All Publications

  • Sigma-1 receptor expression in a subpopulation of lumbar spinal cord microglia in response to peripheral nerve injury. Scientific reports Schonfeld, E., Johnstone, T. M., Haider, G., Shah, A., Marianayagam, N. J., Biswal, S., Veeravagu, A. 2023; 13 (1): 14762


    Sigma-1 Receptor has been shown to localize to sites of peripheral nerve injury and back pain. Radioligand probes have been developed to localize Sigma-1 Receptor and thus image pain source. However, in non-pain conditions, Sigma-1 Receptor expression has also been demonstrated in the central nervous system and dorsal root ganglion. This work aimed to study Sigma-1 Receptor expression in a microglial cell population in the lumbar spine following peripheral nerve injury. A publicly available transcriptomic dataset of 102,691 L4/5 mouse microglial cells from a sciatic-sural nerve spared nerve injury model and 93,027 age and sex matched cells from a sham model was used. At each of three time points-postoperative day 3, postoperative day 14, and postoperative month 5-gene expression data was recorded for both spared nerve injury and Sham cell groups. For all cells, 27,998 genes were sequenced. All cells were clustered into 12 distinct subclusters and gene set enrichment pathway analysis was performed. For both the spared nerve injury and Sham groups, Sigma-1 Receptor expression significantly decreased at each time point following surgery. At the 5-month postoperative time point, only one of twelve subclusters showed significantly increased Sigma-1 Receptor expression in spared nerve injury cells as compared to Sham cells (p = 0.0064). Pathway analysis of this cluster showed a significantly increased expression of the inflammatory response pathway in the spared nerve injury cells relative to Sham cells at the 5-month time point (p = 6.74e-05). A distinct subcluster of L4/5 microglia was identified which overexpress Sigma-1 Receptor following peripheral nerve injury consistent with neuropathic pain inflammatory response functioning. This indicates that upregulated Sigma-1 Receptor in the central nervous system characterizes post-acute peripheral nerve injury and may be further developed for clinical use in the differentiation between low back pain secondary to peripheral nerve injury and low back pain not associated with peripheral nerve injury in cases where the pain cannot be localized.

    View details for DOI 10.1038/s41598-023-42063-8

    View details for PubMedID 37679500

    View details for PubMedCentralID PMC10484902

  • Demonstrating the successful application of synthetic learning in spine surgery for training multi-center models with increased patient privacy. Scientific reports Schonfeld, E., Veeravagu, A. 2023; 13 (1): 12481


    From real-time tumor classification to operative outcome prediction, applications of machine learning to neurosurgery are powerful. However, the translation of many of these applications are restricted by the lack of "big data" in neurosurgery. Important restrictions in patient privacy and sharing of imaging data reduce the diversity of the datasets used to train resulting models and therefore limit generalizability. Synthetic learning is a recent development in machine learning that generates synthetic data from real data and uses the synthetic data to train downstream models while preserving patient privacy. Such an approach has yet to be successfully demonstrated in the spine surgery domain. Spine radiographs were collected from the VinDR-SpineXR dataset, with 1470 labeled as abnormal and 2303 labeled as normal. A conditional generative adversarial network (GAN) was trained on the radiographs to generate a spine radiograph and normal/abnormal label. A modified conditional GAN (SpineGAN) was trained on the same task. A convolutional neural network (CNN) was trained using the real data to label abnormal radiographs. A CNN was trained to label abnormal radiographs using synthetic images from the GAN and in a separate experiment from SpineGAN. Using the real radiographs, an AUC of 0.856 was achieved in abnormality classification. Training on synthetic data generated by the standard GAN (AUC of 0.814) and synthetic data generated by our SpineGAN (AUC of 0.830) resulted in similar classifier performance. SpineGAN generated images with higher FID and lower precision scores, but with higher recall and increased performance when used for synthetic learning. The successful application of synthetic learning was demonstrated in the spine surgery domain for the classification of spine radiographs as abnormal or normal. A modified domain-relevant GAN is introduced for the generation of spine images, evidencing the importance of domain-relevant generation techniques in synthetic learning. Synthetic learning can allow neurosurgery to use larger and more diverse patient imaging sets to train more generalizable algorithms with greater patient privacy.

