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The ability of diffusion tensor MRI to detect the preferential diffusion of water in cerebral white matter tracts enables neurosurgeons to noninvasively visualize the relationship of lesions to functional neural pathways. Although viewed as a research tool in its infancy, diffusion tractography has evolved into a neurosurgical tool with applications in glioma surgery that are enhanced by evolutions in crossing fiber visualization, edema correction, and automated tract identification. In this paper the current literature supporting the use of tractography in brain tumor surgery is summarized, highlighting important clinical studies on the application of diffusion tensor imaging (DTI) for preoperative planning of glioma resection, and risk assessment to analyze postoperative outcomes. The key methods of tractography in current practice and crucial white matter fiber bundles are summarized. After a review of the physical basis of DTI and post-DTI tractography, the authors discuss the methodologies with which to adapt DT image processing for surgical planning, as well as the potential of connectomic imaging to facilitate a network approach to oncofunctional optimization in glioma surgery.

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Maximal safe resection is the modern goal for surgery of intrinsic brain tumors located in or close to brain eloquent areas. Nowadays different neuroimaging techniques provide important anatomical and functional information regarding the brain functional organization that can be used to plan a customized surgical strategy to preserve functional networks, and to increase the extent of tumor resection. Among these techniques, navigated transcranial magnetic stimulation (nTMS) has recently gained great favor among the neurosurgical community for preoperative mapping and planning prior to brain tumor surgery. It represents an advanced neuroimaging technique based on the neurophysiological mapping of the functional cortical brain organization. Moreover, it can be combined with other neuroimaging techniques such as diffusion tensor imaging tractography, thus providing a reliable reconstruction of brain eloquent networks. Consequently, nTMS mapping may provide reliable noninvasive brain functional mapping, anticipating information that otherwise may be available to neurosurgeons only in the operating theater by using direct electrical stimulation. The authors describe the reliability and usefulness of the preoperative nTMS-based approach in neurosurgical practice, and briefly discuss their experience using nTMS as well as currently available evidence in the literature supporting its clinical use. In particular, special attention is reserved for the discussion of the role of nTMS as a novel tool for the preoperative neurophysiological mapping of motor and language networks prior to surgery of intrinsic brain tumors located in or close to eloquent networks, as well as for future and promising applications of nTMS in neurosurgical practice.

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OBJECTIVE: Surgical treatment of convexity meningiomas is usually considered a low-risk procedure. Nevertheless, the risk of postoperative motor deficits is higher (7.1%-24.7% of all cases) for lesions located in the rolandic region, especially when an arachnoidal cleavage plane with the motor pathway is not identifiable. The authors analyzed the possible role of navigated transcranial magnetic stimulation (nTMS) for planning resection of rolandic meningiomas and predicting the presence or lack of an intraoperative arachnoidal cleavage plane as well as the postoperative motor outcome. METHODS: Clinical data were retrospectively collected from surgical cases involving patients affected by convexity, parasagittal, or falx meningiomas involving the rolandic region, who received preoperative nTMS mapping of the motor cortex (M1) and nTMS-based diffusion tensor imaging (DTI) fiber tracking of the corticospinal tract before surgery at 2 different neurosurgical centers. Surgeons' self-reported evaluation of the impact of nTMS-based mapping on surgical strategy was analyzed. Moreover, the nTMS mapping accuracy was evaluated in comparison with intraoperative neurophysiological mapping (IONM). Lastly, we assessed the role of nTMS as well as other pre- and intraoperative parameters for predicting the patients' motor outcome and the presence or absence of an intraoperative arachnoidal cleavage plane. RESULTS: Forty-seven patients were included in this study. The nTMS-based planning was considered useful in 89.3% of cases, and a change of the surgical strategy was observed in 42.5% of cases. The agreement of nTMS-based planning and IONM-based strategy in 35 patients was 94.2%. A new permanent motor deficit occurred in 8.5% of cases (4 of 47). A higher resting motor threshold (RMT) and the lack of an intraoperative arachnoidal cleavage plane were the only independent predictors of a poor motor outcome (p = 0.04 and p = 0.02, respectively). Moreover, a higher RMT and perilesional edema also predicted the lack of an arachnoidal cleavage plane (p = 0.01 and p = 0.03, respectively). Preoperative motor status, T2 cleft sign, contrast-enhancement pattern, and tumor volume had no predictive value. CONCLUSIONS: nTMS-based motor mapping is a useful tool for presurgical assessment of rolandic meningiomas, especially when a clear cleavage plane with M1 is not present. Moreover, the RMT can indicate the presence or absence of an intraoperative cleavage plane and predict the motor outcome, thereby helping to identify high-risk patients before surgery.

