Implementation of Opioid Safety Efforts: Influence of Academic Detailing on Adverse Outcomes Among Patients in the Veterans Health Administration.

BACKGROUND: The Veterans Health Administration (VA) implemented academic detailing (AD) to support safer opioid prescribing and overdose prevention initiatives. METHODS: Patient-level data were extracted monthly from VA's electronic health record to evaluate whether AD implementation was associated with changes in all-cause mortality, opioid poisoning inpatient admissions, and opioid poisoning emergency department (ED) visits in an observational cohort of patients with long-term opioid prescriptions (≥45-day supply of opioids 6 months prior to a given month with ≤15 days between prescriptions). A single-group interrupted time series analysis using segmented logistic regression for mortality and Poisson regression for counts of inpatient admissions and ED visits was used to identify whether the level and slope of these outcomes changed in response to AD implementation. RESULTS: Among 955 376 unique patients (19 431 241 person-months), there were 53 369 deaths (29 025 pre-AD; 24 344 post-AD), 1927 opioid poisoning inpatient admissions (610 pre-AD; 1317 post-AD), and 408 opioid poisoning ED visits (207 pre-AD; 201 post-AD). Immediately after AD implementation, there was a 5.8% reduction in the odds of all-cause mortality (95% confidence interval [CI]: 0.897, 0.990). However, patients had a significantly increased incidence rate of inpatient admissions for opioid poisoning immediately after AD implementation (incidence rate ratio = 1.523; 95% CI: 1.118, 2.077). No significant differences in ED visits for opioid poisoning were observed. CONCLUSIONS: AD was associated with decreased all-cause mortality but increased inpatient hospitalization for opioid poisoning among patients prescribed long-term opioids. Mechanisms via which AD's efforts influenced opioid-related outcomes should be explored.

Comparison of virtual to in-person academic detailing on naloxone prescribing rates at three U.S. Veterans Health Administration regional networks.

INTRODUCTION: Academic detailing, an educational outreach that promotes evidence-based practices to improve the quality of care for patients, has primarily been delivered using one-on-one in-person interactions. In 2018, the U.S. Department of Veterans Affairs (VA) Pharmacy Benefits Management implemented a pilot virtual academic detailing program to increase naloxone prescribing among veterans at risk for opioid overdose or death. The aim of this evaluation was to compare virtual and in-person academic detailing on naloxone prescribing rates at VA. METHODS: A retrospective quasi-experimental pretest-posttest non-equivalent groups design was used to compare virtual academic detailing and in-person academic detailing on naloxone prescribing rates 12 months before and after providers received a naloxone-specific encounter at three VA regional networks between January 1, 2018 to May 31, 2020. Subgroup analysis was performed on rural providers. Generalized estimating equation models were constructed to compare the difference in naloxone prescribing rates before and after receiving virtual or in-person academic detailing controlling for provider-level characteristics. RESULTS: Providers who received virtual (N = 67) or in-person (N = 186) academic detailing had significant increases in naloxone prescribing, but the differences in the naloxone rates between the groups were not statistically significant (difference in changes in naloxone rates=+0.63; 95% CI: -2.23, 3.48). Similar findings were reported for rural providers. DISCUSSION: Providers who received naloxone-related in-person or virtual academic detailing had increased naloxone prescribing rates; however, there were no differences between the two types of modalities. Virtual academic detailing is a viable alternative for delivering academic detailing and allows academic detailers to expand their reach to rural providers.

Ventral pallidum regulates the default mode network, controlling transitions between internally and externally guided behavior.

Daily life requires transitions between performance of well-practiced, automatized behaviors reliant upon internalized representations and behaviors requiring external focus. Such transitions involve differential activation of the default mode network (DMN), a group of brain areas associated with inward focus. We asked how optogenetic modulation of the ventral pallidum (VP), a subcortical DMN node, impacts task switching between internally to externally guided lever-pressing behavior in the rat. Excitation of the VP dramatically compromised acquisition of an auditory discrimination task, trapping animals in a DMN state of automatized internally focused behavior and impairing their ability to direct attention to external sensory stimuli. VP inhibition, on the other hand, facilitated task acquisition, expediting escape from the DMN brain state, thereby allowing rats to incorporate the contingency changes associated with the auditory stimuli. We suggest that VP, instant by instant, regulates the DMN and plays a deterministic role in transitions between internally and externally guided behaviors.

