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Sustained rescue of prefrontal circuit dysfunction by antidepressant-induced spine formation
A better understanding of the mechanisms underlying the action of antidepressants is urgently needed. Moda-Sava et al. explored a possible mode of action for the drug ketamine, which has recently been shown to help patients recover from depression (see the Perspective by Beyeler). Ketamine rescued behavior in mice that was associated with depression-like phenotypes by selectively reversing stress-induced spine loss and restoring coordinated multicellular ensemble activity in prefrontal microcircuits. The initial induction of ketamine's antidepressant effect on mouse behavior occurred independently of effects on spine formation. Instead, synaptogenesis in the prefrontal region played a critical role in nourishing these effects over time. Interventions aimed at enhancing the survival of restored synapses may thus be useful for sustaining the behavioral effects of fast-acting antidepressants. Science , this issue p. eaat8078 ; see also p. 129 Spine formation in the prefrontal cortex is central to the long-term antidepressant effects of ketamine. The neurobiological mechanisms underlying the induction and remission of depressive episodes over time are not well understood. Through repeated longitudinal imaging of medial prefrontal microcircuits in the living brain, we found that prefrontal spinogenesis plays a critical role in sustaining specific antidepressant behavioral effects and maintaining long-term behavioral remission. Depression-related behavior was associated with targeted, branch-specific elimination of postsynaptic dendritic spines on prefrontal projection neurons. Antidepressant-dose ketamine reversed these effects by selectively rescuing eliminated spines and restoring coordinated activity in multicellular ensembles that predict motivated escape behavior. Prefrontal spinogenesis was required for the long-term maintenance of antidepressant effects on motivated escape behavior but not for their initial induction.
Journal Article
Rapid Golgi Analysis Method for Efficient and Unbiased Classification of Dendritic Spines
Dendritic spines are the primary recipients of excitatory synaptic input in the brain. Spine morphology provides important information on the functional state of ongoing synaptic transmission. One of the most commonly used methods to visualize spines is Golgi-Cox staining, which is appealing both due to ease of sample preparation and wide applicability to multiple species including humans. However, the classification of spines is a time-consuming and often expensive task that yields widely varying results between individuals. Here, we present a novel approach to this analysis technique that uses the unique geometry of different spine shapes to categorize spines on a purely objective basis. This rapid Golgi spine analysis method successfully conveyed the maturational shift in spine types during development in the mouse primary visual cortex. This approach, built upon freely available software, can be utilized by researchers studying a broad range of synaptic connectivity phenotypes in both development and disease.
Journal Article
Teriparatide improves volumetric bone mineral density and fine bone structure in the UIV+1 vertebra, and reduces bone failure type PJK after surgery for adult spinal deformity
Summary
We conducted a prospective comparative study of the effect of teriparatide therapy for preventing vertebral-failure-type PJK after reconstructive surgery for adult spinal deformity. Prophylactic teriparatide improved the volumetric bone mineral density and fine bone structure of the vertebra above the upper-instrumented vertebra and reduced the incidence of vertebral-failure-type PJK.
Introduction
Proximal junctional kyphosis (PJK) is a complication after corrective surgery for spinal deformity. This study sought to determine whether teriparatide (TP) is an effective prophylactic against PJK type 2 (vertebral fracture) in surgically treated patients with adult spinal deformity (ASD).
Methods
Forty-three patients who started TP therapy immediately after surgery and 33 patients who did not receive TP were enrolled in this prospective case series. These patients were female, over 50, surgically treated for ASD, and followed for at least 2 years. Preoperative and postoperative standing whole-spine X-rays and dual-energy X-ray absorptiometry scans, and multidetector CT images obtained before and 6 months after surgery were used to analyze the bone strength in the vertebra above the upper-instrumented vertebra (UIV+1).
Results
Mean age was 67.9 years. After 6 months of treatment, mean hip-bone mineral density (BMD) increased from 0.721 to 0.771 g/cm
2
in the TP group and decreased from 0.759 to 0.729 g/cm
2
in the control group. This percent BMD change between groups was significant (
p
< 0.05). The volumetric BMD (326 to 366 mg/cm
3
) and bone mineral content (BMC) (553 to 622 mg) at UIV+1 were also significantly increased in TP group. The bone volume/tissue volume ratio increased from 46 to 54 % in the TP group, and the trabecular bone thickness and number increased by 14 and 5 %, respectively. At the 2-year follow-up, the PJK type 2 incidence was significantly lower in the TP group (4.6 %) than in the control group (15.2 %;
p
= .02).
Conclusions
Prophylactic TP treatment improved the volumetric BMD and fine bone structure at UIV+1 and reduced the PJK-type 2 incidence.
