Mild respiratory COVID can cause multi-lineage neural cell and myelin dysregulation.

COVID survivors frequently experience lingering neurological symptoms that resemble cancer-therapy-related cognitive impairment, a syndrome for which white matter microglial reactivity and consequent neural dysregulation is central. Here, we explored the neurobiological effects of respiratory SARS-CoV-2 infection and found white-matter-selective microglial reactivity in mice and humans. Following mild respiratory COVID in mice, persistently impaired hippocampal neurogenesis, decreased oligodendrocytes, and myelin loss were evident together with elevated CSF cytokines/chemokines including CCL11. Systemic CCL11 administration specifically caused hippocampal microglial reactivity and impaired neurogenesis. Concordantly, humans with lasting cognitive symptoms post-COVID exhibit elevated CCL11 levels. Compared with SARS-CoV-2, mild respiratory influenza in mice caused similar patterns of white-matter-selective microglial reactivity, oligodendrocyte loss, impaired neurogenesis, and elevated CCL11 at early time points, but after influenza, only elevated CCL11 and hippocampal pathology persisted. These findings illustrate similar neuropathophysiology after cancer therapy and respiratory SARS-CoV-2 infection which may contribute to cognitive impairment following even mild COVID.

Myelin plasticity in the ventral tegmental area is required for opioid reward.

All drugs of abuse induce long-lasting changes in synaptic transmission and neural circuit function that underlie substance-use disorders1,2. Another recently appreciated mechanism of neural circuit plasticity is mediated through activity-regulated changes in myelin that can tune circuit function and influence cognitive behaviour3-7. Here we explore the role of myelin plasticity in dopaminergic circuitry and reward learning. We demonstrate that dopaminergic neuronal activity-regulated myelin plasticity is a key modulator of dopaminergic circuit function and opioid reward. Oligodendroglial lineage cells respond to dopaminergic neuronal activity evoked by optogenetic stimulation of dopaminergic neurons, optogenetic inhibition of GABAergic neurons, or administration of morphine. These oligodendroglial changes are evident selectively within the ventral tegmental area but not along the axonal projections in the medial forebrain bundle nor within the target nucleus accumbens. Genetic blockade of oligodendrogenesis dampens dopamine release dynamics in nucleus accumbens and impairs behavioural conditioning to morphine. Taken together, these findings underscore a critical role for oligodendrogenesis in reward learning and identify dopaminergic neuronal activity-regulated myelin plasticity as an important circuit modification that is required for opioid reward.

Microbial modulation via cross-fostering prevents the effects of pervasive environmental stressors on microglia and social behavior, but not the dopamine system.

Environmental toxicant exposure, including air pollution, is increasing worldwide. However, toxicant exposures are not equitably distributed. Rather, low-income and minority communities bear the greatest burden, along with higher levels of psychosocial stress. Both air pollution and maternal stress during pregnancy have been linked to neurodevelopmental disorders such as autism, but biological mechanisms and targets for therapeutic intervention remain poorly understood. We demonstrate that combined prenatal exposure to air pollution (diesel exhaust particles, DEP) and maternal stress (MS) in mice induces social behavior deficits only in male offspring, in line with the male bias in autism. These behavioral deficits are accompanied by changes in microglial morphology and gene expression as well as decreased dopamine receptor expression and dopaminergic fiber input in the nucleus accumbens (NAc). Importantly, the gut-brain axis has been implicated in ASD, and both microglia and the dopamine system are sensitive to the composition of the gut microbiome. In line with this, we find that the composition of the gut microbiome and the structure of the intestinal epithelium are significantly shifted in DEP/MS-exposed males. Excitingly, both the DEP/MS-induced social deficits and microglial alterations in males are prevented by shifting the gut microbiome at birth via a cross-fostering procedure. However, while social deficits in DEP/MS males can be reversed by chemogenetic activation of dopamine neurons in the ventral tegmental area, modulation of the gut microbiome does not impact dopamine endpoints. These findings demonstrate male-specific changes in the gut-brain axis following DEP/MS and suggest that the gut microbiome is an important modulator of both social behavior and microglia.

