Distinct changes to hippocampal and medial entorhinal circuits emerge across the progression of cognitive deficits in epilepsy.

Temporal lobe epilepsy (TLE) causes pervasive and progressive memory impairments, yet the specific circuit changes that drive these deficits remain unclear. To investigate how hippocampal-entorhinal dysfunction contributes to progressive memory deficits in epilepsy, we performed simultaneous in vivo electrophysiology in hippocampus (HPC) and medial entorhinal cortex (MEC) of control and epileptic mice 3 or 8 weeks after pilocarpine-induced status epilepticus (Pilo-SE). We found that HPC synchronization deficits (including reduced theta power, coherence, and altered interneuron spike timing) emerged within 3 weeks of Pilo-SE, aligning with early-onset, relatively subtle memory deficits. In contrast, abnormal synchronization within MEC and between HPC-MEC emerged later, by 8 weeks after Pilo-SE, when spatial memory impairment was more severe. Furthermore, a distinct subpopulation of MEC layer 3 excitatory neurons (active at theta troughs) was specifically impaired in epileptic mice. Together, these findings suggest that hippocampal-entorhinal circuit dysfunction accumulates and shifts as cognitive impairment progresses in TLE.

Transforming Outcomes of Spine Surgery-Exploring the Power of Enhanced Recovery After Surgery Protocol: A Systematic Review and Meta-Analyses of 15 198 Patients.

BACKGROUND AND OBJECTIVES: Enhanced recovery after surgery (ERAS) protocols aim to optimize patient outcomes by reducing the surgical stress response, expediting recovery, and reducing care costs. We aimed to evaluate the impact of implementing ERAS protocols on the perioperative surgical outcomes and financial implications associated with spine surgeries. METHODS: A systematic review and meta-analysis of peer-reviewed studies directly comparing outcome differences between spine surgeries performed with and without utilization of ERAS pathways was conducted along Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. RESULTS: Of 676 unique articles identified, 59 with 15 198 aggregate patients (7748 ERAS; 7450 non-ERAS) were included. ERAS-treated patients had shorter operative times (mean difference [MD]: 10.2 mins; P < .01), shorter hospitalizations (MD: 1.41 days, P < .01), fewer perioperative complications (relative risk [RR] = 0.64, P < .01), lower postoperative opioid use (MD of morphine equivalent dose: 164.36 mg; P < .01), and more rapid mobilization/time to first out-of-bed ambulation (MD: 0.92 days; P < .01). Spine surgeries employing ERAS were also associated with lower total costs (MD: $1140.26/patient; P < .01), especially in the United States (MD: $2869.11/patient, P < .01) and lower postoperative visual analog pain scores (MD = 0.56, P < .01), without any change in odds of 30-day readmission (RR: 0.80, P = .13) or reoperation (RR: 0.88, P = .60). Subanalyses based on the region of spine showed significantly lower length of stay in both cervical and lumbar surgeries implementing ERAS. Type of procedure showed a significantly lesser time-to-initiate mobilization in fusion surgeries using ERAS protocols compared with decompression. CONCLUSION: The present meta-analysis indicates that current literature supports ERAS implementation as a means of reducing care costs and safely accelerating hospital discharge for patients undergoing spine surgery.

Aversive experience drives offline ensemble reactivation to link memories across days.

Memories are encoded in neural ensembles during learning and stabilized by post-learning reactivation. Integrating recent experiences into existing memories ensures that memories contain the most recently available information, but how the brain accomplishes this critical process remains unknown. Here we show that in mice, a strong aversive experience drives the offline ensemble reactivation of not only the recent aversive memory but also a neutral memory formed two days prior, linking the fear from the recent aversive memory to the previous neutral memory. We find that fear specifically links retrospectively, but not prospectively, to neutral memories across days. Consistent with prior studies, we find reactivation of the recent aversive memory ensemble during the offline period following learning. However, a strong aversive experience also increases co-reactivation of the aversive and neutral memory ensembles during the offline period. Finally, the expression of fear in the neutral context is associated with reactivation of the shared ensemble between the aversive and neutral memories. Taken together, these results demonstrate that strong aversive experience can drive retrospective memory-linking through the offline co-reactivation of recent memory ensembles with memory ensembles formed days prior, providing a neural mechanism by which memories can be integrated across days.

