Department of Neurological Surgery Works

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A Flexible Platform for Biofeedback-driven Control and Personalization of Electrical Nerve Stimulation Therapy
(IEEE, 2015) Ward, Matthew P.; Qing, Kurt Y.; Otto, Kevin J.; Worth, Robert M.; John, Simon W. M.; Irazoqui, Pedro; Department of Neurological Surgery, IU School of Medicine
Electrical vagus nerve stimulation is a treatment alternative for many epileptic and depressed patients whose symptoms are not well managed with pharmaceutical therapy. However, the fixed stimulus, open loop dosing mechanism limits its efficacy and precludes major advances in the quality of therapy. A real-time, responsive form of vagus nerve stimulation is needed to control nerve activation according to therapeutic need. This personalized approach to therapy will improve efficacy and reduce the number and severity of side effects. We present autonomous neural control, a responsive, biofeedback-driven approach that uses the degree of measured nerve activation to control stimulus delivery. We demonstrate autonomous neural control in rats, showing that it rapidly learns how to most efficiently activate any desired proportion of vagal A, B, and/or C fibers over time. This system will maximize efficacy by minimizing patient response variability and by minimizing therapeutic failures resulting from longitudinal decreases in nerve activation with increasing durations of treatment. The value of autonomous neural control equally applies to other applications of electrical nerve stimulation.
Blood Supply to the Human Spinal Cord. II. Imaging and Pathology
(Wiley, 2015-01) Bosmia, Anand N.; Tubbs, R. Shane; Hogan, Elizabeth; Bohnstedt, Bradley N.; DeNardo, Andrew J.; Loukas, Marios; Cohen-Gadol, Aaron A.; Department of Neurological Surgery, IU School of Medicine
The blood supply of the spinal cord is a complex system based on multilevel sources and anastomoses. Diseases often affect this vascular supply and imaging has been developed that better investigates these structures. The authors review the literature regarding pathology and imaging modalities for the blood supply of the spinal cord. Knowledge of the disease processes and imaging modalities used to investigate these arterial lesions of the spinal cord will assist the clinician when treating patients with spinal cord lesions.
Blood Supply to the Human Spinal Cord. I. Anatomy and Hemodynamics
(Wiley, 2015-01) Bosmia, Anand N.; Hogan, Elizabeth; Loukas, Marios; Tubbs, R. Shane; Cohen-Gadol, Aaron A.; Department of Neurological Surgery, IU School of Medicine
The arterial network that supplies the human spinal cord, which was once thought to be similar to that of the brain, is in fact much different and more extensive. In this article, the authors attempt to provide a comprehensive review of the literature regarding the anatomy and known hemodynamics of the blood supply to the human spinal cord. Additionally, as the medical literature often fails to provide accurate terminology for the arteries that supply the cord, the authors attempt to categorize and clarify this nomenclature. A complete understanding of the morphology of the arterial blood supply to the human spinal cord is important to anatomists and clinicians alike.
When “altering brain function” becomes “mind control”
(Frontiers Media SA, 2014-10-14) Koivuniemi, Andrew; Otto, Kevin; Department of Neurological Surgery, School of Medicine
Functional neurosurgery has seen a resurgence of interest in surgical treatments for psychiatric illness. Deep brain stimulation (DBS) technology is the preferred tool in the current wave of clinical experiments because it allows clinicians to directly alter the functions of targeted brain regions, in a reversible manner, with the intent of correcting diseases of the mind, such as depression, addiction, anorexia nervosa, dementia, and obsessive compulsive disorder. These promising treatments raise a critical philosophical and humanitarian question. “Under what conditions does ‘altering brain function’ qualify as ‘mind control’?” In order to answer this question one needs a definition of mind control. To this end, we reviewed the relevant philosophical, ethical, and neurosurgical literature in order to create a set of criteria for what constitutes mind control in the context of DBS. We also outline clinical implications of these criteria. Finally, we demonstrate the relevance of the proposed criteria by focusing especially on serendipitous treatments involving DBS, i.e., cases in which an unintended therapeutic benefit occurred. These cases highlight the importance of gaining the consent of the subject for the new therapy in order to avoid committing an act of mind control.
Transsylvian selective amygdalohippocampectomy for treatment of medial temporal lobe epilepsy: Surgical technique and operative nuances to avoid complications
(Medknow Publications And Media Pvt. Ltd., part of Wolters Kluwer Health, 2014) Kovanda, Timothy J.; Tubbs, R. Shane; Cohen-Gadol, Aaron A.; Department of Neurological Surgery, School of Medicine
Background: A number of different surgical techniques are effective for treatment of drug-resistant medial temporal lobe epilepsy. Of these, transsylvian selective amygdalohippocampectomy (SA), which was originally developed to maximize temporal lobe preservation, is arguably the most technically demanding to perform. Recent studies have suggested that SA may result in better neuropsychological outcomes with similar postoperative seizure control as standard anterior temporal lobectomy, which involves removal of the lateral temporal neocortex. Methods: In this article, the authors describe technical nuances to improve the safety of SA. Results: Wide sylvian fissure opening and use of neuronavigation allows an adequate exposure of the amygdala and hippocampus through a corticotomy within the inferior insular sulcus. Avoidance of rigid retractors and careful manipulation and mobilization of middle cerebral vessels will minimize ischemic complications. Identification of important landmarks during amygdalohippocampectomy, such as the medial edge of the tentorium and the third nerve within the intact arachnoid membranes covering the brainstem, further avoids operator disorientation. Conclusion: SA is a safe technique for resection of medial temporal lobe epileptogenic foci leading to drug-resistant medial temporal lobe epilepsy.
