REGULAR ARTICLE
Regional Cerebral Blood Flow After Recovery from
Anorexia or Bulimia Nervosa
Guido K. Frank, MD1,2
Ursula F. Bailer, MD1,3
Carolyn C. Meltzer, MD1,4
Julie C. Price, PhD5
Chester A. Mathis, PhD5
Angela Wagner, MD6
Carl Becker, BS5
Walter H. Kaye, MD1*
ABSTRACT
Objective: Abnormalities of regional
cerebral blood flow (rCBF) have been
found in individuals who are ill with anorexia (AN) or bulimia nervosa (BN). Little
is known about whether rCBF normalizes
after recovery from AN and BN.
Method: Eighteen control women (CW),
10 recovered restricting type AN, 8 recovered AN with a binging history, and 9
recovered BN participants without a history of AN were studied using positron
emission tomography and [15O]water in
order to assess rCBF.
Results: Partial volume corrected rCBF
values in cortical and subcortical brain
Introduction
Anorexia (AN) and bulimia nervosa (BN) are severe
psychiatric disorders1 that are associated with
physiological abnormalities of most organ systems
during the ill state. Resting regional cerebral blood
flow (rCBF), a marker for baseline brain function,2
is altered in ill AN and BN. That is, studies using
positron emission tomography (PET) or single photon emission computed tomography (SPECT)
Accepted 4 April 2007
Supported by MH046001, MH042984, K05-MD01894, T32MH18399 from NIMH and by Price Foundation.
*Correspondence to: Walter H. Kaye, MD, Western Psychiatric
Institute and Clinic, University of Pittsburgh, Iroquois Building,
Suite 600, 3811 O’Hara Street, Pittsburgh, PA 15213.
E-mail: kayewh@msx.upmc.edu
1
Department of Psychiatry, Western Psychiatric Institute and
Clinic, University of Pittsburgh School of Medicine, Pittsburgh,
Pennsylvania
2
Department of Child and Adolescent Psychiatry, San Diego
School of Medicine, University of California, San Diego, California
3
Department of Biological Psychiatry, University Hospital of
Psychiatry and Psychotherapy, Medical University of Vienna,
Vienna, Austria
4
Department of Radiology, Emory University Hospital, Atlanta,
Georgia
5
Department of Radiology, Presbyterian University Hospital,
University of Pittsburgh School of Medicine,
Pittsburgh, Pennsylvania
6
Department of Child and Adolescent Psychiatry and
Psychotherapy, J.W. Goethe University, Frankfurt, Germany
Published online 24 May 2007 in Wiley InterScience
(www.interscience.wiley.com). DOI: 10.1002/eat.20395
C 2007 Wiley Periodicals, Inc.
V
488
regions were similar between groups.
Neither current body mass index nor age
correlated with rCBF values.
Conclusion: The results from this
study indicate that rCBF normalizes
with long-term recovery. Thus, altered
rCBF is unlikely to confound functional
imaging studies in AN or BN after reC 2007 by Wiley Periodicals,
covery. V
Inc.
Keywords: anorexia nervosa; bulimia
nervosa; cerebral blood flow; brain
(Int J Eat Disord 2007; 40:488–492)
found either unilateral or bilateral reduction of
rCBF in women ill with AN3–8 in frontal, temporal,
and parietal regions. Women ill with BN had
increased frontal cortical resting rCBF, which fluctuated in relation to food restriction and binging
behavior.9,10
To avoid the possible confounding effect of starvation and emaciation, we have been studying individuals who are long-term remitted from AN and
BN (REC AN or REC BN). These individuals have
normal weight and nutrition, but often continue to
have mild to moderate persistent dysphoric mood
and behavioral symptoms that are also present in
childhood before the onset of AN or BN.11 Numerous studies found that REC AN and BN have altered
serotonin or dopamine function on PET imaging or
altered response to stimuli on functional magnetic
resonance imaging (fMRI).12–14 Thus, it is possible
that symptoms after recovery from weight loss
and normalization of caloric intake reflect traits
that contribute to vulnerabilities to developing AN
or BN.
