Migraine and peripheral pain models show differential alterations in neuronal complexity.

OBJECTIVE: Our laboratory has recently shown that there is a decrease in neuronal complexity in head pain processing regions in mouse models of chronic migraine-associated pain and aura. Importantly, restoration of this neuronal complexity corresponds with anti-migraine effects of known and experimental pharmacotherapies. The objective of the current study was to expand this work and examine other brain regions involved with pain or emotional processing. We also investigated the generalizability of our findings by analyzing neuronal cytoarchitectural changes in a model of complex regional pain syndrome (CRPS), a peripheral pain disorder. METHODS: We used the nitroglycerin (NTG) model of chronic migraine-associated pain in which mice receive 10 mg/kg NTG every other day for 9 days. Cortical spreading depression (CSD), a physiological corelate of migraine aura, was evoked in anesthetized mice using KCl. CRPS was induced by tibial fracture followed by casting. Neuronal cytoarchitecture was visualized with Golgi stain and analyzed with Simple Neurite Tracer. RESULTS: In the NTG model, we previously showed decreased neuronal complexity in the trigeminal nucleus caudalis (TNC) and periaqueductal gray (PAG). In contrast, we found increased neuronal complexity in the thalamus and no change in the amygdala or caudate putamen in this study. Following CSD, we observed decreased neuronal complexity in the PAG, in line with decreases in the somatosensory cortex and TNC reported with this model previously. In the CRPS model there was decreased neuronal complexity in the hippocampus, as reported by others; increased complexity in the PAG; and no change within the somatosensory cortex. CONCLUSIONS: Collectively these results demonstrate that alterations in neuronal complexity are a feature of both chronic migraine and chronic CRPS. However, each type of pain presents a unique cytoarchitectural signature, which may provide insight on how these pain states differentially transition from acute to chronic conditions.

Discharge within 1 day following elective single-level transforaminal lumbar interbody fusion: a propensityscore-matched analysis of predictors, complications, and readmission.

STUDY DESIGN: This was a retrospective case-control study using 8 years of data from a nationwide database of surgical outcomes in the United States. PURPOSE: This study aimed to improve our understanding of the risk factors associated with a length of stay (LOS) >1 day and aid in reducing postoperative hospitalization and complications. OVERVIEW OF LITERATURE: Despite the proven safety of transforaminal lumbar interbody fusion (TLIF), some patients face prolonged postoperative hospitalization. METHODS: Data were collected from the American College of Surgeons National Surgical Quality Improvement Program dataset from 2011 to 2018. The cohort was divided into patients with LOS up to 1 day (LOS ≤1 day), defined as same day or next-morning discharge, and patients with LOS >1 day (LOS >1 day). Univariable and multivariable regression analyses were performed to evaluate predictors of LOS >1 day. Propensity-score matching was performed to compare pre- and postdischarge complication rates. RESULTS: A total of 12,664 eligible patients with TLIF were identified, of which 14.8% had LOS ≤1 day and 85.2% had LOS >1 day. LOS >1 day was positively associated with female sex, Hispanic ethnicity, diagnosis of spondylolisthesis, American Society of Anesthesiologists classification 3, and operation length of >150 minutes. Patients with LOS >1 day were more likely to undergo intraoperative/postoperative blood transfusion (0.3% vs. 4.5%, p<0.001) and reoperation (0.1% vs. 0.6%, p=0.004). No significant differences in the rates of postdischarge complications were found between the matched groups. CONCLUSIONS: Patients with worsened preoperative status, preoperative diagnosis of spondylolisthesis, and prolonged operative time are more likely to require prolonged hospitalization and blood transfusions and undergo unplanned reoperation. To reduce the risk of prolonged hospitalization and associated complications, patients indicated for TLIF should be carefully selected.

The Impact of Social Determinants of Health in Pediatric Shunted Hydrocephalus.