Saving Lives: The Veterans Health Administration (VHA) Rapid Naloxone Initiative.

BACKGROUND: The United States is in the midst of an opioid epidemic within the COVID-19 pandemic, and veterans are twice as likely to die from accidental overdose compared to non-veterans. This article describes the Veterans Health Administration (VHA) Rapid Naloxone Initiative, which aims to prevent opioid overdose deaths among veterans through (1) opioid overdose education and naloxone distribution (OEND) to VHA patients at risk for opioid overdose, (2) VA Police naloxone, and (3) select automated external defibrillator (AED) cabinet naloxone. METHODS: VHA has taken a multifaceted, theory-based approach to ensuring the rapid availability of naloxone to prevent opioid overdose deaths. Strategies targeted at multiple levels (for example, patient, provider, health care system) have enabled synergies to speed diffusion of this lifesaving practice. RESULTS: As of April 2021, 285,279 VHA patients had received naloxone from 31,730 unique prescribers, with 1,880 reported opioid overdose reversals with naloxone; 129 VHA facilities had equipped 3,552 VA Police officers with naloxone, with 136 reported opioid overdose reversals with VA Police naloxone; and 77 VHA facilities had equipped 1,095 AED cabinets with naloxone, with 10 reported opioid overdose reversals with AED cabinet naloxone. Remarkably, the COVID-19 pandemic had minimal impact on naloxone dispensing to VHA patients. CONCLUSION: The VHA Rapid Naloxone Initiative saves lives. VHA is sharing many of the tools and resources it has developed to support uptake across other health care systems. Health care systems need to work together to combat this horrific epidemic within a pandemic and prevent a leading cause of accidental death (opioid overdose).

Impact of Implementing an Academic Detailing Program on Opioid-Benzodiazepine Co-Prescribing Trends at the U.S. Department of Veterans Affairs.

OBJECTIVES: To assess the process and outcomes of academic detailing to enhance the Opioid Safety Initiative and the Psychotropic Drug Safety Initiative to reduce co-prescribing of opioid-benzodiazepine combinations in veterans. METHODS: A retrospective cohort design was conducted to evaluate the impact of implementing an academic detailing program on opioid-benzodiazepine co-prescribing between October 2014 through March 2019 at the U.S. Department of Veterans Affairs (VA). The primary outcome was the monthly prevalence of veterans (number per 1,000 population) who were co-prescribed opioid-benzodiazepine combination. Process measure was evaluated using implementation reach (proportion of providers who received academic detailing). Station-level analysis was performed using a linear fixed effects regression model to evaluate the rate of change in the prevalence of veterans co-prescribed opioid-benzodiazepine. RESULTS: Altogether 130 VA stations was included for analysis; 119 stations implemented opioid-related or benzodiazepine-related academic detailing, and 11 stations did not. Stations that had implemented academic detailing had a 33% greater monthly reduction on the opioid-benzodiazepine co-prescribing prevalence compared to stations that did not implement academic detailing (P = .036). In the linear fixed effects regression model, stations that were expected to have 100% of providers exposed to academic detailing were statistically associated with a greater decrease in the monthly prevalence of Veterans co-prescribed opioid-benzodiazepine by 4.9 veterans per 1,000 population (P < .001) compared to stations with 0% of providers exposed to academic detailing. CONCLUSIONS: Stations that implemented academic detailing and had a higher proportion of providers who were exposed to opioid- or benzodiazepine-related academic detailing had a significant decrease in the monthly prevalence of Veterans co-prescribed opioid-benzodiazepine combinations.

Opioid Prescribing and Opioid Risk Mitigation Strategies in the Veterans Health Administration.

