Combating an invisible enemy: the American military response to global pandemics.

The present moment is not the first time that America has found itself at war with a pathogen during a time of international conflict. Between crowded barracks at home and trenches abroad, wartime conditions helped enable the spread of influenza in the fall of 1918 during World War I such that an estimated 20-40% of U.S. military members were infected. While the coronavirus disease 2019 (COVID-19) pandemic is unparalleled for most of today's population, it is essential to not view it as unprecedented lest the lessons of past pandemics and their effect on the American military be forgotten. This article provides a historical perspective on the effect of the most notable antecedent pandemic, the Spanish Influenza epidemic, on American forces with the goal of understanding the interrelationship of global pandemics and the military, highlighting the unique challenges of the current pandemic, and examining how the American military has fought back against pandemics both at home and abroad, both 100 years ago and today.

Development of Rapid Response Capabilities in a Large COVID-19 Alternate Care Site Using Failure Modes and Effect Analysis with In Situ Simulation.

Preparedness measures for the anticipated surge of coronavirus disease 2019 (COVID-19) cases within eastern Massachusetts included the establishment of alternate care sites (field hospitals). Boston Hope hospital was set up within the Boston Convention and Exhibition Center to provide low-acuity care for COVID-19 patients and to support local healthcare systems. However, early recognition of the need to provide higher levels of care, or critical care for the potential deterioration of patients recovering from COVID-19, prompted the development of a hybrid acute care-intensive care unit. We describe our experience of implementing rapid response capabilities of this innovative ad hoc unit. Combining quality improvement tools for hazards detection and testing through in situ simulation successfully identified several operational hurdles. Through rapid continuous analysis and iterative change, we implemented appropriate mitigation strategies and established rapid response and rescue capabilities. This study provides a framework for future planning of high-acuity services within a unique field hospital setting.

Prepectoral Direct-to-Implant Breast Reconstruction: Safety Outcome Endpoints and Delineation of Risk Factors.

BACKGROUND: Continued evolution of implant-based breast reconstruction involves immediate placement of the implant above the pectoralis muscle. The shift to prepectoral breast reconstruction is driven by goals of decreasing morbidity such as breast animation deformity, range-of-motion problems, and pain, and is made possible by improvements in mastectomy skin flap viability. To define clinical factors to guide patient selection for direct-to-implant prepectoral implant reconstruction, this study compares safety endpoints and risk factors between prepectoral and subpectoral direct-to-implant breast reconstruction cohorts. The authors hypothesized that prepectoral direct-to-implant breast reconstruction is a safe alternative to subpectoral direct-to-implant breast reconstruction. METHODS: Retrospective chart review identified patients who underwent prepectoral and subpectoral direct-to-implant breast reconstruction, performed by a team of five surgical oncologists and two plastic surgeons. Univariate analysis compared patient characteristics between cohorts. A penalized logistic regression model was constructed to identify relationships between postoperative complications and covariate risk factors. RESULTS: A cohort of 114 prepectoral direct-to-implant patients was compared with 142 subpectoral direct-to-implant patients. The results of the penalized regression model demonstrated equivalence in safety metrics between prepectoral direct-to-implant and subpectoral direct-to-implant breast reconstruction, including seroma (p = 0.0883), cancer recurrence (p = 0.876), explantation (p = 0.992), capsular contracture (p = 0.158), mastectomy skin flap necrosis (p = 0.769), infection (p = 0.523), hematoma (p = 0.228), and revision (p = 0.122). CONCLUSIONS: This study demonstrates that prepectoral direct-to-implant reconstruction is a safe alternative to subpectoral direct-to-implant reconstruction. Given the low morbidity and elimination of animation deformity, prepectoral direct-to-implant reconstruction should be considered when the mastectomy skin flap is robust. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III.

Reconstruction of Severe Burns to the Breast in Pediatric Patients: A 10-Year Experience.

