Brain Tumors: The Influence of Tumor Type and Routine MR Imaging Characteristics at BOLD Functional MR Imaging in the Primary Motor Gyrus.

Purpose To evaluate the effects of histologic features and anatomic magnetic resonance (MR) imaging characteristics of brain tumors on the functional MR imaging signal in the primary motor cortex (PMC), as false-negative blood oxygen level-dependent (BOLD) functional MR imaging activation can limit the accurate localization of eloquent cortices. Materials and Methods Institutional review board approval was obtained, and informed consent was waived for this HIPAA-compliant retrospective study. It comprised 63 patients referred between 2006 and 2014 for preoperative functional MR imaging localization of the Rolandic cortex. The patients had glioblastoma multiforme (GBM) (n = 20), metastasis (n = 21), or meningioma (n = 22). The volumes of functional MR imaging activation were measured during performance of a bilateral hand motor task. Ratios of functional MR imaging activation were normalized to PMC volume. Statistical analysis was performed for the following: (a) differences between hemispheres within each histologic tumor type (paired Wilcoxon test), (b) differences across tumor types (Kruskal-Wallis and Fisher tests), (c) pairwise tests between tumor types (Mann-Whitney U test), (d) relationships between fast fluid-attenuated inversion recovery (FLAIR) data and enhancement volume with activation (Spearman rank correlation coefficient), and (e) differences in activation volumes by tumor location (Mann-Whitney U test). Results A significant interhemispheric difference was found between the activation volumes in GBMs (mean, 511.43 voxels ± 307.73 [standard deviation] and 330.78 voxels ± 278.95; P < .01) but not in metastases (504.68 voxels ± 220.98 and 460.22 voxels ± 276.83; P = .15) or meningiomas (424.07 voxels ± 247.58 and 415.18 voxels ± 222.36; P = .85). GBMs showed significantly lower activation ratios (median, 0.49; range, 0.04-1.15) than metastases (median, 0.79; range, 0.28-1.66; P = .043) and meningiomas (median, 0.91; range, 0.52-2.05; P < .01). There was a moderate correlation with the volumes of FLAIR abnormality in metastases (ρ = -0.50) and meningiomas (ρ = -0.55). Enhancement volume (ρ = -0.11) and tumor distance from the PMC (median, 0.73 and range, 0.04-2.05 for near and median, 0.82 and range, 0.39-1.66 for far; P = .14) did not influence activation. Conclusion BOLD functional MR imaging activation in the ipsilateral PMC is influenced by tumor type and is significantly reduced in GBMs. FLAIR abnormality correlates moderately with the activation ratios in metastases and meningiomas. © RSNA, 2016 Online supplemental material is available for this article.

fMRI activation in the middle frontal gyrus as an indicator of hemispheric dominance for language in brain tumor patients: a comparison with Broca's area.

INTRODUCTION: Functional MRI (fMRI) can assess language lateralization in brain tumor patients; however, this can be limited if the primary language area-Broca's area (BA)-is affected by the tumor. We hypothesized that the middle frontal gyrus (MFG) can be used as a clinical indicator of hemispheric dominance for language during presurgical workup. METHODS: Fifty-two right-handed subjects with solitary left-hemispheric primary brain tumors were retrospectively studied. Subjects performed a verbal fluency task during fMRI. The MFG was compared to BA for fMRI voxel activation, language laterality index (LI), and the effect of tumor grade on the LI. RESULTS: Language fMRI (verbal fluency) activated more voxels in MFG than in BA (MFG = 315, BA = 216, p < 0.001). Voxel activations in the left-hemispheric MFG and BA were positively correlated (r = 0.69, p < 0.001). Mean LI in the MFG was comparable to that in BA (MFG = 0.48, BA = 0.39, p = 0.06). LIs in MFG and BA were positively correlated (r = 0.62, p < 0.001). Subjects with high-grade tumors demonstrate lower language lateralization than those with low-grade tumors in both BA and MFG (p = 0.02, p = 0.02, respectively). CONCLUSION: MFG is comparable to BA in its ability to indicate hemispheric dominance for language using a measure of verbal fluency and may be an adjunct measure in the clinical determination of language laterality for presurgical planning.

