Comparing the Mutual Interchangeability of ECOM, FloTrac/Vigileo, 3D-TEE, and ITD-PAC Cardiac Output Measuring Systems in Coronary Artery Bypass Grafting.

OBJECTIVE: The aim of this study was to compare the mutual interchangeability of 4 cardiac output measuring devices by comparing their accuracy, precision, and trending ability. DESIGN: A single-center prospective observational study. DESIGN: Nonuniversity teaching hospital, single center. PARTICIPANTS: Forty-four consecutive patients scheduled for elective, nonemergent coronary artery bypass grafting (CABG). INTERVENTIONS: The cardiac output was measured for each participant using 4 methods: intermittent thermodilution via pulmonary artery catheter (ITD-PAC), Endotracheal Cardiac Output Monitor (ECOM), FloTrac/Vigileo System (FLOTRAC), and 3-dimensional transesophageal echocardiography (3D-TEE). MEASUREMENTS AND MAIN RESULTS: Measurements were performed simultaneously at 5 time points: presternotomy, poststernotomy, before cardiopulmonary bypass, after cardiopulmonary bypass, and after sternal closure. A series of statistical and comparison analyses including ANOVA, Pearson correlation, Bland-Altman plots, quadrant plots, and polar plots were performed, and inherent precision for each method and percent errors for mutual interchangeability were calculated. For the 6 two-by-two comparisons of the methods, the Pearson correlation coefficients (r), the percentage errors (% error), and concordance ratios (CR) were as follows: ECOM_versus_ITD-PAC (r = 0.611, % error = 53%, CR = 75%); FLOTRAC_versus_ITD-PAC (r = 0.676, % error = 49%, CR = 77%); 3D-TEE versus ITD-PAC (r = 0.538, % error = 64%, CR = 67%); FLOTRAC_versus_ECOM (r = 0.627, % error = 51%, CR = 75%); 3D-TEE_versus ECOM (r = 0.423, % error = 70%, CR = 60%), and 3D-TEE_versus_FLOTRAC (r = 0.602, % error = 59%, CR = 61%). CONCLUSIONS: Based on the recommended statistical measures of interchangeability, ECOM, FLOTRAC, and 3D-TEE are not interchangeable with each other or to the reference standard invasive ITD-PAC method in patients undergoing nonemergent cardiac bypass surgery. Despite the negative result in this study and the majority of previous studies, these less-invasive methods of CO have continued to be used in the hemodynamic management of patients. Each device has its own distinct technical features and inherent limitations; it is clear that no single device can be used universally for all patients. Therefore, different methods or devices should be chosen based on individual patient conditions, including the degree of invasiveness, measurement performance, and the ability to provide real-time, continuous CO readings.

Development of manganese-enhanced magnetic resonance imaging of the rostral ventrolateral medulla of conscious rats: Importance of normalization and comparison with other regions of interest.

Spinally projecting neurons in the rostral ventrolateral medulla (RVLM) are believed to contribute to pathophysiological alterations in sympathetic nerve activity and the development of cardiovascular disease. The ability to identify changes in the activity of RVLM neurons in conscious animals and humans, especially longitudinally, would represent a clinically important advancement in our understanding of the contribution of the RVLM to cardiovascular disease. To this end, we describe the initial development of manganese-enhanced magnetic resonance imaging (MEMRI) for the rat RVLM. Manganese (Mn2+ ) has been used to estimate in vivo neuronal activity in other brain regions because of both its paramagnetic properties and its entry into and accumulation in active neurons. In this initial study, our three goals were as follows: (1) to validate that Mn2+ enhancement occurs in functionally and anatomically localized images of the rat RVLM; (2) to quantify the dose and time course dependence of Mn2+ enhancement in the RVLM after one systemic injection in conscious rats (66 or 33 mg/kg, intraperitoneally); and (3) to compare Mn2+ enhancement in the RVLM with other regions to determine an appropriate method of normalization of T1 -weighted images. In our proof-of-concept and proof-of-principle studies, Mn2+ was identified by MRI in the rat RVLM after direct microinjection or via retrograde transport following spinal cord injections, respectively. Systemic injections in conscious rats produced significant Mn2+ enhancement at 24 h (p < 0.05). Injections of 66 mg/kg produced greater enhancement than 33 mg/kg in the RVLM and paraventricular nucleus of the hypothalamus (p < 0.05 for both), but only when normalized to baseline scans without Mn2+ injection. Consistent with findings from our previous functional and anatomical studies demonstrating subregional neuroplasticity, Mn2+ enhancement was higher in the rostral regions of the RVLM (p < 0.05). Together with important technical considerations, our studies support the development of MEMRI as a potential method to examine RVLM activity over time in conscious animal subjects.

