Publications by authors named "Jonathon J Parker"

22 Publications

  • Page 1 of 1

The insulo-opercular cortex encodes food-specific content under controlled and naturalistic conditions.

Nat Commun 2021 06 14;12(1):3609. Epub 2021 Jun 14.

Department of Neurosurgery, Stanford University, Stanford, CA, USA.

The insulo-opercular network functions critically not only in encoding taste, but also in guiding behavior based on anticipated food availability. However, there remains no direct measurement of insulo-opercular activity when humans anticipate taste. Here, we collect direct, intracranial recordings during a food task that elicits anticipatory and consummatory taste responses, and during ad libitum consumption of meals. While cue-specific high-frequency broadband (70-170 Hz) activity predominant in the left posterior insula is selective for taste-neutral cues, sparse cue-specific regions in the anterior insula are selective for palatable cues. Latency analysis reveals this insular activity is preceded by non-discriminatory activity in the frontal operculum. During ad libitum meal consumption, time-locked high-frequency broadband activity at the time of food intake discriminates food types and is associated with cue-specific activity during the task. These findings reveal spatiotemporally-specific activity in the human insulo-opercular cortex that underlies anticipatory evaluation of food across both controlled and naturalistic settings.
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http://dx.doi.org/10.1038/s41467-021-23885-4DOI Listing
June 2021

Status epilepticus after intracranial neurosurgery: incidence and risk stratification by perioperative clinical features.

J Neurosurg 2021 May 14:1-13. Epub 2021 May 14.

Departments of1Neurosurgery and.

Objective: Status epilepticus (SE) is associated with significant mortality, cost, and risk of future seizures. In one of the first studies of SE after neurosurgery, the authors assess the incidence, risk factors, and outcome of postneurosurgical SE (PNSE).

Methods: Neurosurgical admissions from the MarketScan Claims and Encounters database (2007 through 2015) were assessed in a longitudinal cross-sectional sample of privately insured patients who underwent qualifying cranial procedures in the US and were older than 18 years of age. The incidence of early (in-hospital) and late (postdischarge readmission) SE and associated mortality was assessed. Procedural, pathological, demographic, and anatomical covariates parameterized multivariable logistic regression and Cox models. Multivariable logistic regression and Cox proportional hazards models were used to study the incidence of early and late PNSE. A risk-stratification simulation was performed, combining individual predictors into singular risk estimates.

Results: A total of 197,218 admissions (218,217 procedures) were identified. Early PNSE occurred during 637 (0.32%) of 197,218 admissions for cranial neurosurgical procedures. A total of 1045 (0.56%) cases of late PNSE were identified after 187,771 procedure admissions with nonhospice postdischarge follow-up. After correction for comorbidities, craniotomy for trauma, hematoma, or elevated intracranial pressure was associated with increased risk of early PNSE (adjusted OR [aOR] 1.538, 95% CI 1.183-1.999). Craniotomy for meningioma resection was associated with an increased risk of early PNSE compared with resection of metastases and parenchymal primary brain tumors (aOR 2.701, 95% CI 1.388-5.255). Craniotomies for infection or abscess (aHR 1.447, 95% CI 1.016-2.061) and CSF diversion (aHR 1.307, 95% CI 1.076-1.587) were associated with highest risk of late PNSE. Use of continuous electroencephalography in patients with early (p < 0.005) and late (p < 0.001) PNSE rose significantly over the study time period. The simulation regression model predicted that patients at high risk for early PNSE experienced a 1.10% event rate compared with those at low risk (0.07%). Similarly, patients predicted to be at highest risk for late PNSE were significantly more likely to eventually develop late PNSE than those at lowest risk (HR 54.16, 95% CI 24.99-104.80).

Conclusions: Occurrence of early and late PNSE was associated with discrete neurosurgical pathologies and increased mortality. These data provide a framework for prospective validation of clinical and perioperative risk factors and indicate patients for heightened diagnostic suspicion of PNSE.
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http://dx.doi.org/10.3171/2020.10.JNS202895DOI Listing
May 2021

Anticipatory human subthalamic area beta-band power responses to dissociable tastes correlate with weight gain.

Neurobiol Dis 2021 Jul 26;154:105348. Epub 2021 Mar 26.

Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA, 94305, USA. Electronic address:

The availability of enticing sweet, fatty tastes is prevalent in the modern diet and contribute to overeating and obesity. In animal models, the subthalamic area plays a role in mediating appetitive and consummatory feeding behaviors, however, its role in human feeding is unknown. We used intraoperative, subthalamic field potential recordings while participants (n = 5) engaged in a task designed to provoke responses of taste anticipation and receipt. Decreased subthalamic beta-band (15-30 Hz) power responses were observed for both sweet-fat and neutral tastes. Anticipatory responses to taste-neutral cues started with an immediate decrease in beta-band power from baseline followed by an early beta-band rebound above baseline. On the contrary, anticipatory responses to sweet-fat were characterized by a greater and sustained decrease in beta-band power. These activity patterns were topographically specific to the subthalamic nucleus and substantia nigra. Further, a neural network trained on this beta-band power signal accurately predicted (AUC ≥ 74%) single trials corresponding to either taste. Finally, the magnitude of the beta-band rebound for a neutral taste was associated with increased body mass index after starting deep brain stimulation therapy. We provide preliminary evidence of discriminatory taste encoding within the subthalamic area associated with control mechanisms that mediate appetitive and consummatory behaviors.
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http://dx.doi.org/10.1016/j.nbd.2021.105348DOI Listing
July 2021

Contemporaneous evaluation of patient experience, surgical strategy, and seizure outcomes in patients undergoing stereoelectroencephalography or subdural electrode monitoring.

Epilepsia 2021 01 25;62(1):74-84. Epub 2020 Nov 25.

Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA, USA.

Objective: Intracranial electrographic localization of the seizure onset zone (SOZ) can guide surgical approaches for medically refractory epilepsy patients, especially when the presurgical workup is discordant or functional cortical mapping is required. Minimally invasive stereotactic placement of depth electrodes, stereoelectroencephalography (SEEG), has garnered increasing use, but limited data exist to evaluate its postoperative outcomes in the context of the contemporaneous availability of both SEEG and subdural electrode (SDE) monitoring. We aimed to assess the patient experience, surgical intervention, and seizure outcomes associated with these two epileptic focus mapping techniques during a period of rapid adoption of neuromodulatory and ablative epilepsy treatments.

Methods: We retrospectively reviewed 66 consecutive adult intracranial electrode monitoring cases at our institution between 2014 and 2017. Monitoring was performed with either SEEG (n = 47) or SDEs (n = 19).

Results: Both groups had high rates of SOZ identification (SEEG 91.5%, SDE 88.2%, P = .69). The majority of patients achieved Engel class I (SEEG 29.3%, SDE 35.3%) or II outcomes (SEEG 31.7%, SDE 29.4%) after epilepsy surgery, with no significant difference between groups (P = .79). SEEG patients reported lower median pain scores (P = .03) and required less narcotic pain medication (median = 94.5 vs 594.6 milligram morphine equivalents, P = .0003). Both groups had low rates of symptomatic hemorrhage (SEEG 0%, SDE 5.3%, P = .11). On multivariate logistic regression, undergoing resection or ablation (vs responsive neurostimulation/vagus nerve stimulation) was the only significant independent predictor of a favorable outcome (adjusted odds ratio = 25.4, 95% confidence interval = 3.48-185.7, P = .001).

Significance: Although both SEEG and SDE monitoring result in favorable seizure control, SEEG has the advantage of superior pain control, decreased narcotic usage, and lack of routine need for intensive care unit stay. Despite a heterogenous collection of epileptic semiologies, seizure outcome was associated with the therapeutic surgical modality and not the intracranial monitoring technique. The potential for an improved postoperative experience makes SEEG a promising method for intracranial electrode monitoring.
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http://dx.doi.org/10.1111/epi.16762DOI Listing
January 2021

Adverse Events and Bundled Costs after Cranial Neurosurgical Procedures: Validation of the LACE Index Across 40,431 Admissions and Development of the LACE-Cranial Index.

World Neurosurg 2021 Feb 28;146:e431-e451. Epub 2020 Oct 28.

Department of Neurosurgery, Stanford University School of Medicine, Stanford, California, USA. Electronic address:

Objective: Anticipating postdischarge complications after neurosurgery remains difficult. The LACE index, based on 4 hospitalization descriptors, stratifies patients by risk of 30-day postdischarge adverse events but has not been validated in a procedure-specific manner in neurosurgery. Our study sought to explore the usefulness of the LACE index in a population undergoing cranial neurosurgery and to develop an enhanced model, LACE-Cranial.

Methods: The OptumClinformatics Database was used to identify cranial neurosurgery admissions (2004-2017). Procedures were grouped as trauma/hematoma/intracranial pressure, open vascular, functional/pain, skull base, tumor, or endovascular. Adverse events were defined as postdischarge death/readmission. LACE-Cranial was developed using a logistic regression framework incorporating an expanded feature set in addition to the original LACE components.

Results: A total of 40,431 admissions were included. Predictions of 30-day readmissions was best for skull base (area under the curve [AUC], 0.636) and tumor (AUC, 0.63) admissions but was generally poor. Predictive ability of 30-day mortality was best for functional/pain admissions (AUC, 0.957) and poorest for trauma/hematoma/intracranial pressure admissions (AUC, 0.613). Across procedure types except for functional/pain, a high-risk LACE score was associated with higher postdischarge bundled payment costs. Incorporating features identified to contribute independent predictive value, the LACE-Cranial model achieved procedure-specific 30-day mortality AUCs ranging from 0.904 to 0.98. Prediction of 30-day and 90-day readmissions was also improved, with tumor and skull base cases achieving 90-day readmission AUCs of 0.718 and 0.717, respectively.