    View details for DOI 10.1038/s41598-023-39458-y

    View details for PubMedID 37528216

    View details for PubMedCentralID 9099011

  • Artificial Intelligence in Neurosurgery: A State-of-the-Art Review from Past to Future. Diagnostics (Basel, Switzerland) Tangsrivimol, J. A., Schonfeld, E., Zhang, M., Veeravagu, A., Smith, T. R., Härtl, R., Lawton, M. T., El-Sherbini, A. H., Prevedello, D. M., Glicksberg, B. S., Krittanawong, C. 2023; 13 (14)


    In recent years, there has been a significant surge in discussions surrounding artificial intelligence (AI), along with a corresponding increase in its practical applications in various facets of everyday life, including the medical industry. Notably, even in the highly specialized realm of neurosurgery, AI has been utilized for differential diagnosis, pre-operative evaluation, and improving surgical precision. Many of these applications have begun to mitigate risks of intraoperative and postoperative complications and post-operative care. This article aims to present an overview of the principal published papers on the significant themes of tumor, spine, epilepsy, and vascular issues, wherein AI has been applied to assess its potential applications within neurosurgery. The method involved identifying high-cited seminal papers using PubMed and Google Scholar, conducting a comprehensive review of various study types, and summarizing machine learning applications to enhance understanding among clinicians for future utilization. Recent studies demonstrate that machine learning (ML) holds significant potential in neuro-oncological care, spine surgery, epilepsy management, and other neurosurgical applications. ML techniques have proven effective in tumor identification, surgical outcomes prediction, seizure outcome prediction, aneurysm prediction, and more, highlighting its broad impact and potential in improving patient management and outcomes in neurosurgery. This review will encompass the current state of research, as well as predictions for the future of AI within neurosurgery.

    View details for DOI 10.3390/diagnostics13142429

    View details for PubMedID 37510174

  • Understanding transfer learning for chest radiograph clinical report generation with modified transformer architectures. Heliyon Vendrow, E., Schonfeld, E. 2023; 9 (7): e17968


    The image captioning task is increasingly prevalent in artificial intelligence applications for medicine. One important application is clinical report generation from chest radiographs. The clinical writing of unstructured reports is time consuming and error-prone. An automated system would improve standardization, error reduction, time consumption, and medical accessibility. In this paper we demonstrate the importance of domain specific pre-training and propose a modified transformer architecture for the medical image captioning task. To accomplish this, we train a series of modified transformers to generate clinical reports from chest radiograph image input. These modified transformers include: a meshed-memory augmented transformer architecture with visual extractor using ImageNet pre-trained weights, a meshed-memory augmented transformer architecture with visual extractor using CheXpert pre-trained weights, and a meshed-memory augmented transformer whose encoder is passed the concatenated embeddings using both ImageNet pre-trained weights and CheXpert pre-trained weights. We use BLEU(1-4), ROUGE-L, CIDEr, and the clinical CheXbert F1 scores to validate our models and demonstrate competitive scores with state of the art models. We provide evidence that ImageNet pre-training is ill-suited for the medical image captioning task, especially for less frequent conditions (e.g.: enlarged cardiomediastinum, lung lesion, pneumothorax). Furthermore, we demonstrate that the double feature model improves performance for specific medical conditions (edema, consolidation, pneumothorax, support devices) and overall CheXbert F1 score, and should be further developed in future work. Such a double feature model, including both ImageNet pre-training as well as domain specific pre-training, could be used in a wide range of image captioning models in medicine.

    View details for DOI 10.1016/j.heliyon.2023.e17968

    View details for PubMedID 37519756

  • Clinical Outcomes and Cost Profiles for Cage and Allograft Anterior Cervical Discectomy and Fusion Procedures in the Adult Population: A Propensity Score-Matched Study ASIAN SPINE JOURNAL Rodrigues, A., Varshneya, K., Stienen, M., Schonfeld, E., Than, K., Veeravagu, A. 2023
  • The Impact of Preoperative Myelopathy on Postoperative Outcomes among Anterior Cervical Discectomy and Fusion Procedures in the Nonelderly Adult Population: A Propensity-Score Matched Study. Asian spine journal Rodrigues, A. J., Schonfeld, E., Varshneya, K., Stienen, M. N., Veeravagu, A. 2023