BACKGROUND: Social risk factors have been shown to negatively affect health outcomes in children. However, this has not been characterized regarding pediatric shunted hydrocephalus. OBJECTIVE: To explore the impact of social risk factors on outcomes in pediatric shunted hydrocephalus with the goal of identifying specific areas of intervention that might improve the outcomes of children undergoing cerebrospinal fluid (CSF) diversion. METHODS: In an all-payer administrative database, records between January 2010 and October 2020 were analyzed to identify children undergoing CSF shunting procedures. Children with social risk factors were compared with those without regarding rates of infection, shunt-related interventions, and mortality within 5 years of their shunting procedure. RESULTS: Among the 5420 children who underwent first-time shunting procedures, 263 (4.9%) were identified to have social risk factors. Children with identified social risk factors had increased odds of central nervous system infection (odds ratio [OR] 2.06, 95% CI 1.45-2.91), revision (OR 2.43, 95% I 1.89-3.12), and mortality (OR 2.86, 95% CI 1.23-5.72). The mean numbers of computed tomography studies (14.60 ± 17.78 vs 6.34 ± 6.10), MRI studies (18.76 ± 24.37 vs 7.88 ± 24.37), and shunt series X-rays (17.22 ± 19.04 vs 7.66 ± 8.54) were increased among children with social risk factors. CONCLUSION: Children with social risk factors had increased rates of central nervous system infection, shunt-related interventions, and mortality within 5 years of CSF shunting. We underscore the importance of characterizing the impact of social risk factors in specific conditions, such as pediatric shunted hydrocephalus, and look to future directions aimed to mitigate these risk factors with coordination and direction of individualized resources, encouragement of advocacy, and community partnership.

Thrombocytopenia as an Independent Prognostic Indicator Following Extradural Spinal Tumor Resection.

OBJECTIVE: Few studies have examined the prognosis for patients with baseline thrombocytopenia undergoing extradural spine tumor resection. Our objective was to evaluate mortality, readmission, and other 30-day outcomes in patients with varying degrees of preoperative thrombocytopenia undergoing osseous extradural tumor excision. METHODS: A multicenter registry was queried for patients treated from 2011-2019. Patients were categorized according to baseline preoperative platelet count, in 25,000/µL increments: 125,000-149,000/µL, 100,000-125,000/µL, 75,000-100,000/µL, and <75,000/µL. These were compared to a control group with platelet count >150,000/µL. Outcomes in each cohort were analyzed using multivariate logistic regression analysis. RESULTS: The database search revealed 3574 patients undergoing extradural tumor resection; 2171 (60.7%) patients with platelets 125,000-149,000/µL, 114 (3.2%) with 100,000-125,000/µL, 43 (1.2%) with 75,000-100,000/µL, and 42 (1.2%) with <75,000/µL. Platelet counts <100,000/µL was associated with perioperative blood transfusion, cardiac complications, non-home discharge, and 30-day mortality. On subgroup analysis for mortality, an interaction was present between individuals with moderate/severe thrombocytopenia and cervical tumors. CONCLUSIONS: In patients undergoing surgery for extradural spine tumor, degree of baseline thrombocytopenia-rather than presence alone-is an independent predictor of several adverse events. Wherever possible, optimization of preoperative platelet count to at least 100,000/µL may improve outcomes.

Delta opioid receptors in Nav1.8 expressing peripheral neurons partially regulate the effect of delta agonist in models of migraine and opioid-induced hyperalgesia.

