Regional Differences in the Coupling between Resting Cerebral Blood Flow and Metabolism may Indicate Action Preparedness as a Default State

Article (PDF Available)inCerebral Cortex 19(2):375-82 · July 2008with20 Reads
DOI: 10.1093/cercor/bhn087 · Source: PubMed
Although most functional neuroimaging studies examine task effects, interest intensifies in the "default" resting brain. Resting conditions show consistent regional activity, yet oxygen extraction fraction constancy across regions. We compared resting cerebral metabolic rates of glucose (CMRgl) measured with 18F-labeled 2-fluoro-2-deoxy-D-glucose to cerebral blood flow (CBF) 15O-H2O measures, using the same positron emission tomography scanner in 2 samples (n = 60 and 30) of healthy right-handed adults. Region to whole-brain ratios were calculated for 35 standard regions of interest, and compared between CBF and CMRgl to determine perfusion relative to metabolism. Primary visual and auditory areas showed coupling between CBF and CMRgl, limbic and subcortical regions--basal ganglia, thalamus and posterior fossa structures--were hyperperfused, whereas association cortices were hypoperfused. Hyperperfusion was higher in left than right hemisphere for most cortical and subcallosal limbic regions, but symmetric in cingulate, basal ganglia and somatomotor regions. Hyperperfused regions are perhaps those where activation is anticipated at short notice, whereas downstream cortical modulatory regions have longer "lead times" for deployment. The novel observation of systematic uncoupling of CBF and CMRgl may help elucidate the potential biological significance of the "default" resting state. Whether greater left hemispheric hyperperfusion reflects lateral dominance needs further examination.
Cerebral Cortex February 2009;19:375--382
Advance Access publication June 4, 2008
Regional Differences in the Coupling
between Resting Cerebral Blood Flow and
Metabolism may Indicate Action
Preparedness as a Default State
Ruben C. Gur
, J. Daniel Ragland
, Martin Reivich
, Joel
H. Greenberg
, Abass Alavi
and Raquel E. Gur
Section of Neuropsychiatry, Department of Psychiatry and the
Philadelphia Veterans Administration Medical Center
Philadelphia, PA 19104, USA,
Department of Radiology,
Cerebrovascular Research Center of the Department of
Neurology, University of Pennsylvania, Philadelphia, PA 19104,
USA and
Current address: Imaging Research Center,
Department of Psychiatry and Behavioral Sciences, University
of California at Davis, Sacramento, CA 95817, USA
Although most functional neuroimaging studies examine task
effects, interest intensifies in the ‘default’ resting brain. Resting
conditions show consistent regional activity, yet oxygen extraction
fraction constancy across regions. We compared resting cerebral
metabolic rates of glucose (CMRgl) measured with
F-labeled 2-
D-glucose to cerebral blood flow (CBF)
measures, using the same positron emission tomography scanner in
2 samples (n 5 60 and 30) of healthy right-handed adults. Region to
whole-brain ratios were calculated for 35 standard regions of
interest, and compared between CBF and CMRgl to determine
perfusion relative to metabolism. Primary visual and auditory areas
showed coupling between CBF and CMRgl, limbic and subcortical
regions—basal ganglia, thalamus and posterior fossa structures—
were hyperperfused, whereas association cortices were hypoper-
fused. Hyperperfusion was higher in left than right hemisphere for
most cortical and subcallosal limbic regions, but symmetric in
cingulate, basal ganglia and somatomotor regions. Hyperperfused
regions are perhaps those where activation is anticipated at short
notice, whereas downstream cortical modulatory regions have
longer ‘lead times’’ for deployment. The novel observation of
systematic uncoupling of CBF and CMRgl may help elucidate the
potential biological significance of the ‘default’ resting state.
Whether greater left hemispheric hyperperfusion reflects lateral
dominance needs further examination.
Keywords: functional neuroimaging, metabolic coupling, resting brain
Most functional neuroimaging studies have focused on identi-
fying neural networks activated by specific tasks (Brinkley and
Rosse 2002; Friston et al. 2002) but Raichle et al. (2001) have
pointed out the significance of the resting state as a ‘‘default
mode of brain function.’ (p. 676) Definitions of the ‘resting
state’ vary; there has even been concern that a ‘‘resting brain
state’ is theoretically untenable and measurements of cerebral
activity should only be done under structured task conditions
(Buchsbaum et al. 1984). However, as several studies (Baron
et al. 1982; Warach et al. 1987; Gur et al. 1995; Raichle 1998)
have demonstrated, conditions where no specific tasks are
given produce reliable and specific landscapes of metabolic
activity. Furthermore, such resting measures have shown
reliability of regional topography (Gur et al. 1987; Warach
et al. 1987), and some regional variability has been related to
habituation (Warach et al. 1992) and individual differences
(Goldstein et al. 2002; Wang et al. 2002).
Relationships between rates of cerebral metabolism and
blood flow have been examined in animals and humans and
these values were shown to be tightly coupled (Reivich 1974).
Studies in rats in which blood flow and glucose metabolism
have been measured in the same animal (Lear et al. 1981), or in
separate groups of animals (McCulloch et al. 1982; Frietsch
et al. 2000) have shown an excellent correlation between
blood flow and glucose metabolism. The animal data were
derived from autoradiographic measurements using ligands
labeled with radionuclides providing high spatial resolution.
This strong correlation was observed in spite of a significant
heterogeneity in capillary density throughout the brain (Klein
et al. 1986). In humans, positron emission tomography (PET)
studies have likewise reported high correlations among meas-
ures of metabolism and cerebral blood flow (CBF) (Baron et al.