Multimodal Clinical Pathway With Adductor Canal Block Decreases Hospital Length of Stay, Improves Pain Control, and Reduces Opioid Consumption in Total Knee Arthroplasty Patients: A Retrospective Review.

BACKGROUND: Total knee arthroplasty volume is increasing significantly in the United States. Reducing hospital length of stay may represent the best method for accommodating expanding volume and reducing costs. We hypothesized that tailoring a clinical pathway to facilitate early ambulation would decrease costs and resource utilization. METHODS: We conducted a sequential before-and-after study of total knee arthroplasty patients after a phased implementation of a clinical pathway that includes multimodal oral analgesic protocols, adductor canal nerve block, and standardized day of surgery ambulation protocols. Primary outcomes measured were hospital length of stay, total opioid consumption, total antiemetic use, and perioperative pain scores. RESULTS: Two hundred ninety-five patients were divided into 3 sequential cohorts. Cohort 1 received spinal anesthesia, femoral nerve block, and was not placed into postop day 0 ambulation therapy. Cohort 2 received spinal anesthesia, adductor canal block, and postop day 0 ambulation therapy. Cohort 3 received spinal anesthesia, adductor canal block, postop day 0 ambulation therapy, and standardized oral multimodal analgesic protocol. Cohort 3 had significantly reduced hospital length of stay. Cohorts 2 and 3 had significantly less opioid consumption. Cohort 3 had significantly less total ondansetron consumption compared with cohort 1. Cohort 3 had significantly reduced average pain scores compared with cohort 1. CONCLUSION: The data demonstrate that tailored clinical pathways designed to facilitate early ambulation can reduce hospital length of stay, reduce opioid consumption, reduce antiemetic use, and improve pain control. The results establish that refined clinical pathways can assist in improving care while increasing value to patients, providers, and systems.

Altered metabolomic-genomic signature: A potential noninvasive biomarker of epilepsy.

OBJECTIVE: This study aimed to identify noninvasive biomarkers of human epilepsy that can reliably detect and localize epileptic brain regions. Having noninvasive biomarkers would greatly enhance patient diagnosis, patient monitoring, and novel therapy development. At the present time, only surgically invasive, direct brain recordings are capable of detecting these regions with precision, which severely limits the pace and scope of both clinical management and research progress in epilepsy. METHODS: We compared high versus low or nonspiking regions in nine medically intractable epilepsy surgery patients by performing integrated metabolomic-genomic-histological analyses of electrically mapped human cortical regions using high-resolution magic angle spinning proton magnetic resonance spectroscopy, cDNA microarrays, and histological analysis. RESULTS: We found a highly consistent and predictive metabolite logistic regression model with reduced lactate and increased creatine plus phosphocreatine and choline, suggestive of a chronically altered metabolic state in epileptic brain regions. Linking gene expression, cellular, and histological differences to these key metabolites using a hierarchical clustering approach predicted altered metabolic vascular coupling in the affected regions. Consistently, these predictions were validated histologically, showing both neovascularization and newly discovered, millimeter-sized microlesions. SIGNIFICANCE: Using a systems biology approach on electrically mapped human cortex provides new evidence for spatially segregated, metabolic derangements in both neurovascular and synaptic architecture in human epileptic brain regions that could be a noninvasively detectable biomarker of epilepsy. These findings both highlight the immense power of a systems biology approach and identify a potentially important role that magnetic resonance spectroscopy can play in the research and clinical management of epilepsy.

Sign-trackers have elevated myo-inositol in the nucleus accumbens and ventral hippocampus following Pavlovian conditioned approach.

