Department of Neurological Surgery Works

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AAV-KLF7 Promotes Descending Propriospinal Neuron Axonal Plasticity after Spinal Cord Injury
(hindawi publishing corporation, 2017) Li, Wen-Yuan; Wang, Ying; Zhai, Feng-Guo; Sun, Ping; Cheng, Yong-Xia; Deng, Ling-Xiao; Wang, Zhen-Yu; Neurological Surgery, School of Medicine
DPSN axons mediate and maintain a variety of normal spinal functions. Unsurprisingly, DPSN tracts have been shown to mediate functional recovery following SCI. KLF7 could contribute to CST axon plasticity after spinal cord injury. In the present study, we assessed whether KLF7 could effectively promote DPSN axon regeneration and synapse formation following SCI. An AAV-KLF7 construct was used to overexpress KLF7. In vitro, KLF7 and target proteins were successfully elevated and axonal outgrowth was enhanced. In vivo, young adult C57BL/6 mice received a T10 contusion followed by an AAV-KLF7 injection at the T7–9 levels above the lesion. Five weeks later, overexpression of KLF7 was expressed in DPSN. KLF7 and KLF7 target genes (NGF, TrkA, GAP43, and P0) were detectably increased in the injured spinal cord. Myelin sparring at the lesion site, DPSN axonal regeneration and synapse formation, muscle weight, motor endplate morphology, and functional parameters were all additionally improved by KLF7 treatment. Our findings suggest that KLF7 promotes DPSN axonal plasticity and the formation of synapses with motor neurons at the caudal spinal cord, leading to improved functional recovery and further supporting the potential of AAV-KLF7 as a therapeutic agent for spinal cord injury.
Aberrant Adult Neurogenesis in the Subventricular Zone-Rostral Migratory Stream-Olfactory Bulb System Following Subchronic Manganese Exposure
(Oxford University Press, 2016-04) Fu, Sherleen; Jiang, Wendy; Gao, Xiang; Zeng, Andrew; Cholger, Daniel; Cannon, Jason; Chen, Jinhui; Zheng, Wei; Department of Neurological Surgery, School of Medicine
Adult neurogenesis occurs in brain subventricular zone (SVZ). Our recent data reveal an elevated proliferation of BrdU(+) cells in SVZ following subchronic manganese (Mn) exposure in rats. This study was designed to distinguish Mn effect on the critical stage of adult neurogenesis, ie, proliferation, migration, survival and differentiation from the SVZ via the rostral migratory stream to the olfactory bulb (OB). Adult rats received a single ip-dose of BrdU at the end of 4-week Mn exposure to label proliferating cells. Immunostaining and cell-counting showed a 48% increase of BrdU(+) cells in Mn-exposed SVZ than in controls (P< .05). These BrdU(+) cells were identified as a mixed population of mainly GFAP(+) type-B neural stem cells, Nestin(+) type-C transit progenitor cells, DCX(+) migratory neuroblasts and Iba1(+) microglial cells. Another group of adult rats received 3 daily ip-injections of BrdU followed by subchronic Mn exposure. By 4-week post BrdU labeling, most of the surviving BrdU(+) cells in the OB were differentiated into NeuN(+) matured neurons. However, survival rates of BrdU/NeuN/DAPI triple-labeled cells in OB were 33% and 64% in Mn-exposed and control animals, respectively (P< .01). Infusion of Cu directly into the lateral ventricle significantly decreased the cell proliferation in the SVZ. Taken together, these results suggest that Mn exposure initially enhances the cell proliferation in adult SVZ. In the OB, however, Mn exposure significantly reduces the surviving adult-born cells and markedly inhibits their differentiation into mature neurons, resulting in an overall decreased adult neurogenesis in the OB.
Acridine Orange as a Novel Photosensitizer for Photodynamic Therapy in Glioblastoma
(Elsevier, 2018) Osman, Hany; Elsahy, Deena; Saadatzadeh, M. Reza; Pollok, Karen E.; Yocom, Steven; Hattab, Eyas; Georges, Joseph; Cohen-Gadol, Aaron A.; Neurological Surgery, School of Medicine
Object Photodynamic therapy is an exciting treatment modality that combines the effects of a chemical agent with the physical energy from light or radiation to result in lysis of cells of interest. Acridine orange is a molecule with fluorescence properties that was demonstrated to possess photosensitizing properties. The objective of this study was to investigate the photodynamic effect of acridine orange on glioblastoma cell viability and growth. Methods Glioblastoma cells (n = 8000 cells/well at 0 hours) were exposed to acridine orange followed by white unfiltered light-emitting diodes (LED) light. Cultures were exposed to either 10 or 30 minutes of light. The cell number per well was determined at 0, 24, 48, and 72 hours after exposure. Results A dramatic cytocidal effect of acridine orange after exposure to as little as 10 minutes of white light was observed. There was almost complete eradication of the glioblastoma cells over a 72-hour period. Although acridine orange or light alone exhibited some effect on cell growth, it was not as pronounced as the combination of acridine orange and light. Conclusions This is the first study to demonstrate the photodynamic effect of acridine orange in glioblastoma cells. This data supports the need for further studies to characterize and evaluate whether this striking cytotoxic effect can be achieved in vivo. The combination of acridine orange and exposure to white unfiltered LED light may have potential future applications in management of glioblastoma.
