Neurocase

The Neural Basis of Cognition

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Brain structure alterations associated with weight

changes in young females with anorexia nervosa:
a case series

Tone Seim Fuglset, Tor Endestad, Nils Inge Landrø & Øyvind Rø

To cite this article: Tone Seim Fuglset, Tor Endestad, Nils Inge Landrø & Øyvind Rø (2015) Brain
structure alterations associated with weight changes in young females with anorexia nervosa: a
case series, Neurocase, 21:2, 169-177, DOI: 10.1080/13554794.2013.878728

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Neurocase, 2015
Vol. 21, No. 2, 169–177, http://dx.doi.org/10.1080/13554794.2013.878728

Brain structure alterations associated with weight changes in young females with anorexia
nervosa: a case series
Tone Seim Fuglseta*, Tor Endestadb, Nils Inge Landrøb and Øyvind Røa
a
Oslo University Hospital, Oslo, Norway; bDepartment of Psychology, University of Oslo, Oslo, Norway
(Received 12 March 2013; accepted 18 October 2013)

Structural brain changes associated with starvation and clinical measurements were explored in four females with anorexia
nervosa with different clinical course, at baseline and 1-year follow-up, after receiving intensive inpatient treatment at a
specialized eating disorder unit. Global volume alterations were associated with weight changes. Regional volume altera-
tions were also associated with weight changes, with the largest changes occurring in the nucleus accumbens, amygdala,
pallidum, and putamen. Largest changes in cortical thickness occurred in the frontal and temporal lobes. The results are
preliminary; however, they show that fluctuations in weight are associated with brain volume alterations, especially gray
matter. We suggest that these parts of the brain are vulnerable to starvation and malnutrition, and could be a part of the
pathophysiology of AN.
Keywords: eating disorders; anorexia nervosa; weight changes; neuroimaging; magnetic resonance imaging

Anorexia nervosa (AN) is a possible fatal mental illness if
left untreated, with a prevalence rate among community
samples of 0.3% (Hoek, 2006) and one of the highest
mortality rates of all mental disorders (Arcelus, Mitchell,
Wales, & Nielsen, 2011). Onset typically occurs during
early adolescence. The illness is characterized by restricted
eating, an extreme fear of gaining weight and becoming
fat, and is often accompanied by a distorted body image
(American Psychiatric Association, 2000). AN includes
two subtypes that describe different behavioral patterns:
restrictive eating and binge/purge. The relationship
between AN and physical and biological manifestations
in the brain is complex and to date not fully understood.
The most frequently reported structural brain findings
in adult patients with AN compared to healthy controls are
brain alterations at a global level, which involves an over-
all reduction of white matter (myelinated axons) and gray
matter (cell bodies of neurons and glial cells), and
increased volume of the ventricles and cerebrospinal
fluid (CSF) (Frank, Bailer, Henry, Wagner, & Kaye,
2004). Studies have also reported regional brain abnorm-
alities in patients with AN (Brooks et al., 2011; Joos et al.,
2010; McCormick et al., 2008; Suchan et al., 2010).
However, the results from these studies are inconsistent,
and there is no agreement upon which regions of the brain
are most affected.
Although the underlying mechanisms responsible for
anatomical brain alterations in AN are not fully under-
stood, it is feasible that changes in the brain are directly
attributable to malnutrition and underweight. However,
only a few studies have investigated brain structure in
patients before and after weight restoration. Some studies
report that the brain normalizes completely at both a
global and regional level after weight restoration
(Wagner et al., 2006) while other studies have reported
nonreversible regional changes in gray matter in the ante-
rior cingulate cortex (Friederich et al., 2012; Muhlau et al.,
2007), supplementary motor area (Friederich et al., 2012),
and precuneus (Joos et al., 2011). Collectively, these latter
studies suggest that gray matter is more affected than
white matter in patients with AN, and gray matter reduc-
tions may be only partially reversible. The majority of
these studies have focused largely on adults, however,
while structural magnetic resonance imaging (sMRI) stu-
dies including adolescents and young individuals with AN
remain scarce. Adolescence represents an important devel-
opmental stage warranting additional study, as the teenage
brain is still developing and undergoing major changes,
such as synaptic pruning, dendritic arborization, and
increased myelination. Further, the onset of eating disor-
ders frequently occurs during adolescence and adolescent
AN samples are typically less confounded by a long dura-
tion of illness compared to adults. To our knowledge, there
are five sMRI studies that have investigated adolescents
and young females with AN. Gaudio et al. (2010) inves-
tigated morphometric gray matter changes in a sample of
AN restrictive subtype aged 12–18 years in the early
stages of the illness (16 patients with AN vs. 16 healthy
controls). The results showed a significant decrease in
global gray matter in patients, as well as a significant
region-specific decrease in gray matter volume bilaterally
in the middle cingulate cortex, the precuneus, and the