Pavlovian conditioned approach (PCA) is a behavioral procedure that can be used to assess individual differences in the addiction vulnerability of drug-naïve rats and identify addiction vulnerability factors. Using proton magnetic resonance spectroscopy (1 H-MRS) ex vivo, we simultaneously analyzed concentrations of multiple neurochemicals throughout the mesocorticolimbic system 2 weeks after PCA training in order to identify potential vulnerability factors to addiction in drug-naïve rats for future investigations. Levels of myo-inositol (Ins), a 1 H-MRS-detectable marker of glial activity/proliferation, were increased in the nucleus accumbens (NAc) and ventral hippocampus, but not dorsal hippocampus or medial prefrontal cortex, of sign-trackers compared to goal-trackers or intermediate responders. In addition, Ins levels positively correlated with PCA behavior in the NAc and ventral hippocampus. Because the sign-tracker phenotype is associated with increased drug-seeking behavior, these results observed in drug-naïve rats suggest that alterations in glial activity/proliferation within these regions may represent an addiction vulnerability factor. Sign-tracking rats preferentially approach reward cues during Pavlovian conditioning, while goal-trackers instead approach the location of impending reward. Sign-trackers are also more prone to cue-induced drug-seeking behavior. We used magnetic resonance spectroscopy to show that myo-inositol levels are higher in the ventral hippocampus and nucleus accumbens of sign-trackers relative to goal-trackers. Thus, elevated myo-inositol may be a vulnerability factor for addiction.

Cocaine-induced locomotor sensitization in rats correlates with nucleus accumbens activity on manganese-enhanced MRI.

A long-standing goal of substance abuse research has been to link drug-induced behavioral outcomes with the activity of specific brain regions to understand the neurobiology of addiction behaviors and to search for drug-able targets. Here, we tested the hypothesis that cocaine produces locomotor (behavioral) sensitization that correlates with increased calcium channel-mediated neuroactivity in brain regions linked with drug addiction, such as the nucleus accumbens (NAC), anterior striatum (AST) and hippocampus, as measured using manganese-enhanced MRI (MEMRI). Rats were treated with cocaine for 5 days, followed by a 2-day drug-free period. The following day, locomotor sensitization was quantified as a metric of cocaine-induced neuroplasticity in the presence of manganese. Immediately following behavioral testing, rats were examined for changes in calcium channel-mediated neuronal activity in the NAC, AST, hippocampus and temporalis muscle, which was associated with behavioral sensitization using MEMRI. Cocaine significantly increased locomotor activity and produced behavioral sensitization compared with saline treatment of control rats. A significant increase in MEMRI signal intensity was determined in the NAC, but not AST or hippocampus, of cocaine-treated rats compared with saline-treated control rats. Cocaine did not increase signal intensity in the temporalis muscle. Notably, in support of our hypothesis, behavior was significantly and positively correlated with MEMRI signal intensity in the NAC. As neuronal uptake of manganese is regulated by calcium channels, these results indicate that MEMRI is a powerful research tool to study neuronal activity in freely behaving animals and to guide new calcium channel-based therapies for the treatment of cocaine abuse and dependence.

Blast neurotrauma impairs working memory and disrupts prefrontal myo-inositol levels in rats.

Working memory, which is dependent on higher-order executive function in the prefrontal cortex, is often disrupted in patients exposed to blast overpressure. In this study, we evaluated working memory and medial prefrontal neurochemical status in a rat model of blast neurotrauma. Adult male Sprague-Dawley rats were anesthetized with 3% isoflurane and exposed to calibrated blast overpressure (17 psi, 117 kPa) while sham animals received only anesthesia. Early neurochemical effects in the prefrontal cortex included a significant decrease in betaine (trimethylglycine) and an increase in GABA at 24 h, and significant increases in glycerophosphorylcholine, phosphorylethanolamine, as well as glutamate/creatine and lactate/creatine ratios at 48 h. Seven days after blast, only myo-inositol levels were altered showing a 15% increase. Compared to controls, short-term memory in the novel object recognition task was significantly impaired in animals exposed to blast overpressure. Working memory in control animals was negatively correlated with myo-inositol levels (r=-.759, p<0.05), an association that was absent in blast exposed animals. Increased myo-inositol may represent tardive glial scarring in the prefrontal cortex, a notion supported by GFAP changes in this region after blast overexposure as well as clinical reports of increased myo-inositol in disorders of memory.

CONSUMPTION TRENDS OF RESCUE ANTI-PSYCHOTICS FOR DELIRIUM IN INTENSIVE CARE UNITS (ICU DELIRIUM) SHOW INFLUENCE OF CORRESPONDING LUNAR PHASE CYCLES: A RETROSPECTIVE AUDIT STUDY FROM ACADEMIC UNIVERSITY HOSPITAL IN THE UNITED STATES.