Resection of glioma in an fMRI-defined "split" Broca's area.

Gross total resection of gliomas can be limited by the involvement of tumor in eloquent areas. Moreover, lesions can impart cortical reorganization and make the precise determination of hemispheric dominance and localization of language function even more difficult. Preoperative mapping with functional magnetic resonance imaging (fMRI), intraoperative imaging modalities, and intraoperative direct cortical stimulation enable surgeons to map the functional topography of the brain in relation to the tumor and perform a safe maximal resection. In this report, we present a patient with left frontal glioma of complex morphology, wherein the tumor was enveloped by Broca's area on fMRI. Intraoperative mapping and intraoperative magnetic resonance imaging (iMRI) allowed gross total resection of the tumor with preservation of language function and illustrate the utility of multiple contemporary modalities in the surgical management of low-grade gliomas located in eloquent cortices.

Probabilistic fiber tracking of the language and motor white matter pathways of the supplementary motor area (SMA) in patients with brain tumors.

BACKGROUND AND PURPOSE: Accurate localization of anatomically and functionally separate SMA tracts is important to improve planning prior to neurosurgery. Using fMRI and probabilistic DTI techniques, we assessed the connectivity between the frontal language area (Broca's area) and the rostral pre-SMA (language SMA) and caudal SMA proper (motor SMA). MATERIALS AND METHODS: Twenty brain tumor patients completed motor and language fMRI paradigms and DTI. Peaks of functional activity in the language SMA, motor SMA and Broca's area were used to define seed regions for probabilistic tractography. RESULTS: fMRI and probabilistic tractography identified separate and unique pathways connecting the SMA to Broca's area - the language SMA pathway and the motor SMA pathway. For all subjects, the language SMA pathway had a larger number of voxels (P<0.0001) and higher connectivity (P<0.0001) to Broca's area than did the motor SMA pathway. In each patient, the number of voxels was greater in the language and motor SMA pathways than in background pathways (P<0.0001). No differences were found between patients with ipsilateral and those with contralateral tumors for either the language SMA pathway (degree of connectivity: P<0.36; number of voxels: 0.35) or the motor SMA pathway (degree of connectivity, P<0.28; number of voxels, P<0.74). CONCLUSION: Probabilistic tractography can identify unique white matter tracts that connect language SMA and motor SMA to Broca's area. The language SMA is more significantly connected to Broca's area than is the motor subdivision of the SMA proper.

Management of isocitrate dehydrogenase 1/2 mutated acute myeloid leukemia.

The emergence of next generation sequencing and widespread use of mutational profiling in acute myeloid leukemia (AML) has broadened our understanding of the heterogeneous molecular basis of the disease. Since genetic sequencing has become a standard practice, several driver mutations have been identified. Accordingly, novel targeted therapeutic agents have been developed and are now approved for the treatment of subsets of patients that carry mutations in FLT3, IDH1, and IDH2 [1, 2]. The emergence of these novel agents in AML offers patients a new modality of therapy, and shifts treatment paradigms toward individualized medicine. In this review, we outline the role of IDH mutations in malignant transformation, focus in on a novel group of targeted therapeutic agents directed toward IDH1- and IDH2-mutant AML, and explore their impact on prognosis in patients with AML.

Congenital right subclavian artery aneurysm resection in a 30-year-old woman.

Right-sided subclavian artery aneurysms (SAAs) are exceedingly rare. The most common cause of intrathoracic SAAs is atherosclerosis; however, causes can also include infection, trauma, cystic medial degeneration, Marfan syndrome, and Takayasu arteritis. Symptoms present most commonly with compression of surrounding structures, although adverse events, including rupture, thrombosis, and embolization, can also occur. We present a case of a 30-year-old woman with an asymptomatic, 15-mm, right-sided SAA, which was successfully resected with subsequent end-to-end primary anastomosis.

Patient Preparation and Paradigm Design in fMRI.

Functional magnetic resonance imaging (fMRI) is useful for localizing eloquent cortex in the brain prior to neurosurgery. Language and motor paradigms offer a wide range of tasks to test brain regions within the language and motor networks. With the help of fMRI, hemispheric language dominance can be determined. It also is possible to localize specific motor and sensory areas within the motor and sensory gyri. These findings are critical for presurgical planning. The most important factor in presurgical fMRI is patient performance. Patient interview and instruction time are crucial to ensure that patients understand and comply with the fMRI paradigm.