*Corresponding author. Email: tonefuglset@hotmail.com

© 2014 Taylor & Francis

170 T.S. Fuglset et al.
inferior and superior parietal lobules. In a more resent
study (Bomba et al., 2013), 11 patients with AN showed
decreased total GM and WM volumes. Mainz and collea-
gues (Mainz, Schulte-Ruther, Fink, Herpertz-Dahlmann, &
Konrad, 2012) found in 19 patients with AN (age 12–17
years) reduced GM in several regions along the cortical
midline, which were mostly reversible after weight
restoration. The strongest association between regional
GM increase and weight gain was found in the cerebellum.
In another study, 12 adolescents with AN (age 11–17
years) had reduced global gray matter volume compared
to a healthy control group at initial assessment (Castro-
Fornieles et al., 2009). Regional analyses showed reduc-
tions in several temporal and parietal gray matter regions
in the patients. At follow-up, no global group differences
existed; however, some regional gray matter reductions
were detected in the patient group. Results suggest that
gray matter is more affected than white matter, mainly
involving the posterior regions of the brain. Lazaro et al.
(2013) wanted to assess brain differences in treated,
weight-stabilized adolescents with AN compared to con-
trols. In a sample of 35 weight-recovered AN patients,
they found no differences in global GM and WM volumes,
and no differences in the regional analyses. The results
suggest that there are no brain abnormalities in adolescents
following weight restoration.
In this case series, we investigated four young females
diagnosed with AN who underwent two MRI scanning ses-
sions. The aim of this study was to investigate whether
changes in weight and other clinical measurements were
accompanied by alterations in global and regional brain
volume, and if so, which regions of the brain are most affected.
Methods
Participants and procedure
Participants were four females aged 13.9, 17.7, 18.2, and
18.9 years at baseline. All cases were recruited from the
Regional Eating Disorder Unit at Oslo University Hospital,
where they received treatment at an inpatient unit for eating
disorders. The unit provides specialized treatment for com-
plicated and severely ill cases with eating disorders. The
treatment is focusing on re-nutrition and weight gain with a
strict daily meal plan as these patients have not responded on
previous treatment. The theoretical approach is based on
family therapy involving the parents in the daily treatment
of their child. One patient had already normalized her weight
at T1; however, she was still admitted to inpatient treatment
for AN since the cognitive symptoms of AN were still pre-
sent. Diagnostically, this patient was eating disorder not
otherwise specified (EDNOS)-AN. sMRI scanning and clin-
ical measures were assessed at two time points. The first
scanning session took place during inpatient treatment, and
the second assessment occurred at 1 year after the initial
assessment (follow-up = 14 months, range 12–17 months),
regardless of weight recovery or treatment status.
All participants signed written informed content after
receiving information about the study. The study was
approved by the Regional Ethical Committee in Oslo,
Norway.
Clinical measures
Body mass index (BMI) was calculated from weight and
height (kg/m2). The BMI criteria for an AN diagnosis in
clinical studies is usually below 17.5 (BMI normal
range = 18.5–24.9; World Health Organization, 2005).
As BMI is not a useful measure for children and young
adolescents, however, age and gender-adjusted BMI per-
centile were also calculated for all four cases.
The Eating Disorders Examination Questionnaire
(EDE-Q) is derived from the Eating Disorder
Examination Interview (EDE; Fairburn, 2008). The EDE-
Q provides a comprehensive assessment of specific eating
disorder psychopathology and behavior. It is a 28-item
self-report questionnaire covering a period of 28 days.
The items are rated on a seven-point Likert scale, and
higher scores indicate greater eating pathology. Research
suggests that a 1–1.5 score increase or decrease constitutes
clinically significant improvement or worsening (Watson,
Allen, Fursland, Byrne, & Nathan, 2012).
The State/Trait Anxiety Inventory (STAI) is a com-
monly used measure of trait and state anxiety (Spielberger,
Gorsuch, Lushene, Vagg, & Jacobs, 1983). The STAI is a
self-report measure and has 20 items that measure trait
anxiety and 20 items that assess state anxiety. All items are
rated on a four-point scale, and higher scores indicate
more anxiety.
Beck’s Depression Inventory (BDI) is a 21-item self-
report questionnaire used to measure severity of depres-
sion (Beck, Ward, Mendelson, Mock, & Erbaugh, 1961).
The items are related to various symptoms of depression,
such as hopelessness and irritability, cognitions of guilt, or
feelings of being punished. Higher scores indicate more
depression.
The Body Checking Questionnaire (BCQ) is a 23 item
self-report measure that measures the global construct of
body checking behaviors with three correlated subfactors
that assess checking related to overall appearance, check-
ing of specific body parts, and idiosyncratic body parts
(Reas, Whisenhunt, Netemeyer, & Williamson, 2002).
Each item is scored on a five-point Likert-type scale,
ranging from 1 (= never) to 5 (= very often). Higher scores
are associated with more body checking.
Image acquisition
Structural images were acquired at Curato X-ray institute
in Oslo, Norway, using a 1.5 T Philips scanner. A standard
 Neurocase 171