1982; Fox et al. 1988; Bentourkia et al. 2000; Mintun et al. 2001).
Raichle et al. (2001; Raichle and Snyder 2007) pointed out
that task-induced changes in blood flow are accompanied by
smaller changes in oxygen consumption (Fox and Raichle
1986). This leads to decreased oxygen extraction fraction
(OEF) from blood when blood flow increases, and an increase
in oxygen extraction when blood flow decreases. Using PET
O labeled water, Raichle et al. (2001) found a stable
pattern of OEF during resting states, indicating deactivation
mainly in visual areas when the eyes are closed. They
interpreted the uniformity of OEF at rest to reflect an
equilibrium ‘‘between the local metabolic requirements nec-
essary to sustain a long-term modal level of neural activity and
the level of blood flow in that region.’ (Raichle et al. 2001, pp.
677--678). Raichle et al. (2001) also pointed out that although
task-induced activation occurs in a variety of regions depend-
ing on the task, specific regions become deactivated, relative to
a resting baseline condition, across a range of tasks. They
suggested that this network constitutes ‘an organized mode of
brain function that is present as a baseline or default state and is
suspended during specific goal-directed behaviors.’’ (Raichle
et al. 2001, p. 676). This hypothesis received considerable
attention and support in recent studies (e.g., Mason et al. 2007;
Shulman et al. 2007).
Notwithstanding the insights into the default brain state
provided by examination of the OEF, we still ‘do not fully
understand why the relationship between oxygen delivery and
oxygen consumption changes during changes in brain activity’’
(Raichle et al. 2001, p. 677). Further understanding can be
attained by examining the relationship between CBF and
cerebral metabolic rates for glucose (CMRgl). It has long been
recognized that the brain uses glucose as a metabolic substrate
almost exclusively, for energetic and even biosynthetic needs
(Siesjo¨ 1978; Sokoloff 1981; Clarke and Sokoloff 1999; Nehlig
and Coles 2007). Indeed, an abundant supply of glucose
through CBF is vital for brain function, as evidenced by nearly
instantaneous unconsciousness induced by supply interruption
2008 The Authors
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(Clarke and Sokoloff 1999). Furthermore, ‘[i]n the resting
brain, oxygen is almost entirely used for the oxidation of
glucose with only a small excess of glucose being metabolized
to lactate as a final product’’ (Nehlig and Coles 2007, p. 1239).
Task-related activation is associated with much smaller oxygen
consumption increases than either CBF or CMRgl (~5%
compared with ~54%, see Fox and Raichle 1986; Fox et al.
1988). Examining the relationship between CBF and CMRgl
could help explain the excess CBF relative to oxygen
metabolism increase associated with activation. Comparison
of such values at a resting state could help determine whether
the coupling between CBF and CMRgl is uniform across
regions, as is the case for OEF, or whether there are regions
that are either hyperperfused or hypoperfused at a resting
state, relative to CMRgl. With a larger CMRgl compared with
oxygen metabolism increase during activation, and an esti-
mated average extraction fraction of glucose from the blood
being about 8% (Hawkins et al. 1983), we hypothesized that the
CMRgl coupling with CBF will not be as uniform as for oxygen
metabolism. Specifically, resting hyperperfusion would confer
advantage to regions that are at the ‘frontline’ of the
information-processing cascade, such as subcortical limbic
areas, whereas regions involved in downstream modulation
could afford relative hypoperfusion at rest. Both CMRgl and
CBF have been measured with PET, using
glucose and
O labeled water respectively, and we compared
region to whole-brain (R/WB) ratios of resting CBF with CMRgl
in a standard set of regions of interest (ROIs).
Materials and Methods
Data were examined from healthy participants in previously published
studies, which yielded 2 data sets. The first consisted of resting baseline
measures of CMRgl assessed with the
F-labeled 2-fluoro-
D-glucose) method and published in Gur et al. (1995). That
sample included 60 healthy volunteers (37 men, 23 women), age
± SD
± 6.8 years (range 18.1--44.1), and 14.6 ± 2.0 years of education.
The second data set consisted of resting baseline measures of CBF
determined with the
O ‘‘ramped infusion’ method (Ragland et al.
1997). The sample included 30 healthy subjects (16 men, 14 women),
± 6.3 years old (range 18.3--43.4), with 15.3 ± 1.9 years of
education. All participants were right-handed (Raczkowski et al. 1974).
The same recruitment and assessment procedures were applied in
both studies. Participants were recruited through advertisements in the
community and underwent medical, neurological and psychiatric
evaluation, including a structured interview, and laboratory tests.
Individuals with a history of any illnesses affecting brain function, such
as head trauma with loss of consciousness and substance use, were
excluded. The protocol was approved by the institutional review board
and written informed consent was obtained from each participant after
the nature and possible consequences of the study were explained.
Participants were all scanned in the morning after an overnight fast and
placed in the scanner in a supine position. Studies began by cannulating
a radial artery under local anesthesia with 2% xylocaine. A venous line
was placed in the contralateral antebrachium. Both lines were kept
patent with solutions of physiological saline. Imaging was performed on
the UGM 240H volume imaging scanner (Smith et al. 1994), with a 12.8
cm axial field of view and spatial resolution of 5.5-mm full width half
maximum in all directions (UGM Medical Systems, Philadelphia, PA)
(Karp et al. 1993). Participants’ heads were aligned along the orbito-
meatal line and manual head holder restraints reduced movement. During
resting baseline scans participants were recumbent in a quiet, dimly lit
room for the FDG study and in the scanner for the CBF study. In both they
were with eyes open and ears unoccluded, and instructed to stay quiet
and relaxed without either exerting mental effort or falling asleep.