Conclusions: Although the unmodified LACE index shows inconsistent classification performance, the enhanced LACE-Cranial model offers excellent prediction of short-term postdischarge mortality across procedure groups and significantly improved anticipation of short-term postdischarge readmissions.
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http://dx.doi.org/10.1016/j.wneu.2020.10.103DOI Listing
February 2021

Case Report on Deep Brain Stimulation Rescue After Suboptimal MR-Guided Focused Ultrasound Thalamotomy for Essential Tremor: A Tractography-Based Investigation.

Front Hum Neurosci 2020 26;14:191. Epub 2020 Jun 26.

Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA, United States.

Essential tremor (ET) is the most prevalent movement disorder in adults, and can often be medically refractory, requiring surgical intervention. MRI-guided focused ultrasound (MRgFUS) is a less invasive procedure that uses ultrasonic waves to induce lesions in the ventralis intermedius nucleus (VIM) to treat refractory ET. As with all procedures for treating ET, optimal targeting during MRgFUS is essential for efficacy and durability. Various studies have reported cases of tremor recurrence following MRgFUS and long-term outcome data is limited to 3-4 years. We present a tractography-based investigation on a case of DBS rescue for medically refractory ET that was treated with MRgFUS that was interrupted due to the development of dysarthria during the procedure. After initial improvement, her hand tremor started to recur within 6 months after treatment, and bilateral DBS was performed targeting the VIM 24 months after MRgFUS. DBS induced long-term tremor control with monopolar stimulation. Diffusion MRI tractography was used to reconstruct the dentatorubrothalamic (DRTT) and corticothalmic (CTT) tracts being modulated by the procedures to understand the variability in efficacy between MRgFUS and DBS in treating ET in our patient. By comparing the MRgFUS lesion and DBS volume of activated tissue (VAT), we found that the MRgFUS lesion was located ventromedially to the VAT, and was less than 10% of the size of the VAT. While the lesion encompassed the same proportion of DRTT streamlines, it encompassed fewer CTT streamlines than the VAT. Our findings indicate the need for further investigation of targeting the CTT when using neuromodulatory procedures to treat refractory ET for more permanent tremor relief.
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http://dx.doi.org/10.3389/fnhum.2020.00191DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7333679PMC
June 2020

Postoperative outcomes following pediatric intracranial electrode monitoring: A case for stereoelectroencephalography (SEEG).

Epilepsy Behav 2020 03 3;104(Pt A):106905. Epub 2020 Feb 3.

Department of Neurosurgery, Stanford University School of Medicine, United States of America; Division of Pediatric Neurosurgery, Lucile Packard Children's Hospital Stanford, United States of America. Electronic address:

Background: For patients with medically refractory epilepsy, intracranial electrode monitoring can help identify epileptogenic foci. Despite the increasing utilization of stereoelectroencephalography (SEEG), the relative risks or benefits associated with the technique when compared with the traditional subdural electrode monitoring (SDE) remain unclear, especially in the pediatric population. Our aim was to compare the outcomes of pediatric patients who received intracranial monitoring with SEEG or SDE (grids and strips).

Methods: We retrospectively studied 38 consecutive pediatric intracranial electrode monitoring cases performed at our institution from 2014 to 2017. Medical/surgical history and operative/postoperative records were reviewed. We also compared direct inpatient hospital costs associated with the two procedures.

Results: Stereoelectroencephalography and SDE cohorts both showed high likelihood of identifying epileptogenic zones (SEEG: 90.9%, SDE: 87.5%). Compared with SDE, SEEG patients had a significantly shorter operative time (118.7 versus 233.4 min, P < .001) and length of stay (6.2 versus 12.3 days, P < .001), including days spent in the intensive care unit (ICU; 1.4 versus 5.4 days, P < .001). Stereoelectroencephalography patients tended to report lower pain scores and used significantly less narcotic pain medications (54.2 versus 197.3 mg morphine equivalents, P = .005). No complications were observed. Stereoelectroencephalography and SDE cohorts had comparable inpatient hospital costs (P = .47).

Conclusion: In comparison with subdural electrode placement, SEEG results in a similarly favorable clinical outcome, but with reduced operative time, decreased narcotic usage, and superior pain control without requiring significantly higher costs. The potential for an improved postoperative intracranial electrode monitoring experience makes SEEG especially suitable for pediatric patients.
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http://dx.doi.org/10.1016/j.yebeh.2020.106905DOI Listing
March 2020

Interobserver Agreement for the Computed Tomography Severity Grading Scales for Acute Traumatic Brain Injury.

J Neurotrauma 2020 06 11;37(12):1445-1451. Epub 2020 Mar 11.

Department of Radiology, Stanford University, Stanford, California, USA.