Dissociable contributions of the amygdala and ventral hippocampus to stress-induced changes in defensive behavior.

Severe stress can produce multiple persistent changes in defensive behavior. While much is known about the circuits supporting stress-induced associative fear responses, how circuit plasticity supports the broader changes in defensive behavior observed after severe stress remains unclear. Here, we find that stress-induced plasticity in the ventral hippocampus (vHC) and basolateral amygdala (BLA) support doubly dissociable defensive behavioral changes. Stress-induced protein synthesis in the BLA was found to support lasting enhancements in stress sensitivity but not enhancements in exploratory anxiety-related behaviors, whereas protein synthesis in the vHC was found to support enhancements in anxiety-related behavior but not enhancements in stress sensitivity. Like protein synthesis, neuronal activity of the BLA and vHC were found to differentially support the expression of these same defensive behaviors. Lastly, blockade of associative fear had no impact on stress-induced changes in anxiety-related behavior. These findings highlight that multiple memory-systems support stress-induced defensive behavior changes.

Minian, an open-source miniscope analysis pipeline.

Miniature microscopes have gained considerable traction for in vivo calcium imaging in freely behaving animals. However, extracting calcium signals from raw videos is a computationally complex problem and remains a bottleneck for many researchers utilizing single-photon in vivo calcium imaging. Despite the existence of many powerful analysis packages designed to detect and extract calcium dynamics, most have either key parameters that are hard-coded or insufficient step-by-step guidance and validations to help the users choose the best parameters. This makes it difficult to know whether the output is reliable and meets the assumptions necessary for proper analysis. Moreover, large memory demand is often a constraint for setting up these pipelines since it limits the choice of hardware to specialized computers. Given these difficulties, there is a need for a low memory demand, user-friendly tool offering interactive visualizations of how altering parameters at each step of the analysis affects data output. Our open-source analysis pipeline, Minian (miniscope analysis), facilitates the transparency and accessibility of single-photon calcium imaging analysis, permitting users with little computational experience to extract the location of cells and their corresponding calcium traces and deconvolved neural activities. Minian contains interactive visualization tools for every step of the analysis, as well as detailed documentation and tips on parameter exploration. Furthermore, Minian has relatively small memory demands and can be run on a laptop, making it available to labs that do not have access to specialized computational hardware. Minian has been validated to reliably and robustly extract calcium events across different brain regions and from different cell types. In practice, Minian provides an open-source calcium imaging analysis pipeline with user-friendly interactive visualizations to explore parameters and validate results.

Hypothermia Therapy for Traumatic Spinal Cord Injury: An Updated Review.

Although hypothermia has shown to protect against ischemic and traumatic neuronal death, its potential role in neurologic recovery following traumatic spinal cord injury (TSCI) remains incompletely understood. Herein, we systematically review the safety and efficacy of hypothermia therapy for TSCI. The English medical literature was reviewed using PRISMA guidelines to identify preclinical and clinical studies examining the safety and efficacy of hypothermia following TSCI. Fifty-seven articles met full-text review criteria, of which twenty-eight were included. The main outcomes of interest were neurological recovery and postoperative complications. Among the 24 preclinical studies, both systemic and local hypothermia significantly improved neurologic recovery. In aggregate, the 4 clinical studies enrolled 60 patients for treatment, with 35 receiving systemic hypothermia and 25 local hypothermia. The most frequent complications were respiratory in nature. No patients suffered neurologic deterioration because of hypothermia treatment. Rates of American Spinal Injury Association (AIS) grade conversion after systemic hypothermia (35.5%) were higher when compared to multiple SCI database control studies (26.1%). However, no statistical conclusions could be drawn regarding the efficacy of hypothermia in humans. These limited clinical trials show promise and suggest therapeutic hypothermia to be safe in TSCI patients, though its effect on neurological recovery remains unclear. The preclinical literature supports the efficacy of hypothermia after TSCI. Further clinical trials are warranted to conclusively determine the effects of hypothermia on neurological recovery as well as the ideal means of administration necessary for achieving efficacy in TSCI.

