The PTSD Criterion A debate: A brief history, current status, and recommendations for moving forward.

Posttraumatic stress disorder (PTSD) Criterion A, also known as the "stressor criterion," has been a major source of debate ever since PTSD was added to the third edition of the Diagnostic and Statistical Manual for Mental Disorders (DSM) in 1980. Since then, the traumatic stress field has held an ongoing debate about how to best define Criterion A and the events that it covers. Because of the COVID-19 pandemic and recent race-based incidents, the Criterion A debate has been reinvigorated. In this paper, we review briefly the history of Criterion A and changes in its language across different editions of the DSM. We then describe the four main positions held by scholars involved in the Criterion A debate and carefully examine the support for those positions. We conclude by offering recommendations for moving forward.

An empirical investigation of definitions of subthreshold posttraumatic stress disorder.

Subthreshold posttraumatic stress disorder (PTSD) has long been recognized as an important construct that identifies a subgroup of individuals who report significant PTSD symptoms and associated disability but do not endorse enough symptoms to meet the criteria for a full PTSD diagnosis. Different investigators have defined subthreshold PTSD in various ways, making it difficult to interpret findings across studies. To address this problem, we systematically compared individuals who met criteria for nine different subthreshold PTSD definitions with individuals diagnosed with either full PTSD or no PTSD (i.e., failed to meet the criteria for a subthreshold definition) with respect to prevalence and associated clinical outcomes of interest. Participants were 1,082 veterans enrolled in the Veterans After Discharge Longitudinal Registry. PTSD and subthreshold PTSD diagnostic status were determined using the Structured Clinical Interview for DSM-5 (SCID-5) and validated self-report instruments were used to assess clinical outcomes. Across outcomes, subthreshold definitions generally identified a group of participants that was distinguishable from participants in both the PTSD and no PTSD groups, rs = .02-.47. We discuss the benefits and drawbacks of various subthreshold definitions and highlight the need for additional work evaluating these definitions across additional outcomes and samples. In the interim, we propose a working case definition of subthreshold PTSD as meeting any three of the four DSM-5 symptom criteria (i.e., Criteria B, C, D, and E) along with Criterion A and Criteria F-H. The results suggest subthreshold PTSD is a clinically meaningful construct.

Induction of Activity-Dependent Plasticity at Auditory Nerve Synapses.

Exposure to nontraumatic noise in vivo drives long-lasting changes in auditory nerve synapses, which may influence hearing, but the induction mechanisms are not known. We mimicked activity in acute slices of the cochlear nucleus from mice of both sexes by treating them with high potassium, after which voltage-clamp recordings from bushy cells indicated that auditory nerve synapses had reduced EPSC amplitude, quantal size, and vesicle release probability (P r). The effects of high potassium were prevented by blockers of nitric oxide (NO) synthase and protein kinase A. Treatment with the NO donor, PAPA-NONOate, also decreased P r, suggesting NO plays a central role in inducing synaptic changes. To identify the source of NO, we activated auditory nerve fibers specifically using optogenetics. Strobing for 2 h led to decreased EPSC amplitude and P r, which was prevented by antagonists against ionotropic glutamate receptors and NO synthase. This suggests that the activation of AMPA and NMDA receptors in postsynaptic targets of auditory nerve fibers drives release of NO, which acts retrogradely to cause long-term changes in synaptic function in auditory nerve synapses. This may provide insight into preventing or treating disorders caused by noise exposure.SIGNIFICANCE STATEMENT Auditory nerve fibers undergo long-lasting changes in synaptic properties in response to noise exposure in vivo, which may contribute to changes in hearing. Here, we investigated the cellular mechanisms underlying induction of synaptic changes using high potassium and optogenetic stimulation in vitro and identified important signaling pathways using pharmacology. Our results suggest that auditory nerve activity drives postsynaptic depolarization through AMPA and NMDA receptors, leading to the release of nitric oxide, which acts retrogradely to regulate presynaptic neurotransmitter release. These experiments revealed that auditory nerve synapses are unexpectedly sensitive to activity and can show dramatic, long-lasting changes in a few hours that could affect hearing.

Time Course of Activity-Dependent Changes in Auditory Nerve Synapses Reveals Multiple Underlying Cellular Mechanisms.