Measures of CMRgl with
Approximately, 185 MBq (5 mCi) of FDG were administered intrave-
nously. To determine the input function, arterial samples were obtained
over 90 min. Activity of
F in 250-lL aliquots was measured in a dose
calibrator. Image acquisition began 40 min after isotope administration.
Tissue activity concentration per unit time was calculated using scanner
calibration and dead time correction factors. Together with calibrated
blood activity concentration values, metabolism was calculated using
lumped and rate constants (Reivich et al. 1985).
Measures of CBF with
Participants received intravenous injections of
O-water using
a modified bolus ramped infusion technique (Lammertsma et al.
1981; Smith et al. 1995). A programmed infusion of approximately
1665 MBq (45 mCi) of
O-water was delivered over 3.3 min. This
results in rapid elevation of tissue activity to the peak of the count rate
capability of the camera. The measuring period continued over 4.21
min., and dynamic scans were obtained continuously. Tissue activity
concentrations peak over the first 1.5 min of the measurement period
and then level off because of increased washout (Smith et al. 1995). To
determine the input function, arterial blood samples were obtained
through a 3-way stopcock coupled to the arterial catheter. The arterial
concentration of radioactivity was measured from 0.25-mL aliquots of
whole blood in a calibrated (6.4 kcps/mCi) NaI(Tl) well counter
(Tennelec 707, Memphis, TN). Aliquots of spun plasma were measured
as a cross check, but the whole blood values were used in the
Image Processing and Statistical Analysis
PET scans from the CMRgl and CBF studies were processed identically.
They were corrected for attenuation, scatter, and dead time, and were
cross--registered with corresponding magnetic resonance images (MRI)
using established procedures (Gur et al. 1987, 1995; Ragland et al.
1997). Templates with ROIs were custom fitted to MRI slices by
investigators trained to an inter-rater reliability criterion of
(intraclass correlation) for 39 of the 42 regions, and of these, 35 with
0.90 were included in the statistical analysis. Figure 1
illustrates the regional boundaries for the ROIs.
R/WB ratios were calculated based on the absolute metabolic rates
and CBF values. A Generalized Estimating Equations (GEE) logistic
regression (SAS Procedure Genmod) model, that accommodates
multiple nonindependent measurements without requiring sphericity,
was employed for data analysis with one between-group factor (CMRgl
vs. CBF) and one within-group factor (region). To contain type-I
(experimenter-wise) error probability, the analyses were done for 8
groups of regions as follows: 1) frontal: superior frontal; dorsal
prefrontal—lateral; dorsal prefrontal—medial; mid-frontal; inferior
frontal. 2) Parietal: sensorimotor; superior parietal; supramarginal gyrus.
3) Occipital: occipital cortex, lateral; occipital cortex, medial; lingual
gyrus; fusiform gyrus. 4) Temporal: occipital temporal; superior
temporal; mid-temporal; inferior temporal; temporal pole. 5) Limbic:
parahippocampal gyrus; hippocampus; amygdala; insula; orbital frontal;
rectal gyrus; cingulate gyrus—anterior; cingulate gyrus—genu; cingu-
late gyrus—posterior. 6) Corpus callosum: anterior; posterior. 7) Basal
ganglia--hypothalamus: caudate nucleus; lenticular—medial (globus
pallidus); lenticular—lateral (putamen); thalamus. 8) Somatomotor:
midbrain; pons; cerebellum. To examine effects of laterality, follow-up
GEE analyses were performed adding hemisphere as a within factor. To
contain type-I error, we first tested for the significance of the measure
hemisphere interaction, relevant to the issue of CBF/CMRgl coupling, and
if that was significant we tested higher-order measure
3 hemisphere 3
region interactions.
The regional resting baseline values for CMRgl and CBF in each
hemisphere are presented in Table 1. As expected, regions with
376 VariationinCBF--CMRglCoupling
Gur et al.
higher metabolic activity also had generally higher CBF. This
was reflected in a cross-sample correlation of r
= 0.563, df = 33,
= 0.0004. A scatterplot of regional values for CMRgl and CBF
(Fig. 2) indicates a smooth relationship across the range of
values, with greater inter-regional variability in CBF (average
variance of 0.0801
± 0.0292 for CBF compared with 0.022 ±
0.0081 for CMRgl, t = 10.71, df = 31.3, P
0.0001 [degrees of
freedom were Satterthwaite corrected for unequal variance
because F#
= 12.81, df = 29,59, P
0.0001]). Notably, the
amygdala (appearing as an outlier above the identity line in
Fig. 2) has disproportionately higher CBF than expected from
its CMRgl, and when it is removed the inter-regional cor-
relation improves to r
= 0.653, df = 32, P
The GEE comparing resting CMRgl and CBF for the frontal
regions showed no main effect of measure, v
(1) = 0.85, P =
0.3563, but a strong main effect of region, v
(4) = 52.51, P