    Retrospective cohort study.Anterior cervical discectomy and fusion (ACDF) is a common surgical intervention for patients diagnosed with cervical degenerative diseases with or without myelopathy. A thorough understanding of outcomes in patients with and without myelopathy undergoing ACDF is required because of the widespread utilization of ACDF for these indications.Non-ACDF approaches achieved inferior outcomes in certain myelopathic cases. Studies have compared patient outcomes across procedures, but few have compared outcomes concerning myelopathic versus nonmyelopathic cohorts.The MarketScan database was queried from 2007 to 2016 to identify adult patients who were ≤65 years old, and underwent ACDF using the international classification of diseases 9th version and current procedural terminology codes. Nearest neighbor propensity-score matching was employed to balance patient demographics and operative characteristics between myelopathic and nonmyelopathic cohorts.Of 107,480 patients who met the inclusion criteria, 29,152 (27.1%) were diagnosed with myelopathy. At baseline, the median age of patients with myelopathy was higher (52 years vs. 50 years, p <0.001), and they had a higher comorbidity burden (mean Charlson comorbidity index, 1.92 vs. 1.58; p <0.001) than patients without myelopathy. Patients with myelopathy were more likely to undergo surgical revision at 2 years (odds ratio [OR], 1.63; 95% confidence interval [CI], 1.54-1.73) or are readmitted within 90 days (OR, 1.27; 95% CI, 1.20-1.34). After patient cohorts were matched, patients with myelopathy remained at elevated risk for reoperation at 2 years (OR, 1.55; 95% CI, 1.44-1.67) and postoperative dysphagia (2.78% vs. 1.68%, p <0.001) compared to patients without myelopathy.We found inferior postoperative outcomes at baseline for patients with myelopathy undergoing ACDF compared to patients without myelopathy. Patients with myelopathy remained at significantly greater risk for reoperation and readmission after balancing potential confounding variables across cohorts, and these differences in outcomes were largely driven by patients with myelopathy undergoing 1-2 level fusions.

    View details for DOI 10.31616/asj.2022.0347

    View details for PubMedID 37226379

  • Clinical Outcomes and Cost Profiles for Cage and Allograft Anterior Cervical Discectomy and Fusion Procedures in the Adult Population: A Propensity Score-Matched Study. Asian spine journal Rodrigues, A. J., Varshneya, K., Stienen, M. N., Schonfeld, E., Than, K. D., Veeravagu, A. 2023


    Retrospective cohort study.To characterize the postoperative outcomes and economic costs of anterior cervical discectomy and fusion (ACDF) procedures using synthetic biomechanical intervertebral cage (BC) and structural allograft (SA) implants.ACDF is a common spine procedure that typically uses an SA or BC for the cervical fusion. Previous studies that compared the outcomes between the two implants were limited by small sample sizes, short-term postoperative outcomes, and procedures with single-level fusion.Adult patients who underwent an ACDF procedure in 2007-2016 were included. Patient records were extracted from MarketScan, a national registry that captures person-specific clinical utilization, expenditures, and enrollments across millions of inpatient, outpatient, and prescription drug services. Propensity-score matching (PSM) was employed to match the patient cohorts across demographic characteristics, comorbidities, and treatments.Of 110,911 patients, 65,151 (58.7%) received BC implants while 45,760 (41.3%) received SA implants. Patients who underwent BC surgeries had slightly higher reoperation rates within 1 year after the index ACDF procedure (3.3% vs. 3.0%, p=0.004), higher postoperative complication rates (4.9% vs. 4.6%, p=0.022), and higher 90-day readmission rates (4.9% vs. 4.4%, p =0.001). After PSM, the postoperative complication rates did not vary between the two cohorts (4.8% vs. 4.6%, p=0.369), although dysphagia (2.2% vs. 1.8%, p<0.001) and infection (0.3% vs. 0.2%, p=0.007) rates remained higher for the BC group. Other outcome differences, including readmission and reoperation, decreased. Physician's fees remained high for BC implantation procedures.We found marginal differences in clinical outcomes between BC and SA ACDF interventions in the largest published database cohort of adult ACDF surgeries. After adjusting for group-level differences in comorbidity burden and demographic characteristics, BC and SA ACDF surgeries showed similar clinical outcomes. Physician's fees, however, were higher for BC implantation procedures.

