Brain-wide Electrical Spatiotemporal Dynamics Encode Depression Vulnerability.

Brain-wide fluctuations in local field potential oscillations reflect emergent network-level signals that mediate behavior. Cracking the code whereby these oscillations coordinate in time and space (spatiotemporal dynamics) to represent complex behaviors would provide fundamental insights into how the brain signals emotional pathology. Using machine learning, we discover a spatiotemporal dynamic network that predicts the emergence of major depressive disorder (MDD)-related behavioral dysfunction in mice subjected to chronic social defeat stress. Activity patterns in this network originate in prefrontal cortex and ventral striatum, relay through amygdala and ventral tegmental area, and converge in ventral hippocampus. This network is increased by acute threat, and it is also enhanced in three independent models of MDD vulnerability. Finally, we demonstrate that this vulnerability network is biologically distinct from the networks that encode dysfunction after stress. Thus, these findings reveal a convergent mechanism through which MDD vulnerability is mediated in the brain.

Discovery and Optimization of Tambjamines as a Novel Class of Antileishmanial Agents.

Leishmaniasis is a neglected tropical disease that is estimated to afflict over 12 million people. Current drugs for leishmaniasis suffer from serious deficiencies, including toxicity, high cost, modest efficacy, primarily parenteral delivery, and emergence of widespread resistance. We have discovered and developed a natural product-inspired tambjamine chemotype, known to be effective against Plasmodium spp, as a novel class of antileishmanial agents. Herein, we report in vitro and in vivo antileishmanial activities, detailed structure-activity relationships, and metabolic/pharmacokinetic profiles of a large library of tambjamines. A number of tambjamines exhibited excellent potency against both Leishmania mexicana and Leishmania donovani parasites with good safety and metabolic profiles. Notably, tambjamine 110 offered excellent potency and provided partial protection to leishmania-infected mice at 40 and/or 60 mg/kg/10 days of oral treatment. This study presents the first account of antileishmanial activity in the tambjamine family and paves the way for the generation of new oral antileishmanial drugs.

Prenatal environmental stressors impair postnatal microglia function and adult behavior in males.

Gestational exposure to environmental toxins and socioeconomic stressors is epidemiologically linked to neurodevelopmental disorders with strong male bias, such as autism. We model these prenatal risk factors in mice by co-exposing pregnant dams to an environmental pollutant and limited-resource stress, which robustly activates the maternal immune system. Only male offspring display long-lasting behavioral abnormalities and alterations in the activity of brain networks encoding social interactions. Cellularly, prenatal stressors diminish microglial function within the anterior cingulate cortex, a central node of the social coding network, in males during early postnatal development. Precise inhibition of microglial phagocytosis within the anterior cingulate cortex (ACC) of wild-type (WT) mice during the same critical period mimics the impact of prenatal stressors on a male-specific behavior, indicating that environmental stressors alter neural circuit formation in males via impairing microglia function during development.

Brain-wide electrical dynamics encode individual appetitive social behavior.

The architecture whereby activity across many brain regions integrates to encode individual appetitive social behavior remains unknown. Here we measure electrical activity from eight brain regions as mice engage in a social preference assay. We then use machine learning to discover a network that encodes the extent to which individual mice engage another mouse. This network is organized by theta oscillations leading from prelimbic cortex and amygdala that converge on the ventral tegmental area. Network activity is synchronized with cellular firing, and frequency-specific activation of a circuit within this network increases social behavior. Finally, the network generalizes, on a mouse-by-mouse basis, to encode individual differences in social behavior in healthy animals but fails to encode individual behavior in a 'high confidence' genetic model of autism. Thus, our findings reveal the architecture whereby the brain integrates distributed activity across timescales to encode an appetitive brain state underlying individual differences in social behavior.

The impact of conversion to International Classification of Diseases, 10th revision (ICD-10) on an academic ophthalmology practice.

PURPOSE: To determine the financial and clinical impact of conversion from International Classification of Disease, 9th revision (ICD-9) to ICD-10 coding. DESIGN: Retrospective, database study. MATERIALS AND METHODS: Monthly billing and coding data from 44,564 billable patient encounters at an academic ophthalmology practice were analyzed by subspecialty in the 1-year periods before (October 1, 2014, to September 30, 2015) and after (October 1, 2015, to September 30, 2016) conversion from ICD-9 to ICD-10. MAIN OUTCOMES AND MEASURES: Primary outcome measures were payments per visit, relative value units per visit, number of visits, and percentage of high-level visits; secondary measures were denials due to coding errors, charges denied due to coding errors, and percentage of unspecified codes used as a primary diagnosis code. RESULTS: Conversion to ICD-10 did not significantly impact payments per visit ($306.56±$56.50 vs $321.43±$38.12, P=0.42), relative value units per visit (7.15±0.56 vs 7.13±0.84, P=0.95), mean volume of visits (1,887.08±375.02 vs 1,863.83±189.81, P=0.71), or percentage of high-level visits (29.7%±4.9%, 548 of 1,881 vs 30.0%±1.7%, 558 of 1,864, P=0.81). For every 100 visits, the number of coding-related denials increased from 0.98±0.60 to 1.84±0.31 (P<0.001), and denied charges increased from $307.42±$443.39 to $660.86±$239.47 (P=0.002). The monthly percentage of unspecified codes used increased from 25.8%±1.1% (485 of 1,881) to 35.0%±2.3% (653 of 1,864, P<0.001). CONCLUSION: The conversion to ICD-10 did not impact overall revenue or clinical volume in this practice setting, but coding-related denials, denied charges, and the use of unspecified codes increased significantly. We expect these denials to increase in the next year in the absence of Medicare's 1-year grace period.

Dysregulation of Prefrontal Cortex-Mediated Slow-Evolving Limbic Dynamics Drives Stress-Induced Emotional Pathology.

Circuits distributed across cortico-limbic brain regions compose the networks that mediate emotional behavior. The prefrontal cortex (PFC) regulates ultraslow (<1 Hz) dynamics across these networks, and PFC dysfunction is implicated in stress-related illnesses including major depressive disorder (MDD). To uncover the mechanism whereby stress-induced changes in PFC circuitry alter emotional networks to yield pathology, we used a multi-disciplinary approach including in vivo recordings in mice and chronic social defeat stress. Our network model, inferred using machine learning, linked stress-induced behavioral pathology to the capacity of PFC to synchronize amygdala and VTA activity. Direct stimulation of PFC-amygdala circuitry with DREADDs normalized PFC-dependent limbic synchrony in stress-susceptible animals and restored normal behavior. In addition to providing insights into MDD mechanisms, our findings demonstrate an interdisciplinary approach that can be used to identify the large-scale network changes that underlie complex emotional pathologies and the specific network nodes that can be used to develop targeted interventions.