BACKGROUND: The etiology of delirium in intensive care units (ICU) is usually multi-factorial. There is common "myth" that lunar phases affect human body especially human brains (and minds). OBJECTIVE: In the absence of any pre-existing studies in ICU patients, the current retrospective study was planned to investigate whether lunar phases play any role in ICU delirium by assessing if lunar phases correlate with prevalence of ICU delirium as judged by the corresponding consumptions of rescue anti-psychotics used for delirium in ICU. MATERIALS AND METHODS: After institutional review board approval with waived consent, the daily census of ICU patients from the administrative records was accessed at an academic university's Non-Cancer Hospital in a Metropolitan City of United States. Thereafter, the ICU pharmacy's electronic database was accessed to obtain data on the use of haloperidol and quetiapine over the two time periods for patients aged 18 years or above. Subsequently the data was analyzed for whether the consumption of haloperidol or quetiapine followed any trends corresponding to the lunar phase cycles. RESULTS: A total of 5382 pharmacy records of haloperidol equivalent administrations were analyzed for this study. The cumulative prevalence of incidents of haloperidol equivalent administrations peaked around the full moon period and troughed around the new moon period. As compared to male patients, female patients followed much more uniform trends of haloperidol equivalent administrations' incidents which peaked around the full moon period and troughed around the new moon period. Further sub-analysis of 70-lunar cycles across the various solar months of the total 68-month study period revealed that haloperidol equivalent administrations' incidents peaked around the full moon periods during the months of November-December and around the new moon periods during the month of July which all are interestingly the major holiday months (a potential confounding factor) in the United States. CONCLUSION: Consumption trends of rescue anti-psychotics for ICU delirium revealed an influence by lunar phase cycles particularly that of full moon periods on female patients in the ICU.

Effects of blast-induced neurotrauma on the nucleus accumbens.

Blast-induced neurotrauma (BINT) leads to deterioration at the cellular level, with adverse cognitive and behavioral outcomes. The nucleus accumbens (NAC) plays an important role in reward, addiction, aggression, and fear pathways. To identify the molecular changes and pathways affected at an acute stage in the NAC, this study focused on a time course analysis to determine the effects of blast on neurochemical and apoptotic pathways. By using a rodent model of BINT, acute damage to the NAC was assessed by proton magnetic resonance spectroscopy (¹H-MRS), high-performance liquid chromatography, immunohistochemistry, and Western blotting. The results demonstrated ongoing neuroprotective effects from elevated levels of Bcl-2, an antiapoptotic marker, at 24 hr and N-acetyl aspartate glutamate at 48 hr following blast exposure. Selective loss of serotonin levels at 24 hr, increased levels of inflammation (elevated glycerophosphocholine at 48 and 72 hr), and increased levels of glial fibrillary acidic protein were also observed at 24 and 48 hr, leading to disruptive energy status. Furthermore, active cell death was indicated by the increased levels of the apoptotic marker Bax, decreased actin levels, and signs excitotoxicity (glutamate/creatine). In addition, increased levels of caspase-3, an apoptotic marker, confirm active cell death in NAC. It is hypothesized that blast overpressure causes inflammation and neurochemical changes that trigger apoptosis in NAC. This cascade of events may lead to stress-related behavioral outcomes and psychiatric sequelae.

Blast-induced neurotrauma leads to neurochemical changes and neuronal degeneration in the rat hippocampus.

Blast-induced neurotrauma is a major concern because of the complex expression of neuropsychiatric disorders after exposure. Disruptions in neuronal function, proximal in time to blast exposure, may eventually contribute to the late emergence of clinical deficits. Using magic angle spinning ¹H MRS and a rodent model of blast-induced neurotrauma, we found acute (24-48 h) decreases in succinate, glutathione, glutamate, phosphorylethanolamine and γ-aminobutyric acid, no change in N-acetylaspartate and increased glycerophosphorylcholine, alterations consistent with mitochondrial distress, altered neurochemical transmission and increased membrane turnover. Increased levels of the apoptotic markers Bax and caspase-3 suggested active cell death, consistent with increased FluoroJade B staining in the hippocampus. Elevated levels of glial fibrillary acidic protein suggested ongoing inflammation without diffuse axonal injury measured by no change in ß-amyloid precursor protein. In conclusion, blast-induced neurotrauma induces a metabolic cascade associated with neuronal loss in the hippocampus in the acute period following exposure.

