Adding dynamics to the Human Connectome Project with MEG.

The Human Connectome Project (HCP) seeks to map the structural and functional connections between network elements in the human brain. Magnetoencephalography (MEG) provides a temporally rich source of information on brain network dynamics and represents one source of functional connectivity data to be provided by the HCP. High quality MEG data will be collected from 50 twin pairs both in the resting state and during performance of motor, working memory and language tasks. These data will be available to the general community. Additionally, using the cortical parcellation scheme common to all imaging modalities, the HCP will provide processing pipelines for calculating connection matrices as a function of time and frequency. Together with structural and functional data generated using magnetic resonance imaging methods, these data represent a unique opportunity to investigate brain network connectivity in a large cohort of normal adult human subjects. The analysis pipeline software and the dynamic connectivity matrices that it generates will all be made freely available to the research community.

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.

Predictive value of hippocampal MR imaging-based high-dimensional mapping in mesial temporal epilepsy: preliminary findings.

BACKGROUND AND PURPOSE: We objectively assessed surface structural changes of the hippocampus in mesial temporal sclerosis (MTS) and assessed the ability of large-deformation high-dimensional mapping (HDM-LD) to demonstrate hippocampal surface symmetry and predict group classification of MTS in right and left MTS groups compared with control subjects. METHODS: Using eigenvector field analysis of HDM-LD segmentations of the hippocampus, we compared the symmetry of changes in the right and left MTS groups with a group of 15 matched controls. To assess the ability of HDM-LD to predict group classification, eigenvectors were selected by a logistic regression procedure when comparing the MTS group with control subjects. RESULTS: Multivariate analysis of variance on the coefficients from the first 9 eigenvectors accounted for 75% of the total variance between groups. The first 3 eigenvectors showed the largest differences between the control group and each of the MTS groups, but with eigenvector 2 showing the greatest difference in the MTS groups. Reconstruction of the hippocampal deformation vector fields due solely to eigenvector 2 shows symmetrical patterns in the right and left MTS groups. A "leave-one-out" (jackknife) procedure correctly predicted group classification in 14 of 15 (93.3%) left MTS subjects and all 15 right MTS subjects. CONCLUSION: Analysis of principal dimensions of hippocampal shape change suggests that MTS, after accounting for normal right-left asymmetries, affects the right and left hippocampal surface structure very symmetrically. Preliminary analysis using HDM-LD shows it can predict group classification of MTS and control hippocampi in this well-defined population of patients with MTS and mesial temporal lobe epilepsy (MTLE).

Local convection enhanced delivery of IL4-Pseudomonas exotoxin (NBI-3001) for treatment of patients with recurrent malignant glioma.

PURPOSE: This was an open-label, dose-escalation trial of intratumoral administration of IL-4 Pseudomonas Exotoxin (NBI-3001) in patients with recurrent malignant glioma. PATIENTS AND METHODS: A total of 31 patients with histologically verified supratentorial grade 3 and 4 astrocytoma were studied. Of these, twenty-five patients were diagnosed with glioblastoma multiforme (GBM) while six were diagnosed with anaplastic astrocytoma (AA). Patients were over 18 years of age and had Karnofsky performance scores > or = 60. Patients were assigned to one of four dose groups in a dose-escalation fashion: 6 microg/ml x 40 ml, 9 microg/ml x 40 ml, 15 microg/ml x 40 ml, or 9 microg/ml x 100 ml of NBI-3001 administered intratumorally via 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 microg/ml x 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.

New strategy for the cultivation of microalgae using microencapsulation.

The four species of microalgae (Dunaliella bardawil, Chlorella minutissima, Pavlova lutheri and Haematococcus pluvialis) were immobilized in Ca-alginate capsules as a basic study for the development of the economic cultivation process. Under the batch culture of aerobic conditions, the thickness of the capsule membrane and CO2 supply did not affect the growth of the immobilized microalgae, Dunaliella bardawil. Cell concentration of immobilized microalgae in the capsule was higher than those of immobilized microalgae in beads and free cells. The cell concentrations of microencapsulated Dunaliella bardawil and Haematococcus pluvialis were five times greater than that of free cells. Based on these results, microencapsulation for the culture of microalgae was an effective method for the high-density cultivation. In comparison to the immobilized cultivation on the bioreactor type, it was more effective for the cultivation in the bubble column bioreactor than that in the stirrer tank bioreactor.

