Gjedde and Marrett:

In Search of Baseline: Absolute and Relative Measures of Blood Flow and Oxidative Metabolism in Visual Cortex Stimulated at Three Levels of Complexity

Albert Gjeddeabc*, Sean Marretta

aMcConnell Brain Imaging Center, Montreal Neurological Institute, McGill University, Montreal, Canada
bDepartment of Neuroscience & Pharmacology, University of Copenhagen, Copenhagen, Denmark
cCenter of Functionally Integrative Neuroscience, Aarhus University, Aarhus, Denmark

Albert Gjedde, M.D., D.Med.(hafn.), F.R.S.C. Department of Neuroscience and Pharmacology, University of Copenhagen, Blegdamsvej 3, DK-2200 Copenhagen N, Denmark. Tel: +45-30104961, Email: gjedde@sund.ku.dk

Received: 2016-04-03
Accepted: 2016-04-21

DOI: 10.13183/jecns.v3i1.42


Objective: Functional imaging of regional cerebral blood flow (rCBF) or the blood-oxygenation-level dependent (BOLD) signal is based on the premise that changes of flow and energy metabolism are linked to the same incremental excitation of neurons. The baseline conjecture holds that a single default mode of brain function gives rise to coupled changes of blood flow and oxidative metabolism that raise oxygen’s extraction fraction, when activity falls, and lower the extraction fraction when activity rises. To locate the hypothetical baseline in visual cortex in relation to functional demands, we compared increments of (rCBF) and oxidative metabolism (rCMRO2) during stimulation of visual cortex at three different levels of complexity.

Materials and Methods: Healthy volunteers underwent positron emission tomography (PET) with [15O] water and [15O] oxygen while they viewed three stimuli in random order; a cross-hair fixation stimulus without color or spatial frequency (FX), an achromatic white disc stimulus with an 8 Hz on-off rate (WD), and a circular yellow-blue chromatic checkerboard with an 8 Hz color-reversing frequency (YB). For the baseline conjecture to hold, the sum of any pair of contrasts must equal the third at any site of significant change, such that the sum of the contrasts [YB-WD] and [WD-FX] must equal the contrast [YB-FX].

Results: The rCMRO2 and rCBF changes averaged 21% and 52% of the whole-brain average, implying excitation by increasing stimulus complexity. The color reversal contrast ([YB-WD]) revealed bilateral sites of significant change of rCMRO2 and a single left hemisphere site of significant rCBF change in the general region of Brodmann’s areas (BA) 17 and 18 of the lingual gyrus. The spatial frequency contrasts ([YB-FX] and [WD-FX]) revealed single sites of significant change of rCMRO2 and rCBF also in the lingual gyrus but close to the midline. For the midline sites, the [YB-FX] and [WD-FX] contrasts were identical and revealed a baseline between the FX and WD/YB stimulus conditions. For the lateral sites, the [YB-WD] stimulus contrast revealed a baseline between the YB and WD stimulus conditions.

Conclusion: The intermediate positions of the baselines indicated the existence in BA 17/18 of at least two populations of cells, a lateral group responding to the absence and presence of color reversal in the presence of a spatial frequency, and a midline group responding only to the absence and presence of spatial frequency.

Keywords: Brodmann Areas 17/18,Cerebral Blood Flow, Oxygen Consumption, Positron Emission Tomography, Visual Cortex.

© 2016 Swedish Science Pioneers, All rights reserved.


Experimental findings show approximately the same relation between brain energy metabolism and blood flow at steady-state of the many parts of the brain, indicating approximately uniform extraction of oxygen and oxygen-glucose indices [1-3]. The steady-state measures are believed to establish a common baseline of activity, which reflects the most commonly encountered relation between flow and metabolism.

During transients of brain function, there is evidence of mismatched changes of blood flow and energy metabolism in brain regions. Yet, the convention underlying functional brain imaging holds that increases of blood flow are informative of brain function because they indirectly reflect the metabolic needs imposed by experimentally induced increments or decrements of brain work. This reasoning also applies to the interpretation of the blood-oxygenation-level-dependent (BOLD) signal in functional magnetic resonance imaging (fMRI) as more than just an index of oxygen extraction. The mechanism responsible for changes of the BOLD signal is the corresponding changes of the amount of deoxyhemoglobin in brain vessels.

To use the signal as more than an index of oxygen extraction implies that the relation between changes of blood flow and brain work, although non-linear, must nonetheless be fixed and predictable [4]. This in turn means that the position of the steady-state baseline must be known because the relative changes of blood flow and oxygen consumption have opposite signs, depending on the direction of the functional change: When activity declines relative to the baseline, oxygen consumption declines more than blood flow, while blood flow increases more than oxygen consumption when activity rises relative to the baseline [5]. This findings reported in this paper imply that brain function and brain work are perfectly matched in the steady-state, yet undergo dissociation during rapid transients of brain work, depending on the direction of change. In the earliest examples of functional brain imaging by positron emission tomography, measures of energy metabolism revealed little change compared to substantial changes of blood flow imposed by aerobic glucose consumption [6-8], directly or indirectly related to production of lactate [9,10].

Thus, the interpretation of measures of brain function based on the BOLD signal is complicated by uncertainty about the baseline. Stimulation of brain tissue is known in some instances to raise blood flow in regions in which neurons do not respond with changes of spike frequency or oxidative brain energy metabolism [11,12], indicating dissociation of measured blood flow rates from direct measures of brain activity [13-16], as well as increases of brain energy metabolism in regions of the brain in which blood flow appears to remain constant [17], or preserved metabolic rates in the face of declines of blood flow [18], all potentially related to the unknown position of the physiological baseline.

