Frahm, J.

Kleinschmidt, A.

Krueger, G.

English

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Dynamic MRI sensitized to cerebral blood oxygenation and flow during sustained activation of human visual cortex

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Dynamic MRI Sensitized to Cerebral Blood Oxygenation and Flow During Sustained Activation of Human Visual Cortex Gunnar Kriiger, Andreas Kleinschmidt, Jens Frahm Changes in cerebral blood oxygenation and flow during pro- longed activation of human visual cortex (6-min video projec- tion) were monitored using high-resolution T2*- and T,-weighted gradient-echo MRI in identical sessions. Oxygen- ation-sensitive recordings displayed an initial signal increase (oxygenation “overshoot”), a subsequent signal decrease ex- tending over 4-5 min (relative deoxygenation), and a signal drop after the end of stimulation that mirrored the initial re- sponse (oxygenation “undershoot”). Flow-sensitive MRI dem- onstrated that the inflow effect remained elevated during the entire period of Stimulation. The observation of gradually de- creasing cerebral blood oxygenation, despite persisting ele- vation of blood flow, may be understood to be an accumula- tion of deoxyhemoglobin due to the progressive up-regulation of oxidative phosphorylation. The present findings support a concept in which transitions between functional states lead to an uncoupling of perfusion (oxygen delivery) from oxidative metabolism (oxygen consumption) whereas steady-state ac- tivity achieves their recoupling. Key Words: brain perfusion; cerebral blood flow; cerebral blood oxygenation; brain; metabolism. INTRODUCTION In a recent study involving the use of combined proton MRS and gradient-echo MRI sensitized to changes in cerebral blood oxygenation (CBO), we provided evidence for a merely initial prevalence of previously suggested nonoxidative glycolysis in human cortex (1, 2) in re- sponse to a major increase in neural activity (3). During such transitions of neuronal activity, blood flow and glucose uptake increase and show a physiological “un- coupling” from largely unaffected oxygen consumption. In the aforementioned study, we detailed its temporal evolution and thereby reconciled this observation with the classic understanding of the general coupling of per- fusion and oxidative metabolism (4). Within a 6-min period of visual stimulation, CBO-sensitive MRS and MRM 35:797-800 (1W) From the Biomedizinische NMR Forschungs GmbH am Max-Planck-lnstitut filr biophysikalische Chemie Am Fassberg 11, 0-37077 Gottingen, Ger- many. Address correspondence to: Jens Frahm, Ph.D., Biomedizinische NMR Forschungs GmbH am Max-Planck-lnstitut fijr biophysikalische Chemie Am Fassberg 11, D-37077 Gottingen, Germany. Received September 7.1995; revised December 4,1995 accepted Febru- ary 1,1996. Copyright 8 1996 by Williams & Wilkins All rights of reproduction in any form resewed. 0740-31 94/96 $3.00 MRI independently revealed a signal intensity decrease to prestimulus baseline, indicating that steady-state con- ditions are accompanied by “recoupling.” However, the assignment of these signal decreases to an up-regulation of oxidative metabolism, and concomitantly enhanced oxygen consumption assumes that blood flow remains constantly elevated throughout the experiment. This study specifically addresses this issue by parallel inves- tigations of stimulus-related changes in both regional CBO and blood flow using dynamic gradient-echo MRI with respective contrasts. METHODS Studies of 10 healthy human subjects (age 24-52 years, mean 29.5 years) were conducted at 2.0 T (Siemens Mag- netom SP4000, Erlangen, Germany) using the standard imaging headcoil. Visual stimulation involved a 6-min video presentation (medical education, color, no sound) with use of a specially designed MRI projection setup covering 40” x 30” of the visual field (Schafter and Kirch- hoff, Hamburg, Germany). The material contained dem- onstrations of diagnostic equipment and procedures. No part of the video was presented twice, and subjects were free to move their eyes. Attention was ensured by inform- ing subjects that they would be interviewed on the con- tent of the clips after the session. Total protocol duration was 1 2  min. Additionally, subjects underwent a repeti- tive protocol comprising six cycles with 18 s of stimula- tion (same video) and 36 s of darkness each. These mea- surements were immediately evaluated and served to verify sufficient visual responsiveness in the sections chosen on anatomical grounds. Dynamic CBO-sensitive MRI (RF-spoiled FLASH, TR/TE = 62.5/30 ms, flip angle 10”) was performed using spin-density weighting with T,* sensitivity (5). Flow- sensitive recordings were obtained by emphasizing in- flow phenomena with strong TI weighting but T2* insen- sitivity (RF-spoiled FLASH, TR/TE = 