The purpose of this study was to determine the interobserver variability among providers of different specialties and levels of experience across five established computed tomography (CT) scoring systems for acute traumatic brain injury (TBI). One hundred cases were selected at random from a retrospective population of adult patients transported to our emergency department and subjected to a non-contrast head CT due to suspicion of TBI. Eight neuroradiologists and neurosurgeons in trainee (residents and fellows) and attending roles independently scored each non-contrast head CT scan on the Marshall, Rotterdam, Helsinki, Stockholm, and NeuroImaging Radiological Interpretation System (NIRIS) head CT scales. Interobserver variability of scale scores-overall and by specialty and level of training-was quantified using the intraclass correlation coefficient (ICC), and agreement with respect to National Institutes of Health Common Data Elements (NIH CDEs) was assessed using Cohen's kappa. All CT severity scoring systems showed high interobserver agreement as evidenced by high ICCs, ranging from 0.75-0.89. For all scoring systems, neuroradiologists (ICC range from 0.81-0.94) tended to have higher interobserver agreement than neurosurgeons (ICC range from 0.63-0.76). For all scoring systems, attendings (ICC range from 0.76-0.89) had similar interobserver agreement to trainees (ICC range from 0.73-0.89). Agreement with respect to NIH CDEs was high for ascertaining presence/absence of hemorrhage, skull fracture, and mass effect, with estimated kappa statistics of least 0.89. Acute TBI CT scoring systems demonstrate high interobserver agreement. These results provide scientific rigor for future use of these systems for the classification of acute TBI.
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http://dx.doi.org/10.1089/neu.2019.6871DOI Listing
June 2020

Adjunctive repetitive transcranial magnetic stimulation delivers superior quality of life for focal epilepsy compared to anti-epileptic drugs: A meta-analytic utility prediction study.

Brain Stimul 2020 Mar - Apr;13(2):430-432. Epub 2019 Dec 12.

Department of Neurosurgery, Stanford University Medical Center, 300 Pasteur Drive, Stanford, CA, 94305, USA. Electronic address:

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http://dx.doi.org/10.1016/j.brs.2019.12.006DOI Listing
December 2019

Robot-assisted versus manual navigated stereoelectroencephalography in adult medically-refractory epilepsy patients.

Epilepsy Res 2020 01 9;159:106253. Epub 2019 Dec 9.

Division of Pediatric Neurosurgery, Lucile Packard Children's Hospital Stanford, United States. Electronic address:

Objective: Stereoelectroencephalography (SEEG) has experienced a recent growth in adoption for epileptogenic zone (EZ) localization. Advances in robotics have the potential to improve the efficiency and safety of this intracranial seizure monitoring method. We present our institutional experience employing robot-assisted SEEG and compare its operative efficiency, seizure reduction outcomes, and direct hospital costs with SEEG performed without robotic assistance using navigated stereotaxy.

Methods: We retrospectively identified 50 consecutive adult SEEG cases at our institution in this IRB-approved study, of which 25 were navigated with image guidance (hereafter referred to as "navigated") (02/2014-10/2016) and 25 were robot-assisted (09/2016-12/2017). A thorough review of medical/surgical history and operative records with imaging and trajectory plans was done for each patient. Direct inpatient costs related to each technique were compared.

Results: Most common seizure etiologies for patients undergoing navigated and robot-assisted SEEG included non-lesional and benign temporal lesions. Despite having a higher mean number of leads-per-patient (10.2 ± 3.5 versus 7.2 ± 2.6, P = 0.002), robot-assisted cases had a significantly shorter mean operative time than navigated cases (125.5±48.5 versus 173.4±84.3 min, P = 0.02). Comparison of robot-assisted cases over the study interval revealed no significant difference in mean operative time (136.4±51.4 min for the first ten cases versus 109.9±75.8 min for the last ten cases, P = 0.25) and estimated operative time-per-lead (13.4±6.0 min for the first ten cases versus 12.9±7.7 min for the last ten cases, P = 0.86). The mean depth, radial, target, and entry point errors for robot-assisted cases were 2.12±1.89, 1.66±1.58, 3.05±2.02 mm, and 1.39 ± 0.75 mm, respectively. The two techniques resulted in equivalent EZ localization rate (navigated 88 %, robot-assisted 96 %, P = 0.30). Common types of epilepsy surgery performed consisted of implantation of responsive neurostimulation (RNS) device (56 %), resection (19.1 %), and laser ablation (23.8 %) for navigated SEEG. For robot-assisted SEEG, either RNS implantation (68.2 %) or laser ablation (22.7 %) were performed or offered. A majority of navigated and robot-assisted patients who underwent epilepsy surgery achieved either Engel Class I (navigated 36.8 %, robot-assisted 31.6 %) or II (navigated 36.8 %, robot-assisted 15.8 %) outcome with no significant difference between the groups (P = 0.14). Direct hospital cost for robot-assisted SEEG was 10 % higher than non-robotic cases.

