Psychiatry Research: Neuroimaging Section 100 Ž2000. 31᎐39
Regional cerebral blood flow after recovery from
bulimia nervosa
Guido K. Frank, Walter H. KayeU , Phil Greer, Carolyn C. Meltzer,
Julie C. Price
Western Psychiatric Institute and Clinic, Uni¨ ersity of Pittsburgh Medical Center, 3811 O’Hara Street, E-724, Pittsburgh,
PA 15213, USA
Received 27 June 2000; received in revised form 13 September 2000; accepted 14 September 2000
Abstract
When ill, women with bulimia nervosa ŽBN. show alterations of regional cerebral blood flow ŽrCBF.. In this study
we investigated rCBF in nine women in long-term recovery from BN ŽRBN, n s 9., i.e. more than 1 year without
bingeingrpurging behavior, normal weight, stable food intake, and regular menses, and compared them with
age-matched healthy control women ŽCW, n s 13.. Positron emission tomography ŽPET. was used for the assessment
of rCBF. There were no significant differences in rCBF between groups. However, rCBF was significantly inversely
related to length of recovery in RBN for the left and right prefrontal cortex ŽBA 10., right medial orbital frontal
cortex ŽBA 11., left subgenual cingulate ŽBA 25., right anterior cingulate ŽBA 32., left sensory motor cortex ŽBA
1,2,3,4., left and right lateral temporal ŽBA 21., and left occipital cortex ŽBA 17., as well as left thalamus. This finding
suggests that previously reported alterations in rCBF during the ill state of BN may be a state-related phenomenon
that remits with recovery. It is also possible that reductions in rCBF occur in a later stage of recovery from BN.
䊚 2000 Elsevier Science Ireland Ltd. All rights reserved.
Keywords: Bulimia nervosa; Recovery; Cerebral blood flow; Positron emission tomography
U
Corresponding author. Tel.: q1-412-624-3507; fax: q1-412-624-6618.
E-mail address: kayewh@msx.upmc.edu ŽW.H. Kaye..
0925-4927r00r$ - see front matter 䊚 2000 Elsevier Science Ireland Ltd. All rights reserved.
PII: S 0 9 2 5 - 4 9 2 7 Ž 0 0 . 0 0 0 6 9 - X
32
G.K. Frank et al. r Psychiatry Research: Neuroimaging 100 (2000) 31᎐39
1. Introduction
Bulima nervosa ŽBN. is a psychiatric disorder
characterized by regular bingeing and purging
behavior that typically has its onset during adolescence ŽAmerican Psychiatric Association, 1994..
Psychosocial factors have been implicated in the
development of this disorder ŽStice, 1999; Troop
and Treasure, 1997.. However, family and genetic
studies suggest a hereditary transmission of BN
ŽKendler et al., 1991; Lilenfeld and Kaye, 1998..
In addition, disturbances of the serotonin system
after long-term recovery suggest a biologic traitrelated disturbance in BN ŽKaye et al., 1998;
Smith et al., 1999..
Functional brain imaging provides us with the
opportunity to investigate brain mechanisms in
vivo, and helps localize regional disturbances associated with psychiatric disorders ŽWeight and
Bigler, 1998.. Several brain-imaging studies have
investigated cerebral blood flow and metabolism
in BN. Nozoe et al. Ž1995. found that regional
cerebral blood flow ŽrCBF. in acutely ill BN was
elevated in inferior frontal and left temporal cortical areas, and changed in relation to a test meal.
It was suggested that frontal andror temporal
cortical areas might be involved in the pathophysiology of BN. Most recently, it was proposed that
CBF in BN may vary in relation to restricting or
binge-eating phases ŽHirano et al., 1999.. Regional relative glucose metabolism was found to be
lower in the parietal cortex in ill BN compared to
controls in one study ŽDelvenne et al., 1997.,
whereas another group did not find such alterations ŽAndreason et al., 1992.. Glucose
metabolism, however, correlates with blood flow
in healthy subjects ŽFox et al., 1988.. Thus, such
alterations could be associated with alterations in
rCBF.
