Cortical Zinc Signaling Is Necessary for Changes in Mouse Pupil Diameter That Are Evoked by Background Sounds with Different Contrasts.

Luminance-independent changes in pupil diameter (PD) during wakefulness influence and are influenced by neuromodulatory, neuronal, and behavioral responses. However, it is unclear whether changes in neuromodulatory activity in a specific brain area are necessary for the associated changes in PD or whether some different mechanisms cause parallel fluctuations in both PD and neuromodulation. To answer this question, we simultaneously recorded PD and cortical neuronal activity in male and female mice. Namely, we measured PD and neuronal activity during adaptation to sound contrast, which is a well-described adaptation conserved in many species and brain areas. In the primary auditory cortex (A1), increases in the variability of sound level (contrast) induce a decrease in the slope of the neuronal input-output relationship, neuronal gain, which depends on cortical neuromodulatory zinc signaling. We found a previously unknown modulation of PD by changes in background sensory context: high stimulus contrast sounds evoke larger increases in evoked PD compared with low-contrast sounds. To explore whether these changes in evoked PD are controlled by cortical neuromodulatory zinc signaling, we imaged single-cell neural activity in A1, manipulated zinc signaling in the cortex, and assessed PD in the same awake mouse. We found that cortical synaptic zinc signaling is necessary for increases in PD during high-contrast background sounds compared with low-contrast sounds. This finding advances our knowledge about how cortical neuromodulatory activity affects PD changes and thus advances our understanding of the brain states, circuits, and neuromodulatory mechanisms that can be inferred from pupil size fluctuations.

Enhancing utility of interfacility triage guidelines using machine learning: Development of the Geriatric Interfacility Trauma Triage score.

BACKGROUND: Undertriage of injured older adults to tertiary trauma centers (TTCs) has been demonstrated by many studies. In predominantly rural regions, a majority of trauma patients are initially transported to nontertiary trauma centers (NTCs). Current interfacility triage guidelines do not highlight the hierarchical importance of risk factors nor do they allow for individual risk prediction. We sought to develop a transfer risk score that may simplify secondary triage of injured older adults to TTCs. METHODS: This was a retrospective prognostic study of injured adults 55 years or older initially transported to an NTC from the scene of injury. The study used data reported to the Oklahoma State Trauma Registry between 2009 and 2019. The outcome of interest was either mortality or serious injury (Injury Severity Score, ≥16) requiring an interventional procedure at the receiving facility. In developing the model, machine-learning techniques including random forests were used to reduce the number of candidate variables recorded at the initial facility. RESULTS: Of the 5,913 injured older adults initially transported to an NTC before subsequent transfer to a TTC, 32.7% (1,696) had the outcome of interest at the TTC. The final prognostic model (area under the curve, 75.4%; 95% confidence interval, 74-76%) included the following top four predictors and weighted scores: airway intervention (10), traffic-related femur fracture (6), spinal cord injury (5), emergency department Glasgow Coma Scale score of ≤13 (5), and hemodynamic support (4). Bias-corrected and sample validation areas under the curve were 74% and 72%, respectively. A risk score of 7 yields a sensitivity of 78% and specificity of 56%. CONCLUSION: Secondary triage of injured older adults to TTCs could be enhanced by use of a risk score. Our study is the first to develop a risk stratification tool for injured older adults requiring transfer to a higher level of care. LEVEL OF EVIDENCE: Prognostic and Epidemiolgical; Level III.

Neuromodulatory Mechanisms Underlying Contrast Gain Control in Mouse Auditory Cortex.