Superficial Parasternal Intercostal Plane Blocks (SPIB) With Buprenorphine, Magnesium, and Bupivacaine for Management of Pain in Coronary Artery Bypass Grafting.

Introduction Management of post-operative pain after cardiac surgery continues to be a challenge; inadequate management of pain can lead to increased morbidity, impaired physical function with potential delay in recovery, increased perioperative and chronic opioid consumption, increased cost of care, and a decreased quality of life. This study aimed to evaluate the effect of adding buprenorphine and magnesium to bupivacaine for superficial parasternal intercostal plane blocks (SPIB) on pain and opioid consumption in the first 24 hours after coronary artery bypass grafting (CABG). Methods Patients undergoing CABG were divided into the following four groups: saline SPIB, SPIB with bupivacaine (BPVC), SPIB with bupivacaine and buprenorphine (BPVC+BPRN), and SPIB with bupivacaine, buprenorphine, and magnesium (BPVC+BPRN+MG). The primary outcomes were pain scores and opioid consumption after SPIB; the secondary outcomes were post-operative nausea and vomiting, time to extubation, and length of stay (LOS) in the intensive care unit and hospital. Results One hundred thirty-four eligible patients undergoing CABG were randomized to either the saline (n=27), BPVC (n=20), BPVC+BPRN (n=24), or BPVC+BPRN+MG (n=29) group. All of the intervention groups combined (BPVC, BPVC+BPRN, and BPVC+BPRN+MG) had decreased pain scores and decreased opioid consumption when compared to the saline group; although not statistically significant, visual analog scale (VAS) scores trended downward at most time points with BPVC versus saline, BPVC+BPRN versus BPVC, and BPVC+BPRN+MG versus BPVC+BPRN. There was no difference among the study groups in the incidence of post-operative nausea and/or vomiting (PONV), time to extubation, hospital LOS, and ICU LOS. Conclusion In this prospective, double-blind, placebo-controlled trial, we found that SPIB with local anesthetic is effective at reducing VAS scores and opioid consumption after CABG. Further study is needed to determine whether the addition of adjuvants can further improve pain control and opioid consumption.

Adductor Canal Blocks With Bupivacaine and Magnesium After Same-day Discharge Total Knee Arthroplasty Improve Postoperative Pain Relief and Decrease Opioid Consumption: A Prospective Randomized Controlled Trial.

OBJECTIVES: Adequate pain management is a critical component of facilitating same-day discharge for total knee arthroplasty (TKA). Adductor canal blocks (ACB) have been shown to be an effective technique for managing pain after TKA. The objective of this study was to investigate the impact of adding magnesium to local anesthetic in ACB on postoperative pain, opioid consumption, nausea, and overall patient satisfaction. MATERIALS AND METHODS: A sample of 119 adults undergoing elective unilateral TKA were included. Patients were randomly assigned to receive ACB with magnesium and bupivacaine (n=56) or with bupivacaine only (n=63). Primary outcomes were total opioid consumption in the first 48 hours after surgery and pain scores. Secondary outcomes were the incidence of nausea in the first 48 hours after surgery and total overall satisfaction. RESULTS: Opioid consumption decreased significantly in the Mg group compared with the no-Mg group over the first 24 hours (33.2±3.0 vs. 21.3±2.4, P=0.003), the second 24 hours (35.4±2.7 vs. 27.3±2.3, P=0.026), and the first 48 hours total after surgery (68.6±5.1 vs. 48.6±4.3, P=0.004). Pain scores were reduced in the Mg group (24 h: 5.1±2.3 vs. 3.5±2.0, P=0.000; 48 h: 5.1±1.6 vs. 3.9±1.6, P=0.000). Secondary outcomes showed no difference in the incidence of nausea over the first 48 hours and overall satisfaction. CONCLUSION: The addition of magnesium to local anesthetic in ACB decreases pain scores and opioid consumption, without increasing nausea, when compared with ACB with local anesthetic alone.

Neuroplasticity in N-methyl-d-aspartic acid receptor signaling in subregions of the rat rostral ventrolateral medulla following sedentary versus physically active conditions.