image acquisition protocol was followed: T1-weighted
images gradient echo sequence were obtained in the obli-
que plane with a flip angle = 90º, TE = 4 ms, TR = 30 ms,
field of view = 24 × 24 cm, matrix size = 128 × 128, and
slice thickness = 3.0 mm.
thickness. Results are presented in terms of change in
percentage for each of the four cases. Rather than making
a priori decisions regarding specific regions of interest, we
opted to present the complete data set and highlight the
most affected regions for each case.

Cortical reconstruction and calculation of brain volume Results

MR images were processed and calculations of global and
regional brain volume were performed using Freesurfer
(Fischl, 2012). A neuroanatomical label was automatically
assigned to each voxel in an MRI volume based on prob-
abilistic information automatically estimated from a manu-
ally labeled training set (Fischl et al., 2002). The
segmentation was performed in a series of steps. First, an
optimal linear transform was computed that maximizes the
likelihood of the input image, given an atlas constructed
from manually labeled images. Then, a nonlinear trans-
form was initialized with the linear one, and the image was
allowed to further deform to better match the atlas. Finally,
a Bayesian segmentation procedure was carried out, and
the maximum a posteriori (MAP) estimate of the labeling
was computed. The segmentation uses three pieces of
information to disambiguate labels: (1) the prior probabil-
ity of a given tissue class occurring at a specific atlas
location, (2) the likelihood of the image given that tissue
class, and (3) the probability of the local spatial configura-
tion of labels given the tissue class. This latter term repre-
sents a large number of constraints on the space of
allowable segmentations and prohibits label configurations
that never occur in the training set (e.g., hippocampus is
never anterior to amygdala). The technique has previously
been shown to be comparable in accuracy to manual
labeling. The segmentations were visually inspected for
accuracy.
We wanted to assess pre-post differences in (1) global
brain volume, (2) regional brain volume, and (3) cortical
Case 1
Clinical measures
Case 1 was 18.2 years old at initial assessment, with a very
low weight of 37.7 kg (BMI = 13.5). Global EDE-Q score
was above the normal range. Depression rates indicated
severe depression. Measures of state and trait anxiety were
above normal, and body checking measures were also
high. At follow-up, her weight had increased to 46.6 kg
(BMI = 16.5), which represents an increase of 3 BMI
units; however, BMI remained in the underweight cate-
gory. Global EDE-Q score increased and level of depres-
sion had increased, as well as state and trait anxiety. Body
checking scores remained high (Table 1).
Brain volume and cortical thickness
There were almost no changes in total white matter
volume; however, total gray matter volume increased
with 10%. CSF was reduced by 17%. All the ventricles
reduced with various degrees, up to 82% reduction, except
the fifth ventricle, which increased by 300%. Case 1 had
the largest changes in brain volume, with large increases in
the accumbens 30%, amygdala 24%, putamen 16%, and
the hippocampus 12% (Table 2). In general, an overall
increase of cortical thickness was observed in case 1.
The largest changes were found in the frontal lobe, with
an increase in the left frontal pole of 27%, and the tem-
poral lobe (Table 3). In sum, case 1 did not improve on

Table 1. Clinical measures of each case from sessions 1 and 2.

