Microscopic Origin of the Entropy of Astrophysical Black Holes.

We construct an infinite family of microstates for black holes in Minkowski spacetime which have effective semiclassical descriptions in terms of collapsing dust shells in the black hole interior. Quantum mechanical wormholes cause these states to have exponentially small, but universal, overlaps. We show that these overlaps imply that the microstates span a Hilbert space of log dimension equal to the event horizon area divided by four times the Newton constant, explaining the statistical origin of the Bekenstein-Hawking entropy.

Physical effects of learning.

Interacting many-body physical systems ranging from neural networks in the brain to folding proteins to self-modifying electrical circuits can learn to perform diverse tasks. This learning, both in nature and in engineered systems, can occur through evolutionary selection or through dynamical rules that drive active learning from experience. Here, we show that learning in linear physical networks with weak input signals leaves architectural imprints on the Hessian of a physical system. Compared to a generic organization of the system components, (a) the effective physical dimension of the response to inputs decreases, (b) the response of physical degrees of freedom to random perturbations (or system "susceptibility") increases, and (c) the low-eigenvalue eigenvectors of the Hessian align with the task. Overall, these effects embody the typical scenario for learning processes in physical systems in the weak input regime, suggesting ways of discovering whether a physical network may have been trained.

Oral Treprostinil is Associated with Improved Survival in FREEDOM-EV and its Open-Label Extension.

INTRODUCTION: In the event-driven FREEDOM-EV trial, oral treprostinil delayed clinical worsening in patients with pulmonary arterial hypertension (PAH). Open-label extension studies offer additional data about tolerability, efficacy, and survival, especially for those initially assigned placebo. The aim of the current study was to determine if oral treprostinil changed survival when considering the parent and extension study, if treprostinil provides functional benefits for participants initially assigned to placebo, and if the benefits observed for those treated with treprostinil were durable. METHODS: Both active and placebo participants from FREEDOM-EV could enroll in the FREEDOM-EV open-label extension (OLE) study after experiencing an investigator-assessed clinical worsening event or after parent study closure. All participants in the OLE were offered open-label oral treprostinil. Previously assigned placebo participants titrated to maximally tolerated doses; previously assigned treprostinil participants continued dose titration. We repeated assessments including functional class and 6-min walk distance (6MWD) at 12-week intervals and measured N-terminal pro-brain natriuretic peptide (NT-proBNP) at week 48. Survival was estimated by Kaplan-Meier analysis, and we estimated hazard ratio (HR) using Cox proportional hazards. RESULTS: Of 690 FREEDOM-EV participants, 470 enrolled in the OLE; vital status was available for 89% of initial Freedom-EV participants. When considering the combined parent and open-label data, initial assignment to oral treprostinil reduced mortality (HR 0.64, 95% confidence interval 0.46-0.91, p = 0.013); absolute risk reduction was 9%. Participants randomized to placebo who initiated oral treprostinil after clinical worsening and tolerated treatment through week 48 demonstrated favorable shifts in functional class (p < 0.0001), 6MWD improvements of + 84 m (p < 0.0001), and a reduction in NT-proBNP of - 778 pg/mL (p = 0.02), compared to OLE baseline. Modest trends toward benefit were measured for those initially assigned placebo who did not have clinical worsening, and 132/144 (92%) of treprostinil assigned participants without clinical worsening remained on drug at week 48 in the OLE study. Adverse events were consistent with FREEDOM-EV. CONCLUSION: Initial treprostinil assignment improved survival in the entire data set; those who began treprostinil after a clinical worsening in the placebo arm and tolerated drug to week 48 enjoyed substantial functional gains. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT01560637.

Parenteral treprostinil induction for rapid attainment of therapeutic doses of oral treprostinil.