The breast and anterior chest are the most commonly burned part of the trunk. Burn injuries to the breast can be associated with pain, asymmetries, and significant social stigma. Burns to the breast bud in the young female may inhibit normal breast development and result in either significant asymmetries or amastia, making the treatment of breast burn injuries challenging. A retrospective chart review was conducted on all female patients under the age of 21 years admitted to our institution for breast burn injuries from January 1, 2008 to December 30, 2018. Patients were included if they had follow-up reconstructive procedures for breast burn injuries many days after their acute-phase treatment. Ninety-six patients aged 1 to 20 years have been admitted to our institution with burned breast injuries. The mean age of this cohort (n = 96) was 6.4 ± 4.8 years with a mean percent TBSA of 36.3 ± 21.4 and a mean time since injury from admission of 2279.1 ± 2284.1 days. Flame burns (66.8 percent) were the most common etiology for breast burn injuries, followed by scald burns (22.8 percent), in this cohort. The mean body mass index was 22.7 ± 6.3 kg/m2. Follow-up for reconstructive procedures was 7.2 ± 5.6 years after injury date. Our institution's 10-year experience of 96 female patients with severe burn injuries has enhanced our understanding of reconstructive techniques. The location, size, anatomic extent, type of deformity, and symmetry must all be assessed before any treatment plans, which may need to include a combination of modalities.

Evaluation of capsular contracture following immediate prepectoral versus subpectoral direct-to-implant breast reconstruction.

Capsular contracture is a common adverse outcome following implant breast reconstruction, often associated with radiation treatment. The authors hypothesize that muscle fibrosis is the main contributor of breast reconstruction contracture after radiation. Retrospective chart review identified patients that underwent DTI reconstruction with pre-or post-operative breast irradiation. Signs of capsular contracture were assessed using clinic notes and independent graders reviewing two-dimensional images and anatomic landmarks. Capsular contracture rate was greater in the subpectoral vs. prepectoral group (n = 28, 51.8% vs. n = 12, 30.0%, p = 0.02). When compared to prepectoral DTI reconstruction in irradiated patients, subpectoral implant placement was nearly 4 times as likely to result in capsular contracture (p < 0.01). Rates of explantation, infection, tissue necrosis, and hematoma were comparable between groups. We also found that when subpectoral patients present with breast contracture, chemoparalysis of the muscle alone can resolve breast asymmetry, corroborating that muscle is a key contributor to breast contracture. As prepectoral breast reconstruction is gaining popularity, there have been questions regarding outcome following radiation treatment. This study suggest that prepectoral breast reconstruction is safe in an irradiated patient population, and in fact compares favorably with regard to breast contracture.

Multidisciplinary Treatment to Restore Vision in Ocular Burns.

Periorbital burns generate contraction and distortion of periorbital soft tissue, causing eyelid malfunction, further contributing to loss of vision from corneal scarring or perforation. We present our multidisciplinary algorithm to restore vision in patients with burn-related bilateral corneal blindness with light perception. Chart review was performed for four consecutive burn patients requiring periocular reconstruction and keratoprosthesis. Initial treatment included globe coverage with eyelid releases and grafts. Strategy of corneal replacement was determined by eyelid position and function and sufficiency of tear production. All patients were corneal blind with light perception only and cicatricial ectropion. The eye with better visual prognosis was reconstructed. Eyelid reconstruction procedures consisted of lid releases with full-thickness skin graft (FTSG) or split-thickness skin graft (STSG). Two patients regained adequate lid function and underwent standard keratoprosthesis placement. Two underwent mucous membrane grafts followed by keratoprosthesis. All patients experienced improved postoperative vision in their reconstructed eye. Corneal injury due to periocular burns can lead to blindness. Early involvement of ophthalmology, protective measures, and early ectropion release are critical. For severe burns, a multidisciplinary approach, where adequate globe protection is followed by keratoprosthesis placement, can effectively restore vision in patients with burn-related corneal blindness.

Preputial Grafts: The Forgotten Donor Site.