Case 1 Case 2 Case 3 Case 4

Measure Session 1 Session 2 Session 1 Session 2 Session 1 Session 2 Session 1 Session 2

Age 18.2 19.3 18.9 21.2 17.7 18.7 13.9 15.0

Weight 37.7 46.6 45.0 56.2 46.0 44.3 53.9 48.0
BMI 13.5 16.5 14.0 17.7 17.5 16.9 18.7 16.6
BMI percentile <5th <5th <5th 5 7 <5th 39 9
Global EDE-Q 3.7 4.7 3.8 1.7 5.0 4.7 4.7 3.9
BDI 33 45 20 11 47 48 32 34
STAI trait (t-score) 61 77 69 59 77 77 63 70
STAI state (t-score) 43 77 60 51 75 75 65 69
BCQ 102 100 51 40 111 100 92 99
Notes: BMI, body mass index; EDE-Q, Eating Disorder Examination Questionnaire; BDI, Beck’s Depression Inventory; STAI, State Trait Anxiety
Inventory; BCQ, body checking questionnaire. BDI: <10, no/minimal depression; 10–18, mild to moderate depression; 19–29, moderate to serious
depression; 30–63, serious depression. The norms for clinical measures are based on mean scores of clinical eating disorder samples ± 1 SD and are as
follows: Global EDE-Q: 2,9–6, STAI, state: 24–39, trait: 25–41, BCQ: 32–46.
172 T.S. Fuglset et al.

Table 2. Volume changes (%) in each case from session 1 to session 2.

Case 1 Case 2 Case 3 Case 4

BMI ↑ 3 BMI ↑ 3.7 BMI ↓ 0.6 BMI ↓ 2.1

Total cortical WM volume −1 4 0 0

Total GM volume 10 2 −1 −5
Corpus callosum 5 5 −1 0
Brain stem 4 5 0 0
CSF −17 −18 5 2
Third ventricle −30 −7 −3 3
Fourth ventricle −27 −14 7 3
Fifth ventricle 300 0 0 −62

Left hem Right hem Left hem Right hem Left hem Right hem Left hem Right hem

Lateral ventricle −36 −39 −19 −26 1 0 7 12

Inferior lateral ventricle −82 −51 −11 −6 −2 113 7 2
Cerebellum white matter 4 11 2 2 −8 9 −13 −1
Cerebellum cortex 9 8 2 0 0 −2 −2 −3
Thalamus proper 5 8 11 4 3 0 7 −6
Caudate −1 3 5 −4 −4 −2 3 −3
Putamen 16 10 12 5 −2 −3 1 −1
Pallidum 9 −7 20 −5 −5 −8 −3 −3
Hippocampus 12 8 4 4 10 −3 −6 2
Amygdala 24 4 11 8 2 −10 −6 6
Accumbens 2 30 −1 −7 −2 1 −21 0
Ventral diencephalon −3 7 −6 −6 −2 −2 6 1
Notes: The largest changes in each case are highlighted in bold. BMI, body mass index; Hem, hemisphere; WM, white matter; GM, gray matter; CSF,
cerebrospinal fluid.