The etiology of BN is not known. In addition to
pathologic eating behavior, BN is characterized
by disturbed emotional states such as increased
anxiety and depressive feelings in the ill and
recovered states ŽKaye et al., 1998.. Emotional
states are thought to be related to brain regions
such as the amygdala, orbital frontal and cingulate cortex, and the thalamus ŽDrevets and
Raichle, 1992; Charney and Deutch, 1996., and
altered mood states might be associated with disturbances of cerebral activity, i.e. blood flow, in
these regions ŽReiman, 1997; Krishnan, 1999..
Thus, pathologic behaviors in BN could be reflected by localized alterations of brain cortical
activity.
However, studies of ill BN women are potentially confounded by the many physiologic disturbances associated with bingeing and purging. A
strategy to avoid confounding factors of the ill
state is to study women after recovery from BN.
If alterations persist after recovery, it is possible
that such alterations may be traits that might
contribute to the onset of the disorder. Alternatively, persistent alterations could be the consequence of abnormal eating behavior. In this study
we investigated rCBF in women in long-term recovery from BN ŽRBN. compared to healthy control women ŽCW., in order to investigate if rCBF
alterations persist after recovery.
2. Methods
2.1. Subjects
Nine women who had previously met DSM-IIIR criteria for BN were recruited. No subject had
a history of anorexia nervosa ŽAN., and they must
have maintained a body weight of greater than
85% of average body weight Ž%ABW, Metropolitan Life Insurance Company, 1959. since development of an eating disorder. Subjects were previously treated in the eating disorders treatment
program at the Western Psychiatric Institute and
Clinic, University of Pittsburgh, PA, USA or were
recruited through advertisements. To be considered ‘recovered’, subjects had to ᎏ for at least
1 year before the study ᎏ Ž1. maintain a weight
above 90% ABW, Ž2. have regular menstrual
cycles, and Ž3. have not binged, purged, or engaged in restrictive eating patterns. Additional
exclusion criteria were the use of psychoactive
medication such as antidepressants and alcohol
or drug abuse or dependence within 3 months of
the study. Thirteen healthy CW were recruited
through local advertisements. The CW had no
history of an eating disorder or any psychiatric,
G.K. Frank et al. r Psychiatry Research: Neuroimaging 100 (2000) 31᎐39
major medical, or neurologic illness. They had no
first-degree relatives with an eating disorder. They
had normal menstrual cycles, and had been within
a normal weight range since menarche. All subjects completed a diary in which they listed individual food items consumed for individual meals,
portion sizes, and exercise frequency. The Schedule for Affective Disorders and SchizophreniaLifetime Version ŽSADS-L, Endicott and Spitzer,
1978., modified by Merikangas and co-workers,
was used to assess subjects for lifetime Axis I
DSM-III-R diagnoses. The SADS-L was administered by a trained Master’s or doctoral level clinical interviewer, and reviewed by a psychiatrist
Žblind to clinical information., who validated final
DSM-III-R Axis I diagnoses. Positron emission
tomography ŽPET. imaging was performed during
the first 10 days of the follicular phase of the
menstrual cycle for all subjects. Subjects were
admitted to a research laboratory on the eating
disorders unit of the Western Psychiatric Institute
and Clinic at 21.00 h of the day prior to the PET
study for adaptation to the laboratory and for
psychological assessments. The PET study was
done the following day. All subjects were served
the same standardized diet Žlow in protein breakfast., approximately 4 h prior to PET scanning.
All subjects gave written informed consent according to local IRB regulations.
2.2. MR scanning
All subjects underwent magnetic resonance
ŽMR. imaging prior to the PET scan on a Signa
1.5 Tesla scanner ŽGE Medical Systems, Milwaukee, WI, USA. using a standard head coil. A
volumetric spoiled gradient recalled ŽSPGR. sequence ŽTE s 5, TRs 25, flip angle s 40⬚, NEX
s 1; field of views 24 cm, image matrix s 256 =
192 pixels. acquired in the coronal plane was used
to guide region-of-interest ŽROI. selection. Fast
spin echo T2 and proton density weighted images
were also routinely acquired to exclude significant
neuropathology. Pixels that corresponded to scalp
and calvarium were removed from the SPGR MR
images ŽSandor and Leahy, 1997. and the MR
and PET image data were then co-registered
ŽWoods et al., 1993..
