Neuroprogressão bipolaridade

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Review Article
Neuroprogression in bipolar disorder
Introduction
Bipolar disorder is a major psychiatric illness
typically characterized by recurrent episodes of
mania and depression (1). In the United States, the
lifetime prevalence estimate of bipolar I disorder is
�1.1%, with an estimated annual cost of $45
billion (2). While the pathophysiology of bipolar
disorder remains incompletely understood, evi-
dence suggests that people with bipolar disorder
show progressive changes in symptomatology over
the course of illness. Specifically, patients with
bipolar disorder may exhibit progressive increases
in the frequency and severity of affective episodes
over time (3), and a worsening of long-term
outcome (4). Furthermore, several studies have
noted episode-related decrements in cognitive
function potentially indicative of underlying neu-
ropathologic changes (5–8). Over the last few
years, investigators have begun to link these
clinical observations with emerging neuroimaging
findings, and to explore whether these findings
represent aberrant neurodevelopmental processes
or evidence of illness-related epiphenomena.
Nonetheless, the effects of time and illness
exposure on individuals with, and at risk for,
bipolar disorder have been only scantily studied.
The studies that have been performed may be
divided into cross-sectional, usually retrospective,
studies and more prospective, longitudinal studies.
The former raise obvious issues of historical
reliability and the interpretation of correlational
findings, whereas the latter are necessarily limited
in scope and timing. Both of these methodologies
Schneider MR, DelBello MP, McNamara RK, Strakowski SM, Adler
CM. Neuroprogression in bipolar disorder.
Bipolar Disord 2012: 14: 356–374. � 2012 The Authors.
Journal compilation � 2012 John Wiley & Sons A ⁄S.
Objective: Recent theories regarding the neuropathology of bipolar
disorder suggest that both neurodevelopmental and neurodegenerative
processes may play a role. While magnetic resonance imaging has
provided significant insight into the structural, functional, and
connectivity abnormalities associated with bipolar disorder, research
assessing longitudinal changes has been more limited. However, such
research is essential to elucidate the pathophysiology of the disorder. The
aim of our review is to examine the extant literature for developmental
and progressive structural and functional changes in individuals with and
at risk for bipolar disorder.
Methods: We conducted a literature review using MEDLINE and the
following search terms: bipolar disorder, risk, child, adolescent, bipolar
offspring, MRI, fMRI, DTI, PET, SPECT, cross-sectional, longitudinal,
progressive, and developmental. Further relevant articles were identified
by cross-referencing with identified manuscripts.
Conclusions: There is some evidence for developmental and progressive
neurophysiological alterations in bipolar disorder, but the interpretation
of correlations between neuroimaging findings and measures of illness
exposure or age in cross-sectional studies must be performed with care.
Prospective longitudinal studies placed in the context of normative
developmental and atrophic changes in neural structures and pathways
thought to be involved in bipolar disorder are needed to improve our
understanding of the neurodevelopmental underpinnings and progressive
changes associated with bipolar disorder.
Marguerite Reid Schneidera, Melissa
P DelBellob, Robert K McNamarab,
Stephen M Strakowskib and Caleb M
Adlerb
aPhysician Scientist Training Program,
Neuroscience Graduate Program, bDepartment of
Psychiatry and Behavioral Neuroscience, Division
of Bipolar Disorders Research, University of
Cincinnati College of Medicine, Cincinnati, OH,
USA
doi: 10.1111/j.1399-5618.2012.01024.x
Key words: bipolar disorder – degeneration –
development – magnetic resonance imaging
(MRI) neuroimaging – progression.
Received 6 January 2011, revised and accepted
for publication 23 March 2012
Corresponding author:
Caleb M. Adler, M.D.
Department of Psychiatry and Behavioral
Neuroscience
University of Cincinnati College of Medicine
260 Stetson Street, Suite 3200
Cincinnati, OH 45219-0516
USA
Fax: (513) 558-3399
E-mail: adlercb@ucmail.uc.edu
Bipolar Disorders 2012: 14: 356–374 � 2012 John Wiley and Sons A/S
BIPOLAR DISORDERS
356
have now been applied to patients with bipolar
disorder across the age and illness spectrum, with
varied results. In this review, we will summarize
some of these findings and attempt to place them in
the larger context of recent advances in our
understanding of bipolar disorder. To do so, we
review the findings from both adult and pediatric
samples, as well as findings from multiple at-risk
populations, including child, adolescent, and adult
offspring of parents with bipolar disorder; twins
discordant for bipolar disorder; and unaffected
siblings of patients with bipolar disorder.