BACKGROUND: The prepuce is an excellent donor site for skin grafts with minimal donor site morbidity. Full-thickness grafts are often required for correction of congenital syndactyly and in burn contractures. METHODS: Preputial skin was used for grafting in 18 children: 5 with burn contractures and 13 with congenital syndactyly. RESULTS: Excellent graft take was achieved with appropriate postoperative care. Postoperatively, there were occasional milia (42%) and hyperpigmentation. These grafts were noted to have superior mobility and elasticity. There was no donor site morbidity. CONCLUSIONS: Preputial skin is accessible, easy to harvest, and hairless and has minimal donor site morbidity. It is especially well suited for the hands and fingers when elasticity of the graft is beneficial.

Penis Transplantation: First US Experience.

OBJECTIVE: We describe the first successful penis transplant in the United States in a patient with a history of subtotal penectomy for penile cancer. BACKGROUND: Penis transplantation represents a new paradigm in restoring anatomic appearance, urine conduit, and sexual function after genitourinary tissue loss. To date, only 2 penis transplants have been performed worldwide. METHODS: After institutional review board approval, extensive medical, surgical, and radiological evaluations of the patient were performed. His candidacy was reviewed by a multidisciplinary team of surgeons, physicians, psychiatrists, social workers, and nurse coordinators. After appropriate donor identification and recipient induction with antithymocyte globulin, allograft procurement and recipient preparation took place concurrently. Anastomoses of the urethra, corpora, cavernosal and dorsal arteries, dorsal vein, and dorsal nerves were performed, and also inclusion of a donor skin pedicle as the composite allograft. Maintenance immunosuppression consisted of mycophenolate mofetil, tacrolimus, and methylprednisolone. RESULTS: Intraoperative, the allograft had excellent capillary refill and strong Doppler signals after revascularization. Operative reinterventions on postoperative days (PODs) 2 and 13 were required for hematoma evacuation and skin eschar debridement. At 3 weeks, no anastomotic leaks were detected on urethrogram, and the catheter was removed. Steroid resistant-rejection developed on POD 28 (Banff I), progressed by POD 32 (Banff III), and required a repeat course of methylprednisolone and antithymocyte globulin. At 7 months, the patient has recovered partial sensation of the penile shaft and has spontaneous penile tumescence. Our patient reports increased overall health satisfaction, dramatic improvement of self-image, and optimism for the future. CONCLUSIONS: We have shown that it is feasible to perform penile transplantation with excellent results. Furthermore, this experience demonstrates that penile transplantation can be successfully performed with conventional immunosuppression. We propose that our successful penile transplantation pilot experience represents a proof of concept for an evolution in reconstructive transplantation.

Quarterly Reporting of Computed Tomography Ordering History Reduces the Use of Imaging in an Emergency Department.

BACKGROUND: Computed tomography (CT) is a useful and necessary part of many emergency department (ED) assessments. However, the costs of imaging and the health risks associated with radiation exposure have sparked national efforts to reduce CT ordering in EDs. STUDY OBJECTIVE: We analyzed CT ordering habits prior to and following implementation of a feedback tool at a community hospital. METHODS: In this intervention study, we identified the CT-ordering habits of physicians and mid-level care providers (physician assistants and nurse practitioners) at baseline and after implementation of a system that sent quarterly feedback reports comparing their ordering habits with those of their peers. Variability in ordering and subgroup analyses by body region were included in these reports. RESULTS: We examined the records of 104,454 patients seen between October 1, 2013 and December 31, 2014. There were 5552 or 21.0% of patients seen during the baseline period that underwent CT imaging. We observed an absolute reduction in imaging of 2.3% (95% confidence interval 1.7-2.8%) after implementation, avoiding approximately $400,000 in costs, 22 days of scanning time, and radiation exposure equivalent to 33,000 chest films annually. These changes occurred across physicians and mid-level providers, regardless of the number years of practice or board certification. CONCLUSIONS: Implementation of a feedback mechanism reduced CT use by emergency medicine practitioners, with concomitant reductions in cost and radiation exposure. The change was similar across levels of medical care. Future studies will examine the effect of the feedback reporting system at other institutions in our hospital network.