33
2.3. PET imaging
w 15 Ox water was used as a radiotracer. Subjects
were positioned in a Siemens 951Rr31 PET scanner ŽCTI PET Systems, Knoxville, TN, USA. with
the head oriented so that the lowest imaging
plane was approximately 1 cm above and parallel
to the cantho-meatal line. A softened thermoplastic mold with generous holes for eyes, nose, and
ears was fitted closely around the head and attached to the headholder to minimize subject
motion. Subjects were advised to keep their eyes
closed. The subjects’ ears were unplugged. A 10min transmission scan was obtained and used for
attenuation correction. Following bolus intravenous injection of 50 mCi of w 15 Ox water, a
20-frame dynamic emission scan was acquired
over 3 min in two-dimensional imaging mode.
Arterial blood was sampled at a rate of 6 mlrmin
over 3.5 min, using a Siemens liquid activity monitoring system. This device detects radioactivity
events with dual BGO scintillation crystals. PET
data were corrected for radioactive decay, attenuation and scatter, and reconstructed using a Hanning cut-off at 0.8 of the Nyquist rate.
2.4. Data analyses
ROIs were hand drawn on the co-registered
MR images and applied to the dynamic PET data
to generate time᎐activity curves. The following
ROIs were selected: prefrontal cortex wBrodmann
area ŽBA. 10x, medial orbital frontal cortex ŽBA
11., lateral orbital frontal cortex ŽBA 47., medial
temporal cortex Žamygdalo-hippocampal complex., lateral temporal cortex ŽBA 21., striatum,
anterior cingulate ŽBA 32., anterior mesial cingulate ŽBA 24., subgenual cingulate ŽBA 25., sensory motor cortex ŽBA 1,2,3,4., parietal cortex
ŽBA 7., occipital cortex ŽBA 17., thalamus and
striatum. ROI sampling of the cerebellum ŽCer.
was also performed. ROIs were expressed as left
and right separately, except for the cerebellum.
The w 15 Ox water data were analyzed using a traditional one-tissue compartment model ŽRaichle et
al., 1983.. In this model, blood flow was measured
as the clearance of w 15 Ox water from blood to
brain ŽK 1 , ml miny1 mly1 . while accounting for
34
G.K. Frank et al. r Psychiatry Research: Neuroimaging 100 (2000) 31᎐39
arterial input function timing delays. Cerebral
blood flow was assessed on a regional basis ŽrCBF.
via regional values of K 1.
In addition, we calculated relative rCBF measures similar to previous studies ŽDrevets et al.,
1992.. These measures were based on average
w 15 Ox water tissue activity images determined over
all 20 dynamic frames. Regional measures of relative blood flow were determined as the ratio of
the regional average w 15 Ox water tissue uptake to
the whole brain w 15 Ox water uptake.
radioactivity ratios. Similarly, this method does
not show significant group differences among all
ROIs sampled. However, for RBN women, there
were significant negative relationships between
rCBF Ž K 1 . and length of recovery in several ROIs
such as the frontal and lateral temporal cortical
areas ŽTable 4.. Fig. 1 shows a representative
relationship in the left prefrontal cortex. There
were no significant relationships between rCBF
and the remaining demographic variables shown
in Table 1 for either RBN or CW.
2.5. Statistical analyses
4. Discussion
The SPSS software package was used for analyses ŽBarcikowski, 1984.. Due to small sample sizes,
between-group comparisons were made using the
non-parametric Mann᎐Whitney U-test. Correlations were examined with Spearman correlation
coefficients. All values are expressed as mean "
standard deviation ŽS.D... Statistical significance
was defined as P- 0.05.
3. Results
CW and RBN women ŽTable 1. were of similar
age, and current, as well as, lifetime low ABW.
Lifetime high weight was significantly higher in
RBN. Absolute rCBF values expressed as K 1 ,
ŽTable 2. were similar between CW and RBN
women for all right and left hemispheric ROI.
Cer K 1 values were similar between groups ŽCW:
mean 0.65, S.D. 0.09; RBN: mean 0.63, S.D. 0.09;
Ps ns.. Table 3 shows the relative rCBF measures that were based on the w 15 Ox water tissue
These data suggest that RBN and CW have
similar rCBF for the cortical and subcortical regions sampled. However, in the RBN, rCBF was
negatively associated with duration of recovery in
a large portion of cerebral cortical regions. In the
acute phase of the illness, BN women have been
found to have increased rCBF in the right inferior frontal cortex, and in the left temporal cortex
compared to CW ŽNozoe et al., 1995.. In addition,
a recent case report suggested rCBF changes in
relation to the state of illness. That is, there was
increased rCBF in the right temporal, parietal
and occipital cortex during a binge-eatingrpurging phase compared to a phase with food restriction ŽHirano et al., 1999.. The findings in our
study support the possibility that altered blood
flow previously found during the ill state of BN
could be a state-related phenomenon that normalizes with recovery. In addition, the negative
relationship with recovery in multiple cortical areas could indicate more of a global than regio-
Table 1
Demographic variables a
Age Žyears.
