Limbic Changes Identifi ed by
Imaging in Bipolar Patients
Paolo Brambilla, MD, PhD, John P. Hatch, PhD, and Jair C. Soares, MD
Jair C. Soares, MD
Department of Psychiatry, University of North Carolina Center
of Excellence for Research and Treatment of Bipolar Disorders
(CERT-BD), 10616 Neuroscience Hospital, CB# 7160,
University of North Carolina School of Medicine,
Chapel Hill, NC 27599-7160, USA.
Current Psychiatry Reports 2008, 10:505–509
Current Medicine Group LLC ISSN 1523-3812
Copyright © 2008 by Current Medicine Group LLC
The hippocampus and amygdala are key limbic regions
for memory formation and emotion modulation that
are potentially involved in the cognitive and affective
symptoms of bipolar disorder. Here we discuss the most
consistent MRI literature in bipolar disorder, focusing
on the role of the hippocampus and amygdala. In child
and adolescent patients, a unique pattern of abnormali-
ties has begun to emerge, with volume defi cits in the
hippocampus and amygdala already detectable early in
the illness course. In adults, it is unclear whether hippo-
campal volumes are abnormal, whereas the amygdala
is reported to be larger and hyperactive to external
emotional stimuli. However, available fi ndings are often
confl icting, and most studies suffer from limitations.
Future longitudinal magnetic resonance studies should
focus on juvenile patients; fi rst-episode, drug-free
patients; and unaffected family members. Jointly with
genetic, postmortem, and neuropsychological studies,
these studies will be extremely valuable in separating
state from trait brain abnormalities and further charac-
terizing the pathophysiology of bipolar disorder.
Bipolar disorder is a chronic and disabling psychiatric
illness characterized by depressive, manic, mixed, and
euthymic phases and cognitive disturbances. In the past
two decades, imaging techniques, particularly MRI, have
allowed identifi cation of subtle brain changes in individu-
als suffering from mood disorders. MRI is a noninvasive
technique allowing in vivo exploration of the anatomy
(structural MRI or diffusion tensor MRI), biochemistry
(magnetic resonance spectroscopy [MRS]), and function
(functional MRI [fMRI]) of the human brain. In indi-
viduals with bipolar disorder, these techniques reveal
changes in limbic structures, including hippocampus and
amygdala, which are key regions in modulating mood
and emotions. Indeed, an altered anterior-limbic network
has been suggested to be involved in pathophysiology
. In fact, the hippocampus and amygdala, together
with the prefrontal cortex, are instrumental in informa-
tion processing and in creating emotional and declarative
memories. In this review, we discuss the most consistent
fi ndings from imaging studies investigating the hippocam-
pus and amygdala in bipolar disorder, with an emphasis
on future approaches for examining this illness.
The hippocampus participates in the formation of declar-
ative memory, which involves the conscious recollection,
verbal refl ection, and explicit expression of facts and
events . The hippocampus is also crucial for memory
consolidation, the process of converting short-term mem-
ory into long-lasting memory in the neocortex. Thus, the
hippocampus provides input for long-term memory and
reinforcement of synaptic connections for memory traces.
Within the declarative memory system, the hippocampus
is specialized for the learning of context, including tem-
poral context, and is crucial for formation of declarative
memories. Therefore, the hippocampus plays a major role
in cognition, and abnormalities in this brain structure
lead to impaired cognitive functions and possibly abnor-
A decrease in size of the hippocampus has been noted
in patients with bipolar disorder [3,4], particularly in those
carrying the Met allele of the brain-derived neurotrophic
factor (BDNF) gene. This is signifi cant because BDNF
is a crucial factor in neuroplasticity . Also, a recent
prospective MRI study found that bipolar patients show
accelerated decline of gray matter in the hippocampus
compared with healthy individuals . Moreover, a small
twin study showed smaller right hippocampal volumes in
six affected bipolar twins compared with their well co-
twins . Furthermore, positron emission tomography
and postmortem studies demonstrate abnormal neuro-
modulatory systems (ie, dopamine, glutamate, serotonin,
506 Bipolar Disorders
and γ-aminobutyric acid) [8–10] and altered neuroplastic-
ity [11,12] in the hippocampus of adult patients suffering
from bipolar disorder. Collectively, these studies support
the role of hippocampal abnormalities in this disorder. In
addition, even during euthymia, bipolar disorder patients
show abnormalities of declarative memory, a neuropsy-
chological dimension crucial for learning and language
that is sustained by the hippocampus [13,14], suggest-
ing that hippocampal alterations may affect cognition in
these patients. In juvenile bipolar disorder, which may be
considered a more severe phenotype of the illness , hip-
pocampal volume defi cits have been found in some [16,17]
but not all MRI studies [18,19]. In particular, our group
recently showed hippocampal atrophy predominantly
in the subicular region in children and adolescents with
bipolar disorder [20•] by using a novel three-dimensional
mapping technique. However, some other structural MRI
studies and systematic reviews with meta-analyses did not
detect changes in hippocampal volumes [21–25]. Discrep-
ancies among the studies in the adult population may be
explained in part by methodological differences. Indeed,
two main variables should be taken into account when
exploring the hippocampus: subregions and development.