    View details for DOI 10.31616/asj.2022-0261

    View details for PubMedID 37226385

  • Comparison of Deep Learning and Classical Machine Learning Algorithms to Predict Post-operative Outcomes for Anterior Cervical Discectomy and Fusion Procedures with State-of-the-art Performance. Spine Rodrigues, A. J., Schonfeld, E., Varshneya, K., Stienen, M. N., Staartjes, V. E., Jin, M. C., Veeravagu, A. 2022


    STUDY DESIGN: Retrospective cohort.OBJECTIVE: Due to Anterior cervical discectomy and fusion (ACDF) popularity, it is important to predict post-operative complications, unfavorable 90-day readmissions, and 2-year re-operations to improve surgical decision making, prognostication and planning.SUMMARY OF BACKGROUND DATA: Machine learning has been applied to predict post-operative complications for ACDF; however, studies were limited by sample size and model type. These studies achieved 0.70 AUC. Further approaches, not limited to ACDF, focused on specific complication types, and resulted in AUC between 0.70-0.76.METHODS: The IBM MarketScan Commercial Claims and Encounters Database and Medicare Supplement were queried from 2007-2016 to identify adult patients who underwent an ACDF procedure (N=176,816). Traditional machine learning algorithms, logistic regression, support vector machines, were compared with deep neural networks to predict: 90-day post-operative complications, 90-day readmission, and 2-year reoperation. We further generated random deep learning model architectures and trained them on the 90-day complication task to approximate an upper bound. Lastly, using deep learning, we investigated the importance of each input variable for the prediction of 90-day post-operative complications in ACDF.RESULTS: For the prediction of 90-day complication, 90-day readmission, and 2-year reoperation, the deep neural network-based models achieved area under the curve (AUC) of 0.832, 0.713, and 0.671. Logistic regression achieved AUCs of 0.820, 0.712, and 0.671. SVM approaches were significantly lower. The upper bound of deep learning performance was approximated as 0.832. Myelopathy, age, HIV, previous myocardial infarctions, obesity, and documentary weakness were found to be the strongest variable to predict 90-day post-operative complications.CONCLUSIONS: The deep neural network may be used to predict complications for clinical applications after multi-center validation. The results suggest limited added knowledge exists in interactions between the input variables used for this task. Future work should identify novel variables to increase predictive power.

    View details for DOI 10.1097/BRS.0000000000004481

    View details for PubMedID 36149852

  • Chronic opioid use prior to ACDF surgery is associated with inferior post-operative outcomes: a propensity-matched study of 17,443 chronic opioid users. World neurosurgery Rodrigues, A. J., Varshneya, K., Schonfeld, E., Malhotra, S., Stienen, M. N., Veeravagu, A. 2022


    STUDY DESIGN: Retrospective cohort OBJECTIVE: Candidates for anterior cervical discectomy and fusion (ACDF) have a higher rate of opioid use than does the public, but studies on pre-operative opioid use have not been conducted. We aimed to understand how pre-operative opioid use affects post-ACDF outcomes.METHODS: The MarketScan Database was queried from 2007-2015 to identify adult patients who underwent an ACDF. Patients were classified into separate cohorts based on the number of separate opioid prescriptions in the year before their ACDF. 90-day post-operative complications, post-operative readmission, re-operation, and total inpatient costs were compared between opioid strata. Propensity-score matching (PSM) matched patient cohorts across observed comorbidities.RESULTS: Of 81,671 ACDF patients, 31,312 (38.3%) were non-users, 30,302 (37.1%) were mild users, and 20,057 (24.6%) were chronic users. Chronic opioid users had a higher comorbidity burden, on average, than patients with less frequent opioid use (p<0.001). Chronic opioid users had higher rates of post-operative complications (9.1%) than mild opioid users (6.0%) and non-users (5.3%) (p<0.001), and higher rates of readmission and reoperation. After balancing opioid non-users vs. chronic opioid users along demographic, pre-operative comorbidity, and operative characteristics, post-operative complications remained elevated for chronic opioid users relative to opioid non-users (8.6% vs. 5.7%; p<0.001), as did rates of readmission and reoperation.CONCLUSIONS: Chronic opioid users had more comorbidities than opioid non-users and mild opioid users, longer hospitalizations, and higher rates of post-operative complication, readmission, and reoperation. After balancing patients across covariates, the outcome differences persisted, suggesting a durable association between pre-operative opioid use and negative post-operative outcomes.