The baseline conjecture predicts a steady-state of brain activity from which departures occur when adequate stimuli raise or lower the neuronal activity assumed to be associated with the baseline. Recognizing that functions associated with the baseline cannot be distinguished accurately from the functions associated with a decrement or an increment, Gusnard et al. [2] proposed that a “default” state of brain tissue nonetheless can be identified by consideration of a baseline of the oxygen extraction fraction that equals the temporal and global average of extractions of oxygen. This means that the position of the baseline cannot be inferred from changes of extraction alone, but must be determined at steady-state, in which a functional state is known to represent a stable temporal and global average [19,20].

The null hypothesis of the present study is the conjecture that the baseline can be inferred from unmatched changes of linked flow and metabolism changes in relevant stimulus contrasts. Specifically, the contrasts established by a three-way differential stimulation of the visual cortex must be mutually consistent at any site of significantly altered activity. A missing contrast there foremarks an intermediate baseline activity.

For the contrasts among three different visual stimuli, this baseline conjecture makes two specific predictions that arise from the axiomatic claim that all functional states relate to a baseline associated with the average and hencemost common stimulus condition:

First, the baseline hypothesis predicts that the relative magnitudes of flow and metabolism increments imposed by differentially complex stimuli reflect the direction of functional change consistent with the change of complexity: If flow changes more than brain energy metabolism, the change represents an excitation, and conversely, if flow changes less than metabolism, the change represents an inhibition of functional activity.

Second, the baseline hypothesis predicts that the sum of any pair of contrasts must equal the third and remaining contrast, within the limits set by the accuracy of the measurement, and hence that each site must be revealed in at least two of the three contrasts. If such a contrast is missing, the activity is unresponsive to the stimulus contrast and hence engaged in baseline activity, which must be intermediate to the activities of the two stimulus conditions to eliminate the contrast.

We tested the predictions by measuring regional oxygen consumption (rCMRO2) and blood flow (rCBF) with positron emission tomography (PET) of healthy volunteers during stimulation with three different stimuli known to differentially excite the visual cortex [21-23].

Materials and Methods

Nine healthy right-handed volunteers without apparent neurological deficits (aged 25±6 years) gave informed consent to a protocol approved by the Montreal Neurological Institute Research and Ethics Committee. The PET measurements of rCBF and rCMRO2 were performed with a Scanditronix PC2048-15B head tomograph (spatial resolution 6.5 mm FWHM) and corrected for tissue attenuation, dead-time and scatter. The subjects were positioned in the tomograph with their heads immobilized by a self-inflating foam head-rest. A short in-dwelling catheter was placed in the left radial artery. Blood samples were automatically collected and calibrated with respect to the tomograph [24]. Three measurements of CBF, one for each condition, were made with the two-compartment intravenous [15O] water bolus method (35 mCi) [25] followed by three measurements of CMRO2 using a single bolus inhalation (60-80 mCi) [26]. Images were reconstructed as a 128x128 matrix of 2x2 mm pixels using filtered back-projection with a 20 mm FWHM Hanning filter.

Measurements of blood flow and oxygen metabolism were made while the subjects viewed binocularly one of three different stimuli. The tomograph was enclosed by a dark cloth shroud during the scan to isolate the subject from any extraneous stimulation.

Stimuli were presented on a 21-inch colour video monitor suspended 36-40 cm from the eyes of the subject. Subjects were instructed to maintain the center of the screen during the presentation of all three stimuli, and practiced briefly with all three stimuli prior to the start of scanning. In the simplest fixation stimulus (FX) condition, the subjects viewed the small central target (cross-hair) for 30 seconds prior to the PET session. In the two activation conditions, the subjects were presented with the stimulus for 3 minutes prior to and throughout the PET scan, as shown in Figure 1.


Figure 1. Time course of rCBF and rCMRO2 measurements. Note longer exposure time for WD and YB stimulus conditions.

The three different stimuli were chosen to replicate previous studies by the authors with similar stimuli [23]. The achromatic stimulus (WD) was a white disk (approximately 15° of visual angle in diameter) that flickered at a rate of 8Hz. The chromatic stimulus (YB) was a radial yellow-blue checkerboard disk (approximately 15° of visual angle in diameter) that reversed contrast at a rate of 8Hz. Each check was approximately 1 degree in size (not scaled for radius).

Parametric maps of CMRO2 and the clearance of radioactive water by brain tissue, an index of CBF, were computed for all 15 image planes and normalized for differences in global CMRO2 or CBF. For each subject, magnetic resonance images (MRI; 160 contiguous 1-mm thick sagittal slices) were also obtained from a Philips Gyroscan ASC (1.5 T). The PET images from each subject were co-registered with the corresponding MRI volume [27] and transformed to stereotaxic coordinates [28] by means of an automated feature-matching algorithm [29]. Difference volumes of all three stimulus conditions [8] were computed and averaged across all subjects. A t-statistic volume was obtained by dividing every intra-cerebral voxel in the difference volume by the mean standard deviation in normalized units of CBF or CMRO2. The significance of a given change in CMRO2 or CBF was assessed by application of an intensity threshold to the t-statistic images [30]. Relative and absolute differences were computed for all sites of significant change.


