a whole blood program.

BACKGROUND: Postpartum hemorrhage (PPH) is one of the leading causes of obstetric complications. The goal of this study was to identify risk factors for obstetric (OB) massive transfusion (MT) and determine the feasibility of developing a low-titer group O RhD-positive whole blood (LTO + WB) protocol for OB hemorrhage. STUDY DESIGN AND METHODS: A retrospective study of OB patients who received transfusion within 24 h. MT patients were those who received >3 U of pRBC within 1 h or > 10 U in 24 h. Patient demographics, OB history, comorbidities, blood type, antibody status, and known risk factors for PPH and maternal-fetal outcomes were compared. Logistic regression was used for univariate and multivariate analyses. RESULTS: Of the 610 transfused OB patients, 12.0% (n = 73) required MT. Groups were well matched for body mass index (BMI), maternal comorbidities, and history of spontaneous vaginal deliveries. The incidence of the previous cesarean section was higher in the MT group. Exactly 93.9% of patients were RhD-positive and 3.77% of all patients possessed an antibody on pretransfusion testing. Patients with MT had a longer length of stay (LOS), higher rate of intensive care unit (ICU) admission, fetal death, and hysterectomy. Multivariate analysis found age >35, PPH, placenta percreta, accreta, and increta to be significant (p < .05) risk factors for MT. DISCUSSION: Patients over 35 years and those with abnormal placentation are at increased risk of requiring MT. With a time to delivery of 2 days, potential MT patients can be identified early, and with a 94% rate of RhD-positive+, they are eligible to receive low-titer O whole blood (LTOWB) providing hemostatic resuscitation with reduced donor exposure.

Association of Traumatic Brain Injury With Vestibular Dysfunction and Dizziness in Post-9/11 Veterans.

OBJECTIVE: To describe the prevalence and impact of vestibular dysfunction and nonspecific dizziness diagnoses and explore their associations with traumatic brain injury (TBI) severity, mechanism, and postconcussive comorbidities among post-9/11 veterans. SETTING: Administrative medical record data from the US Departments of Defense and Veterans Affairs (VA). PARTICIPANTS: Post-9/11 veterans with at least 3 years of VA care. DESIGN: Cross-sectional, retrospective, observational study. MAIN MEASURES: International Classification of Diseases, Ninth Revision, Clinical Modification diagnosis codes for TBI, vestibular dysfunction, dizziness, and other commonly associated postconcussive conditions; Neurobehavioral Symptom Inventory. RESULTS: Of the 570 248 post-9/11 veterans in this sample, 0.45% had a diagnosis of vestibular dysfunction and 2.57% had nonspecific dizziness. Those with either condition were more likely to have evidence of TBI (57.11% vs 28.51%) and reported more disruption from neurobehavioral symptoms. Blast and nonblast injuries were associated with greater symptom disruption, particularly in combination. CONCLUSIONS: There was a consistent, significant association between TBI and vestibular dysfunction or nonspecific dizziness, after controlling for sociodemographic factors, injury mechanism, and comorbid conditions. Given that most deployed post-9/11 veterans report blast and/or nonblast injuries, the need for prompt identification and management of these conditions and symptoms is clear.

Self-directed down-regulation of auditory cortex activity mediated by real-time fMRI neurofeedback augments attentional processes, resting cerebral perfusion, and auditory activation.