Neural adaptation enables the brain to efficiently process sensory signals despite large changes in background noise. Previous studies have established that recent background spectro- or spatio-temporal statistics scale neural responses to sensory stimuli via a canonical normalization computation, which is conserved among species and sensory domains. In the auditory pathway, one major form of normalization, termed contrast gain control, presents as decreasing instantaneous firing-rate gain, the slope of the neural input-output relationship, with increasing variability of background sound levels (contrast) across time and frequency. Despite this gain rescaling, mean firing-rates in auditory cortex become invariant to sound level contrast, termed contrast invariance. The underlying neuromodulatory mechanisms of these two phenomena remain unknown. To study these mechanisms in male and female mice, we used a 2-photon calcium imaging preparation in layer 2/3 neurons of primary auditory cortex (A1), along with pharmacological and genetic KO approaches. We found that neuromodulatory cortical synaptic zinc signaling is necessary for contrast gain control but not contrast invariance in mouse A1.SIGNIFICANCE STATEMENT When sound levels in the acoustic environment become more variable across time and frequency, the brain decreases response gain to maintain dynamic range and thus stimulus discriminability. This gain adaptation accounts for changes in perceptual judgments in humans and mice; however, the underlying neuromodulatory mechanisms remain poorly understood. Here, we report context-dependent neuromodulatory effects of synaptic zinc that are necessary for contrast gain control in A1. Understanding context-specific neuromodulatory mechanisms, such as contrast gain control, provides insight into A1 cortical mechanisms of adaptation and also into fundamental aspects of perceptual changes that rely on gain modulation, such as attention.

Can a targeted educational approach improve situational awareness in paramedicine during 911 emergency calls?

BACKGROUND: Paramedics must be situationally aware in order to avoid human error and protect themselves, their partner, their patient, and the public. Previous research has suggested that paramedics lack situational awareness (SA), possibly due to a lack of an organized approach, distraction, and a poor understanding of SA. There is no educational approach provided to paramedics that is known to improve their levels of SA. If such an approach were provided, it could possibly reduce human error and lead to improved outcomes. OBJECTIVE: The aim of this study is to determine whether providing paramedics with a targeted educational approach, including aspects from crew resource management (CRM) such as sterile cockpit and Endsley's model for SA, can improve overall SA during emergency calls. METHODS: A prospective, quasi-experimental before-and-after study was used, in which out-of hospital paramedics were observed during 911 emergency calls. Baseline SA was measured using the situational awareness global assessment technique (SAGAT). Paramedics were then given a targeted educational lesson focusing on elements of SA and CRM as well as a novel quick reference tool to utilize during 911 calls. Post intervention SA was then measured again, and before-and-after results were compared for difference of mean scores. RESULTS: The overall baseline SA was 62% increasing to 86% following the educational intervention. The Wilcoxon Ranked Sum was used to assess for statistically significant differences between mean SA performance in the same group of paramedics before and after the intervention. The increase in SA was found to be statistically significant where p = 0.011. CONCLUSIONS: A targeted educational approach focusing on CRM and a novel quick reference tool may increase SA levels of paramedics during 911 emergency calls. Further studies are needed with bigger cohorts. Paramedicine educational institutions and out-of-hospital agencies should consider implementing this targeted approach with their students and currently practicing providers.

Survival Benefit of Treatment at or Transfer to a Tertiary Trauma Center among Injured Older Adults.