Current weight Ž% ABW.
Lifetime high weight Žin %ABW.
Lifetime low weight Žin %ABW.
Length of recovery Žmonths.
CW Ž n s 13.
RBN Ž n s 9.
U
P
27.1" 6.1
102.4" 5.9
107.7" 6.6
96.0" 5.7
᎐
29.9" 4.5
111.0" 14.8
123.9" 9.8
95.0" 12.2
56.8" 45.4
40
37
6
37
᎐
0.1
0.2
-0.01
0.4
᎐
a
Notes. Values are expressed as mean " standard deviation; Mann᎐Whitney U statistic, U; percent average body weight,
%ABW; control women, CW; recovered bulimic women, RBN.
Region Žcorresponding Brodmann area.
Prefrontal cortex ŽBA 10.
Medial orbital frontal cortex ŽBA 11.
Lateral orbital frontal cortex ŽBA 47.
Subgenual cingulate ŽBA 25.
Anterior mesial cingulate ŽBA 24.
Anterior cingulate ŽBA 32.
Sensory motor cortex ŽBA 1,2,3,4.
Parietal cortex ŽBA 7.
Medial temporal cortex Žamygdalohippocampal complex.
Lateral temporal cortex ŽBA 21.
Occipital cortex ŽBA 17.
Thalamus
Striatum
a
Left brain hemispheric rCBF
Ž K1 , ml miny1 mly1 .
Right brain hemispheric rCBF
Ž K1 , ml miny1 mly1 .
CW Ž n s 13.
RBN Ž n s 9.
U
P
CW Ž n s 13.
RBN Ž n s 9.
U
P
0.61" 0.13
0.59" 0.12
0.64" 0.12
0.71" 0.15
0.62" 0.13
0.68" 0.14
0.59" 0.10
0.58" 0.09
0.56" 0.11
0.55" 0.09
0.53" 0.11
0.62" 0.13
0.64" 0.18
0.61" 0.11
0.64" 0.11
0.56" 0.06
0.58" 0.08
0.48" 0.07
45.0
45.5
53.5
40.0
57.0
52.5
47.0
58.0
29.0
0.4
0.4
0.7
0.2
0.9
0.7
0.5
1.0
0.1
0.59" 0.12
0.63" 0.12
0.62" 0.12
0.64" 0.12
0.66" 0.16
0.60" 0.12
0.58" 0.12
0.57" 0.10
0.53" 0.09
0.54" 0.11
0.54" 0.09
0.60" 0.15
0.60" 0.14
0.57" 0.12
0.58" 0.09
0.56" 0.07
0.57" 0.06
0.48" 0.10
44.5
31.0
46.5
51.0
38.0
54.5
53.0
48.5
35.5
0.3
0.1
0.4
0.7
0.2
0.8
0.7
0.5
0.1
0.53" 0.09
0.75" 0.15
0.76" 0.15
0.66" 0.12
0.51" 0.08
0.77" 0.14
0.68" 0.11
0.61" 0.09
48.5
53.5
42.5
42.0
0.5
0.7
0.3
0.3
0.54" 0.10
0.73" 0.16
0.71" 0.16
0.67" 0.13
0.49" 0.09
0.70" 0.10
0.69" 0.09
0.64" 0.08
40.0
53.0
52.0
51.5
0.2
0.7
0.7
0.7
Notes. Values are expressed as mean " standard deviation; Mann᎐Whitney U statistic, U; Brodmann area, BA; regional cerebral blood flow, rCBF; rCBF
expressed as unidirectional clearance of tracer from blood, K 1 ; control women, CW; recovered bulimic women, RBN.
G.K. Frank et al. r Psychiatry Research: Neuroimaging 100 (2000) 31᎐39
Table 2
Absolute regional cerebral blood flow ŽrCBF. values a
35
36
Region Žcorresponding Brodmann area.
