Jay J. Pillai

Nuclear Overhauser Enhancement (NOE) Imaging in the Human Brain at 7 T

Chemical exchange saturation transfer (CEST) is a magnetization transfer (MT) technique to indirectly detect pools of exchangeable protons through the water signal. CEST MRI has focused predominantly on signals from exchangeable protons downfield (higher frequency) from water in the CEST spectrum. Low power radiofrequency (RF) pulses can slowly saturate protons with minimal interference of conventional semi-solid based MT contrast (MTC). When doing so, saturation-transfer signals are revealed upfield from water, which is the frequency range of non-exchangeable aliphatic and olefinic protons. The visibility of such signals indicates the presence of a relayed transfer mechanism to the water signal, while their finite width reflects that these signals are likely due to mobile solutes. It is shown here in protein phantoms and the human brain that these signals build up slower than conventional CEST, at a rate typical for intramolecular nuclear Overhauser enhancement (NOE) effects in mobile macromolecules such as proteins/peptides and lipids. These NOE-based saturation transfer signals show a pH dependence, suggesting that this process is the inverse of the well-known exchange-relayed NOEs in high resolution NMR protein studies, thus a relayed-NOE CEST process. When studying 6 normal volunteers with a low-power pulsed CEST approach, the relayed-NOE CEST effect was about twice as large as the CEST effects downfield and larger in white matter than gray matter. This NOE contrast upfield from water provides a way to study mobile macromolecules in tissue. First data on a tumor patient show reduction in both relayed NOE and CEST amide proton signals leading to an increase in magnetization transfer ratio asymmetry, providing insight into previously reported amide proton transfer (APT) effects in tumors.

Cerebrovascular Reactivity Mapping: An Evolving Standard for Clinical Functional Imaging

SUMMARY: This review article explains the methodology of breath-hold cerebrovascular reactivity mapping, both in terms of acquisition and analysis, and reviews applications of this method to presurgical mapping, particularly with respect to blood oxygen level–dependent fMRI. Its main application in clinical fMRI is for the assessment of neurovascular uncoupling potential. Neurovascular uncoupling is potentially a major limitation of clinical fMRI, particularly in the setting of mass lesions in the brain such as brain tumors and intracranial vascular malformations that are associated with alterations in regional hemodynamics on either an acquired or congenital basis. As such, breath-hold cerebrovascular reactivity mapping constitutes an essential component of quality control analysis in clinical fMRI, particularly when performed for presurgical mapping of eloquent cortex. Exogenous carbon dioxide challenges used for cerebrovascular reactivity mapping will also be discussed, and their applications to the evaluation of cerebrovascular reserve and cerebrovascular disease will be described.

Cerebrovascular reactivity mapping in patients with low grade gliomas undergoing presurgical sensorimotor mapping with BOLD fMRI.

(i) to validate blood oxygenation level dependent (BOLD) breathhold cerebrovascular reactivity (BH CVR) mapping as an effective technique for potential detection of neurovascular uncoupling (NVU) in a cohort of patients with perirolandic low grade gliomas undergoing presurgical functional MRI (fMRI) for sensorimotor mapping, and (ii) to determine whether NVU potential, as assessed by BH CVR mapping, is prevalent in this tumor group.

Comparison of BOLD cerebrovascular reactivity mapping and DSC MR perfusion imaging for prediction of neurovascular uncoupling potential in brain tumors.

