Songbai Ji

Quantitative fluorescence in intracranial tumor: implications for ALA-induced PpIX as an intraoperative biomarker.

OBJECT Accurate discrimination between tumor and normal tissue is crucial for optimal tumor resection. Qualitative fluorescence of protoporphyrin IX (PpIX), synthesized endogenously following δ-aminolevulinic acid (ALA) administration, has been used for this purpose in high-grade glioma (HGG). The authors show that diagnostically significant but visually imperceptible concentrations of PpIX can be quantitatively measured in vivo and used to discriminate normal from neoplastic brain tissue across a range of tumor histologies. METHODS The authors studied 14 patients with diagnoses of low-grade glioma (LGG), HGG, meningioma, and metastasis under an institutional review board-approved protocol for fluorescence-guided resection. The primary aim of the study was to compare the diagnostic capabilities of a highly sensitive, spectrally resolved quantitative fluorescence approach to conventional fluorescence imaging for detection of neoplastic tissue in vivo. RESULTS A significant difference in the quantitative measurements of PpIX concentration occurred in all tumor groups compared with normal brain tissue. Receiver operating characteristic (ROC) curve analysis of PpIX concentration as a diagnostic variable for detection of neoplastic tissue yielded a classification efficiency of 87% (AUC = 0.95, specificity = 92%, sensitivity = 84%) compared with 66% (AUC = 0.73, specificity = 100%, sensitivity = 47%) for conventional fluorescence imaging (p < 0.0001). More than 81% (57 of 70) of the quantitative fluorescence measurements that were below the threshold of the surgeons visual perception were classified correctly in an analysis of all tumors. CONCLUSIONS These findings are clinically profound because they demonstrate that ALA-induced PpIX is a targeting biomarker for a variety of intracranial tumors beyond HGGs. This study is the first to measure quantitative ALA-induced PpIX concentrations in vivo, and the results have broad implications for guidance during resection of intracranial tumors.

Coregistered fluorescence-enhanced tumor resection of malignant glioma: relationships between δ-aminolevulinic acid–induced protoporphyrin IX fluorescence, magnetic resonance imaging enhancement, and neuropathological parameters: Clinical article

OBJECT The aim of this study was to investigate the relationships between intraoperative fluorescence, features on MR imaging, and neuropathological parameters in 11 cases of newly diagnosed glioblastoma multiforme (GBM) treated using protoporphyrin IX (PpIX) fluorescence-guided resection. METHODS In 11 patients with a newly diagnosed GBM, δ-aminolevulinic acid (ALA) was administered to enhance endogenous synthesis of the fluorophore PpIX. The patients then underwent fluorescence-guided resection, coregistered with conventional neuronavigational image guidance. Biopsy specimens were collected at different times during surgery and assigned a fluorescence level of 0-3 (0, no fluorescence; 1, low fluorescence; 2, moderate fluorescence; or 3, high fluorescence). Contrast enhancement on MR imaging was quantified using two image metrics: 1) Gd-enhanced signal intensity (GdE) on T1-weighted subtraction MR image volumes, and 2) normalized contrast ratios (nCRs) in T1-weighted, postGd-injection MR image volumes for each biopsy specimen, using the biopsy-specific image-space coordinate transformation provided by the navigation system. Subsequently, each GdE and nCR value was grouped into one of two fluorescence categories, defined by its corresponding biopsy specimen fluorescence assessment as negative fluorescence (fluorescence level 0) or positive fluorescence (fluorescence level 1, 2, or 3). A single neuropathologist analyzed the H & E-stained tissue slides of each biopsy specimen and measured three neuropathological parameters: 1) histopathological score (0-IV); 2) tumor burden score (0-III); and 3) necrotic burden score (0-III). RESULTS Mixed-model analyses with random effects for individuals show a highly statistically significant difference between fluorescing and nonfluorescing tissue in GdE (mean difference 8.33, p = 0.018) and nCRs (mean difference 5.15, p < 0.001). An analysis of association demonstrated a significant relationship between the levels of intraoperative fluorescence and histopathological score (χ(2) = 58.8, p < 0.001), between fluorescence levels and tumor burden (χ(2) = 42.7, p < 0.001), and between fluorescence levels and necrotic burden (χ(2) = 30.9, p < 0.001). The corresponding Spearman rank correlation coefficients were 0.51 (p < 0.001) for fluorescence and histopathological score, and 0.49 (p < 0.001) for fluorescence and tumor burden, suggesting a strongly positive relationship for each of these variables. CONCLUSIONS These results demonstrate a significant relationship between contrast enhancement on preoperative MR imaging and observable intraoperative PpIX fluorescence. The finding that preoperative MR image signatures are predictive of intraoperative PpIX fluorescence is of practical importance for identifying candidates for the procedure. Furthermore, this study provides evidence that a strong relationship exists between tumor aggressiveness and the degree of tissue fluorescence that is observable intraoperatively, and that observable fluorescence has an excellent positive predictive value but a low negative predictive value.