In this work, we investigated the use of real-time functional magnetic resonance imaging (fMRI) with neurofeedback training (NFT) to teach volitional down-regulation of the auditory cortex (AC) using directed attention strategies as there is a growing interest in the application of fMRI-NFT to treat neurologic disorders. Healthy participants were separated into two groups: the experimental group received real feedback regarding activity in the AC; the control group was supplied sham feedback yoked from a random participant in the experimental group and matched for fMRI-NFT experience. Each participant underwent five fMRI-NFT sessions. Each session contained 2 neurofeedback runs where participants completed alternating blocks of "rest" and "lower" conditions while viewing a continuously-updated bar representing AC activation and listening to continuous noise. Average AC deactivation was extracted from each closed-loop neuromodulation run and used to quantify the control over AC (AC control), which was found to significantly increase across training in the experimental group. Additionally, behavioral testing was completed outside of the MRI on sessions 1 and 5 consisting of a subjective questionnaire to assess attentional control and two quantitative tests of attention. No significant changes in behavior were observed; however, there was a significant correlation between changes in AC control and attentional control. Also, in a neural assessment before and after fMRI-NFT, AC activity in response to continuous noise stimulation was found to significantly decrease across training while changes in AC resting perfusion were found to be significantly greater in the experimental group. These results may be useful in formulating effective therapies outside of the MRI, specifically for chronic tinnitus which is often characterized by hyperactivity of the primary auditory cortex and altered attentional processes. Furthermore, the modulation of attention may be useful in developing therapies for other disorders such as chronic pain.

Retrospective Review: Effectiveness of Cervical Proprioception Retraining for Dizziness After Mild Traumatic Brain Injury in a Military Population With Abnormal Cervical Proprioception.

OBJECTIVE: This study aimed to assess the outcomes of 2 treatments for patients with dizziness after mild traumatic brain injury (mTBI) who demonstrate abnormal cervical spine proprioception (CSP). METHODS: A retrospective records review was conducted on the medical charts of patients treated for dizziness after mTBI who received either standard care (vestibular rehabilitation therapy [VRT]) or cervical spine proprioceptive retraining (CSPR) from 2009 to 2013. All patients included in the analysis were active-duty military with recurring dizziness after mTBI who had at least 1 abnormal CSP test. Patients were excluded for dizziness with a clear peripheral vestibular or central symptom origin, incomplete data, or no CSP assessment, or if both treatments were administered. Forty-eight total patients were included in the final dataset (22 VRT; 26 CSPR). Traditional VRT was compared with CSPR when abnormal CSP tests were present, regardless of the presence or absence of neck pain. A clinician review of records was used to determine improvement of dizziness based on patient reports of symptoms at discharge evaluation (ie, no symptoms for at least 2 weeks). RESULTS: Patients who received CSPR were 30 times more likely to report improvement in dizziness symptoms compared with those who received VRT (adjusted odds ratio: 30.12; 95% confidence interval 4.44-204.26, P < .001) when abnormal CSP tests were present. Patients with dizziness over 1 year were significantly less likely to improve. CONCLUSION: These results suggest that patients with dizziness after mTBI and who had abnormal CSP assessments responded better to CSPR compared with those who received VRT.

Sensory dysfunction and traumatic brain injury severity among deployed post-9/11 veterans: a chronic effects of neurotrauma consortium study.

OBJECTIVES: To describe the prevalence of sensory dysfunction (i.e. auditory, visual, vestibular, chemosensory and multiple sensory problems) and explore associations with traumatic brain injury (TBI) severity and injury mechanism among deployed Post-9/11 Veterans. METHODS: This retrospective cohort analysis used Departments of Defense and Veterans Affairs diagnostic codes and administrative data. RESULTS: Among the 570,248 Veterans in this cohort, almost 23% had at least one diagnosis of sensory dysfunction. In the multinomial regression analysis, the odds of all types of sensory dysfunction were greater among those with any TBI relative to those with no TBI. The odds for auditory or multisensory problems were higher among those that indicated exposure to blast. In particular, exposure to quaternary blast injury (e.g. crush, respiratory and burn injuries) was associated with increased odds for auditory, visual, vestibular and multisensory problems. CONCLUSIONS: Sensory problems affect a substantial number of deployed Post-9/11 Veterans and are more common among those with TBI or with exposure to deployment-related blast exposure. Because sensory problems profoundly impact quality of life, their identification and enhanced education and therapy are vital tools to improve prognosis for these relatively young Veterans.

Identification of fibroblast growth factor receptor 3 (FGFR3) as a protein receptor for botulinum neurotoxin serotype A (BoNT/A).