The rostral ventrolateral medulla (RVLM) is a brain region involved in normal regulation of the cardiovascular system and heightened sympathoexcitatory states of cardiovascular disease (CVD). Among major risk factors for CVD, sedentary lifestyles contribute to higher mortality than other modifiable risk factors. Previous studies suggest excessive glutamatergic excitation of presympathetic neurons in the RVLM occurs in sedentary animals. Therefore, the purpose of this study was to examine neuroplasticity in the glutamatergic system in the RVLM of sedentary and physically active rats. We hypothesized that relative to active rats, sedentary rats would exhibit higher expression of glutamate N-methyl-d-aspartic acid receptor subunits (GluN), phosphoGluN1, and the excitatory scaffold protein postsynaptic density 95 (PSD95), while achieving higher glutamate levels. Male Sprague-Dawley rats (4 weeks old) were divided into sedentary and active (running wheel) conditions for 10-12 weeks. We used retrograde tracing/triple-labeling techniques, western blotting, and magnetic resonance spectroscopy. We report in sedentary versus physically active rats: 1) fewer bulbospinal non-C1 neurons positive for GluN1, 2) significantly higher expression of GluN1 and GluN2B but lower levels of phosphoGluN1 (pSer896) and PSD95, and 3) higher levels of glutamate in the RVLM. Higher GluN expression is consistent with enhanced sympathoexcitation in sedentary animals; however, a more complex neuroplasticity occurs within subregions of the ventrolateral medulla. Our results in rodents may also indicate that alterations in glutamatergic excitation of the RVLM contribute to the increased incidence of CVD in humans who lead sedentary lifestyles. Thus, there is a strong need to further pursue mechanisms of inactivity-related neuroplasticity in the RVLM.

Anesthesiology Handoff Simulation Case: A Handoff From Intensive Care Unit to Operating Room for Anesthesiology Learners.

Introduction: Handoffs have been shown to be a potential cause of communication failures, leading to possible inefficiencies and patient harm. We noticed that our CA-1 residents were struggling with patient handoffs and designed this simulation to improve their handoff skills. Methods: This anesthesiology-specific simulation introduced learners to the perioperative handoff process. We designed it for anesthesiology learners, including junior residents, medical students, and student nurse anesthetists. The simulation centered upon an anesthesiology resident taking care of an ICU patient and handing that patient off to another anesthesiology provider, who took the patient to the OR. We charged learners with reviewing the patient's history and hospital course and giving a complete handoff. We evaluated learners on the completeness and quality of the handoff, as well as on their performance during the session. Results: Twenty-seven learners participated in this handoff simulation. The participants reported that the simulation improved their understanding of the anesthetic implications of medical conditions and gave them a better understanding of the essential elements of a handoff. Learners also indicated that the debriefing portion of the simulation was effective in filling some of their medical knowledge gaps and improving their handoff skills. Discussion: This simulation was found to be an effective educational experience for our CA-1 and CA-3 residents, medical students, and student nurse anesthetists. Feedback was positive from all learners. As a result, this simulation will be implemented in the early learning curriculum for all of our CA-1 residents.

Cardiac effects of MDMA on the metabolic profile determined with 1H-magnetic resonance spectroscopy in the rat.

Despite the potential for deleterious (even fatal) effects on cardiac physiology, 3,4-methylenedioxymethamphetamine (MDMA; ecstasy) abuse abounds driven mainly by its euphoric effects. Acute exposure to MDMA has profound cardiovascular effects on blood pressure and heart rate in humans and animals. To determine the effects of MDMA on cardiac metabolites in rats, MDMA (0, 5, or 10 mg/kg) was injected every 2 h for a total of four injections; animals were sacrificed 2 h after the last injection (8 h drug exposure), and their hearts removed and tissue samples from left ventricular wall dissected. High resolution magic angle spinning proton magnetic resonance spectroscopy ((1)H-MRS) at 11.7 T, a specialized version of MRS aptly suited for analysis of semi-solid materials such as intact tissue samples, was used to measure the cardiac metabolomic profile, including alanine, lactate, succinate, creatine, and carnitine, in heart tissue from rats treated with MDMA. MDMA effects on MR-visible choline, glutamate, glutamine, and taurine were also determined. Body temperature was measured following each MDMA administration and serotonin and norepinephrine (NE) levels were measured by high pressure liquid chromatography (HPLC) in heart tissue from treated animals. MDMA significantly and dose-dependently increased body temperature, a hallmark of amphetamines. Serotonin, but not NE, levels were significantly and dose-dependently decreased by MDMA in the heart wall. MDMA significantly altered the MR-visible profile with an increase in carnitine and no change in other key compounds involved in cardiomyocyte energy metabolomics. Finally, choline levels were significantly decreased by MDMA in heart. The results are consistent with the notion that MDMA has significant effects on cardiovascular serotonergic tone and disrupts the metabolic homeostasis of energy regulation in cardiac tissue, potentially increasing utilization of fatty acid metabolism. The contributions of serotonergic signaling on MDMA-induced changes in cardiac metabolism remain to be determined.