Mutual-information-based image to patient re-registration using intraoperative ultrasound in image-guided neurosurgery

An image-based re-registration scheme has been developed and evaluated that uses fiducial registration as a starting point to maximize the normalized mutual information (nMI) between intraoperative ultrasound (iUS) and preoperative magnetic resonance images (pMR). We show that this scheme significantly (p<0.001) reduces tumor boundary misalignment between iUS pre-durotomy and pMR from an average of 2.5 mm to 1.0 mm in six resection surgeries. The corrected tumor alignment before dural opening provides a more accurate reference for assessing subsequent intraoperative tumor displacement, which is important for brain shift compensation as surgery progresses. In addition, we report the translational and rotational capture ranges necessary for successful convergence of the nMI registration technique (5.9 mm and 5.2 deg, respectively). The proposed scheme is automatic, sufficiently robust, and computationally efficient (<2 min), and holds promise for routine clinical use in the operating room during image-guided neurosurgical procedures.

Glioblastoma Multiforme Treatment with Clinical Trials for Surgical Resection (Aminolevulinic Acid)

5-Aminolevulinic acid (5-ALA)-induced tumor fluorescence can be used to identify tissue for resection using an adapted operating microscope. A multi-institutional clinical trial comparing fluorescence-guided versus white light tumor resection reported significant improvement in completeness of resection and 6-month progression-free survival. The degree of 5-ALA-induced fluorescence correlates with histopathologic grade of tumor, degree of tumor cell infiltration, and proliferation indices. Quantitative methodologies for assessment of tissue fluorescence have significantly improved the ability to detect tumor tissue and intraoperative diagnostic performance. These developments extend the applicability of this technology to additional tumor histologies and provide the rationale for further instrumentation development.

Estimation of brain deformation for volumetric image updating in protoporphyrin IX fluorescence-guided resection.

Introduction: Fluorescence-guided resection (FGR) of brain tumors is an intuitive, practical and emerging technology for visually delineating neoplastic tissue exposed intraoperatively. Image guidance is the standard technique for producing 3-dimensional spatially coregistered information for surgical decision making. Both technologies together are synergistic: the former detects surface fluorescence as a biomarker of the current surgical margin while the latter shows coregistered volumetric neuroanatomy but can be degraded by intraoperative brain shift. We present the implementation of deformation modeling for brain shift compensation in protoporphyrin IX FGR, integrating these two sources of information for maximum surgical benefit. Methods: Two patients underwent FGR coregistered with conventional image guidance. Histopathological analysis, intraoperative fluorescence and image space coordinates were recorded for biopsy specimens acquired during surgery. A biomechanical brain deformation model driven by intraoperative ultrasound data was used to generate updated MR images. Results: Combined use of fluorescence signatures and updated MR image information showed substantially improved accuracy compared to fluorescence or the original (i.e., nonupdated) MR images, detecting only true positives and true negatives, and no instances of false positives or false negatives. Conclusion: Implementation of brain deformation modeling in FGR shows promise for increasing the accuracy of neurosurgical guidance in the delineation and resection of brain tumors.

Cortical surface shift estimation using stereovision and optical flow motion tracking via projection image registration.

Stereovision is an important intraoperative imaging technique that captures the exposed parenchymal surface noninvasively during open cranial surgery. Estimating cortical surface shift efficiently and accurately is critical to compensate for brain deformation in the operating room (OR). In this study, we present an automatic and robust registration technique based on optical flow (OF) motion tracking to compensate for cortical surface displacement throughout surgery. Stereo images of the cortical surface were acquired at multiple time points after dural opening to reconstruct three-dimensional (3D) texture intensity-encoded cortical surfaces. A local coordinate system was established with its z-axis parallel to the average surface normal direction of the reconstructed cortical surface immediately after dural opening in order to produce two-dimensional (2D) projection images. A dense displacement field between the two projection images was determined directly from OF motion tracking without the need for feature identification or tracking. The starting and end points of the displacement vectors on the two cortical surfaces were then obtained following spatial mapping inversion to produce the full 3D displacement of the exposed cortical surface. We evaluated the technique with images obtained from digital phantoms and 18 surgical cases - 10 of which involved independent measurements of feature locations acquired with a tracked stylus for accuracy comparisons, and 8 others of which 4 involved stereo image acquisitions at three or more time points during surgery to illustrate utility throughout a procedure. Results from the digital phantom images were very accurate (0.05 pixels). In the 10 surgical cases with independently digitized point locations, the average agreement between feature coordinates derived from the cortical surface reconstructions was 1.7-2.1mm relative to those determined with the tracked stylus probe. The agreement in feature displacement tracking was also comparable to tracked probe data (difference in displacement magnitude was <1mm on average). The average magnitude of cortical surface displacement was 7.9 ± 5.7 mm (range 0.3-24.4 mm) in all patient cases with the displacement components along gravity being 5.2 ± 6.0 mm relative to the lateral movement of 2.4 ± 1.6 mm. Thus, our technique appears to be sufficiently accurate and computationally efficiency (typically ∼15 s), for applications in the OR.