Bipolar disorder is arguably one of the most
heritable of the Axis I disorders. Family studies
have found that individuals with a first-degree
relative with bipolar disorder have a substantially
elevated risk for developing bipolar disorder com-
pared with the general population (9, 10), with
prevalence estimates in this population as high as
10–16% (11, 12). Furthermore, approximately
55% of the offspring of parents with bipolar
disorder are ultimately diagnosed with a psychia-
tric illness of some kind, most commonly mood,
anxiety, or disruptive behavior disorders (11, 13,
14). Emerging evidence has identified a number of
other potential endophenotypes that may precede
and ⁄or increase risk for overt bipolar symptom-
atology (15–17). Approximately 50% of bipolar
disorder patients report a history of severe trauma
or abuse during childhood, which may be associ-
ated with an earlier age of onset and a more severe
course of illness (18–22). In addition, some emerg-
ing evidence suggests that long-term exposure to
psychostimulant and antidepressant medications
may precipitate and accelerate the onset of mania
in vulnerable individuals (23–26). Lastly, some
evidence from cross-sectional and preliminary
intervention studies suggests that nutritional defi-
ciencies, including essential vitamin and fatty acid
insufficiency, may also exacerbate the course of
mood and psychotic disorders (27–31).
Offspring of parents with bipolar disorder often
exhibit a range of subsyndromal mood symptoms,
including depression, anxiety, sleep disturbances,
and irritability, as well as other clinical manifesta-
tions of underlying psychopathology that may
precede the initial onset of mania by as much as
10 years (32). One prospective study found that
25% of children and adolescents initially diagnosed
with subsyndromal symptoms of bipolar disorder
(e.g., bipolar disorder, not otherwise specified), and
20% diagnosed with type II bipolar disorder, were
ultimately diagnosed with type I bipolar disorder
during a two-year follow-up period (33). Cognitive
symptoms, particularly deficits in concentration
and attention, may also precede the onset of
mania. Studying neurofunctional and neurostruc-
tural changes occurring prior to illness onset in
these individuals at increased risk for developing
bipolar disorder is crucial to understanding the
development and progression of the illness. Fur-
thermore, conducting neuroimaging studies on
individuals with a known risk for developing
bipolar disorder may lead to identification of
potential neuronal endophenotypes, as well as
possible neurostructural and neurofunctional risk
and resiliance factors.
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Schneider et al.
374neurodevelop-
mental abnormalities associated with bipolar dis-
order during childhood and adolescence, but
several studies have reported neurostructural find-
ings in youth that differ from those seen in adults.
Only a small number of these imaging studies are
longitudinal—and only a single study obtained
scans both before and after the onset of full bipolar
disorder symptoms (36). Rather, a majority of
published research addresses potential alterations
in neurodevelopmental trajectories and other pro-
gressive changes by evaluating correlations of
structural measurements with age or with measures
of illness burden (e.g., duration of illness and
number of mood episodes). However, the typical
developmental trajectories of brain structures
thought to be involved in bipolar disorder are
often non-linear, have large variability even within
typically developing youth, and demonstrate
important sex differences (37). Therefore, linear
correlations with age or illness burden identified in
cross-sectional studies are extremely difficult to
interpret. Longitudinal studies are needed to pro-
spectively explore the developmental abnormalities
detected via correlation in these cross-sectional
investigations.
While illness-related changes in children and
adolescents with bipolar disorder are often inter-
preted as demonstrating neurodevelopmental
abnormalities, changes in adults may represent
areas of bipolar-related neuropathology that reflect
either underlying neurophysiological progression
or epiphenomena of recurrent affective episodes.