Abnormal levels of acoustic activity can result in hearing problems such as tinnitus and language processing disorders, but the underlying cellular and synaptic changes triggered by abnormal activity are not well understood. To address this issue, we studied the time course of activity-dependent changes that occur at auditory nerve synapses in mice of both sexes after noise exposure and conductive hearing loss. We found that EPSC amplitude and synaptic depression decreased within 2 d of noise exposure through a decrease in the probability of vesicle release (Pr). This was followed by a gradual increase in EPSC amplitude through a larger pool of releasable vesicles (N). Occlusion of the ear canal led to a rapid decrease in EPSC amplitude through a decrease in N, which was followed by an increase in EPSC amplitude and synaptic depression through an increase in Pr After returning to normal sound levels, synaptic depression recovered to control levels within 1-2 d. However, repeated exposure to noise for as little as 8 h/d caused synaptic changes after 7 d, suggesting recovery did not fully offset changes. Thus, there appear to be three activity-dependent mechanisms in auditory nerve synapses-bidirectional changes in Pr in 1-2 d, slower bidirectional changes in N through synaptic growth or retraction, and rapid downregulation of N with low activity. The dynamic changes indicate that multiple mechanisms are present to fine-tune synaptic fidelity across different acoustic conditions in a simple relay.SIGNIFICANCE STATEMENT Hearing impairments can arise from exposure to noise or conductive hearing loss. This appears to result from changes in the brain, but the mechanisms are not well understood. We study this issue by studying the synapses made by auditory nerve fibers called endbulbs of Held. These synapses undergo bidirectional changes in size and release probability of neurotransmitter in response to increased or decreased activity. Here, we made a close examination of how quickly these synaptic characteristics change, which indicates there are at least three cellular mechanisms underlying changes. Furthermore, repeated exposure to brief periods of noise can produce cumulative effects. These changes could significantly affect hearing, especially because they occur at the start of the central auditory pathway.

Early-Onset Ventilator-Associated Pneumonia in Pediatric Severe Traumatic Brain Injury.

BACKGROUND: Early-onset ventilator-associated pneumonia (VAP) is associated with poor outcomes in patients with severe traumatic brain injury (TBI). The primary aim of this study was to describe VAP, including the microbiology of VAP and differences in frequency of VAP when various definitions are applied. The secondary aim was to determine the clinical variables associated with the development of VAP in children with severe TBI. METHODS: This is a retrospective cohort study at a quaternary referral children's hospital with a level I trauma center designation. Inclusion criteria were patients aged 0-18 years admitted to the pediatric intensive care unit between 2015 and 2020 with severe TBI requiring at least 2 days of invasive ventilation. VAP was defined by using Center of Disease Control (CDC) definition or clinical VAP, based on physician diagnosis. We compared general demographics, reviewed trauma and injury data, and outcomes to assess any differences between patients with VAP and non-VAP patients. Associations were tested with regression models. RESULTS: After applying all inclusion and exclusion criteria, 90 patients were included in the analysis. Patients with VAP were older (8.5 vs. 5.6 years, P = 0.03). Patients with VAP were less likely to have suffered from abusive head trauma (P = 0.01). Patients who received continuous neuromuscular blockade or targeted temperature management did not have different frequencies of VAP. CDC-defined VAP was diagnosed in 27% of patients. Number of patients with VAP increased to 41% for physician-diagnosed or clinical VAP. Methicillin-sensitive Staphylococcus aureus was the most common isolate grown, followed by Hemophilus influenza, with most VAP occurring on days 2-5 of intubation. VAP was not associated with mortality but was associated with worse functional status scale in patients who survived to discharge (8 vs. 7.5, P = 0.048). Over a cumulative period of days, nebulized 3% and albuterol were associated with decreased incidence of VAP. CONCLUSIONS: Ventilator-associated pneumonia occurs commonly in children with severe TBI, with rates of 27-41%, depending on CDC-defined VAP or clinical VAP. The discrepancy between clinical VAP and CDC-defined VAP further illustrates the need for a standardized definition for VAP. Although most interventions were not associated with VAP, nebulized 3% saline and albuterol were associated with reduced incidence of VAP; future investigation is needed to determine whether mucolytic agents can decrease the rate of VAP in children with severe TBI.

Neuromonitoring During ECMO Support in Children.

