A. Gregory Sorensen

Currently, the most widely used criteria for assessing response to therapy in high-grade gliomas are based on two-dimensional tumor measurements on computed tomography (CT) or magnetic resonance imaging (MRI), in conjunction with clinical assessment and corticosteroid dose (the Macdonald Criteria). It is increasingly apparent that there are significant limitations to these criteria, which only address the contrast-enhancing component of the tumor. For example, chemoradiotherapy for newly diagnosed glioblastomas results in transient increase in tumor enhancement (pseudoprogression) in 20% to 30% of patients, which is difficult to differentiate from true tumor progression. Antiangiogenic agents produce high radiographic response rates, as defined by a rapid decrease in contrast enhancement on CT/MRI that occurs within days of initiation of treatment and that is partly a result of reduced vascular permeability to contrast agents rather than a true antitumor effect. In addition, a subset of patients treated with antiangiogenic agents develop tumor recurrence characterized by an increase in the nonenhancing component depicted on T2-weighted/fluid-attenuated inversion recovery sequences. The recognition that contrast enhancement is nonspecific and may not always be a true surrogate of tumor response and the need to account for the nonenhancing component of the tumor mandate that new criteria be developed and validated to permit accurate assessment of the efficacy of novel therapies. The Response Assessment in Neuro-Oncology Working Group is an international effort to develop new standardized response criteria for clinical trials in brain tumors. In this proposal, we present the recommendations for updated response criteria for high-grade gliomas.

Cortical spreading depression (CSD) has been suggested to underlie migraine visual aura. However, it has been challenging to test this hypothesis in human cerebral cortex. Using high-field functional MRI with near-continuous recording during visual aura in three subjects, we observed blood oxygenation level-dependent (BOLD) signal changes that demonstrated at least eight characteristics of CSD, time-locked to percept/onset of the aura. Initially, a focal increase in BOLD signal (possibly reflecting vasodilation), developed within extrastriate cortex (area V3A). This BOLD change progressed contiguously and slowly (3.5 +/- 1.1 mm/min) over occipital cortex, congruent with the retinotopy of the visual percept. Following the same retinotopic progression, the BOLD signal then diminished (possibly reflecting vasoconstriction after the initial vasodilation), as did the BOLD response to visual activation. During periods with no visual stimulation, but while the subject was experiencing scintillations, BOLD signal followed the retinotopic progression of the visual percept. These data strongly suggest that an electrophysiological event such as CSD generates the aura in human visual cortex.

Previous research in non-human primates has shown that the superior longitudinal fascicle (SLF), a major intrahemispheric fiber tract, is actually composed of four separate components. In humans, only post-mortem investigations have been available to examine the trajectory of this tract. This study evaluates the hypothesis that the four subcomponents observed in non-human primates can also be found in the human brain using in vivo diffusion tensor magnetic resonance imaging (DT-MRI). The results of our study demonstrated that the four subdivisions could indeed be identified and segmented in humans. SLF I is located in the white matter of the superior parietal and superior frontal lobes and extends to the dorsal premotor and dorsolateral prefrontal regions. SLF II occupies the central core of the white matter above the insula. It extends from the angular gyrus to the caudal-lateral prefrontal regions. SLF III is situated in the white matter of the parietal and frontal opercula and extends from the supramarginal gyrus to the ventral premotor and prefrontal regions. The fourth subdivision of the SLF, the arcuate fascicle, stems from the caudal part of the superior temporal gyrus arches around the caudal end of the Sylvian fissure and extends to the lateral prefrontal cortex along with the SLF II fibers. Since DT-MRI allows the precise definition of only the stem portion of each fiber pathway, the origin and termination of the subdivisions of SLF are extrapolated from the available data in experimental material from non-human primates.