Andrei I. Holodny

Effect of brain tumor neovasculature defined by rCBV on BOLD fMRI activation volume in the primary motor cortex.

We utilized blood oxygenation level dependent (BOLD) functional magnetic resonance imaging (fMRI) and MR perfusion imaging methods to study the influence of brain tumor neovascularity on the BOLD fMRI activation volume in the primary motor cortex (PMC). The results from 57 brain tumor cases demonstrated that, for grade IV gliomas only, decreases in the BOLD fMRI activation volumes within the ipsilateral PMC, when compared with that observed in the contralateral PMC, correlated with increases in the relative regional cerebral blood volume (rCBV) in the PMC. In addition, relative increases in the activation volumes, corresponding to decreases in the rCBV, exhibited a linear dependence on the distance between the grade IV glioma and PMC. These findings lend support to the hypothesis that decreases in the fMRI activation volumes adjacent to a GBM may, in part, be due to the increased contribution of aberrant tumor neovascularity, with the resultant de-coupling of blood flow from neuronal activity. The nature of the relationship between the resulting activation volumes and adjacent tumor characteristics is complex, but is found to be dependent on the tumor grade and type, as well as the distance of the tumor to the PMC.

Potential utility of conventional MRI signs in diagnosing pseudoprogression in glioblastoma

Objective: To examine the potential utility of conventional MRI signs in differentiating pseudoprogression (PsP) from early progression (EP). Methods: This retrospective study reviewed initial postradiotherapy MRI scans of 321 patients with glioblastoma undergoing chemotherapy and radiotherapy. A total of 93 patients were found to have new or increased enhancing mass lesions, raising the possibility of PsP. Final diagnosis of PsP or EP was established upon review of surgical specimens from a second resection or by clinical and radiologic follow-up. A total of 11 MRI signs potentially helpful in the differentiation between PsP and EP were examined on the initial post-RT MRI and were correlated with the final diagnosis through χ2 or Fisher exact test. Results: Sixty-three (67.7%) of the 93 patients had EP, of which 22 (34.9%) were diagnosed by pathology. Thirty patients (32.3%) had PsP; 6 (16.7% of the 30) were diagnosed by pathology. Subependymal enhancement was predictive for EP (p = 0.001) with 38.1% sensitivity, 93.3% specificity, and 41.8% negative predictive value. The other 10 signs had no predictive value (p = 0.06–1.0). Conclusions: Conventional MRI signs have limited utility in diagnosing PsP in patients with recently treated glioblastomas and worsening enhancing lesions. We did not find a sign with a high negative predictive value for PsP that would have been the most useful for the clinical physician. When present, subependymal spread of the enhancing lesion is a useful MRI marker in identifying EP rather than PsP.

Translocation of Broca's area to the contralateral hemisphere as the result of the growth of a left inferior frontal glioma

We report a case of a patient with a left inferior frontal glioma in whom language functional magnetic resonance imaging (fMRI) paradigms produced activation of Brocas area on the right and Wernickes area on the left. We propose that tumor invasion of the left frontal operculum led to cortical reorganization and interhemispheric transfer of Brocas area. This case emphasizes the importance of preoperative fMRI in assessing the location of eloquent cortices adjacent to a tumor and in guiding neurosurgical decision-making.

Functional magnetic resonance imaging (fMRI) changes and saliva production associated with acupuncture at LI-2 acupuncture point: a randomized controlled study

BackgroundClinical studies suggest that acupuncture can stimulate saliva production and reduce xerostomia (dry mouth). We were interested in exploring the neuronal substrates involved in such responses.MethodsIn a randomized, sham acupuncture controlled, subject blinded trial, twenty healthy volunteers received true and sham acupuncture in random order. Cortical regions that were activated or deactivated during the interventions were evaluated by functional magnetic resonance imaging (fMRI). Saliva production was also measured.ResultsUnilateral manual acupuncture stimulation at LI-2, a point commonly used in clinical practice to treat xerostomia, was associated with bilateral activation of the insula and adjacent operculum. Sham acupuncture at an adjacent site induced neither activation nor deactivation. True acupuncture induced more saliva production than sham acupuncture.ConclusionAcupuncture at LI-2 was associated with neuronal activations absent during sham acupuncture stimulation. Neuroimaging signal changes appear correlated to saliva production.