Botulinum neurotoxin serotype A (BoNT/A) causes transient muscle paralysis by entering motor nerve terminals (MNTs) where it cleaves the SNARE protein Synaptosomal-associated protein 25 (SNAP25206) to yield SNAP25197. Cleavage of SNAP25 results in blockage of synaptic vesicle fusion and inhibition of the release of acetylcholine. The specific uptake of BoNT/A into pre-synaptic nerve terminals is a tightly controlled multistep process, involving a combination of high and low affinity receptors. Interestingly, the C-terminal binding domain region of BoNT/A, HC/A, is homologous to fibroblast growth factors (FGFs), making it a possible ligand for Fibroblast Growth Factor Receptors (FGFRs). Here we present data supporting the identification of Fibroblast Growth Factor Receptor 3 (FGFR3) as a high affinity receptor for BoNT/A in neuronal cells. HC/A binds with high affinity to the two extra-cellular loops of FGFR3 and acts similar to an agonist ligand for FGFR3, resulting in phosphorylation of the receptor. Native ligands for FGFR3; FGF1, FGF2, and FGF9 compete for binding to FGFR3 and block BoNT/A cellular uptake. These findings show that FGFR3 plays a pivotal role in the specific uptake of BoNT/A across the cell membrane being part of a larger receptor complex involving ganglioside- and protein-protein interactions.

Enhancing vigilance in operators with prefrontal cortex transcranial direct current stimulation (tDCS).

Sustained attention, often referred to as vigilance in humans, is the ability to maintain goal-directed behavior for extended periods of time and respond to intermittent targets in the environment. With greater time-on-task the ability to detect targets decreases and reaction time increases-a phenomenon termed the vigilance decrement. The purpose of this study was to examine the role of dorsolateral prefrontal cortex in the vigilance decrement. Subjects (n=19) received prefrontal transcranial direct current stimulation (tDCS) at one of two different time points during a vigilance task (early or late). The impact of tDCS was examined using measures of behavior, hemispheric blood flow velocity, and regional blood oxygenation relative to sham stimulation. In the sham condition greater time-on-task was accompanied by fewer target detections and slower reaction times, indicating a vigilance decrement, and decreased blood flow velocity. tDCS significantly altered baseline task-induced physiologic and behavioral changes, dependent on the time of stimulation administration and electrode configuration (determining polarity of stimulation). Compared to the sham condition, with more time-on-task blood flow velocity decreased less and cerebral oxygenation increased more in the tDCS condition. Behavioral measures showed a significant improvement in target detection performance with tDCS compared to the sham stimulation. Signal detection analysis revealed a significant change in operator discriminability and response bias with increased time-on-task, as well as interactions between time of stimulation administration and electrode configuration. Current density modeling of tDCS showed high densities in the medial prefrontal cortex and anterior cingulate cortex. These findings confirm that cerebral hemodynamic measures provide an index of resource utilization and point to the central role of the frontal cortex in vigilance. Further, they suggest that modulation of the frontal cortices-and connected structures-influences the availability of vigilance resources. These findings indicate that tDCS may be well-suited to mitigate performance degradation in work settings requiring sustained attention or as a possible treatment for neurological or psychiatric disorders involving sustained attention.

Molecular epidemiology of KPC-producing Escherichia coli: occurrence of ST131-fimH30 subclone harboring pKpQIL-like IncFIIk plasmid.

Of 20 Klebsiella pneumoniae carbapenemase (KPC)-producing Escherichia coli isolates identified at hospitals in western Pennsylvania, 60% belonged to the epidemic ST131-fimH30 subclone. IncFIIk was the most common replicon type for the blaKPC-carrying plasmids (n = 8). All IncFIIk plasmids possessed a scaffold similar to that of pKpQIL, and seven of them were borne by ST131-fimH30 isolates. IncN plasmids conferred resistance to trimethoprim-sulfamethoxazole, and IncA/C plasmids conferred resistance to gentamicin. Three blaKPC-carrying plasmids (IncA/C and IncN) possessed blaSHV-7/12 and qnrA1 or qnrS1.

Transforming Nursing Education: Developing Augmented Reality Procedural Training.