RATIONALE: Oral treprostinil slows disease progression and improves exercise capacity in pulmonary arterial hypertension; however, titration can be prolonged. Published data suggests prostacyclin-naïve patients achieve total daily oral treprostinil doses of about 6 mg by Week 16, while those on prior parenteral treprostinil reach higher doses at the same timepoint. OBJECTIVES: EXPEDITE (NCT03497689), a single-arm, multicenter study, assessed the efficacy of rapid parenteral treprostinil induction to quickly reach higher doses of oral treprostinil for the treatment of pulmonary arterial hypertension. METHODS: Parenteral treprostinil was titrated for 2-8 weeks, followed by cross-titration of oral treprostinil. The primary endpoint was percentage of patients reaching ≥12 mg daily of oral treprostinil at Week 16. Secondary endpoints included clinical changes from baseline to Week 16. RESULTS: Twenty-nine prostacyclin-naïve patients were included in efficacy analyses. At Week 16, the mean daily oral treprostinil dose was 16.4 mg; 79% of patients met the primary endpoint. From baseline to Week 16, median REVEAL Lite 2 score improved (decreased) from 6 to 3.5 (p = 0.0006). Statistically significant improvements were also seen in World Health Organization Functional Class, N-terminal-pro brain natriuretic peptide levels, 6-minute walk distance, right atrial area, Borg Dyspnea Score, and emPHasis-10 score. Favorable trends were seen in risk stratification, echocardiography parameters, disease symptoms, and treatment satisfaction. CONCLUSION: Short-course parenteral treprostinil induction resulted in oral treprostinil doses over twice those reported in de novo initiations and may be a useful approach to quickly achieve the therapeutic benefits of oral treprostinil.

Implementing the EXPEDITE parenteral induction protocol: Rapid parenteral treprostinil titration and transition to oral treprostinil.

Treprostinil is a prostacyclin analogue that targets multiple cellular receptors to treat pulmonary arterial hypertension (PAH). In certain scenarios, patients may require aggressive treprostinil titration. Several studies have demonstrated that higher doses of treprostinil lead to greater clinical benefit. Data supports successful transitions from parenteral to oral treprostinil; however, administration routes, transition duration, and transition setting vary in the real-world. The EXPEDITE clinical trial (NCT03497689) prospectively studied whether rapid parenteral treprostinil induction can be used to achieve high doses of oral treprostinil (total daily dose: ≥12 mg) in prostacyclin naïve PAH patients. Parenteral prostacyclin induction may be more appropriate for patients who need to reach therapeutic dosing more urgently than longer titration durations reported with conventional de novo oral treprostinil initiation. This summary provides strategies utilized in EXPEDITE. Parenteral treprostinil was initiated at 2 ng/kg/min intravenously or subcutaneously; clinicians determined the frequency and dose increment of up-titration. Two distinct transition schedules from parenteral to oral treprostinil were employed: rapid cross-titration in an inpatient setting (median: 2 days) or gradual cross-titration in an outpatient setting (median: 5 days). Patient status was closely monitored after transition; oral treprostinil dose was titrated to clinical effect and tolerability. Factors considered when individualizing dosing strategies included parenteral and oral treprostinil target doses, nursing support, patient education, medication counseling and adverse events management. EXPEDITE demonstrated the time to a therapeutic dose of oral treprostinil is significantly shorter when utilizing a short-term parenteral induction strategy and may be suitable for patients requiring aggressive titration of oral treprostinil.

Playing it safe: information constrains collective betting strategies.

Every interaction of a living organism with its environment involves the placement of a bet. Armed with partial knowledge about a stochastic world, the organism must decide its next step or near-term strategy, an act that implicitly or explicitly involves the assumption of a model of the world. Better information about environmental statistics can improve the bet quality, but in practice resources for information gathering are always limited. We argue that theories of optimal inference dictate that "complex" models are harder to infer with bounded information and lead to larger prediction errors. Thus, we propose a principle of playing it safe where, given finite information gathering capacity, biological systems should be biased towards simpler models of the world, and thereby to less risky betting strategies. In the framework of Bayesian inference, we show that there is an optimally safe adaptation strategy determined by the Bayesian prior. We then demonstrate that, in the context of stochastic phenotypic switching by bacteria, implementation of our principle of "playing it safe" increases fitness (population growth rate) of the bacterial collective. We suggest that the principle applies broadly to problems of adaptation, learning and evolution, and illuminates the types of environments in which organisms are able to thrive.

Playing it safe: information constrains collective betting strategies.

