Richard D. Bucholz

The Human Connectome Project: A data acquisition perspective

The Human Connectome Project (HCP) is an ambitious 5-year effort to characterize brain connectivity and function and their variability in healthy adults. This review summarizes the data acquisition plans being implemented by a consortium of HCP investigators who will study a population of 1200 subjects (twins and their non-twin siblings) using multiple imaging modalities along with extensive behavioral and genetic data. The imaging modalities will include diffusion imaging (dMRI), resting-state fMRI (R-fMRI), task-evoked fMRI (T-fMRI), T1- and T2-weighted MRI for structural and myelin mapping, plus combined magnetoencephalography and electroencephalography (MEG/EEG). Given the importance of obtaining the best possible data quality, we discuss the efforts underway during the first two years of the grant (Phase I) to refine and optimize many aspects of HCP data acquisition, including a new 7T scanner, a customized 3T scanner, and improved MR pulse sequences.

Very early hypothermia induction in patients with severe brain injury (the National Acute Brain Injury Study: Hypothermia II): a randomised trial

BACKGROUND The inconsistent effect of hypothermia treatment on severe brain injury in previous trials might be because hypothermia was induced too late after injury. We aimed to assess whether very early induction of hypothermia improves outcome in patients with severe brain injury. METHODS The National Acute Brain Injury Study: Hypothermia II (NABIS: H II) was a randomised, multicentre clinical trial of patients with severe brain injury who were enrolled within 2·5 h of injury at six sites in the USA and Canada. Patients with non-penetrating brain injury who were 16-45 years old and were not responsive to instructions were randomly assigned (1:1) by a random number generator to hypothermia or normothermia. Patients randomly assigned to hypothermia were cooled to 35°C until their trauma assessment was completed. Patients who had none of a second set of exclusion criteria were either cooled to 33°C for 48 h and then gradually rewarmed or treated at normothermia, depending upon their initial treatment assignment. Investigators who assessed the outcome measures were masked to treatment allocation. The primary outcome was the Glasgow outcome scale score at 6 months. Analysis was by modified intention to treat. This trial is registered with ClinicalTrials.gov, NCT00178711. FINDINGS Enrolment occurred from December, 2005, to June, 2009, when the trial was terminated for futility. Follow-up was from June, 2006, to December, 2009. 232 patients were initially randomised a mean of 1·6 h (SD 0·5) after injury: 119 to hypothermia and 113 to normothermia. 97 patients (52 in the hypothermia group and 45 in the normothermia group) did not meet any of the second set of exclusion criteria. The mean time to 35°C for the 52 patients in the hypothermia group was 2·6 h (SD 1·2) and to 33°C was 4·4 h (1·5). Outcome was poor (severe disability, vegetative state, or death) in 31 of 52 patients in the hypothermia group and 25 of 56 in the normothermia group (relative risk [RR] 1·08, 95% CI 0·76-1·53; p=0·67). 12 patients in the hypothermia group died compared with eight in the normothermia group (RR 1·30, 95% CI 0·58-2·52; p=0·52). INTERPRETATION This trial did not confirm the utility of hypothermia as a primary neuroprotective strategy in patients with severe traumatic brain injury.

The NeurostationTM—A highly accurate, minimally invasive solution to frameless stereotactic neurosurgery

The NeuroStation is an image-guided neurosurgery workstation designed to deliver frameless stereotaxy within an ergonomic, integrated surgical environment. Generally, stereotaxy can provide the neurosurgeon with important intra-operative localization information using diagnostic images such as computerized tomography (CT) or magnetic resonance imaging (MRI). To date, however, stereotaxy has not been widely accepted by neurosurgeons due to the procedural difficulties of incorporating conventional stereotaxy. The NeuroStation addresses the problems of conventional stereotaxy through the use of frameless stereotactic methods wherein state-of-the-art instrumentation and computer innovations allow: a) standard surgical instruments to be used as the localization device; b) multipoint registration methods in place of frame-based registration; and c) real-time interactive surgical localization. The NeuroStation can thus be transparently integrated into the neurosurgical procedure providing the neurosurgeon with image-guidance for surgical planning, biopsies, craniotomies, endoscopy, intra-operative ultrasound, radiation therapy, etc.