    View details for DOI 10.1016/j.wneu.2022.07.002

    View details for PubMedID 35809840

  • Vertebrae segmentation in reduced radiation CT imaging for augmented reality applications. International journal of computer assisted radiology and surgery Schonfeld, E., de Lotbiniere-Bassett, M., Jansen, T., Anthony, D., Veeravagu, A. 1800


    PURPOSE: There is growing evidence for the use of augmented reality (AR) navigation in spinal surgery to increase surgical accuracy and improve clinical outcomes. Recent research has employed AR techniques to create accurate auto-segmentations, the basis of patient registration, using reduced radiation dose intraoperative computed tomography images. In this study, we aimed to determine if spinal surgery AR applications can employ reduced radiation dose preoperative computed tomography (pCT) images.METHODS: We methodically decreased the imaging dose, with the addition of Gaussian noise, that was introduced into pCT images to determine the image quality threshold that was required for auto-segmentation. The Gaussian distribution's standard deviation determined noise level, such that a scalar multiplier (L: [0.00, 0.45], with steps of 0.03) simulated lower doses as L increased. We then enhanced the images with denoising algorithms to evaluate the effect on the segmentation.RESULTS: The pCT radiation dose was decreased to below the current lowest clinical threshold and the resulting images produced segmentations that were appropriate for input into AR applications. This held true at simulated dose L=0.06 (estimated 144 mAs) but not at L=0.09 (estimated 136 mAs). The application of denoising algorithms to the images resulted in increased artifacts and decreased bone density.CONCLUSIONS: The pCT image quality that is required for AR auto-segmentation is lower than that which is currently employed in spinal surgery. We recommend a reduced radiation dose protocol of approximately 140 mAs. This has the potential to reduce the radiation experienced by patients in comparison to procedures without AR support. Future research is required to identify the specific, clinically relevant radiation dose thresholds required for surgical navigation.

    View details for DOI 10.1007/s11548-022-02561-y

    View details for PubMedID 35025073

  • Autocatalytic-protection for an unknown locus CRISPR-Cas countermeasure for undesired mutagenic chain reactions. Journal of theoretical biology Schonfeld, E., Schonfeld, E., Schonfeld, D. 2021; 528: 110831


    The mutagenic chain reaction (MCR) is a genetic tool to use a CRISPR-Cas construct to introduce a homing endonuclease, allowing gene drive to influence whole populations in a minimal number of generations (Esvelt et al., 2014; Gantz and Bier, 2015; Gantz and Bier, 2016). The question arises: if an active genetic terror event is released into a population, could we prevent the total spread of the undesired allele (Gantz, et al., 2015; Webber et al., 2015)? Thus far, effective protection methods require knowledge of the terror locus (Grunwald et al., 2019). Here we introduce a novel approach, an autocatalytic-Protection for an Unknown Locus (a-PUL), whose aim is to spread through a population and arrest and decrease an active terror event's spread without any prior knowledge of the terror-modified locus, thus allowing later natural selection and ERACR drives to restore the normal locus (Hammond et al., 2017). a-PUL, using a mutagenic chain reaction, includes (i) a segment encoding a non-Cas9 endonuclease capable of homology-directed repair suggested as Type II endonuclease Cpf1 (Cas12a), (ii) a ubiquitously-expressed gene encoding a gRNA (gRNA1) with a U4AU4 3'-overhang specific to Cpf1 and with crRNA specific to some desired genomic sequence of non-coding DNA, (iii) a ubiquitously-expressed gene encoding two gRNAs (gRNA2/gRNA3) both with tracrRNA specific to Cas9 and crRNA specific to two distinct sites of the Cas9 locus, and (iv) homology arms flanking the Cpf1/gRNA1/gRNA2/gRNA3 cassette that are identical to the region surrounding the target cut directed by gRNA1 (Khan, 2016; Zetsche et al., 2015). We demonstrate the proof-of-concept and efficacy of our protection construct through a Graphical Markov model and computer simulation.