any of the clinical measures, except for BMI, which had
increased considerably, although she remained under-
weight. This was associated with both decreased and
increased ventricles, no changes in total white matter;
however, both total and regional gray matter volume
increased and cortical thickness increased.
Case 2
Clinical measures
Case 2 was 18.9 years old at initial assessment, with a very
low weight of 45.0 kg (BMI = 14.0). Global EDE-Q score
was within the clinical range. Depression score indicated
moderate to severe depression. State and trait anxiety were
high, as well as the level of body checking. At follow-up,
her weight had increased considerably to 56.2 kg
(BMI = 17.7). Global EDE-Q score was within the normal
range, and depression had decreased from moderate/severe
to mild. State and trait anxiety scores also decreased, but
still remained above normal levels. Body checking scores
fell within the normal range (Table 1).
Brain volume and cortical thickness
In case 2, there were some small changes in total white
matter, which increased by 4%. Even smaller changes
were observed in total gray matter, which increased by
2%. CSF was reduced by 18%, and there were also some
reductions of the ventricles, with up to a 26% decrease in
the right lateral ventricle. There were some changes in
regional gray matter volume. The largest changes were
observed in the pallidum, which increased by 20%, the
putamen had an increase of 12%, and the thalamus and
amygdala both increased by 11% (Table 2). Cortical thick-
ness both increased and decreased in various regions of the
cortex; the largest effect was found in the frontal, tem-
poral, and parietal lobes (Table 3). To sum up, case 2
improved on several of the clinical measures, and her
BMI increased to an almost normal level. This was asso-
ciated with decreased ventricles, very small changes in
total gray and white matter volume, some increases in
regional gray matter volume, and both increased and
decreased cortical thickness.
Case 3
Clinical measures
Case 3 was 17.7 years old at initial assessment, with a
weight of 46.0 kg (BMI = 17.5), which is underweight.
Global EDE-Q score was in the clinical range. The depres-
sion measures indicated severe depression. She had also
high levels of both trait and state anxiety. Body checking
measure indicated high degree of problems with body
checking. At follow-up, her weight had decreased to
 Neurocase 173

Table 3. Cortical thickness change (%) in each case from session 1 to session 2.

Case 1 Case 2 Case 3 Case 4

BMI ↑ 3 BMI ↑ 3.7 BMI ↓ 0.6 BMI ↓ 2.1

Left Right Right Right Right

hemi hemi Left hemi hemi Left hemi hemi Left hemi hemi

Frontal lobe Caudal middle frontal gyrus 11 15 1 4 −3 −1 −3 −2

Lateral orbitofrontal cortex 9 9 4 0 −7 −1 −2 −5
Medial orbitofrontal cortex 4 20 0 9 −2 −3 5 −4
Pars opercularis 11 9 2 1 2 −3 −5 −4
Pars orbitalis 19 8 −5 3 −6 −10 −6 −5
Pars triangularis 10 14 3 2 −13 −2 −10 −6
Precentral gyrus 6 10 −2 0 0 0 1 1
Rostral middle frontal gyrus 12 23 11 3 −6 −9 −7 −4
Superior frontal gyrus 18 14 2 5 −2 −1 −2 −6
Frontal pole 27 22 −6 −16 −4 −12 −10 −29
Frontal and Paracentral lobule 9 9 6 5 0 2 −2 −3
parietal lobe
Temporal lobe Entorhinal cortex 4 7 −16 −3 −13 −13 −9 4
Fusiform gyrus 13 19 0 0 −6 −7 −3 1
Inferior temporal gyrus 12 14 3 5 −8 −4 −2 −3
Middle temporal gyrus 12 12 2 6 −9 −5 −4 −4
Parahippocampal gyrus 3 7 −3 2 −3 −9 −2 −1
Superior temporal gyrus 11 14 −2 4 −6 −3 −4 −3
Temporal pole 3 3 −3 −2 −11 −6 −6 −1
Transverse temporal cortex 3 17 −1 −9 −5 −1 5 −9
Banks of the superior 19 24 13 8 −5 −3 −1 2
temporal sulcus
Parietal lobe Inferior parietal cortex 15 17 11 7 1 −1 −4 −6
Pericalcarine cortex 6 4 16 11 −1 −8 0 1
Precuneus cortex 12 15 8 4 −1 −1 −3 −6
Superior parietal cortex 11 11 8 3 6 −1 −7 −2
Supramarginal gyrus 11 13 5 3 3 3 −5 −3
Postcentral gyrus 14 7 4 4 −1 4 −2 −1
Occipital lobe Cuneus cortex 7 11 7 0 −1 3 0 4
Lateral occipital cortex 15 16 4 6 0 −3 −4 −3
Lingual gyrus 17 15 13 1 −3 −2 1 1
Cingulate cortex Posterior cingulate 10 14 3 0 −8 −2 −1 −5
Rostral anterior cingulate 2 13 4 11 1 −2 0 −4
Caudal anterior cingulate 5 3 −12 −4 −5 2 1 −3
Isthmus cingulate 10 13 7 −1 −2 −4 4 2
Insular lobe Insular cortex 5 5 −4 −1 −2 −7 −7 −4
Notes: The regions with the largest change in each case are highlighted in bold. Hemi, hemisphere; BMI, body mass index.