The whole-brain CBF and CMRO2 values with standard errors averaged 46±4 ml/hg/min and 170±17 mmol/hg/min, respectively. They remained constant (47, 46, 45 ml/hg/min and 169, 174, 168 mmol/hg/min) across the three stimulus conditions (YB, WD, and FX), with an average oxygen extraction fraction of 0.41+0.01. The YB-WD, YB-FX, and WD-FX stimulus contrast images are shown in Figures 1 and 3. The focal changes of rCMRO2 and rCBF averaged 21% and 52% of the respective whole-brain averages, with an extraction fraction of the incremental oxygen delivery of 0.165, which is well below the whole-brain average, indicating excitation by all three contrasts.


Figure 2. Changes of rCMRO2 in YB-WD, YB-FX, and WD-FX stimulus contrasts. Images show locations of significant changes for each of three contrasts established by viewing flickering white disk (WD), yellow-blue color-reversing checkerboard (YB) at same size as WD stimulus, or fixation-point cross-hair (FX). Underlying MRI images are averages of nine subjects. Coordinates are given in mm using the Talairach and Tournoux (1988) stereotaxic atlas as a reference. Image t-maps were computed according to method of Worsley et al. (1992). Values above t=3.75 yield a false-positive rate of 0.58 in 458 resolution elements if the volume of grey matter is taken as 500 ml. Figure 2 (left panel) shows location of two rCMRO2 changes associated with YB-WD contrast, one in each hemisphere. Stimulus contrasts WD-FX and YB-FX both were associated with single peaks close to the midline in posterior lingual gyrus (foveal V1, Figure 2, third and fourth panels to the right). Images in Figure 3 illustrate corresponding rCBF changes. Note higher magnitude of rCBF changes compared to rCMRO2 changes. Standard error of mean (SEM) was calculated using global variance of intracranial voxels.


Figure 3. Changes of rCBF in YB-WD, YB-FX, and WD-FX stimulus contrasts. Images show locations of significant changes for each of three contrasts established by viewing flickering white disk (WD), yellow-blue color-reversing checkerboard (YB) as same size as WD stimulus, or fixation-point cross-hair (FX). Underlying MRI images are averages of nine subjects. Coordinates are given in mm using the Talairach and Tournoux (1988) stereotaxic atlas as a reference. Image t-maps were computed according to method of Worsley et al. (1992). Values above t=3.75 yield a false-positive rate of 0.58 in 458 resolution elements if the volume of grey matter is taken as 500 ml. Images in Figure 2 illustrate corresponding rCMRO2 changes. Note higher magnitude of rCBF changes compared to rCMRO2 changes. Standard error of mean (SEM) was calculated using global variance of intracranial voxels.

The sites of significant rCMRO2 increments are shown in Figure 2, located in Brodmann’s areas (BA) 17 and 18 of the lingual gyrus. The general region of BA 17 and 18 was also the location of the sites of altered rCBF, shown in Figure 3. The statistical analysis of the CBF and CMRO2 contrast images is summarized in Table 1. The peaks were projected onto a single two-dimensional cartoon plane in Figure 4.

Table 1. Significant changes in rCMRO2 in primary visual cortex. The x, y, z coordinate represent the peak value in the t-statistic map (across all 9 subjects). Values over 4.5 are significant at the P = 0.05 level. The % change represents the average change at the peak-location x, y, z. The D represents the change in absolute units of CBF or CMRO2. Columns show values for three paired contrasts: WD-FX (8Hz flickering white disk vs.1° cross fixation); YB-FX (yellow-blue checkerboard reversing contrast at 8Hz vs. 1° cross fixation) and YB-WD (8 Hz phase-reversing yellow-blue vs. 8Hz flickering white disk). CBF and CMRO2 changes in visual cortex for different stimuli.


Figure 4. Talairach coordinates of peak CBF and CMRO2 changes in Brodmann’s areas 17 and 18 of lingual gyrus projected on transaxial cartoon planes at z = -8 mm and z = -16 mm (corners of the latter which protrudes below the -8 mm plane in the midline). The four planes present the three stimulus conditions and the inferred baseline condition, which arise from the experimental conditions. The colors indicate activity below (white), at (gray), or above (black) the inferred baseline for both rCBF and rCMRO2 changes.

Sites of Significant rCMRO2 Increment

The chromatic [YB-WD] stimulus contrast revealed changes of rCMRO2 of 20% in the rightlingual gyrus, and 18% in the left lingual gyrus, both of the inferior occipital cortices. The sites are close to the borders between BA 17 and 18, as defined anatomically by Amunts et al. [31] The change represents the incremental oxygen metabolism of neurons that responded to the color reversal of the [YB-WD] stimulus contrast. The distance between the two peaks is 27 mm.

The spatial frequency contrasts [YB-FX] and [WD-FX] both revealed 23% increments of rCMRO2 at sites closer to the midline of the occipital pole, within a few mm of the calcarine sulcus in ventral BA 17 of the lingual gyrus.

Sites of Significant rCBF Increment

The [YB-WD], [YB-FX], and [WD-FX] stimulus contrasts revealed significant increments of rCBF in ventral BA 17 of the primary visual cortex. For the chromatic [YB-WD] stimulus contrast, blood flow changed 34% at a site in the left lingual gyrus. This site (defined as the connected area above an isocontour value of t=3.0) did not coincide with the bilateral sites of corresponding rCMRO2 changes in left and right lingual gyrus, but the single rCBF site could represent either the fusion of two sites at the same locations as the excentric rCMRO2 sites, or could be the twin of a site of insignificant change in the right hemisphere, although no such site was suggested by the data.