62.517.5 ms, flip angle 50”). The 12-min span of the sustained stimulation protocol comprised of 60 sequential images (two aver- ages of 6-s acquisitions). Sections (4 mm) were individ- ually aligned to cover major parts of calcarine cortex with two to three repetitions of CBO-sensitive and flow-sensi- tive recordings each. Activation was determined by correlating signal inten- sity time courses of each pixel with a reference waveform (6). For multiple repetitions of short stimuli, the refer- ence was a box-car waveform shifted by one image (6 s) 797 798 Kriiger et al. FIG. 1. Rapid low-flip-angle gradi- ent-echo MRI covering the calcar- ine cortex of a healthy volunteer. (a) CEO-sensitive acquisition using spin-density weighting with T2‘ sen- sitivity (RF-spoiled FLASH, TR = 62.5 ms, TE = 30 ms, flip angle lo”, in plane resolution 0.78 x 1.56 mm2 interpolated to 0.78 x 0.78 mm2, slice thickness 4 mm). (b) Flow-sen- sitive acquisition using strong T, weighting without T2* sensitivity (E = 7.5 rns, flip angle 50°, other pa- rameters as indicated for a). a b relative to the protocol. For sustained stimulation, spe- cific response functions for CBO- and flow-sensitive measurements were obtained by averaging signal-inten- sity time courses across subjects in areas identified by a correlation with the stimulus protocol. Separate “over- shoot” and “undershoot” activation maps were obtained by correlating signal intensities from either the first or last 6 min of the 12-min MFU data set with respective parts of the mean CBO-sensitive response function. Quantitative maps of correlation coefficients were ana- lyzed, thresholded, and color-coded as described previ- ously (7). No temporal or spatial filters were applied. Regional time courses of signal-intensity changes were derived from all pixels showing significant alterations, i.e., with a P 5 0.0001 corresponding to about three false-positive pixels admitted per dynamic MRI series. RESULTS AND DISCUSSION Figure 1 shows typical high-resolution T,*- and T,- weighted single-slice gradient-echo images used to mon- itor changes dynamically in CBO and flow, respectively. Pertinent time courses from activated regions are de- picted in Fig. 2 for CBO- and flow-sensitive recordings and demonstrate the grand average response observed in the study group (mean values 2 SD). In general agree- ment with previous studies of sustained flickerlight stim- ulation using both proton M R S  and gradient-echo MRI (3). the CBO data (Fig. 2a) revealed a rapid signal increase or hyperoxygenation associated with stimulus onset fol- lowed by a signal decrease or relative deoxygenation extending over 4-5 min. Signal intensities toward the end of stimulation remained slightly elevated in compar- ison with prestimulus baseline (statistically not signifi- cant). After the end of stimulation, a pronounced and rapid signal drop or deoxygenation occurred that mir- rored the initial hyperoxygenation in magnitude and re- covery time. In contrast, the flow-sensitive data (Fig. 2b) revealed a constant elevation of signal intensity due to inflow en- hancement during sustained stimulation. Poststimulus intensity showed no undershoot phenomenon. Although there is not direct access to neuronal activity in func- ’“1 IT I Oxygenation & 9 -10 8 0 3 6 9 12 Flow 4 * t  0 3 6 9 12 Time / min FIG. 2. Normalized regional time courses of MRI signal intensities (12-s temporal resolution) sensitized to changes in (a) CBO and (b) blood flow during a 12-min protocol comprising 6 min of visual stimulation (cross-hatched bar). The values represent mean 2 SD for all subjects (n = 10) in areas exhibiting stimulus-related signal alterations. As demonstrated by the small fluctuations of the mean response, the error bars mostly reflect interindividual differences rather than physiological noise during the individual recordings. Sustained Activation of Human Visual Cortex 799 FIG. 3. Color-coded activation maps superimposed onto an anatomical reference image for the same subject as in Fig. 1. The maps demonstrate spatial congruence of brain regions that exhibit (a) an initial oxygenation overshoot after stimulus onset, (b) a terminal oxygenation undershoot after ending stimulation, and (c) MRI responses in correlation with a repetiive protocol comprising six cycles of 18 s of stimulation and 36 s of darkness each. (d) Correlation map of flow-sensitive responses during 6 min of stimulation. tional neuroimaging, the persistence of flow-sensitive responses as well as the marked poststimulus undershoot of CBO-sensitive responses argue against contributions from diminished attention or habituation. Another PO- tential source of CBO signal reduction could be a slow increase in cerebral blood volume by (presumably ve- nous) vasodilation, but it seems unlikely that this should exclusively affect CBO- but not