44.3 kg (BMI = 16.9), which is severely underweight.
Global EDE-Q score remained high and within the clinical
range. Levels of depression, state and trait anxiety, and
body checking remained the same (Table 1).
Brain volume and cortical thickness
There were no changes in total white matter volume and
very small reductions in total gray matter volume. CSF
increased by 5%. Very small changes in the lateral, third,
and fourth ventricles were detected; however, the right
inferior lateral ventricle increased by 113%. There were
some changes in regional brain volume, increased
hippocampus, and decreased amygdala, both by 10%.
The pallidum decreased by 8%, and the caudate decreased
by 4% (Table 2). There was a reduction of cortical thick-
ness, most evident in the frontal and temporal lobes
(Table 3). In sum, case 3 did not improve on any of the
clinical measures 1 year after the first assessment, and she
was slightly more underweight at the second assessment.
This was associated with a large increase in the right
inferior lateral ventricle, no changes in total white matter
volume, and very small changes in total gray matter. Some
regional brain volume changes also occurred, which con-
sisted of both reduced and increased volume. Cortical
thickness was reduced.
174 T.S. Fuglset et al.
Case 4
Clinical measures
Case 4 was 13.9 years old at initial assessment, and her
weight was within normal range, 53.9 kg (BMI = 18.7,
percentile 39). Global EDE-Q score was clinical.
Depression level was severe, and state and trait levels
were also high. Body checking levels were considered
high. At follow-up, her weight had decreased to 48 kg and
she was underweight (BMI = 16.6, percentile 9). Global
EDE-Q score was within clinical range. Depression level
was still severe, and state trait anxiety had increased and
was still above normal. Scores on body checking had
increased and were above normal level (Table 1).
Brain volume and cortical thickness
There were no changes in total white matter volume, and
very small total gray matter volume reductions, 5%. Very
small changes occurred in CSF and the ventricles, except
an increase of the fifth ventricle with 62%. There were also
some reductions of regional gray matter volume; the lar-
gest change was found in the left accumbens, which
reduced by 21%, left thalamus increased by 7%, hippo-
campus, amygdala, and right thalamus decreased by 6%,
and the right amygdala and ventral diencephalons
increased by 6% (Table 2). There was a general reduction
of cortical thickness; the largest change was in the frontal
lobe (Table 3). In sum, case 4 did not improve on any
clinical levels besides EDE-Q, and her BMI decreased.
This was associated with very small changes in total
brain volume and some reductions of regional gray matter
and reduced cortical thickness.
Discussion
The aim of this study was to assess pre-post differences in
(1) global brain volume, (2) regional brain volume, and (3)
cortical thickness in three cases with AN and one with
EDNOS-AN. The major findings in this study were that
weight gain was associated with increased brain volume
and cortical thickness, and weight loss was associated with
decreased brain volume and cortical thickness. Further,
global gray matter was more affected by weight changes
than global white matter. The largest regional changes
were found in the accumbens, amygdala, pallidum, and
putamen. The largest changes in cortical thickness were
found in the frontal and temporal lobes.
An overall reduction of brain mass is commonly
thought of as a result of starvation and malnutrition since
starving the body will also starve the brain. Interestingly,
we found minor changes in global brain volume, whereas
larger effects were observed at a regional level. This could
indicate that (1) these brain structures are more vulnerable
to starvation and malnutrition than others, and (2) these
brain structures are a part of the pathophysiology of AN.
It is worth noting that the participants in this study
were severely ill, and the clinical outcome at the second
assessment was quite poor. Only one of the four cases
(case 2) clearly showed improvements on both weight and
clinical measures. Case 1 also gained weight at follow-up;
however, according to the clinical measures, she was still
very ill. Case 3 showed approximately no changes in
neither weight nor clinical measures. Case 4 actually
decreased in weight after discharge from hospital treat-
ment and remained very ill.
An increased global white matter and gray matter in
AN patients after weight recovery has been described in