The hippocampus comprises specifi c subregions that have
different developmental trajectories, cortical connections,
and behavioral functions . During normal develop-
ment, total hippocampal size does not change during
adolescence , whereas the posterior areas increase
and the anterior regions decrease over time . There-
fore, conventional MRI studies that examine only global
hippocampus volume may not identify size differences,
particularly when studying adults. Furthermore, long-
term exposure to medications, a common confounding
factor in studies involving adult patients, could be revers-
ing some of the size abnormalities reported in pediatric
MRS studies also have been carried out to help us fur-
ther understand the role of hippocampal abnormalities in
bipolar disorder. MRS allows noninvasive exploration of
the brain biochemistry in vivo, detecting specifi c metabo-
lites such as N-acetylaspartate (NAA), choline-containing
compounds, glutamate, and myoinositol. Reduced NAA
levels [28–30] and increased glutamate concentrations
 have been reported in the hippocampus in some 1H-
MRS studies of adults with bipolar disorder. As NAA is
located mainly in neurons and is considered a marker of
neuronal integrity, viability, and activity, and excessive
glutamatergic neurotransmission is neurotoxic, it can be
argued that hippocampal dendritic/synaptic development
may be abnormal, or hippocampal neural degeneration
may be present in bipolar disorder. fMRI is another neu-
roimaging technique used to study neurophysiology and
function. It is a noninvasive technique that can quantify
changes in regional cerebral blood fl ow and blood oxygen-
ation during a sensory or cognitive challenge. Two fMRI
studies showed increased activation of the hippocampus
in response to emotional stimuli in patients with bipolar
Taken together, these fi ndings indicate that subtle size
abnormalities of hippocampus are detectable early in the
illness course, although it is unclear whether they persist
into adulthood. If they do not, one has to consider the
possibility that medication effects may normalize these
abnormalities. In fact, lithium administration has been
shown to partially reverse hippocampal atrophy in adults
suffering from bipolar disorder [4,34]. The remodeling
action of lithium on the hippocampus has been demon-
strated in animal studies [35,36]. Both structural and
biochemical (ie, decreased NAA levels) hippocampal
defi cits could result from altered neurodevelopment and
may play a key role in the cognitive disturbances seen
in patients with bipolar disorder [37,38•]. Although the
process underlying hippocampal maldevelopment remains
unclear, several remodeling mechanisms can be hypoth-
esized to explain it (eg, dendrite retraction, glial cell loss,
reduced neurogenesis, and abnormal pruning/apoptosis)
. In this context, it is interesting to note that myelina-
tion of the subicular and presubicular subregions of the
hippocampus continues throughout adolescence , and
abnormalities in these processes could be involved in the
pathophysiology of bipolar disorder.
The amygdala is located within the medial temporal lobe
adjacent to the hippocampus. It connects to several corti-
cal regions, receiving input from the frontal and temporal
lobes and sending output information to limbic areas such
as the hippocampus, entorhinal cortex, thalamus, and
neocortex. The amygdala is involved in a wide range of
functions, such as the activation of the sympathetic ner-
vous system; the release of dopamine, norepinephrine,
and epinephrine; and the modulation of facial expres-
sions. The amygdala plays a key role in modulating human
emotions and is crucial for the formation of emotional
memory or memory for emotionally arousing events. As
fi rst described in Klüver-Bucy syndrome, monkeys with
damaged amygdaloid complex had dramatically reduced
fear reactions . The amygdala’s role in processing fear
and emotion has been confi rmed in humans by several
functional imaging studies showing increased amyg-
dala activation by faces expressing happiness, sadness,
and fear [42,43]. Therefore, the amygdala is considered
another key region possibly involved in the pathophysi-
ology of bipolar disorder, as patients with this disorder
show impaired ability to process and modulate emotion.