Trends in the Regulation of Per- and Polyfluoroalkyl Substances (PFAS): A Scoping Review.

Products containing per- and polyfluoroalkyl substances (PFAS) have been used for decades in industrial and consumer products. These compounds are persistent in the environment, bioaccumulative, and some are toxic to humans and other animals. Since the early 2000s, laws, policies, and regulations have been implemented to reduce the prevalence of PFAS in the environment and exposures to PFAS. We conducted a scoping literature review to identify how PFAS are regulated internationally, at the U.S. national level, and at the U.S. state level, as well as drivers of and challenges to implementing PFAS regulations in the U.S. This review captured peer-reviewed scientific literature (e.g., PubMed), grey literature databases (e.g., SciTech Premium Collection), Google searches, and targeted websites (e.g., state health department websites). We identified 454 relevant documents, of which 61 discussed the non-U.S. PFAS policy, 214 discussed the U.S. national-level PFAS policy, and 181 discussed the U.S. state-level PFAS policy. The drivers of and challenges to PFAS regulation were identified through qualitative analysis. The drivers of PFAS policy identified were political support for regulation, social awareness of PFAS, economic resource availability, and compelling scientific evidence. The challenges to implementing PFAS regulations were political limitations, economic challenges, unclear scientific evidence, and practical challenges. The implications for PFAS policy makers and other stakeholders are discussed.

Functional MRI in the presurgical evaluation of patients with brain tumors: characterization of the statistical threshold.

We investigated whether an optimal statistical threshold could be obtained in healthy controls and patients with brain tumors undergoing presurgical functional MRI assessment. The volumes of activation of the primary motor cortex (PMC) and the lateral prefrontal cortex (PFC) were measured for the tumor and nontumor sides in 24 patients and 8 controls using four parameters; p values ranged between 10(-2) and 10(-31). The mean r value for first activation in the PMC was higher in controls than for both the tumor and nontumor sides in patients. The mean r value for 'first activation in the noise area' and 'PMC and PFC ratio' in controls was significantly different from the mean r value for the tumor and nontumor sides in patients (p < 0.05). The magnitude of the range of r values for the nontumor side was closer to the tumor side data than to the control data. It is imperative to evaluate functional MRI data with a wide range of statistical parameters, especially in the assessment of tumor patients.

The role of the Supplementary Motor Area (SMA) in the execution of primary motor activities in brain tumor patients: functional MRI detection of time-resolved differences in the hemodynamic response.

BACKGROUND: Interpreting volume of activation maps of brain tumor patients remains difficult using blood oxygenation-level dependent (BOLD) functional magnetic resonance imaging (fMRI) methods. A time-resolved fMRI may offer an informative strategy for investigating the possibility of functional reorganization by elucidating temporal variations in the activation of cortical structures . The aim of this study is to use time-resolved fMRI to investigate potential alterations in the spatially-varying and time-dependent hemodynamic response function within the supplementary motor area (SMA) and primary motor cortex (PMC) in the presence of an adjacent brain tumor, relative to normal control subjects. MATERIAL/METHODS: Fifteen patients and eight healthy volunteers were recruited. By utilizing a brief motor paradigm that exerts a differential effect on the activation of these structures, latency differences in the hemodynamic responses of such areas may be sensitively investigated. The present study determines the utility of this approach in brain tumor patients by examining the time to peak of the BOLD hemodynamic response within the SMA and PMC. RESULTS: In patients with glial tumors involving the PMC, the activation of the SMA was delayed and approached that of the PMC with time-to-peak difference between the PMC and SMA averaging 0.2 s. This delay in SMA activation was seen in all patients with glial tumors involving the PMC. CONCLUSIONS: The results suggest that in patients with high-grade brain tumors invading the PMC , the SMA may assume a greater role in the execution of primary motor activities, in addition to its role in executive motor planning.

A vascular-task response dependency and its application in functional imaging of brain tumors.