Aging impairs dendrite morphogenesis of newborn neurons and is rescued by 7, 8-dihydroxyflavone
(Wiley Blackwell (Blackwell Publishing), 2017-04) Wang, Xiaoting; Romine, Jennifer Lynn; Gao, Xiang; Chen, Jinhui; Neurological Surgery, School of Medicine
All aging individuals will develop some degree of decline in cognitive capacity as time progresses. The molecular and cellular mechanisms leading to age-related cognitive decline are still not fully understood. Through our previous research, we discovered that active neural progenitor cells selectively become more quiescent in response to aging, thus leading to the decline of neurogenesis in the aged hippocampus. Here, we further find that aging impaired dendrite development of newborn neurons. Currently, no effective approach is available to increase neurogenesis or promote dendrite development of newborn neurons in the aging brain. We found that systemically administration of 7, 8-dihydroxyflavone (DHF), a small molecule imitating brain-derived neurotrophic factor (BDNF), significantly enhanced dendrite length in the newborn neurons, while it did not promote survival of immature neurons, in the hippocampus of 12-month-old mice. DHF-promoted dendrite development of newborn neurons in the hippocampus may enhance their function in the aging animal leading to a possible improvement in cognition.
Analysis of human gliomas by swab touch spray-mass spectrometry: applications to intraoperative assessment of surgical margins and presence of oncometabolites
(Royal Society of Chemistry, 2017-10-23) Pirro, Valentina; Llor, Raquel Sero; Jarmusch, Alan K.; Alfaro, Clint M.; Cohen-Gadol, Aaron A.; Hattab, Eyas M.; Cooks, R. Graham; Neurological Surgery, School of Medicine
Touch spray mass spectrometry using medical swabs is an ambient ionization technique (ionization of unprocessed sample in the open air) that has potential intraoperative application in quickly identifying the disease state of tissue and in better characterizing the resection margin. To explore this potential, we studied 29 human brain tumor specimens and obtained evidence that this technique can provide diagnostic molecular information that is relevant to brain cancer. Touch spray using medical swabs involves the physical sampling of tissue using a medical swab on a spatial scale of a few mm2 with subsequent ionization occurring directly from the swab tip upon addition of solvent and application of a high voltage. Using a tertiary mixture of acetonitrile, N,N-dimethylformamide, and ethanol, membrane-derived phospholipids and oncometabolites are extracted from the tissue, incorporated into the sprayed microdroplets, vacuumed into the mass spectrometer, and characterized in the resulting mass spectra. The tumor cell load was assessed from the complex phospholipid pattern in the mass spectra and also separately by measurement of N-acetylaspartate. Mutation status of the isocitrate dehydrogenase gene was determined via detection of the oncometabolite 2-hydroxyglutarate. The lack of sample pretreatment makes touch spray mass spectrometry using medical swabs a feasible intraoperative strategy for rapid surgical assessment.