Conclusion: This single-institutional study suggests that robotic assistance can enhance efficiency of SEEG without compromising safety or precision when compared to image guidance only. Adoption of this technique with uniform safety and efficacy over a short period of time is feasible with favorable epilepsy outcomes.
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http://dx.doi.org/10.1016/j.eplepsyres.2019.106253DOI Listing
January 2020

Targeted genomic CRISPR-Cas9 screen identifies MAP4K4 as essential for glioblastoma invasion.

Sci Rep 2019 Sep 30;9(1):14020. Epub 2019 Sep 30.

Stanford University School of Medicine, Department of Neurosurgery, 300 Pasteur Dr, Stanford, CA, 94305, USA.

Among high-grade brain tumors, glioblastoma is particularly difficult to treat, in part due to its highly infiltrative nature which contributes to the malignant phenotype and high mortality in patients. In order to better understand the signaling pathways underlying glioblastoma invasion, we performed the first large-scale CRISPR-Cas9 loss of function screen specifically designed to identify genes that facilitate cell invasion. We tested 4,574 genes predicted to be involved in trafficking and motility. Using a transwell invasion assay, we discovered 33 genes essential for invasion. Of the 11 genes we selected for secondary testing using a wound healing assay, 6 demonstrated a significant decrease in migration. The strongest regulator of invasion was mitogen-activated protein kinase 4 (MAP4K4). Targeting of MAP4K4 with single guide RNAs or a MAP4K4 inhibitor reduced migration and invasion in vitro. This effect was consistent across three additional patient derived glioblastoma cell lines. Analysis of epithelial-mesenchymal transition markers in U138 cells with lack or inhibition of MAP4K4 demonstrated protein expression consistent with a non-invasive state. Importantly, MAP4K4 inhibition limited migration in a subset of human glioma organotypic slice cultures. Our results identify MAP4K4 as a novel potential therapeutic target to limit glioblastoma invasion.
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http://dx.doi.org/10.1038/s41598-019-50160-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6768851PMC
September 2019

Anatomic and Thermometric Analysis of Cranial Nerve Palsy after Laser Amygdalohippocampotomy for Mesial Temporal Lobe Epilepsy.

Oper Neurosurg (Hagerstown) 2020 06;18(6):684-691

Department of Neurosurgery, School of Medicine, Stanford University, Stanford, California.

Background: Laser interstitial thermal therapy (LITT) is a minimally invasive therapy for treating medication-resistant mesial temporal lobe epilepsy. Cranial nerve (CN) palsy has been reported as a procedural complication, but the mechanism of this complication is not understood.

Objective: To identify the cause of postoperative CN palsy after LITT.

Methods: Four medial temporal lobe epilepsy patients with CN palsy after LITT were identified for comparison with 22 consecutive patients with no palsy. We evaluated individual variation in the distance between CN III and the uncus, and CN IV and the parahippocampal gyrus using preoperative T1- and T2-weighted magnetic resonance (MR) images. Intraoperative MR thermometry was used to estimate temperature changes.

Results: CN III (n = 2) and CN IV palsies (n = 2) were reported. On preoperative imaging, the majority of identified CN III (54%) and CN IV (43%) were located within 1 to 2 mm of the uncus and parahippocampal gyrus tissue border, respectively. Affected CN III and CN IV were more likely to be found < 1 mm of the tissue border (PCNIII = .03, PCNIV < .01; chi-squared test). Retrospective assessment of thermal profile during ablation showed higher temperature rise along the mesial temporal lobe tissue border in affected CNs than unaffected CNs after controlling for distance (12.9°C vs 5.8°C; P = .03; 2-sample t-test).

Conclusion: CN palsy after LITT likely results from direct heating of the respective CN running at extreme proximity to the mesial temporal lobe. Low-temperature thresholds set at the border of the mesial temporal lobe in patients whose CNs are at close proximity may reduce this risk.
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http://dx.doi.org/10.1093/ons/opz279DOI Listing
June 2020

Stereotactic laser ablation for completion corpus callosotomy.

J Neurosurg Pediatr 2019 Aug 2:1-9. Epub 2019 Aug 2.

Departments of1Neurosurgery.

Objective: Completion corpus callosotomy can offer further remission from disabling seizures when a prior partial corpus callosotomy has failed and residual callosal tissue is identified on imaging. Traditional microsurgical approaches to section residual fibers carry risks associated with multiple craniotomies and the proximity to the medially oriented motor cortices. Laser interstitial thermal therapy (LITT) represents a minimally invasive approach for the ablation of residual fibers following a prior partial corpus callosotomy. Here, the authors report clinical outcomes of 6 patients undergoing LITT for completion corpus callosotomy and characterize the radiological effects of ablation.

Methods: A retrospective clinical review was performed on a series of 6 patients who underwent LITT completion corpus callosotomy for medically intractable epilepsy at Stanford University Medical Center and Lucile Packard Children's Hospital at Stanford between January 2015 and January 2018. Detailed structural and diffusion-weighted MR images were obtained prior to and at multiple time points after LITT. In 4 patients who underwent diffusion tensor imaging (DTI), streamline tractography was used to reconstruct and evaluate tract projections crossing the anterior (genu and rostrum) and posterior (splenium) parts of the corpus callosum. Multiple diffusion parameters were evaluated at baseline and at each follow-up.