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OBJECTIVE: Convection-enhanced delivery (CED) has been explored as a therapeutic strategy for diffuse intrinsic pontine glioma (DIPG). Variables that may affect tolerance include infusate volume, infusion rate, catheter trajectory, and target position. Supratentorial approaches for catheter placement and infusate distribution patterns may conflict with corticospinal tracts (CSTs). The clinical relevance of these anatomical constraints has not been described. The authors report their experience using CED in the brainstem as it relates to anatomical CST conflict and association with clinical tolerance. METHODS: In a phase I clinical trial of CED for DIPG (clinical trial registration no. NCT01502917, clinicaltrials.gov), a flexible infusion catheter was placed with MRI guidance for infusion of 124I-8H9, a radioimmunotherapeutic agent. Intra- and postprocedural MR images were analyzed to identify catheter trajectories and changes in T2-weighted signal intensity to approximate volume of distribution (Vd). Intersection of CST by the catheter and overlap between Vd and CST were recorded and their correlation with motor deficits was evaluated. RESULTS: Thirty-one patients with a mean age of 7.6 years (range 3.2-18 years) underwent 39 catheter insertions for CED between 2012 and 2017. Thirty catheter insertions had tractography data available for analysis. The mean trajectory length was 105.5 mm (range 92.7-121.6 mm). The mean number of intersections of CST by catheter was 2.2 (range 0-3) and the mean intersecting length was 18.9 mm (range 0-44.2 mm). The first 9 infusions in the highest dose level (range 3.84-4.54 ml infusate) were analyzed for Vd overlap with CST. In this group, the mean age was 7.6 years (range 5.8-10.3 years), the mean trajectory length was 109.5 mm (range 102.6-122.3 mm), and the mean overlap between Vd and CST was 5.5 cm3. For catheter placement-related adverse events, 1 patient (3%) had worsening of a contralateral facial nerve palsy following the procedure with two CST intersections, an intersecting distance of 31.7 mm, and an overlap between Vd and CST of 3.64 cm3. For infusion-related adverse events, transient postinfusion deficits were noted in 3 patients in the highest dose level, with a mean number of 2 intersections of CST by catheter, mean intersecting length of 12.9 mm, and mean overlap between Vd and CST of 6.3 cm3. CONCLUSIONS: A supratentorial approach to the brainstem crossing the CST resulted in one worsened neurological deficit. There does not appear to be a significant risk requiring avoidance of dominant motor fiber tracts with catheter trajectory planning. There was no correlation between Vd-CST overlap and neurological adverse events in this cohort.Clinical trial registration no.: NCT01502917 (clinicaltrials.gov).

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OBJECTIVE: Herein, the authors report their experience with intraoperative stimulation mapping to locate the descending subcortical motor pathways in patients undergoing surgery for hemispheric gliomas within or adjacent to the rolandic cortex, with particular description of the morbidity and functional outcomes associated with this technique. METHODS: This is a retrospective analysis of patients who, in the period between 1997 and 2016, had undergone resection of hemispheric perirolandic gliomas within or adjacent to descending motor pathways. Data regarding intraoperative stimulation mapping and patient postoperative neurological status were collected. RESULTS: Of 702 patients, stimulation mapping identified the descending motor pathways in 300 cases (43%). A new or worsened motor deficit was seen postoperatively in 210 cases (30%). Among these 210 cases, there was improvement in motor function to baseline levels by 3 months postoperatively in 161 cases (77%), whereas the deficit remained in 49 cases (23%). The majority (65%) of long-term deficits (persisting beyond 3 months) were mild or moderate (antigravity strength or better). On multivariate analysis, patients in whom the subcortical motor pathways had been identified with stimulation mapping during surgery were more likely to develop an additional and/or worsened motor deficit postoperatively than were those in whom the subcortical pathways had not been found (45% vs 19%, respectively, p < 0.001). This difference remained when considering the likelihood of a long-term deficit (i.e., persisting > 3 months; 12% vs 3.2%, p < 0.001). A higher tumor grade and the presence of a preoperative motor deficit were also associated with higher rates of motor deficits persisting long-term. A region of restricted diffusion adjacent to the resection cavity was seen in 20 patients with long-term deficits (41%) and was more common in cases in which the motor pathways were not identified (69%). Long-term deficits that occur in settings in which the subcortical motor pathways are not identified seem in large part due to ischemic injury to descending tracts. CONCLUSIONS: Stimulation mapping allows surgeons to identify the descending motor pathways during resection of tumors in perirolandic regions and to attain an acceptable rate of morbidity in these high-risk cases.