INTRODUCTION: The Veterans Health Administration (VHA) has taken a multifaceted approach to addressing opioid safety and promoting system-wide opioid stewardship. AIM: To provide a comprehensive evaluation of current opioid prescribing practices and implementation of risk mitigation strategies in VHA. SETTING: VHA is the largest integrated health care system in the United States. PROGRAM DESCRIPTION: VHA prescribing data in conjunction with implementation of opioid risk mitigation strategies are routinely tracked and reviewed by VHA's Pharmacy Benefits Management Services (including Academic Detailing Service) and the Pain Management Program Office. Additional data are derived from the Partnered Evidence-Based Policy Resource Center (PEPReC) and from a 2019 survey of interdisciplinary pain management teams at VHA facilities. Prescribing data are reported quarterly until first quarter fiscal year 2020 (Q1FY2020), ending December 31, 2019. PROGRAM EVALUATION: VHA opioid dispensing peaked in 2012 with 679,376 Veterans receiving an opioid prescription, and when including tramadol, in 2013 with 869,956 Veterans. Since 2012, the number of Veterans dispensed an opioid decreased 56% and co-prescribed opioid/benzodiazepine decreased 83%. Veterans with high-dose opioids (≥ 100 mg morphine equivalent daily dose) decreased 77%. In Q1FY2020, among Veterans on long-term opioid therapy (LTOT), 91.1% had written informed consent, 90.8% had a urine drug screen, and 89.0% had a prescription drug monitoring program query. Naloxone was issued to 217,469 Veterans and resulted in > 1,000 documented overdose reversals. In 2019, interdisciplinary pain management teams were fully designated at 68%, partially designated at 28%, and not available at 4% of 140 VA parent facilities. Fifty percent of Veterans on opioids at very high risk for overdose/suicide received interdisciplinary team reviews. IMPLICATIONS: VHA clinicians have greatly reduced their volume of opioid prescribing for pain management and expanded implementation of opioid risk mitigation strategies. IMPACTS: VHA's integrated health care system provides a model for opioid stewardship and interdisciplinary pain care.

The Hearing Health Care Journey: Putting Beans in Your Cups.

One of the areas MarkeTrak has explored is the customer journey through hearing health care. The survey has asked question regarding how long they had a hearing loss before they took some type of action, where did they start their journey, why did they obtain hearing instruments or not, and what the hearing instruments cost. To put that journey in perspective, this article looks at the journey of one specific individual and explores their attitudes about their hearing loss through the eyes of a psychologist.

Impact of academic detailing on benzodiazepine use among veterans with posttraumatic stress disorder.

Background: Benzodiazepine use in the US Veterans Administration (VA) has been decreasing; however, a small number of veterans with posttraumatic stress disorder (PTSD) continue to receive benzodiazepine. Academic detailing, a targeted-educational outreach intervention, was implemented at VA to help reduce the disparity between existing and evidence-based practices, including the reduction in benzodiazepine use in veterans with PTSD. Since evidence to support the national implementation of academic detailing in this clinical scenario was scarce, we performed a quality improvement evaluation on academic detailing's impact on benzodiazepine use in veterans with PTSD. Methods: A retrospective cohort design was used to evaluate the impact of academic detailing on benzodiazepine prescribing in veterans with PTSD from January 1, 2016, to December 31, 2016. Providers exposed to academic detailing (AD-exposed) were compared with providers unexposed to academic detailing (AD-unexposed) using generalized estimating equations (GEEs) controlling for baseline covariates. Secondary aims evaluated academic detailing's impact on average lorazepam equivalent daily dose (LEDD), total LEDD, and benzodiazepine day supply. Results: Overall, there was a decrease in the prevalence in benzodiazepine use in veterans with PTSD from 115.5 to 103.3 per 1000 population (P < .001). However, the decrease was greater in AD-exposed providers (18.37%; P < .001) compared with AD-unexposed providers (8.74%; P < .001). In the GEE models, AD-exposed providers had greater reduction in the monthly prevalence of veterans with PTSD and a benzodiazepine prescription compared with AD-unexposed providers, by -1.30 veterans per 1000 population (95% confidence interval [CI]: -2.14, -0.46). Similar findings were reported for the benzodiazepine day supply; however, no significant differences were reported for total and average LEDD. Conclusions: Although benzodiazepine use has been decreasing in veterans with PTSD, opportunities to improve prescribing continue to exist at the VA. In this quality improvement evaluation, AD-exposed providers were associated with a greater reduction in the prevalence of veterans with PTSD and a benzodiazepine prescription compared with AD-unexposed providers.