PURPOSE: Preoperative functional MRI (fMRI) is limited by a muted BOLD response caused by abnormal vasoreactivity and resultant neurovascular uncoupling adjacent to malignant brain tumors. We propose to overcome this limitation and more accurately identify eloquent areas adjacent to brain tumors by independently assessing vasoreactivity using breath-holding and incorporating these data into the fMRI analysis. METHODS: Local vasoreactivity using a breath-holding paradigm with the same timing as the functional motor and language tasks was determined in 16 patients (9 glioblastomas, 1 anaplastic astrocytoma, 5 low grade astrocytomas, and 1 metastasis) and 6 healthy control subjects. We derived an fMRI model based on an observed vaso-task response dependency that takes into account the altered hemodynamics adjacent to brain tumors. RESULTS: In both healthy controls and brain tumor subjects, we found a statistical dependency between breath-hold and task BOLD response. In tumor subjects, activation maps that take into account this vaso-task dependency demonstrated clinically meaningful areas of activation that were not seen using the task-only analysis in about half of the cases studied. This included localization of language areas adjacent to brain tumors. CONCLUSIONS: The present preliminary results demonstrate that neurovascular uncoupling known to affect the accuracy of BOLD fMRI adjacent to brain tumors may be, at least partially, overcome by incorporating an observed vaso-task dependency in the BOLD signal analysis.

Functional Translocation of Broca's Area in a Low-Grade Left Frontal Glioma: Graph Theory Reveals the Novel, Adaptive Network Connectivity.

We describe frontal language reorganization in a 50-60 year-old right-handed patient with a low-grade left frontotemporal insular glioma. Pre-operative fMRI revealed robust activation in the left superior temporal gyrus (Wernicke Area, WA) and in the right inferior frontal gyrus (right anatomical homolog of Broca Area, BA). Intra-operative cortical stimulation of the left inferior frontal gyrus and adjacent cortices elicited no speech deficits, and gross total resection including the expected location of BA resulted in no speech impairment. We employed statistical inference methods to reconstruct the functional brain network and determined how different brain areas connect with one another. We found that the right homolog of the BA in this patient functionally connected to the same areas as the left BA in a typical healthy control. As opposed to the functional connection of the left BA in a healthy brain, the right BA did not connect directly with the left WA, but connected indirectly, mediated by the pre-Supplementary Motor Area and the Middle Frontal Gyrus. This case illustrates that pre-surgical fMRI may be used to identify atypical hemispheric language reorganization in the presence of brain tumor and that network theory opens the possibility for future insight into the neural mechanism underlying the language reorganization.

Diffusion Tensor Imaging Shows Corpus Callosum Differences between High-Grade Gliomas and Metastases.

BACKGROUND AND PURPOSE: The corpus callosum (CC) has an important role in regulating interhemispheric transfer and is thought to be instrumental in contralateral brain reorganization in patients with brain tumors, as suggested by a previous study reporting callosal differences between language dominance groups through diffusion tensor imaging (DTI) characteristics. The purpose of this study was to explore the structural differences in the CC between high-grade gliomas (HGGs) and metastatic tumors (METs) using the DTI characteristics of fractional anisotropy (FA), mean diffusivity (MD), and axial diffusivity (AD). METHODS: HGG (n = 30) and MET (n = 20) subjects with Magnetic Resonance Imaging (MRI) scans including DTI were retrospectively studied. The tumor and CC were segmented using the 3-dimensional T1-weighted scans to determine their volumes. The region of interest (ROI; mean volume of the ROI = 3,090 ± 464 mm3 ) of the body of the CC was overlaid onto the DTI parametric maps to obtain the averaged FA, MD, and AD values. RESULTS: There were significant differences in the distributions of FA and MD values between the two patient groups (mean FA for HGG/MET = .691/.646, P < .05; mean MD for HGG/MET = .894×10-3 mm 2/ second /.992×10-3 mm2 /second, P < .01), while there was no correlation between the DTI parameters and the anatomical volumes. CONCLUSION: These results suggest that there is more contralateral brain reorganization in HGG patients than MET patients and that neither the tumor nor callosal volume impact the degree of contralateral brain reorganization.

Left-lateralization of resting state functional connectivity between the presupplementary motor area and primary language areas.

