Effect of basal conditions on the magnitude and dynamics of the blood oxygenation level-dependent fMRI response.

Abstract

The effect of the basal cerebral blood flow (CBF) on both the magnitude and dynamics of the functional hemodynamic response in humans has not been fully investigated. Thus, the hemodynamic response to visual stimulation was measured using blood oxygenation level-dependent (BOLD) functional magnetic resonance imaging (fMRI) in human subjects in a 7-T magnetic field under different basal conditions: hypocapnia, normocapnia, and hypercapnia. Hypercapnia was induced by inhalation of a 5% carbon dioxide gas mixture and hypocapnia was produced by hyperventilation. As the fMRI baseline signal increased linearly with expired CO2 from hypocapnic to hypercapnic levels, the magnitude of the BOLD response to visual stimulation decreased linearly. Measures of the dynamics of the visually evoked BOLD response (onset time, full-width-at-half-maximum, and time-to-peak) increased linearly with the basal fMRI signal and the end-tidal CO2 level. The basal CBF level, modulated by the arterial partial pressure of CO2, significantly affects both the magnitude and dynamics of the BOLD response induced by neural activity. These results suggest that caution should be exercised when comparing stimulus-induced fMRI responses under different physiologic or pharmacologic states.

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Effect of Basal Conditions on the Magnitude and Dynamics of
the Blood Oxygenation Level–Dependent fMRI Response
*†Eric R. Cohen, *Kamil Ugurbil, and *Seong-Gi Kim
*Center for Magnetic Resonance Research, Department of Radiology, University of Minnesota Medical School,
Minneapolis, Minnesota; and †Graduate Program in Neuroscience, State University of New York Upstate Medical University,
Syracuse, New York, U.S.A.
Summary: The effect of the basal cerebral blood flow (CBF)
on both the magnitude and dynamics of the functional hemo-
dynamic response in humans has not been fully investigated.
Thus, the hemodynamic response to visual stimulation was
measured using blood oxygenation level–dependent (BOLD)
functional magnetic resonance imaging (fMRI) in human sub-
jects in a 7-T magnetic field under different basal conditions:
hypocapnia, normocapnia, and hypercapnia. Hypercapnia was
induced by inhalation of a 5% carbon dioxide gas mixture and
hypocapnia was produced by hyperventilation. As the fMRI
baseline signal increased linearly with expired CO2from hy-
pocapnic to hypercapnic levels, the magnitude of the BOLD
response to visual stimulation decreased linearly. Measures of
the dynamics of the visually evoked BOLD response (onset
time, full-width-at-half-maximum, and time-to-peak) increased
linearly with the basal fMRI signal and the end-tidal CO2level.
The basal CBF level, modulated by the arterial partial pressure
of CO2, significantly affects both the magnitude and dynamics
of the BOLD response induced by neural activity. These results
suggest that caution should be exercised when comparing
stimulus-induced fMRI responses under different physiologic
or pharmacologic states. Key Words: Functional MRI—
Pharmacological MRI—Cerebral blood flow—Hypercapnia—
Hypocapnia—Brain mapping—Autoregulation.
It is well known that global cerebral blood flow (CBF)
can be modulated by changes in arterial partial pressures
of carbon dioxide and oxygen. It has also been shown or
suggested that the intake of commonly used substances
(e.g., caffeine, nicotine, alcohol), changes in the concen-
tration of endogenous substances (e.g., estrogen, adrena-
line), the experimental administration of various drugs
(e.g., cocaine, acetazolamide), and the use of anesthetic
agents can cause global perturbations of CBF. It is there-
fore important to examine how modulation of the global
CBF baseline affects the local hemodynamic response to
neural activity.
The change in the steady-state magnitude of the task-
induced hemodynamic response during manipulation of
the basal CBF has been extensively studied (Corfield et
al., 2001; Hoge et al., 1999a; Kemna et al., 2001; Maxi-
millian et al., 1980; Ramsay et al., 1993; Shimosegawa et
al., 1995). These findings can be divided into two mod-
els. The proportional model describes the functionally
induced CBF change as being proportional to the basal
CBF, resulting in a constant relative CBF change. The
additive model describes the absolute CBF change as
being constant and independent of the basal CBF.
Which model is the most appropriate is still a source of
controversy.