The [YB-FX] and [WD-FX] stimulus contrasts both revealed significant increments of rCBF in midline BA 17 of the lingual gyrus. Relative to the whole-brain, the changes averaged 72% for the YB-FX contrast and 49% for the WD-FX contrast. The sites of these increments approximately coincided with the corresponding sites of rCMRO2 change.

Functional Neuroanatomical Correlates

The significant changes of rCBF and rCMRO2 were given functional neuroanatomical assignment by comparison with the average anatomical maps of Brodmann´s areas 17 and 18 reported by Amunts et al. (2000) with functional imaging studies of primary visual cortex [32,33]. However, there is no agreement on whether V2 resides in primary or secondary visual cortex [34]. Depending on the definition, all sites resided either in the V1/V2 and V3v (VP) [32] or, more likely, the V1 and V2 [33] regions of visual cortex.

All significant changes of the two variables were found in the lingual gyri, below the zero plane of the z-dimension between the -85 and -95 mm planes of the y-dimension, as shown in Figure 4. Locations inside these borders all reside within the conventional borders of primary and prestriate visual cortex [31-33].


In this study, differential stimulation of the visual cortex appeared to result in significant focal changes of rCMRO2 and rCBF at locations in left and right lingual gyrus, generally associated with the V1/V2 and possibly V3v (VP) regions of the primary visual cortex [32,33]. Most sites resided in BA 17 but the lateral sites skirted BA 18 in both hemispheres.

In the early study by Ribeiro et al. [35], no change of oxygen consumption was found when a dark-adapted baseline was compared to photic stimulation at 8 Hz. Therefore, we did not predict the 23% changes associated with the YB-FX and WD-FX contrasts of the present study. Post-hoc comparison of the 2-dimensional discrete Fourier transforms of the two activity conditions showed that the distributions of spatial frequencies overlapped in the achromatic and chromatic stimuli used in comparison with the fixation stimulus. The overlapping spatial frequencies suggest that the major deactivating feature of the achromatic disk was the absence of color reversal, which relegated the change of metabolism to the V2 regions bilaterally, while the major deactivating feature of the fixation stimulus was the absence of spatial frequency, which relegated the change of metabolism to the foveal V1 region.

Insights from the study of neuroenergetics imply that oxygen consumption is the proper measure of neuronal work [3,36-38]. Whether a change of oxygen consumption therefore is the sole valid measure of a change of functional activity, or whether incremental or decremental changes of blood flow and glucose consumption matter as well, is controversial because the direction and magnitude of increments depend on the relative properties of possibly uncorrelated baseline states [19,39,40].

Previous measurements of oxygen consumption revealed variable increments by stimulation of visual cortex [5,7,23,35,41,42]. In the earliest experiments, the stimulation raised regional cerebral blood flow (rCBF) and glucose metabolism (rCMRglc) by more than 40% but rCMRO2 by 5% or less. However, the subsequently voiced assertion that increased neuronal activity therefore is independent of oxygen metabolism cannot be reconciled with the biochemical evidence of coupling of oxidative enzyme activity to functional activity [10,21,22,43-46].

The average changes of rCBF and rCMRO2 in the present study (52% vs 21%) are consistent with a more recent claim of non-linear but nonetheless preserved flow-metabolism coupling [18,46-51]. This claim holds that blood flow increments in excess of the increments of oxygen consumption are necessary to maintain the necessary oxygen tension in mitochondria during activation above a default state of operation. In the present study, this general excess was preserved across stimulus conditions, in general agreement with the relative changes of rCMRO2 and rCBF previously reported for the visual cortex under similar viewing conditions and retinal fields [40,41,52,53].

There are several reasons to interpret the sites of significant change in the lingual gyrus of both hemispheres as reflections of the activity in two groups of neurons, one placed laterally and close to or in BA 18 in both hemispheres and one placed near the midline in BA 17, of which the lateral sites are likely to represent the BA 18 region of the lingual gyrus, whether this regions is part of the V3v (VP) [31] or V2 [32] region.

First, the dual sites of rCMRO2 change emerging in the [YB-WD] contrast were separated by a distance of 27.3 mm, which exceeds the standard error of the point-spread function (4.3 mm) by a factor of 6. For this standard error, all twin peaks with peak-to-peak distances greater than 17.2 mm are unlikely to be single with probabilities of 0.05 or less.

Second, in many previous studies, particularly of visuospatial memory and silent reading, secondary visual cortex underwent bilateral changes of activation in the BA 18 region of the lingual gyrus [4,18,54-66]. The average coordinates of this activation (x,y,z,±SD) were (-20±10, -87±11, -8±5) mm in the left hemisphere and (23±10, -88±9, -8±5) mm in the right hemisphere, i.e., within 1 SD of the sites of activation in the [YB-WD] contrast.

Third, the center of mass of all sites of significant change (mm) was 1,-90,-10 (x,y,z). The distances to the peaks of the two sites of significant rCMRO2 change in the [YB-WD] contrast were 14 and 15 mm, both distances close to the significant distance of 17.2 mm. In contrast, there was no evidence of significant segregation of the rCMRO2 and rCBF changes in lingual gyrus in the [YB-FX] and [WD-FX] stimulus contrasts. The rCBF change corresponding to the rCMRO2 changes in the [YB-WD] contrast had a single location lateral to the midline in apparent BA 17. It is possible that this single locus represents the fusion of two sites, enabled by a wider distribution of the blood flow change in combination with a greater absolute change, or that it is the twin of a site that did not emerge in the right hemisphere.