other studies (Castro-Fornieles et al., 2009; Wagner et al.,
2006). However, we found very small changes in global
brain volume, both gray and white matter, in the two cases
that gained weight at follow-up. Our results further sug-
gest that global gray matter is more affected by starvation
than white matter, which is in line with some studies
(Friederich et al., 2012; Joos et al., 2010), but contra-
dictory to another study that found reductions in global
white matter but not in gray matter (Boghi et al., 2011).
Besides minor changes in global brain volume, weight
gain was associated with reduced ventricles and lower
weight was associated with enlarged ventricles. This is
not a surprising finding as it is well established in the
literature that reduced weight is related to enlarged ven-
tricles and vice versa (Golden et al., 1996; Neumarker,
Bzufka, Dudeck, Hein, & Neumarker, 2000; Swayze et al.,
1996). Interestingly, a very large increase of the fifth
ventricle was observed in one case who actually gained
weight. This finding contradicts previous research as enlar-
gement of this ventricle was not associated with weight
reduction.
When focusing on specific regional volume changes in
the brain, we observed that weight changes were accom-
panied by alterations in a variety of brain structures. In
general, we found that weight gain was associated with
increased regional gray matter volume, and weight reduc-
tions were associated with reduced regional gray matter
volume. Some regions changed more than others. First, the
nucleus accumbens volume increased when weight
increased, and decreased when weight reduced. The
nucleus accumbens is an important element for reward
and motivation as it integrates inputs from limbic and
cortical regions, linking motivation and action (Carlezon
& Thomas, 2009). Likewise, amygdala volume alterations
were associated with weight increase and reduction. The
amygdala is a part of the ventral limbic circuit and is
involved in identifying rewarding and emotionally signifi-
cant stimuli required to generate affective responses to
these stimuli (Phillips, Drevets, Rauch, & Lane, 2003).
Reduced volume of the amygdala in patients with AN
compared to controls has also been reported in previous
studies (Friederich et al., 2012; Giordano et al., 2001). In
addition, functional magnetic resonance imaging (fMRI)
 Neurocase
studies have repeatedly reported abnormal activation in
this region in patients with AN (Ellison et al., 1998;
Miyake et al., 2010, 2012; Seeger, Braus, Ruf,
Goldberger, & Schmidt, 2002; Vocks et al., 2010; Vocks,
Herpertz, Rosenberger, Senf, & Gizewski, 2011). Further,
pallidum increase was associated with weight gain. In
recent years, the (ventral) pallidum has become of great
interest as the mechanism for reward and motivation
(Smith, Tindell, Aldridge, & Berridge, 2009). The puta-
men, which is a part of the striatum, also has an essential
role in the reward system (Haruno & Kawato, 2006).
Increased gray matter volume in the putamen was found
in both cases who gained weight. In a recent study, AN
patients showed decreased gray matter volume in this
region compared to AN weight-restored patients
(Friederich et al., 2012), suggesting that this alteration is
state-dependent as it was only found in underweight
patients. Thalamus increase was also associated with
weight increase. The major role of the thalamus is to
gate and modulate the flow of information to the cortex
(Sherman & Guillery, 2002). Further, hippocampus reduc-
tion was observed in association with weight reduction. A
similar finding has been reported by Connan et al. (2006),
who found reduced hippocampal volume in AN patients
compared to controls.
Regarding cortical thickness alterations, there was a
clear tendency that the largest changes occurred in the
frontal and temporal lobes. The frontal lobe has been
associated with higher cognitive functions, such as atten-
tion, working memory, inhibition, and executive functions
(Foster, Eskes, & Stuss, 1994; Siddiqui, Chatterjee,
Kumar, Siddiqui, & Goyal, 2008). Previously, it has been
suggested that the mechanisms involved in developing AN
are related to dysfunctions within frontostriatal circuits,
associated with either the strength of the connection
between frontal and subcortical areas (Southgate,
Tchanturia, & Treasure, 2005), habit learning as in obses-
sive-compulsive disorder (Steinglass & Walsh, 2006), self-
regulation (Marsh, Maia, & Peterson, 2009), reward pro-
cessing difficulties (Kaye, Fudge, & Paulus, 2009), and
emotion processing (Hatch et al., 2010). The temporal lobe