Spine Image Guidance and Robotics: Exposure, Education, Training, and the Learning Curve.

The use of intraoperative robotics and imaging for spine surgery has been shown to be safe, efficacious, and beneficial to patients, offering accurate placement of instrumentation, decreased operative time and blood loss, and improved postoperative outcomes. Despite these proven benefits, it has yet to be uniformly adopted. One of the major barriers for universal adoption of intraoperative robotics is the learning curve for this complex technology, in conjunction with a lack of formalized training. These same obstacles for universal adoption were faced in the introduction of surgical technology in other disciplines, and the use of this technology has become the standard of care in some of those specialties. Part of the success and widespread implementation of prior novel technology was the introduction of formalized training systems, which are currently lacking in advanced spine surgical technology. Therefore, the future success of intraoperative robotics and imaging for spine surgery depends on the creation of a formalized training system. We detail the best techniques for surgical pedagogy, as well as propose a comprehensive curriculum.

ezTrack-A Step-by-Step Guide to Behavior Tracking.

Tracking animal behavior by video is one of the most common tasks in neuroscience. Previously, we have validated ezTrack, a free, flexible, and easy-to-use software for the analysis of animal behavior. ezTrack's Location Tracking Module can be used for the positional analysis of an individual animal and is applicable to a wide range of behavioral tasks. Separately, ezTrack's Freeze Analysis Module is designed for the analysis of defensive freezing behavior. ezTrack supports a range of desirable tools, including options for cropping and masking portions of the field of view, defining regions of interest, producing summary data for specified portions of time, algorithms to remove the influence of electrophysiology cables and other tethers, batch processing of multiple videos, and video down-sampling. Moreover, ezTrack produces a range of interactive plots and visualizations to promote users' confidence in their results. In this protocols paper, we provide step-by-step instructions for the use of ezTrack, from tips for recording behavior to instructions for using the software for video analysis. © 2021 Wiley Periodicals LLC. Basic Protocol 1: Software environment installation Basic Protocol 2: Using the Location Tracking Module Basic Protocol 3: Using the Freeze Analysis Module.

The Medial Orbitofrontal Cortex-Basolateral Amygdala Circuit Regulates the Influence of Reward Cues on Adaptive Behavior and Choice.

Adaptive reward-related decision making requires accurate prospective consideration of the specific outcome of each option and its current desirability. Often this information must be inferred based on the presence of predictive environmental events. The basolateral amygdala (BLA) and medial orbitofrontal cortex (mOFC) are two key nodes in the circuitry supporting such outcome expectations, but very little is known about the function of direct connections between these regions. Here, in male rats, we first anatomically confirmed the existence of bidirectional, direct projections between the mOFC and BLA and found that BLA projections to mOFC are largely distinct from those to lateral OFC (lOFC). Next, using pathway-specific chemogenetic inhibition and the outcome-selective Pavlovian-to-instrumental transfer and devaluation tests, we interrogated the function of the bidirectional mOFC-BLA connections in reward-directed behavior. We found evidence that the mOFC→BLA pathway mediates the use of environmental cues to understand which specific reward is predicted, information needed to infer which action to choose, and how desirable that reward is to ensure adaptive responses to the cue. By contrast, the BLA→mOFC pathway is not needed to use the identity of an expected reward to guide choice but does mediate adaptive responses to cues based on the current desirability of the reward they predict. These functions differ from those we previously identified for the lOFC-BLA circuit. Collectively, the data reveal the mOFC-BLA circuit as critical for the cue-dependent reward outcome expectations that influence adaptive behavior and decision making.SIGNIFICANCE STATEMENT To make good decisions we evaluate how advantageous a particular course of action would be. This requires understanding what rewarding outcomes can be expected and how desirable they currently are. Such prospective considerations are critical for adaptive decision making but disrupted in many psychiatric diseases. Here, we reveal that direct connections between the medial orbitofrontal cortex and basolateral amygdala mediate these functions. These findings are especially important in light of evidence of dysfunction in this circuit in substance use disorder and mental illnesses marked by poor decision making.