It is not clear whether rCBF normalizes after recovery from AN, as different studies show both normalization5 and failure to normalize.7 Moreover,
few studies were stratified by restricting and bingeeating/purging type of AN. Naruo et al. found
reduced rCBF in the anterior cingulate in restricting
type AN, which seemed to persist with weight
recovery.6,15 Our group found normal rCBF in BN
after long-term recovery16; however, to our knowl-
International Journal of Eating Disorders 40:6 488–492 2007—DOI 10.1002/eat
NORMAL BRAIN BLOOD FLOW IN ED AFTER RECOVERY
edge, no studies have investigated AN after longterm recovery.
Our group recently published normal brain volume measures for gray and white matter in longterm recovered AN and BN participants compared
with controls,17 indicating a normalization of structural brain compared with the ill state.18 In this
study, we investigated rCBF of long-term recovered
AN and BN participants.
Analysis methods in receptor imaging studies
aim to correct for nonspecific binding and blood
flow, but fMRI usually does not have a baseline
blood flow measure. It is important to characterize
rCBF in REC AN and BN in order to determine
whether altered rCBF confounds the interpretation
of PET and fMRI results.
Method
Ten recovered restricting type AN (RRAN), 8 recovered
AN with binging history (RBAN), and 9 recovered BN
(RBN) participants were recruited, all women. RRAN
never had BN, and BN participants had never had AN
(DSM-IV). To be considered ‘‘recovered,’’ participants
had to, for at least 6 months before the study: (1) maintain a weight above 90% average body weight; (2) have
regular menstrual cycles; (3) have not binged, purged, or
engaged in restrictive eating patterns. Eighteen healthy
control women (CW) were recruited who had no history
of an eating disorder or any psychiatric, major medical,
or neurologic illness. Detailed methods have been published previously.19 All participants underwent magnetic
resonance (MR) imaging prior to PET-scanning. PETscanning was performed during the first 10 days of the
follicular menstrual cycle phase. [15O]water was used as
radiotracer. Participants were positioned in a Siemens
HR+PET scanner (CTI PET Systems, Knoxville, TN). Following 12 mCi [15O]water bolus intravenous injection
(automated injection system), 20-frame dynamic PETscanning in three-dimensional imaging mode was acquired over 3 min. Arterial blood samples were obtained
(6 ml/min), and radioactive events were detected with
dual 50 mm 3 25 mm BGO scintillation crystals and
blood was monitored over 210 s. Regions of interest
(ROIs) were hand drawn on the coregistered MR images
and applied to the dynamic PET data to generate time–
activity curves.16
The [15O]water data were analyzed using a one-tissue
two-compartment model in which blood flow was measured as the clearance of [15O]water from blood to brain
(K1, ml min1 ml1) while accounting for arterial input
function timing delays.20 rCBF was assessed on a regional
basis via regional K1 values. PET data were initially ana-
lyzed without and then with partial volume correction21
in order to correct for potential brain volume differences.
SPSS software was used for statistical analyses.22
Because of small sample sizes, between-group comparisons were made using the nonparametric four-group
comparison Kruskal–Wallis Test. Correlations were examined with Spearman correlation coefficients (q). All values are expressed as mean 6 standard deviation. Statistical significance was defined as p < 0.05.
Results
Groups were similar in age (CW, 26 6 6; RRAN, 24 6
5; RBAN, 28 6 7; RBN, 24 6 5 years), and lifetime
high body mass index (BMI) (CW, 23 6 2; RRAN, 22 6
3; RBAN, 24 6 2; RBN, 25 6 2). RRAN (20 6 2) had
significantly lower current BMI compared with CW
(22 6 2, p ¼ 0.02) and RBN (23 6 3, p ¼ 0.02), but
similar compared with RBAN (21 6 2). Lifetime low
BMI was higher in CW (20 6 1) compared with RRAN
(14 6 2, p < 0.001), RBAN (15 6 2, p < 0.001), and
RBN (19 6 1, p < 0.01), as well as higher in RBN compared with RRAN (p < 0.001) and RBAN (p < 0.001).