is associated with auditory (Binder et al., 2000) and visual
(Doyon & Milner, 1991) sensory information processing,
language comprehension and speech (Scott, Blank, Rosen,
& Wise, 2000), and storing new memories (Squire & Zola-
Morgan, 2013). Results from functional imaging studies
suggest that anorexia could be related to a dysfunction in
the temporal lobes as these studies have reported unilateral
hypoperfusion in the temporal region (Gordon, Lask,
Bryant-Waugh, Christie, & Timimi, 1997) and distur-
bances in the mesial temporal lobe related to altered ser-
otonin function (Frank et al., 2002). It has also been
demonstrated that lesions occurring in the frontal and
temporal lobes have caused characteristic eating disorder
pathology (Uher & Treasure, 2005).
175
Although there is an increased knowledge about brain
anatomy in patients with AN, questions about the functional
significance of this knowledge remain unclear. Due to the
limitations of the present study as a case series, caution
should be exercised when interpreting results. However, it
is of interest that the specific regions that appear most
vulnerable to changes in weight are related to reward and
the reward system. These structures include the nucleus
accumbens, amygdala, putamen, and pallidum. Findings
are noteworthy in light of prior suggestions that patients
with AN have a dysfunctional reward system (Kaye et al.,
2009; Keating, Tilbrook, Rossell, & Fitzgerald, 2012). In
addition, the results from a recent meta-analysis of struc-
tural imaging studies suggest that AN is linked to reduced
brain structure in reward and somatosensory regions
(Titova, Hjorth, Schioth, & Brooks, 2013).
Limitations and strengths
This is a case study of four cases with different clinical
courses. Due to the small sample size, our data are therefore
limited to addressing the extent of the changes from session
1 to session 2, in what regions these changes occurred, and
how these changes co-varied with degree of weight gain
and clinical improvement. No conclusions regarding caus-
ality can be drawn between weight changes and brain
alterations, and our results cannot be generalized to the
entire AN population. We have emphasized the structures
that demonstrated the largest changes in volume from ses-
sion 1 to session 2. However, this might be problematic due
to the potential risk of overlooking smaller alterations in
brain structure, which may prove equally important. There
is an outlier in age of the four cases; three cases are young
adults and similar in age, but the fourth case is aged 14. We
do not have information about medication, which is a factor
that could potentially impact the data. In addition, the
developmental structural brain changes could also impact
the results in this study; however, these changes would be
of minor importance compared to structural brain changes
due to weight fluctuations.
This study provided an in-depth investigation of cere-
bral tissue alterations associated with different clinical and
weight outcomes in young females with AN.
Characteristic of case studies, a large amount of detailed
information is presented, whereas in larger group studies
valuable data pertaining to each individual might disap-
pear. Although the study is limited in generalizability, data
could provide a basis for the development of hypotheses
regarding the pathophysiology of AN. Additionally, from
a clinical perspective, it might be useful for therapists to
demonstrate for the patients that their brains are physically
affected by underweight and malnutrition. It might also
prove useful for AN patients to obtain an increased under-
standing of their own illness from a neurobiological
176 T.S. Fuglset et al.
perspective, which in turn might reduce the guilt and
shame that these patients often experience.
Conclusions
This study supported previous notions that weight changes
are associated with cerebral tissue alterations, and that
gray matter seems to be more affected than white matter.
Results contribute to increased knowledge regarding the
specific brain regions associated with changes in weight
and clinical measurements in patients with AN. It could be
speculated that these findings are related to a dysfunctional
reward system, which could account for the core symp-
toms associated with AN, such as restrictive eating and
excessive exercise.
Acknowledgment
We would like to thank Eva Hilland for helpful work with
imaging analyses.
Funding
Funding for this work was provided by grant support from South-
Eastern Norway Regional Health Authority.
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