Comparison of naloxone prescribing patterns due to educational outreach conducted by full-time and part-time academic detailers at the U.S. Veterans Health Administration.

OBJECTIVE: To examine the impact of full-time equivalent employee (FTEE) allocation to academic detailers on naloxone prescribing at the U.S. Veterans Health Administration (VA). DESIGN: Longitudinal nonequivalent control group posttest-only design using a random effects model. SETTING AND PARTICIPANTS: Closed cohort of primary care providers exposed to academic detailing between September 1, 2016, and September 20, 2018, at VA. OUTCOME MEASURES: Previous analysis identified a cutoff of 0.40 FTEE was associated with a greater return on investment. We evaluated whether this level of FTEE allocation was associated with increases in naloxone prescribing rates and compared providers who had an interaction with an academic detailer allocated 0.4 FTEE or greater (high FTEE) to providers who interacted with an academic detailer allocated less than 0.4 FTEE (low FTEE). RESULTS: Among VA primary care providers who received academic detailing, 1770 (68%) had interactions with a high FTEE academic detailer. There were no differences in demographics between providers who interacted with high FTEE and low FTEE academic detailers except for the distribution of provider classes (P = 0.004) and geographic districts (P < 0.001). Providers who interacted with high FTEE academic detailers had a greater average monthly number of naloxone prescriptions prescribed compared with low FTEE academic detailers (0.60 vs. 0.53; P = 0.005). In the random effects model, there was a 65% greater increase in the average monthly number of naloxone prescriptions prescribed among providers who interacted with a high FTEE academic detailer compared with providers who interacted with low FTEE academic detailers (P = 0.027). We also observed a dose-dependent relationship between the number of naloxone prescribed and the amount of FTEE allocated. CONCLUSION: This observational study highlights the potential benefits (e.g., increased naloxone prescribing) of academic detailers having more FTEE allocated. Hence, implementation of academic detailing needs to consider the amount of dedicated time for academic detailers, given competing VA priorities.

Implementation evaluation of academic detailing on naloxone prescribing trends at the United States Veterans Health Administration.

OBJECTIVE: Academic detailing in partnership with the Opioid Overdose Education and Naloxone Distribution (OEND) program was implemented to increase naloxone access for the prevention of opioid overdose mortality in veterans at the U.S. Department of Veterans Affairs (VA). However, implementation was not uniform leading to varying levels of intervention exposure potentially impacting naloxone prescribing. We examined the impact of implementation strength (proportion of providers exposed to academic detailing) at each station on naloxone prescribing from September 2014 to December 2017. STUDY DESIGN AND SETTING: Retrospective cohort design with fixed effects models at the VA. DATA COLLECTION/EXTRACTION METHODS: We used VA Corporate Data Warehouse for data on pharmacy dispensing, station-, provider- and patient-level characteristics. OEND-specific academic detailing activities came from data recorded by academic detailers using Salesforce.com. PRINCIPAL FINDINGS: VA stations wherein 100 percent of providers exposed to an OEND-related academic detailing educational outreach visit experienced an increased incident rate of naloxone prescribing that was 5.52 times the incident rate of stations where no providers were exposed; alternatively, this is equivalent to an average monthly increase of 2.60 naloxone prescriptions per 1000 population at risk for opioid overdose. CONCLUSIONS: Our findings highlight the importance of academic detailing's implementation strength on naloxone prescribing. Decision makers must carefully consider the implementation process to achieve the greatest effectiveness from the intervention.