Study of the biodistribution of fluorescein in glioma infiltrated mouse brain and histopathologic correlation of intraoperative findings in high-grade gliomas resected under fluorescein fluorescence-guidance
(AANS, 2015-06) Diaz, Roberto Jose; Dios, Roberto Rey; Hattab, Eyas M.; Burrell, Kelly; Rakopoulos, Patricia; Sabha, Nesrin; Hawkins, Cynthia; Zadeh, Gelareh; Rutka, James T.; Cohen-Gadol, Aaron A.; Department of Neurological Surgery, IU School of Medicine
OBJECT Intravenous fluorescein sodium has been used during resection of high-grade gliomas to help the surgeon visualize tumor margins. Several studies have reported improved rates of gross-total resection (GTR) using high doses of fluorescein sodium under white light. The recent introduction of a fluorescein-specific camera that allows for high-quality intraoperative imaging and use of very low dose fluorescein has drawn new attention to this fluorophore. However, the ability of fluorescein to specifically stain glioma cells is not yet well understood. METHODS The authors designed an in vitro model to assess fluorescein uptake in normal human astrocytes and U251 malignant glioma cells. An in vivo experiment was also subsequently designed to study fluorescein uptake by intracranial U87 malignant glioma xenografts in male nonobese diabetic/severe combined immunodeficient mice. A genetically induced mouse glioma model was used to adjust for the possible confounding effect of an inflammatory response in the xenograft model. To assess the intraoperative application of this technology, the authors prospectively enrolled 12 patients who underwent fluorescein-guided resection of their high-grade gliomas using low-dose intravenous fluorescein and a microscope-integrated fluorescence module. Intraoperative fluorescent and nonfluorescent specimens at the tumor margins were randomly analyzed for histopathological correlation. RESULTS The in vitro and in vivo models suggest that fluorescein demarcation of glioma-invaded brain is the result of distribution of fluorescein into the extracellular space, most likely as a result of an abnormal blood-brain barrier. Glioblastoma tumor cell–specific uptake of fluorescein was not observed, and tumor cells appeared to mostly exclude fluorescein. For the 12 patients who underwent resection of their high-grade gliomas, the histopathological analysis of the resected specimens at the tumor margin confirmed the intraoperative fluorescent findings. Fluorescein fluorescence was highly specific (up to 90.9%) while its sensitivity was 82.2%. False negatives occurred due to lack of fluorescence in areas of diffuse, low-density cellular infiltration. Margins of contrast enhancement based on intraoperative MRI–guided StealthStation neuronavigation correlated well with fluorescent tumor margins. GTR of the contrast-enhancing area as guided by the fluorescent signal was achieved in 100% of cases based on postoperative MRI. CONCLUSIONS Fluorescein sodium does not appear to selectively accumulate in astrocytoma cells but in extracellular tumor cell-rich locations, suggesting that fluorescein is a marker for areas of compromised blood-brain barrier within high-grade astrocytoma. Fluorescein fluorescence appears to correlate intraoperatively with the areas of MR enhancement, thus representing a practical tool to help the surgeon achieve GTR of the enhancing tumor regions.
PTEN inhibitor bisperoxovanadium protects oligodendrocytes and myelin and prevents neuronal atrophy in adult rats following cervical hemicontusive spinal cord injury
(Elsevier, 2014-06-24) Walker, Chandler L.; Xu, Xiao-Ming; Department of Neurological Surgery, IU School of Medicine
Cervical spinal cord injury (SCI) damages axons and motor neurons responsible for ipsilateral forelimb function and causes demyelination and oligodendrocyte death. Inhibition of the phosphatase and tensin homologue, PTEN, promotes neural cell survival, neuroprotection and regeneration in vivo and in vitro. PTEN inhibition can also promote oligodendrocyte-mediated myelination of axons in vitro likely through Akt activation. We recently demonstrated that acute treatment with phosphatase PTEN inhibitor, bisperoxovanadium (bpV)-pic reduced tissue damage, neuron death, and promoted functional recovery after cervical hemi-contusion SCI. Evidence suggests bpV can promote myelin stability; however, bpV effects on myelination and oligodendrocytes in contusive SCI models are unclear. We hypothesized that bpV could increase myelin around the injury site through sparing or remyelination, and that bpV treatment may promote increased numbers of oligodendrocytes. Using histological and immunofluorescence labeling, we found that bpV treatment promoted significant spared white matter (30%; p < 0.01) and Luxol Fast Blue (LFB)+ myelin area rostral (Veh: 0.56 ± 0.01 vs. bpV: 0.64 ± 0.02; p < 0.05) and at the epicenter (Veh: 0.4175 ± 0.03 vs. bpV: 0.5400 ± 0.03; p < 0.05). VLF oligodendrocytes were also significantly greater with bpV therapy (109 ± 5.3 vs. Veh: 77 ± 2.7/mm2; p < 0.01). In addition, bpV increased mean motor neuron soma area versus vehicle-treatment (1.0 ± 0.02 vs. Veh: 0.77 ± 0.02) relative to Sham neuron size. This study provides key insight into additional cell and tissue effects that could contribute to bpV-mediated functional recovery observed after contusive cervical SCI.