Neonatal immune challenge induces female-specific changes in social behavior and somatostatin cell number.

Decreases in social behavior are a hallmark aspect of acute "sickness behavior" in response to infection. However, immune insults that occur during the perinatal period may have long-lasting consequences for adult social behavior by impacting the developmental organization of underlying neural circuits. Microglia, the resident immune cells of the central nervous system, are sensitive to immune stimulation and play a critical role in the developmental sculpting of neural circuits, making them likely mediators of this process. Here, we investigated the impact of a postnatal day (PND) 4 lipopolysaccharide (LPS) challenge on social behavior in adult mice. Somewhat surprisingly, neonatal LPS treatment decreased sociability in adult female, but not male mice. LPS-treated females also displayed reduced social interaction and social memory in a social discrimination task as compared to saline-treated females. Somatostatin (SST) interneurons within the anterior cingulate cortex (ACC) have recently been suggested to modulate a variety of social behaviors. Interestingly, the female-specific changes in social behavior observed here were accompanied by an increase in SST interneuron number in the ACC. Finally, these changes in social behavior and SST cell number do not appear to depend on microglial inflammatory signaling, because microglia-specific genetic knock-down of myeloid differentiation response protein 88 (MyD88; the removal of which prevents LPS from increasing proinflammatory cytokines such as TNFα and IL-1ß) did not prevent these LPS-induced changes. This study provides novel evidence for enduring effects of neonatal immune activation on social behavior and SST interneurons in females, largely independent of microglial inflammatory signaling.

Provider's exposure to diversity contributes to socioeconomic disparities in lumbar and cervical fusion outcomes.

Background: Studies report patient race, income, and education influence spinal fusion outcomes; fewer studies, however, examine the influence of provider factors such as exposure to diversity or cultural sensitivity. Objective: To examine how providers' experience with diverse patient populations affects spinal fusion outcomes. Methods: Retrospective review of 39,680 patients undergoing lumbar and cervical fusions, 2003-2021, in Clinformatics® Data Mart national database. We used the provider patient racial diversity index (pRDI)-a published metric of physician exposure to diverse patients-to divide patients into groups based their provider's category (I, II, III) where patients treated by category III providers had surgeons with the most diverse patient populations. Multivariate regression models on propensity score-matched cohorts examined the association between patient SES and provider category on post-operative outcomes. Results: Black patients had decreased discharge home (OR 0.67; 95% CI 0.54-0.83) compared to white patients. Patients treated by category III providers had increased length of stay (Coeff. 0.62; 95% CI 0.43-0.81), charge (Coeff. 36800; 95% CI 29,200-44,400), and decreased discharge home (OR 0.90; 95% CI 0.83-0.97) compared to patients treated by category I providers. Asian patients treated by category II providers had decreased readmission (OR 0.38; 95% CI 0.14-0.96), and Black patients treated by category III providers had increased discharge home (OR 1.41; 95% CI 1.1-1.9) compared to those treated by category I providers. Conclusion: While our study found two specific instances of improved spine surgery outcomes for minority patients treated by providers serving diverse patient populations, we present mixed findings overall. This study serves as the foundation for future research to better understand how provider pRDI affects outcomes in patients undergoing lumbar and cervical spine surgery.

Costs and Outcomes of Total Joint Arthroplasty in Medicare Beneficiaries Are Not Meaningfully Associated with Industry Payments.