Nicotine receptor subtype-specific effects on auditory evoked oscillations and potentials.

BACKGROUND: Individuals with schizophrenia show increased smoking rates which may be due to a beneficial effect of nicotine on cognition and information processing. Decreased amplitude of the P50 and N100 auditory event-related potentials (ERPs) is observed in patients. Both measures show normalization following administration of nicotine. Recent studies identified an association between deficits in auditory evoked gamma oscillations and impaired information processing in schizophrenia, and there is evidence that nicotine normalizes gamma oscillations. Although the role of nicotine receptor subtypes in augmentation of ERPs has received some attention, less is known about how these receptor subtypes regulate the effect of nicotine on evoked gamma activity. METHODOLOGY/PRINCIPAL FINDINGS: We examined the effects of nicotine, the α7 nicotine receptor antagonist methyllycaconitine (MLA) the α4ß4/α4ß2 nicotine receptor antagonist dihydro-beta-erythroidine (DHßE), and the α4ß2 agonist AZD3480 on P20 and N40 amplitude as well as baseline and event-related gamma oscillations in mice, using electrodes in hippocampal CA3. Nicotine increased P20 amplitude, while DHßE blocked nicotine-induced enhancements in P20 amplitude. Conversely, MLA did not alter P20 amplitude either when presented alone or with nicotine. Administration of the α4ß2 specific agonist AZD3480 did not alter any aspect of P20 response, suggesting that DHßE blocks the effects of nicotine through a non-α4ß2 receptor specific mechanism. Nicotine and AZD3480 reduced N40 amplitude, which was blocked by both DHßE and MLA. Finally, nicotine significantly increased event-related gamma, as did AZD3480, while DHßE but not MLA blocked the effect of nicotine on event-related gamma. CONCLUSIONS/SIGNIFICANCE: These results support findings showing that nicotine-induced augmentation of P20 amplitude occurs via a DHßE sensitive mechanism, but suggests that this does not occur through activation of α4ß2 receptors. Event-related gamma is strongly influenced by activation of α4ß2, but not α7, receptor subtypes, while disruption of N40 amplitude requires the activation of multiple receptor subtypes.

Subchronic ketamine treatment leads to permanent changes in EEG, cognition and the astrocytic glutamate transporter EAAT2 in mice.

Ketamine is an NMDA receptor antagonist with psychotomimetic, dissociative, amnestic and euphoric effects. When chronically abused, ketamine users display deficits in cognition and information processing, even following long-term abstinence from the drug. While animal studies have shown evidence of behavioral changes and cognitive deficits that mimic those seen in humans within the period immediately following subchronic ketamine, a few animal studies have assessed long-term changes following cessation of ketamine exposure. To this end, the present study assessed event related potentials (ERPs) and EEG oscillations in mice exposed to subchronic ketamine following a 6month period of abstinence from the drug. Ketamine-treated mice showed no change in P20, but did show marked reductions in amplitude of the later N40 and P80 components, consistent with previous studies of acute ketamine exposure. Additionally, ketamine-treated animals showed a significant reduction in stimulus evoked theta oscillations. To assess the functional significance of these changes, mice were also assessed on a series of behavioral and cognitive tests, including progressive ratio (motivation), extinction (behavioral flexibility) and win-shift radial maze (spatial memory). Subchronic ketamine produced marked disruptions in reversal learning and spatial memory. Analysis of brains from ketamine-treated mice failed to show evidence of neuronal degeneration as determined by NueN immunohistochemistry, but did show increased astrocyte proliferation and decreased expression of the glial specific glutamate transporter, GLT-1. These results strongly suggest: 1) that subchronic ketamine induces significant changes in brain function that long exceed exposure to the drug; 2) that ketamine exposure in mice induces lasting cognitive impairments closely resembling those observed in human ketamine abusers; 3) that ERP and EEG measures are highly sensitive to alterations in brain function associated with reduced cognitive function; and 4) that the brain changes induced by chronic ketamine treatment are suggestive of long-term adaptive or plastic, rather than degenerative, changes.