The dependence of the dynamic properties of the
stimulus-induced hemodynamic response on basal CBF
conditions has not been thoroughly explored. Some in-
vestigators have approached this problem theoretically
by developing models to describe the dependence of the
blood oxygenation level–dependent (BOLD) functional
magnetic resonance imaging (fMRI) signal on the blood
flow into the venous compartment of the vasculature
(Buxton et al., 1998; Friston et al., 2000; Mandeville et
al., 1999). According to these models, the hemodynamic
response will be faster when the basal CBF is elevated
and other parameters are kept constant (Friston et al.,
2000). However, this prediction has not been demon-
strated empirically and, in general, few studies have
Received January 7, 2002; final version received April 29, 2002;
accepted April 30, 2002.
This work was supported in part by Grants NIH RR08079, NS38295,
NS40719, and MH57180, and the National Alliance of Schizophrenia
and Depression. The 7-T imaging system was funded by Grants NSF
DBI9907842, NIH S10 RR13957, the MIND Institute, and the Keck
Foundation.
Address correspondence and reprint requests to Dr. Seong-Gi Kim,
Center for Magnetic Resonance Research, 2021 6th Street SE, Minne-
apolis, MN 55455, U.S.A.; e-mail: kim@cmrr.umn.edu
Journal of Cerebral Blood Flow & Metabolism
22:1042–1053 © 2002 The International Society for Cerebral Blood Flow and Metabolism
Published by Lippincott Williams & Wilkins, Inc., Philadelphia
1042

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experimentally investigated the dependence of the tem-
poral characteristics of metabolically induced hemody-
namic changes on basal cerebrovascular conditions.
Moreover, with one very recent exception (Kemna and
Posse, 2001), most of these investigations have been
conducted in anesthetized animals (Ances et al., 2001;
Bakalova et al., 2001; Matsuura et al., 2000; Silva et al.,
1999).
In this study, we used hypercapnia and hypocapnia to
alter the global CBF baseline and compared the visually
evoked BOLD responses to those obtained during nor-
mocapnia. We demonstrate that the magnitude and dy-
namic characteristics of the BOLD response in the visual
cortex are a function of basal cerebrovascular conditions,
and our data support the notion that the vascular changes
brought about by changes in the arterial partial pressure
of carbon dioxide (PaCO2) strongly influence the BOLD-
response temporal profile. Specifically, our results illus-
trate that, within the PaCO2range employed in this study,
as measured by the end-tidal CO2(ETCO2), the stimulus-
evoked BOLD response becomes slower and peaks
lower with increasing ETCO2level and the increasing
basal MRI signal. A portion of these results has previ-
ously been presented in abstract form (Cohen et al.,
2001a).
MATERIALS AND METHODS
General
The study was conducted in two separate sessions, one in
which hypercapnia was induced and the other in which hypo-
capnia was induced. Seven subjects participated in both the
hypercapnia and hypocapnia experiments. One subject’s data
were discarded owing to a poor signal-to-noise ratio. The re-
sults of the remaining six subjects (five women, one man; mean
age, 30.8 ± 9.9 years) are reported. All participants were in
good health. Informed consent was obtained from all subjects
in accordance with the guidelines of the University of Minne-
sota Medical School’s Institutional Review Board.
Each subject lay supine inside the magnet bore with his/her
head situated in the surface coil such that the occipital cortex
was centered in the coil loops. The sides of the head were
packed with foam cushions to minimize head motion. A mirror
was attached to the coil so that the subject could view a backlit
projection screen, situated near the top of his/her head, on
which the visual stimulus was presented from an LCD video
projector (NEC Technologies, Inc., Itasca, IL, U.S.A.). The
subject’s pulse and respiration waveforms were continuously
monitored with a pulse oximeter and a respiration belt, and
these data were collected by a desktop computer running Ac-
knowledge software (Biopac Systems, Inc., Santa Barbara, CA,
U.S.A.). MRI data acquisition, visual stimulation, and physi-
ologic recording were synchronized.
Magnetic resonance imaging
The experiments were performed in a 7-T magnet (Magnex
Scientific, Abingdon, U.K.), controlled from a Varian UnityINOVA
(Varian, Inc., Palo Alto, CA, U.S.A.) console, with a home-
built, dual-loop quadrature surface coil (oval loop diameters ?