Several structural MRI studies have found abnormally
large amygdala volumes in adults with bipolar disorder
[21,44,45], although normal  and smaller [46,47] amyg-
dala volumes also have been shown. In contrast, smaller
amygdala size in children and adolescents with bipolar
disorder has been reported consistently [18,19,48]. In
Limbic Changes Identifi ed by Imaging Brambilla et al. 507
pediatric bipolar disorder patients, our group reported a
direct correlation between age and left amygdala volume,
whereas an inverse correlation was shown in matched
healthy controls . This suggests an altered develop-
mental trajectory of the amygdala in bipolar disorder
that may result from abnormal neuronal pruning in child-
hood and adolescence, ultimately leading to relatively
larger volumes in adulthood. Alternatively, the anatomic
changes of the amygdala in adulthood could be explained
by compensatory mechanisms operating over time or by
lithium’s neuroprotective effects [19,34].
Consistent with the fi ndings of an enlarged amyg-
dala in adult bipolar patients, increased blood fl ow and
glucose metabolism have been reported in the amygdala
[49,50] and in the temporal lobes [51,52]. Interestingly,
a single-photon emission computed tomography study
found a direct relationship between the severity of execu-
tive function impairment and temporal lobe perfusion in
individuals with bipolar disorder . Also, during the
processing of emotionally charged stimuli, fMRI stud-
ies showed overactivation of the amygdala [54,55,56•],
which can be modulated by mood stabilizers [57,58], and
impaired connectivity between the amygdala and fronto-
temporal cortical regions [59,60] in patients with bipolar
disorder. Therefore, in parallel to hyperplasia, augmented
metabolism at rest and hyperactivation during emotion
modulation may be present in the amygdala of patients
with bipolar disorder.
The available imaging literature suggests structural,
chemical, and functional abnormalities in the hippocam-
pus and amygdala of individuals with bipolar disorder.
These two structures represent the limbic component of
an altered anterior-limbic network underlying the phe-
notypic expression of bipolar disorder that link with key
prefrontal regions, such as the dorsolateral prefrontal cor-
tex and anterior cingulate. This impaired prefronto-limbic
neural network would be crucial to support the pathogen-
esis of bipolar disorder . Specifi cally, size defi cits of
the hippocampus and the amygdala are identifi able early
in pediatric patients. In contrast, hippocampal volumes
appear largely normal in adulthood, but the amygdala
volume seems to increase, possibly as this structure
becomes hyperactive in response to external emotional
stimuli. Abnormal amygdala development may be specifi c
to bipolar disorder, whereas hippocampus abnormalities
have been consistently reported in schizophrenia and
unipolar disorder [1,12,44]. However, the current litera-
ture is limited by several confounders, such as small and
heterogeneous samples, clinical and medication status,
and cross-sectional design, that do not allow clarifi ca-
tion of whether such limbic abnormalities are related to
neurodevelopment or to neurodegeneration. Also, both
maldevelopment and neurodegeneration play a role, and a
“unitary model” can be proposed. In this potential model,
excessive neuronal pruning/apoptosis, abnormal synaptic
plasticity, or altered myelination may take place during
childhood and adolescence, when bipolar disorder usu-
ally has its onset. Subsequently, neurotoxic mechanisms,
impaired neuroplasticity, and cellular resilience may
potentially sustain further disease progression and cogni-
tive anomalies. Imaging studies with larger samples will
be needed to clarify the current literature fi ndings, which
are somewhat discrepant. To reduce variability in patient
populations and imaging techniques, such studies should
have a longitudinal design starting during adolescence;
use better standardized and innovative approaches, such
as three-dimensional mapping and dipyridamole-thallium
imaging; and recruit unaffected family members, as well
as childhood-onset and drug-free adult bipolar patients.
These research strategies, coupled with genetic, post-
mortem, and neuropsychological studies, will be crucial
to examine regional abnormalities in hippocampus and
amygdala and to unravel their maturational trajectory
in bipolar disorder. They will also help us to understand
whether such limbic abnormalities are present before the
appearance of symptoms or develop as a result of illness
course or treatment.
Dr. Brambilla was partially supported by grants from the
American Psychiatric Institute for Research and Educa-
tion (APIRE Young Minds in Psychiatry Award) and
from Veneto StartCup 2007. Dr. Soares was supported
by National Institutes of Health grants MH 68766, MH
69774, and RR 20571.
Dr. Soares has received grants from Pfi zer and Glaxo-
SmithKline, has served on the speakers’ bureau for Eli
Lilly and Company and AstraZeneca Pharmaceuticals,
and has served as a consultant for Organon and Shire. No
other potential confl icts of interest relevant to this article
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