There is a fourth reason to conclude that the lateral sites of activation are functionally separated from the midline sites. The bilateral activation in one contrast ([YB-WD]), and unilateral or midline activations in two other contrasts ([YB-FX] and [WD-FX]), are suggestive of recurrent processing in primary and secondary visual cortex. The brain appears to use visual information to test the veracity of an internal preconstruction of hypothetical sources of the visual sensation [67]. Primates, including humans, experience illusions and ambiguities of sight or sound that have no source outside the brain [68]. According to recent revisions of the premise of interpretation of functional brain imaging, activation begins as such a preconstruction that alerts relevant functional units of the brain [16] by means of “central command” or “predictive coding” [50,69-71] in anticipation of future sensory input activity [72].

Lamme & Roelfsma [73] identified two phases in the processing of visual stimuli, respectively termed the fast feedforward sweep (FFS) from V1 to V2 in the first 50 ms of stimulation, and the subsequent recurrent processing (RP) or backprojection from V2 and more distant regions to V1 after 100 ms [73,74].

PET measurements of CMRO2 integrate events over much longer periods of time than characteristic of the FFS, typically of the order of minutes as in the present study. Recurrent processing, if present, is therefore the predominant activity affecting the transient relations of flow and metabolism measurements in the primary visual and secondary visual cortices [75,76].

The study did not identify a specific baseline for the YB-FX and WD-FX contrasts. When adequate color-reversal was not part of the spatial frequency stimulus, focal changes of oxygen consumption and blood flow were limited to the midline sites of BA 17. However, for the [YB-WD] contrast, when adequate color reversal supplemented the spatial frequency stimulus, oxygen consumption and blood flow changed significantly in lateral regions of the lingual gyrus that did not respond to the [YB-FX] and [WD-FX] contrasts. The missing contrasts in the lateral regions of the lingual gyrus indicated the presence of a baseline condition intermediate to the YB and WD conditions in this part of the lingual gyrus.

To illustrate this result, we reconstructed the time-course of successive changes of each variable at the two main regions of significant change, lateral and midline, as shown in Figure 5. The individual states of stimulation suggest a baseline, which is intermediate to the YB/WD and FX conditions in the midline and intermediate to the YB and WD conditions at the lateral sites, as shown graphically in Figure 4. In Figure 5, the variable activity is shown as arbitrary sinus curves, drawn (although not to scale) to reflect the low frequency (0.1-0.2 Hz) fluctuations of intracranial pressure, oxygen tension, and circulation recorded in brain tissue by different methods [77].


Figure 5. Reconstructed time courses of changes of rCMRO2 and rCBF at the four independent locations identified in the present study and labeled on the graph. The abscissa presents an approximate time axis corresponding to the duration of the PET sessions and their intervals. In reality stimulus conditions were ordered randomly but they are shown sequentially in the Figure. The ordinates present the maximum range of the recorded changes from the whole-brain average. The circles and bars indicate actually determined changes and their standard errors. In the absence of an observed change, the variations are unknown, represented in the Figure as an arbitrary sinus curve. The connectivity suggested by the limited changes is shown to the right where sites of oxygen consumption change are shown as squares and sites of blood flow change as circles, in agreement with the symbols used in Figure 4. The labels indicate the stimulus contrasts associated with the suggested connections.

From this reconstruction, we deduced the simple code underlying the functional states associated with the YB, WD, and FX stimuli from the changes of rCMRO2 and rCBF shown in Figures 2 and 3: The oxygen metabolism and linked blood flow in the midline (V1 or V1/V2, depending on the definition) reflect the absence or presence of spatial frequency in the visual stimulus, while the oxygen metabolism and blood flow in V2 or V3v (VP) reflect the absence or presence of color reversal in a visual stimulus of an adequate spatial frequency, as shown in Figure 4.


In conclusion, we found significant focal changes of rCMRO2 and rCBF with differentially complex stimulation of the visual cortex. The changes of the two variables occurred at two main locations. The stimulus contrasts indicated the presence of a baseline below the activity of the intermediately complex WD stimulus at the midline sites and above this activity at the more lateral sites. The findings imply that baselines vary in and among regions and therefore affect the interpretation of the presence or absence of changes of the magnitude of BOLD signals that depend on the changes of cerebral blood flow and oxygen consumption in relation to an uncertain baseline.


The authors thank Sasan Andalib, PhD, for his assistance with the preparation of the manuscript. This study was first supported by grants from the Medical Research Council of Canada to the McConnell Brain Imaging Centre, Montreal Neurological Institute, McGill University, Montreal, Canada, and second from the Danish National Research Council’s Centers-of-Excellence Program to the Center of Functionally Integrative Neuroscience, University of Aarhus, Aarhus, Denmark.


1. Widen L, How shall we measure regional brain work? Proceedings of the Alfred Benzon Symposium;Brain work and mental activityQuantitative studies with radioactive tracers 1991; 31: 127-139.

2. Gusnard D.A, Akbudak E, Shulman G.L, Raichle M.E, Medial prefrontal cortex and self-referential mental activity. Relation to a default mode of brain functionProc. Nat. Acad. Sci. U.S.A 2001; 98: 4259-4264.