Extracorporeal membrane oxygenation is a potentially lifesaving intervention for children with severe cardiac or respiratory failure. It is used with increasing frequency and in increasingly more complex and severe diseases. Neurological injuries are important causes of morbidity and mortality in children treated with extracorporeal membrane oxygenation and include ischemic stroke, intracranial hemorrhage, hypoxic-ischemic injury, and seizures. In this review, we discuss the epidemiology and pathophysiology of neurological injury in patients supported with extracorporeal membrane oxygenation, and we review the current state of knowledge for available modalities of monitoring neurological function in these children. These include structural imaging with computed tomography and ultrasound, cerebral blood flow monitoring with near-infrared spectroscopy and transcranial Doppler ultrasound, and physiological monitoring with electroencephalography and plasma biomarkers. We highlight areas of need and emerging advances that will improve our understanding of neurological injury related to extracorporeal membrane oxygenation and help to reduce the burden of neurological sequelae in these children.

Increased Smoking Cessation Among Veterans With Large Decreases in Posttraumatic Stress Disorder Severity.

INTRODUCTION: Improvement in posttraumatic stress disorder (PTSD) is associated with better health behavior such as better medication adherence and greater use of nutrition and weight loss programs. However, it is not known if reducing PTSD severity is associated with smoking cessation, a poor health behavior common in patients with PTSD. AIMS AND METHODS: Veterans Health Affairs (VHA) medical record data (2008-2015) were used to identify patients with PTSD diagnosed in specialty care. Clinically meaningful PTSD improvement was defined as ≥20 point PTSD Checklist (PCL) decrease from the first PCL ≥50 and the last available PCL within 12 months and at least 8 weeks later. The association between clinically meaningful PTSD improvement and smoking cessation within 2 years after baseline among 449 smokers was estimated in Cox proportional hazard models. Entropy balancing controlled for confounding. RESULTS: On average, patients were 39.4 (SD = 12.9) years of age, 86.6% were male and 71.5% were white. We observed clinically meaningful PTSD improvement in 19.8% of participants. Overall, 19.4% quit smoking in year 1 and 16.6% in year 2. More patients with versus without clinically meaningful PTSD improvement stopped smoking (n = 36, cumulative incidence = 40.5% vs. 111, cumulative incidence = 30.8%, respectively). After controlling for confounding, patients with versus without clinically meaningful PTSD improvement were more likely to stop smoking within 2 years (hazard ratio = 1.57; 95% confidence interval: 1.04-2.36). CONCLUSIONS: Patients with clinically meaningful PTSD improvement were significantly more likely to stop smoking. Further research should determine if targeted interventions are needed or whether improvement in PTSD symptoms is sufficient to enable smoking cessation. IMPLICATIONS: Patients with PTSD are more likely to develop chronic health conditions such as heart disease and diabetes. Poor health behaviors, including smoking, partly explain the risk for chronic disease in this patient population. Our results demonstrate that clinically meaningful PTSD improvement is followed by greater likelihood of smoking cessation. Thus, PTSD treatment may enable healthier behaviors and reduce risk for smoking-related disease.

Tracheostomy Practices and Outcomes in Children During Respiratory Extracorporeal Membrane Oxygenation.

OBJECTIVES: Children receiving prolonged extracorporeal membrane oxygenation (ECMO) support may benefit from tracheostomy during ECMO by facilitating rehabilitation; however, the procedure carries risks, especially hemorrhagic complications. Knowledge of tracheostomy practices and outcomes of ECMO-supported children who undergo tracheostomy on ECMO may inform decision-making. DESIGN: Retrospective cohort study. SETTING: ECMO centers contributing to the Extracorporeal Life Support Organization registry. PATIENTS: Children from birth to 18 years who received ECMO support for greater than or equal to 7 days for respiratory failure from January 1, 2015, to December 31, 2019. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Three thousand six hundred eighty-five children received at least 7 days of ECMO support for respiratory failure. The median duration of ECMO support was 13.0 days (interquartile range [IQR], 9.3-19.9 d), and inhospital mortality was 38.7% (1,426/3,685). A tracheostomy was placed during ECMO support in 94/3,685 (2.6%). Of those who received a tracheostomy on ECMO, the procedure was performed at a median 13.2 days (IQR, 6.3-25.9 d) after initiation of ECMO. Surgical site bleeding was documented in 26% of children who received a tracheostomy (12% after tracheostomy placement). Among children who received a tracheostomy, the median duration of ECMO support was 24.2 days (IQR, 13.0-58.7 d); inhospital mortality was 30/94 (32%). Those that received a tracheostomy before 14 days on ECMO were older (median age, 15.8 yr [IQR, 4.7-15.5] vs 11.7 yr [IQR, 11.5-17.3 yr]; p =0.002) and more likely to have been supported on venovenous-ECMO (84% vs 52%; p = 0.001). Twenty-two percent (11/50) of those who received a tracheostomy before 14 days died in the hospital, compared with 19/44 (43%) of those who received a tracheostomy at 14 days or later (p = 0.03). CONCLUSIONS: Tracheostomies during ECMO were uncommon in children. One in four patients who received a tracheostomy on ECMO had surgical site bleeding. Children who had tracheostomies placed after 14 days were younger and had worse outcomes, potentially representing tracheostomy as a "secondary" strategy for prolonged ECMO support.