Clinical dashboard development and use for academic detailing in the U.S. Department of Veterans Affairs.

OBJECTIVE: To describe the U.S. Department of Veterans Affairs (VA) Academic Detailing Service's (ADS) experience with the development and use of clinical dashboards across the VA's national clinical campaigns. We focused only on dashboards developed by the VA ADS national clinical program managers. SETTING: U.S. Department of Veterans Affairs Pharmacy Benefits Management National Academic Detailing Service. PRACTICE DESCRIPTION: Academic detailing is a multifaceted, educational outreach intervention that services providers through interactions with academic detailers (at the VA, these are specially trained clinical pharmacy specialists) using evidence-based research, educational brochures, and clinical dashboards to align prescribing behavior with best practices. The VA ADS developed clinical dashboards to benchmark and monitor academic detailing activities and performance and to identify opportunities for redistributing resources. We used the opioid crisis as an example to highlight key steps in the development of a clinical dashboard. EVALUATION: Testing is an important part of clinical dashboard development. Evaluations of the users perceptions contributed to lessons learned. RESULTS: Data validation, missing data, data availability, standardization, user engagement, and technical limitations were among several challenges the VA ADS encountered during dashboard development. Stakeholder engagement, communication, and flexibility with development time allowed us to develop efficient dashboards. CONCLUSIONS: Health care data and health analytics have transformed the type of clinical care that can be practiced by creating the ability to implement system-wide processes for both population management and quality improvement processes. End users of these VA ADS clinical dashboards can generate priority panel reports and data visualization of key performance indicators to identify areas for improvement or action.

Divergent Solutions to Visual Problem Solving across Mammalian Species.

Our understanding of the neurobiological underpinnings of learning and behavior relies on the use of invasive techniques, which necessitate the use of animal models. However, when different species learn the same task, to what degree are they actually producing the same behavior and engaging homologous neural circuitry? This question has received virtually no recent attention, even as the most powerful new methodologies for measuring and perturbing the nervous system have become increasingly dependent on the use of murine species. Here, we test humans, rats, monkeys, and an evolutionarily intermediate species, tree shrews, on a three alternative, forced choice, visual contrast discrimination task. As anticipated, learning rate, peak performance, and transfer across contrasts was lower in the rat compared to the other species. More interestingly, rats exhibited two major behavioral peculiarities: while monkeys and tree shrews based their choices largely on visual information, rats tended to base their choices on past reward history. Furthermore, as the task became more difficult, rats largely disengaged from the visual stimulus, reverting to innate spatial predispositions in order to collect rewards near chance probability. Our findings highlight the limitation of muridae as models for translational research, at least in the area of visually based decision making.

Breaking the Excitation-Inhibition Balance Makes the Cortical Network's Space-Time Dynamics Distinguish Simple Visual Scenes.

Brain dynamics are often taken to be temporal dynamics of spiking and membrane potentials in a balanced network. Almost all evidence for a balanced network comes from recordings of cell bodies of few single neurons, neglecting more than 99% of the cortical network. We examined the space-time dynamics of excitation and inhibition simultaneously in dendrites and axons over four visual areas of ferrets exposed to visual scenes with stationary and moving objects. The visual stimuli broke the tight balance between excitation and inhibition such that the network exhibited longer episodes of net excitation subsequently balanced by net inhibition, in contrast to a balanced network. Locally in all four areas the amount of net inhibition matched the amount of net excitation with a delay of 125 ms. The space-time dynamics of excitation-inhibition evolved to reduce the complexity of neuron interactions over the whole network to a flow on a low-(3)-dimensional manifold within 80 ms. In contrast to the pure temporal dynamics, the low dimensional flow evolved to distinguish the simple visual scenes.

Trends in naloxone prescriptions prescribed after implementation of a National Academic Detailing Service in the Veterans Health Administration: A preliminary analysis.