This interpretation is buttressed by long-standing
clinical and cognitive findings. For instance, while
Kraepelin (38) highlighted the gradual cognitive
decline associated with dementia praecox he also
Neuroprogression in bipolar disorder
357
published data suggesting that bipolar disorder
patients demonstrated progressively shorter euthy-
mic periods over the course of their illness, findings
that have been repeated in much more recent
cohorts (39). Data published over the last few
decades echo this clinical observation. Several
studies have reported cognitive deficits associated
with illness duration or number of affective epi-
sodes (5–8, 40). The nature, or even presence, of
the neuropathologic underpinnings of these obser-
vations, however, remains controversial. While
extensive findings have documented the presence
of neurostructural and neurofunctional differences
in patients with bipolar disorder, evidence of
illness-related neuropathologic changes remains
scant and conflicting.
Structural findings
Global neurostructural studies
As early as 1983, Rieder and colleagues (41) found
a correlation between age and ventricle-to-brain
ratios in a group of adult bipolar disorder patients.
Since that time, several studies identified evidence
of atrophic changes in the brains of older patients
with bipolar disorder, reflected in decreased total
gray matter volume and increased lateral and third
ventricle volumes. Positive findings in adult bipolar
disorder samples have been far from universal,
however (42, 43). The majority of studies employ-
ing proxies for illness exposure have been
unrevealing; age of onset and illness duration, for
instance, have generally correlated poorly with
total gray matter volume (44–46), although two
studies did report an inverse correlation between
length of illness and total gray matter volume (47),
and at least a trend toward increased lateral
ventricle size (48). In addition, a recent meta-
analysis found an inverse correlation between
illness duration and total cerebral volume (49).
The number of affective episodes constitutes an
arguably more direct measure of illness exposure;
although this metric has not, for the most part,
been found to correlate with total gray matter
volume (44, 45, 47). One study found lateral
ventricle size to be larger in multiple- versus first-
episode patients (48). Two small studies using a
prospective design failed to identify changes in
cerebral volume over spans of a few years (50, 51).
The at least equivocal evidence for global
structural changes in adult bipolar disorder
patients must be reconciled with the relative
absence of conclusive findings in children and
adolescents with bipolar disorder. Several studies
have failed to detect overall differences in gray
matter (52, 53), white matter (52), total brain
volume (52, 54, 55), or intracranial volume (56–60)
between young patients with bipolar disorder and
healthy subjects, though there have also been
several reports of smaller total cerebral or brain
volumes in young bipolar disorder patients (61–
65). Thus far, studies that examined correlations
between age at onset (62) or duration of illness (53)
and overall volumes have been negative. However,
it is difficult to intrepret these findings, as studies
did not specifically consider the non-linear trajec-
tory of typical brain development in childhood and
adolescence.
Ventricular findings in pediatric patient samples
are similarly mixed, and often complicated by
significant clinical heterogeneity including the
presence of psychotic symptoms. The two positive
reports of increased ventricular volumes in young
patients with bipolar disorder suggest that ventric-
ular enlargement may be associated broadly with
psychosis rather than bipolar disorder specifically.
In one study, enlargement was only detected in the
subset of paitents with psychotic bipolar disorder
(66), while another study reported results from a
mixed patient sample of youth with either bipolar
disorder or schizophrenia (67). To date, no
differences in ventricular volumes (66, 68) or
ventricle-to-brain ratios (53) have been reported
for pediatric or adolescent bipolar disorder pa-
tients without psychosis. In addition, no correla-
tion was detected between age or medication use
and ventricular volumes in youth with bipolar
disorder, either with or without psychosis (66). It is
possible that the discrepancy in results between
adult and younger bipolar disorder patients is
explained by failure in many adult bipolar disorder
studies to control for normal age-related neuronal
changes.
Similarly, there is no evidence for global volu-
metric or neurostructural changes in relatives of
patients with bipolar disorder or those at risk for
the illness, and there have been several negative
reports. One study using voxel-based morphometry
to assess relationships of brain structure to genetic
liability for bipolar disorder and schizophrenia
concluded that there was no relationship between
genetic liability and either gray or white matter
volumes in the former (69). In another study,
unaffected relatives of patients with bipolar disor-
der did not exhibit abnormalities in ventricular
volumes (70).