Seizures in Children with Cardiac Disease on Extracorporeal Membrane Oxygenation.

BACKGROUND: Children supported with extracorporeal membrane oxygenation (ECMO) have been shown to be at risk for developing seizures. However, previous studies have consisted of heterogeneous patient populations. We aimed to describe the rate of seizures in pediatric patients receiving ECMO for cardiac indications and to identify risk factors for the occurrence of this complication. METHODS: This is a retrospective cohort study of consecutive pediatric patients on ECMO for congenital or acquired cardiac disease between 2014 and 2018 at a tertiary care pediatric hospital. RESULTS: We reviewed 110 children, of whom 104 (95%) received continuous electroencephalogram for at least 48 h after ECMO initiation. Seizures were observed in 20 (18%) children. Seizures were subclinical only in 13 (65%) patients, and 8 (40%) developed status epilepticus. The median time from ECMO initiation to first seizure was 34 h (25%, 75%: 19, 44). Children with seizures were more likely to have suffered pre-ECMO cardiac arrest (odds ratio 5.7, 95% confidence interval 2.0-16.1, p < 0.001), require extracorporeal cardiopulmonary resuscitation (odds ratio 5.2, 95% confidence interval 1.9-14.7, p < 0.001), and have been cannulated via the cervical vessels (p = 0.029). Children with seizures also had lower pH nadir prior to ECMO (p = 0.015) and had higher peak lactate prior to ECMO (p = 0.002). Patients with seizures had significantly a longer median intensive care unit length of stay, (43 versus 32 days, p = 0.02), had a significantly worse pediatric cerebral performance score (2 versus 1, p = 0.03), and tended to have worse survival to hospital discharge (50% versus 71%, p = 0.069). CONCLUSIONS: Seizures in pediatric patients on ECMO for cardiac indications are common, occurring in nearly one in five patients. Seizures are frequently subclinical only and often progress to status epilepticus. Continuous electroencephalogram is therefore warranted for this patient population, especially in the setting of cardiac arrest, extracorporeal cardiopulmonary resuscitation, or severe metabolic acidosis.

Low Intensity Noise Exposure Enhanced Auditory Loudness and Temporal Processing by Increasing Excitability of DCN.

Sound stimulation is generally used for tinnitus and hyperacusis treatment. Recent studies found that long-term noise exposure can change synaptic and firing properties in the central auditory system, which will be detected by the acoustic startle reflex. However, the perceptual consequences of long-term low-intensity sound exposure are indistinct. This study will detect the effects of moderate-level noise exposure (83 dB SPL) on auditory loudness, and temporal processing was evaluated using CBA/CaJ mice. C-Fos staining was used to detect neural activity changes in the central auditory pathway. With two weeks of 83 dB SPL noise exposure (8 hours per day), no persistent threshold shift of the auditory brainstem response (ABR) was identified. On the other hand, noise exposure enhanced the acoustic startle response (ASR) and gap-induced prepulse inhibition significantly (gap-PPI). Low-level noise exposure, according to the findings, can alter temporal acuity. Noise exposure increased the number of c-Fos labeled neurons in the dorsal cochlear nucleus (DCN) and caudal pontine reticular nucleus (PnC) but not at a higher level in the central auditory nuclei. Our results suggested that noise stimulation can change acoustical temporal processing presumably by increasing the excitability of auditory brainstem neurons.

Mechanisms and Functional Consequences of Presynaptic Homeostatic Plasticity at Auditory Nerve Synapses.