Integration of 2-hydroxyglutarate-proton magnetic resonance spectroscopy into clinical practice for disease monitoring in isocitrate dehydrogenase-mutant glioma

BACKGROUND The majority of WHO grades II and III gliomas harbor a missense mutation in the metabolic gene isocitrate dehydrogenase (IDH) and accumulate the metabolite R-2-hydroxyglutarate (R-2HG). Prior studies showed that this metabolite can be detected in vivo using proton magnetic-resonance spectroscopy (MRS), but the sensitivity of this methodology and its clinical implications are unknown. METHODS We developed an MR imaging protocol to integrate 2HG-MRS into routine clinical glioma imaging and examined its performance in 89 consecutive glioma patients. RESULTS Detection of 2-hydroxyglutarate (2HG) in IDH-mutant gliomas was closely linked to tumor volume, with sensitivity ranging from 8% for small tumors (<3.4 mL) to 91% for larger tumors (>8 mL). In patients undergoing 2HG-MRS prior to surgery, tumor levels of 2HG corresponded with tumor cellularity but not with tumor grade or mitotic index. Cytoreductive therapy resulted in a gradual decrease in 2HG levels with kinetics that closely mirrored changes in tumor volume. CONCLUSIONS Our study demonstrates that 2HG-MRS can be linked with routine MR imaging to provide quantitative measurements of 2HG in glioma and may be useful as an imaging biomarker to monitor the abundance of IDH-mutant tumor cells noninvasively during glioma therapy and disease monitoring.

Isolated diffusion restriction precedes the development of enhancing tumor in a subset of patients with glioblastoma.

We know that tumor contrast enhancement is preceded by development of increased perfusion and abnormal MR spectroscopy findings. Here, the authors determined that restricted diffusion also occurs before contrast enhancement in some glioblastomas. Visibly restricted apparent diffusion coefficient was found in 32% of patients undergoing treatment and 85% of those with nonenhancing low-ADC lesions went on to develop contrast enhancement at the site of restricted diffusion, implying tumor progression regardless of type of therapy. Conclusion: In a subset of patients with glioblastoma, development of a new focus of restricted diffusion during treatment may precede the development of new enhancing tumor. BACKGROUND AND PURPOSE: Most response criteria for patients with glioblastoma rely on increases in the contrast enhancing abnormality to determine tumor progression. Our aim was to determine retrospectively in patients with glioblastoma whether diffusion restriction can predict the development of new enhancing mass lesions. MATERIALS AND METHODS: We reviewed the brain MR imaging scans (including DWI and ADC maps) of 208 patients with glioblastoma. Patients with restricted diffusion in or adjacent to the tumor were identified, with further analysis only performed on those patients with low-ADC lesions without enhancement. These patients were followed to determine if new concordant enhancement developed at the site of the low-ADC lesion. A Wilcoxon signed rank test, competing risk analysis, and Kaplan-Meier curves were used to compare the mean drop in ADC values, assess enhancement-free survival, and determine overall survival, respectively. RESULTS: In 67 of the 208 patients (32.2%), visibly detectable restricted diffusion was seen during treatment. The study cohort was formed by the 27 patients with low-ADC lesions and no corresponding enhancement. Twenty-three (85.2%) patients developed gadolinium-enhancing tumor at the site of restricted diffusion a median of 3.0 months later (95% CI, 2.6–4.1 months). The mean decrease in ADC was 22.9% from baseline (P < .001). The 3-month enhancement-free survival probability was 0.481 (95% CI, 0.288–0.675). The 12-month overall survival probability was 0.521 (95% CI, 0.345–0.788). Restricted diffusion predicted enhancement regardless of antiangiogenic therapy with bevacizumab. CONCLUSIONS: In a subset of patients with glioblastoma, development of a new focus of restricted diffusion during treatment may precede the development of new enhancing tumor.