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OBJECTIVE: Surgical management of brainstem lesions is challenging due to the highly compact, eloquent anatomy of the brainstem. This study aimed to evaluate the safety and efficacy of preoperative diffusion tensor imaging (DTI) and diffusion tensor tractography (DTT) in brainstem cavernous malformations (CMs). METHODS: A prospective randomized controlled clinical trial was performed by using stratified blocked randomization. The primary eligibility criterion of the study was being a surgical candidate for brainstem CMs (with informed consent). The study enrolled 23 patients who underwent preoperative DTI/DTT and 24 patients who did not (the control group). The pre- and postoperative muscle strength of both limbs and modified Rankin Scale (mRS) scores were evaluated. Muscle strength of any limb at 12 months after surgery at the clinic visit was the primary outcome; worsened muscle strength was considered to be a poor outcome. Outcome assessors were blinded to patient management. This study reports the preliminary results of the interim analysis. RESULTS: The cohort included 47 patients (22 women) with a mean age of 35.7 years. The clinical baselines between these 2 groups were not significantly different. In the DTI/DTT group, the corticospinal tract was affected in 17 patients (73.9%): it was displaced, deformed/partially interrupted, or completely interrupted in 6, 7, and 4 patients, respectively. The surgical approach and brainstem entry point were adjusted in 3 patients (13.0%) based on DTI/DTT data. The surgical morbidity of the DTI/DTT group (7/23, 30.4%) was significantly lower than that of the control group (19/24, 79.2%, p = 0.001). At 12 months, the mean mRS score (1.1, p = 0.034) and percentage of patients with worsened motor deficits (4.3%, p = 0.006) were significantly lower in the DTI/DTT group than in the control group (1.7% and 37.5%). Multivariate logistic regression identified the absence of preoperative DTI/DTT (OR 0.06, 95% CI 0.01-0.73, p = 0.028) and use of the 2-point method (OR 4.15, 95% CI 1.38-12.49, p = 0.011) as independent adverse factors for a worsened motor deficit. The multivariate model found a significant correlation between poor mRS score and both an increased preoperative mRS score (t = 3.559, p = 0.001) and absence of preoperative DTI/DTT (t = -2.747, p = 0.009). CONCLUSIONS: DTI/DTT noninvasively allowed for visualization of the anatomical relationship between vital tracts and pathologies as well as facilitated the brainstem surgical approach and entry-point decision making. The technique was valuable for complex neurosurgical planning to reduce morbidity. Nonetheless, DTI/DTT data should be interpreted cautiously.■ CLASSIFICATION OF EVIDENCE Type of question: therapeutic; study design: randomized controlled trial; evidence: class I. Clinical trial registration no.: NCT01758211 (ClinicalTrials.gov).

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OBJECTIVE Navigated transcranial magnetic stimulation (nTMS) and diffusion tensor imaging fiber tracking (DTI FT) based on nTMS data are increasingly used for preoperative planning and resection guidance in patients suffering from motor-eloquent brain tumors. The present study explores whether nTMS-based DTI FT can also be used for individual preoperative risk assessment regarding surgery-related motor impairment. METHODS Data derived from preoperative nTMS motor mapping and subsequent nTMS-based tractography in 86 patients were analyzed. All patients suffered from high-grade glioma (HGG), low-grade glioma (LGG), or intracranial metastasis (MET). In this context, nTMS-based DTI FT of the corticospinal tract (CST) was performed at a range of fractional anisotropy (FA) levels based on an individualized FA threshold ([FAT]; tracking with 50%, 75%, and 100% FAT), which was defined as the highest FA value allowing for visualization of fibers (100% FAT). Minimum lesion-to-CST distances were measured, and fiber numbers of the reconstructed CST were assessed. These data were then correlated with the preoperative, postoperative, and follow-up status of motor function and the resting motor threshold (rMT). RESULTS At certain FA levels, a statistically significant difference in lesion-to-CST distances was observed between patients with HGG who had no impairment and those who developed surgery-related transient or permanent motor deficits (75% FAT: p = 0.0149; 100% FAT: p = 0.0233). In this context, no patient with a lesion-to-CST distance ≥ 12 mm suffered from any new surgery-related permanent paresis (50% FAT and 75% FAT). Furthermore, comparatively strong negative correlations were observed between the rMT and lesion-to-CST distances of patients with surgery-related transient paresis (Spearman correlation coefficient [rs]; 50% FAT: rs = -0.8660; 75% FAT: rs = -0.8660) or surgery-related permanent paresis (50% FAT: rs = -0.7656; 75% FAT: rs = -0.6763). CONCLUSIONS This is one of the first studies to show a direct correlation between imaging, clinical status, and neurophysiological markers for the integrity of the motor system in patients with brain tumors. The findings suggest that nTMS-based DTI FT might be suitable for individual risk assessment in patients with HGG, in addition to being a surgery-planning tool. Importantly, necessary data for risk assessment were obtained without significant additional efforts, making this approach potentially valuable for direct clinical use.