The shortage of nursing faculty and the scarcity of clinical placements have compelled researchers to investigate innovative solutions for procedural development to bridge the gap between didactic teaching and clinical experiences. This feasibility study uses augmented reality (AR) with Microsoft HoloLens2 and Dynamics 365 Guides to train graduate nursing students on advanced nursing procedures, focusing on lumbar puncture. A convenience sample of 24 nurse practitioner students participated in the study. The System Usability Scale, Acceptability Scale, and Engagement Scale were used to assess participant's experiences and perceptions. The results are positive for the feasibility and acceptance of AR technology for procedural training. Participants found the HoloLens2 device easy to use and showed confidence in its functionality. The step-by-step instructions provided by Microsoft 365 Guides were understandable, useful, and satisfactory. The students reported high levels of engagement and found the AR experience to be helpful and motivating for learning. Faculty time was significantly reduced using the HoloLens2 for procedural training compared to traditional methods. This study demonstrates the potential for AR as an effective and efficient modality for nursing education. The findings support the integration of AR technology to enhance procedural development, address the challenges of limited clinical sites, and provide students with an immersive and self-paced learning experience. Additional studies will need to explore the impact of AR on clinical competency, patient outcomes, and cost-effectiveness. Overall, the use of AR technology may be useful and effective for nursing pedagogy.

Training to Improve Spatial Hearing and Situation Awareness when Wearing Hearing Protection.

INTRODUCTION: Hearing protection devices (HPDs) are standard personal protective equipment in military settings, but many service members may choose to not use HPDs because they impair spatial hearing and situation awareness. In an effort to reduce barriers to compliance by improving situation awareness while wearing HPDs, this study investigated whether brief training could counteract spatial hearing deficits when wearing HPDs. Participant's ability to correctly apply the HPDs across days was also examined. MATERIALS AND METHODS: Young adults were randomly assigned to one of two groups: training or control (n = 25/group). Participants in each group performed a spatial hearing task while wearing HPDs and in an open ear condition without HPDs. Individual targets were battlefield sounds or white noise presented from a speaker array that surrounded the participant in the horizontal plane. After presentation of each target sound, the participant then controlled a white noise "auditory pointer," which they moved to the perceived location of the target. The two primary measures were the percent of trials with very large errors (> 45°), which were usually due to confusing front and back locations, and absolute localization, which is the difference between the pointer location and the true sound location. Both groups were tested on Days 1 (baseline) and 5 (post-test). On Days 2 to 4, the training group wore HPDs while receiving auditory and visual feedback after each trial. RESULTS: Across all participants on Day 1, wearing HPDs increased the frequency of very large errors by about 3× and impaired localization by about 40%, relative to the open ear condition. When comparing performance at baseline (Day 1) and post-training Day 5, the training group with HPDs had significant reductions in very large errors and improved absolute localization (P values < .001). The training group also had significant improvements from Days 1 to 5 in the open ear condition. When the control group wore HPDs, there were also significant improvements from Days 1 to 5 (fewer very large errors and better localization), with smaller effect sizes vs. the training group. Controls did not have significant improvement in the open ear condition, but had similar trends. Most participants consistently applied the HPDs, but a subset of ∼20% frequently failed to achieve the criterion attenuation of 15 dB (over 0.25-4.0 kHz) in both ears. CONCLUSIONS: These findings show that simple, relatively brief practice and training can substantially reduce HPD impairments on spatial hearing and situation awareness. The gains from training and practice can inform the development of relatively simple, brief methods to reduce HPD spatial hearing impairments, potentially leading to increased HPD compliance. Longitudinal data show that a subset of participants would not have received the full benefit of hearing protection because of improper application of the HPDs.

Possible autonomic or cranial nerve symptoms triggered during sustained neck rotation in persistent headache post-concussion: a retrospective observational cross-sectional study.