Objective: It is well established that seriously injured older adults are under-triaged to tertiary trauma centers. However, the survival benefit of tertiary trauma centers (TC) compared to a non-tertiary trauma centers (Non-TCs) remains unclear for this patient population. Using improved methodology and a larger sample, we hypothesized that there was a difference in hospital mortality between injured older adults treated at TCs and those treated at Non-TCs. Methods: This was a retrospective cohort study of injured older adults (> =55 years) reported to the Oklahoma statewide trauma registry between 2005 and 2014. The outcome of interest was 30-day in-hospital mortality and the exposure variable of interest was level of definitive trauma care (TC vs Non-TC). Overall survival benefit of treatment at a TC as well as the survival benefit of transferring injured older adults to a TC were evaluated using multivariable survival analyses as well as propensity score-adjusted analyses. Results: Of the 25,288 patients eligible for analysis, 43% (10,927) were treated at TCs. Multivariable Cox regression analyses revealed effect modification by age group and time. After adjusting for potential confounders within the age strata, overall, patients treated at TCs were significantly less likely to die within 7 days of admission and this effect was stronger for patients aged 55-64 years (HR 0.41, 95% CI 0.31-0.52) compared to those > =65 years (HR 0.62, 95% CI 0.55-0.70). Overall survival benefit of TCs beyond 7 days was also observed (HR 0.68, 95% CI 0.56-0.83). Similarly, for the survival benefit of transferring injured older adults, after adjusting for the propensity to be transferred and other confounders, transfer to a TC was associated with lower 30-day mortality both for patients less than 65 years old (HR 0.36, 95% CI: 0.27-0.49) and those 65 years and older (HR 0.55, 95% CI: 0.48-0.64). Conclusions: Our results suggest a survival benefit for injured older adults treated at TCs. This benefit was also observed for patients transferred from non-tertiary trauma centers. Further research should focus on identifying specific subgroups of patients who would especially benefit from this level of care to minimize trauma triage inefficiencies.

Unique electrophysiological and impedance signatures between encapsulation types: An analysis of biological Utah array failure and benefit of a biomimetic coating in a rat model.

Intracortical microelectrode arrays, especially the Utah array, remain the most common choice for obtaining high dimensional recordings of spiking neural activity for brain computer interface and basic neuroscience research. Despite the widespread use and established design, mechanical, material and biological challenges persist that contribute to a steady decline in recording performance (as evidenced by both diminished signal amplitude and recorded cell population over time) or outright array failure. Device implantation injury causes acute cell death and activation of inflammatory microglia and astrocytes that leads to a chronic neurodegeneration and inflammatory glial aggregation around the electrode shanks and often times fibrous tissue growth above the pia along the bed of the array within the meninges. This multifaceted deleterious cascade can result in substantial variability in performance even under the same experimental conditions. We track both impedance signatures and electrophysiological performance of 4 × 4 floating microelectrode Utah arrays implanted in the primary monocular visual cortex (V1m) of Long-Evans rats over a 12-week period. We employ a repeatable visual stimulation method to compare signal-to-noise ratio as well as single- and multi-unit yield from weekly recordings. To explain signal variability with biological response, we compare arrays categorized as either Type 1, partial fibrous encapsulation, or Type 2, complete fibrous encapsulation and demonstrate performance and impedance signatures unique to encapsulation type. We additionally assess benefits of a biomolecule coating intended to minimize distance to recordable units and observe a temporary improvement on multi-unit recording yield and single-unit amplitude.

Cortical hierarchy governs rat claustrocortical circuit organization.

The claustrum is a telencephalic gray matter structure with various proposed functions, including sensory integration and attentional allocation. Underlying these concepts is the reciprocal connectivity of the claustrum with most, if not all, areas of the cortex. What remains to be elucidated to inform functional hypotheses further is whether a pattern exists in the strength of connectivity between a given cortical area and the claustrum. To this end, we performed a series of retrograde neuronal tract tracer injections into rat cortical areas along the cortical processing hierarchy, from primary sensory and motor to frontal cortices. We observed that the number of claustrocortical projections increased as a function of processing hierarchy; claustrum neurons projecting to primary sensory cortices were scant and restricted in distribution across the claustrum, whereas neurons projecting to the cingulate cortex were densely packed and more evenly distributed throughout the claustrum. This connectivity pattern suggests that the claustrum may preferentially subserve executive functions orchestrated by the cingulate cortex. J. Comp. Neurol. 525:1347-1362, 2017. © 2016 Wiley Periodicals, Inc.

Enhanced dopamine detection sensitivity by PEDOT/graphene oxide coating on in vivo carbon fiber electrodes.