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OBJECTIVE In the past, the outcome of surgical treatment for thalamic tumor was poor. These lesions were often considered inoperable. However, contemporary microsurgical techniques, together with improvements in neuroimaging that enable accurate presurgical planning, allow resection to be accomplished in a safer way. METHODS The medical records, imaging studies, and operative and pathology reports obtained for pediatric patients who were treated for thalamic tumors at the authors' department were reviewed. Neuronavigation and intraoperative monitoring of motor and somatosensory evoked potentials were used. Preoperative tractography, which helped to identify internal capsule fibers, was very important in selecting the surgical strategy. Postoperatively, an MRI study performed within 24 hours was used to assess the extent of tumor resection as partial (≤ 90%), subtotal (> 90%), or gross total (no residual tumor). RESULTS Since 2002, 27 children with thalamic tumors have been treated at the authors' department. There were 9 patients with unilateral thalamic tumors, 16 with thalamopeduncular tumors, and 2 with a bilateral tumor. These last 2 patients underwent endoscopic biopsy and implantation of a ventriculoperitoneal shunt. Thirty-nine tumor debulking procedures were performed in the remaining 25 patients. Different surgical approaches were chosen according to tumor location and displacement of the posterior limb of the internal capsule (as studied on axial T2-weighted MRI) and corticospinal tract (as studied on diffusion tensor imaging with tractography, after it became available). In 12 cases, multiple procedures were performed; in 7 cases, these were done as part of a planned multistage resection. In the remaining 5 cases, the second procedure was necessary because of late recurrence or regrowth of residual tumor. At the end of the surgical phase, of 25 patients, 15 (60%) achieved a gross-total resection, 4 (16%) achieved a subtotal resection, and 6 (24%) achieved a partial resection. Eighteen patients harbored low-grade tumors in our series. In this group, the mean follow-up was 45 months (range 4-132 months). At the end of follow-up, 1 patient was dead, 12 patients were alive with no evidence of disease, 4 patients were alive with stable disease, and 1 was lost to follow-up. All patients were independent in their daily lives. The outcome of high-grade tumors in 9 patients was very poor: 2 patients died immediately after surgery, 6 died of progressive disease, and 1 was alive with residual disease at the time of this report. CONCLUSIONS This institutional review seems to offer further evidence in favor of attempts at radical resection in pediatric patients harboring unilateral thalamic or thalamopeduncular tumors. In low-grade gliomas, radical resection in a single or staged procedure can be curative without complementary treatment. Recurrences or residual regrowth can be safely managed surgically. In high-grade tumors, the role of and opportunity for radical or partial resection remains a matter of debate.

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Acute traumatic spinal cord injury (SCI) is a devastating event with far-reaching physical, emotional, and economic consequences for patients, families, and society at large. Timely delivery of specialized care has reduced mortality; however, long-term neurological recovery continues to be limited. In recent years, a number of exciting neuroprotective and regenerative strategies have emerged and have come under active investigation in clinical trials, and several more are coming down the translational pipeline. Among ongoing trials are RISCIS (riluzole), INSPIRE (Neuro-Spinal Scaffold), MASC (minocycline), and SPRING (VX-210). Microstructural MRI techniques have improved our ability to image the injured spinal cord at high resolution. This innovation, combined with serum and cerebrospinal fluid (CSF) analysis, holds the promise of providing a quantitative biomarker readout of spinal cord neural tissue injury, which may improve prognostication and facilitate stratification of patients for enrollment into clinical trials. Given evidence of the effectiveness of early surgical decompression and growing recognition of the concept that "time is spine," infrastructural changes at a systems level are being implemented in many regions around the world to provide a streamlined process for transfer of patients with acute SCI to a specialized unit. With the continued aging of the population, central cord syndrome is soon expected to become the most common form of acute traumatic SCI; characterization of the pathophysiology, natural history, and optimal treatment of these injuries is hence a key public health priority. Collaborative international efforts have led to the development of clinical practice guidelines for traumatic SCI based on robust evaluation of current evidence. The current article provides an in-depth review of progress in SCI, covering the above areas.

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OBJECTIVE Surgical approaches to the ventrolateral pons pose a significant challenge. In this report, the authors describe a safe entry zone to the brainstem located just above the trigeminal entry zone which they refer to as the "epitrigeminal entry zone." METHODS The approach is presented in the context of an illustrative case of a cavernous malformation and is compared with the other commonly described approaches to the ventrolateral pons. The anatomical nuances were analyzed in detail with the aid of surgical images and video, anatomical dissections, and high-definition fiber tractography (HDFT). In addition, using the HDFT maps obtained in 77 normal subjects (154 sides), the authors performed a detailed anatomical study of the surgically relevant distances between the trigeminal entry zone and the corticospinal tracts. RESULTS The patient treated with this approach had a complete resection of his cavernous malformation, and improvement of his symptoms. With regard to the HDFT anatomical study, the average direct distance of the corticospinal tracts from the trigeminal entry zone was 12.6 mm (range 8.7-17 mm). The average vertical distance was 3.6 mm (range -2.3 to 8.7 mm). The mean distances did not differ significantly from side to side, or across any of the groups studied (right-handed, left-handed, and ambidextrous). CONCLUSIONS The epitrigeminal entry zone to the brainstem appears to be safe and effective for treating intrinsic ventrolateral pontine pathological entities. A possible advantage of this approach is increased versatility in the rostrocaudal axis, providing access both above and below the trigeminal nerve. Familiarity with the subtemporal transtentorial approach, and the reliable surgical landmark of the trigeminal entry zone, should make this a straightforward approach.