Multiple forms of homeostasis influence synaptic function under diverse activity conditions. Both presynaptic and postsynaptic forms of homeostasis are important, but their relative impact on fidelity is unknown. To address this issue, we studied auditory nerve synapses onto bushy cells in the cochlear nucleus of mice of both sexes. These synapses undergo bidirectional presynaptic and postsynaptic homeostatic changes with increased and decreased acoustic stimulation. We found that both young and mature synapses exhibit similar activity-dependent changes in short-term depression. Experiments using chelators and imaging both indicated that presynaptic Ca2+ influx decreased after noise exposure, and increased after ligating the ear canal. By contrast, Ca2+ cooperativity was unaffected. Experiments using specific antagonists suggest that occlusion leads to changes in the Ca2+ channel subtypes driving neurotransmitter release. Furthermore, dynamic-clamp experiments revealed that spike fidelity primarily depended on changes in presynaptic depression, with some contribution from changes in postsynaptic intrinsic properties. These experiments indicate that presynaptic Ca2+ influx is homeostatically regulated in vivo to enhance synaptic fidelity.SIGNIFICANCE STATEMENT Homeostatic mechanisms in synapses maintain stable function in the face of different levels of activity. Both juvenile and mature auditory nerve synapses onto bushy cells modify short-term depression in different acoustic environments, which raises the question of what the underlying presynaptic mechanisms are and the relative importance of presynaptic and postsynaptic contributions to the faithful transfer of information. Changes in short-term depression under different acoustic conditions were a result of changes in presynaptic Ca2+ influx. Spike fidelity was affected by both presynaptic and postsynaptic changes after ear occlusion and was only affected by presynaptic changes after noise-rearing. These findings are important for understanding regulation of auditory synapses under normal conditions and also in disorders following noise exposure or conductive hearing loss.

Does COVID-19 count?: Defining Criterion A trauma for diagnosing PTSD during a global crisis.

INTRODUCTION: The ongoing coronavirus disease 2019 (COVID-19) pandemic is a globally significant crisis with a rapid spread worldwide, high rates of illness and mortality, a high degree of uncertainty, and a disruption of daily life across the sociodemographic spectrum. The clinically relevant psychological consequences of this catastrophe will be long-lasting and far-reaching. There is an emerging body of empirical literature related to the mental health aspects of this pandemic and this body will likely expand exponentially. The COVID-19 pandemic is an example of a historic catastrophe from which we can learn much and from which the field will need to archive, interpret, and synthesize a multitude of clinical and research observations. METHODS: In this commentary, we discuss situations and contexts in which a diagnosis of posttraumatic stress disorder (PTSD) may or may not apply within the context of diagnostic and statistical manual of mental disorders, fifth edition (DSM-5) criteria. RESULTS: Our consensus is that a COVID-related event cannot be considered traumatic unless key aspects of DSM-5's PTSD Criterion A have been established for a specific type of COVID-19 event (e.g., acute, life-threatening, and catastrophic). CONCLUSION: The application of a more liberal interpretation of Criterion A will dilute the PTSD diagnosis, increase heterogeneity, confound case-control research, and create an overall sample pool with varying degrees of risk and vulnerability factors.

Progression of Respiratory Support Following Pediatric Extubation.

OBJECTIVES: High-flow nasal cannula and noninvasive positive pressure ventilation have become ubiquitous in contemporary PICUs. Practice patterns associated with the use of these modalities have not been well described. In this study, we aimed to describe the use of high-flow nasal cannula and noninvasive positive pressure ventilation in children after extubation and analyze the progression of usage in association with patient factors. Our secondary aim was to describe interventions used for postextubation stridor. DESIGN: Single-center retrospective cohort study. SETTING: A 36-bed quaternary medical-surgical PICU. PATIENTS: Mechanically ventilated pediatric patients admitted between April 2017 and March 2018. Exclusions were patients in the cardiac ICU, patients requiring a tracheostomy or chronic ventilatory support, and patients with limited resuscitation status. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Data regarding respiratory modality use was collected for the first 72 hours after extubation. There were 427 patients included in the analysis; 51 patients (11.9%) were extubated to room air, 221 (51.8%) to nasal cannula, 132 (30.9%) to high-flow nasal cannula, and 23 (5.4%) to noninvasive positive pressure ventilation. By 72 hours, 314 patients (73.5%) were on room air, 52 (12.2%) on nasal cannula, 29 (6.8%) on high-flow nasal cannula, eight (1.9%) on noninvasive positive pressure ventilation, and 24 (5.6%) were reintubated. High-flow nasal cannula was the most used respiratory modality for postextubation stridor. Multivariate analysis demonstrated that longer duration of invasive mechanical ventilation increased the odds of initial high-flow nasal cannula and noninvasive positive pressure ventilation use, and a diagnosis of cerebral palsy increased the odds of escalating from high-flow nasal cannula to noninvasive positive pressure ventilation in the first 24 hours post extubation. CONCLUSIONS: High-flow nasal cannula is commonly used immediately after pediatric extubation and the development of postextubation stridor; however, its usage sharply declines over the following 72 hours. Larger multicenter trials are needed to identify high-risk patients for extubation failure that might benefit the most from prophylactic use of high-flow nasal cannula and noninvasive positive pressure ventilation after extubation.