OBJECTIVES: To examine and categorize symptoms occurring within 60 s of vertebrobasilar-insufficiency (VBI) testing (left- and right-neck rotation) in individuals with persistent post-traumatic headache. BACKGROUND: As part of routine clinical cervical screening in our patients, we found extended VBI testing often triggered additional symptoms. Therefore, we aimed to document the prevalence and precise symptoms occurring during each movement direction of this test and determine any demographic or baseline signs or symptoms associated with a positive test. METHODS: A retrospective medical record review on military personnel receiving treatment for persistent post-traumatic headache was performed. Participants were grouped according to presence of non-headache related symptoms triggered during the tests. Frequency, onset, and symptom characteristics reported were categorized as potentially vascular and/or possible autonomic or cranial nerve in nature. RESULTS: At least one symptom was reported by 81.3% of 123 patients. Of these, 54% reported symptoms in one and 46% in both directions of rotation, yielding 146 abnormal tests. Most reported symptoms were tear disruption (41%), altered ocular-motor-control (25%), and blepharospasm (16%). Enlisted individuals and those with altered baseline facial sensation were more likely to have a positive test. CONCLUSIONS: The majority reported symptoms not typical of VBI within 60 seconds of sustained neck rotation. Further study is needed to better understand the mechanisms and clinical relevance.

Grooved Pegboard adds incremental value over memory-apparent performance validity tests in predicting psychiatric symptom report.

The present study evaluated whether Grooved Pegboard (GPB), when used as a performance validity test (PVT), can incrementally predict psychiatric symptom report elevations beyond memory-apparent PVTs. Participants (N = 111) were military personnel and were predominantly White (84%), male (76%), with a mean age of 43 (SD = 12) and having on average 16 years of education (SD = 2). Individuals with disorders potentially compromising motor dexterity were excluded. Participants were administered GPB, three memory-apparent PVTs (Medical Symptom Validity Test, Non-Verbal Medical Symptom Validity Test, Reliable Digit Span), and a symptom validity test (Personality Assessment Inventory Negative Impression Management [NIM]). Results from the three memory-apparent PVTs were entered into a model for predicting NIM, where failure of two or more PVTs was categorized as evidence of non-credible responding. Hierarchical regression revealed that non-dominant hand GPB T-score incrementally predicted NIM beyond memory-apparent PVTs (F(2,108) = 16.30, p < .001; R2 change = .05, ß = -0.24, p < .01). In a second hierarchical regression, GPB performance was dichotomized into pass or fail, using T-score cutoffs (≤29 for either hand, ≤31 for both). Non-dominant hand GPB again predicted NIM beyond memory-apparent PVTs (F(2,108) = 18.75, p <.001; R2 change = .08, ß = -0.28, p < .001). Results indicated that noncredible/failing GPB performance adds incremental value over memory-apparent PVTs in predicting psychiatric symptom report.

Modulating the brain at work using noninvasive transcranial stimulation.

This paper proposes a shift in the way researchers currently view and use transcranial brain stimulation technologies. From a neuroscience perspective, the standard application of both transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS) has been mainly to explore the function of various brain regions. These tools allow for noninvasive and painless modulation of cortical tissue. In the course of studying the function of an area, many studies often report enhanced performance of a task during or following the stimulation. However, little follow-up research is typically done to further explore these effects. Approaching this growing pool of cognitive neuroscience literature with a neuroergonomics mindset (i.e., studying the brain at work), the possibilities of using these stimulation techniques for more than simply investigating the function of cortical areas become evident. In this paper, we discuss how cognitive neuroscience brain stimulation studies may complement neuroergonomics research on human performance optimization. And, through this discussion, we hope to shift the mindset of viewing transcranial stimulation techniques as solely investigatory basic science tools or possible clinical therapeutic devices to viewing transcranial stimulation techniques as interventional tools to be incorporated in applied science research and systems for the augmentation and enhancement of human operator performance.

Extended Reality International Grand Rounds: An Innovative Approach to Medical Education in the Pandemic Era.