10 × 7 cm; Adriany et al., 2000). Axial and sagittal scout
images were obtained to assess proper head position, following
which localized, automated shimming (Gruetter, 1993; Gruetter
and Tkac, 2000) was performed to achieve a water proton line
width of approximately 20 Hz or less over a spherical volume
with a radius of 35 mm. Anatomic images were acquired with
a 2-D, inversion-prepared fast low-angle shot (TurboFLASH)
imaging sequence (repetition time [TR] ? 0.011 seconds, echo
time [TE] ? 5 milliseconds, inversion time [TI] ? 1.4 sec-
onds, matrix size ? 128 × 128, field of view ? 18 × 18 cm2,
slice thickness ? 5 mm). From the sagittal anatomic images, a
single oblique slice, positioned approximately parallel to the
calcarine sulcus, was chosen for the fMRI experiments. Func-
tional images were obtained with a T2*-weighted echo-planar
imaging (EPI) sequence (TR ? 0.333 seconds, TE ? 25 mil-
liseconds, matrix size ? 64 × 64, field of view ? 18 × 18 cm2,
slice thickness ? 5 mm). To achieve the desired echo time of
25 milliseconds in a single-shot image, a shifted gradient echo
approach was used. This TE provides a maximal contrast-to-
noise ratio at 7 T (Yacoub et al., 2001a). The radio frequency
excitation pulse was calibrated to the Ernst flip angle of ap-
proximately 36 degrees within the primary visual cortex of
each subject. At low flip angle, the contribution of inflow ef-
fects to BOLD signal change is minimal (Kim et al., 1994).
Experiment protocol
Each run of the combined fMRI (visual stimulation) and
global CBF modulation experiment consisted of 1,305 images
(7.25 minutes) during which the subject fixated on a small, red,
circular fixation point on a uniform gray background of the
approximate mean luminance of the visual stimulus. Following
the first 90 control images, a visual stimulus was presented on
the screen for four seconds every 135 images (45 seconds). The
visual stimulus, generated by a Macintosh computer with Vi-
sion Shell software (St-Hyacinthe, Quebec, Canada), consisted
of a full-field black-and-white checkerboard at 90% contrast,
counter phase flickering at 4.5 Hz, with the same central fixa-
tion point described previously. During the fMRI studies, glob-
al blood flow was simultaneously modulated for 3 minutes by
inducing hypercapnia or hypocapnia. Basal blood flow modu-
lation started at the onset of the third stimulus and ended at the
beginning of the seventh stimulus (i.e., between image numbers
361 and 900). The ETCO2was monitored using a capnometer
(Datex-Ohmeda, Madison, WI, U.S.A.) and recorded by the
physiologic monitoring computer. The experiment run was re-
peated three to six times.
During each run of the experiment, the subject’s nose was
closed with a nose clip and the subject breathed through a
plastic mouthpiece. Air, either normal or enriched with 5%
CO2, was filtered and humidified with a heat-moisture ex-
changer (Baxter Healthcare Corp., Deerfield, IL, U.S.A.) and
delivered to the subject at approximately 15 to 25 L/min
through corrugated tubing attached to the mouthpiece. For the
3-minute elevation of ETCO2in the hypercapnia experiments, a
three-way valve was used to manually switch between normal
air and 5% CO2-enriched air. Reduction of ETCO2during the
hypocapnia experiments was achieved by having subjects hy-
perventilate. Just prior to the hypocapnia experiments, subjects
breathed through the breathing apparatus and practiced hyper-
ventilating outside of the magnet while being monitored with
the capnometer. Subjects were instructed to concentrate pri-
marily on inspiring and expiring fully and secondarily on in-
creasing breathing rate in order to reduce their ETCO2steadily
and to a target level that was comfortable to maintain for the
3-minute period (i.e., between approximately 22–32 mm Hg).
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When a steady level of hypocapnia was achieved during the
hyperventilation practice period, the subject’s breathing rate
was noted and, during the actual experiment, a computer-
generated tone was played at the same rate via plastic tubes in
the subject’s earplugs using an MRI-compatible stereo system
(Resonance Technology Company, Inc., Los Angeles, CA,
U.S.A.). The subjects were instructed to use the metronome as
a rough guide for pacing breathing during the hyperventilation
periods to reproduce the results achieved in the practice
session.