GABA is a modulator, rather than a classical transmitter, in the medial nucleus of the trapezoid body-lateral superior olive sound localization circuit.

KEY POINTS: The lateral superior olive (LSO), a brainstem hub involved in sound localization, integrates excitatory and inhibitory inputs from the ipsilateral and the contralateral ear, respectively. In gerbils and rats, inhibition to the LSO reportedly shifts from GABAergic to glycinergic within the first three postnatal weeks. Surprisingly, we found no evidence for synaptic GABA signalling during this time window in mouse LSO principal neurons. However, we found that presynaptic GABAB Rs modulate Ca2+ influx into medial nucleus of the trapezoid body axon terminals, resulting in reduced synaptic strength. Moreover, GABA elicited strong responses in LSO neurons that were mediated by extrasynaptic GABAA Rs. RNA sequencing revealed highly abundant δ subunits, which are characteristic of extrasynaptic receptors. Whereas GABA increased the excitability of neonatal LSO neurons, it reduced the excitability around hearing onset. Collectively, GABA appears to control the excitability of mouse LSO neurons via extrasynaptic and presynaptic signalling. Thus, GABA acts as a modulator, rather than as a classical transmitter. ABSTRACT: GABA and glycine mediate fast inhibitory neurotransmission and are coreleased at several synapse types. Here we assessed the contribution of GABA and glycine in synaptic transmission between the medial nucleus of the trapezoid body (MNTB) and the lateral superior olive (LSO), two nuclei involved in sound localization. Whole-cell patch-clamp experiments in acute mouse brainstem slices at postnatal days (P) 4 and 11 during pharmacological blockade of GABAA receptors (GABAA Rs) and/or glycine receptors demonstrated no GABAergic synaptic component on LSO principal neurons. A GABAergic component was absent in evoked inhibitory postsynaptic currents and miniature events. Coimmunofluorescence experiments revealed no codistribution of the presynaptic GABAergic marker GAD65/67 with gephyrin, a postsynaptic marker for GABAA Rs, corroborating the conclusion that GABA does not act synaptically in the mouse LSO. Imaging experiments revealed reduced Ca2+ influx into MNTB axon terminals following activation of presynaptic GABAB Rs. GABAB R activation reduced the synaptic strength at P4 and P11. GABA appears to act on extrasynaptic GABAA Rs as demonstrated by application of 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol, a δ-subunit-specific GABAA R agonist. RNA sequencing showed high mRNA levels for the δ-subunit in the LSO. Moreover, GABA transporters GAT-1 and GAT-3 appear to control extracellular GABA. Finally, we show an age-dependent effect of GABA on the excitability of LSO neurons. Whereas tonic GABA increased the excitability at P4, leading to spike facilitation, it decreased the excitability at P11 via shunting inhibition through extrasynaptic GABAA Rs. Taken together, we demonstrate a modulatory role of GABA in the murine LSO, rather than a function as a classical synaptic transmitter.

Outcomes of pediatric oncology and hematopoietic cell transplant patients receiving extracorporeal membrane oxygenation.