PROBLEM: While bedside training has always presented its own unique challenges, the COVID-19 pandemic era has intensified barriers to suitable provider and trainee experiences for both patient care and medical education. APPROACH: This project introduced an innovative solution with the Extended Reality International Grand Rounds, a collaboration between the University of Michigan Center for Medical and Surgical Extended Reality and Imperial College London. Three complex cases were presented to trainees through a wireless, extended reality (XR) headset and augmented by holographic visual aids and expert commentary. This pilot rounding experience was performed through the first-person view of one clinician at the bedside. OUTCOMES: In 2020, 140 attendees participated in XR International Grand Rounds, and 82 (59%) and 61 (44%) completed pre- and postsurveys, respectively. Survey analysis showed that the majority of respondents (65, 79.3%) had very little to no baseline experience with XR technologies and nearly all (75, 91.5%) agreed that the development and implementation of XR curricula are important in medical training, indicating an unmet need. Nearly all respondents (59, 96.7%) found value in the ability to visualize patients' clinical findings in the XR rounding experience and 60 (98.4%) found value in the ability to visualize patient-specific imaging and test findings in an XR format. Limiting exposure to high-risk patients and care team members with this innovative format was believed to be important to 79 (96.3%) respondents at baseline and that perception was unchanged following the event. NEXT STEPS: This solution to a long-standing dilemma, newly stressed by a unique era in medicine, was a successful collaboration using state-of-the-art XR technology. Next steps will include introducing more advanced physical exam visualization and detection and comprehensive evaluation of the patient experience, as well as expanding the international experience in a format that is scalable to other interested institutions.

International Mixed Reality Immersive Experience: Approach via Surgical Grand Rounds.

BACKGROUND: Coronavirus disease 2019 created unintended but significant experiential barriers for surgical learners to interact at the bedside for teaching/case presentations. We hypothesized that an international grand rounds using the Microsoft HoloLens 2 extended reality (XR) headset would create an improved bedside-learning experience compared to traditional grand rounds formats. STUDY DESIGN: From December 2020 to March 2021, the world's first 2 international mixed reality grand rounds events using the HoloLens 2 headset were held, broadcasting transatlantically (between the University of Michigan and the Imperial College of London) bedside rounding experiences on 5 complex surgical patients to an international audience of 325 faculty, residents, and medical trainees. Participants completed pre- and post-event surveys to assess their experience. RESULTS: Of the 325 participants, 267 (80%) completed pre-surveys, and 95 (29%) completed both the pre- and post-surveys. Respondents (average age, 38 y; 44% women, 56% men; 211 US, 56 UK) included 92 (34%) medical students and residents and 175 faculty and staff. In the pre-event survey, 76% had little or no earlier experience with XR devices, and 94% thought implementation of XR into medical curricula was valuable. In the post-survey, 96% thought telerounding using XR technology was important for the current era, and 99% thought the ability to visualize the examination, imaging, and laboratory results at bedside via XR rounding was highly valuable and that this format was superior to traditional grand rounds. CONCLUSIONS: Almost all of the participants in the mixed reality international grand rounds felt the immersive XR experiences-allowing visualization of clinical findings, imaging, and laboratory results at the patient's bedside-were superior to a traditional grand rounds format, and that it could be a valuable tool for surgical teaching and telerounding.

Auditory spatial attention gradients and cognitive control as a function of vigilance.

Selection and effort are central to attention, yet it is unclear whether they draw on a common pool of cognitive resources, and if so, whether there are differences for early versus later stages of cognitive processing. This study assessed effort by quantifying the vigilance decrement, and spatial processing at early and later stages as a function of time-on-task. Participants performed an auditory spatial attention task, with occasional "catch" trials requiring no response. Psychophysiological measures included bilateral cerebral blood flow (transcranial Doppler), pupil dilation, and blink rate. The shape of attention gradients using reaction time indexed early processing, and did not significantly vary over time. Later stimulus-response conflict was comparable over time, except for a reduction to left hemispace stimuli. Target and catch trial accuracy decreased with time, with a more abrupt decrease for catch versus target trials. Diffusion decision modeling found progressive decreases in information accumulation rate and non-decision time, and the adoption of more liberal response criteria. Cerebral blood flow increased from baseline and then decreased over time, particularly in the left hemisphere. Blink rate steadily increased over time, while pupil dilation increased only at the beginning and then returned towards baseline. The findings suggest dissociations between resources for selectivity and effort. Measures of high subjective effort and temporal declines in catch trial accuracy and cerebral blood flow velocity suggest a standard vigilance decrement was evident in parallel with preserved selection. Different attentional systems and classes of computations that may account for dissociations between selectivity versus effort are discussed.