Comparison of Scientific Calipers and Computer-Enabled CT Review for the Measurement of Skull Base and Craniomaxillofacial Dimensions.

Traditionally, cadaveric studies and plain-film cephalometrics provided information about craniomaxillofacial proportions and measurements; however, advances in computer technology now permit software-based review of computed tomography (CT)-based models. Distances between standardized anatomic points were measured on five dried human skulls with standard scientific calipers (Geneva Gauge, Albany, NY) and through computer workstation (StealthStation 2.6.4, Medtronic Surgical Navigation Technology, Louisville, CO) review of corresponding CT scans. Differences in measurements between the caliper and CT model were not statistically significant for each parameter. Measurements obtained by computer workstation CT review of the cranial skull base are an accurate representation of actual bony anatomy. Such information has important implications for surgical planning and clinical research.

Three-dimensional localization: from image-guided surgery to information-guided therapy.

Image-guided surgery has become the standard of care for intracranial procedures. However, significant development is required before the benefits of this technology are brought to the majority of patients undergoing surgery. This article categorizes the areas wherein progress is needed, and indicates recent advances that may form the basis for the broad acceptance of this exciting technology. Emphasis is placed on a technique whereby preoperative imaging can be updated using low-resolution intraoperative imaging to reflect changes in anatomy caused by surgery, and on transforming image-guided surgery to information-guided therapy, in which diverse sources can be brought to bear at the time of greatest possible benefit, when the patient's anatomy is exposed for therapeutic intervention.

Automated rejection of contaminated surface measurements for improved surface registration in image guided neurosurgery.

Most image guided Neurosurgery employs adhesively mounted external fiducials for registration of medical images to the surgical workspace. Due to high logistical costs associated with these artificial landmarks, we strive to eliminate the need for these markers. At our institution, we developed a handheld laser stripe triangulation device to capture the surface contours of the patient's head while oriented for surgery. Anatomical surface registration algorithms rely on the assumption that the patient's anatomy bears the same geometry as the 3D model of the patient constructed from the imaging modality employed. During the time interval from which the patient is imaged and placed in the Mayfield head clamp in the operating room, the skin of the head bulges at the pinsite and the skull fixation equipment itself optically interferes with the image capture laser. We have developed software to reject points belonging to objects of known geometry while calculating the registration. During the course of development of the laser scanning unit, we have acquired surface contours of 13 patients and 2 cadavers. Initial analysis revealed that this automated rejection of points improved the registrations in all cases, but the accuracy of the fiducial method was not surpassed. Only points belonging to the offending instrument are removed. Skin bulges caused by the clamps and instruments remain in the data. We anticipate that careful removal of the points in these skin bulges will yield registrations that at least match the accuracy of the fiducial method.

Mesial temporal sclerosis and temporal lobe epilepsy: MR imaging deformation-based segmentation of the hippocampus in five patients.

In five patients with mesial temporal sclerosis, the authors verified the precision and reproducibility of hippocampal segmentations with deformation-based magnetic resonance (MR) imaging. The overall percentage overlap between automated segmentations was 92.8% (SD, 3.5%), between manual segmentations was 73.1% (SD, 9.5%), and between automated and manual segmentations was 74.8% (SD, 10.3%). Deformation-based hippocampal segmentations provided a precise method of hippocampal volume measurement in this patient population.

Shape analysis of hippocampal surface structure in patients with unilateral mesial temporal sclerosis.

Structural hippocampal magnetic resonance (MR) imaging-based analysis is helpful in the diagnosis and treatment of mesial temporal epileptic seizures. Computational anatomic techniques provide a framework for objective assessment of three-dimensional hippocampal structure. We applied a previously validated technique of deformation-based hippocampal segmentations in 20 subjects with documented unilateral mesial temporal sclerosis (MTS) and temporal lobe epilepsy. Using composite images, we then measured shape differences between the epileptogenic, smaller hippocampus, and contralateral hippocampus. Final shape differences were projected on the contralateral "normal" side. We calculated results for the left MTS group (10 patients) and right MTS group (10 patients) separately. Both groups showed similar regions of maximal inward deformation in the affected hippocampus, which were the medial and lateral aspect of the head, and posterior aspect of the tail. These results suggest that there are specific three-dimensional patterns of volume loss in patients with mesial temporal epilepsy.