BACKGROUND/OBJECTIVES: There is controversy regarding the utilization of extracorporeal membrane oxygenation in pediatric patients with an underlying oncologic diagnosis or who have undergone hematopoietic cell transplant. We hypothesized that these patients have higher mortality, more bleeding complications, more blood product utilization, and a higher rate of new infections than the general pediatric intensive care unit population supported with extracorporeal membrane oxygenation. DESIGN/METHODS: This is a retrospective chart review at a single center quaternary care pediatric hospital including all pediatric intensive care unit extracorporeal membrane oxygenation patients from 2011 to 2016. Patients were categorized as either oncology/hematopoietic cell transplant or general pediatric intensive care unit. Patients from the cardiovascular intensive care unit or the neonatal intensive care unit were excluded. RESULTS: A total of 38 patients met inclusion criteria of which 7 were oncology/hematopoietic cell transplant patients. The oncology/hematopoietic cell transplant group had lower platelets at the start of extracorporeal membrane oxygenation (p = 0.02) but other pre-extracorporeal membrane oxygenation characteristics were similar. Extracorporeal membrane oxygenation survival was lower in the oncology/hematopoietic cell transplant group (29% vs 77%, p = 0.02). The incidence of bleeding complications and new infections did not differ. The oncology/hematopoietic cell transplant group received more platelets (median of 15.9 mL/kg/day (interquartile range 8.4, 36.6) vs 7.9 mL/kg/day (3.3, 21.9), p = 0.04) and fresh frozen plasma (14.0 mL/kg/day (3, 15.7) vs 1.8 mL/kg/day (0.5, 5.9), p = 0.04). CONCLUSION: Oncology and hematopoietic cell transplant patients had a higher mortality and received more blood products while on extracorporeal membrane oxygenation than the general pediatric intensive care unit patients despite similar pre-extracorporeal membrane oxygenation characteristics. Physicians should use caution when deciding whether or not to utilize extracorporeal membrane oxygenation in this population.

Changes in Properties of Auditory Nerve Synapses following Conductive Hearing Loss.

Auditory activity plays an important role in the development of the auditory system. Decreased activity can result from conductive hearing loss (CHL) associated with otitis media, which may lead to long-term perceptual deficits. The effects of CHL have been mainly studied at later stages of the auditory pathway, but early stages remain less examined. However, changes in early stages could be important because they would affect how information about sounds is conveyed to higher-order areas for further processing and localization. We examined the effects of CHL at auditory nerve synapses onto bushy cells in the mouse anteroventral cochlear nucleus following occlusion of the ear canal. These synapses, called endbulbs of Held, normally show strong depression in voltage-clamp recordings in brain slices. After 1 week of CHL, endbulbs showed even greater depression, reflecting higher release probability. We observed no differences in quantal size between control and occluded mice. We confirmed these observations using mean-variance analysis and the integration method, which also revealed that the number of release sites decreased after occlusion. Consistent with this, synaptic puncta immunopositive for VGLUT1 decreased in area after occlusion. The level of depression and number of release sites both showed recovery after returning to normal conditions. Finally, bushy cells fired fewer action potentials in response to evoked synaptic activity after occlusion, likely because of increased depression and decreased input resistance. These effects appear to reflect a homeostatic, adaptive response of auditory nerve synapses to reduced activity. These effects may have important implications for perceptual changes following CHL. SIGNIFICANCE STATEMENT: Normal hearing is important to everyday life, but abnormal auditory experience during development can lead to processing disorders. For example, otitis media reduces sound to the ear, which can cause long-lasting deficits in language skills and verbal production, but the location of the problem is unknown. Here, we show that occluding the ear causes synapses at the very first stage of the auditory pathway to modify their properties, by decreasing in size and increasing the likelihood of releasing neurotransmitter. This causes synapses to deplete faster, which reduces fidelity at central targets of the auditory nerve, which could affect perception. Temporary hearing loss could cause similar changes at later stages of the auditory pathway, which could contribute to disorders in behavior.

Activity-dependent, homeostatic regulation of neurotransmitter release from auditory nerve fibers.

Information processing in the brain requires reliable synaptic transmission. High reliability at specialized auditory nerve synapses in the cochlear nucleus results from many release sites (N), high probability of neurotransmitter release (Pr), and large quantal size (Q). However, high Pr also causes auditory nerve synapses to depress strongly when activated at normal rates for a prolonged period, which reduces fidelity. We studied how synapses are influenced by prolonged activity by exposing mice to constant, nondamaging noise and found that auditory nerve synapses changed to facilitating, reflecting low Pr. For mice returned to quiet, synapses recovered to normal depression, suggesting that these changes are a homeostatic response to activity. Two additional properties, Q and average excitatory postsynaptic current (EPSC) amplitude, were unaffected by noise rearing, suggesting that the number of release sites (N) must increase to compensate for decreased Pr. These changes in N and Pr were confirmed physiologically using the integration method. Furthermore, consistent with increased N, endbulbs in noise-reared animals had larger VGlut1-positive puncta, larger profiles in electron micrographs, and more release sites per profile. In current-clamp recordings, noise-reared BCs had greater spike fidelity even during high rates of synaptic activity. Thus, auditory nerve synapses regulate excitability through an activity-dependent, homeostatic mechanism, which could have major effects on all downstream processing. Our results also suggest that noise-exposed bushy cells would remain hyperexcitable for a period after returning to normal quiet conditions, which could have perceptual consequences.