Frameless stereotactic ultrasonography: Method and applications

In stereotactic neurosurgery, computed tomography (CT) and magnetic resonance (MR) images are registered in a coordinate system defined with respect to the skull. By intraoperatively tracking the coordinate position of a surgical instrument, various displays can be formed which show the position of the instrument in the MR and/or CT images. However, the accuracy of this display varies because intracranial structures may shift or warp from their position prior to surgery. Ultrasonic imaging systems provide real-time images of the brain, but structures in these images are difficult to interpret because the images are based on ultrasonic echoes. A method has been developed for the real-time registration of these images. With this registration, software continuously updates a corresponding image constructed from the set of MR and/or CT images used for guidance. By developing this second view of the structures in the ultrasound image, the surgeon can easily interpret the ultrasound image, and it becomes possible to determine the extent of the intra-operative structure shift between the two images.

Poor drug distribution as a possible explanation for the results of the PRECISE trial

OBJECT Convection-enhanced delivery (CED) is a novel intracerebral drug delivery technique with considerable promise for delivering therapeutic agents throughout the CNS. Despite this promise, Phase III clinical trials employing CED have failed to meet clinical end points. Although this may be due to inactive agents or a failure to rigorously validate drug targets, the authors have previously demonstrated that catheter positioning plays a major role in drug distribution using this technique. The purpose of the present work was to retrospectively analyze the expected drug distribution based on catheter positioning data available from the CED arm of the PRECISE trial. METHODS Data on catheter positioning from all patients randomized to the CED arm of the PRECISE trial were available for analyses. BrainLAB iPlan Flow software was used to estimate the expected drug distribution. RESULTS Only 49.8% of catheters met all positioning criteria. Still, catheter positioning score (hazard ratio 0.93, p = 0.043) and the number of optimally positioned catheters (hazard ratio 0.72, p = 0.038) had a significant effect on progression-free survival. Estimated coverage of relevant target volumes was low, however, with only 20.1% of the 2-cm penumbra surrounding the resection cavity covered on average. Although tumor location and resection cavity volume had no effect on coverage volume, estimations of drug delivery to relevant target volumes did correlate well with catheter score (p < 0.003), and optimally positioned catheters had larger coverage volumes (p < 0.002). Only overall survival (p = 0.006) was higher for investigators considered experienced after adjusting for patient age and Karnofsky Performance Scale score. CONCLUSIONS The potential efficacy of drugs delivered by CED may be severely constrained by ineffective delivery in many patients. Routine use of software algorithms and alternative catheter designs and infusion parameters may improve the efficacy of drugs delivered by CED.

Safety, Tolerability, and Tumor Response of IL4-Pseudomonas Exotoxin (NBI-3001) in Patients with Recurrent Malignant Glioma

SummaryPurpose: This was an open-label, dose-escalation trial of intratumoral administration of IL-4Pseudomonas exotoxin (NBI-3001) in patients with recurrent malignant glioma. Patients and methods: A total of 31 patients with histologically verified supratentorial grades 3 and 4 astrocytoma were studied. Of these, 25 patients were diagnosed with glioblastoma multiforme (GBM) while six were diagnosed with anaplastic astrocytoma. Patients were over 18 years of age and had Karnofsky performance scores ≥60. Patients were assigned to one of four dose groups in a dose-escalation fashion: 6 µg/ml × 40 ml, 9 µg/ml × 40 ml, 15 µg/ml × 40 ml, or 9 µg/ml × 100 ml of NBI-3001 administered via convection-enhanced delivery intratumorally using stereotactically placed catheters. Patients were followed with serial MRI scans and clinical assessments every four weeks for the first 16 weeks and then every eight weeks until week 26. Results: No drug-related systemic toxicity, as evident by lack of hematological or serum chemical changes, was apparent in any patients; treatment-related adverse effects were limited to the central nervous system. No deaths were attributable to treatment. Drug-related grade 3 or 4 toxicity was seen in 39% of patients in all dose groups and 22% of patients at the maximum tolerated dose of 6 µg/ml × 40 ml. The overall median survival was 8.2 months with a median survival of 5.8 months for the GBM patients. Six-month survival was 52% and 48%, respectively. Gadolinium-enhanced magnetic resonance imaging of the brain showed areas of decreased signal intensity within the tumor consistent with tumor necrosis following treatment in many patients. Conclusions: NBI-3001 appears to have an acceptable safety and toxicity profile when administered intratumorally in patients with recurrent malignant glioma.