BACKGROUND: Prior studies have demonstrated that industry payments affect physician prescribing patterns, but their effect on orthopaedic surgical costs is unknown. This study examines the relationship between industry payments and the total costs of primary total joint arthroplasty, as well as operating room cost, length of stay, 30-day mortality, and 30-day readmission. METHODS: Open Payments data were matched across a 20% sample of Medicare-insured patients undergoing primary elective total hip arthroplasty (THA) (n = 130,872) performed by 7,539 surgeons or primary elective total knee arthroplasty (TKA) (n = 230,856) performed by 8,977 surgeons from 2013 to 2015. Patient, hospital, and surgeon-specific factors were gathered. Total and operating room costs, length of stay, mortality, and readmissions were recorded. Multivariable linear and logistic regression models were used to identify the risk-adjusted relationships between industry payments and the primary and secondary outcomes. RESULTS: In this study, 96.7% of THA surgeons and 97.4% of TKA surgeons received industry payments. After multivariable risk adjustment, for each $1,000 increase in industry payments, the total costs of THA increased by $0.50 (0.003% of total costs) and the operating room costs of THA increased by $0.20 (0.003% of total costs). Industry payments were not associated with TKA cost. Industry payments were not associated with 30-day mortality after either THA or TKA. Higher industry payments were independently associated with a marginal decrease in the length of stay for patients undergoing THA (0.0045 days per $1,000) or TKA (0.0035 days per $1,000) and a <0.1% increase in the odds of 30-day readmission after THA for every $1,000 in industry payments. The median total THA costs were $300 higher (p < 0.001), whereas the median TKA costs were $150 lower (p < 0.001), for surgeons receiving the highest 5% of industry payments. These surgical procedures were more often performed in large urban areas, in hospitals with a higher number of beds, with a higher wage index, and by more experienced surgeons and were associated with a 0.4 to 1-day shorter length of stay (p < 0.001). CONCLUSIONS: Although most arthroplasty surgeons received industry payments, a minority of surgeons received the majority of payments. Overall, arthroplasty costs and outcomes were not meaningfully impacted by industry relationships. LEVEL OF EVIDENCE: Prognostic Level III . See Instructions for Authors for a complete description of levels of evidence.

Barriers to neurosurgery for medical students: a national study focused on the intersectionality of gender and race.

OBJECTIVE: Despite 51.2% of medical school graduates being female, only 29.8% of neurosurgery residency applicants are female. Furthermore, only 12.6% of neurosurgery applicants identify as underrepresented in medicine (URM). Evaluating the entry barriers for female and URM students is crucial in promoting the equity and diversity of the neurosurgical workforce. The objective of this study was to evaluate barriers to neurosurgery for medical students while considering the interaction between gender and race. METHODS: A Qualtrics survey was distributed widely to US medical students, assessing 14 factors of hesitancy toward neurosurgery. Likert scale responses, representing statement agreeability, converted to numeric values on a 7-point scale were analyzed by Mann-Whitney U-test and ANOVA comparisons with Bonferroni correction. RESULTS: Of 540 respondents, 68.7% were female and 22.6% were URM. There were 22.6% male non-URM, 7.4% male URM, 53.5% female non-URM, and 15.2% female URM respondents. The predominant reasons for hesitancy toward neurosurgery included work/life integration, length of training, competitiveness of residency position, and perceived malignancy of the field. Females were more hesitant toward neurosurgery due to maternity/paternity needs (p = 0.005), the absence of seeing people like them in the field (p < 0.001), and opportunities to pursue health equity work (p < 0.001). Females were more likely to have difficulties finding a mentor in neurosurgery who represented their identities (p = 0.017). URM students were more hesitant toward neurosurgery due to not seeing people like them in the field (p < 0.001). Subanalysis revealed that when students were stratified by both gender and URM status, there were more reasons for hesitancy toward neurosurgery that had significant differences between groups (male URM, male non-URM, female URM, and female non-URM students), suggesting the importance of intersectionality in this analysis. CONCLUSIONS: The authors highlight the implications of gender and racial diversity in the neurosurgical workforce on medical student interest and recruitment. Their findings suggest the importance of actively working to address these barriers, including 1) maternity/paternity policy reevaluation, standardization, and dissemination; and 2) actively providing resources for the creation of mentorship relationships for both women and URM students in an effort to create a workforce that aligns with the changing demographics of medical graduates to continue to improve diversity in neurosurgery.

Nf1 mutation disrupts activity-dependent oligodendroglial plasticity and motor learning in mice.