OBJECTIVES: To evaluate the effects of the U.S. Veterans Health Administration (VA) National Academic Detailing Service alongside the Opioid Overdose Education and Naloxone Distribution (OEND) program on naloxone prescriptions prescribed from October 2014 to September 2016. METHODS: A retrospective, repeated measures cohort study was conducted to evaluate the effectiveness of a real-world application of academic detailing (AD) alongside OEND on providers' outpatient naloxone prescribing from October 2014 to September 2016. Outcome was the number of naloxone prescriptions prescribed per month per provider. During the study period, VA providers were aware of OEND, but may not have been exposed to academic detailing. Therefore, providers were categorized as exposed when the first OEND-specific academic detailing session was provided during the study period. Generalized estimating equations were used to estimate the association between exposure to academic detailing and monthly naloxone prescriptions prescribed while taking into account the correlation within each provider. Incident rate ratios with 95% CIs were reported. RESULTS: Seven hundred fifty (22.6%) of 3313 providers received at least 1 OEND-specific academic detailing visit. At 1 year, the average number of naloxone prescriptions per month was 3-times greater in AD-exposed providers compared with AD-unexposed providers (95% CI 2.0-5.3); and at 2 years, the average number of naloxone prescriptions was 7-times greater (95% CI 3.0-17.9). Moreover, the average difference in naloxone prescribing from baseline to 2 years was 7.1% greater in AD-exposed providers compared with AD-unexposed providers (95% CI 2.0%-12.5%). CONCLUSIONS: This preliminary analysis provides the first evidence that academic detailing influenced naloxone prescribing rates in a large, integrated health care system at 1 and 2 years. In addition, AD-exposed providers had a higher average difference in naloxone prescribing rate compared with AD-unexposed providers after 2 years of follow-up.

The Second Spiking Threshold: Dynamics of Laminar Network Spiking in the Visual Cortex.

Most neurons have a threshold separating the silent non-spiking state and the state of producing temporal sequences of spikes. But neurons in vivo also have a second threshold, found recently in granular layer neurons of the primary visual cortex, separating spontaneous ongoing spiking from visually evoked spiking driven by sharp transients. Here we examine whether this second threshold exists outside the granular layer and examine details of transitions between spiking states in ferrets exposed to moving objects. We found the second threshold, separating spiking states evoked by stationary and moving visual stimuli from the spontaneous ongoing spiking state, in all layers and zones of areas 17 and 18 indicating that the second threshold is a property of the network. Spontaneous and evoked spiking, thus can easily be distinguished. In addition, the trajectories of spontaneous ongoing states were slow, frequently changing direction. In single trials, sharp as well as smooth and slow transients transform the trajectories to be outward directed, fast and crossing the threshold to become evoked. Although the speeds of the evolution of the evoked states differ, the same domain of the state space is explored indicating uniformity of the evoked states. All evoked states return to the spontaneous evoked spiking state as in a typical mono-stable dynamical system. In single trials, neither the original spiking rates, nor the temporal evolution in state space could distinguish simple visual scenes.

Rate and timing of cortical responses driven by separate sensory channels.

The sense of touch comprises multiple sensory channels that each conveys characteristic signals during interactions with objects. These neural signals must then be integrated in such a way that behaviorally relevant information about the objects is preserved. To understand the process of integration, we implement a simple computational model that describes how the responses of neurons in somatosensory cortex-recorded from awake, behaving monkeys-are shaped by the peripheral input, reconstructed using simulations of neuronal populations that reproduce natural spiking responses in the nerve with millisecond precision. First, we find that the strength of cortical responses is driven by one population of nerve fibers (rapidly adapting) whereas the timing of cortical responses is shaped by the other (Pacinian). Second, we show that input from these sensory channels is integrated in an optimal fashion that exploits the disparate response behaviors of different fiber types.

Multiplexing stimulus information through rate and temporal codes in primate somatosensory cortex.