The coupling mechanism between neuronal firing and cerebrovascular dilatation can be significantly compromised in cerebral diseases, making it difficult to identify eloquent cortical areas near or within resectable lesions by using Blood Oxygen Level Dependent (BOLD) fMRI. Several metabolic and vascular factors have been considered to account for this lesion-induced neurovascular uncoupling (NVU), but no imaging gold standard exists currently for the detection of NVU. However, it is critical in clinical fMRI studies to evaluate the risk of NVU because the presence of NVU may result in false negative activation that may result in inadvertent resection of eloquent cortex, resulting in permanent postoperative neurologic deficits. Although NVU results from a disruption of one or more components of a complex cellular and chemical neurovascular coupling cascade (NCC) MR imaging is only able to evaluate the final step in this NCC involving the ultimate cerebrovascular response. Since anything that impairs cerebrovascular reactivity (CVR) will necessarily result in NVU, regardless of its effect more proximally along the NCC, we can consider mapping of CVR as a surrogate marker of NVU potential. We hypothesized that BOLD breath-hold (BH) CVR mapping can serve as a better marker of NVU potential than T2* Dynamic Susceptibility Contrast gadolinium perfusion MR imaging, because the latter is known to only reflect NVU risk associated with high grade gliomas by determining elevated relative cerebral blood volume (rCBV) and relative cerebral blood flow (rCBF) related to tumor angiogenesis. However, since low and intermediate grade gliomas are not associated with such tumoral hyperperfusion, BOLD BH CVR mapping may be able to detect such NVU potential even in lower grade gliomas without angiogenesis, which is the hallmark of glioblastomas. However, it is also known that glioblastomas are associated with variable NVU, since angiogenesis may not always result in NVU. Perfusion metrics obtained by T2* gadolinium perfusion MR imaging were compared to BOLD percentage signal change on BH CVR maps in a group of 19 patients with intracranial brain tumors of different nature and grade. Single pixel maximum rCBV and rCBF within holotumoral regions of interest (i.e., “ipsilesional” ROIs) were normalized to contralateral hemispheric homologous (i.e., “contralesional”) normal tissue. Furthermore, percentage signal change on BH CVR maps within ipsilesional ROIs were normalized to the percentage signal change within contralesional homologous ROIs. Inverse linear correlation was found between normalized rCBF (rflow) or rCBV (rvol) and normalized CVR percentage signal change (rCVR) in grade IV lesions. In the grade III lesions a less steep inverse linear trend was seen that did not reach statistical significance, whereas no correlation at all was seen in the grade II group. Statistically significant difference was present for rflow and rvol between the grade II and IV groups and between the grade III and IV groups but not for rCVR. The rCVR was significantly lower than 1 in every group. Our results demonstrate that while T2* MR perfusion maps and CVR maps are both adequate to map tumoral regions at risk of NVU in high grade gliomas, CVR maps can detect areas of decreased CVR also in low and intermediate grade gliomas where NVU may be caused by factors other than tumor neovascularity alone. Comparison of areas of abnormally decreased regional CVR with areas of absent BOLD task-based activation in expected eloquent cortical regions infiltrated by or adjacent to the tumors revealed overall 95% concordance, thus confirming the capability of BH CVR mapping to effectively demonstrate areas of NVU.

Effectiveness of four different clinical fMRI paradigms for preoperative regional determination of language lateralization in patients with brain tumors

IntroductionBlood oxygen level-dependent functional magnetic resonance imaging (fMRI) has demonstrated its capability to provide comparable results to gold standard intracarotid sodium amobarbital (Wada) testing for preoperative determination of language hemispheric dominance. However, thus far, no consensus has been established regarding which fMRI paradigms are the most effective for the determination of hemispheric language lateralization in specific categories of patients and specific regions of interest (ROIs).MethodsForty-one brain tumor patients who performed four different language tasks—rhyming (R), silent word generation (SWG) sentence completion, and sentence listening comprehension (LC)—for presurgical language mapping by fMRI were included in this study. A statistical threshold-independent lateralization index (LI) was calculated and compared among the paradigms in four different ROIs for language activation: functional Broca’s (BA) and Wernicke’s areas (WA) as well as larger anatomically defined expressive (EA) and receptive (RA) areas.ResultsThe two expressive paradigms evaluated in this study are very good lateralizing tasks in expressive language areas; specifically, a significantly higher mean LI value was noted for SWG (0.36 ± 0.25) compared to LC (0.16 ± 0.24, p = 0.009) and for R (0.40 ± 0.22) compared to LC (0.16 ± 0.24, p = 0.001) in BA. SWG LI (0.28 ± 0.19) was higher than LC LI (0.12 ± 0.16, p = 0.01) also in EA. No significant differences in LI were found among these paradigms in WA or RA.ConclusionsSWG and R are sufficient for the determination of lateralization in expressive language areas, whereas new semantic or receptive paradigms need to be designed for an improved assessment of lateralization in receptive language areas.