0.0001 and a region 3 measure interaction, v
(3) = 27.42, P
0.0001, indicating that the effect was not uniform across
regions. All frontal regions showed relative hypoperfusion
except for the mid-frontal region, which showed marked
hyperperfusion. The parietal regions showed main effects of
measure, v
(1) = 7.75, P = 0.0054, CBF lower than CMRgl;
region, v
(2) = 41.63, P
0.0001, and a region 3 measure
interaction, v
(2) = 12.41, P = 0.0020, indicating that here too
the effect was not uniform across regions. Specifically, all
parietal regions showed hypoperfusion, but it was most
pronounced in the superior parietal compared with sensori-
motor and supramarginal regions. The occipital regions showed
no main effect of measure, v
(1) = 0.55, P = 0.4594, but a large
main effect for region, v
(3) = 56.90, P
0.0001; and a region 3
measure interaction, v
(2) = 31.42, P
0.0001, indicating that
here too the effect was not uniform across regions. The medial
occipital and lingual gyrus showed tight coupling between CBF
and CMRgl, the lateral occipital region was hypoperfused,
whereas the fusiform gyrus showed about equally marked
hyperperfusion. The temporal regions showed a main effect of
measure, v
(1) = 6.67, P = 0.0098, indicating overall
hypoperfusion. There was a main effect for region, v
(4) =
49.59, P
0.0001; and a region 3 measure interaction, v
(4) = 33.70, P
0.0001. The interaction indicated that although
2 temporal regions (occipito-temporal and superior temporal
gyrus) showed coupling between CBF and CMRgl, all other
temporal cortex regions showed hypoperfusion. For limbic
regions, the main effect of measure was significant in the
opposite direction, with CBF higher than CMRgl, v
(1) = 24.57,
0.0001. There was a main effect for region, v
(8) = 54.23,
0.0001; and a region 3 measure interaction, v
(8) =
48.33, P
0.0001. The interaction indicated that relative
hyperperfusion in limbic areas was attenuated in orbital frontal
cortex and the genu and posterior cingulate gyrus. For the
corpus callosum, the main effect of measure was significant in
the direction of relatively higher CBF than CMRgl, v
(1) =
19.53, P
0.0001. The main effect for region and region 3
measure interactions were not significant (v
(1) = 2.39, P =
0.1219 and v
(1) = 0.01, P = 0.9932, respectively). For the
basal ganglia and thalamus, there were main effects of measure,
(1) = 6.80, P = 0.0091, with CBF higher than CMRgl, region,
(3) = 46.48, P
0.0001, and a region 3 measure interaction,
(3) = 31.78, P
0.0001. The interaction indicated that
although the caudate nucleus was only mildly hyperperfused,
the lenticular nuclei and thalamus showed pronounced hyper-
perfusion. For the somatomotor regions, there was again a main
effect of measure, with CBF higher than CMRgl, v
(1) = 18.78,
0.0001. There was a main effect for region, v
(2) = 45.41,
0.0001; and a region 3 measure interaction, v
(2) = 8.47,
= 0.0017. The interaction indicated that hyperperfusion was
somewhat diminished in the pons and cerebellum relative to
midbrain. The regional distribution of hyperperfused and
hypoperfused regions is illustrated in Figure 1, with hyper-
perfused regions (i.e., significantly higher CBF than CMRgl) in
red, hypoperfused regions in blue, and coupled regions in green.
The GEE examining laterality effects showed for the fron-
tal regions both a hemisphere
3 measure, v
(1) = 32.07, P
0.0001, and a hemisphere 3 measure 3 region interaction,
(8) = 42.12, P
0.0001. To clarify this and subsequent 3-way
Figure 1. Placement of representative ROIs on MR images. The following regions
were examined (abbreviations on left hemispheres): superior frontal (SF), dorsolateral
prefrontal (DL), dorsomedial prefrontal (DM), mid-frontal (MF), inferior frontal (IF),
sensorimotor (SM), superior parietal (SP), supramarginal gyrus (SG), occipital—me-
dial (OM), occipital—lateral (OL), lingual gyrus (LI), fusiform gyrus (FG), occipital
temporal (OT), superior temporal (ST), mid-temporal (MT), inferior temporal (IT),
temporal pole (TP), parahippocampal gyrus (PH), hippocampus (HI), uncus (UN),
amygdala (AM), insula (IN), orbital frontal (OF), rectal gyrus (RG), cingulate
gyrus—anterior (CA), cingulate gyrus (CG), cingulate gyrus—posterior (CP), corpus
callosum—anterior (C1), corpus callosum—posterior (C2), caudate nucleus (CN),
lenticular—medial (globus pallidus) (LM), lenticular—lateral [putamen] (LL), thalamus
(TH), midbrain (MI), pons (PO), cerebellum (CE). The color-coding on the right
hemisphere is based on the results (see Results section) and indicates hyperperfusion
(red), hypoperfusion (blue) and coupling (green).
Cerebral Cortex February 2009, V 19 N 2 377
interactions, Figure 3 displays the CBF/CMRgl ratios for each
hemisphere, where hyperperfusion is indicated by distance
from unity. As can be seen in Figure 3, the average frontal
hypoperfusion is largely driven by the right hemispheric values.