Nanomedicine for treating spinal cord injury
(Royal Society of Chemistry, 2013-10-07) Tyler, Jacqueline Y.; Xu, Xiao-Ming; Cheng, Ji-Xin; Department of Neurological Surgery, IU School of Medicine
Spinal cord injury results in significant mortality and morbidity, lifestyle changes, and difficult rehabilitation. Treatment of spinal cord injury is challenging because the spinal cord is both complex to treat acutely and difficult to regenerate. Nanomaterials can be used to provide effective treatments; their unique properties can facilitate drug delivery to the injury site, enact as neuroprotective agents, or provide platforms to stimulate regrowth of damaged tissues. We review recent uses of nanomaterials including nanowires, micelles, nanoparticles, liposomes, and carbon-based nanomaterials for neuroprotection in the acute phase. We also review the design and neural regenerative application of electrospun scaffolds, conduits, and self-assembling peptide scaffolds.
A new segment of the trochlear nerve: cadaveric study with application to skull base surgery
(Thieme, 2014-02) Tubbs, R. Shane; Veith, Philip; Griessenauer, Christoph J.; Loukas, Marios; Cohen-Gadol, Aaron A.; Department of Neurological Surgery, IU School of Medicine
Objectives The trochlear nerve is important to preserve during approaches to the skull base. Traditionally, this nerve has been divided into cisternal, cavernous, and orbital segments. However, the authors anecdotally observed an additional segment during routine cadaveric dissections. Therefore, they performed this study to better elucidate this anatomy. Design Twenty latex-injected cadaveric sides (10 adult cadavers) were dissected with the aid of an operating microscope. Standard microdissection techniques were used to examine the course of the distal cisternal and precavernous segments of the trochlear nerve. Setting Cadaver laboratory. Main Outcome Measures Measurements were made using a microcaliper. Digital images were made of the dissections. Results The authors identified a previously undescribed segment of the trochlear nerve in all specimens. This part of the nerve coursed between the entrance of the trochlear nerve into the posterior corner of the oculomotor trigone to the posterior wall of the cavernous sinus. This segment of trochlear nerve was, on average, 4 mm in length. Conclusions The authors have identified a new segment of the trochlear nerve not previously described. They propose that this be referred to as the trigonal segment. Knowledge of the microanatomy of the trochlear nerve is useful to skull base surgeons.
Neuroprotective Ferulic Acid (FA)-Glycol Chitosan (GC) Nanoparticles for Functional Restoration of Traumatically Injured Spinal Cord
(Elsevier B.V., 2014-02) Wu, Wei; Lee, Seung-Young; Wu, Xiangbing; Tyler, Jacqueline Y.; Wang, He; Ouyang, Zheng; Park, Kinam; Xu, Xiao-Ming; Cheng, Ji-Xin; Department of Neurological Surgery, IU School of Medicine
An urgent unmet need exists for early-stage treatment of spinal cord injury (SCI). Currently methylprednisolone is the only therapeutic agent used in clinics, for which the efficacy is controversial and the side effect is well-known. We demonstrated functional restoration of injured spinal cord by self-assembled nanoparticles composed of ferulic acid modified glycol chitosan (FA-GC). Chitosan and ferulic acid are strong neuroprotective agents but their systemic delivery is difficult. Our data has shown a prolonged circulation time of the FA-GC nanoparticles allowing for effective delivery of both chitosan and ferulic acid to the injured site. Furthermore, the nanoparticles were found both in the gray matter and white matter. The in vitro tests demonstrated that nanoparticles protected primary neurons from glutamate-induced excitotoxicity. Using a spinal cord contusion injury model, significant recovery in locomotor function was observed in rats that were intravenously administered nanoparticles at 2 h post injury, as compared to non-improvement by methylprednisolone administration. Histological analysis revealed that FA-GC treatment significantly preserved axons and myelin and also reduced cavity volume, astrogliosis, and inflammatory response at the lesion site. No obvious adverse effects of nanoparticles to other organs were found. The restorative effect of FA-GC presents a promising potential for treating human SCIs.

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