Low Somatic Sodium Conductance Enhances Action Potential Precision in Time-Coding Auditory Neurons.

Auditory nerve fibers encode sounds in the precise timing of action potentials (APs), which is used for such computations as sound localization. Timing information is relayed through several cell types in the auditory brainstem that share an unusual property: their APs are not overshooting, suggesting that the cells have very low somatic sodium conductance (gNa). However, it is not clear how gNa influences temporal precision. We addressed this by comparing bushy cells (BCs) in the mouse cochlear nucleus with T-stellate cells (SCs), which do have normal overshooting APs. BCs play a central role in both relaying and refining precise timing information from the auditory nerve, whereas SCs discard precise timing information and encode the envelope of sound amplitude. Nucleated-patch recording at near-physiological temperature indicated that the Na current density was 62% lower in BCs, and the voltage dependence of gNa inactivation was 13 mV hyperpolarized compared with SCs. We endowed BCs with SC-like gNa using two-electrode dynamic clamp and found that synaptic activity at physiologically relevant rates elicited APs with significantly lower probability, through increased activation of delayed rectifier channels. In addition, for two near-simultaneous synaptic inputs, the window of coincidence detection widened significantly with increasing gNa, indicating that refinement of temporal information by BCs is degraded by gNa Thus, reduced somatic gNa appears to be an adaption for enhancing fidelity and precision in time-coding neurons. SIGNIFICANCE STATEMENT: Proper hearing depends on analyzing temporal aspects of sounds with high precision. Auditory neurons that specialize in precise temporal information have a suite of unusual intrinsic properties, including nonovershooting action potentials and few sodium channels in the soma. However, it was not clear how low sodium channel availability in the soma influenced the temporal precision of action potentials initiated in the axon initial segment. We studied this using dynamic clamp to mimic sodium channels in the soma, which yielded normal, overshooting action potentials. Increasing somatic sodium conductance had major negative consequences: synaptic activity evoked action potentials with lower fidelity, and the precision of coincidence detection was degraded. Thus, low somatic sodium channel availability appears to enhance fidelity and temporal precision.

VA's National PTSD Brain Bank: a National Resource for Research.

The National PTSD Brain Bank (NPBB) is a brain tissue biorepository established to support research on the causes, progression, and treatment of PTSD. It is a six-part consortium led by VA's National Center for PTSD with participating sites at VA medical centers in Boston, MA; Durham, NC; Miami, FL; West Haven, CT; and White River Junction, VT along with the Uniformed Services University of Health Sciences. It is also well integrated with VA's Boston-based brain banks that focus on Alzheimer's disease, ALS, chronic traumatic encephalopathy, and other neurological disorders. This article describes the organization and operations of NPBB with specific attention to: tissue acquisition, tissue processing, diagnostic assessment, maintenance of a confidential data biorepository, adherence to ethical standards, governance, accomplishments to date, and future challenges. Established in 2014, NPBB has already acquired and distributed brain tissue to support research on how PTSD affects brain structure and function.

Skipped-stimulus approach reveals that short-term plasticity dominates synaptic strength during ongoing activity.

All synapses show activity-dependent changes in strength, which affect the fidelity of postsynaptic spiking. This is particularly important at auditory nerve synapses, where the presence and timing of spikes carry information about a sound's structure, which must be passed along for proper processing. However, it is not clear how synaptic plasticity influences spiking during ongoing activity. Under these conditions, conventional analyses erroneously suggest that synaptic plasticity has no influence on EPSC amplitude or spiking. Therefore, we developed new approaches to study how ongoing activity influences synaptic strength, using voltage- and current-clamp recordings from bushy cells in brain slices from mouse anteroventral cochlear nucleus. We applied identical trains of stimuli, except for one skipped stimulus, and found that EPSC amplitude was affected for 60 ms following a skipped stimulus. We further showed that the initial probability of release, calcium-dependent mechanisms of recovery, and desensitization all play a role even during ongoing activity. Current-clamp experiments indicated that these processes had a significant effect on postsynaptic spiking, as did the refractory period to a smaller extent. Thus short-term plasticity has real, important functional consequences.