    View details for DOI 10.1016/j.jtbi.2021.110831

    View details for PubMedID 34274311

  • On the relation of gene essentiality to intron structure: a computational and deep learning approach LIFE SCIENCE ALLIANCE Schonfeld, E., Vendrow, E., Vendrow, J., Schonfeld, E. 2021; 4 (6)


    Essential genes have been studied by copy number variants and deletions, both associated with introns. The premise of our work is that introns of essential genes have distinct characteristic properties. We provide support for this by training a deep learning model and demonstrating that introns alone can be used to classify essentiality. The model, limited to first introns, performs at an increased level, implicating first introns in essentiality. We identify unique properties of introns of essential genes, finding that their structure protects against deletion and intron-loss events, especially centered on the first intron. We show that GC density is increased in the first introns of essential genes, allowing for increased enhancer activity, protection against deletions, and improved splice site recognition. We find that first introns of essential genes are of remarkably smaller size than their nonessential counterparts, and to protect against common 3' end deletion events, essential genes carry an increased number of (smaller) introns. To demonstrate the importance of the seven features we identified, we train a feature-based model using only these features and achieve high performance.

    View details for DOI 10.26508/lsa.202000951

    View details for Web of Science ID 000654748200008

    View details for PubMedID 33906938

    View details for PubMedCentralID PMC8127325

  • Lateralized Deficits in Motor, Sensory, and Olfactory Domains in Dementia JOURNAL OF ALZHEIMERS DISEASE Schonfeld, E., Schonfeld, E., Aman, C., Gill, N., Kim, D., Rabin, S., Shamshuddin, B., Sealey, L., Senno, R. 2021; 79 (3): 1033-1040


    There exist functional deficits in motor, sensory, and olfactory abilities in dementias. Measures of these deficits have been discussed as potential clinical markers.We measured the deficit of motor, sensory, and olfactory functions on both the left and right body side, to study potential body lateralizations.This IRB-approved study (N = 84) performed left/right clinical tests of gross motor (dynamometer test), sensory (Von Frey test), and olfactory (peppermint oil test) ability. The Mini-Mental Status Exam was administered to determine level of dementia; medical and laboratory data were collected.Sensory and olfactory deficits lateralized to the left side of the body, while motor deficits lateralized to the right side. We found clinical correlates of motor lateralization: female, depression, MMSE <15, and diabetes. While clinical correlates of sensory lateralization: use of psychotherapeutic agent, age ≥85, MMSE <15, and male. Lastly, clinical correlates of olfactory lateralization: age <85, number of medications >10, and male.These lateralized deficits in body function can act as early clinical markers for improved diagnosis and treatment. Future research should identify correlates and corresponding therapies to strengthen at-risk areas.

    View details for DOI 10.3233/JAD-201216

    View details for Web of Science ID 000618072600010

    View details for PubMedID 33459707

  • OnabotulinumtoxinA injections: treatment of reversible cerebral vasoconstriction syndrome chronic daily headaches BMJ CASE REPORTS Senno, R., Schonfeld, E., Nagar, C. 2019; 12 (5)


    Reversible cerebral vasoconstriction syndrome (RCVS) is a rare condition characterised by repetitive, multifocal, vasofluctuations of cerebral arteries. A key symptom is chronic, disabling 'thunderclap' headaches, which are extremely difficult to treat as established medications may exacerbate the pathophysiology of RCVS. OnabotulinumtoxinA (OBT-A) injections are used for the prophylaxis of chronic daily headaches (CDH). The mechanism of action of OBT-A significantly differs from oral headache treatments. Thus, OBT-A may be an effective, safe treatment of RCVS-CDH. A 51-year-old woman with RCVS-CDH presented to outpatient clinic. This case report describes the first, believed, documented treatment of RCVS-CDH by OBT-A injections. In 2018, the consented patient received a total of 200 units of OBT-A, 155 units to the 31 approved U.S. Food and Drug Administration (FDA) sites and 45 units injected into the bilateral occipital belly of occipitofrontalis muscles. The patient reported 3 months of excellent pain relief (60% reduction). Three rounds of OBT-A injection, each 3 months apart, resulted in 80% reduction. OBT-A injections may prove a successful, novel treatment for RCVS-CDH.

    View details for DOI 10.1136/bcr-2018-228562

    View details for Web of Science ID 000661395200086

    View details for PubMedID 31151973

    View details for PubMedCentralID PMC6557340