MeCP2+/- mouse model of RTT reproduces auditory phenotypes associated with Rett syndrome and replicate select EEG endophenotypes of autism spectrum disorder.

Impairments in cortical sensory processing have been demonstrated in Rett syndrome (RTT) and Autism Spectrum Disorders (ASD) and are thought to contribute to high-order phenotypic deficits. However, underlying pathophysiological mechanisms for these abnormalities are unknown. This study investigated auditory sensory processing in a mouse model of RTT with a heterozygous loss of MeCP2 function. Cortical abnormalities in a number of neuropsychiatric disorders, including ASD are reflected in auditory evoked potentials and fields measured by EEG and MEG. One of these abnormalities, increased latency of cortically sourced components, is associated with language and developmental delay in autism. Additionally, gamma-band abnormalities have recently been identified as an endophenotype of idiopathic autism. Both of these cortical abnormalities are potential clinical endpoints for assessing treatment. While ascribing similar mechanisms of idiopathic ASD to Rett syndrome (RTT) has been controversial, we sought to determine if mouse models of RTT replicate these intermediate phenotypes. Mice heterozygous for the null mutations of the gene MeCP2, were implanted for EEG. In response to auditory stimulation, these mice recapitulated specific latency differences as well as select gamma and beta band abnormalities associated with ASD. MeCP2 disruption is the predominant cause of RTT, and reductions in MeCP2 expression predominate in ASD. This work further suggests a common cortical pathophysiology for RTT and ASD, and indicates that the MeCP2+/- model may be useful for preclinical development targeting specific cortical processing abnormalities in RTT with potential relevance to ASD.

Validating γ oscillations and delayed auditory responses as translational biomarkers of autism.

BACKGROUND: Difficulty modeling complex behavioral phenotypes in rodents (e.g., language) has hindered pathophysiological investigation and treatment development for autism spectrum disorders. Recent human neuroimaging studies, however, have identified functional biomarkers that can be more directly related to the abnormal neural dynamics of autism spectrum disorders. This study assessed the translational potential of auditory evoked-response endophenotypes of autism in parallel mouse and human studies of autism. METHODS: Whole-cortex magnetoencephalography was recorded in 17 typically developing and 25 autistic children during auditory pure-tone presentation. Superior temporal gyrus activity was analyzed in time and frequency domains. Auditory evoked potentials were recorded in mice prenatally exposed to valproic acid (VPA) and analyzed with analogous methods. RESULTS: The VPA-exposed mice demonstrated selective behavioral alterations related to autism, including reduced social interactions and ultrasonic vocalizations, increased repetitive self-grooming, and prepulse inhibition deficits. Autistic subjects and VPA-exposed mice showed a similar 10% latency delay in the N1/M100 evoked response and a reduction in γ frequency (30-50 Hz) phase-locking factor. Electrophysiological measures were associated with mouse behavioral deficits. In mice, γ phase-locking factor was correlated with expression of the autism risk gene neuroligin-3 and neural deficits were modulated by the mGluR5-receptor antagonist MPEP. CONCLUSIONS: Results demonstrate a novel preclinical approach toward mechanistic understanding and treatment development for autism.

Mouse behavioral endophenotypes for schizophrenia.