Calcium/calmodulin-stimulated adenylyl cyclases 1 and 8 regulate reward-related brain activity and ethanol consumption.

Evidence suggests a predictive link between elevated basal activity within reward-related networks (e.g., cortico-basal ganglia-thalamic networks) and vulnerability for alcoholism. Both calcium channel function and cyclic adenosine monophosphate (cAMP)/protein kinase A-mediated signaling are critical modulators of reward neurocircuitry and reward-related behaviors. Calcium/calmodulin-stimulated adenylyl cyclases (AC) 1 and 8 are sensitive to activity-dependent increases in intracellular calcium and catalyze cAMP production. Therefore, we hypothesized AC1 and 8 regulate brain activity in reward regions of the cortico-basal ganglia-thalamic circuit and that this regulatory influence predicts voluntary ethanol drinking responses. This hypothesis was evaluated by manganese-enhanced magnetic resonance imaging and chronic, intermittent ethanol access procedures. Ethanol-naïve mice with genetic deletion of both AC1 and 8 (DKO mice) exhibited bilateral reductions in baseline activity within cortico-basal ganglia-thalamic regions associated with reward processing compared to wild-type controls (WT, C57BL/6 mice). Significant activity changes were not evident in regions either outside of the cortico-basal ganglia-thalamic network or within the network that are not associated with reward processing. Parallel studies demonstrated that reward network hypoactivity in DKO mice predicted a significant attenuation in consumption and preference levels to escalating ethanol concentrations (12, 20 and 30%) compared to WT mice, an effect that was maintained over extended access (14 sessions) to 20% ethanol. Summarizing, these data support a contribution of AC1 and 8 in cortico-basal ganglia-thalamic activity and the predictive value of this regulatory influence on ethanol drinking behavior, which merits the future evaluation of calcium-stimulated ACs in the neural processes that engender vulnerability to maladaptive alcohol drinking.

Single-Prolonged Stress Impairs Prefrontal Cortex Control of Amygdala and Striatum in Rats.

Medial prefrontal cortex (mPFC), amygdala, and striatum neurocircuitry has been shown to play an important role in post-traumatic stress disorder (PTSD) pathology in humans. Clinical studies show hypoactivity in the mPFC and hyperactivity in the amygdala and striatum of PTSD patients, which has been associated with decreased mPFC glutamate levels. The ability to refine neurobiological characteristics of PTSD in an animal model is critical in furthering our mechanistic understanding of the disease. To this end, we exposed male rats to single-prolonged stress (SPS), a validated model of PTSD, and hypothesized that traumatic stress would differentially activate mPFC subregions [prelimbic (PL) and infralimbic (IL) cortices] and increase striatal and amygdalar activity, which would be associated with decreased mPFC glutamate levels. in vivo, neural activity in the subregions of the mPFC, amygdala, and striatum was measured using manganese-enhanced magnetic resonance imaging (MEMRI), and glutamate and N-acetylaspartate (NAA) levels in the mPFC and the dorsal striatum (dSTR) were measured using proton magnetic resonance spectroscopy (1H-MRS) longitudinally, in rats exposed to SPS or control conditions. As hypothesized, SPS decreased MEMRI-based neural activity in the IL, but not PL, cortex concomitantly increasing activity within the basolateral amygdala (BLA) and dorsomedial striatum (dmSTR). 1H-MRS studies in a separate cohort revealed SPS decreased glutamate levels in the mPFC and increased NAA levels in the dSTR. These results confirm previous findings that suggest SPS causes mPFC hypoactivation as well as identifies concurrent hyperactivation in dmSTR and BLA, effects which parallel the clinical neuropathology of PTSD.

Absence of Claudin 11 in CNS Myelin Perturbs Behavior and Neurotransmitter Levels in Mice.