Image postprocessing and data analysis
Functional images were corrected for artifacts due to heart-
beat and respiration using a linear k-space phase correction
algorithm (Pfeuffer et al., 2002) and/or a physiologic correction
program (Hu et al., 1995). Data from experiment runs that were
free of motion artifacts, determined by the absence of large,
abrupt changes in the time series of the center of mass of the
images, were averaged together to create one functional image
time series for each subject. To reduce the incidence of false-
positive activations outside of the brain and at large vessels,
only those pixels whose standard deviation relative to the base-
line signal during the initial control period was ?3% (Kim et
al., 1994) were further analyzed. Active pixels were determined
by performing a pixel-by-pixel cross-correlation analysis with a
model hemodynamic response function using Stimulate soft-
ware (Strupp, 1996). The hemodynamic response function was
created by convolving a Poisson function with a boxcar train
that emulated the visual stimulus time course (Friston et al.,
1994). Pixels whose cross-correlation coefficient (cc) evaluated
to P < 0.01 were considered active (Bandettini et al., 1993).
With a vector of 1,294 points, a cc of 0.07 corresponds to a P
value of 0.01 and a cc of 0.4 corresponds to a P value < 1 ×
10–4(Bandettini et al., 1993). A rectangular region of interest
(ROI) was drawn in the posteromedial region of the cortex (Fig.
2a) to include approximately 75 of the active pixels (75.0 ± 1.3
pixels for the hypercapnia data; 74.0 ± 3.5 for the hypocapnia
data). From these pixels, an average time course was generated.
The average time course from each subject was divided into
nine epochs of 135 images, each epoch beginning 10 images
prior to stimulus onset. A time course was considered as con-
sisting of three periods: prehyper-/hypocapnia, hyper-
/hypocapnia, and posthyper-/hypocapnia. Epochs that fell
within transition periods from one condition to another were
discarded. Hence, two prehyper-/hypocapnia epochs (referred
to as normocapnia epochs), two hyper-/hypocapnia epochs, and
one posthyper-/hypocapnia epoch from each subject were used
for further analysis.
To accurately determine the magnitude and temporal char-
acteristics of the hemodynamic response, each epoch was low-
pass filtered with a finite impulse response filter with a Ham-
ming window and a cutoff frequency of 0.45 Hz using
programs written in Matlab (The MathWorks, Inc., Natick,
MA, U.S.A.). The averaged time courses shown in the figures,
however, have not been temporally filtered. The following pa-
rameters were calculated for the visually evoked BOLD re-
sponse of each epoch: baseline signal, relative signal change
(i.e., peak height), full-width-at-half-maximum (FWHM), nor-
malized area of the BOLD response above baseline, onset time,
time to 50% of peak height, time to 90% of peak height, and
time-to-peak (TTP). The baseline signal was obtained from the
mean MRI signal of the 10 images prior to stimulus onset
relative to the mean signal of the 50 normocapnic images prior
to the first stimulus of the entire run. The onset time was
defined as the time to reach 10% of the peak height. The TTP
is defined as the time from stimulus onset to the peak of the
BOLD response. Data are reported as the mean ± one standard
deviation. Data collected during the normocapnia epochs and
hyper-/hypocapnia epochs were tested for significant differ-
ences by paired t-tests. Group data were assessed for linear
trends by least squares regression using Matlab. Slopes were
tested against zero and their statistical significances are re-
ported as two-tailed P values (Mendenhall et al., 1990).
RESULTS
Physiologic and blood oxygenation level–dependent
responses to hypercapnia and hypocapnia
The ETCO2, heart rates, and respiration rates during
and after the altered ETCO2episodes were compared with
their respective normocapnia values (Table 1). During
hypocapnia, the average ETCO2decreased by approxi-
mately 8 mm Hg from 35.1 ± 1.4 to 27.0 ± 4.0 mm Hg
(n ? 6 subjects, P < 0.005). The mean posthypocapnia
ETCO2did not differ significantly from that during hy-
pocapnia. The ETCO2from one subject was not recorded
during the hypercapnia experiments. Based on all other
measurements (n ? 5 subjects), the average ETCO2dur-
ing hypercapnia increased by approximately 10 mm Hg
from 36.8 ± 4.1 to 46.7 ± 3.2 mm Hg (P < 0.0001) and
returned to 36.6 ± 3.5 mm Hg (P < 0.0001) following
hypercapnia. Heart rate (n ? 5) and respiration rate (n ?
6) were not significantly changed by hypercapnia. Dur-
ing hypocapnia, however, heart rate increased by less
than 5 beats/min (P < 0.005). The mean respiration rate
increased insignificantly during hypocapnia by less than
5 breaths/min.
In Figure 1, the normalized T2*-weighted baseline sig-
nal is plotted as a function of the average ETCO2level
calculated from the baseline periods of the experiments.