3. Hyder F, Herman P, Bailey CJ, Møller A, Globinsky R, Fulbright RK, Rothman DL, Gjedde A, Uniform distributions of glucose oxidation and oxygen extraction in gray matter of normal human brain. No evidence of regional differences of aerobic glycolysisJ Cereb Blood Flow Metab 2016 2016; Jan11Epub ahead of print

4. Maggioni E, Zucca C, Reni G, Cerutti S, Triulzi FM, Bianchi AM, Arrigoni F, Investigation of the electrophysiological correlates of negative BOLD response during intermittent photic stimulation, An EEG-fMRI studyHum Brain Mapp 2016 2016; Mar14doi:10.1002/hbm.23170. [Epub ahead of print]

5. Vafaee M.S, Gjedde A, Model of blood-brain transfer of oxygen explains nonlinear flow-metabolism coupling during stimulation of visual cortexJ. Cereb. Blood Flow Metab 2000; 20: 747-754.

6. Fox P, Raichle M, Focal physiological uncoupling of cerebral blood flow and oxidative metabolism during somatosensory stimulation in human subjectsProc. Natl. Acad. Sci. U.S.A 1986; 83: 1140-1144.

7. Fox P, Raichle M, Mintun M, Dence C, Nonoxidative glucose consumption during focal physiological activityScience 1988; 241: 462-464.

8. Fox P.T, Mintun M.A, Noninvasive functional brain mapping by change-distribution analysis of averaged PET images of H215O tissue activityJ. Nucl. Med 1989; 30: 141-149.

9. Bergersen LH, Gjedde A, Is lactate a volume transmitter of metabolic states of the brain?Front Neuroenergetics 2012; 4: 5-doi: 10.3389/fnene.2012.00005. eCollection 2012

10. Vafaee MS, Vang K, Bergersen LH, Gjedde A, Oxygen consumption and blood flow coupling in human motor cortex during intense finger tapping. implication for a role of lactateJ Cereb Blood Flow Metab 2012 2012; 32: 1859-1868.

11. Hyder F, Rothman D.L, Shulman R.G, Total neuroenergetics support localized brain activity. implications for the interpretation of fMRIProc. Natl. Acad. Sci. U.S.A 2002; 99: 10771-10776.

12. Thompson J.K, Peterson M.R, Freeman R.D, Single-neuron activity and tissue oxygenation in the cerebral cortexScience 2003; 299: 1070-1072.

13. Logothetis N.K, Pauls J, Augath M, Trinath T, Oeltermann A, Neurophysiological investigation of the basis of the fMRI signalNature 2001; 412: 150-157.

14. Gold L, Lauritzen M, Neuronal deactivation explains decreased cerebellar blood flow in response to focal cerebral ischemia or suppressed neocortical functionProc. Natl. Acad. Sci. U.S.A 2002; 99: 7699-7704.

15. Gallagher H.L, Jack A.I, Roepstorff A, Frith C.D, Imaging the intentional stance in a competitive gameNeuroimage 2002; 16: 814-821.

16. Jack A.I, Roepstorff A, Introspection and cognitive brain mapping. from stimulus-response to script-reportTrends Cogn. Sci 2002; 6: 333-339.

17. Vafaee M.S, Østergaard K, Sunde N, Gjedde A, Dupont E, Cumming P, Focal changes of oxygen consumption in cerebral cortex of patients with Parkinson’s disease during subthalamic stimulationNeuroimage 2004; 22: 966-974.

18. Gjedde A, Johannsen P, Cold G, Østergaard L, Cerebral metabolic response to low blood flow. Possible role of cytochrome oxidase inhibitionJ. Cereb. Blood Flow Metab 2005; 25: 1183-1196.

19. Shulman RG, Hyder F, Rothman DL, Baseline brain energy supports the state of consciousnessProc Natl Acad Sci U S A 2009; 106: 11096-1101.

20. Shulman R.G, Rothman D.L, Behar K.L, Hyder F, Energetic basis of brain activity. implications for neuroimagingTrends Neurosci 2004; 27: 489-495.

21. Livingstone M, Hubel D, Psychophysical evidence for separate channels for the perception of form, color, movement, and depthJ. Neurosci 1997; 7: 3416-3468.

22. Tootell R.B, Silverman M.S, Hamilton S.L, De Valois R.L, Switkes E, Functional anatomy of macaque striate cortex. III. ColorJ. Neurosci 1988; 8: 1569-1593.

23. Tootell R.B, Hamilton S.L, Switkes E, Functional anatomy of macaque striate cortex. IV. Contrast and magno-parvo streamsJ. Neurosci 1988; 8: 1594-1609.

24. Vafaee M.S, Meyer E, Marrett S, Evans A.C, Gjedde A, Increased oxygen consumption in human visual cortex. response to visual stimulationActa Neurol. Scand 1998; 98: 85-89.

25. Ohta S, Meyer E, Fujita H, Reutens D.C, Evans A, Gjedde A, Cerebral [15O]water clearance in humans determined by PET. I. Theory and normal valuesJ. Cereb. Blood Flow Metab 1996; 16: 765-780.

26. Ohta S, Meyer E, Thompson C.J, Gjedde A, Oxygen consumption of the living human brain measured after a single inhalation of positron emitting oxygenJ. Cereb. Blood Flow Metab 1992; 12: 179-192.

27. Woods R.P, Mazziotta J.C, Cherry S.R, Rapid Automated Algorithm for Aligning and Reslicing PET ImagesJ. Comput. Assist. Tomogr 1992; 16: 620-633.

28. Talairach J, Tournoux P, Co-planar stereotaxic atlas of the human brain 1988; Stuttgart: George Thieme Verlag;

29. Collins D.L, Neelin P, Peters T.M, Evans A.C, Automatic 3D intersubject registration of MR volumetric data in standardized Talairach spaceJ. Comput. Assist. Tomogr 1994; 18: 192-205.