An endophenotype is a heritable trait that is generally considered to be more highly, associated with a gene-based neurological deficit than a disease phenotype itself. Such, endophenotypic deficits may therefore be observed in the non-affected relatives of disease patients. Once endophenotypes have been established for a given illness, such as schizophrenia, mechanisms of, action may then be established and treatment options developed in order to target such measures. The, current paper describes and assesses the merits and limitations of utilizing behavioral and, electrophysiological endophenotypes of schizophrenia in mice. Such endophenotypic deficits include: decreased auditory event related potential (ERP) amplitude and gating (specifically, that of the P20, N40, P80 and P120); impaired mismatch negativity (MMN); changes in theta and gamma frequency, analyses; decreased pre-pulse inhibition (PPI); impaired working and episodic memories (for instance, novel object recognition [NOR], contextual and cued fear conditioning, latent inhibition, Morris and, radial arm maze identification and nose poke); sociability; and locomotor activity. A variety of, pharmacological treatments, including ketamine, MK-801 and phencyclidine (PCP) can be used to, induce some of the deficits described above, and numerous transgenic mouse strains have been, developed to address the mechanisms responsible for such endophenotypic differences. We also, address the viability and validity of using such measures regarding their potential clinical implications, and suggest several practices that could increase the translatability of preclinical data.

Ketamine modulates theta and gamma oscillations.

Ketamine, an N-methyl-D-aspartate (NMDA) receptor glutamatergic antagonist, has been studied as a model of schizophrenia when applied in subanesthetic doses. In EEG studies, ketamine affects sensory gating and alters the oscillatory characteristics of neuronal signals in a complex manner. We investigated the effects of ketamine on in vivo recordings from the CA3 region of mouse hippocampus referenced to the ipsilateral frontal sinus using a paired-click auditory gating paradigm. One issue of particular interest was elucidating the effect of ketamine on background network activity, poststimulus evoked and induced activity. We find that ketamine attenuates the theta frequency band in both background activity and in poststimulus evoked activity. Ketamine also disrupts a late, poststimulus theta power reduction seen in control recordings. In the gamma frequency range, ketamine enhances both background and evoked power, but decreases relative induced power. These findings support a role for NMDA receptors in mediating the balance between theta and gamma responses to sensory stimuli, with possible implications for dysfunction in schizophrenia.

Neuregulin 1 transgenic mice display reduced mismatch negativity, contextual fear conditioning and social interactions.

INTRODUCTION: Neuregulin-1 (NRG1) is one of susceptibility genes for schizophrenia and plays critical roles in glutamatergic, dopaminergic and GABAergic signaling. Using mutant mice heterozygous for Nrg1 (Nrg1(+/-)) we studied the effects of Nrg1 signaling on behavioral and electrophysiological measures relevant to schizophrenia. EXPERIMENTAL PROCEDURE: Behavior of Nrg1(+/-) mice and their wild type littermates was evaluated using pre-pulse inhibition, contextual fear conditioning, novel object recognition, locomotor, and social choice paradigms. Event-related potentials (ERPs) were recorded to assess auditory gating and novel stimulus detection. RESULTS: Gating of ERPs was unaffected in Nrg1(+/-) mice, but mismatch negativity in response to novel stimuli was attenuated. The Nrg1(+/-) mice exhibited behavioral deficits in contextual fear conditioning and social interactions, while locomotor activity, pre-pulse inhibition and novel object recognition were not impaired. SUMMARY: Nrg1(+/-) mice had impairments in a subset of behavioral and electrophysiological tasks relevant to the negative/cognitive symptom domains of schizophrenia that are thought to be influenced by glutamatergic and dopaminergic neurotransmission. These mice are a valuable tool for studying endophenotypes of schizophrenia, but highlight that single genes cannot account for the complex pathophysiology of the disorder.

Novel environment and GABA agonists alter event-related potentials in N-methyl-D-aspartate NR1 hypomorphic and wild-type mice.