One hypocapnia epoch from one subject was contami-
nated by large physiologic fluctuations that could not be
TABLE 1. Values of physiologic parameters
Prehypocapnia HypocapniaPosthypocapnia PrehypercapniaHypercapniaPosthypercapnia
ETCO2(mm Hg)
Heart rate (beats/min)
Respiration rate (breaths/min)
35.07 (1.42)‡
66.49 (9.45)‡
11.77 (2.69)
27.01 (4.00)
71.21 (9.04)
16.57 (9.14)
30.65 (6.60)*
68.69 (9.69)†
12.56 (2.44)
36.83 (4.15)*‡
75.73 (17.12)*
13.11 (4.45)
46.70 (3.20)*
76.72 (15.72)*
13.69 (4.19)
36.61 (3.52)*‡
76.68 (16.85)*
14.27 (4.83)
The values represent the mean of the physiologic parameters over all subjects (n ? 6), except where noted (*n ? 5), followed by one SD in
parentheses. Significant differences (t-test, one-tailed) between the pre- and post-perturbation periods and their hypercapnia or hypocapnia counter-
parts: †P < 0.005, ‡P < 0.0001.
ETCO2, end-tidal CO2.
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removed by the postprocessing methods. The remaining
11 hypocapnia epochs were used for further analysis and
are included here. As expected, the normalized T2*-
weighted baseline signal increased monotonically with
ETCO2in the ETCO2range examined in this study (Grubb
et al., 1974), and a significant linear trend was found (R2
? 0.79) with a slope of 0.0039 ± 0.0003/mm Hg (P < 1
× 10–4). Therefore, the ETCO2and baseline signal are
considered here as interchangeable parameters for the
purpose of determining the dependence of BOLD signal
parameters on basal conditions.
Characteristics of the ETCO2and blood oxygenation
level–dependent time courses
The BOLD time courses averaged over all six subjects
are shown along with the average time courses of the
ETCO2(Fig. 2B). Individual BOLD time courses were
obtained from an ROI drawn in the primary visual cor-
tex, similar to that shown for a single subject in Fig. 2A.
Significant activation was seen in and around the calca-
rine sulcus. The contribution of large venous vessels,
particularly the sagittal sinus, was reduced due to the use
of a very high static magnetic field strength (Yacoub et
al., 2001a). During ETCO2manipulation, the MRI signal
changed concomitantly with the ETCO2but with a slight
observable lag. This delay between the change in ETCO2
and the change in the T2*-weighted baseline signal can
be explained by the time between gas exchange in the
lungs and the subsequent change in cerebral venous
blood oxygenation (i.e., the transit time of blood from the
lungs to the heart, then to the cerebral arterial vessels,
and finally through the capillary beds to the venous ves-
sels). The hypercapnic ETCO2and BOLD time courses
promptly returned to baseline following cessation of the
CO2-enriched air delivery and the switch to normal air.
Recovery from hypocapnia was more prolonged and less
coupled to the T2*-weighted baseline signal following
hyperventilation. This finding is likely due to the fact
that, after the hyperventilation episode, subjects’ breath-
ing became shallower in a natural response to retain CO2.
As a result, ETCO2measurements during this period are
less indicative of the PaCO2, on which the magnitude
of the fMRI baseline signal actually relies. Therefore,
the posthyper-/hypocapnic responses were not further
evaluated.
Before further analyzing changes in the magnitude and
dynamics of the average signal, it was important to in-
vestigate whether all active pixels behaved similarly dur-
ing the hypocapnic and hypercapnic conditions, respec-
tively. Thus, stimulus-induced BOLD fMRI responses
during prehypocapnia, hypocapnia, prehypercapnia, and
hypercapnia were examined on a pixel-by-pixel basis.
Data from two representative subjects are shown in Fig.
3. The relative peak height of the BOLD response during
hypocapnia and hypercapnia (Figs. 3A and 3B) is plotted
for each pixel versus its preperturbation normocapnic
level. It can be seen that the majority of active pixels
under each altered condition responded in relatively the
same manner, shifting to larger amplitudes during hypo-
capnia and lower amplitudes during hypercapnia. Simi-
larly, in Figs. 3C and 3D, the TTP of each pixel during
hypercapnia and hypocapnia is plotted versus its preper-
turbation value. The general tendency is apparent, with
the TTP becoming longer during hypercapnia and shorter
during hypocapnia. The results of this analysis were
similar for all subjects. This finding demonstrated that
changes in the fMRI characteristics of all active pixels
were similar, and that the average response of the active
pixels is a reliable indicator of the cortical response.