Prediction Models in Degenerative Spine Surgery: A Systematic Review.

STUDY DESIGN: Systematic review. OBJECTIVES: To review the existing literature of prediction models in degenerative spinal surgery. METHODS: Review of PubMed/Medline and Embase databases was conducted to identify articles between January 1, 2000 and March 1, 2020 that reported prediction model performance for outcomes following elective degenerative spine surgery. RESULTS: Thirty-one articles were included. Twenty studies were of thoracolumbar, 5 were of cervical, and 6 included all spine patients. Five studies were externally validated. Prediction models were developed using machine learning (42%) and logistic regression (42%) as well as other techniques. Web-based calculators were included in 45% of published articles. Various outcomes were investigated, including complications, infection, length of stay, discharge disposition, reoperation, readmission, disability score, back pain, leg pain, return to work, and opioid dependence. CONCLUSIONS: Significant heterogeneity exists in methods used to develop prediction models of postoperative outcomes after degenerative spine surgery. Most internally validate their scores, but a few have been externally validated. Areas under the curve for most models range from 0.6 to 0.9. Techniques for development are becoming increasingly sophisticated with different machine learning tools. With further external validation, these models can be deployed online for patient, physician, and administrative use, and have the potential to optimize outcomes and maximize value in spine surgery.

A Basomedial Amygdala to Intercalated Cells Microcircuit Expressing PACAP and Its Receptor PAC1 Regulates Contextual Fear.

Trauma can cause dysfunctional fear regulation leading some people to develop disorders, such as post-traumatic stress disorder (PTSD). The amygdala regulates fear, whereas PACAP (pituitary adenylate activating peptide) and PAC1 receptors are linked to PTSD symptom severity at genetic/epigenetic levels, with a strong link in females with PTSD. We discovered a PACAPergic projection from the basomedial amygdala (BMA) to the medial intercalated cells (mICCs) in adult mice. In vivo optogenetic stimulation of this pathway increased CFOS expression in mICCs, decreased fear recall, and increased fear extinction. Selective deletion of PAC1 receptors from the mICCs in females reduced fear acquisition, but enhanced fear generalization and reduced fear extinction in males. Optogenetic stimulation of the BMA-mICC PACAPergic pathway produced EPSCs in mICC neurons, which were enhanced by the PAC1 receptor antagonist, PACAP 6-38. Our findings show that mICCs modulate contextual fear in a dynamic and sex-dependent manner via a microcircuit containing the BMA and mICCs, and in a manner that was dependent on behavioral state.SIGNIFICANCE STATEMENT Traumatic stress can affect different aspects of fear behaviors, including fear learning, generalization of learned fear to novel contexts, how the fear of the original context is recalled, and how fear is reduced over time. While the amygdala has been studied for its role in regulation of different aspects of fear, the molecular circuitry of this structure is quite complex. In addition, aspects of fear can be modulated differently in males and females. Our findings show that a specific circuitry containing the neuropeptide PACAP and its receptor, PAC1, regulates various aspects of fear, including acquisition, generalization, recall, and extinction in a sexually dimorphic manner, characterizing a novel pathway that modulates traumatic fear.

Split cord malformation in adults: Literature review and classification.

The objective of this study was to summarize the available literature describing the presentation, diagnostic evaluation, and management for adults with Type 1 and Type 2 split spinal cord malformations. A review of the literature was performed using the CINAHL, PubMed, Embase, and Web of Science database, alongside all associated bibliographies, to include studies describing Type 1 and Type 2 split cord malformations diagnosed in patients above the age of 18. All relevant studies of split cord malformations were included, regardless of the year published and terminology used to describe the dysraphism. Clinical case series (≥ 2 patients), cohort studies, and review articles comprising adult patients with radiographically diagnosed diastematomyelia, diplomyelia, or dimyelia were included (Class of Evidence I-IV). A total of 17 unique articles, describing 146 unique adult spinal cord malformation subjects, were included. The most common associated condition was tethered cord syndrome (59.8 %). Operative management for symptomatic split cord malformation was performed in 72.3 % of cases. For those with preoperative neurologic deficits, operative management resulted in symptomatic improvement in 96.6 %, compared to 0 % conservative management (p < 0.05). For those with pain alone, operative management resulted in improvement of 91.1 %, compared to 12.5 % conservative management (p < 0.05). To date, this is the only literature review to include all split cord malformations (SCM Types I and II) presenting in adulthood, with clinical characteristics, associated conditions, and long-term treatment outcomes.

