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SUMMARY Defects in brain development are believed to contribute towards on-set of neuropsychiatric disorders but identifying specific underlying mechanisms has proven difficult. Here, we took a multi-faceted approach to investigate why 15q11.2 copy number variants are prominent risk factors for schizophrenia and autism. First, we show that human iPSC-derived neural progenitors carrying 15q11.2 microdeletion exhibit deficits in adherens junctions and apical polarity. This results from haploinsufficiency of CYFIP1, a gene within 15q11.2 that encodes a subunit of the WAVE complex, which regulates cytoskeletal dynamics. In developing mouse cortex, deficiency in CYFIP1 and WAVE signaling similarly affects radial glial cells, leading to their ectopic localization outside of the ventricular zone. Finally, targeted human genetic association analyses revealed an epistatic interaction between CYFIP1 and WAVE signalling mediator ACTR2 and risk for schizophrenia. Our findings provide insight into how CYFIP1 regulates neural stem cell function and may contribute to the susceptibility of neuropsychiatric disorders.

Adult neurogenesis, the process of generating new neurons from neural stem cells, plays significant roles in synaptic plasticity, memory, and mood regulation. In the mammalian brain, it continues to occur well into adulthood in discrete regions, namely, the hippocampus and olfactory bulb. During the past decade, significant progress has been made in understanding the mechanisms regulating adult hippocampal neurogenesis and its role in the etiology of mental disorders. In addition, adult hippocampal neurogenesis is highly correlated with the remission of the antidepressant effect. In this paper, we discuss three major psychiatric disorders, depression, schizophrenia, and drug addiction, in light of preclinical evidence used in establishing the neurobiological significance of adult neurogenesis. We interpret the significance of these results and pose questions that remain unanswered. Potential treatments which include electroconvulsive therapy, deep brain stimulation, chemical antidepressants, and exercise therapy are discussed. While consensus lacks on specific mechanisms, we highlight evidence which indicates that these treatments may function via an increase in neural progenitor proliferation and changes to the hippocampal circuitry. Establishing a significant role of adult neurogenesis in the pathogenicity of psychiatric disorders may hold the key to potential strategies toward effective treatment.

In an effort to better understand and treat mental disorders, the Wnt pathway and adult hippocampal neurogenesis have received increased attention in recent years. One is a signaling pathway regulating key aspects of embryonic patterning, cell specification, and adult tissue homeostasis. The other is the generation of newborn neurons in adulthood that integrate into the neural circuit and function in learning and memory, and mood behavior. In this review, we discuss the growing relationship between Wnt signaling-mediated regulation of adult hippocampal neurogenesis as it applies to neuropsychiatric disorders. Evidence suggests dysfunctional Wnt signaling may aberrantly regulate new neuron development and cognitive function. Indeed, altered expression of key Wnt pathway components are observed in the hippocampus of patients suffering from neuropsychiatric disorders. Clinically-utilized mood stabilizers also proceed through modulation of Wnt signaling in the hippocampus, while Wnt pathway antagonists can regulate the antidepressant response. Here, we review the role of Wnt signaling in disease etiology and pathogenesis, regulation of adult neurogenesis and behavior, and the therapeutic targeting of disease symptoms.

OBJECTIVES Certain patients ultimately undergo explantation of their spinal cord stimulation (SCS) devices. Understanding the predictors and rates of SCS explantation has important implications for healthcare resource utilization (HCRU) and pain management. The present study identifies explant predictors and discerns differences in HCRU for at-risk populations. METHODS We designed a large, retrospective analysis using the Truven MarketScan Database. We included all adult patients who underwent a SCS trial from 2007 to 2012. Patients were grouped into cohorts that remained explant-free or underwent explantation over a 3-year period, and multivariate models evaluated differences in healthcare resource utilization. RESULTS A total of 8,727 unique instances of trial implants between 2007 and 2012 were identified. Overall, 805 (9.2%) patients underwent device explantation. One year prior to SCS implantation, the explant cohort had significantly higher median baseline costs ($42,140.3 explant vs. $27,821.7 in non-explant groups; p<0.0001), total number of pain encounters (180 vs. 103 p<0.0001), and associated costs ($15,446.9 vs. $9,227.9; p<0.0001). The explant cohort demonstrated increased use of procedures (19.0 vs. 9.0; p<0.0001) compared to non-explanted patients. For each month after initial SCS implantation, explanted patients had a slower decrease in total costs (4% vs. 6% in non-explant; p<0.01). At the month of explant, explant patients were expected to have incurred 2.65 times the total cost compared to the non-explant cohort (CR 2.65, 95% CI [1.83, 3.84]; p<0.001). Medium volume providers had lower rates of explantation at 1-year and 3-years compared to low volume providers (p=0.042). Increased age and Charlson index were independent predictors of explantation during the same periods. CONCLUSIONS In this nationwide analysis, we identified that SCS device explantation is correlated with patients who have higher baseline costs, higher total cost post-SCS implantation, and increased use of procedures to control pain. The higher rates of explantation at 3-years post-implant among low volume providers suggest that variations in provider experience and approach also contributes to differences in explantation rates.