Results: Three pediatric (age 8-18 years) and 3 adult patients (age 30-40 years) who underwent completion corpus callosotomy by LITT were identified. Mean length of follow-up postoperatively was 21.2 (range 12-34) months. Two patients had residual splenium, rostrum, and genu of the corpus callosum, while 4 patients had residual splenium only. Postoperative complications included asymptomatic extension of ablation into the left thalamus and transient disconnection syndrome. Ablation of the targeted area was confirmed on immediate postoperative diffusion-weighted MRI in all patients. Engel class I-II outcomes were achieved in 3 adult patients, whereas all 3 pediatric patients had Engel class III-IV outcomes. Tractography in 2 adult and 2 pediatric patients revealed time-dependent reduction of fractional anisotropy after LITT.

Conclusions: LITT is a safe, minimally invasive approach for completion corpus callosotomy. Engel outcomes for completion corpus callosotomy by LITT were similar to reported outcomes of open completion callosotomy, with seizure reduction primarily observed in adult patients. Serial DTI can be used to assess the presence of tract projections over time but does not classify treatment responders or nonresponders.
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http://dx.doi.org/10.3171/2019.5.PEDS19117DOI Listing
August 2019

Intratumoral heterogeneity of endogenous tumor cell invasive behavior in human glioblastoma.

Sci Rep 2018 12 20;8(1):18002. Epub 2018 Dec 20.

Inova Neuroscience and Spine Institute, Inova Health Systems, Falls Church, VA, USA.

Intratumoral genetic heterogeneity is a widely accepted characteristic of human cancer, including the most common primary malignant brain tumor, glioblastoma. However, the variability in biological behaviors amongst cells within individual tumors is not well described. Invasion into unaffected brain parenchyma is one such behavior, and a leading mechanism of tumor recurrence unaddressed by the current therapeutic armamentarium. Further, providing insight into variability of tumor cell migration within individual tumors may inform discovery of novel anti-invasive therapeutics. In this study, ex vivo organotypic slice cultures from EGFR-wild type and EGFR-amplified patient tumors were treated with the EGFR inhibitor gefitinib to evaluate potential sub-population restricted intratumoral drug-specific responses. High-resolution time-lapse microscopy and quantitative path tracking demonstrated migration of individual cells are punctuated by intermittent bursts of movement. Elevation of population aggregate mean speeds were driven by subpopulations of cells exhibiting frequent high-amplitude bursts, enriched within EGFR-amplified tumors. Treatment with gefitinib specifically targeted high-burst cell subpopulations only in EGFR-amplified tumors, decreasing bursting frequency and amplitude. We provide evidence of intratumoral subpopulations of cells with enhanced migratory behavior in human glioblastoma, selectively targeted via EGFR inhibition. These data justify use of direct human tumor slice cultures to investigate patient-specific therapies designed to limit tumor invasion.
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http://dx.doi.org/10.1038/s41598-018-36280-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6301947PMC
December 2018

Frontal and occipital horn ratio is associated with multifocal intraparenchymal hemorrhages in neonatal shunted hydrocephalus.

J Neurosurg Pediatr 2017 Nov 8;20(5):432-438. Epub 2017 Sep 8.

Radiology, and.

OBJECTIVE Placement of a cerebrospinal fluid diversion device (i.e., shunt) is a routine pediatric neurosurgical procedure, often performed in the first weeks of life for treatment of congenital hydrocephalus. In the postoperative period, shunt placement may be complicated by subdural, catheter tract, parenchymal, and intraventricular hemorrhages. The authors observed a subset of infants and neonates who developed multifocal intraparenchymal hemorrhages (MIPH) following shunt placement and sought to determine any predisposing perioperative variables. METHODS A retrospective review of the electronic medical record at a tertiary-care children's hospital was performed for the period 1998-2015. Inclusion criteria consisted of shunt placement, age < 30 days, and available pre- and postoperative brain imaging. The following data were collected and analyzed for each case: ventricular size ratios, laboratory values, clinical presentation, shunt and valve type, and operative timing and approach. RESULTS A total of 121 neonates met the inclusion criteria for the study, and 11 patients (9.1%) had MIPH following shunt placement. The preoperative frontal and occipital horn ratio (FOR) was significantly higher in the patients with MIPH than in those without (0.65 vs 0.57, p < 0.001). The change in FOR (∆FOR) after shunt placement was significantly greater in the MIPH group (0.14 vs 0.08, p = 0.04). Among neonates who developed MIPH, aqueductal stenosis was the most common etiology (45%). The type of shunt valve was associated with incidence of MIPH (p < 0.001). Preoperative clinical parameters, including head circumference, bulging fontanelle, and coagulopathy, were not significantly associated with development of MIPH. CONCLUSIONS MIPH represents an underrecognized complication of neonatal shunted hydrocephalus. Markers of severity of ventriculomegaly (FOR) and ventricular response to CSF diversion (∆FOR) were significantly associated with occurrence of MIPH. Choice of shunt and etiology of hydrocephalus were also significantly associated with MIPH. After adjusting for corrected age, etiology of hydrocephalus, and shunt setting, the authors found that ∆FOR after shunting was still associated with MIPH. A prospective study of MIPH prevention strategies and assessment of possible implications for patient outcomes is needed.
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http://dx.doi.org/10.3171/2017.6.PEDS16481DOI Listing
November 2017