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OBJECTIVE The objective of this study was to evaluate the utility of diffusion tensor imaging (DTI) tractography-based targeting of the dentatorubrothalamic tract (DRT) for magnetic resonance-guided focused ultrasound (MRgFUS) thalamotomy in patients with essential tremor (ET) and correlate postprocedural tract disruption with clinical outcomes. METHODS Four patients received preprocedural and immediate postprocedural DTI in addition to traditional anatomical MRI sequences for MRgFUS thalamotomy. Optimal ablation sites were selected based on the patient-specific location of the DRT as demonstrated by DTI (direct targeting) and correlated with traditional atlas-based measurements for thalamic ventral intermediate nucleus (Vim) lesioning (indirect targeting). Fiber tracts were displayed three-dimensionally during the procedure and used in conjunction with clinical signs of tremor control for fine correction of the ablation site. Immediately following the conclusion of the procedure, the MRgFUS head frame was removed and patients were placed in a 32-channel MRI head coil for follow-up DTI and anatomical MRI sequences. RESULTS All patients had excellent postoperative tremor control and successful pre- and postprocedural DTI fiber tracking of the corticospinal tract, medial lemniscus, and DRT. Immediate postprocedure DTI failed to track the DRT ipsilateral to the lesion site with a preserved contralateral DRT, coincident with substantial resolution of contralateral tremor. CONCLUSIONS DTI can reliably identify the optimal ablation target and demonstrates tract disruption on immediate postprocedural imaging. A clinical improvement of ET was observed immediately following the procedure, correlating with DRT disruption and suggesting that interruption of the DRT is a consequence of clinically successful MRgFUS thalamotomy. These findings may have utility for both MRgFUS procedure planning in surgically naive patients and retreatment of patients who have previously undergone unsuccessful thalamic Vim lesioning.

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OBJECTIVE Thalamopeduncular tumors are a group of pediatric low-grade gliomas that arise at the interface of the thalamus and brainstem peduncle. They typically occur within the first 2 decades of life, presenting with progressive spastic hemiparesis. Treatment strategies, including surgical intervention, have varied significantly. The authors present their experience in the treatment of 13 children, ages 2-15 years, with non-neurofibromatosis-related pilocytic astrocytomas located in the thalamopeduncular region. METHODS Between 2003 and 2016, 13 children presenting with progressive spastic hemiparesis due to a pilocytic astrocytoma at the interface of the thalamus and cerebral peduncles were identified. Medical records were reviewed retrospectively for clinical, radiological, pathological, and surgical data. Formalin-fixed, paraffin-embedded tissue was obtained for 12 cases and tested for KIAA1549-BRAF fusion and BRAF V600E point mutation. RESULTS On preoperative diffusion tensor imaging tractography (performed in 12 patients), the ipsilateral corticospinal tract was displaced laterally in 1 case (8.3%), medially in 1 case (8.3%), anterolaterally in 10 cases (83%), and posteriorly in no cases. Ten patients underwent resection via a transtemporal, transchoroidal approach, which was chosen to avoid further damage to motor function in cases of tumors that caused anterolateral or medial corticospinal tract displacement. With this approach, complications included hemianopia, oculomotor palsy, and tremor at a rate of 50%. Among the 12 patients with obtainable follow-up (mean 50.9 months), none received adjuvant therapy, and only 2 (17%) experienced recurrence or progression. KIAA1549-BRAF fusions were present in 10 cases (83%), while BRAF V600E was absent (0%). The 2 fusion-negative tumors had clinical features atypical for the series, including multi-focality and infiltration. CONCLUSIONS Transcortical, transchoroidal resection of thalamopeduncular tumors through the middle temporal gyrus allows for a high rate of gross-total resection and cure. Diffuse tensor tractography is a critical component of the preoperative planning process to determine the location of white matter tracts in proximity. Molecular status may correlate with clinical features, and the presence of BRAF lesions offers an additional target for future novel therapeutics.

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Intramedullary spinal cord tumors (IMSCTs) represent a rare entity, accounting for 4%-10% of all central nervous system tumors. Microsurgical resection of IMSCTs is currently considered the primary treatment modality. Intraoperative neurophysiological monitoring (IONM) has been shown to aid in maximizing tumor resection and minimizing neurological morbidity, consequently improving patient outcome. The gold standard for IONM to date is multimodality monitoring, consisting of both somatosensory evoked potentials, as well as muscle-based transcranial electric motor evoked potentials (tcMEPs). Monitoring of tcMEPs is optimal when combining transcranial electrically stimulated muscle tcMEPs with D-wave monitoring. Despite continuous monitoring of these modalities, when classic monitoring techniques are used, there can be an inherent delay in time between actual structural or vascular-based injury to the corticospinal tracts (CSTs) and its revelation. Often, tcMEP stimulation is precluded by the surgeon's preference that the patient not twitch, especially at the most crucial times during resection. In addition, D-wave monitoring may require a few seconds of averaging until updating, and can be somewhat indiscriminate to laterality. Therefore, a method that will provide immediate information regarding the vulnerability of the CSTs is still needed. The authors performed a retrospective series review of resection of IMSCTs using the tip of an ultrasonic aspirator for continuous proximity mapping of the motor fibers within the spinal cord, along with classic muscle-based tcMEP and D-wave monitoring. The authors present their preliminary experience with 6 patients who underwent resection of an IMSCT using the tip of an ultrasonic aspirator for continuous proximity mapping of the motor fibers within the spinal cord, together with classic muscle-based tcMEP and D-wave monitoring. This fusion of technologies can potentially assist in optimizing resection while preserving neurological function in these challenging surgeries.