Breakdown of spatial coding and interneuron synchronization in epileptic mice.

Temporal lobe epilepsy causes severe cognitive deficits, but the circuit mechanisms remain unknown. Interneuron death and reorganization during epileptogenesis may disrupt the synchrony of hippocampal inhibition. To test this, we simultaneously recorded from the CA1 and dentate gyrus in pilocarpine-treated epileptic mice with silicon probes during head-fixed virtual navigation. We found desynchronized interneuron firing between the CA1 and dentate gyrus in epileptic mice. Since hippocampal interneurons control information processing, we tested whether CA1 spatial coding was altered in this desynchronized circuit, using a novel wire-free miniscope. We found that CA1 place cells in epileptic mice were unstable and completely remapped across a week. This spatial instability emerged around 6 weeks after status epilepticus, well after the onset of chronic seizures and interneuron death. Finally, CA1 network modeling showed that desynchronized inputs can impair the precision and stability of CA1 place cells. Together, these results demonstrate that temporally precise intrahippocampal communication is critical for spatial processing.

Horner Syndrome After Anterior Cervical Discectomy and Fusion: Case Series and Systematic Review.

BACKGROUND: Horner syndrome is an infrequently seen complication of anterior cervical discectomy and fusion (ACDF). Multicenter studies have reported a very low incidence, less than 0.1%. OBJECTIVE: To identify the incidence in, characteristics of, and postoperative course in patients in whom postoperative Horner syndrome developed after ACDF. METHODS: We performed a retrospective review of all patients who experienced Horner syndrome after ACDF for cervical degenerative disease at a single tertiary care institution between 2017 and 2018. A systematic review was then performed to identify studies investigating prevalence, diagnosis, and treatment of postoperative Horner syndrome after ACDF. RESULTS: Of 1116 patients at our institution who underwent ACDF, the incidence of Horner syndrome was 0.45%. C4/5 and C5/6 were the 2 most common surgical levels. The complication was noted to occur immediately after surgery, and at least partial improvement was identified in all patients an average 3.5 months after surgery (range, 10 days to 6 months). These findings were consistent with our systematic review of 21 studies that showed an incidence of 0.6% (range, 0.02% to 4.0%), the most common surgical level C5/6 (64%), and 82% of patients experiencing at least partial resolution of symptoms within 1 year (60.7% complete, 21.4% partial resolution). CONCLUSION: Horner syndrome occurs in 0.6% of patients undergoing ACDF. Careful postoperative examination should reveal this complication, which may be underdiagnosed or underreported in larger multicenter case series. The majority of patients experience complete resolution of symptoms within 6 months to 1 year and can be treated conservatively and expectantly.

The effect of renin-angiotensin system blockers on spinal cord dysfunction and imaging features of spinal cord compression in patients with symptomatic cervical spondylosis.