SummaryAging causes significant declines in adult hippocampal neurogenesis and leads to cognitive disability. Emerging evidence demonstrates that decline in the mitotic checkpoint kinase BubR1 level occurs with natural aging and induces progeroid features in both mice and children with mosaic variegated aneuploidy syndrome. Whether BubR1 contributes to age‐related deficits in hippocampal neurogenesis is yet to be determined. Here we report that BubR1 expression is significantly reduced with natural aging in the mouse brain. Using established progeroid mice expressing low amounts of BubR1, we demonstrate these mice exhibit deficits in neural progenitor proliferation and maturation, leading to reduction in new neuron production. Collectively, our identification of BubR1 as a new and critical factor controlling sequential steps across neurogenesis raises the possibility that BubR1 may be a key mediator regulating aging‐related hippocampal pathology. Targeting BubR1 may represent a novel therapeutic strategy for age‐related cognitive deficits.

Objectives Conversion rates from trial leads to permanent spinal cord stimulation (SCS) systems have important implications for healthcare resource utilization (HCRU) and pain management. We hypothesized conversion rates differ based on provider implant volume. Materials and Methods We designed a large, retrospective analysis using the Truven MarketScan database analyzing adult SCS patients with provider information available, with or without IPG implantation from the years 2007 to 2012. Patients were divided into three provider-based groups: high (>25), medium (9–24), and low (3–8) volume providers. Univariate and multivariate models identified factors associated with successful conversion. Results A total of 17,850 unique trial implants were performed by 3,028 providers. Of 13,879 patients with baseline data available, 8,981 (64.7%) progressed to permanent SCS. Higher volume providers were associated with slightly higher conversion rates (65.9% vs. 63.3% low volume, p=0.029), explant rates (9.2% vs. 7.7% medium volume, p=0.026), younger age (52.0 ± 13.4 years vs. 53.0 ± 13.4 years, p=0.0026), Medicare/Medicaid (47.8% vs. 35.0% low volume, p<0.0001), Southern region (53.5% vs. 38.9% low volume, p<0.0001), and higher Charlson comorbidity scores (1.0 (SD=1.4), p=0.0002). Multivariate regression results showed female gender (1.13 [95% CI: 1.05–1.22], p<0.001) and high volume providers associated with higher odds of successful trial conversion (1.12 [95% CI: 1.02–1.22], p=0.014). Conclusions In this nationwide analysis, high volume providers achieved higher trial-to-permanent SCS conversion rates than lower volume providers. The study has implications for both training requirements and referral patterns to delineate minimum implant experience necessary for provider proficiency. Future studies may be useful to understand HCRU differences.

Myelination, the process by which oligodendrocytes form the myelin sheath around axons, is key to axonal signal transduction and related motor function in the central nervous system (CNS). Aging is characterized by degenerative changes in the myelin sheath, although the molecular underpinnings of normal and aberrant myelination remain incompletely understood. Here we report that axon myelination and related motor function are dependent on BubR1, a mitotic checkpoint protein that has been linked to progeroid phenotypes when expressed at low levels and healthy lifespan when overabundant. We found that oligodendrocyte progenitor cell proliferation and oligodendrocyte density is markedly reduced in mutant mice with low amounts of BubR1 (BubR1H/H mice), causing axonal hypomyelination in both brain and spinal cord. Expression of essential myelin-related genes such as MBP and PLP1 was significantly reduced in these tissues. Consistent with defective myelination, BubR1H/H mice exhibited various motor deficits, including impaired motor strength, coordination, and balance, irregular gait patterns and reduced locomotor activity. Collectively, these data suggest that BubR1 is a key determinant of oligodendrocyte production and function and provide a molecular entry point to understand age-related degenerative changes in axon myelination.