Neurogenetic disorders, such as neurofibromatosis type 1 (NF1), can cause cognitive and motor impairments, traditionally attributed to intrinsic neuronal defects such as disruption of synaptic function. Activity-regulated oligodendroglial plasticity also contributes to cognitive and motor functions by tuning neural circuit dynamics. However, the relevance of oligodendroglial plasticity to neurological dysfunction in NF1 is unclear. Here we explore the contribution of oligodendrocyte progenitor cells (OPCs) to pathological features of the NF1 syndrome in mice. Both male and female littermates (4-24 weeks of age) were used equally in this study. We demonstrate that mice with global or OPC-specific Nf1 heterozygosity exhibit defects in activity-dependent oligodendrogenesis and harbor focal OPC hyperdensities with disrupted homeostatic OPC territorial boundaries. These OPC hyperdensities develop in a cell-intrinsic Nf1 mutation-specific manner due to differential PI3K/AKT activation. OPC-specific Nf1 loss impairs oligodendroglial differentiation and abrogates the normal oligodendroglial response to neuronal activity, leading to impaired motor learning performance. Collectively, these findings show that Nf1 mutation delays oligodendroglial development and disrupts activity-dependent OPC function essential for normal motor learning in mice.

Operative Versus Nonoperative Management of Unstable Spine Fractures in the Elderly: Outcomes and Mortality.

STUDY DESIGN: Retrospective cohort study. OBJECTIVE: To assess outcomes and mortality in elderly patients following unstable spine fractures depending on treatment modality. SUMMARY OF BACKGROUND DATA: Operative management of unstable spine fractures in the elderly remains controversial due to increased risk of perioperative complications. Mortality rates after operative versus nonoperative treatment of these injuries have not been well-characterized. MATERIALS AND METHODS: Patients aged above 65 with unstable spine fractures without neurologic injury from 2015 to 2021 were identified from the Clinformatics ® Data Mart (CDM) Database. Demographics, complications, and mortality were collected. Multivariable logistic regression was used to adjust for the effect of baseline characteristics on mortality following unstable fracture diagnosis. RESULTS: Of the 3688 patients included, 1330 (36.1%) underwent operative management and 2358 (63.9%) nonoperative. At baseline, nonoperative patients were older, female, had higher Elixhauser comorbidity scores, and were more likely to have a cervical fracture. Operative patients had a longer length of stay in the hospital compared with nonoperative patients (9.7 vs. 7.7 days; P <0.001). Although patients in the operative group had higher rates of readmission at 30, 60, 90, and 120 days after diagnosis ( P <0.01), they had lower mortality rates up to five years after injury. After adjusting for covariates, nonoperative patients had a 60% greater risk of mortality compared with operative patients (hazard ratio: 1.60, 95% confidence interval: 1.40-1.78, P <0.001). After propensity score matching, operative patients age 65 to 85 had greater survivorship compared with their nonoperative counterparts. CONCLUSIONS: Elderly patients with an unstable spine fracture who undergo surgery experience lower mortality rates up to five years postdiagnosis compared with patients who received nonoperative management, despite higher hospital readmission rates and an overall perioperative complication rate of 37.3%. Operating on elderly patients with unstable spine fractures may outweigh the risks and should be considered as a viable treatment option in appropriately selected patients.

Trends in Management of Osteoporosis Following Primary Vertebral Compression Fracture.

Purpose: Osteoporosis affects more than 200 million individuals worldwide and predisposes to vertebral compression fractures (VCFs). Given undertreatment of fragility fractures, including VCFs, we investigate current anti-osteoporotic medication prescribing trends. Methods: Patients 50 and older with a diagnosis of primary closed thoracolumbar VCF between 2004 and 2019 were identified from the Clinformatics® Data Mart database. Multivariate analysis was performed for demographic and clinical treatment and outcome variables. Results: Of 143 081 patients with primary VCFs, 16 780 (11.7%) were started on anti-osteoporotic medication within a year; 126 301 (88.3%) patients were not started on medication. The medication cohort was older (75.4 ± 9.3 vs 74.0 ± 12.3 years, P < .001), had higher Elixhauser Comorbidity Index scores (4.7 ± 6.2 vs 4.3 ± 6.7, P < .001), was more likely to be female (81.1% vs 64.4%, P < .001), and was more likely to have a formal osteoporosis diagnosis (47.8% vs 32.9%) than the group that did not receive medication. Alendronate (63.4%) and calcitonin (27.8%) were the most commonly initiated medications. The proportion of individuals receiving anti-osteoporotic medication within the year following VCF peaked in 2008 (15.2%), then declined until 2012 with a modest increase afterward. Conclusions: Osteoporosis remains undertreated after low-energy VCFs. New anti-osteoporotic medication classes have been approved in recent years. Bisphosphonates remain the most prescribed class. Increasing recognition and treatment of osteoporosis is paramount to decreasing the risk of subsequent fractures.