BACKGROUND CONTEXT: Cervical spondylosis may lead to spinal cord compression, poor vascular perfusion, and ultimately, cervical myelopathy. Studies suggest a neuroprotective effect of renin-angiotensin system (RAS) inhibitors in the brain, but limited data exist regarding their impact on the spinal cord. PURPOSE: To investigate whether RAS blockers and other antihypertensive drugs are correlated with preoperative functional status and imaging markers of cord compression in patients with symptomatic cervical spondylosis. STUDY DESIGN: Retrospective observational study. PATIENT SAMPLE: Individuals with symptomatic degenerative cervical stenosis who underwent surgery. OUTCOME MEASURES: Imaging features of spinal cord compression and functional status (modified Japanese Orthopedic Association [mJOA] and Nurick grading scales). METHODS: Two hundred sixty-six operative patients with symptomatic degenerative cervical stenosis were included. Demographic data, comorbidities, antihypertensive medications, and functional status (including mJOA and Nurick grading scales) were collected. We evaluated canal compromise, cord compromise, surface area of T2 signal cord change, and pixel intensity of signal cord change compared with normal cord on T2-weighted magnetic resonance imaging sequences. RESULTS: Of 266 patients, 41.7% were women, 58.3% were men; median age was 57.2 years; 20.6% smoked tobacco; 24.7% had diabetes mellitus. One hundred forty-nine patients (55.8%) had hypertension, 142 (95.3%) of these were taking antihypertensive medications (37 angiotensin-II receptor blockers [ARBs], 44 angiotensin-converting enzyme inhibitors, and 61 other medications). Patients treated with ARBs displayed a higher signal intensity ratio (ie, less signal intensity change in the compressed cord area) compared with untreated patients without hypertension (p=.004). Patients with hypertension had worse preoperative mJOA and Nurick scores than those without (p<.001). In the multivariate analysis, ARBs remained an independent beneficial factor for lower signal intensity change (p=.04), whereas hypertension remained a risk factor for worse preoperative neurological status (p<.01). CONCLUSIONS: In our study, patients with hypertension who were treated with RAS inhibitors had decreased T2-weighted signal intensity change than untreated patients without hypertension. Patients with hypertension also had worse preoperative functional status. Prospective case-control studies may deepen understanding of RAS modulators in the imaging and functional status of chronic spinal cord compression.

Assessment of a Triage Protocol for Emergent Neurosurgical Cases at a Single Institution.

BACKGROUND: Level I trauma centers use patient triaging systems to deploy neurosurgical resources and pursue good outcomes; however, data describing the effectiveness these triage systems are lacking. We reviewed the leveling protocol (cases designated urgent and emergent) of a regional Level I trauma center to obtain epidemiologic data about the efficiency of that system and identify areas for improvement. METHODS: We retrospectively reviewed leveled neurosurgical cases from January 2015 to October 2017, assessing surgery date, neurosurgical procedure, posted surgical urgency level (levels 1-3, with 1 being most urgent), and post-to-room (PTR) time (i.e., the time between initial leveling and admission of the patient to the operating room). Mean PTR times were compared between case types using one-way analysis of variance with post hoc Tukey honestly significant difference analysis. RESULTS: Of 1469 cases, 577 (39.3%) were shunt placement or revision, 231 (15.7%) were craniectomy or craniotomy for hematoma, 147 (10.0%) were craniectomy or craniotomy for tumor, and 514 (35.0%) were for other indications. Among level 1 cases, PTR time was lowest for craniotomies to evacuate intracranial hematoma (mean 16.2 minutes) and highest for spinal decompression procedures and wound washouts (mean 36.2 and 42.4 minutes, respectively). CONCLUSIONS: To our knowledge, this is the first study of variability in PTR timing as a function of surgical urgency or indication. The most common leveled cases were craniectomies or craniotomies to relieve increased intracranial pressure, which were also the most common level 1 cases. Significant variability occurred within each leveling category; thus, further investigation is required.

Chronic opioid pretreatment potentiates the sensitization of fear learning by trauma.

Despite the large comorbidity between PTSD and opioid use disorders, as well as the common treatment of physical injuries resulting from trauma with opioids, the ability of opioid treatments to subsequently modify PTSD-related behavior has not been well studied. Using the stress-enhanced fear learning (SEFL) model for PTSD, we characterized the impact of chronic opioid regimens on the sensitization of fear learning seen following traumatic stress in mice. We demonstrate for the first time that chronic opioid pretreatment is able to robustly augment associative fear learning. Highlighting aversive learning as the cognitive process mediating this behavioral outcome, these changes were observed after a considerable period of drug cessation, generalized to learning about multiple aversive stimuli, were not due to changes in stimulus sensitivity or basal anxiety, and correlated with a marker of synaptic plasticity within the basolateral amygdala. Additionally, these changes were not observed when opioids were given after the traumatic event. Moreover, we found that neither reducing the frequency of opioid administration nor bidirectional manipulation of acute withdrawal impacted the subsequent enhancement in fear learning seen. Given the fundamental role of associative fear learning in the generation and progression of PTSD, these findings are of direct translational relevance to the comorbidity between opioid dependence and PTSD, and they are also pertinent to the use of opioids for treating pain resulting from traumas involving physical injuries.

ezTrack: An open-source video analysis pipeline for the investigation of animal behavior.