Each subject’s average response was obtained from
approximately 75 active pixels within a rectangular ROI
in the posteromedial aspect of the visual cortex and sub-
sequently used for intersubject averaging. Using a mean
signal generated from a similar number of pixels with a
high signal-to-noise ratio (i.e., pixels in V1 that were
close to the surface coil) ensured that each subject’s data
were equally weighted. This compensated for potential
biases arising from the fact that the signal-to-noise ratio
varied across subjects and therefore activation maps for
individual subjects generally contained different num-
bers of active pixels. It should be noted, however, that an
analysis of the average of all active pixels was consistent
with that described for the ROI-based approach.
The influence of the basal ETCO2on the stimulus-
induced BOLD signal can be examined clearly in Fig. 4
in which the BOLD responses during hypocapnia (n ? 6
FIG. 1. Normalized baseline magnetic resonance imaging (MRI)
signal versus end-tidal CO2(ETCO2). One subject’s ETCO2was
not recorded during the hypercapnia experiment. One hypocap-
nia epoch from one subject contained large physiologic fluctua-
tions and was excluded from further analysis. The data shown
were obtained from the remaining hypocapnia (n = 2 hypocapnia
epochs × 6 subjects − 1 = 11), normocapnia (n = 2 prehypercap-
nia epochs × 5 subjects + 2 prehypocapnia epochs × 6 subjects
= 22), and hypercapnia (n = 2 hypercapnia epochs × 5 subjects
= 10) epochs. The global baseline T2*-weighted signal shows a
significant linear dependence on the ETCO2. The linear regres-
sion equation is displayed on the plot (R2= 0.79). The data are
plotted with four different symbols representing the four experi-
mental periods analyzed: prehypocapnia (squares), hypocapnia
(circles), prehypercapnia (triangles), and hypercapnia (dia-
monds). The flattening of the slope in the normocapnia range is
due to the normalization of the prehypocapnia and prehypercap-
nia baselines to 1.0.
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subjects), normocapnia (n ? 2 experiments × 6 subjects
? 12), and hypercapnia (n ? 6 subjects) were averaged,
respectively. Detailed characteristics of these responses
are provided in Table 2. The visually evoked BOLD
response displayed a profoundly strong dependence on
the baseline condition. As the baseline ETCO2increased
during hypercapnia, the visually evoked BOLD response
became distinctively lower, slower, and broader. During
hypocapnia, when the baseline ETCO2decreased, the
evoked BOLD response increased in magnitude and be-
came faster and narrower. The original pattern of the
BOLD response returned after the recovery of the base-
line signals to their normocapnic levels (Fig. 2b). Despite
the dependence of the magnitude and TTP on the ETCO2,
the integrated area of the BOLD signal above baseline
did not change significantly during hypocapnia relative
to normocapnia and decreased by 18% during hypercap-
nia (n ? 6, P ? 0.007).
In Figure 4, it is apparent that a poststimulus under-
shoot exists during hypocapnia and normocapnia but not
during hypercapnia. An early negative response or “ini-
tial dip” following the onset of stimulation was not ob-
served here under any basal condition. The initial dip has
recently been observed in visual cortex at 7 T and its
magnitude has been shown to increase with magnetic
field strength (Yacoub et al. 2001b). It is unlikely, how-
ever, to detect the initial dip in humans in the average
time course generated from a large ROI. Rather, a tem-
plate of the initial dip must be used in the cross-
correlation analysis to identify pixels exhibiting an early
negative response (Yacoub et al. 2001b). Further, in or-
der to detect the dip, extensive signal averaging is re-
quired. In our study, only limited signal averaging was
performed and our cross-correlation template did not in-
clude a model of the initial dip. Hence, an early negative
response is not apparent in the time courses presented here.
FIG. 2. (A) A representative activation map, overlaid on a T1-
weighted image, and a region of interest from which a time
course was generated for this subject. The map colors corre-
spond to cross-correlation (cc) values, coded according to the
color bar. (B) Averaged blood oxygenation level–dependent
(BOLD) time courses (thick lines) and averaged end-tidal CO2
(ETCO2) level (thin lines) during the normocapnia/hypercapnia
(red lines) and the normocapnia/hypocapnia (blue lines) experi-
ments. Data from all six subjects were averaged. Hypercapnia or
hypocapnia was induced for a 3-minute period, indicated by the
shaded portion of the graph.
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