RRAN were recovered for 41 6 26, RBAN for 24 6 13,
and RBN for 18 6 10 months. Five CW, 2 RRAN, 1
RBAN, and 1 RBN were on birth control pills at the
time of the study. All RBAN had a history of regular
binging and associated purging. Among RRAN, six
had a history of purging, but no binging lifetime.
rCBF was similar across groups in the analysis
without partial volume correction (data not shown).
Similarly, partial volume corrected data were not
significantly different between groups: Table 1
shows regional rCBF data, and Figure 1 shows exemplary scatterplots for selected regions. No statistical relationship was found between current BMI
and rCBF. Length of recovery correlated negatively
with rCBF for most ROIs in the RBN cohort, but this
was significant only for the occipital cortex (q ¼
0.8, p ¼ 0.04); no significant correlation was found
in the other eating disordered (ED) groups individually or in ED participants combined. Past low BMI
in RRAN was positively related to rCBF in the lateral
(r ¼ 0.8, p ¼ 0.003) and medial orbitofrontal (q ¼
0.8, p ¼ 0.005), mesial (q ¼ 0.6, p ¼ 0.05) and lateral
temporal (q ¼ 0.7, p ¼ 0.03), parietal (q ¼ 0.7, p ¼
0.02) and sensorimotor cortex (q ¼ 0.8, p ¼ 0.01).
Conclusion
This study found normal rCBF in RRAN, RBAN,
and RBN after long-term recovery compared
International Journal of Eating Disorders 40:6 488–492 2007—DOI 10.1002/eat
489
FRANK ET AL.
TABLE 1.
Regional cerebral blood flow (rCBF) across subject groups
rCBF (K1, ml min1 ml1)
Cerebellum
Anterior cingulate cortex
Subgenual cingulate cortex
Pregenual cingulate cortex
Middle striatum
Lateral orbitofrontal cortex
Lateral temporal cortex
Mesial temporal cortex
Occipital cortex
Orbitofrontal cortex
Parietal cortex
Prefrontal cortex
Sensorimotor cortex
Thalamus
CW (n ¼ 18)
RRAN (n ¼ 10)
RBAN (n ¼ 8)
RBN (n ¼ 9)
pb
0.55 (0.1)a
0.55 (0.2)
0.56 (0.1)
0.57 (0.1)
0.58 (0.1)
0.67 (0.2)
0.56 (0.1)
0.47 (0.1)
0.66 (0.2)
0.61 (0.1)
0.63 (0.2)
0.65 (0.1)
0.55 (0.1)
0.59 (0.1)
0.54 (0.1)
0.56 (0.1)
0.57 (0.1)
0.58 (0.1)
0.59 (0.1)
0.64 (0.1)
0.57 (0.1)
0.47 (0.1)
0.69 (0.2)
0.57 (0.1)
0.60 (0.1)
0.63 (0.1)
0.52 (0.1)
0.59 (0.1)
0.56 (0.1)
0.51 (0.1)
0.54 (0.1)
0.55 (0.1)
0.58 (0.1)
0.68 (0.1)
0.56 (0.1)
0.45 (0.1)
0.64 (0.1)
0.62 (0.2)
0.56 (0.1)
0.64 (0.1)
0.53 (0.1)
0.59 (0.1)
0.66 (0.2)
0.64 (0.2)
0.62 (0.2)
0.66 (0.2)
0.64 (0.1)
0.70 (0.2)
0.59 (0.2)
0.55 (0.2)
0.70 (0.2)
0.67 (0.2)
0.65 (0.2)
0.68 (0.2)
0.60 (0.2)
0.66 (0.2)
.20
.24
.73
.51
.38
.91
.65
.27
.59
.60
.56
.93
.60
.59
CW, control women; RRAN, recovered restricting type anorexic women; RBAN, recovered binge eating/purging type anorexic women; RBN, recovered
bulimic women; p, value based on Kruskal–Wallis nonparametric test.