Every interaction of a living organism with its environment involves the placement of a bet. Armed with partial knowledge about a stochastic world, the organism must decide its next step or near-term strategy, an act that implicitly or explicitly involves the assumption of a model of the world. Better information about environmental statistics can improve the bet quality, but in practice resources for information gathering are always limited. We argue that theories of optimal inference dictate that "complex" models are harder to infer with bounded information and lead to larger prediction errors. Thus, we propose a principle of playing it safe where, given finite information gathering capacity, biological systems should be biased towards simpler models of the world, and thereby to less risky betting strategies. In the framework of Bayesian inference, we show that there is an optimally safe adaptation strategy determined by the Bayesian prior. We then demonstrate that, in the context of stochastic phenotypic switching by bacteria, implementation of our principle of "playing it safe" increases fitness (population growth rate) of the bacterial collective. We suggest that the principle applies broadly to problems of adaptation, learning and evolution, and illuminates the types of environments in which organisms are able to thrive.

Time as a supervisor: temporal regularity and auditory object learning.

Sensory systems appear to learn to transform incoming sensory information into perceptual representations, or "objects," that can inform and guide behavior with minimal explicit supervision. Here, we propose that the auditory system can achieve this goal by using time as a supervisor, i.e., by learning features of a stimulus that are temporally regular. We will show that this procedure generates a feature space sufficient to support fundamental computations of auditory perception. In detail, we consider the problem of discriminating between instances of a prototypical class of natural auditory objects, i.e., rhesus macaque vocalizations. We test discrimination in two ethologically relevant tasks: discrimination in a cluttered acoustic background and generalization to discriminate between novel exemplars. We show that an algorithm that learns these temporally regular features affords better or equivalent discrimination and generalization than conventional feature-selection algorithms, i.e., principal component analysis and independent component analysis. Our findings suggest that the slow temporal features of auditory stimuli may be sufficient for parsing auditory scenes and that the auditory brain could utilize these slowly changing temporal features.

Barriers and facilitators to interhospital transfer of acute pulmonary embolism: An inductive qualitative analysis.

Background: Interhospital transfer (IHT) of patients with acute life-threatening pulmonary embolism (PE) is necessary to facilitate specialized care and access to advanced therapies. Our goal was to understand what barriers and facilitators may exist during this transfer process from the perspective of both receiving and referring physicians. Methods: This qualitative descriptive study explored physician experience taking care of patients with life threatening PE. Subject matter expert physicians across several different specialties from academic and community United States hospitals participated in qualitative semi-structured interviews. Interview transcripts were subsequently analyzed using inductive qualitative description approach. Results: Four major themes were identified as barriers that impede IHT among patients with life threatening PE. Inefficient communication which mainly pertained to difficulty when multiple points of contact were required to complete a transfer. Subjectivity in the indication for transfer which highlighted the importance of physicians understanding how to use standardized risk stratification tools and to properly triage these patients. Delays in data acquisition were identified in regards to both obtaining clinical information and imaging in a timely fashion. Operation barriers which included difficulty finding available beds for transfer and poor weather conditions inhibiting transportation. In contrast, two main facilitators to transfer were identified: good communication and reliance on colleagues and dedicated team for transferring and treating PE patients. Conclusion: The most prominent themes identified as barriers to IHT for patients with acute life-threatening PE were: (1) inefficient communication, (2) subjectivity in the indication for transfer, (3) delays in data acquisition (imaging or clinical), and (4) operational barriers. Themes identified as facilitators that enable the transfer of patients were: (1) good communication and (2) a dedicated transfer team. The themes presented in our study are useful in identifying opportunities to optimize the IHT of patients with acute PE and improve patient care. These opportunities include instituting educational programs, streamlining the transfer process, and formulating a consensus statement to serve as a guideline regarding IHT of patients with acute PE.

How Occam's razor guides human decision-making.

Occam's razor is the principle that, all else being equal, simpler explanations should be preferred over more complex ones. This principle is thought to play a role in human perception and decision-making, but the nature of our presumed preference for simplicity is not understood. Here we use preregistered behavioral experiments informed by formal theories of statistical model selection to show that, when faced with uncertain evidence, human subjects exhibit preferences for particular, theoretically grounded forms of simplicity of the alternative explanations. These forms of simplicity can be understood in terms of geometrical features of statistical models treated as manifolds in the space of the probability distributions, in particular their dimensionality, boundaries, volume, and curvature. The simplicity preferences driven by these features, which are also exhibited by artificial neural networks trained to optimize performance on comparable tasks, generally improve decision accuracy, because they minimize over-sensitivity to noisy observations (i.e., overfitting). However, unlike for artificial networks, for human subjects these preferences persist even when they are maladaptive with respect to the task training and instructions. Thus, these preferences are not simply transient optimizations for particular task conditions but rather a more general feature of human decision-making. Taken together, our results imply that principled notions of statistical model complexity have direct, quantitative relevance to human and machine decision-making and establish a new understanding of the computational foundations, and behavioral benefits, of our predilection for inferring simplicity in the latent properties of our complex world.