30. Worsley K, Evans A, Marrett S, Neelin P, A three-dimensional statistical analysis for CBF activation studies in human brainJ. Cereb. Blood Flow Metab 1992; 12: 900-918.

31. Amunts K, Malikovic A, Mohlberg H, Schormann T, Zilles K, Brodmann’s areas 17 and 18 brought into stereotaxic space - where and how variable?Neuroimage 2000; 11: 66-84.

32. Watson J.D.G, Toga A.W, Mazziotta J.C, The human visual systemBrain Mapping. The Systems 2003; San Diego: Academic Press; 263-289.

33. Tong F, Primary visual cortex and visual awarenessNat. Rev. Neurosci 2003; 4: 219-229.

34. Liu L, She L, Chen M, Liu T, Lu HD, Dan Y, Poo MM, Spatial structure of neuronal receptive field in awake monkey secondary visual cortex (V2)Proc Natl Acad Sci U S A 2016; 113: 1913-1918.

35. Ribeiro L, Kuwabara H, Meyer E, Fujita H, Marrett S, Evans A.C, Gjedde A, Uemura K, Lassen N, Jones T, Kanno I, Cerebral Blood flow and metabolism during non-specific bilateral visual stimulation in normal subjectsQuantification of Brain Function: Tracer kinetics and image analysis in brain PET 1993; Amsterdam: Elsevier; 229-234.

36. Gjedde A, Marrett S, Vafaee M, Oxidative and nonoxidative metabolism of excited neurons and astrocytesJ. Cereb. Blood Flow Metab 2002; 22: 1-14.

37. Hyder F, Patel AB, Gjedde A, Rothman DL, Behar KL, Shulman RG, Neuronal-glial glucose oxidation and glutamatergic-GABAergic functionJ Cereb Blood Flow Metab 2006; 26: 865-877.

38. Aanerud J, Borghammer P, Chakravarty MM, Vang K, Rodell AB, Jónsdottir KY, Møller A, Ashkanian M, Vafaee MS, Iversen P, Johannsen P, Gjedde A, Brain energy metabolism and blood flow differences in healthy agingJ Cereb Blood Flow Metab 2012; 32: 1177-1187.

39. Shulman R.G, Rothman D.L, Interpreting functional imaging studies in terms of neurotransmitter cyclingProc. Natl. Acad. Sci. U.S.A 1998; 95: 11993-11998.

40. Shulman RG, Hyder F, Rothman DL, Insights from neuroenergetics into the interpretation of functional neuroimaging. an alternative empirical model for studying the brain’s support of behaviorJ Cereb Blood Flow Metab 2014; 34: 1721-1735.

41. Hoge R.D, Atkinson J, Gill B, Crelier G.R, Marrett S, Pike G.B, Linear coupling between cerebral blood flow and oxygen consumption in activated human cortexProc. Natl. Acad. Sci. U.S.A 1999; 96: 9403-9408.

42. Gjedde A, Marrett S, Glycolysis in neurons, not astrocytes, delays oxidative metabolism of human visual cortex during sustained checkerboard stimulation in vivoJ. Cereb. Blood Flow Metab 2001; 21: 1384-1392.

43. Tootell R.B, Silverman M.S, Hamilton S.L, Switkes E, De Valois R.L, Functional anatomy of macaque striate cortex. V. Spatial frequencyJ. Neurosci 1988c 1988c; 8: 1610-1624.

44. Hyder F, Kennan RP, Kida I, Mason GF, Behar KL, Rothman D, Dependence of oxygen delivery on blood flow in rat brain. a 7 tesla nuclear magnetic resonance studyJ Cereb Blood Flow Metab 2000; 20: 485-98.

45. Bailey CJ, Sanganahalli BG, Herman P, Blumenfeld H, Gjedde A, Hyder F, Analysis of time and space invariance of BOLD responses in the rat visual systemCereb Cortex 2006; 23: 210-222.

46. Vafaee MS, Gjedde A, Imamirad N, Vang K, Chakravarty MM, Lerch JP, Cumming P, Smoking normalizes cerebral blood flow and oxygen consumption after 12-hour abstentionJ Cereb Blood Flow Metab 2015; 35: 699-705.

47. Buxton R.B, Frank L.R, A model for the coupling between cerebral blood flow and oxygen metabolism during neural stimulationJ. Cereb. Blood Flow Metab 1997; 17: 64-72.

48. Gjedde A, Batjer H.H, The relation between brain function and cerebral blood flow and metabolismCerebrovascular Disease 1997; Philadelphia: Lippincott-Raven; 23-40.

49. Aubert A, Costalat R, Valabregue R, Modelling of the coupling between brain electrical activity and metabolismActa Biotheor 2001; 49: 301-326.

50. Valabregue R, Aubert A, Burger J, Bittoun J, Costalat R, Relation between cerebral blood flow and metabolism explained by a model of oxygen exchangeJ. Cereb. Blood Flow Metab 2003; 23: 536-545.

51. Vafaee M.S, Gjedde A, Spatially dissociated flow-metabolism coupling in brain activationNeuroImage 2004; 21: 507-515.

52. Mintun M, Raichle M, Martin W, Herscovitch P, Brain oxygen utilization measured with O-15 radiotracers and positron emission tomographyJ. Nucl. Med 1984; 25: 177-187.