a
Values are mean (SD).
b
p values are nonsignificant.
with healthy CW. It is well known that ill and
short-term recovered AN and BN have brain volume abnormalities,23 which return to normal
with long-term recovery.17 Our study suggests
that a similar normalization phenomenon occurs
with rCBF. It is important to note that the participants in our study had been at stable weight
and normalized nutrition for more than 6
months. Other studies of AN individuals soon
after weight recovery have found unilateral
temporal lobe hypoperfusion4 or reduced
temporo-parietal and orbitofrontal perfusion.7
Normalization of rCBF appears to lag behind
weight recovery: ill AN had bilateral cortical hypoperfusion that normalized after 3 months of
remission,5 and weight recovery in AN was
shown to be associated with increases in rCBF.24
In summary, rCBF returns to normal with longterm recovery, and it is unlikely that altered
rCBF contributes to altered serotonin or dopamine function12 or to stimulus-specific fMRI
brain activation13,25,26 in recovered AN or BN
individuals.
A previous study16 from our group found a negative correlation of rCBF with length of recovery
in a separate cohort of RBN participants. In the
current study, only the occipital cortex showed a
significantly negative correlation with rCBF in
RBN, although most other regions showed a nonsignificant negative correlation (data not shown).
The participants in the previous study had a longer length of recovery (57 6 45 months), but it is
not known whether this accounts for those findings. No significant correlations of length of re490
covery and rCBF were found within the other ED
groups or when taking all ED participants together.
Curiously, past low lifetime BMI was associated
with current rCBF in only RRAN but no other
group. The small number of participants makes
drawing conclusions from this finding problematic,
and the meaning is not clear. Thus, this finding
needs to be replicated before the implication of a
potential ‘‘scar’’ can be determined.
The major limitation of this study is the small
sample size. However, participants were carefully
selected, assessed during relative hormonal stability, and grouped by ED subtype. Furthermore,
although brain volumes are normal in ED participants after recovery,17 altered gray matter volume
could still change rCBF results. The raw data did
not show group differences, and we then applied
a partial volume correction algorithm to correct
for potential partial volume effects. Still, rCBF was
similar across groups. This indicates both similar
rCBF as well as a lack of partial volume effects
after long-term recovery. We did not study the
participants prospectively and thus cannot draw
firm conclusions about their rCBF during their
previous ill state. However, recent data27 indicate
that resting rCBF may not be abnormal in ill AN
participants when a partial volume correction
algorithm is applied that corrects for brain volume loss. Lastly, nonparametric tests, which
include all four groups, each of small size, may be
insufficiently powered to detect group differences. However, additional individual two-group
comparisons (Mann–Whitney, data not shown)
International Journal of Eating Disorders 40:6 488–492 2007—DOI 10.1002/eat
NORMAL BRAIN BLOOD FLOW IN ED AFTER RECOVERY
FIGURE 1 Regional rCBF (K1, ml min1 ml1) in CW,
women recovered from RRAN, RBAN, and RBN. [Color figure can be viewed in the online issue, which is available
at www.interscience.wiley.com.]
did not show significant rCBF differences compared with CW. Most studies in the past have used
SPECT, but PET signal quantification is considered more reliable.28
In conclusion, rCBF is normal in long-term
recovered AN and BN. It is therefore unlikely that
rCBF confounds task-related functional neuroimaging studies in this subject population.
We thank Tyson Oberndorfer, M.S. and Katherine Plotnicov, Ph.D. for their editorial assistance.
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