Magnetic resonance imaging deformation-based segmentation of the hippocampus in patients with mesial temporal sclerosis and temporal lobe epilepsy.

We compared manual and automated segmentations of the hippocampus in patients with mesial temporal sclerosis. This comparison showed good precision of the deformation-based automated segmentations.

Acellular dermal allograft for sellar reconstruction after transsphenoidal hypophysectomy.

Obliteration of the sphenoid sinus using fat is often used after transsphenoidal hypophysectomy. The morbidity of this approach includes donor site complications, fat necrosis, and delayed mucocele formation. As obliteration with fat is intended to prevent cerebrospinal fluid (CSF) leakage, an alternative for this technique would be techniques used for CSF rhinorrhea repair. Instead of sinus obliteration, these defects are repaired with fascial autografts, which are unfortunately associated with donor site complications. To avoid sinus obliteration and donor site complications, we have reconstructed the sella with acellular dermal allograft in lieu of sinus obliteration. Transsphenoidal hypophysectomy was performed under combined microscopic and endoscopic visualization. For closure, the sellar anterior wall was reconstructed with acellular dermal allograft, septal cartilage/bone autograft, and fibrin glue. The sinus mucosa was then draped over the reconstruction and held in place with microfibrillar collagen hemostat slurry. The sphenoid sinus was not obliterated. Postoperatively, all patients underwent serial nasal endoscopy. Thirteen patients underwent the procedure as described for removal of pituitary adenoma. Postoperative discomfort and pain were minimal. Intraoperative CSF leaks were identified in five patients; none of these patients experienced a postoperative CSF leak. The microfibrillar collagen hemostat was cleared by sphenoid mucociliary clearance. One patient developed acute sphenoid sinusitis several weeks after surgery; this patient did not develop meningitis. One postoperative CSF leak occurred in an obese patient, in whom an intraoperative CSF leak was not identified; this leak resolved with bedrest and delayed lumbar drainage alone. Sellar reconstruction with acellular dermal allograft may eliminate the need for sphenoid sinus obliteration after transsphenoidal hypophysectomy. Acellular dermal allograft sellar reconstruction ultimately provides for an aerated, functioning sphenoid sinus without increased CSF leak risk or potential donor site morbidity.

Triple-technique (MR imaging, single-photon emission CT, and CT) coregistration for image-guided surgical evaluation of patients with intractable epilepsy.

Ictal and interictal single-photon emission CT (SPECT) play an increasingly important role in the surgical evaluation of patients with epilepsy. We present a method of coregistration of MR, SPECT, and CT images to correlate structural data (MR imaging), blood flow changes (SPECT), and location of subdural electrodes (CT) for patients undergoing image-guided surgical treatment of epilepsy. MR-SPECT root mean square (rms) mismatch distances were 2.1 to 2.5 mm, and MR-CT rms mismatch distances were 1.0 to 4.5 mm. Coregistration assisted in image-guided placement of subdural electrodes and in surgical resection of the suspected epileptogenic focus.

Three-dimensional collagen gel culture promotes osteoblastic phenotype in bone marrow derived cells.

When calvarial cells or osteogenic cell lines were cultured in type I collagen gel, calcification was observed early and diffusely compared to monolayer culture. Bone marrow derived cells were cultured in three-dimensional type I collagen gel to investigate whether the cells can differentiate into osteogenic cells. In terms of efficient induction of osteogenic differentiation, we compared collagen gel culture to type I collagen coated dish culture and collagen-free plastic dish culture by morphology, alkaline phosphatase activity, and mRNA expression for type I collagen and osteopontin. Bone marrow derived primary cells formed colonies consisting of fibroblastic cells positively expressing alkaline phosphatase activity. Mineral deposition was observed in both primary and the 3rd passaged cells cultured in collagen gel, whereas the 3rd passaged cells on plastic dishes failed to be mineralized. Cells in collagen gel showed higher alkaline phosphatase activity than those in the other two methods suggesting that three-dimensional collagen network stimulated osteoblastic differentiation effectively. The expression level for type I collagen mRNA of the cells in collagen gel was three times higher in the 3rd passaged cells, and was slightly decreased in primary cells compared to the other two methods. The osteopontin mRNA expression of the cells in collagen gel was four times higher in the 3rd passaged cell culture but lower in primary cell cultures. These results suggested that collagen gel culture might be a useful environment for osteogenic induction of passaged cells derived from bone marrow.