Neuronal origins of behavioral disorders have been examined for decades to construct frameworks for understanding psychiatric diseases and developing useful therapeutic strategies with clinical application. Despite abundant anecdotal evidence for white matter etiologies, including altered tractography in neuroimaging and diminished oligodendrocyte-specific gene expression in autopsy studies, mechanistic data demonstrating that dysfunctional myelin sheaths can cause behavioral deficits and perturb neurotransmitter biochemistry have not been forthcoming. At least in part, this impasse stems from difficulties in identifying model systems free of degenerative pathology to enable unambiguous assessment of neuron biology and behavior in a background of myelin dysfunction. Herein we examine myelin mutant mice lacking expression of the Claudin11 gene in oligodendrocytes and characterize two behavioral endophenotypes: perturbed auditory processing and reduced anxiety/avoidance. Importantly, these behaviors are associated with increased transmission time along myelinated fibers as well as glutamate and GABA neurotransmitter imbalances in auditory brainstem and amygdala, in the absence of neurodegeneration. Thus, our findings broaden the etiology of neuropsychiatric disease to include dysfunctional myelin, and identify a preclinical model for the development of novel disease-modifying therapies.

Tinnitus and temporary hearing loss result in differential noise-induced spatial reorganization of brain activity.

Loud noise frequently results in hyperacusis or hearing loss (i.e., increased or decreased sensitivity to sound). These conditions are often accompanied by tinnitus (ringing in the ears) and changes in spontaneous neuronal activity (SNA). The ability to differentiate the contributions of hyperacusis and hearing loss to neural correlates of tinnitus has yet to be achieved. Towards this purpose, we used a combination of behavior, electrophysiology, and imaging tools to investigate two models of noise-induced tinnitus (either with temporary hearing loss or with permanent hearing loss). Manganese (Mn2+) uptake was used as a measure of calcium channel function and as an index of SNA. Manganese uptake was examined in vivo with manganese-enhanced magnetic resonance imaging (MEMRI) in key auditory brain regions implicated in tinnitus. Following acoustic trauma, MEMRI, the SNA index, showed evidence of spatially dependent rearrangement of Mn2+ uptake within specific brain nuclei (i.e., reorganization). Reorganization of Mn2+ uptake in the superior olivary complex and cochlear nucleus was dependent upon tinnitus status. However, reorganization of Mn2+ uptake in the inferior colliculus was dependent upon hearing sensitivity. Furthermore, following permanent hearing loss, reduced Mn2+ uptake was observed. Overall, by combining testing for hearing sensitivity, tinnitus, and SNA, our data move forward the possibility of discriminating the contributions of hyperacusis and hearing loss to tinnitus.

Addition of buprenorphine to local anesthetic in adductor canal blocks after total knee arthroplasty improves postoperative pain relief: a randomized controlled trial.

BACKGROUND AND OBJECTIVES: For the hundreds of thousands of patients who undergo total knee arthroplasty (TKA) in the United States each year, early mobilization has been demonstrated to improve functional outcomes and reduce complications. Management of postoperative pain is a critical factor in achieving early mobilization. Recent studies have shown that the use of an adductor canal block (ACB) after TKA results in increased preservation of quadriceps muscle strength, without significant difference in postoperative pain when compared to femoral nerve block. This increased preservation of quadriceps muscle strength leads to earlier mobilization. Studies have also demonstrated a prolongation of analgesia with the addition of buprenorphine to local anesthetic for regional block placement. This study examined the effect on postoperative opioid consumption when adding buprenorphine to an ACB vs an ACB with local anesthetic alone, for postoperative analgesia after unilateral TKA. METHODS: A total of 100 patients scheduled for TKA were randomized to receive postoperative ACB with local anesthetic alone or with local anesthetic and buprenorphine. The primary outcome examined was total opioid analgesic (milligrams of hydrocodone equivalent) consumption in the first 24 hours postsurgery. The secondary outcomes examined were the reported incidence of the opioid side effects nausea, vomiting, and pruritis. RESULTS: Postoperative opioid consumption decreased significantly in the group that received an ACB with local anesthetic and buprenorphine compared to an ACB with local anesthetic only (25.34±2.62 vs 35.84±2.86; P=.0076). Secondary outcomes showed no statistical difference between the 2 groups in terms of the incidence of nausea, vomiting, or pruritus. CONCLUSION: The addition of buprenorphine to an adductor canal block decreases postoperative opioid consumption when compared to an ACB with local anesthetic alone. This reduction in opioid consumption, without significant increase in side effects, makes this an attractive anesthetic adjunct for TKA.