Effects of COVID-19 pandemic on the management of pulmonary hypertension.

The coronavirus of 2019 (COVID-19) disrupted delivery of healthcare. Patients with pulmonary hypertension (PH), especially pulmonary arterial hypertension (PAH), require significant resources for both diagnosis and management and are at high risk for decompensation due to disruption in their care. A survey consisting of 47 questions related to the care of patients with PH was designed by the American College of Chest Physicians 2020-2021 Pulmonary Vascular Disease (PVD) NetWork Steering Committee and sent to all members of the PVD NetWork, as well as the multiple other professional networks for PH. Participation was voluntary and anonymous. Responses were collected from November 2020 through February 2021. Ninety-five providers responded to this survey. The majority (93%) believe that care of PH patients has been affected by the pandemic. Sixty-seven percent observed decreased referrals for PH evaluation. Prior to the pandemic, only 15% used telemedicine for management of PH patients compared to 84% during the pandemic. Telemedicine was used most for follow up of selected low-risk patients (49%). While 22% respondents were completely willing to prescribe new PAH therapy via telemedicine, 11% respondents were completely unwilling. Comfort levels differed based on type of medication being prescribed. Over 90% of providers experienced disruptions in obtaining testing and 31% experienced disruptions in renewal or approval of medications. Overall, providers perceived that the COVID-19 pandemic caused significant disruption of care for PH patients. Telemedicine utilization increased but was used mostly in low-risk patients. Some providers had a decreased level of comfort prescribing PAH therapy via telemedicine encounters.

Efficient processing of natural scenes in visual cortex.

Neural circuits in the periphery of the visual, auditory, and olfactory systems are believed to use limited resources efficiently to represent sensory information by adapting to the statistical structure of the natural environment. This "efficient coding" principle has been used to explain many aspects of early visual circuits including the distribution of photoreceptors, the mosaic geometry and center-surround structure of retinal receptive fields, the excess OFF pathways relative to ON pathways, saccade statistics, and the structure of simple cell receptive fields in V1. We know less about the extent to which such adaptations may occur in deeper areas of cortex beyond V1. We thus review recent developments showing that the perception of visual textures, which depends on processing in V2 and beyond in mammals, is adapted in rats and humans to the multi-point statistics of luminance in natural scenes. These results suggest that central circuits in the visual brain are adapted for seeing key aspects of natural scenes. We conclude by discussing how adaptation to natural temporal statistics may aid in learning and representing visual objects, and propose two challenges for the future: (1) explaining the distribution of shape sensitivity in the ventral visual stream from the statistics of object shape in natural images, and (2) explaining cell types of the vertebrate retina in terms of feature detectors that are adapted to the spatio-temporal structures of natural stimuli. We also discuss how new methods based on machine learning may complement the normative, principles-based approach to theoretical neuroscience.

A scale-dependent measure of system dimensionality.

A fundamental problem in science is uncovering the effective number of degrees of freedom in a complex system: its dimensionality. A system's dimensionality depends on its spatiotemporal scale. Here, we introduce a scale-dependent generalization of a classic enumeration of latent variables, the participation ratio. We demonstrate how the scale-dependent participation ratio identifies the appropriate dimension at local, intermediate, and global scales in several systems such as the Lorenz attractor, hidden Markov models, and switching linear dynamical systems. We show analytically how, at different limiting scales, the scale-dependent participation ratio relates to well-established measures of dimensionality. This measure applied in neural population recordings across multiple brain areas and brain states shows fundamental trends in the dimensionality of neural activity-for example, in behaviorally engaged versus spontaneous states. Our novel method unifies widely used measures of dimensionality and applies broadly to multivariate data across several fields of science.

Disorder and the Neural Representation of Complex Odors.