An abundance of evidence points to the role of a presupplementary motor area (pre-SMA) in human language. This study explores the pre-SMA resting state connectivity network and the nature of its connections to known language areas. We tested the hypothesis that by seeding the pre-SMA, one would be able to establish language laterality to known cortical and subcortical language areas. We analyzed data from 30 right-handed healthy controls and performed the resting state functional MRI. A seed-based analysis using a manually drawn pre-SMA region of interest template was applied. Time-course signals in the pre-SMA region of interest were averaged and cross-correlated to every voxel in the brain. Results show that the pre-SMA has significant left-lateralized functional connectivity to the pars opercularis within Broca's area. Among cortical regions, pre-SMA functional connectivity is strongest to the pars opercularis In addition, pre-SMA connectivity was shown to exist to other cortical language-association regions, including Wernicke's Area, supramarginal gyri, angular gyri, and middle frontal gyri. Among subcortical areas, considerable left-lateralized functional connectivity occurs to the caudate and thalamus, whereas cerebellar subregions show right lateralization. The current study shows that the pre-SMA most strongly connects to the pars opercularis within Broca's area and that cortical connections to language areas are left lateralized among a sample of right-handed patients. We provide resting state functional MRI evidence that the functional connectivity of the pre-SMA is involved in semantic language processing and that this identification may be useful for establishing language laterality in preoperative neurosurgical planning.

Comparison of compressed sensing diffusion spectrum imaging and diffusion tensor imaging in patients with intracranial masses.

PURPOSE: To compare compressed diffusion spectrum imaging (CS-DSI) with diffusion tensor imaging (DTI) in patients with intracranial masses. We hypothesized that CS-DSI would provide superior visualization of the motor and language tracts. MATERIALS AND METHODS: We retrospectively analyzed 25 consecutive patients with intracranial masses who underwent DTI and CS-DSI for preoperative planning. Directionally-encoded anisotropy maps, and streamline hand corticospinal motor tracts and arcuate fasciculus language tracts were graded according to a 3-point scale. Tract counts, anisotropy, and lengths were also calculated. Comparisons were made using exact marginal homogeneity, McNemar's and Wilcoxon signed-rank tests. RESULTS: Readers preferred the CS-DSI over DTI anisotropy maps in 92% of the cases, and the CS-DSI over DTI tracts in 84%. The motor tracts were graded as excellent in 80% of cases for CS-DSI versus 52% for DTI; 58% of the motor tracts graded as acceptable in DTI were graded as excellent in CS-DSI (p=0.02). The language tracts were graded as excellent in 68% for CS-DSI versus none for DTI; 78% of the language tracts graded as acceptable by DTI were graded as excellent by CS-DSI (p<0.001). CS-DSI demonstrated smaller normalized mean differences than DTI for motor tract counts, anisotropy and language tract counts (p≤0.01). CONCLUSION: CS-DSI was preferred over DTI for the evaluation of motor and language white matter tracts in patients with intracranial masses. Results suggest that CS-DSI may be more useful than DTI for preoperative planning purposes.

Language Mapping Using fMRI and Direct Cortical Stimulation for Brain Tumor Surgery: The Good, the Bad, and the Questionable.

Language functional magnetic resonance imaging for neurosurgical planning is a useful but nuanced technique. Consideration of primary and secondary language anatomy, task selection, and data analysis choices all impact interpretation. In the following chapter, we consider practical considerations and nuances alike for language functional magnetic resonance imaging in the support of and comparison with the neurosurgical gold standard, direct cortical stimulation. Pitfalls and limitations are discussed.

Infiltration of the basal ganglia by brain tumors is associated with the development of co-dominant language function on fMRI.

Studies have shown that some patients with left-hemispheric brain tumors have an increased propensity for developing right-sided language support. However, the precise trigger for establishing co-dominant language function in brain tumor patients remains unknown. We analyzed the MR scans of patients with left-hemispheric tumors and either co-dominant (n=35) or left-hemisphere dominant (n=35) language function on fMRI to investigate anatomical factors influencing hemispheric language dominance. Of eleven neuroanatomical areas evaluated for tumor involvement, the basal ganglia was significantly correlated with co-dominant language function (p<0.001). Moreover, among patients whose tumors invaded the basal ganglia, those with language co-dominance performed significantly better on the Boston Naming Test, a clinical measure of aphasia, compared to their left-lateralized counterparts (56.5 versus 36.5, p=0.025). While further studies are needed to elucidate the role of the basal ganglia in establishing co-dominance, our results suggest that reactive co-dominance may afford a behavioral advantage to patients with left-hemispheric tumors.