Dopamine (DA) is a monoamine neurotransmitter responsible for regulating a variety of vital life functions. In vivo detection of DA poses a challenge due to the low concentration and high speed of physiological signaling. Fast scan cyclic voltammetry at carbon fiber microelectrodes (CFEs) is an effective method to monitor real-time in vivo DA signaling, however the sensitivity is somewhat limited. Electrodeposition of poly(3,4-ethylene dioxythiophene) (PEDOT)/graphene oxide (GO) onto the CFE surface is shown to increase the sensitivity and lower the limit of detection for DA compared to bare CFEs. Thicker PEDOT/GO coatings demonstrate higher sensitivities for DA, but display the negative drawback of slow adsorption and electron transfer kinetics. The moderate thickness resulting from 25 s electrodeposition of PEDOT/GO produces the optimal electrode, exhibiting an 880% increase in sensitivity, a 50% decrease in limit of detection and minimally altered electrode kinetics. PEDOT/GO coated electrodes rapidly and robustly detect DA, both in solution and in the rat dorsal striatum. This increase in DA sensitivity is likely due to increasing the electrode surface area with a PEDOT/GO coating and improved adsorption of DA's oxidation product (DA-o-quinone). Increasing DA sensitivity without compromising electrode kinetics is expected to significantly improve our understanding of the DA function in vivo.

Brain BLAQ: Post-hoc thick-section histochemistry for localizing optogenetic constructs in neurons and their distal terminals.

Optogenetic constructs have revolutionized modern neuroscience, but the ability to accurately and efficiently assess their expression in the brain and associate it with prior functional measures remains a challenge. High-resolution imaging of thick, fixed brain sections would make such post-hoc assessment and association possible; however, thick sections often display autofluorescence that limits their compatibility with fluorescence microscopy. We describe and evaluate a method we call "Brain BLAQ" (Block Lipids and Aldehyde Quench) to rapidly reduce autofluorescence in thick brain sections, enabling efficient axon-level imaging of neurons and their processes in conventional tissue preparations using standard epifluorescence microscopy. Following viral-mediated transduction of optogenetic constructs and fluorescent proteins in mouse cortical pyramidal and dopaminergic neurons, we used BLAQ to assess innervation patterns in the striatum, a region in which autofluorescence often obscures the imaging of fine neural processes. After BLAQ treatment of 250-350 µm-thick brain sections, axons and puncta of labeled afferents were visible throughout the striatum using a standard epifluorescence stereomicroscope. BLAQ histochemistry confirmed that motor cortex (M1) projections preferentially innervated the matrix component of lateral striatum, whereas medial prefrontal cortex projections terminated largely in dorsal striosomes and distinct nucleus accumbens subregions. Ventral tegmental area dopaminergic projections terminated in a similarly heterogeneous pattern within nucleus accumbens and ventral striatum. Using a minimal number of easily manipulated and visualized sections, and microscopes available in most neuroscience laboratories, BLAQ enables simple, high-resolution assessment of virally transduced optogenetic construct expression, and post-hoc association of this expression with molecular markers, physiology and behavior.

Chronic methylphenidate exposure during adolescence reduces striatal synaptic responses to ethanol.

Dopamine (DA) plays an important role in integrative functions contributing to adaptive behaviors. In support of this essential function, DA modulates synaptic plasticity in different brain areas, including the striatum. Many drugs used for cognitive enhancement are psychostimulants, such as methylphenidate (MPH), which enhance DA levels. MPH treatment is of interest during adolescence, a period of enhanced neurodevelopment during which the DA system is in a state of flux. Recent epidemiological studies report the co-abuse of MPH and ethanol in adolescents and young adults. Although repeated MPH treatment produces enduring changes that affect subsequent behavioral responses to other psychostimulants, few studies have investigated the interactions between MPH and ethanol. Here we addressed whether chronic therapeutic exposure to MPH during adolescence predisposed mice to an altered response to ethanol and whether this was accompanied by altered DA release and striatal plasticity. C57BL/6J mice were administered MPH (3-6 mg/kg/day) via the drinking water between post-natal days 30 and 60. Voltammetry experiments showed that sufficient brain MPH concentrations were achieved during adolescence in mice to increase the DA clearance in adulthood. The treatment also increased long-term depression and reduced the effects of ethanol on striatal synaptic responses. Although the injection of 0.4 or 2 g/kg ethanol dose-dependently decreased locomotion in control mice, only the higher dose decreased locomotion in MPH-treated mice. These results suggested that the administration of MPH during development promoted long-term effects on synaptic plasticity in forebrain regions targeted by DA. These changes in plasticity might, in turn, underlie alterations in behaviors controlled by these brain regions into adulthood.