The left hemisphere throughout most frontal regions was more
highly perfused than the right. The exception was the mid-
frontal region, which was hyperperfused bilaterally. The
parietal regions also showed both hemisphere
3 measure, v
(1) = 17.36, P
0.0001, and a hemisphere 3 measure 3 region
interaction, v
(4) = 19.28, P = 0.0007. As can be seen in Figure
3, although the parietal lobe was hypoperfused overall, the left
hemisphere was less so especially in sensorimotor cortex. The
occipital regions showed both hemisphere
3 measure, v
(1) =
23.02, P
0.0001, and a hemisphere 3 measure 3 region
interaction, v
(6) = 37.83, P
0.0001. As can be seen in
Figure 3, left hemispheric ratios were higher in most regions
but especially in fusiform gyrus. The temporal regions likewise
showed both hemisphere
3 measure, v
(1) = 25.18, P
0.0001, and a hemisphere 3 measure 3 region interaction, v
(8) = 39.64, P
0.0001. The interaction indicated that although
one temporal region (occipito-temporal) showed bilateral
coupling between CBF and CMRgl, all other temporal cortex
regions showed less hypoperfusion on the left. Notably,
superior temporal gyrus was hyperperfused on the left and
hypoperfused on the right. For limbic regions, there were both
3 measure, v
(1) = 31.05, P
0.0001, and
3 measure 3 region interactions, v
(16) = 51.49,
0.0001. The interactions indicate that although the left
Table 1
Regional hemispheric means and SDs for CMRgl and CBF in R/WB ratios (region abbreviations as in Fig. 1)
Brodmann area CMRgl (n 5 60) CBF (n 5 30)
Left Right Left Right
Mean SD Mean SD Mean SD Mean SD
SF 6,8,9 0.94 0.10 0.95 0.14 0.96 0.14 0.83 0.14
DL 9,10,46 1.03 0.08 1.03 0.10 1.08 0.12 0.86 0.11
DM 6,8,9,10 0.94 0.07 0.94 0.08 1.01 0.14 0.90 0.10
MF 6,8,10,32 1.16 0.12 1.08 0.13 1.34 0.26 1.24 0.16
IF 44,45,46,47 1.09 0.09 1.07 0.10 1.13 0.13 0.90 0.11
SM 1,2,3,4,6,40,43 1.10 0.08 1.05 0.11 1.09 0.14 0.88 0.10
SP 7,40 1.03 0.11 0.99 0.13 0.89 0.12 0.78 0.10
SG 40 1.01 0.11 0.97 0.12 0.97 0.15 0.82 0.14
OM 17,18,19 1.16 0.10 1.10 0.11 1.20 0.12 1.09 0.07
OL 18,19 0.89 0.10 0.93 0.10 0.80 0.06 0.73 0.05
LI 17,18,19 1.11 0.14 1.09 0.15 1.15 0.14 1.06 0.15
FG 19,37 1.05 0.14 1.09 0.14 1.32 0.26 1.15 0.23
OT 17,18,19 0.97 0.14 0.98 0.15 1.00 0.18 0.94 0.18
ST 12,22,38,42 1.09 0.07 1.06 0.10 1.18 0.11 0.97 0.09
MT 19,21,22,37,39 1.04 0.07 1.04 0.09 0.97 0.08 0.84 0.08
IT 20,21,37 1.08 0.16 1.02 0.18 1.03 0.18 0.83 0.11
TP 20,21,28,34,36,38 0.98 0.20 1.03 0.21 0.89 0.15 0.82 0.13
PH 27,28,30,35,36 0.99 0.09 1.04 0.10 1.29 0.18 1.25 0.17
HI 0.97 0.09 0.96 0.10 1.32 0.19 1.21 0.15
AM 0.90 0.13 0.91 0.13 1.49 0.33 1.47 0.28
IN 1.11 0.07 1.23 0.08 1.53 0.20 1.39 0.19
OF 10,11 1.08 0.14 1.09 0.15 1.23 0.26 1.00 0.17
RG 11 1.16 0.17 1.16 0.15 1.68 0.40 1.52 0.33
CA 24,32 1.11 0.09 1.04 0.10 1.53 0.15 1.37 0.20
CG 23,24,31 1.15 0.16 0.95 0.16 1.20 0.23 1.08 0.23
CP 23,29,30,31 1.21 0.19 1.14 0.14 1.35 0.20 1.25 0.17
C1 0.79 0.09 0.78 0.09 0.88 0.20 0.86 0.17
C2 0.86 0.16 0.76 0.11 0.96 0.18 0.85 0.18
CN 1.14 0.08 1.15 0.09 1.22 0.22 1.23 0.23
LM 1.10 0.08 1.21 0.10 1.36 0.24 1.55 0.27
LL 1.21 0.08 1.27 0.08 1.58 0.27 1.63 0.24
TH 1.09 0.07 1.10 0.08 1.34 0.20 1.37 0.20
MI 0.98 0.12 0.95 0.11 1.31 0.22 1.31 0.20
PO 0.88 0.16 0.83 0.16 1.13 0.19 1.06 0.19
CE 0.95 0.11 1.02 0.14 1.24 0.14 1.23 0.13
Figure 2. An intergroup scatterplot of regional CMRgl (x-axis) and CBF (y-axis)
values, with regression and identity lines. The color-coding indicates regional
membership (Frontal 5 blue diamonds; parietal--occipital 5 orange downward
pointing triangles; Temporal 5 green upward pointing triangles; Limbic 5 red
squares; corpus callosum 5 black circles; basal ganglia and somatomotor regions 5
turquoise downward pointing triangles). Regression lines were calculated separately
for each grouping.
378 VariationinCBF--CMRglCoupling
Gur et al.
hemisphere was consistently hyperperfused relative to the
right, this effect varied by region. It was pronounced for insula
and orbitofrontal cortex, and nearly absent in the amygdala and
cingulate regions. For the corpus callosum, the hemisphere
measure interaction was not significant, v
(1) = 0.00, P =
0.9624. For the basal ganglia and thalamus, as well as for the
somatomotor regions, the hemisphere
3 measure interaction
was not significant, v
(1) = 0.33, P = 0.5672 and v
(1) = 1.55,
= 0.2136, respectively. As can be seen in Figure 3, these
regions are all hyperperfused bilaterally.
The results indicate overall coupling between cerebral glucose
metabolism and blood flow in the resting brain, consistent with
earlier studies (Reivich 1974; Raichle et al. 2001). However, as
hypothesized, some regions are significantly hyperperfused,
with higher relative CBF than CMRgl, whereas others are
hypoperfused. The topographic distribution of these regions
does not seem random. Primary visual and auditory areas
showed coupling between CBF and CMRgl, limbic and sub-
cortical regions—basal ganglia, thalamus, and posterior fossa
structures—were hyperperfused, whereas association cortices
were hypoperfused. Given their role in arousal and early stages
of stimulus encoding, limbic regions (Pourtois and Vuilleumier
2006), thalamus (Aguilar and Castro-Alamancos 2005), and
posterior fossa (Schmahmann and Pandya 1995; Ackermann et al.