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OBJECTIVE The most actively explored therapeutic strategy for overcoming spinal cord injury (SCI) is the delivery of genes encoding molecules that stimulate regeneration. In a mouse model of amyotrophic lateral sclerosis and in preliminary clinical trials in patients with amyotrophic lateral sclerosis, the combined administration of recombinant adenoviral vectors (Ad5-VEGF+Ad5-ANG) encoding the neurotrophic/angiogenic factors vascular endothelial growth factor ( VEGF) and angiogenin ( ANG) was found to slow the development of neurological deficits. These results suggest that there may be positive effects of this combination of genes in posttraumatic spinal cord regeneration. The objective of the present study was to determine the effects of Ad5-VEGF+Ad5-ANG combination therapy on motor function recovery and reactivity of astrocytes in a rat model of SCI. METHODS Spinal cord injury was induced in adult Wistar rats by the weight-drop method. Rats (n = 51) were divided into 2 groups: the experimental group (Ad5-VEGF+Ad5-ANG) and the control group (Ad5-GFP [green fluorescent protein]). Recovery of motor function was assessed using the Basso, Beattie, and Bresnahan scale. The duration and intensity of infectivity and gene expression from the injected vectors were assessed by immunofluorescent detection of GFP. Reactivity of glial cells was assessed by changes in the number of immunopositive cells expressing glial fibrillary acidic protein (GFAP), S100ß, aquaporin 4 (AQP4), oligodendrocyte transcription factor 2, and chondroitin sulfate proteoglycan 4. The level of S100ß mRNA expression in the spinal cord was estimated by real-time polymerase chain reaction. RESULTS Partial recovery of motor function was observed 30 days after surgery in both groups. However, Basso, Beattie, and Bresnahan scores were 35.9% higher in the Ad5-VEGF+Ad5-ANG group compared with the control group. Specific GFP signal was observed at distances of up to 5 mm in the rostral and caudal directions from the points of injection. A 1.5 to 2.0-fold increase in the number of GFAP+, S100ß+, and AQP4+ cells was observed in the white and gray matter at a distance of up to 5 mm from the center of the lesion site in the caudal and rostral directions. At 30 days after injury, a 2-fold increase in S100ß transcripts was observed in the Ad5-VEGF+Ad5-ANG group compared with the control group. CONCLUSIONS Intraspinal injection of recombinant adenoviral vectors encoding VEGF and ANG stimulates functional recovery after traumatic SCI. The increased number of S100ß+ astrocytes induced by this approach may be a beneficial factor for maintaining the survival and function of neurons. Therefore, gene therapy with Ad5-VEGF+Ad5-ANG vectors is an effective therapeutic method for SCI treatment.

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OBJECTIVE Sporadic cases of endonasal intraaxial brainstem surgery have been reported in the recent literature. The authors endeavored to assess the feasibility and limitations of endonasal endoscopic surgery for approaching lesions in the ventral portion of the brainstem. METHODS Five human cadaveric heads were used to assess the anatomy and to record various measurements. Extended transsphenoidal and transclival approaches were performed. After exposing the brainstem, white matter dissection was attempted through this endoscopic window, and additional key measurements were taken. RESULTS The rostral exposure of the brainstem was limited by the sella. The lateral limits of the exposure were the intracavernous carotid arteries at the level of the sellar floor, the intrapetrous carotid arteries at the level of the petrous apex, and the inferior petrosal sinuses toward the basion. Caudal extension necessitated partial resection of the anterior C-1 arch and the odontoid process. The midline pons and medulla were exposed in all specimens. Trigeminal nerves were barely visible without the use of angled endoscopes. Access to the peritrigeminal safe zone for gaining entry into the brainstem is medially limited by the pyramidal tract, with a mean lateral pyramidal distance (LPD) of 4.8 ± 0.8 mm. The mean interpyramidal distance was 3.6 ± 0.5 mm, and it progressively decreased toward the pontomedullary junction. The corticospinal tracts (CSTs) coursed from deep to superficial in a craniocaudal direction. The small caliber of the medulla with very superficial CSTs left no room for a safe ventral dissection. The mean pontobasilar midline index averaged at 0.44 ± 0.1. CONCLUSIONS Endoscopic endonasal approaches are best suited for pontine intraaxial tumors when they are close to the midline and strictly anterior to the CST, or for exophytic lesions. Approaching the medulla is anatomically feasible, but the superficiality of the eloquent tracts and interposed nerves limit the safe entry zones. Pituitary transposition after sellar opening is necessary to access the mesencephalon.