Animals smelling in the real world use a small number of receptors to sense a vast number of natural molecular mixtures, and proceed to learn arbitrary associations between odors and valences. Here, we propose how the architecture of olfactory circuits leverages disorder, diffuse sensing and redundancy in representation to meet these immense complementary challenges. First, the diffuse and disordered binding of receptors to many molecules compresses a vast but sparsely-structured odor space into a small receptor space, yielding an odor code that preserves similarity in a precise sense. Introducing any order/structure in the sensing degrades similarity preservation. Next, lateral interactions further reduce the correlation present in the low-dimensional receptor code. Finally, expansive disordered projections from the periphery to the central brain reconfigure the densely packed information into a high-dimensional representation, which contains multiple redundant subsets from which downstream neurons can learn flexible associations and valences. Moreover, introducing any order in the expansive projections degrades the ability to recall the learned associations in the presence of noise. We test our theory empirically using data from Drosophila. Our theory suggests that the neural processing of sparse but high-dimensional olfactory information differs from the other senses in its fundamental use of disorder.

A scaling law in CRISPR repertoire sizes arises from the avoidance of autoimmunity.

Some prokaryotes possess CRISPR-Cas systems that use DNA segments called spacers, which are acquired from invading phages, to guide immune defense. Here, we propose that cross-reactive CRISPR targeting can, however, lead to "heterologous autoimmunity," whereby foreign spacers guide self-targeting in a spacer-length-dependent fashion. Balancing antiviral defense against autoimmunity predicts a scaling relation between spacer length and CRISPR repertoire size. We find evidence for this scaling through a comparative analysis of sequenced prokaryotic genomes and show that this association also holds at the level of CRISPR types. By contrast, the scaling is absent in strains with nonfunctional CRISPR loci. Finally, we demonstrate that stochastic spacer loss can explain variations around the scaling relation, even between strains of the same species. Our results suggest that heterologous autoimmunity is a selective factor shaping the evolution of CRISPR-Cas systems, analogous to the trade-offs between immune specificity, breadth, and autoimmunity that constrain the diversity of adaptive immune systems in vertebrates.

Delphi consensus recommendation for optimization of pulmonary hypertension therapy focusing on switching from a phosphodiesterase 5 inhibitor to riociguat.

Dual combination therapy with a phosphodiesterase-5 inhibitor (PDE5i) and endothelin receptor antagonist is recommended for most patients with intermediate-risk pulmonary arterial hypertension (PAH). The RESPITE and REPLACE studies suggest that switching from a PDE5i to a soluble guanylate cyclase (sGC) activator may provide clinical improvement in this situation. The optimal approach to escalation or transition of therapy in this or other scenarios is not well defined. We developed an expert consensus statement on the transition to sGC and other treatment escalations and transitions in PAH using a modified Delphi process. The Delphi process used a panel of 20 physicians with expertise in PAH. Panelists answered three questionnaires on the management of treatment escalations and transitions in PAH. The initial questionnaire included open-ended questions. Later questionnaires consolidated the responses into statements that panelists rated on a Likert scale from -5 (strongly disagree) to +5 (strongly agree) to determine consensus. The Delphi process produced several consensus recommendations. Escalation should be considered for patients who are at high risk or not achieving treatment goals, by adding an agent from a new class, switching from oral to parenteral prostacyclins, or increasing the dose. Switching to a new class or within a class should be considered if tolerability or other considerations unrelated to efficacy are affecting adherence. Switching from a PDE5i to an SGC activator may benefit patients with intermediate risk who are not improving on their present therapy. These consensus-based recommendations may be helpful to clinicians and beneficial for patients when evidence-based guidance is unavailable.

Utilization of risk assessment tools in management of PAH: A PAH provider survey.

Pulmonary arterial hypertension (PAH) is a chronically progressive fatal disease. A goal-oriented approach to achieve low risk status has been associated with improved survival. A variety of risk stratification tools are available, but use is low. We conducted a survey to assess potential reasons for under-utilization. We conducted a survey-based study of global PAH disease specialists with a goal of assessing risk assessment utilization and identifying modifiable barriers to use. The survey was designed by the American College of Chest Physicians' Pulmonary Vascular Diseases (PVD) NetWork. Respondents were global members of the PVD NetWork and Pulmonary Hypertension Association. Survey invitations were sent electronically to all members. Participation was anonymous and no provider or patient level data was collected. Participants from four countries responded with the majority (84%) being from the United States. Our survey found suboptimal use of any risk stratification tool with 71/112 (63%) reporting use. A total of 85% of the respondents had more than 5 years of experience in managing PAH. REVEAL 2.0 and European Society of Cardiology/European Respiratory Society risk tools were the most commonly used. A total of 44 (65%) surveyed felt that use of risk tools led to change in PAH therapies. Only 6 (9%) felt they prompted additional testing or changed the frequency of follow-up. A total of 5 (7%) reported they prompted goals of care/palliative care discussions and 2 (3%) that they triggered lung transplant referral. The vast majority indicated that incorporation of risk tools into electronic medical records (EMR) would improve utilization. PAH risk assessment tools remain under-utilized. Most respondents were experienced PAH clinicians. More than one-third were not routinely using risk tools. Most felt that risk tools led to PAH therapy changes but few reported impacts on other aspects of care. The most commonly identified barriers to use were time constraints and lack of integration with EMR.