2007) have in common the potential need for precipitous and
rapid activation. By contrast, regions showing hypoperfusion are
in association or modulatory cortices, where deployment occurs
downstream and is hence more gradual and predictable. The
need for rapid deployment in basal ganglia, which are markedly
hyperperfused, may reflect their important limbic contributions
in ventral portions of the putamen, globus pallidus, and caudate,
as well as basal forebrain, which may be especially important for
arousal and attention (e.g., Mogenson et al. 1980; Floresco et al.
2001; Chudasama and Robbins 2006). These results extend
Raichle et al. (2001) view of the resting state as a default mode of
brain function, suggesting an adaptive anticipatory uncoupling
between blood flow and glucose metabolism.
Other lines of research support this hypothesis, including
evidence that there is a regional increase in oxygen metabolism
prior to any increase in regional blood flow. Specifically during
sensory stimulation, changes in local oxygen metabolism
appear to precede changes in local CBF. Microelectrode
studies in the rat during electrical stimulation of the forepaw
show that the metabolic response occurs almost 1 second prior
to the blood flow response (Ances et al. 2001), consistent with
optical measurements of oxygen and cerebral blood hemody-
namics during visual activation in the cat (Malonek and
Grinvald 1996). Over the past decade a preponderance of
studies in animals and humans using optical imaging, micro-
electrodes, magnetic resonance spectroscopy, and functional
magnetic resonance imaging have observed what has become
known as the ‘‘initial dip,’ or an increase in deoxyhemoglobin
that precedes any changes in cerebral hemodynamics (Ances
2004). These studies indicate that in response to stimulation or
task demands, neuronal activity increases prior to any increases
in blood flow or blood volume. In regions where a quick
response to a stimulus would be beneficial, resting hyper-
perfusion would be the adaptive anticipatory metabolic state.
The hypothesis is further supported by examination of
variability within regions, reflected by the measure
3 region
interactions. Although most frontal regions showed hypoper-
fusion, the medial frontal cortex was quite strongly hyper-
perfused. This may reflect the central role of this region in
motor functions, particularly related to speed (Sawle et al.
1991). Our results suggest that the medial frontal area has both
high metabolic activity (among the highest of all cortical
regions) and an excess of CBF, further supporting its potential
role as contributing ‘‘to the neural instantiation of aspects of
the multifaceted ‘self.’’’(Raichle et al. 2001; see also Gusnard
et al. 2001). Values in the parieto-occipital area seem to adhere
to the same principle. The parietal regions, which serve as
Figure 3. Mean (±SEM) of the ratios of relative regional CBF to glucose metabolism (CMRgl) in frontal, parietal, occipital, temporal, limbic, corpus callosum (CC), basal ganglia,
and thalamus (BG/THAL), and posterior fossa somatomotor (SOM-MOT) areas. Region placement is shown in Figure 1, where the regional labels are spelled out in the legend. The
error bars represent the standard error of the mean for ratios, defined as the relative standard error (RSE) multiplied by the ratio. RSE is standard error relative to the mean; the
RSE squared of (x/y) is equal to the sum of the RSEs squared of x and of y, following which the absolute SE of (x/y) is simply RSE (x/y) times (x/y).
Cerebral Cortex February 2009, V 19 N 2 379
association cortex, are all hypoperfused, whereas variability is
seen in occipital cortex. The medial occipital region, contain-
ing primary visual cortex, has high CMRgl but comparable CBF
ratios, reflecting tight coupling, whereas the lateral occipital
region, containing secondary visual association cortex, is
pronouncedly hypoperfused. Our participants had their eyes
open, but were studied in a dimly lit room with no stimulation.
This differs from participants in Raichle et al., who were
studied with eyes closed. Our findings thus support Raichle
et al.’s (2001) hypothesis that ‘the baseline state of these
[visual] areas is more nearly approximated when subjects rest
quietly with their eyes open.’’ (p. 680). The fusiform cortex,
which plays an early role in the processing of complex spatial
layouts, including faces (e.g., Downing et al. 2006; Iidaka et al.
2006), is substantially hyperperfused. Within limbic regions,
consistent with their role in modulating emotional behavior,
the orbital frontal cortex and the genu and posterior cingulate
areas show less hyperperfusion than the phylogenetically older
regions such as parahippocampal gyrus, hippocampus, and, in
particular, the amygdala. Notably, the amygdala stands out as
having the highest rate of CBF relative to CMRgl. This is
consistent with its role in the processing of threat-related
stimuli (Kluver and Bucy 1939; Damasio et al. 2000; Amaral
2003; Etkin et al. 2004; Coccaro et al. 2007). The corpus
callosum is hyperperfused in both anterior and posterior
sections, as are the basal ganglia and posterior fossa regions.
The marked hyperpefusion in the posterior fossa somatomotor
regions contrasts with the hypoperfusion in sensorimotor
cortex, again suggesting that hypoperfusion characterizes
regions that may have a greater lag time for activation.
The laterality effects indicated higher CBF/CMRgl ratios in the
left hemisphere throughout most cortical regions, and bilaterally
symmetric hyperperfusion in the cingulate, corpus callosum,
basal ganglia, thalamus, and somatomotor regions. In this sample
of right-handed individuals, the finding is consistent with the
hypothesis that higher ratios indicate greater preparedness for
deployment. The laterality finding, however, was not hypothe-
sized and should be further examined in future studies.