Tracking animal behavior by video is one of the most common tasks in the life sciences. Although commercial software exists for executing this task, they often present enormous cost to the researcher and can entail purchasing hardware that is expensive and lacks adaptability. Additionally, the underlying code is often proprietary. Alternatively, available open-source options frequently require model training and can be challenging for those inexperienced with programming. Here we present an open-source and platform independent set of behavior analysis pipelines using interactive Python that researchers with no prior programming experience can use. Two modules are described. One module can be used for the positional analysis of an individual animal, amenable to a wide range of behavioral tasks. A second module is described for the analysis of freezing behavior. For both modules, a range of interactive plots and visualizations are available to confirm that chosen parameters produce the anticipated results. Moreover, batch processing tools for the fast analysis of multiple videos is provided, and frame-by-frame output makes alignment with biological recording data simple. Lastly, options for cropping video frames to mitigate the influence of fiberoptic/electrophysiology cables, analyzing specified portions of time, and defining regions of interest, are readily implemented.

Investigational growth factors utilized in animal models of spinal fusion: Systematic review.

BACKGROUND: Over 400000 Americans annually undergo spinal fusion surgeries, yet up to 40% of these procedures result in pseudoarthrosis even with iliac crest autograft, the current "gold standard" treatment. Tissue engineering has the potential to solve this problem via the creation of bone grafts involving bone-promoting growth factors (e.g., bone morphogenetic protein 2). A broad assessment of experimental growth factors is important to inform future work and clinical potential in this area. To date, however, no study has systematically reviewed the investigational growth factors utilized in preclinical animal models of spinal fusion. AIM: To review all published studies assessing investigational growth factors for spinal fusion in animal models and identify promising agents for translation. METHODS: We conducted a systematic review of the literature using PubMed, Embase, Cochrane Library, and Web of Science databases with searches run on May 29th, 2018. The search query was designed to include all non-human, preclinical animal models of spinal fusion reported in the literature without a timespan limit. Extracted data for each model included surgical approach, level of fusion, animal species and breed, animal age and sex, and any other relevant characteristics. The dosages/sizes of all implant materials, spinal fusion rates, and follow-up time points were recorded. The data were analyzed and the results reported in tables and text. PRISMA guidelines were followed for this systematic review. RESULTS: Twenty-six articles were included in this study, comprising 14 experimental growth factors: AB204 (n = 1); angiopoietin 1 (n = 1); calcitonin (n = 3); erythropoietin (n = 1); basic fibroblast growth factor (n = 1); growth differentiation factor 5 (n = 4), combined insulin-like growth factor 1 + transforming growth factor beta (n = 4); insulin (n = 1); NELL-1 (n = 5); noggin (n = 1); P-15 (n = 1); peptide B2A (n = 2); and secreted phosphoprotein 24 (n = 1). The fusion rates of the current gold standard treatment (autologous iliac crest bone graft, ICBG) and the leading clinically used growth factor (BMP-2) ranged widely in the included studies, from 0-100% for ICBG and from 13%-100% for BMP-2. Among the identified growth factors, calcitonin, GDF-5, NELL-1, and P-15 resulted in fusion rates of 100% in some cases. In addition, six growth factors - AB204, angiopoietin 1, GDF-5, insulin, NELL-1, and peptide B2A - resulted in significantly enhanced fusion rates compared to ICBG, BMP-2, or other internal control in some studies. Large heterogeneity in animal species, fusion method, and experimental groups and time points was observed across the included studies, limiting the direct comparison of the growth factors identified herein. CONCLUSION: Several promising investigational growth factors for spinal fusion have been identified herein; directly comparing the fusion efficacy and safety of these agents may inform clinical translation.