flow-sensitive record- ings. The reason for a discrepancy of the CBO-sensitive data with a preliminary report using echo-planar imaging 800 at a 30-fold lower spatial resolution (8) remains an unre- solved issue. Putative explanations include technical properties that result in different MRI contrasts and im- age sensitivities as well as stimulus properties that elicit responses of different strengths andlor involve other sub- systems and thus may cause variable demands for oxida- tive metabolism. The present findings support a model in which not only hernodynamic but also oxidative metabolic adjust- ments occur in response to functional challenge. As shown in Fig. 3, differences in their temporal evolution are responsible for both the initial hyperoxygenation (Fig. 3a) and the deoxygenation after end of stimulation (Fig. 3b). Pertinent signal changes are equivalent in strength and observed in identical regions. Thus, all brain regions that exhibit an activation-related oxygen- ation overshoot also generate an undershoot with deac- tivation. Moreover, activated areas in such maps are con- gruent with regions defined by conventional “mapping” with several brief cycles of stimulation (Fig. 3c), whereas detectable alterations of flow were confined to more re- stricted areas most likely encompassing larger veins (Fig. In synopsis with the metabolic data presented previ- ously (3), the temporal evolution of focal brain activation may be characterized by the following sequence of events. After the first few seconds of hemodynamic la- tency, the rise in perfusion, i.e., oxygen and glucose delivery, remains without a corresponding increase in oxygen consumption. The resulting postcapillary oxy- genation overshoot provides CBO-sensitive MRI contrast. In the first 2-3 min, increased glucose consumption with transient lactate accumulation indicates enhanced non- oxidative glycolysis. This initial phase is characterized by the uncoupling of perfusion and oxidative metabo- lism. After 4-5 min, the continuous elevation of blood flow and glucose consumption is progressively matched by an up-regulation of oxidative metabolism that re- couples oxygen consumption in a new steady state with CBO reduced close to or identical with baseline values. Finally, terminating activation causes a rapid normaliza- tion in blood flow, i.e., oxygen and glucose delivery, that yields a transient oxygenation undershoot due to the persistence and gradual attenuation of elevated oxygen consumption. Analogous to the onset of activation, the physiological processes linked to deactivation may be 3d). Kriiger et al. considered as a transient “negative” uncoupling of per- fusion and oxidative metabolism. Consequently, the level of blood flow seems to reflect the degree of neuronal activity in a functional state, whereas CBO is mainly sensitive to activation as the switching between func- tional states. ACKNOWLEDGMENTS The authors thank the Gesellschaft fiir wissenschaftliche Daten- verarbeitung Gottingen for data analysis and figure preparation. REFERENCES 1. 2. 3. 4. 5. 6. 7. P. T. Fox, M. E. Raichle, Focal physiological uncoupling of cerebral blood flow and oxidative metabolism during so- matosensory stimulation in human subjects. Proc. Natl. Acad. Sci. USA 83, 1140-1144 (1986). P. T. Fox, M. E. Raichle, M. A. Mintun, C. Dence, Nonoxi- dative glucose consumption during focal physiologic neural activity. Science 241, 462-464 (1988). J. Frahm, G. Kriiger, K. D. Merboldt, A. Kleinschmidt, Dy- namic uncoupling and recoupling of perfusion and oxida- tive metabolism during focal brain activation in man. Magn. Reson. Med. 35, 143-148 (1996). D. D. Clarke, L. Sokoloff, Circulation and energy metabolism of the brain in “Basic Neurochemistry” (G. J. Siegel, B. W. Agranoff, R. W. Albers, P. B. Molinoff, Eds.), pp. 645-680. Raven, New York, 1994. J.  Frahm. K. D. Merboldt, W. Hanicke, A. Kleinschmidt, H. Boecker, Brain or vein-oxygenation or flow? On signal physiology in functional MRI of human brain activation. MMR Biomed. 7 ,  45-53 (1994). P. A. Bandettini, A. Jesmanowicz, E. C. Wong, J. S. Hyde. Processing strategies for time-course data sets in functional MRI of the human brain. Magn. Rsson. Med. 30, 161-173 (1993). A. Kleinschmidt, M. Requardt, K. D. Merboldt, J. Frahm, On the use of temporal correlation coefficients for magnetic resonance mapping of functional brain activation. Individ- ualized thresholds and spatial response delineation. Intern. I. Imaging sys. Techno!. 6 ,  238-244 (1995). 8. P. A. Bidet t ini ,  T. L. Davis, K. K. Kwong, P. T. Fox, A. Jiang, J. R. Baker, J. W. Belliveau, R. M. Weisskoff, B. R. 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Dynamic MRI sensitized to cerebral blood oxygenation and flow during sustained activation of human visual cortex

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