Journal Article
Both structural damage and inflammation of the spine contribute to impairment of spinal mobility in patients with ankylosing spondylitis
Objective To study the relationship between spinal mobility, radiographic damage of the spine and spinal inflammation as assessed by MRI in patients with ankylosing spondylitis (AS). Methods In this subanalysis of the Ankylosing Spondylitis Study for the Evaluation of Recombinant Infliximab Therapy cohort, 214 patients, representing an 80% random sample, were investigated. Only baseline data were used. MRI inflammation was assessed by the AS spinal MRI activity (ASspiMRI-a) score, structural damage by the modified Stoke AS Spine Score (mSASSS) and spinal mobility by the linear definition of the Bath Ankylosing Spondylitis Metrology Index (BASMI). Univariate correlations were calculated on baseline values using Spearman rank correlation. Independent associations between the variables of interest were investigated by multivariate linear regression analysis. Associations with clinical disease activity, C-reactive protein, disease duration, age, gender, body mass index and HLA-B27 status were also investigated. Subanalyses were performed according to disease duration. Results BASMI correlated moderately well with mSASSS (Spearman's ρ=0.6) and weakly with ASspiMRI-a (ρ=0.3). A best-fit model for BASMI included both mSASSS (regression coefficient (B)=0.865, p<0.001) and ASspiMRI-a (B=0.236, p=0.018). In patients with a disease duration ≤3 years, B was greater for ASspiMRI-a than for mSASSS (0.595 vs 0.380), while in patients with a disease duration >3 years B was greater for mSASSS than for ASspiMRI-a (0.924 vs 0.156). Conclusion Spinal mobility impairment in AS is independently determined both by irreversible spinal damage and by reversible spinal inflammation. Spinal mobility impairment is more influenced by spinal inflammation in early disease, and by structural damage in later disease.
Journal Article
The microbiota regulate neuronal function and fear extinction learning
Multicellular organisms have co-evolved with complex consortia of viruses, bacteria, fungi and parasites, collectively referred to as the microbiota
1
. In mammals, changes in the composition of the microbiota can influence many physiologic processes (including development, metabolism and immune cell function) and are associated with susceptibility to multiple diseases
2
. Alterations in the microbiota can also modulate host behaviours—such as social activity, stress, and anxiety-related responses—that are linked to diverse neuropsychiatric disorders
3
. However, the mechanisms by which the microbiota influence neuronal activity and host behaviour remain poorly defined. Here we show that manipulation of the microbiota in antibiotic-treated or germ-free adult mice results in significant deficits in fear extinction learning. Single-nucleus RNA sequencing of the medial prefrontal cortex of the brain revealed significant alterations in gene expression in excitatory neurons, glia and other cell types. Transcranial two-photon imaging showed that deficits in extinction learning after manipulation of the microbiota in adult mice were associated with defective learning-related remodelling of postsynaptic dendritic spines and reduced activity in cue-encoding neurons in the medial prefrontal cortex. In addition, selective re-establishment of the microbiota revealed a limited neonatal developmental window in which microbiota-derived signals can restore normal extinction learning in adulthood. Finally, unbiased metabolomic analysis identified four metabolites that were significantly downregulated in germ-free mice and have been reported to be related to neuropsychiatric disorders in humans and mouse models, suggesting that microbiota-derived compounds may directly affect brain function and behaviour. Together, these data indicate that fear extinction learning requires microbiota-derived signals both during early postnatal neurodevelopment and in adult mice, with implications for our understanding of how diet, infection, and lifestyle influence brain health and subsequent susceptibility to neuropsychiatric disorders.
A diverse intestinal microbiota is required for mice to undergo extinction-related neuronal plasticity and normal fear extinction learning.
Journal Article
IDENTIFYING ACTIONABLE INFORMATION: PREVENTABLE 30-DAY NEUROSURGICAL READMISSIONS
BackgroundHospital readmissions within 30 days after discharge are increasingly recognized as markers of inpatient quality of care and significant contributors to rising healthcare expenditures. Identifying potentially preventable readmission causes and developing targeted interventions is a national priority.ObjectivesTo determine rate, reasons, and potential for prevention for 30-day unplanned neurosurgical readmissions at Yale-New Haven Hospital.MethodsOver a 6-month period, all patients who had been discharged from YNHH after receiving care from the Department of Neurosurgery and readmitted within 30 days were retrospectively identified. In-depth chart analysis was performed to uncover relevant medical/social history and admission/readmission details.ResultsDuring 6 months, 84 (6.6%) of 1,279 patients were readmitted within 30 days. Reasons for readmission were categorized into miscellaneous (34%), non-surgical site infections (15%), postoperative wound complications (14%), intracranial hemorrhage (13%), neurological deficits: brain (10%), CSF device malfunction (8%), neurological deficits: spine (4%), and ischemic CNS events (2%). Most complications were moderate (54%) or mild (31%). Overall, 17% of readmissions were determined to be likely preventable, 10% – potentially preventable, 73% – not preventable. Notably, 42% of postoperative wound complications and 32% of brain-related neurological deficits could have been prevented. 49% of readmissions were related to initial hospitalization and 12% resulted from inappropriate post-discharge care; 34% and 88% of those, respectively, were preventable.ConclusionsOverall, 27% of 30-day neurosurgical readmissions were determined to be potentially preventable. Underlying reasons were identified and will be used to design targeted interventions. Preventing postoperative wound complications and providing appropriate discharge arrangements/instructions are the most promising areas of improvement.