Assessment of the Language Laterality Index in Patients with Brain Tumor Using Functional MR Imaging: Effects of Thresholding, Task Selection, and Prior Surgery

BACKGROUND AND PURPOSE: Functional MR imaging (fMRI) is used to determine preoperatively the laterality of cortical language representation along with the relationship of language areas to adjacent brain tumors. The purpose of this study was to determine whether changing the statistical threshold for different language tasks influences the language laterality index (LI) for a group of controls, patients with tumor without prior surgery, and patients with tumor and prior surgery. MATERIALS AND METHODS: Seven controls, 9 patients with tumor without prior surgery, and 4 patients with tumor and prior surgery performed verb-generation, phonemic fluency, and semantic fluency language tasks during fMRI. Interhemispheric activation differences between the left and right Broca regions of interest were determined by calculating language LIs. LIs were compared within each group, between groups, and between language tasks. Intraoperative electrocortical mapping or the presence of aphasia during postoperative neurology examinations or both were used as ground truth. RESULTS: The language LI varied as a result of statistical thresholding, presence of tumor, prior surgery, and language task. Although patients and controls followed a similar shape in the LI curve, there was no optimal P value for determining the LI. Three patients demonstrated a shift in the LI between hemispheres as a function of statistical threshold. Verb generation was the least variable task both between tasks and across groups. CONCLUSION: For preoperative patients with tumor, the LI should be examined across a spectrum of P values and a range of tasks to ensure reliability. Our data suggest that the LI may be threshold- and task-dependent, particularly in the presence of adjacent tumor.

Functional MRI in the brain tumor patient.

Functional magnetic resonance imaging (fMRI) has been adopted almost universally by disciplines that endeavor to understand how the brain works. As basic scientists tune the technique, clinicians are increasingly able to apply brain mapping with fMRI to their clinical practice. We present here a guide to using fMRI in a clinical setting. We discuss the basic considerations of functional brain mapping in patients with brain tumors including: patient screening and training, paradigm design, data analysis and interpretation of the fMRI scans.

Proton magnetic resonance spectroscopic imaging can predict length of survival in patients with supratentorial gliomas.

OBJECTIVEWe compared the ability of proton magnetic resonance spectroscopic imaging (1H-MRSI) measures with that of standard clinicopathological measures to predict length of survival in patients with supratentorial gliomas. METHODSWe developed two sets of leave-one-out logistic regression models based on either 1) intratumoral 1H-MRSI features, including maximum values of a) choline and b) lactate-lipid, c) number of 1H-MRSI voxels with low N-acetyl group values, and d) number of 1H-MRSI voxels with high lactate-lipid values, all (a–d) of which were normalized to creatine in normal-appearing brain, or 2) standard clinicopathological features, including a) tumor histopathological grade, b) patient age, c) performance of surgical debulking, and d) tumor diagnosis (i.e., oligodendroglioma, astrocytoma). We assessed the accuracy of these two models in predicting patient survival for 6, 12, 24, and 48 months by performing receiver operating characteristic curve analysis. Cox proportional hazards analysis was performed to assess the extent to which patient survival could be explained by the above predictors. We then performed a series of leave-one-out linear multiple regression analyses to determine how well patient survival could be predicted in a continuous fashion. RESULTSThe results of using the models based on 1H-MRSI and clinicopathological features were equally good, accounting for 81 and 64% of the variability (r2) in patients’ actual survival durations. All features except number of 1H-MRSI voxels with lactate-lipid/creatine values of at least 1 were significant predictors of survival in the 1H-MRSI model. Two features (tumor grade and debulking) were found to be significant predictors in the clinicopathological model. Survival as a continuous variable was predicted accurately on the basis of the 1H-MRSI data (r = 0.77, P < 0.001; median prediction error, 1.7 mo). CONCLUSIONOur results suggest that appropriate analysis of 1H-MRSI data can predict survival in patients with supratentorial gliomas at least as accurately as data derived from more invasive clinicopathological features.

Diffusion Tensor Tractography of the Motor White Matter Tracts in Man: Current Controversies and Future Directions

The anatomy of the brain is extremely complex, and certain, even large structures, such as the corticospinal tract (CST), remain poorly understood. Diffusion tractography provides an opportunity to explore the white matter tracts in a fundamentally new way. In the current paper, we show how this technique has already added to our understanding of the anatomy of the CST. We also explore the future projects involving diffusion tractography of the motor white matter tracts that will advance this method and further our understanding of brain anatomy.