Prefrontal cortex ŽBA 10.
Medial orbital frontal cortex ŽBA 11.
Lateral orbital frontal cortex ŽBA 47.
Subgenual anterior inferior cingulate ŽBA 25.
Anterior mesial cingulate ŽBA 24.
Anterior cingulate ŽBA 32.
Sensor motor cortex ŽBA 1,2,3,4.
Parietal cortex ŽBA 7.
Medial temporal cortex Žamygdalohippocampal complex.
Lateral temporal cortex ŽBA 21.
Occipital cortex ŽBA 17.
Thalamus
Striatum
a
Left brain w15 Ox water activity
relative to whole brain activity
Right brain w15 Ox water activity
relative to whole brain activity
CW Ž n s 13.
RBN Ž n s 9.
U
P
CW Ž n s 13.
RBN Ž n s 9.
U
P
1.67" 0.10
1.63" 0.10
1.71" 0.08
1.98" 0.14
1.84" 0.15
1.83" 0.17
1.62" 0.08
1.66" 0.06
1.71" 0.08
1.62" 0.12
1.61" 0.12
1.72" 0.14
1.89" 0.14
1.86" 0.07
1.90" 0.22
1.62" 0.04
1.70" 0.08
1.67" 0.10
44
54
47
33
49
36
52
40
43
0.5
1.0
0.7
0.1
0.8
0.2
0.9
0.3
0.5
1.58" 0.08
1.66" 0.10
1.62" 0.08
1.77" 0.13
1.79" 0.14
1.68" 0.16
1.58" 0.06
1.61" 0.10
1.67" 0.09
1.58" 0.10
1.54" 0.09
1.66" 0.16
1.80" 0.16
1.75" 0.13
1.73" 0.12
1.63" 0.10
1.67" 0.10
1.61" 0.08
49
27
43
49
41
44
41
38
33
0.8
0.1
0.5
0.8
0.4
0.5
0.4
0.3
0.1
1.57" 0.07
1.89" 0.13
1.97" 0.13
1.81" 0.08
1.59" 0.08
2.00" 0.12
1.96" 0.05
1.83" 0.07
43
31
47
43
0.5
0.1
0.7
0.5
1.56" 0.07
1.84" 0.12
1.93" 0.12
1.85" 0.11
1.50" 0.10
1.92" 0.11
1.92" 0.08
1.86 " 0.10
29
33
50
45
0.1
0.1
0.8
0.6
Notes. Values are expressed as mean " standard deviation; Mann᎐Whitney U statistic, U; Brodmann area, BA; regional cerebral blood flow, rCBF; rCBF
expressed as the ratio of the regional average w 15 Ox water tissue uptake to the whole brain w 15 Oxwater uptake; control women, CW; recovered bulimic women, RBN.
G.K. Frank et al. r Psychiatry Research: Neuroimaging 100 (2000) 31᎐39
Table 3
Regional cerebral w 15 Ox water activity in relation to whole brain w 15 Ox water activity Žrelative rCBF. a
G.K. Frank et al. r Psychiatry Research: Neuroimaging 100 (2000) 31᎐39
37
Table 4
Regional cerebral blood flow ŽrCBF. and correlation with length of recovery a
RBN Ž n s 9.
Region Žcorresponding Brodmann area.
Prefrontal cortex ŽBA 10.
Medial orbital frontal cortex ŽBA 11.
Lateral orbital frontal cortex ŽBA 47.
Subgenual anterior inferior cingulate ŽBA 25.
Anterior mesial cingulate ŽBA 24.
Anterior cingulate ŽBA 32.
Sensory motor cortex ŽBA 1,2,3,4.
Parietal cortex ŽBA 7.
Medial temporal cortex Žamygdalo-hippocampal complex.
Lateral temporal cortex ŽBA 21.
Occipital cortex ŽBA 17.