Statistical multiscale mapping of IDH1, MGMT, and microvascular proliferation in human brain tumors from multiparametric MR and spatially-registered core biopsy.

We propose a statistical multiscale mapping approach to identify microscopic and molecular heterogeneity across a tumor microenvironment using multiparametric MR (mp-MR). Twenty-nine patients underwent pre-surgical mp-MR followed by MR-guided stereotactic core biopsy. The locations of the biopsy cores were identified in the pre-surgical images using stereotactic bitmaps acquired during surgery. Feature matrices mapped the multiparametric voxel values in the vicinity of the biopsy cores to the pathologic outcome variables for each patient and logistic regression tested the individual and collective predictive power of the MR contrasts. A non-parametric weighted k-nearest neighbor classifier evaluated the feature matrices in a leave-one-out cross validation design across patients. Resulting class membership probabilities were converted to chi-square statistics to develop full-brain parametric maps, implementing Gaussian random field theory to estimate inter-voxel dependencies. Corrections for family-wise error rates were performed using Benjamini-Hochberg and random field theory, and the resulting accuracies were compared. The combination of all five image contrasts correlated with outcome (P < 10-4) for all four microscopic variables. The probabilistic mapping method using Benjamini-Hochberg generated statistically significant results (α ≤ 0.05) for three of the four dependent variables: (1) IDH1, (2) MGMT, and (3) microvascular proliferation, with an average classification accuracy of 0.984 ± 0.02 and an average classification sensitivity of 1.567% ± 0.967. The images corrected by random field theory demonstrated improved classification accuracy (0.989 ± 0.008) and classification sensitivity (5.967% ± 2.857) compared with Benjamini-Hochberg. Microscopic and molecular tumor properties can be assessed with statistical confidence across the brain from minimally-invasive, mp-MR.

Volitional down-regulation of the primary auditory cortex via directed attention mediated by real-time fMRI neurofeedback.

The present work assessed the efficacy of training volitional down-regulation of the primary auditory cortex (A1) based on real-time functional magnetic resonance imaging neurofeedback (fMRI-NFT). A1 has been shown to be hyperactive in chronic tinnitus patients, and has been implicated as a potential source for the tinnitus percept. 27 healthy volunteers with normal hearing underwent 5 fMRI-NFT sessions: 18 received real neurofeedback and 9 sham neurofeedback. Each session was composed of a simple auditory fMRI followed by 2 runs of A1 fMRI-NFT. The auditory fMRI alternated periods of no auditory with periods of white noise stimulation at 90 dB. A1 activity, defined from a region using the activity during the preceding auditory run, was continuously updated during fMRI-NFT using a simple bar plot, and was accompanied by white noise (90 dB) stimulation for the duration of the scan. Each fMRI-NFT run alternated "relax" periods with "lower" periods. Subjects were instructed to watch the bar during the relax condition and actively reduce the bar by decreasing A1 activation during the lower condition. Average A1 de-activation, representative of the ability to volitionally down-regulate A1, was extracted from each fMRI-NFT run. A1 de-activation was found to increase significantly across training and to be higher in those receiving real neurofeedback. A1 de-activation in sessions 2 and 5 were found to be significantly greater than session 1 in only the group receiving real neurofeedback. The most successful subjects reportedly adopted mindfulness tasks associated with directed attention. For the first time, fMRI-NFT has been applied to teach volitional control of A1 de-activation magnitude over more than 1 session. These are important findings for therapeutic development as the magnitude of A1 activity is altered in tinnitus populations and it is unlikely a single fMRI-NFT session will reverse the effects of tinnitus.