The results of this study must be considered within the
context of its methodological limitations. First, the 2 groups of
subjects were studied in somewhat different environments.
The tracer uptake for FDG was done in a quiet dimly lit room,
whereas the CBF studies involved lying in a scanner with the
subject’s head positioned within the scanner bore. A more
precise estimation of discrepancies between CMRgl and CBF
could be obtained had resting values been available for both
measures in the same sample under identical conditions. Such
data would also permit examination of individual differences
in the degree of CMRgl and CBF coupling during a resting state.
It is noteworthy, however, that in spite of coming from
different samples, the regional values showed rather prominent
correspondence between CMRgl and CBF, supporting overall
coupling. Other limitations of the method include failure to
discern several physiological and technical factors that could
introduce regional differential sensitivity such as proximity to
large arteries, differential density of vascularization, differential
partial volume effects, and differential resolution of
O and
isotopes. Thus, given that limbic and midbrain structures are on
the medial aspect of the brain and may be in close proximity to
large vessels, this factor might be responsible, at least in part,
for the higher apparent hyperperfusion in these regions. The
results are also limited in that we have used a standard
preselected set of ROIs. Applying statistical parametric analysis
could reveal more clearly the distributed network of regions
associated with hyper- or hypoperfusion. Such analysis could
also allow more direct comparability between perfusion status
relative to CMRgl and the distribution of regions implicated in
the default network (Raichle et al. 2001). Some regions
showing hyperperfusion in our study, such as hippocampus,
rectal gyrus and amygdala, are part of the default network,
whereas the medial occipital region has equal CMRgl and CBF.
For cortical regions it would have been especially helpful to
have voxel-wise data to determine comparability with other
studies of the default network. We are in the process of
transferring the PET data to a platform that would permit such
analyses. Finally, there could be alternative explanations and
reasons for the observed variability in the ratio of cerebral
perfusion to glucose metabolic rates. In addition to regional
variability in capillary density (Klein et al. 1986), the effects
could relate to differences in carotid versus vertebrobasilar
circulatory systems, regional differences in neurochemical
innervation (e.g., cholinergic, noradrenergic), or intrinsic
neurochemical innervation (e.g., gamma-aminobutyric acid,
glutamate). The present methodology does not permit resolu-
tion of these explanations and further research is required.
Notwithstanding these limitations, the results offer strong
support for the merit of functional imaging investigations of the
resting landscape of brain metabolic activity. Our results
extend Raichle et al.’s hypothesis of a default brain state, based
on the uniformity of OEF across regions at the resting state.
When CMRgl, which shows greater task-induced changes than
oxygen metabolism, is compared with CBF, the results suggest
that such a default state may also reflect readiness for action,
probably of evolutionary significance. They reveal a novel
relation between cerebral metabolism and blood flow at
a ‘default’ resting state, with systematic variation among brain
regions in the degree to which they are hyper- or hypoper-
fused relative to metabolic demands. Regions related to arousal
and early stages of stimulus processing, including evaluation of
their threat potential, where action can be unpredictable,
have excess CBF relative to CMRgl. By contrast, regions
implicated in secondary association, downstream emotional
modulation and executive processes have relatively less CBF
compared with CMRgl. The extent to which hyperperfusion
relative to CMRgl changes as a result of task-related activation
can be determined in future studies. Such work can help clarify
whether there is a consistent set of regions that show similar
changes across all tasks, as Raichle et al have suggested based
on OEF results. Finally, it would be interesting to examine
whether this principle operates across species. Although the
amygdala, basal ganglia and posterior fossa structures would
likely show hyperperfusion across species, differences may be
observed related to species-specific salience of modulatory
Grants (MH-64045 and MH-60722).
We thank Steven E. Arnold, Graham J. Kemp, the late John S. Leigh, and
Marcus E. Raichle for useful discussions and the PET Center staff for
their invaluable help. Conflict of Interest : None declared.
380 VariationinCBF--CMRglCoupling
Gur et al.
Address correspondence to Ruben C. Gur, PhD, Neuropsychiatry,
10th floor Gates Bldg., University of Pennsylvania, 3400 Spruce St.,
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382 VariationinCBF--CMRglCoupling
Gur et al.
    • "The greater overlap observed in the box plots from our SPECT study suggested that the CIS observed using [ 18 F]FDG-PET might more accurately discriminate patients with DLB from those with AD. Brain perfusion and metabolism are physiologically coupled [27]. The limitations of SPECT include lower image resolution and a large partial volume effect. "
    [Show abstract] [Hide abstract] ABSTRACT: Background In addition to occipital hypoperfusion, preserved metabolism of the posterior cingulate gyri (PCG) relative to the precunei is known as the cingulate island sign (CIS) in the patients with dementia with Lewy bodies (DLB). CIS has been detected using [18F]fluorodeoxyglucose positron emission tomography but not using brain perfusion single-photon emission computed tomography (SPECT). The purpose of this study was to optimize brain perfusion SPECT to enable differentiation of DLB from Alzheimer’s disease (AD) using CIS and occipital hypoperfusion.Eighteen patients with probable DLB and 17 age-matched Pittsburgh compound B-positive patients with AD underwent technetium-99m ethyl cysteinate dimer SPECT. SPECT Z-score maps were generated using the easy Z-score imaging system (eZIS) analysis software (Matsuda H, Mizumura S, Nagao T, Ota T, Iizuka T, Nemoto K, Takemura N, Arai H, Homma A, AJNR Am J Neuroradiol 28(4):731–6, 2007), which included volumes of interest (VOIs) in which a group comparison between patients with AD and cognitively normal subjects revealed significant relative hypoperfusion. We used the Montreal Neurological Institute (MNI) space anatomical border to divide the bilateral PCG to precunei VOIs into two parts, the PCG and precunei. Z-scores in the PCG, precunei, and occipital areas and ratios were analysed and compared with receiver operating characteristic (ROC) curve analyses. ResultsThe largest area under the curve (AUC) value for use in differentiating DLB from AD with the ratio of PCG to medial occipital was 0.87; the accuracy, sensitivity, and specificity were 85.7, 88.9, and 82.4 %, respectively. The AUC with the ratio of PCG to the precuneus was smaller, and it was 0.85, though no significant difference was observed between these two AUCs. Conclusions The Z-score ratio of the PCG within the early-AD-specific VOI to medial-occipital area is clinically useful in discriminating demented patients with DLB from those with AD.