Anterior communicating artery complex aneurysms: anatomic characteristics as predictors of surgical outcome in 300 cases
(Elsevier, 2018) Bohnstedt, Bradley N.; Conger, Andrew R.; Edwards, John; Ziemba-Davis, Mary; Edwards, Gary; Brom, Jacqueline; Shah, Kushal; Cohen-Gadol, Aaron A.; Neurological Surgery, School of Medicine
OBJECTIVE Anterior communicating artery (ACoA) complex aneurysms are challenging to treat microsurgically. The authors report their experience with microsurgical treatment of ACoA aneurysms and examine the anatomic characteristics of these aneurysms as predictors of outcome. METHODS The authors queried their institution’s aneurysm database for records of consecutive patients treated for ACoA aneurysms via microsurgical clip ligation. Data included patient demographics and clinical/radiographic presentation characteristics as well as operative techniques. Glasgow outcome scores (GOS) at hospital discharge and 6-month as well as 1-year follow-up were analyzed. RESULTS Of 319 ACoA aneurysms that underwent treatment, 259 were ruptured and 60 were unruptured. Average GOS at 1-year follow-up for all patients was 4.6. Average GOS for patients with ruptured aneurysms correlated with Hunt and Hess grade at presentation, presence of frontal hemorrhages, and need for multiple clips during surgery. Notably, 142 (44.5%) of aneurysms originated mainly from the ACoA artery; 12 (3.8%) primarily from the A1 branch; 3 (0.9%) from the A2 branch; and 162 (50.8%) from the A1/A2 junction. Aneurysm projection was superior in 118 (37%), inferior in 106 (33.2%), anterior in 88 (27.6%), and posterior in 7 (2.2%). Patients with aneurysms originating from the A1 segment had worse outcomes. Posteriorly-projecting aneurysms were more likely to be unruptured and larger than other aneurysm configurations. CONCLUSIONS The aneurysm’s exact location in relation to the adjacent neurovascular structures is potentially predictive of outcomes in the microsurgical treatment of ACoA aneurysms.
Application of Lean Principles to Neurosurgical Procedures: The Case of Lumbar Spinal Fusion Surgery, a Literature Review and Pilot Series
(Oxford, 2018) Liu, Jesse J.; Raskin, Jeffrey S.; Hardaway, Fran; Holste, Katherine; Brown, Sarah; Raslan, Ahmed M.; Neurological Surgery, School of Medicine
BACKGROUND Delivery of higher value healthcare is an ultimate government and public goal. Improving efficiency by standardization of surgical steps can improve patient outcomes, reduce costs, and lead to higher value healthcare. Lean principles and methodology have improved timeliness in perioperative medicine; however, process mapping of surgery itself has not been performed. OBJECTIVE To apply Plan/Do/Study/Act (PDSA) cycles methodology to lumbar posterior instrumented fusion (PIF) using lean principles to create a standard work flow, identify waste, remove intraoperative variability, and examine feasibility among pilot cases. METHODS Process maps for 5 PIF procedures were created by a PDSA cycle from 1 faculty neurosurgeon at 1 institution. Plan, modularize PIF into basic components; Do, map and time components; Study, analyze results; and Act, identify waste. Waste inventories, spaghetti diagrams, and chartings of time spent per step were created. Procedural steps were broadly defined in order to compare steps despite the variability in PIF and were analyzed with box and whisker plots to evaluate variability. RESULTS Temporal variabilities in duration of decompression vs closure and hardware vs closure were significantly different (P = .003). Variability in procedural step duration was smallest for closure and largest for exposure. Wastes including waiting and instrument defects accounted for 15% and 66% of all waste, respectively. CONCLUSION This pilot series demonstrates that lean principles can standardize surgical workflows and identify waste. Though time and labor intensive, lean principles and PDSA methodology can be applied to operative steps, not just the perioperative period.
Assessment of postoperative outcomes in spinal epidural abscess following surgical decompression
(Elsevier, 2019) Keller, Leonard J.; Alentado, Vincent J.; Tanenbaum, Joseph E.; Lee, Bryan S.; Nowacki, Amy S.; Benzel, Edward C.; Mroz, Thomas E.; Steinmetz, Michael P.; Neurological Surgery, School of Medicine
Background context A spinal epidural abscess (SEA) is a serious condition that may be managed with antibiotics alone or with decompressive surgery combined with antibiotics. Purpose The objectives of this study were to assess the clinical outcomes of SEA after surgical management and to identify the patient-level factors that are associated with outcomes following surgical decompression and removal of SEA. Study design/setting Retrospective chart review analysis. Patient sample An analysis of 154 consecutive patients who initially presented to a tertiary-care, academic medical center with SEA, and were subsequently treated with surgery between 2010 and 2015 was performed. Outcome measures Postoperative predischarge American Spinal Injury Association Impairment Scale (AIS) scores, 6-month follow-up encounter AIS scores, need for revision surgery, and mortality during SEA surgery were the primary outcomes.Physiological Measures: AIS scores. Method Fisher's exact and Wilcoxon rank-sum tests were used to assess the associations between patient-level factors and surgical outcomes. Moreover, an interactive, predictive model for postoperative predischarge AIS score was developed using a proportional odds regression model. There was no funding secured for this study and there is no conflict of interest-associated biases. Results One hundred fifty-four patients (mean age of 58 years) were treated using surgical decompression in addition to antibiotics. The majority of patients were Caucasian (81%) and male (61%). No intraoperative mortality was reported. A second SEA surgery was performed in 8% of patients. A comparison of the preoperative and postoperative predischarge AIS scores showed that 49% of patients maintained a score of E or improved, while 45% remained at their preoperative status and 6% worsened. Among a subset of patients (n=36; 23%) for whom a 6-month follow-up encounter occurred, 75% maintained an AIS score of E or improved, 19% remained at their preoperative status, and 6% worsened. Both the presence and longer duration of preoperative paresis was associated with an increased risk of remaining at the same AIS score or worsening at the predischarge encounter (both p< .001). A predictive model for predischarge AIS scores was developed based on several patient characteristics. Conclusions Surgical decompression can contribute to improving or maintaining AIS scores in a high percentage of SEA patients. The presence and duration of preoperative paresis are prognostic for poorer outcomes and suggest that rapid surgical intervention before paresis develops may lead to improved postoperative outcomes. Our modeling tool enables an estimation of probabilities of patients’ predischarge condition.