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OBJECTIVE Brain metastases are the most frequent intracranial malignant tumor in adults. Surgical intervention for metastases in eloquent areas remains controversial and challenging. Even when metastases are not infiltrating intra-parenchymal tumors, eloquent areas can be affected. Therefore, this study aimed to describe the role of a functional guided approach for the resection of brain metastases in the central region. METHODS Thirty-three patients (19 men and 14 women) with perirolandic metastases who were treated at the authors' institution were reviewed. All participants underwent resection using a functional guided approach, which consisted of using intraoperative brain mapping and/or neurophysiological monitoring to aid in the resection, depending on the functionality of the brain parenchyma surrounding each metastasis. Motor and sensory functions were monitored in all patients, and supplementary motor and language area functions were assessed in 5 and 4 patients, respectively. Clinical data were analyzed at presentation, discharge, and the 6-month follow-up. RESULTS The most frequent presenting symptom was seizure, followed by paresis. Gross-total removal of the metastasis was achieved in 31 patients (93.9%). There were 6 deaths during the follow-up period. After the removal of the metastasis, 6 patients (18.2%) presented with transient neurological worsening, of whom 4 had worsening of motor function impairment and 2 had acquired new sensory disturbances. Total recovery was achieved before the 3rd month of follow-up in all cases. Excluding those patients who died due to the progression of systemic illness, 88.9% of patients had a Karnofsky Performance Scale score greater than 80% at the 6-month follow-up. The mean survival time was 24.4 months after surgery. CONCLUSIONS The implementation of intraoperative electrical brain stimulation techniques in the resection of central region metastases may improve surgical planning and resection and may spare eloquent areas. This approach also facilitates maximal resection in these and other critical functional areas, thereby helping to avoid new postoperative neurological deficits. Avoiding permanent neurological deficits is critical for a good quality of life, especially in patients with a life expectancy of over a year.

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OBJECTIVE Navigated transcranial magnetic stimulation (nTMS) is a noninvasive method for preoperatively localizing functional areas in patients with tumors in presumed motor eloquent areas. The aim of this study was to establish an nTMS-based risk stratification model by examining whether the results of nTMS mapping and its neurophysiological data predict postoperative motor outcome in glioma surgery. METHODS Included in this study were prospectively collected data for 113 patients undergoing bihemispheric nTMS examination prior to surgery for gliomas in presumed motor eloquent locations. Multiple ordinal logistic regression analysis was performed to test for any association between preoperative nTMS-related variables and postoperative motor outcome. RESULTS A new motor deficit or deterioration due to a preexisting deficit was observed in 20% of cases after 7 days and in 22% after 3 months. In terms of tumor location, no new permanent deficit was observed when the distance between tumor and corticospinal tract was greater than 8 mm and the precentral gyrus was not infiltrated (p = 0.014). New postoperative deficits on Day 7 were associated with a pathological excitability of the motor cortices (interhemispheric resting motor threshold [RMT] ratio < 90% or > 110%, p = 0.031). Interestingly, motor function never improved when the RMT was significantly higher in the tumorous hemisphere than in the healthy hemisphere (RMT ratio > 110%). CONCLUSIONS The proposed risk stratification model, based on objective functional-anatomical and neurophysiological measures, enables one to counsel patients about the risk of functional deterioration or the potential for recovery.

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OBJECTIVE Diffusion tensor imaging (DTI) fiber tracking (FT) has been widely used in glioma surgery in recent years. It can provide helpful information about subcortical structures, especially in patients with eloquent space-occupying lesions. This study compared the newly developed navigated transcranial magnetic stimulation (nTMS)-based DTI FT of language pathways with the most reproducible protocol for language pathway tractography, using cubic regions of interest (ROIs) for the arcuate fascicle. METHODS Thirty-seven patients with left-sided perisylvian lesions underwent language mapping by repetitive nTMS. DTI FT was performed using the cubic ROIs-based protocol and the authors' nTMS-based DTI FT approach. The same minimal fiber length and fractional anisotropy were chosen (50 mm and 0.2, respectively). Both protocols were performed with standard clinical tractography software. RESULTS Both methods visualized language-related fiber tracts (i.e., corticonuclear tract, arcuate fascicle, uncinate fascicle, superior longitudinal fascicle, inferior longitudinal fascicle, arcuate fibers, commissural fibers, corticothalamic fibers, and frontooccipital fascicle) in all 37 patients. Using the cubic ROIs-based protocol, 39.9% of these language-related fiber tracts were detected in the examined patients, as opposed to 76.0% when performing nTMS-based DTI FT. For specifically tracking the arcuate fascicle, however, the cubic ROIs-based approach showed better results (97.3% vs 75.7% with nTMS-based DTI FT). CONCLUSIONS The cubic ROIs-based protocol was designed for arcuate fascicle tractography, and this study shows that it is still useful for this intention. However, superior results were obtained using the nTMS-based DTI FT for visualization of other language-related fiber tracts.