A Human Glioblastoma Organotypic Slice Culture Model for Study of Tumor Cell Migration and Patient-specific Effects of Anti-Invasive Drugs.

J Vis Exp 2017 07 20(125). Epub 2017 Jul 20.

Inova Neuroscience Institute.

Glioblastoma (GBM) continues to carry an extremely poor clinical prognosis despite surgical, chemotherapeutic, and radiation therapy. Progressive tumor invasion into surrounding brain parenchyma represents an enduring therapeutic challenge. To develop anti-migration therapies for GBM, model systems that provide a physiologically relevant background for controlled experimentation are essential. Here, we present a protocol for generating slice cultures from human GBM tissue obtained during surgical resection. These cultures allow for ex vivo experimentation without passaging through animal xenografts or single cell cultures. Further, we describe the use of time-lapse laser scanning confocal microscopy in conjunction with cell tracking to quantitatively study the migratory behavior of tumor cells and associated response to therapeutics. Slices are reproducibly generated within 90 min of surgical tissue acquisition. Retrovirally-mediated fluorescent cell labeling, confocal imaging, and tumor cell migration analyses are subsequently completed within two weeks of culture. We have successfully used these slice cultures to uncover genetic factors associated with increased migratory behavior in human GBM. Further, we have validated the model's ability to detect patient-specific variation in response to anti-migration therapies. Moving forward, human GBM slice cultures are an attractive platform for rapid ex vivo assessment of tumor sensitivity to therapeutic agents, in order to advance personalized neuro-oncologic therapy.
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http://dx.doi.org/10.3791/53557DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5612552PMC
July 2017

Cost-effectiveness of focused ultrasound, radiosurgery, and DBS for essential tremor.

Mov Disord 2017 Aug 3;32(8):1165-1173. Epub 2017 Apr 3.

Department of Neurosurgery, Stanford, California, USA.

Background: Essential tremor remains a very common yet medically refractory condition. A recent phase 3 study demonstrated that magnetic resonance-guided focused ultrasound thalamotomy significantly improved upper limb tremor. The objectives of this study were to assess this novel therapy's cost-effectiveness compared with existing procedural options.

Methods: Literature searches of magnetic resonance-guided focused ultrasound thalamotomy, DBS, and stereotactic radiosurgery for essential tremor were performed. Pre- and postoperative tremor-related disability scores were collected from 32 studies involving 83 magnetic resonance-guided focused ultrasound thalamotomies, 615 DBSs, and 260 stereotactic radiosurgery cases. Utility, defined as quality of life and derived from percent change in functional disability, was calculated; Medicare reimbursement was employed as a proxy for societal cost. Medicare reimbursement rates are not established for magnetic resonance-guided focused ultrasound thalamotomy for essential tremor; therefore, reimbursements were estimated to be approximately equivalent to stereotactic radiosurgery to assess a cost threshold. A decision analysis model was constructed to examine the most cost-effective option for essential tremor, implementing meta-analytic techniques.

Results: Magnetic resonance-guided focused ultrasound thalamotomy resulted in significantly higher utility scores compared with DBS (P < 0.001) or stereotactic radiosurgery (P < 0.001). Projected costs of magnetic resonance-guided focused ultrasound thalamotomy were significantly less than DBS (P < 0.001), but not significantly different from radiosurgery.

Conclusions: Magnetic resonance-guided focused ultrasound thalamotomy is cost-effective for tremor compared with DBS and stereotactic radiosurgery and more effective than both. Even if longer follow-up finds changes in effectiveness or costs, focused ultrasound thalamotomy will likely remain competitive with both alternatives. © 2017 International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.26997DOI Listing
August 2017

Vocal Tremor: Novel Therapeutic Target for Deep Brain Stimulation.

Brain Sci 2016 Oct 10;6(4). Epub 2016 Oct 10.

Department of Neurosurgery, Stanford University, 300 Pasteur Dr., Edwards Bldg. R-293, Stanford, CA 94305, USA.