Cerebrovascular reactivity mapping for brain tumor presurgical planning

This article provides a review of Blood Oxygen Level Dependent functional magnetic resonance imaging (BOLD fMRI) applications for presurgical mapping in patients with brain tumors who are being considered for lesion resection. Initially, the physical principle of the BOLD effect is discussed, followed by a general overview of the aims of presurgical planning. Subsequently, a review of sensorimotor, language and visual paradigms that are typically utilized in clinical fMRI is provided, followed by a brief description of studies demonstrating the clinical impact of preoperative BOLD fMRI. After this thorough introduction to presurgical fMRI, a detailed explanation of the phenomenon of neurovascular uncoupling (NVU), a major limitation of fMRI, is provided, followed by a discussion of the different approaches taken for BOLD cerebrovascular reactivity (CVR) mapping, which is an effective method of detecting NVU. We then include one clinical case which demonstrates the value of CVR mapping in clinical preoperative fMRI interpretation. The paper then concludes with a brief review of applications of CVR mapping other than for presurgical mapping.

Clinical utility of cerebrovascular reactivity mapping in patients with low grade gliomas

AIM To evaluate neurovascular uncoupling (NVU) associated with low grade gliomas (LGG) using blood oxygen level dependent (BOLD) cerebrovascular reactivity mapping. METHODS Seven patients with low grade gliomas referred by neurosurgeons for presurgical mapping were included in this pilot study. Cerebrovascular reactivity (CVR) mapping was performed by acquiring BOLD images while patients performed a block-design breath-hold (BH) hypercapnia task. CVR mapping was expressed as BOLD percentage signal change (PSC) from baseline associated with performance of the BH hypercapnia task. Standard T2* Dynamic Susceptibility Contrast perfusion imaging was performed and relative cerebral blood volume (rCBV) and relative cerebral blood flow (rCBF) maps were generated. Structural T1 weighted MR images were also acquired. A correlation analysis between intratumoral normalized (via ratio with contralateral homologous regions) BOLD BH PSC [referred to as (n(CVR))] and intratumoral normalized resting state rCBV (rCBF) values (i.e., n(CBV) and n(CBF), respectively) was performed. RESULTS No significant correlation was seen between the normalized BOLD BH PSC (i.e., n(CBV)) and n(CBV) or n(CBF). However, the average n(CVR) (median = 0.50, z = -2.28, P = 0.01) was significantly less than 1.0, indicating abnormally reduced vascular responses in the tumor regions relative to normal contralesional homologous regions, whereas the average n(CBV) (median = 0.94, z = -0.92, P = 0.375) and n(CBF) (median = 0.93, z = -1.16, P = 0.25) were not significantly higher or lower than 1.0, indicating iso-perfusion in the tumor regions relative to normal contralesional homologous regions. These findings suggest that in LGG, hyperperfusion that is seen in high grade gliomas is not present, but, nevertheless, abnormally decreased regional CVR is present within and adjacent to LGG. Since the patients all demonstrated at least some residual function attributable to the cortical regions of impaired CVR, but were incapable of producing a BOLD response in these regions regardless of the tasks performed, such regionally decreased CVR is indicative of NVU. The low n(CVR) ratios indicate high prevalence of NVU in this LGG cohort, which is an important consideration in the interpretation of clinical presurgical mapping with functional magnetic resonance (MR) imaging. CONCLUSION Our preliminary study shows that BH CVR mapping is clinically feasible and demonstrates an unexpectedly high prevalence of NVU in patients with LGG.