Comparison of two protocols for pulseless cardiopulmonary arrest: vasopressin combined with epinephrine versus epinephrine alone.

INTRODUCTION: Survival from pulseless cardiac arrest typically is dismal. Some suggest that adding vasopressin to epinephrine as a cardiovascular stimulant can improve outcomes. PROBLEM: This study compares survival outcomes using epinephrine verses vasopressin and epinephrine in persons with pulseless cardiac arrest. METHODS: This is a retrospective, cohort evaluation of two resuscitative protocols (P1-epinephrine or P2-vasopressin with epinephrine) in a tiered response, community emergency medical service (EMS) with an approximately 100,000 catchment area. Cases are defined as 18 years or older determined to be in pulseless cardiac arrest. Outcomes were survival to emergency department arrival, to 24 hours, and to hospital discharge. Data were entered into Microsoft Office Excel® and processed using Analyze-it® for continuous and categorical data and Epi-Info® for odds ratios with confidence intervals. RESULTS: There were 204 cases (60.3% males and 39.7% females) who met the inclusion criteria. Thirteen cases received electrical therapy only, and were dropped from analysis, leaving 191 (93.6%) who were included in the study; P1 to 85 (44.5%) and P2 to 106 (55.5%). Younger age was associated with improved survival to discharge home in both protocols, p = 0.003 (95% CI = 0.004-0.010). No difference in survival was noted at the levels of emergency department arrival OR 1.42 (95% CI = 0.73, 2.76) p = 0.26; 24 hour survival OR 0.54 (95% CI = 0.22-1.30) p = 0.133, or discharge home OR = 1.81 (95% CI = 0.49-6.88) p = 0.319. CONCLUSIONS: This study in a community EMS did not demonstrate improved survival with the addition of vasopressin to epinephrine for pulseless cardiac arrest.

Multiple information sources in the analysis of a disaster.

OBJECTIVE: Disasters are complex events making epidemiologic studies and determination of accurate denominators difficult due to the poor nature of available records. However, these data are essential to perform useful calculations and accurate descriptions of disaster medical impacts. This study was undertaken to identify the availability and utility of various information sources in the analysis of a mass casualty disaster. In addition, characteristics of cases presenting for care are described. DESIGN: This is a retrospective cohort study abstracting medical records and other documents relating to an explosion and fire. Public domain documents are obtained by written request or by filing a Freedom of Information Act (FOIA) request. SETTING: A rural EMS and tertiary hospital. CASES: Individuals directly exposed to the forces of the explosion. OUTCOME MEASURES: The number of cases detected by various information sources. In addition, the demographics, dispositions, and nature of the physical injuries of the cases are reported. RESULTS: Seven sources of case information were identified. The most cases were identified by investigative agencies (33) and the fewest by medical records (18). Rates include; injury 0.68, admission 0.20, and operative 0.14, with no deaths. Case locations during the explosion were determined for all cases. No association was noted between admission and location in the building. CONCLUSIONS: This study demonstrates the availability and usefulness of data in the public domain. Using FOIA requests or partnerships with public or private agencies may more clearly define denominator data in epidemiologic evaluations of disasters.