Migraine is one of the most common pain disorders and causes disability in millions of people every year. Delta opioid receptors (DOR) have been identified as a novel therapeutic target for migraine and other headache disorders. DORs are present in both peripheral and central regions and it is unclear which receptor populations regulate migraine-associated effects. The aim of this study was to determine if DOR expressed in peripheral nociceptors regulates headache associated endpoints and the effect of delta agonists within these mouse models. We used a conditional knockout, in which DOR was selectively deleted from Nav1.8 expressing cells. Nav1.8-DOR mice and loxP control littermates were tested in models of chronic migraine-associated allodynia, opioid-induced hyperalgesia, migraine-associated negative affect, and aura. Nav1.8-DOR and loxP mice had comparable effect sizes in all of these models. The anti-allodynic effect of the DOR agonist, SNC80, was slightly diminished in the nitroglycerin model of migraine. Intriguingly, in the OIH model the peripheral effects of SNC80 were completely lost in Nav1.8-DOR mice while the cephalic effects remained intact. Regardless of genotype, SNC80 continued to inhibit conditioned place aversion associated with nitroglycerin and decreased cortical spreading depression events associated with migraine aura. These results suggest that DOR in Nav1.8-expressing nociceptors do not critically regulate the anti-migraine effects of delta agonist; and that brain-penetrant delta agonists would be a more effective drug development strategy.

Neuronal complexity is attenuated in preclinical models of migraine and restored by HDAC6 inhibition.

Migraine is the sixth most prevalent disease worldwide but the mechanisms that underlie migraine chronicity are poorly understood. Cytoskeletal flexibility is fundamental to neuronal-plasticity and is dependent on dynamic microtubules. Histone-deacetylase-6 (HDAC6) decreases microtubule dynamics by deacetylating its primary substrate, α-tubulin. We use validated mouse models of migraine to show that HDAC6-inhibition is a promising migraine treatment and reveal an undiscovered cytoarchitectural basis for migraine chronicity. The human migraine trigger, nitroglycerin, produced chronic migraine-associated pain and decreased neurite growth in headache-processing regions, which were reversed by HDAC6 inhibition. Cortical spreading depression (CSD), a physiological correlate of migraine aura, also decreased cortical neurite growth, while HDAC6-inhibitor restored neuronal complexity and decreased CSD. Importantly, a calcitonin gene-related peptide receptor antagonist also restored blunted neuronal complexity induced by nitroglycerin. Our results demonstrate that disruptions in neuronal cytoarchitecture are a feature of chronic migraine, and effective migraine therapies might include agents that restore microtubule/neuronal plasticity.

Migraines are a common brain disorder that affects 14% of the world's population. For many people the main symptom of a migraine is a painful headache, often on one side of the head. Other symptoms include increased sensitivity to light or sound, disturbed vision, and feeling sick. These sensory disturbances are called aura and they often occur before the headache begins. One particularly debilitating subset of migraines are chronic migraines, in which patients experience more than 15 headache days per month. Migraine therapies are often only partially effective or poorly tolerated, making it important to develop new drugs for this condition, but unfortunately, little is known about the molecular causes of migraines. To bridge this gap, Bertels et al. used two different approaches to cause migraine-like symptoms in mice. One approach consisted on giving mice nitroglycerin, which dilates blood vessels, produces hypersensitivity to touch, and causes photophobia in both humans and mice. In the second approach, mice underwent surgery and potassium chloride was applied onto the dura, a thick membrane that surrounds the brain. This produces cortical spreading depression, an event that is linked to migraine auras and involves a wave of electric changes in brain cells that slowly propagates across the brain, silencing brain electrical activity for several minutes. Using these approaches, Bertels et al. studied whether causing chronic migraine-like symptoms in mice is associated with changes in the structures of neurons, focusing on the effects of migraines on microtubules. Microtubules are cylindrical protein structures formed by the assembly of smaller protein units. In most cells, microtubules assemble and disassemble depending on what the cell needs. Neurons need stable microtubules to establish connections with other neurons. The experiments showed that provoking chronic migraines in mice led to a reduction in the numbers of connections between different neurons. Additionally, Bertels et al. found that inhibiting HDAC6 (a protein that destabilizes microtubules) reverses the structural changes in neurons caused by migraines and decreases migraine symptoms. The same effects are seen when a known migraine treatment strategy, known as CGRP receptor blockade, is applied. These results suggest that chronic migraines may involve decreased neural complexity, and that the restoration of this complexity by HDAC6 inhibitors could be a potential therapeutic strategy for migraine.