Relative utility for hemispheric lateralization of different clinical fMRI activation tasks within a comprehensive language paradigm battery in brain tumor patients as assessed by both threshold-dependent and threshold-independent analysis methods.

The aim of this study was to compare the relative effectiveness of 6 different commonly used language fMRI activation paradigms, including receptive and expressive, as well as semantic and phonological tasks, for hemispheric lateralization in brain tumor patients utilizing both threshold-dependent and threshold-independent approaches. We studied 46 right-handed patients with primary intra-axial brain tumors with BOLD fMRI on a 3-T MRI system. A linear fit of the laterality indices (LIs) as a function of the t-value (which varied from 2.0 to 6.5) was calculated and the slope (M) taken as measure of LI variability in the threshold-dependent LI approach; for the threshold-independent approach, the LIs were determined by comparing the integrated T-score weighted distributions of all positively task-correlated voxels of the left and the right hemispheric regions of interest. We demonstrated that silent word generation (SWG) and rhyming (R) were the two expressive tasks that provided the best hemispheric language lateralization in this group, based on concordant threshold-dependent and threshold-independent analyses. Furthermore, R (mean LI value=61.91, M=7.9±1.5) had a higher mean LI value and was less threshold-dependent than SWG (mean LI=52.97, M=11.40±0.64) for LI determination. SWG and R were able to provide effective language lateralization even in the subgroup of patients with lesions located in the left hemisphere and in the frontal or parietal lobes. The receptive language paradigms examined in this study (passive listening [PL], listening comprehension [LC], and reading comprehension [RC]) were less effective than SWG and R for language lateralization.

Role of semantic paradigms for optimization of language mapping in clinical FMRI studies.

BACKGROUND AND PURPOSE: The optimal paradigm choice for language mapping in clinical fMRI studies is challenging due to the variability in activation among different paradigms, the contribution to activation of cognitive processes other than language, and the difficulties in monitoring patient performance. In this study, we compared language localization and lateralization between 2 commonly used clinical language paradigms and 3 newly designed dual-choice semantic paradigms to define a streamlined and adequate language-mapping protocol. MATERIALS AND METHODS: Twelve healthy volunteers performed 5 language paradigms: Silent Word Generation, Sentence Completion, Visual Antonym Pair, Auditory Antonym Pair, and Noun-Verb Association. Group analysis was performed to assess statistically significant differences in fMRI percentage signal change and lateralization index among these paradigms in 5 ROIs: inferior frontal gyrus, superior frontal gyrus, middle frontal gyrus for expressive language activation, middle temporal gyrus, and superior temporal gyrus for receptive language activation. RESULTS: In the expressive ROIs, Silent Word Generation was the most robust and best lateralizing paradigm (greater percentage signal change and lateralization index than semantic paradigms at P < .01 and P < .05 levels, respectively). In the receptive region of interest, Sentence Completion and Noun-Verb Association were the most robust activators (greater percentage signal change than other paradigms, P < .01). All except Auditory Antonym Pair were good lateralizing tasks (the lateralization index was significantly lower than other paradigms, P < .05). CONCLUSIONS: The combination of Silent Word Generation and ≥1 visual semantic paradigm, such as Sentence Completion and Noun-Verb Association, is adequate to determine language localization and lateralization; Noun-Verb Association has the additional advantage of objective monitoring of patient performance.

Neurovascular uncoupling in resting state fMRI demonstrated in patients with primary brain gliomas.

To demonstrate that the problem of brain tumor‐related neurovascular uncoupling (NVU) is a significant issue with respect to resting state blood oxygen level dependent (BOLD) functional MRI (rsfMRI) similar to task‐based BOLD fMRI, in which signal detectability can be compromised by breakdown of normal neurovascular coupling.