Our ability to perceive and discriminate textures relies on the transduction and processing of complex, high-frequency vibrations elicited in the fingertip as it is scanned across a surface. How naturalistic vibrations, and by extension texture, are encoded in the responses of neurons in primary somatosensory cortex (S1) is unknown. Combining single unit recordings in awake macaques and perceptual judgments obtained from human subjects, we show that vibratory amplitude is encoded in the strength of the response evoked in S1 neurons. In contrast, the frequency composition of the vibrations, up to 800 Hz, is not encoded in neuronal firing rates, but rather in the phase-locked responses of a subpopulation of neurons. Moreover, analysis of perceptual judgments suggests that spike timing not only conveys stimulus information but also shapes tactile perception. We conclude that information about the amplitude and frequency of natural vibrations is multiplexed at different time scales in S1, and encoded in the rate and temporal patterning of the response, respectively.

Cortical Membrane Potential Dynamics and Laminar Firing during Object Motion.

When an object is introduced moving in the visual field of view, the object maps with different delays in each of the six cortical layers in many visual areas by mechanisms that are poorly understood. We combined voltage sensitive dye (VSD) recordings with laminar recordings of action potentials in visual areas 17, 18, 19 and 21 in ferrets exposed to stationary and moving bars. At the area 17/18 border a moving bar first elicited an ON response in layer 4 and then ON responses in supragranular and infragranular layers, identical to a stationary bar. Shortly after, the moving bar mapped as moving synchronous peak firing across layers. Complex dynamics evolved including feedback from areas 19/21, the computation of a spatially restricted pre-depolarization (SRP), and firing in the direction of cortical motion prior to the mapping of the bar. After 350 ms, the representations of the bar (peak firing and peak VSD signal) in areas 19/21 and 17/18 moved over the cortex in phase. The dynamics comprise putative mechanisms for automatic saliency of novel moving objects, coherent mapping of moving objects across layers and areas, and planning of catch-up saccades.

Spontaneous high-frequency (10-80 Hz) oscillations during up states in the cerebral cortex in vitro.

High-frequency oscillations in cortical networks have been linked to a variety of cognitive and perceptual processes. They have also been recorded in small cortical slices in vitro, indicating that neuronal synchronization at these frequencies is generated in the local cortical circuit. However, in vitro experiments have hitherto necessitated exogenous pharmacological or electrical stimulation to generate robust synchronized activity in the beta/gamma range. Here, we demonstrate that the isolated cortical microcircuitry generates beta and gamma oscillations spontaneously in the absence of externally applied neuromodulators or synaptic agonists. We show this in a spontaneously active slice preparation that engages in slow oscillatory activity similar to activity during slow-wave sleep. beta and gamma synchronization appeared during the up states of the slow oscillation. Simultaneous intracellular and extracellular recordings revealed synchronization between the timing of incoming synaptic events and population activity. This rhythm was mechanistically similar to pharmacologically induced gamma rhythms, as it also included sparse, irregular firing of neurons within the population oscillation, predominant involvement of inhibitory neurons, and a decrease of oscillation frequency after barbiturate application. Finally, we show in a computer model how a synaptic loop between excitatory and inhibitory neurons can explain the emergence of both the slow (<1 Hz) and the beta-range oscillations in the neocortical network. We therefore conclude that oscillations in the beta/gamma range that share mechanisms with activity reported in vivo or in pharmacologically activated in vitro preparations can be generated during slow oscillatory activity in the local cortical circuit, even without exogenous pharmacological or electrical stimulation.

Genetic manipulation of adult mouse neurogenic niches by in vivo electroporation.

Targeted ectopic expression of genes in the adult brain is an invaluable approach for studying many biological processes. This can be accomplished by generating transgenic mice or by virally mediated gene transfer, but these methods are costly and labor intensive. We devised a rapid strategy that allows localized in vivo transfection of plasmid DNA within the adult neurogenic niches without detectable brain damage. Injection of plasmid DNA into the ventricular system or directly into the hippocampus of adult mice, followed by application of electrical current via external electrodes, resulted in transfection of neural stem or progenitor cells and mature neurons. We showed that this strategy can be used for both fate mapping and gain- or loss-of-function experiments. Using this approach, we identified an essential role for cadherins in maintaining the integrity of the lateral ventricle wall. Thus, in vivo electroporation provides a new approach to study the adult brain.