53. Gjedde A, Aanerud J, Peterson E, Ashkanian M, Iversen P, Vafaee M, Møller A, Borghammer P, Variable ATP yields and uncoupling of oxygen consumption in human brainAdv Exp Med Biol 2011; 701: 243-248.

54. Nyberg L, Tulving E, Habib R, Nilsson L.G, Kapur S, Houle S, Cabeza R, McIntosh AR, Functional brain maps of retrieval mode and recovery of episodic informationNeuroreport 1995; 7: 249-252.

55. Fink G.R, Markowitsch H.J, Reinkemeier M, Bruckbauer T, Kessler J, Heiss W.D, Cerebral representation of one’s own past. neural networks involved in autobiographical memoryJ. Neurosci 1996; 16: 4275-4282.

56. Fink G.R, Marshall J.C, Halligan P.W, Frith C.D, Frackowiak R.S, Dolan R.J, Hemispheric specialization for global and local processing. the effect of stimulus categoryProc. R. Soc. Lond. B. Biol. Sci 1997; 264: 487-494.

57. Phillips M.L, Young A.W, Senior C, Brammer M, Andrew C, Calder A.J, Bullmore E.T, Perrett D.I, Rowland D, Williams S.C, Gray J.A, David A.S, A specific neural substrate for perceiving facial expressions of disgustNature 1997; 389: 495-498.

58. Ellermann J.M, Siegal J.D, Strupp J.P, Ebner T.J, Ugurbil K, Activation of visuomotor systems during visually guided movements. a functional MRI studyJ. Magn. Reson 1998; 131: 272-85.

59. Casey B.J, Cohen J.D, O’Craven K, Davidson RJ, Irwin W, Nelson CA, Noll DC, Hu XD, Lowe M.J, Rosen B.R, Truwitt C.L, Turski P.A, Reproducibility of fMRI results across four institutions using a spatial working memory taskNeuroImage 1998; 8: 249-261.

60. Duncan J, Seitz R.J, Kolodny J, Bor D, Herzog H, Ahmed A, Newell F.N, Emslie H, A neural basis for general intelligenceScience 2000; 289: 457-4560.

61. Gerlach C, Law I, Gade A, Paulson O.B, Categorization and category effects in normal object recognition. a PET studyNeuropsychologia 2000; 38: 1693-1703.

62. Macaluso E, Frith C.D, Driver J, Modulation of human visual cortex by crossmodal spatial attentionScience 2000; 289: 1206-1208.

63. Parsons L.M, Osherson D, New Evidence for Distinct Right and Left Brain Systems for Deductive versus Probabilistic ReasoningCereb Cortex 2001; 11: 954-965.

64. Aalto S, Naatanen P, Wallius E, Metsahonkala L, Stenman H, Niem P.M, Karlsson H, Neuroanatomical substrata of amusement and sadness. a PET activation study using film stimuliNeuroreport 2002; 13: 67-73.

65. Gerlach C, Aaside C.T, Humphreys G.W, Gade A, Paulson O.B, Law I, Brain activity related to integrative processes in visual object recognition. bottom-up integration and the modulatory influence of stored knowledgeNeuropsychologia 2002; 40: 1254-1127.

66. Buchweitz A, Language and reading development in the brain today. ineuromarkers and the case for predictionJ Pediatr (Rio J) 2016; Mar15pii: S0021-7557(16)00048-6. doi: 10.1016/j.jped.2016.01.005. [Epub ahead of print]

67. Levy E.K, Levy D.E, Goldberg M.E, Art and the brain. The influence of art on Roger Shepard’s studies of mental rotationJ. Hist. Neurosci 2004; 13: 79-90.

68. Peterhans E, Trends Neurosci. Subjective contours--bridging the gap between psychophysics and physiologyTrends Neurosci 1991; 14: 112-9.

69. Rowe J, Friston K, Frackowiak R, Passingham R, Attention to action. specific modulation of corticocortical interactions in humansNeuroimage 2002; 17: 988-998.

70. Rowe J.B, Stephan K.E, Friston K, Frackowiak R.S, Passingham R.E, The prefrontal cortex shows context-specific changes in effective connectivity to motor or visual cortex during the selection of action or colourCereb Cortex 2005; 15: 85-95.

71. Hohwy J, Roepstorff A, Friston K, Predictive coding explains binocular rivalry. an epistemological reviewCognition 2008; 108: 687-701.

72. Ingvar D.H, Memory of the future. an essay on the temporal organization of conscious awarenessHum. Neurobiol 1985; 4: 127-136.

73. Lamme VA, Roelfsema PR, The distinct modes of vision offered by feedforward and recurrent processingTrends Neurosci 2000; 23: 571-9.

74. Zipser K, Lamme VA, Schiller PH, Contextual modulation in primary visual cortexJ Neurosci 1996; 15: 7376-89.

75. Schellekens W, van Wezel RJ, Petridou N, Ramsey NF, Raemaekers M, Predictive coding for motion stimuli in human early visual cortexBrain Struct Funct 2016; 221: 879-890.

76. van Pelt S, Heil L, Kwisthout J, Ondobaka S, van Rooij I, Bekkering H, Beta-and gamma-band activity reflect predictive coding in the processing of causal eventsSoc Cogn Affect Neurosci 2016; Feb12pii: nsw017, [Epub ahead of print]

77. Hudetz A.G, Biswal B.B, Shen H, Lauer K.K, Kampine P, Hudetz A.G, Bruley D, Spontaneous fluctuations in cerebral oxygen supplyOxygen Transport in Tissue 1998; New York: Plenum Press; 551-559.


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