Trends, payments, and costs associated with BMP use in Medicare beneficiaries undergoing spinal fusion.

BACKGROUND CONTEXT: Bone morphogenic protein (BMP) promotes bony fusion but increases costs. Recent trends in BMP use among Medicare patients have not been well-characterized. PURPOSE: To assess utilization trends, complication, payments, and costs associated with BMP use in spinal fusion in a Medicare-insured population. STUDY DESIGN/SETTING: Retrospective cohort study. PATIENT SAMPLE: Total of 316,070 patients who underwent spinal fusion in a 20% sample of Medicare-insured patients, 2006 to 2015. OUTCOME MEASURES: Utilization trends across time and geography, complications, payments, and costs. METHODS: Patients were stratified by fusion type and diagnosis. Multivariable logistic and linear regression were used to adjust for the effect of baseline characteristics on complications and total payments or cost, respectively. RESULTS: BMP was used in 60,249 cases (19.1%). BMP utilization rates decreased from 23.1% in 2006 to 12.0% in 2015, most significantly in anterior cervical (7.5%-3.1%), posterior cervical (17.0%-8.3%), and posterior lumbar fusions (31.5%-15.8%). There are significant state- and region-level geographic differences in BMP utilization. Across all years, states with the highest BMP use were Indiana (28.5%), Colorado (26.6%), and Nevada (25.7%). States with the lowest BMP use were Maine (2.3%), Vermont (8.2%), and Mississippi (10.4%). After multivariate risk adjustment, BMP use was associated with decreased overall complications in thoracic (odds ratios [OR] [95% confidence intervals [CI]): 0.89 [0.81-0.99]) and anterior lumbar fusions (OR [95% CI]: 0.89 [0.84-0.95]), as well as increased reoperation rates in anterior cervical (OR [95% CI]: 1.11 [1.04-1.19]), posterior cervical (OR (95% CI): 1.14 (1.04-1.25)), thoracic (OR (95% CI): 1.32 (1.23-1.41)), and posterior lumbar fusions (OR (95% CI): 1.11 (1.06-1.16)). BMP use was also associated with greater total costs, independent of fusion type, after multivariate risk adjustment (p<.0001). Payments, however, were comparable between groups in anterior and posterior cervical fusion with or without BMP. BMP use was associated with greater total payments in thoracic, anterior lumbar, and posterior lumbar fusions. Notably, the difference in payments was smaller than the associated cost increase in all fusion types. CONCLUSIONS: BMP use has declined across all fusion types over the last decade, after a peak in 2007. While BMP is associated with greater costs, reimbursement does not increase proportionally with BMP cost.

Microbial modulation prevents the effects of pervasive environmental stressors on microglia and social behavior, but not the dopamine system.

Environmental toxicant exposure, including air pollution, is increasing worldwide. However, toxicant exposures are not equitably distributed. Rather, low-income and minority communities bear the greatest burden, along with higher levels of psychosocial stress. Both air pollution and maternal stress during pregnancy have been linked to neurodevelopmental disorders such as autism, but biological mechanisms and targets for therapeutic intervention remain poorly understood. We demonstrate that combined prenatal exposure to air pollution (diesel exhaust particles, DEP) and maternal stress (MS) in mice induces social behavior deficits only in male offspring, in line with the male bias in autism. These behavioral deficits are accompanied by changes in microglial morphology and gene expression as well as decreased dopamine receptor expression and dopaminergic fiber input in the nucleus accumbens (NAc). Importantly, the gut-brain axis has been implicated in ASD, and both microglia and the dopamine system are sensitive to the composition of the gut microbiome. In line with this, we find that the composition of the gut microbiome and the structure of the intestinal epithelium are significantly shifted in DEP/MS-exposed males. Excitingly, both the DEP/MS-induced social deficits and microglial alterations in males are prevented by shifting the gut microbiome at birth via a cross-fostering procedure. However, while social deficits in DEP/MS males can be reversed by chemogenetic activation of dopamine neurons in the ventral tegmental area, modulation of the gut microbiome does not impact dopamine endpoints. These findings demonstrate male-specific changes in the gut-brain axis following DEP/MS and suggest that the gut microbiome is an important modulator of both social behavior and microglia.