Brain–skull contact boundary conditions in an inverse computational deformation model

Biomechanical models simulating brain motion under loading and boundary conditions in the operating room (OR) are gaining attention as alternatives for brain shift compensation during open cranial neurosurgeries. Although the significance of brain-skull boundary conditions (BCs) in these models has been explored in dynamic simulations, it has not been fully investigated in models representing the quasi-static brain motion that prevails during neurosurgery. In this study, we extend the application of a brain-skull contact BC by incorporating it into an inversion estimation scheme for the deformation field using the steepest gradient descent (SGD) framework. The technique allows parenchymal surface motion normal to the skull while maintaining stress-free BCs at the craniotomy and minimizing the effect of measurement noise. Application of the algorithm in five clinical cases using sparse data generated at the tumor boundary confirms the significance of brain-skull BCs in the model response. Specifically, the results demonstrate that the contact BC enhances model flexibility and achieves improved or comparable performance at the tumor boundary (recovering about 85% of the deformation) relative to that obtained when normal motion of the parenchymal surface is not allowed. It also significantly improves model estimation accuracy at the craniotomy (1.6mm on average), especially when the normal motion is large. The importance of the method is that model performance significantly improves when brain-skull contact influences the deformation field but does not degrade when the contact is less critical and simpler BCs would suffice. The computational cost of the technique is currently 3.9 min on average, but may be further reduced by applying an iterative solver to the linear systems of equations involved and/or by local refinement of the mesh in regions of interest.

Stereovision to MR image registration for cortical surface displacement mapping to enhance image‐guided neurosurgery

PURPOSE A surface registration method is presented to align intraoperative stereovision (iSV) with preoperative magnetic resonance (pMR) images, which utilizes both geometry and texture information to extract tissue displacements as part of the overall process of compensating for intraoperative brain deformation in order to maintain accurate neuronavigational image guidance during surgery. METHODS A sum-of-squared-difference rigid image registration was first executed to detect lateral shift of the cortical surface and was followed by a mutual-information-based block matching method to detect local nonrigid deformation caused by distention or collapse of the cortical surface. Ten (N = 10) surgical cases were evaluated in which an independent point measurement of a dominant cortical surface feature location was recorded with a tracked stylus in each case and compared to its surface-registered counterpart. The full three-dimensional (3D) displacement field was also extracted to drive a biomechanical brain deformation model, the results of which were reconciled with the reconstructed iSV surface as another form of evaluation. RESULTS Differences between the tracked stylus coordinates of cortical surface features and their surface-registered locations were 1.94 ± 0.59 mm on average across the ten cases. When the complete displacement map derived from surface registration was utilized, the resulting images generated from mechanical model updates were consistent in terms of both geometry (1-2 mm of model misfit) and texture, and were generated with less than 10 min of computational time. Analysis of the surface-registered 3D displacements indicate that the magnitude of motion ranged from 4.03 to 9.79 mm in the ten patient cases, and the amount of lateral shift was not related statistically to the direction of gravity (p = 0.73 ≫ 0.05) or the craniotomy size (p = 0.48 ≫ 0.05) at the beginning of surgery. CONCLUSIONS The iSV-pMR surface registration method utilizes texture and geometry information to extract both global lateral shift and local nonrigid movement of the cortical surface in 3D. The results suggest small differences exist in surface-registered locations when compared to positions measured independently with a coregistered stylus and when the full iSV surface was aligned with model-updated MR. The effectiveness and efficiency of the registration method is also minimally disruptive to surgical workflow.

Brain pressure responses in translational head impact: a dimensional analysis and a further computational study.

Brain pressure responses resulting from translational head impact are typically related to focal injuries at the coup and contrecoup sites. Despite significant efforts characterizing brain pressure responses using experimental and modeling approaches, a thorough investigation of the key controlling parameters appears lacking. In this study, we identified three parameters specific and important for brain pressure responses induced by isolated linear acceleration