Human inference reflects a normative balance of complexity and accuracy.

We must often infer latent properties of the world from noisy and changing observations. Complex, probabilistic approaches to this challenge such as Bayesian inference are accurate but cognitively demanding, relying on extensive working memory and adaptive processing. Simple heuristics are easy to implement but may be less accurate. What is the appropriate balance between complexity and accuracy? Here we model a hierarchy of strategies of variable complexity and find a power law of diminishing returns: increasing complexity gives progressively smaller gains in accuracy. The rate of diminishing returns depends systematically on the statistical uncertainty in the world, such that complex strategies do not provide substantial benefits over simple ones when uncertainty is either too high or too low. In between, there is a complexity dividend. In two psychophysical experiments, we confirm specific model predictions about how working memory and adaptivity should be modulated by uncertainty.

Real-world dosing characteristics and utilization of parenteral treprostinil in the outpatient setting.

Real-world dosing and titration of parenteral (subcutaneous, SC; intravenous, IV) prostacyclin, a mainstay of pulmonary arterial hypertension (PAH) treatment, is not always consistent with prescribing information or randomized trials and has yet to be adequately characterized. The current study describes real-world outpatient dosing and titration patterns over time, in PAH patients initiated on SC or IV treprostinil. A longitudinal, cross-sectional analysis of medication shipment records from US specialty pharmacy services between 2009 and 2018 was conducted to determine dosing and titration patterns of SC or IV treprostinil in the outpatient setting beginning with the patient's first shipment. The sample for analysis included shipment records for 2647 patients (IV = 1040, SC = 1607). Although more patients were started on SC treprostinil than IV, median initial outpatient IV treprostinil dose (11 ng/kg/min at month on therapy one [MOT1]) was consistently and statistically significantly higher than initial outpatient SC dose (7.5 ng/kg/min at MOT1; p < 0.01). However, the SC treprostinil dose acceleration rate (DAR) was more aggressive from MOT1 to MOT6, MOT12, and MOT24, leading to a higher dose achieved at later timepoints. All between-group DAR differences were statistically significant (p < 0.001). This study provides evidence that real-world prescribing patterns of parenteral treprostinil in the outpatient setting differs from dosing described in pivotal trials, with important differences between SC and IV administration. Although initial outpatient IV treprostinil dosing was higher, SC titration was accelerated more aggressively and a higher dose was achieved by MOT3 suggesting that factors specific to SC administration (e.g., site pain) may not limit dosing and titration as previously thought.

Connectivity and dynamics in the olfactory bulb.

Dendrodendritic interactions between excitatory mitral cells and inhibitory granule cells in the olfactory bulb create a dense interaction network, reorganizing sensory representations of odors and, consequently, perception. Large-scale computational models are needed for revealing how the collective behavior of this network emerges from its global architecture. We propose an approach where we summarize anatomical information through dendritic geometry and density distributions which we use to calculate the connection probability between mitral and granule cells, while capturing activity patterns of each cell type in the neural dynamical systems theory of Izhikevich. In this way, we generate an efficient, anatomically and physiologically realistic large-scale model of the olfactory bulb network. Our model reproduces known connectivity between sister vs. non-sister mitral cells; measured patterns of lateral inhibition; and theta, beta, and gamma oscillations. The model in turn predicts testable relationships between network structure and several functional properties, including lateral inhibition, odor pattern decorrelation, and LFP oscillation frequency. We use the model to explore the influence of cortex on the olfactory bulb, demonstrating possible mechanisms by which cortical feedback to mitral cells or granule cells can influence bulbar activity, as well as how neurogenesis can improve bulbar decorrelation without requiring cell death. Our methodology provides a tractable tool for other researchers.