Journal Article
Phagocyte-mediated synapse removal in cortical neuroinflammation is promoted by local calcium accumulation
Cortical pathology contributes to chronic cognitive impairment of patients suffering from the neuroinflammatory disease multiple sclerosis (MS). How such gray matter inflammation affects neuronal structure and function is not well understood. In the present study, we use functional and structural in vivo imaging in a mouse model of cortical MS to demonstrate that bouts of cortical inflammation disrupt cortical circuit activity coincident with a widespread, but transient, loss of dendritic spines. Spines destined for removal show local calcium accumulations and are subsequently removed by invading macrophages or activated microglia. Targeting phagocyte activation with a new antagonist of the colony-stimulating factor 1 receptor prevents cortical synapse loss. Overall, our study identifies synapse loss as a key pathological feature of inflammatory gray matter lesions that is amenable to immunomodulatory therapy.
Synapse loss is prominent in the cortex in multiple sclerosis (MS). In a cortical MS model, Jafari et al. show that phagocytes remove synapses by engulfment, which is triggered by local calcium accumulations and prevented by blocking colony-stimulating factor 1 signaling.
Journal Article
Intraosseous basivertebral nerve ablation for the treatment of chronic low back pain: a prospective randomized double-blind sham-controlled multi-center study
PurposeTo evaluate the safety and efficacy of radiofrequency (RF) ablation of the basivertebral nerve (BVN) for the treatment of chronic low back pain (CLBP) in a Food and Drug Administration approved Investigational Device Exemption trial. The BVN has been shown to innervate endplate nociceptors which are thought to be a source of CLBP.MethodsA total of 225 patients diagnosed with CLBP were randomized to either a sham (78 patients) or treatment (147 patients) intervention. The mean age within the study was 47 years (range 25–69) and the mean baseline ODI was 42. All patients had Type I or Type II Modic changes of the treated vertebral bodies. Patients were evaluated preoperatively, and at 2 weeks, 6 weeks and 3, 6 and 12 months postoperatively. The primary endpoint was the comparative change in ODI from baseline to 3 months.ResultsAt 3 months, the average ODI in the treatment arm decreased 20.5 points, as compared to a 15.2 point decrease in the sham arm (p = 0.019, per-protocol population). A responder analysis based on ODI decrease ≥ 10 points showed that 75.6% of patients in the treatment arm as compared to 55.3% in the sham control arm exhibited a clinically meaningful improvement at 3 months.ConclusionPatients treated with RF ablation of the BVN for CLBP exhibited significantly greater improvement in ODI at 3 months and a higher responder rate than sham treated controls. BVN ablation represents a potential minimally invasive treatment for the relief of chronic low back pain.Graphical abstractThese slides can be retrieved under Electronic Supplementary Material.
Journal Article
MRI vertebral corner inflammation followed by fat deposition is the strongest contributor to the development of new bone at the same vertebral corner: a multilevel longitudinal analysis in patients with ankylosing spondylitis
ObjectivesTo study the sequential relationship between MRI vertebral corner inflammation (VCI), vertebral corner fat deposition (VCFD) and the development/growth of radiographic syndesmophytes at the same vertebral corner (VC).MethodsBaseline, 24 and 102 weeks spinal MRIs were assessed for the presence/absence of VCI and VCFD. Anterior VCs of lateral radiographs of the cervical and lumbar spine (baseline and 102 weeks) were assessed for the development of new bone (syndesmophyte formation or syndesmophyte formation/growth combined). Data from 161 to 177 patients were analysed at the VC level using two-way and multilevel analyses adjusting for within-patient correlation and MRI reader (generalised estimating equations for binomial outcomes).ResultsThe presence of VCI (adjusted (adj) OR 1.75 to 1.98) as well as the presence of VCFD (adjOR 1.60 to 2.32) at any time point (TP) were significantly associated with the development of new bone. The combination of VCI and VCFD at the same VC increased the strength of the association, both for the sequential or simultaneous presence of VCI and VCFD across the three TPs (adjOR 2.12 to 2.73), as well as for the development of new VCFD preceded by VCI at a previous TP (adjOR 2.12 to 3.01). The complete absence of both VCI and VCFD across the three TPs ‘protected’ against new bone formation (adjOR 0.45 to 0.62). However, 40–66% of new bone still developed in VCs without MRI inflammation or fat degeneration at any of the three TPs.ConclusionsBoth VCI and VCFD contribute to new bone formation in ankylosing spondylitis (AS), especially if VCI precedes VCFD. However, VCI, VCFD and this particular sequence of events only partially explain the development of new bone in AS.
Journal Article