Single Session Low Frequency Left Dorsolateral Prefrontal Transcranial Magnetic Stimulation Changes Neurometabolite Relationships in Healthy Humans.

Background: Dorsolateral prefrontal cortex (DLPFC) low frequency repetitive transcranial magnetic stimulation (LF-rTMS) has shown promise as a treatment and investigative tool in the medical and research communities. Researchers have made significant progress elucidating DLPFC LF-rTMS effects-primarily in individuals with psychiatric disorders. However, more efforts investigating underlying molecular changes and establishing links to functional and behavioral outcomes in healthy humans are needed. Objective: We aimed to quantify neuromolecular changes and relate these to functional changes following a single session of DLPFC LF-rTMS in healthy participants. Methods: Eleven participants received sham-controlled neuronavigated 1 Hz rTMS to the region most activated by a 7-letter Sternberg working memory task (SWMT) within the left DLPFC. We quantified SWMT performance, functional magnetic resonance activation and proton Magnetic resonance spectroscopy (MRS) neurometabolite measure changes before and after stimulation. Results: A single LF-rTMS session was not sufficient to change DLPFC neurometabolite levels and these changes did not correlate with DLPFC activation changes. Real rTMS, however, significantly altered neurometabolite correlations (compared to sham rTMS), both with baseline levels and between the metabolites themselves. Additionally, real rTMS was associated with diminished reaction time (RT) performance improvements and increased activation within the motor, somatosensory and lateral occipital cortices. Conclusion: These results show that a single session of LF-rTMS is sufficient to influence metabolite relationships and causes widespread activation in healthy humans. Investigating correlational relationships may provide insight into mechanisms underlying LF-rTMS.

Hidden Hearing Injury: The Emerging Science and Military Relevance of Cochlear Synaptopathy.

INTRODUCTION: The phenomenon recently described as "hidden hearing loss" was the subject of a meeting co-hosted by the Department of Defense Hearing Center of Excellence and MIT Lincoln Laboratory to consider the potential relevance of noise-related synaptopathic injury to military settings and performance, service-related injury scenarios, and military medical priorities. Participants included approximately 50 researchers and subject matter experts from academic, federal, and military laboratories. Here we present a synthesis of discussion topics and concerns, as well as specific research objectives identified to develop militarily relevant knowledge. MATERIALS AND METHODS: We consider findings from studies to date that have demonstrated cochlear synaptopathy and neurodegenerative processes apparently linked to noise exposure in animal models. We explore the potential relevance of these findings to the prediction and prevention of military hearing injuries, and to comorbid injuries in the neurological domain. RESULTS: Noise-induced cochlear synaptopathic injury is not detected by conventional audiometric assessment of threshold sensitivity. Animal studies suggest there may be a generous window of opportunity for intervention to mitigate or prevent cochlear neurodegenerative processes, e.g., by administration of neurotrophins or antioxidants. However, it is not yet known if the mechanisms that underlie "hidden hearing loss" also occur in human beings or, if so, how to identify them early, and how and when to intervene. CONCLUSION: Neurological injuries resulting from noise exposures via the auditory system have potentially significant implications for military Service Member performance, long-term Veteran health, and noise exposure standards. Mediated via auditory pathways, such injuries have possible relationship to clinical impairments including speech perception, and may be a largely overlooked contributor to cognitive symptoms associated with other military service-related injuries such as blast exposure and brain trauma. The potential health and performance consequences of noise-induced cochlear synaptopathic injury are easily overlooked, especially if it is assumed that hearing threshold sensitivity loss is the major concern. There should be a renewed impetus to further characterize and model synaptopathic mechanisms of auditory injury; study its potential impact on human auditory function, cognition, and performance metrics of military relevance; and develop solutions for auditory protection (including noise dosimetry) and treatment if appropriate following noise or blast exposure in military scenarios. We identify specific problems, solution objectives, and research objectives. Recommended research calls for a multidisciplinary approach to address cochlear nerve synaptopathy, central (brain) dysfunction, noise exposure measurement and metrics, and clinical assessment.