Tremulous voice is characteristically associated with essential tremor, and is referred to as essential vocal tremor (EVT). Current estimates suggest that up to 40% of individuals diagnosed with essential tremor also present with EVT, which is associated with an impaired quality of life. Traditional EVT treatments have demonstrated limited success in long-term management of symptoms. However, voice tremor has been noted to decrease in patients receiving deep brain stimulation (DBS) with the targeting of thalamic nuclei. In this study, we describe our multidisciplinary procedure for awake, frameless DBS with optimal stimulation targets as well as acoustic analysis and laryngoscopic assessment to quantify tremor reduction. Finally, we investigate the most recent clinical evidence regarding the procedure.
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http://dx.doi.org/10.3390/brainsci6040048DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5187562PMC
October 2016

The role of regulatory T cells and microglia in glioblastoma-associated immunosuppression.

J Neurooncol 2015 Jul 30;123(3):405-12. Epub 2015 Jun 30.

Department of Neurological Surgery, Brigham and Women's Hospital, Boston, MA, USA.

Cell-mediated suppression of anti-tumor immunity is multifactorial in patients with cancer, and recent studies have focused on several distinct cellular agents that are associated with this phenomenon. This review will focus on the potential role of regulatory T cells (Tregs) and microglia in the suppression of cellular immunity observed in patients with glioblastoma. We discuss the ontogeny, basic biology, evidence for activity, and potential clinical options for targeting Tregs and microglia as part of immunotherapy in affected patients.
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http://dx.doi.org/10.1007/s11060-015-1849-3DOI Listing
July 2015

Gefitinib selectively inhibits tumor cell migration in EGFR-amplified human glioblastoma.

Neuro Oncol 2013 Aug 7;15(8):1048-57. Epub 2013 Jun 7.

Medical Scientist Training Program, University of Colorado, School of Medicine, Anschutz Medical Campus, Aurora, CO, USA.

Background: Tissue invasion is a hallmark of most human cancers and remains a major source of treatment failure in patients with glioblastoma (GBM). Although EGFR amplification has been previously associated with more invasive tumor behavior, existing experimental models have not supported quantitative evaluation of interpatient differences in tumor cell migration or testing of patient-specific responses to therapies targeting invasion. To explore these questions, we optimized an ex vivo organotypic slice culture system allowing for labeling and tracking of tumor cells in human GBM slice cultures.

Methods: With use of time-lapse confocal microscopy of retrovirally labeled tumor cells in slices, baseline differences in migration speed and efficiency were determined and correlated with EGFR amplification in a cohort of patients with GBM. Slices were treated with gefitinib to evaluate anti-invasive effects associated with targeting EGFR.

Results: Migration analysis identified significant patient-to-patient variation at baseline. EGFR amplification was correlated with increased migration speed and efficiency compared with nonamplified tumors. Critically, gefitinib resulted in a selective and significant reduction of tumor cell migration in EGFR-amplified tumors.

Conclusions: These data provide the first identification of patient-to-patient variation in tumor cell migration in living human tumor tissue. We found that EGFR-amplified GBM are inherently more efficient in their migration and can be effectively targeted by gefitinib treatment. These data suggest that stratified clinical trails are needed to evaluate gefitinib as an anti-invasive adjuvant for patients with EGFR-amplified GBM. In addition, these results provide proof of principle that primary slice cultures may be useful for patient-specific screening of agents designed to inhibit tumor invasion.
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http://dx.doi.org/10.1093/neuonc/not053DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3714155PMC
August 2013

Advances in neurosurgery: Five new things.

Neurol Clin Pract 2012 Sep;2(3):201-207

Department of Neurosurgery, University of Colorado School of Medicine, Aurora.

Surgical options for disease of the nervous system continue to expand in breadth and scope. These advances have been related in large part to progress in technology, translational application of molecular biology, and increasing understanding of the physiologic processes associated with neurologic disease. The current review will outline recent neurosurgical advances in the management of brain tumors, movement disorders, spinal degenerative disease, and neurologic injury. In addition, we include a brief discussion of exciting data from recent trials focusing on the brain-machine interface.
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http://dx.doi.org/10.1212/CPJ.0b013e31826af22bDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5766111PMC
September 2012

Preoperative evaluation of pineal tumors.

Neurosurg Clin N Am 2011 Jul 8;22(3):353-8, vii-viii. Epub 2011 Jun 8.

Department of Neurosurgery, University of Colorado School of Medicine, Academic Office Building, Room 5001, 12631 East, 17th Avenue, Aurora, CO 80045, USA.

The role of the neurosurgeon is critical for initiating preoperative evaluation and care for pineal region tumors. Preoperative evaluation of pineal region tumor can be simplified into a checklist: (1) evaluation for emergent surgical intervention due to symptomatic obstructive hydrocephalus or mass effect; (2) development of a focused differential after acquisition of craniospinal MRI, serum and cerebrospinal fluid oncoprotein levels, and cerebrospinal fluid cytology; and (3) decision on whether a biopsy, surgical resection, or both are necessary. Subsequent biopsy or surgical resection is the first step of tumor management and leads to coordination of consultation with medical and radiation oncology.
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http://dx.doi.org/10.1016/j.nec.2011.04.003DOI Listing
July 2011