Cortical Plasticity in the Setting of Brain Tumors.

Cortical reorganization of function due to the growth of an adjacent brain tumor has clearly been demonstrated in a number of surgically proven cases. Such cases demonstrate the unmistakable implications for the neurosurgical treatment of brain tumors, as the cortical function may not reside where one may initially suspect based solely on the anatomical magnetic resonance imaging (MRI). Consequently, preoperative localization of eloquent areas adjacent to a brain tumor is necessary, as this may demonstrate unexpected organization, which may affect the neurosurgical approach to the lesion. However, in interpreting functional MRI studies, the interpreting physician must be cognizant of artifacts, which may limit the accuracy of functional MRI in the setting of brain tumors.

Vascular Reactivity Maps in Patients with Gliomas Using Breath-Holding BOLD fMRI.

BACKGROUND AND PURPOSE: To evaluate whether breath-holding (BH) blood oxygenation level-dependent (BOLD) fMRI can quantify differences in vascular reactivity (VR), as there is a need for improved contrast mechanisms in gliomas. METHODS: 16 patients (gliomas, grade II = 5, III = 2, IV = 9) were evaluated using the BH paradigm: 4-second single deep breath followed by 16 seconds of BH and 40 seconds of regular breathing for five cycles. VR was defined as the difference in BOLD signal between the minimal signal seen at the end of the deep breath and maximal signal seen at the end of BH (peak-to-trough). VR was measured for every voxel and compared for gray versus white matter and tumor versus normal contralateral brain. VR maps were compared to the areas of enhancement and FLAIR/T2 abnormality. RESULTS: VR was significantly lower in normal white matter than gray matter (P < .05) and in tumors compared to the normal, contralateral brain (P < 0.002). The area of abnormal VR (1103 ± 659 mm²) was significantly greater (P = .019) than the enhancement (543 ± 530 mm²), but significantly smaller (P = .0011) than the FLAIR abnormality (2363 ± 1232 mm²). However, the variability in the areas of gadolinium contrast enhancement versus VR abnormality indicates that the contrast mechanism elicited by BH (caused by abnormal arteriolar smooth muscles) appears to be fundamentally different from the contrast mechanism of gadolinium enhancement (caused by the presence of "leaky" gap junctions). CONCLUSIONS: BH maps based on peak-to-trough can be used to characterize VR in brain tumors. VR maps in brain tumor patients appear to be caused by a different mechanism than gadolinium enhancement.

Corpus Callosum Diffusion and Language Lateralization in Patients with Brain Tumors: A DTI and fMRI Study.

BACKGROUND AND PURPOSE: Examining how left-hemisphere brain tumors might impact both the microstructure of the corpus callosum (CC) as measured by fractional anisotropy (FA) values in diffusion tensor imaging (DTI) as well as cortical language lateralization measured with functional MRI (fMRI). METHODS: fMRI tasks (phonemic fluency and verb generation) were performed in order to detect activation in Broca's and Wernicke's area. Twenty patients with left-hemisphere brain tumors were investigated. fMRI results were divided into left dominant (LD), right dominant (RD), or codominant (CD) for language function. DTI was performed to generate FA maps in the anterior and posterior CC. FA values were correlated with the degree of language dominance. RESULTS: Patients who were LD or RD for language in Broca's area had lower FA in the anterior CC than those who were CD for language (median for CD = .72, LD = .66, RD = .65, P < .09). Lateralized versus CD group level analysis also showed that CD patients had higher FA in the anterior CC than patients who displayed strong lateralization in either hemisphere (median for CD = .72, lateralized = .65, P < .05). CONCLUSION: Our preliminary observations indicate that the greater FA in CD patients may reflect a more directional microstructure for the CC in this region, suggesting a greater need for interhemispheric transfer of information. Because brain tumors can cause compensatory codominance, our findings may suggest a mechanism by which interhemispheric transfer is facilitated during plasticity in the presence of a tumor.