An accurate and ergonomic method of registration for image-guided neurosurgery

Abstract We have developed a system for accurately and conveniently achieving surgical registration for image-guided neurosurgery, based on alignment and matching of patient forehead contours. The system consists of a contour digitizer that its used in the operating room to acquire patient contours, editing software for extracting contours from patient image data sets, and a contour-match algorithm for aligning the two contours and performing data set registration. Initial tests of the individual portions of the system have found each to be robust; we are in the process of refining the design of the optical digitizer in order to further automate the procedure as well as provide increased accuracy.

Cerebrospinal fluid endothelin-1 and endothelin-3 levels in normal and neurosurgical patients: A clinical study and literature review

Endothelins are a family of structurally related, potent, long-lasting vasoconstrictor peptides. There are no established normal human levels of endothelin-1 or endothelin-3 in the cerebrospinal fluid. We measured cerebrospinal fluid endothelin-1 and endothelin-3 levels in five groups of patients: normal controls, patients with subarachnoid hemorrhage and cerebral vasospasm, patients with severe head injuries, patients undergoing temporal lobectomy for intractable epilepsy, and a patient with a gunshot injury to the thoracic spine. Endothelin-3 levels were significantly elevated in patients with subarachnoid hemorrhage and may participate in cerebral vasospasm and subsequent neurologic deterioration.

Transcranial Doppler ultrasound following closed head injury: Vasospasm or vasoparalysis?

Nine patients suffering closed head injury were studied using transcranial Doppler ultrasound recording of the basal cerebral arteries. On admission, six patients had Glasgow Coma Scores of 7 or less, while three had initial scores of 8-10. Eight of the nine patients (82%) developed abnormally high mean velocities (greater than or equal to 110 cm/s) in one or more vessels. The onset, duration, and amplitude of the altered flow velocities were somewhat different from those that are seen with vasospasm after aneurysmal subarachnoid hemorrhage, which tend to occur later. Cerebral angiography in one of the study patients confirmed the presence of vasospasm. Multivariate regression analysis showed a definite correlation between the velocities recorded, even when abnormally elevated, and concurrent pH and PCO2 measurements (p = 0.01, R2 = 0.23). Although these results suggest that the cerebral vasculature retains its vasoreactivity following head injury, arguing against vasoparalysis, inconsistencies found in some of the patients lead us to think that both vasospasm and vasoparalysis may occur following head trauma but that they may have different temporal profiles.

Intracranial neurosurgery guided by functional imaging

Neurosurgery on eloquent cortex entails important risks of functional deficits complicating aggressive lesion resection. In this study, advanced biomagnetic functional imaging of somatosensory and motor cortex combined with surface rendered magnetic resonance imaging displays including vascular anatomy were used in conjunction with a new nonintrusive intraoperative guided instrumentation system to resect a tumor in eloquent cortex. Intraoperative verification of the accuracy of pre-operative motor localization demonstrated highly accurate results comparing direct stimulation and noninvasive presurgical mapping. The applicability of surface rendered combined functional and anatomic maps of cortex is directly evident on comparison of preoperative computer images and intraoperative pictures. This combination of new technologies has a significant potential for reduced risk and improved outcome in neurosurgery of eloquent cortex.