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OBJECTIVE Diffusion-weighted MRI (DWI) and tractography allows noninvasive mapping of the structural connections of the brain, and may provide important information for neurosurgical planning. The hyperdirect pathway, connecting the subthalamic nucleus (STN) with the motor cortex, is assumed to play a key role in mediating the effects of deep brain stimulation (DBS), which is an effective but poorly understood treatment for Parkinson disease. This study aimed to apply recent methodological advances in DWI acquisition and analysis to the delineation of the hyperdirect pathway in patients with Parkinson disease selected for surgery. METHODS High spatial and angular resolution DWI data were acquired preoperatively from 5 patients with Parkinson disease undergoing DBS. The authors compared the delineated hyperdirect pathways and associated STN target maps generated by 2 different tractography methods: a tensor-based deterministic method, typically available in clinical settings, and an advanced probabilistic method based on constrained spherical deconvolution. In addition, 10 high-resolution data sets with the same scanning parameters were acquired from a healthy control participant to assess the robustness of the tractography results. RESULTS Both tractography approaches identified connections between the ipsilateral motor cortex and the STN. However, the 2 methods provided substantially different target regions in the STN, with the target center of gravity differing by > 1.4 mm on average. The probabilistic method (based on constrained spherical deconvolution) plausibly reconstructed a continuous set of connections from the motor cortex, terminating in the dorsolateral region of the STN. In contrast, the tensor-based method reconstructed a comparatively sparser and more variable subset of connections. Furthermore, across the control scans, the probabilistic method identified considerably more consistent targeting regions within the STN compared with the deterministic tensor-based method, which demonstrated a 1.9-2.4 times higher variation. CONCLUSIONS These data provide a strong impetus for the use of a robust probabilistic tractography framework based on constrained spherical deconvolution, or similar advanced DWI models, in clinical settings. The inherent limitations and demonstrated inaccuracy of the tensor-based method leave it questionable for use in high-precision stereotactic DBS surgery. The authors have also described a straightforward method for importing tractography-derived information into any clinical neuronavigation system, based on the generation of track-density images.

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OBJECTIVE The integration of modern neuroimaging into treatment planning has increased the therapeutic potential and safety of stereotactic radiosurgery. The authors report their method of integrating stereotactic diffusion tensor imaging (DTI) tractography into conventional treatment planning for Gamma Knife radiosurgery (GKRS). The aim of this study was to demonstrate the feasibility of this technique and to address some of the technical limitations of previously reported techniques. METHODS Twenty patients who underwent GKRS composed the study cohort. They consisted of 1 initial test case (a patient with a vestibular schwannoma), 5 patients with arteriovenous malformations, 9 patients with cerebral metastases, 1 patient with parasagittal meningioma, and 4 patients with vestibular schwannoma. DT images were obtained at the time of standard GKRS protocol MRI (T1 and T2 weighted) for treatment, with the patient's head secured by a Leksell stereotactic frame. All studies were performed using a 1.5-T magnet with a single-channel head coil. DTI was performed with diffusion gradients in 32 directions and coregistered with the volumetric T1-weighted study. DTI postprocessing by means of commercially available software allowed tensor computation and the creation of directionally encoded color-, apparent diffusion coefficient-, and fractional anisotropy-mapped sequences. In addition, the software allowed visualized critical tracts to be exported as a structural volume and integrated into GammaPlan as an "organ at risk" during shot planning. Combined images were transferred to GammaPlan and integrated into treatment planning. RESULTS Stereotactic DT images were successfully acquired in all patients, with generation of correct directionally encoded color images. Tract generation with the software was straightforward and reproducible, particularly for axial tracts such as the optic radiation and the arcuate fasciculus. Corticospinal tract visualization was hampered by some artifacts from the base of the stereotactic frame, but this was overcome by a combination of frame/MRI volume adjustment and DTI seeding parameters. Coregistration of the DTI series with the T1-weighted treatment volume at the time of imaging was essential for the generation of correct tensor data. All patients with the exception of the vestibular schwannoma cases had treatment pathology in the vicinity of eloquent tracts and/or the cortex. No new neurological deficits due to radiation were recorded at the short-term follow-up. CONCLUSIONS Recent reports in the medical literature have suggested that white matter tracts (particularly the optic radiation and arcuate fasciculus) are more vulnerable to radiation during stereotactic radiosurgery than previously thought. Integration of stereotactic tractography into GKRS represents a promising tool for preventing GKRS complications by reduction in radiation doses to functional organs at risk, including critical cortical areas and subcortical white matter tracts.

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