Assessment of white matter loss using bond-selective photoacoustic imaging in a rat model of contusive spinal cord injury
(Mary Ann Liebert, 2014-12-15) Wu, Wei; Wang, Pu; Cheng, Ji-Xin; Xu, Xiao-Ming; Department of Neurological Surgery, IU School of Medicine
White matter (WM) loss is a critical event after spinal cord injury (SCI). Conventionally, such loss has been measured with histological and histochemical approaches, although the procedures are complex and may cause artifact. Recently, coherent Raman microscopy has been proven to be an emerging technology to study de- and remyelination of the injured spinal cord; however, limited penetration depth and small imaging field prevent it from comprehensive assessments of large areas of damaged tissues. Here, we report the use of bond-selective photoacoustic (PA) imaging with 1730-nm excitation, where the first overtone vibration of CH2 bond is located, to assess WM loss after a contusive SCI in adult rats. By employing the first overtone vibration of CH2 bond as the contrast, the mapping of the WM in an intact spinal cord was achieved in a label-free three-dimensional manner, and the physiological change of the spinal cord before and after injury was observed. Moreover, the recovery of the spinal cord from contusive injury with the treatment of a neuroprotective nanomedicine ferulic-acid-conjugated glycol chitosan (FA-GC) was also observed. Our study suggests that bond-selective PA imaging is a valuable tool to assess the progression of WM pathology after SCI as well as neuroprotective therapeutics in a label-free manner.
At-Risk Tackling Techniques in American Football
(Sage, 2020-02) Stockwell, David W.; Blalock, Richard; Podell, Kenneth; Marco, Rex A.W.; Neurological Surgery, School of Medicine
Background: In American football, fewer fatalities and severe injuries have been seen annually since 1976, after data from 1971 through 1975 were retrospectively reviewed to better understand the mechanisms involved in catastrophic cervical spine injury and rules were enacted to prohibit certain types of aggressive tackling. The National Football Head and Neck Injury Registry was established in 1975. Purpose: To assess (1) tackling techniques that coaches were teaching at 3 levels-youth level (YL; 4th to 5th grades), middle school (MS; 6th to 8th grades), and high school (HS; 9th to 12th grades); (2) tackling techniques used during games; and (3) the successful tackle rates of these techniques. Study design: Descriptive epidemiology study. Methods: Surveys were distributed via email to 500 coaches of YL, MS, and HS football teams in Texas. Coaches provided video recordings of football games, and all tackle attempts were graded by a single reviewer who watched game videos; 1000 consecutive tackles were observed for each group. Survey data included how coaches instructed their players to tackle, the types of tackles, the number of tackles versus missed tackles, the head position, and the initial contact. Data were analyzed with the chi-square test. A subset of 100 consecutive tackles at each level of play was reviewed by 2 blinded reviewers to assess intra- and interrater reliabilities. Results: In all groups, coaches responded that they preferred to teach the at-risk "head across the bow" tackling technique (83% YL, 81% MS, 75% HS). Coaches stated that they instructed players to "keep your head up," as currently recommended, 89% in YL, 100% in MS, and 81% in HS. During games, players used head-up, inside-shoulder tackles more successfully across all groups (97.5% YL, 99.5% MS, 98.8% HS). While intra- and interrater reliabilities were in the good range, these scores were lower in the youth group. Conclusion: Our study supports the effectiveness of tackling with the head up and making the initial contact with the inside shoulder. Lower reliability ratings for the youth group were likely due to lower video quality and the lack of players' tackling experience.

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