    Full-text · Article · Dec 2016
    • "F-FDG PET scans [16, 21]. Conversely, 18 F-AV-45 imaging is useful in the detection of brain Aβ deposition. "
    [Show abstract] [Hide abstract] ABSTRACT: Purpose: We investigated dual-phase (18)F-florbetapir (AV-45/Amyvid) PET imaging for the concomitant detection of brain perfusion deficits and beta-amyloid deposition in patients with Alzheimer's disease (AD) and amnestic mild cognitive impairment (MCI), and in cognitively healthy controls (HCs). Methods: A total of 82 subjects (24 AD patients, 44 MCI patients and 14 HCs) underwent both dual-phase (18)F-AV-45 PET and MRI imaging. Dual-phase dynamic PET imaging consisted of (1) five 1-min scans obtained 1 - 6 min after tracer injection (perfusion (18)F-AV-45 imaging, pAV-45), and (2) ten 1-min scans obtained 50 - 60 min after tracer injection (amyloid (18)F-AV-45 imaging). Amyloid-negative MCI/AD patients were excluded. Volume of interest analysis and statistical parametric mapping of pAV-45 and (18)F-AV-45 images were performed to investigate the perfusion deficits and the beta-amyloid burden in the three study groups. The associations between Mini-Mental State Examination (MMSE) scores and global perfusion deficits and amyloid deposition were investigated with linear and segmental linear correlation analyses. Results: HCs generally had normal pAV-45 findings, whereas perfusion deficits were evident in the hippocampus, and temporal, parietal and middle frontal cortices in both MCI and AD patients. The motor-sensory cortex was relatively preserved. MMSE scores in the entire study cohort were significantly associated with the degree of perfusion impairment as assessed by pAV-45 imaging (r = 0.5156, P < 0.0001). (18)F-AV-45 uptake was significantly higher in AD patients than in the two other study groups. However, the correlation between MMSE scores and (18)F-AV-45 uptake in MCI patients was more of a binary phenomenon and began in MCI patients with MMSE score 23.14 when (18)F-AV-45 uptake was higher and MMSE score lower than in patients with early MCI. Amyloid deposition started in the precuneus and the frontal and temporal regions in early MCI, ultimately reaching the maximum burden in advanced MCI. Conclusion: Our results indicate that brain perfusion deficits and beta-amyloid deposition in AD follow different trajectories that can be successfully traced using dual-phase (18)F-AV-45 PET imaging.
    Full-text · Article · Mar 2016
    • "Results from voxel-by-voxel t-tests between rCBF and rPET demonstrated regions of hyper-or hypo-perfusion not matched to glucose metabolism (Figure 5 andTable 4). These findings, specifically from PET data corrected with Dixon+bone MRAC, are in line with previous findings of increased resting perfusion to resting metabolism in areas of the brain associated with the default mode network (Gur et al., 2009; Cha et al., 2013), suggesting that these brain regions require increased blood flow due to the sustained state of arousal (Vaishnavi et al., 2010). Apparent bias in bone attenuation from standard Dixon MRAC was evident in the comparison between relative perfusion and glucose uptake as demonstrated inFigure 5 and in comparison to previous studies (Newberg et al., 2005; Chen et al., 2011; Cha et al., 2013). "
    [Show abstract] [Hide abstract] ABSTRACT: Purpose: To evaluate a potential approach for improved attenuation correction (AC) of PET in simultaneous PET and MRI brain imaging, a straightforward approach that adds bone information missing on Dixon AC was explored. Methods: Bone information derived from individual T1-weighted MRI data using segmentation tools in SPM8, were added to the standard Dixon AC map. Percent relative difference between PET reconstructed with Dixon+bone and with Dixon AC maps were compared across brain regions of 13 oncology patients. The clinical potential of the improved Dixon AC was investigated by comparing relative perfusion (rCBF) measured with arterial spin labeling to relative glucose uptake (rPETdxbone) measured simultaneously with 18F-flurodexoyglucose in several regions across the brain. Results: A gradual increase in PET signal from center to the edge of the brain was observed in PET reconstructed with Dixon+bone. A 5–20% reduction in regional PET signals were observed in data corrected with standard Dixon AC maps. These regional underestimations of PET were either reduced or removed when Dixon+bone AC was applied. The mean relative correlation coefficient between rCBF and rPETdxbone was r = 0.53 (p < 0.001). Marked regional variations in rCBF-to-rPET correlation were observed, with the highest associations in the caudate and cingulate and the lowest in limbic structures. All findings were well matched to observations from previous studies conducted with PET data reconstructed with computed tomography derived AC maps. Conclusion: Adding bone information derived from T1-weighted MRI to Dixon AC maps can improve underestimation of PET activity in hybrid PET-MRI neuroimaging.
    Full-text · Article · Jan 2015
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