Effect of recombinant human bone morphogenetic protein-2 on fracture healing in a goat tibial fracture model.

Bone morphogenetic proteins (BMPs) are considered to have important regulatory roles in skeletal embryogenesis and bone healing. Recombinant human BMPs (rhBMPs) have been shown to heal critical size defects and promote spinal fusion. We studied the effects of rhBMP-2 in an absorbable collagen sponge (ACS) on bone healing in a large animal tibial fracture model. Bilateral closed tibial fractures were created in 16 skeletally mature goats and reduced and stabilized using external fixation. In each animal, one tibia received the study device (0.86 mg of rhBMP-2/ACS or buffer/ACS), and the contralateral fracture served as control. The device was implanted as a folded onlay or wrapped circumferentially around the fracture. Six weeks following fracture, the animals were sacrificed and the tibiae harvested for torsional testing and histomorphologic evaluation. Radiographs indicated increased callus at 3 weeks in the rhBMP-2/ACS treated tibiae. At 6 weeks, the rhBMP-2/ACS wrapped fractures had superior radiographic healing scores compared with buffer groups and controls. The rhBMP-2/ACS produced a significant increase in torsional toughness (p = 0.02), and trends of increased torsional strength and stiffness (p = 0.09) compared with fracture controls. The device placed in a wrapped fashion around the fracture produced significantly tougher callus (p = 0.02) compared with the onlay application. Total callus new bone volume was significantly increased (p = 0.02) in the rhBMP-2/ACS fractures compared with buffer groups and controls regardless of the method of device application. The rhBMP-2/ACS did not alter the timing of onset of periosteal/endosteal callus formation compared with controls. Neither the mineral apposition rates nor bone formation rates were affected by rhBMP-2/ACS treatment. The increased callus volume associated with rhBMP-2 treatment produced only moderate increases in strength and stiffness.

Treatment of acute fractures with a collagen-calcium phosphate graft material. A randomized clinical trial.

A prospective, randomized clinical trial was conducted concurrently at eighteen medical centers in order to compare the safety and efficacy of two types of graft material for the treatment of fractures of long bones: autogenous bone graft obtained from the iliac crest, and a composite material composed of purified bovine collagen, a biphasic calcium-phosphate ceramic, and autogenous marrow. Two hundred and thirteen patients (249 fractures) were followed for a minimum of twenty-four months to monitor healing and the occurrence of complications. We observed no significant differences between the two treatment groups with respect to rates of union (p = 0.94, power = 88 per cent) or functional measures (use of analgesics, pain with activities of daily living, and impairment in activities of daily living; p > 0.10). The prevalence of complications did not differ between the treatment groups except for the rate of infection, which was higher in the patients who were managed with an autogenous graft. Twelve patients who were managed with a synthetic graft had a positive antibody titer to bovine collagen; seven of them agreed to have intradermal challenge with bovine collagen. One patient had a positive skin response to the challenge but had no complications with regard to healing of the fracture. We concluded that, for traumatic defects of long bones that necessitate grafting, use of the composite graft material appears to be justified on the grounds of safety, efficacy, and elimination of the increased operative time and risk involved in obtaining an autogenous graft from the iliac crest.

Polyglycolide bioabsorbable screws in the treatment of ankle fractures.

Twenty-one patients with unstable medial malleolar, bimalleolar, or trimalleolar ankle fractures underwent open reduction and internal fixation of the medial malleolus with 4.5-mm polyglycolide screws. All lateral malleolar fractures were internally fixed with standard metallic implants. Radiographic and clinical follow-up results were available on 16 of 21 patients. All fractures healed at an average of 3.4 months (range, 3-6 months), and there were no medial wound infections. Eight of 16 patients developed an inflammatory reaction to the biodegradable polyester at 3 to 4 months after implantation, including one who developed a sterile draining sinus tract. No surgical or nonsurgical treatment was required in those eight patients. We conclude that whereas polyester screws yield union rates and functional results similar to those of metallic screws in the treatment of medical malleolar fractures, the use of polyglycolide screws is associated with an unacceptable rate of inflammatory reactions.