Clinical and experimental data suggest dysregulation of N-methyl-d-aspartate receptor (NMDAR)-mediated glutamatergic pathways in schizophrenia. The interaction between NMDAR-mediated abnormalities and the response to novel environment has not been studied. Mice expressing 5 to 10% of normal N-methyl-d-aspartate receptor subunit 1 (NR1) subunits [NR1(neo)(-/-)] were compared with wild-type littermates for positive deflection at 20 ms (P20) and negative deflection at 40 ms (N40) auditory event-related potentials (ERPs). Groups were tested for habituation within and across five testing sessions, with novel environment tested during a sixth session. Subsequently, we examined the effects of a GABA(A) positive allosteric modulator (chlordiazepoxide) and a GABA(B) receptor agonist (baclofen) as potential interventions to normalize aberrant responses. There was a reduction in P20, but not N40 amplitude within each habituation day. Although there was no amplitude or gating change across habituation days, there was a reduction in P20 and N40 amplitude and gating in the novel environment. There was no difference between genotypes for N40. Only NR1(neo)(-/-) mice had reduced P20 in the novel environment. Chlordiazepoxide increased N40 amplitude in wild-type mice, whereas baclofen increased P20 amplitude in NR1(neo)(-/-) mice. As noted in previous publications, the pattern of ERPs in NR1(neo)(-/-) mice does not recapitulate abnormalities in schizophrenia. In addition, reduced NR1 expression does not influence N40 habituation but does affect P20 in a novel environment. Thus, the pattern of P50 (positive deflection at 50 ms) but not N100 (negative deflection at 100 ms) in human studies may relate to subjects' reactions to unfamiliar environments. In addition, NR1 reduction decreased GABA(A) receptor-mediated effects on ERPs while causing increased GABA(B) receptor-mediated effects. Future studies will examine changes in GABA receptor subunits after reductions in NR1 expression.

Chronic ketamine impairs fear conditioning and produces long-lasting reductions in auditory evoked potentials.

Ketamine is an NMDA receptor antagonist with a variety of uses, ranging from recreational drug to pediatric anesthetic and chronic pain reliever. Despite its value in the clinical setting, little is known about the immediate and long-lasting effects of repeated ketamine treatment. We assessed the effects of chronic administration of a subanesthetic dose of ketamine on contextual fear conditioning, detection of pitch deviants and auditory gating. After four, but not two, weeks of daily ketamine injections, mice exhibited decreased freezing in the fear conditioning paradigm. Gating of the P80 component of auditory evoked potentials was also significantly altered by treatment condition, as ketamine caused a significant decrease in S1 amplitude. Additionally, P20 latency was significantly increased as a result of ketamine treatment. Though no interactions were found involving test week, stimulus and treatment condition, these results suggest that repeated ketamine administration impairs fear memory and has lasting effects on encoding of sensory stimuli.

Deviance-elicited changes in event-related potentials are attenuated by ketamine in mice.

BACKGROUND: People with schizophrenia exhibit reduced ability to detect change in the auditory environment, which has been linked to abnormalities in N-methyl-D-aspartate (NMDA) receptor-mediated glutamate neurotransmission. This ability to detect changes in stimulus qualities can be measured with electroencephalography using auditory event-related potentials (ERPs). For example, reductions in the N100 and mismatch negativity (MMN), in response to pitch deviance, have been proposed as endophenotypes of schizophrenia. This study examines a novel rodent model of impaired pitch deviance detection in mice using the NMDA receptor antagonist ketamine. METHODS: ERPs were recorded from unanesthetized mice during a pitch deviance paradigm prior to and following ketamine administration. First, N40 amplitude was evaluated using stimuli between 4 and 10 kHz to assess the amplitude of responses across the frequency range used. The amplitude and latency of the N40 were analyzed following standard (7 kHz) and deviant (5-9 kHz) stimuli. Additionally, we examined which portions of the ERP are selectively altered by pitch deviance to define possible regions for the mouse MMN. RESULTS: Mice displayed increased N40 amplitude that was followed by a later negative component between 50 and 75 msec in response to deviant stimuli. Both the increased N40 and the late N40 negativity were attenuated by ketamine. Ketamine increased N40 latency for both standard and deviant stimuli alike. CONCLUSIONS: The mouse N40 and a subsequent temporal region have deviance response properties similar to the human N100 and, possibly, MMN. Deviance responses were abolished by ketamine, suggesting that ketamine-induced changes in mice mimic deviance detection deficits in schizophrenia.