Thalamus
Striatum
Correlation of length of recovery with rCBF
Left brain hemisphere
Right brain hemisphere
rho
P
rho
P
y0.85
y0.61
y0.61
y0.77
y0.55
0.3
y0.67
y0.66
y0.54
y0.69
y0.67
y0.71
y0.6
0.004
0.084
0.081
0.015
0.128
0.429
0.047
0.051
0.13
0.041
0.047
0.034
0.086
y0.76
y0.82
y0.55
y0.51
y0.54
y0.88
y0.29
y0.53
y0.2
y0.83
y0.43
y0.52
y0.55
0.017
0.006
0.125
0.16
0.13
0.002
0.445
0.139
0.598
0.006
0.252
0.152
0.128
a
Notes. Spearman correlation coefficient, rho; Brodmann area, BA; regional cerebral flow, rCBF; recovered bulimic women,
RBN.
Fig. 1. Scatterplot for length of recovery in relationship to regional cerebral blood flow ŽrCBF. in the recovered bulimic women
ŽRBN. group for the left prefrontal cortex; rCBF expressed as unidirectional clearance of tracer from blood, K 1 wml miny1 mly1 x.
38
G.K. Frank et al. r Psychiatry Research: Neuroimaging 100 (2000) 31᎐39
nally localized effect of BN pathophysiology on
rCBF.
The meaning of changes in cerebral blood flow
are conjectural since multiple factors contribute
to rCBF regulation, such as neuronal-cellular and
microvascular-enzymatic processes ŽReis and
Golanov, 1997; Harder et al., 1998; Raichle, 1998..
Alternatively, cerebral blood pressure and thus
flow may be influenced by the systemic blood
pressure and sympathetic tone. Moreover, the
PET measures of rCBF may depend on the functional integrity of the blood-brain barrier, and
capillary surface area in the brain.
In acutely ill BN women it is possible that
sympathetic tone is contributory to increased
rCBF since there is an increase in adrenergic
tone during bingeing and purging and a reduction
of norepinephrine release when abstinent from
those behaviors ŽKaye et al., 1990; Pirke, 1996..
The strong inverse relationship of rCBF with
length of recovery in the RBN women, however,
could also indicate that rCBF reductions occur in
this group later in recovery. This has to be investigated in subsequent studies. Previous brain
imaging studies have reported that acutely ill BN
have structural changes ŽHoffman et al., 1989;
Krieg, 1991.. Thus, we cannot rule out that other
factors, such as persistent structural alterations in
cortical regions due to pathologic eating behavior
contributed to this finding. In a preliminary analysis in our lab, we compared whole brain gray
ŽGM. and white ŽWM. matter values between the
two groups using customized software ŽIDL, Research Systems, Boulder, CO, USA. that separates GM and WM and calculates corresponding
volumes. However, no significant differences were
found between groups Ždata not shown..
We detected some regional asymmetry in rCBF,
such as in the anterior cingulate cortex, between
the left and the right side in both groups, but no
regional differences were found between groups.
We previously showed that after recovery from
BN, those women still show increased symptoms
of depression or anxiety, and on eating disorders
scales ŽKaye et al., 1998.. Despite this, an exploratory analysis of current depression or anxiety
symptoms in the RBN group did not show significant correlations with rCBF.
A limitation of this study is the relatively small
sample size which limits the statistical power of
this investigation. Thus, in future studies we will
assess rCBF in groups of women currently ill
from eating disorders, and increase the sample
size of recovered BN women in order to replicate
this finding.
Our group recently reported other findings in
this cohort of subjects. That is, the CW showed a
negative relationship between binding of the
serotonin 2A receptor Ž5-HT2A. and age in most
cortical regions whereas no such relationship was
found in the RBN. In addition, the RBN women
had reduced 5HT2A binding in the orbital frontal
cortex ŽKaye et al., submitted.. Moreover, neither
CW nor the RBN women showed a correlation of
rCBF with age which is consistent with previous
reports of a lack of rCBF alterations with increasing age ŽMeltzer et al., in press.. We found no
relationship between 5HT2A binding and blood
flow values in either RBN or CW Ždata not
shown., indicating that radiotracer delivery was
distinguishable from receptor binding.
In conclusion, we did not find differences in
rCBF in RBN women compared to CW women.
However, an inverse relation of rCBF with length
of recovery in multiple cortical regions in RBN
women was found. Thus, increased blood flow in
acutely ill BN that was found in previous studies
could be a state-related phenomenon, possibly
related to noradrenergic activity, that remits with
recovery. However, reduced rCBF in RBN in
later stages of recovery cannot be ruled out. Thus
this finding has to replicated in a larger sample,
and using serial studies during various stages of
recovery.
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