Prenatal opioid exposure inhibits microglial sculpting of the dopamine system selectively in adolescent male offspring.

The current opioid epidemic has dramatically increased the number of children who are prenatally exposed to opioids, including oxycodone. A number of social and cognitive abnormalities have been documented in these children as they reach young adulthood. However, little is known about the mechanisms underlying developmental effects of prenatal opioid exposure. Microglia, the resident immune cells of the brain, respond to acute opioid exposure in adulthood. Moreover, microglia are known to sculpt neural circuits during typical development. Indeed, we recently found that microglial phagocytosis of dopamine D1 receptors (D1R) in the nucleus accumbens (NAc) is required for the natural developmental decline in NAc-D1R that occurs between adolescence and adulthood in rats. This microglial pruning occurs only in males, and is required for the normal developmental trajectory of social play behavior. However, virtually nothing is known as to whether this developmental program is altered by prenatal exposure to opioids. Here, we show in rats that maternal oxycodone self-administration during pregnancy leads to reduced adolescent microglial phagocytosis of D1R and subsequently higher D1R density within the NAc in adult male, but not female, offspring. Finally, we show prenatal and adult behavioral deficits in opioid-exposed offspring, including impaired extinction of oxycodone-conditioned place preference in males. This work demonstrates for the first time that microglia play a key role in translating prenatal opioid exposure to changes in neural systems and behavior.

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.

First reported use of real-time intraoperative computed tomography angiography image registration using the Machine-vision Image Guided Surgery system: illustrative case.

BACKGROUND: Vertebral artery injury is a devastating potential complication of C1-2 posterior fusion. Intraoperative navigation can reduce the risk of neurovascular complications and improve screw placement accuracy. However, the use of intraoperative computed tomography (CT) increases radiation exposure and operative time, and it is unable to image vascular structures. The Machine-vision Image Guided Surgery (MvIGS) system uses optical topographic imaging and machine vision software to rapidly register using preoperative imaging. The authors presented the first report of intraoperative navigation with MvIGS registered using a preoperative CT angiogram (CTA) during C1-2 posterior fusion. OBSERVATIONS: MvIGS can register in seconds, minimizing operative time with no additional radiation exposure. Furthermore, surgeons can better adjust for abnormal vertebral artery anatomy and increase procedure safety. LESSONS: CTA-guided navigation generated a three-dimensional reconstruction of cervical spine anatomy that assisted surgeons during the procedure. Although further study is needed, the use of intraoperative MvIGS may reduce the risk of vertebral artery injury during C1-2 posterior fusion.

Internal state configures olfactory behavior and early sensory processing in Drosophila larvae.

Animals exhibit different behavioral responses to the same sensory cue depending on their internal state at a given moment. How and where in the brain are sensory inputs combined with state information to select an appropriate behavior? Here, we investigate how food deprivation affects olfactory behavior in Drosophila larvae. We find that certain odors repel well-fed animals but attract food-deprived animals and that feeding state flexibly alters neural processing in the first olfactory center, the antennal lobe. Hunger differentially modulates two output pathways required for opposing behavioral responses. Upon food deprivation, attraction-mediating uniglomerular projection neurons show elevated odor-evoked activity, whereas an aversion-mediating multiglomerular projection neuron receives odor-evoked inhibition. The switch between these two pathways is regulated by the lone serotonergic neuron in the antennal lobe, CSD. Our findings demonstrate how flexible behaviors can arise from state-dependent circuit dynamics in an early sensory processing center.