Overall, the heterogeneity of results makes it
difficult to draw conclusions regarding the develop-
mental or progressive nature of global volumetric
and ventricular abnormalities in patients with
bipolar disorder. It seems reasonable to conclude,
Schneider et al.
358
given the lack of findings in patient relatives and
at-risk samples, that these measures are not good
candidate risk factors or endophenotypes for the
disorder. Overall deficits in gray matter volume
may develop early in the course of bipolar illness in
subpopulations of young patients, and there is at
least some evidence for progressive gray matter
loss in adults. However, we do not have enough
evidence to determine if such changes are reflective
of volume loss or the absence of expected devel-
opmental gains in young patients, or reflect accel-
erated neuronal loss in older bipolar disorder
patients. Furthermore, findings of overall volume
decrease may merely reflect more specific regional
volume changes rather than true global volumetric
differences. Future research should explore these
questions longitudinally, and more rigorously
control for the expected age-related changes, both
developmental and degenerative, in the population
being considered.
Regional neurostructural studiesPrefrontal cortical structures
Several regions of the cortex have been implicated
in the pathophysiology of bipolar disorder, due to
both structural and functional imaging evidence
and behavioral and cognitive deficits that are
associated with the illness. The areas with the
most significant evidence for involvement include
the ventral prefrontal cortex and the anterior
cingulate (ACC), although other regions may also
be implicated. It is for this reason that cortical
regions have been studied extensively in at-risk
individuals, as well as pediatric and adult bipolar
disorder patients. Twin studies have identified a
relationship between genetic risk of developing
bipolar disorder and decreased gray matter density
in the right medial frontal and precentral gyri (71,
72). Other studies of unaffected siblings of adults
with bipolar disorder identified an association
between genetic risk for bipolar disorder and gray
matter deficits in the right ACC as well as bilateral
frontal, left temporoparietal, and right parietal
regions (73). However, abnormalities have not
been detected prior to the onset of illness in all
cortical regions studied. For example, no differ-
ences in subgenual cingulate volume were detected
in individuals from families with bipolar disorder
(74). Singh and colleagues (75) reported no volu-
metric differences in the prefrontal cortex between
8- to 12-year-old children with a familial risk for
mania and children of parents without psychopa-
thology. Another study, examining at-risk youths
who were free of any psychiatric disorder, also
found no differences in orbitomedial prefrontal
cortical volumes versus the offspring of healthy
subjects. However, their unusual lack of any
psychiatric symptomatology suggests the possible
presence of protective factors in these individuals,
and this finding may represent a resiliency factor
(76).
Numerous studies have detected structural
abnormalities in cortical gray matter in youth with
bipolar disorder, including decreases in prefrontal
and cingulate volume (58, 77–85). However, the
developmental nature of these findings is often
unclear. Several studies have failed to detect
correlations between cortical volumes and either
age or duration of illness (53, 59, 78–81, 83).
A cross-sectional study of ventrolateral prefrontal
cortex (VLPFC) volume found an interaction
between volume and age, suggesting that there
may be an acceleration of normal age-related
volume loss in late adolescence and early adult-
hood in patients with bipolar disorder (54), but the
underlying mechanism is unknown.
Cross-sectional findings in adults are similarly
unrevealing. Structural abnormalities in portions
of the prefrontal cortex have been widely observed,
and several investigators suggested that progressive
clinical changes in patients with bipolar disorder
may be linked to neuropathology in this region.
However, as in at-risk and youth samples, the
evidence for progressive changes associated with
bipolar symptomology is mixed. While two studies
identified inverse correlations between number of
manic episodes and prefrontal gray matter volume
and density (86, 87), a majority of investigators
failed to observe any relationship between age, age
of onset, illness duration, or even number of
affective episodes and prefrontal volume (45, 54,
86, 88, 89). There is, nonetheless, some evidence
that portions of the VLPFC may be particularly
vulnerable to the effects of bipolar symptomatol-
ogy in adult patients, although the direction of this
association is not clear. Patient age and illness
duration inversely correlated with cortical thick-
ness in the middle frontal cortex and gray matter
volume in the right medial prefrontal gyrus,
including Brodmann�s areas (BA) 8 ⁄10 (43, 90).
Conversely, in other studies, illness duration and
number of affective episodes were found to posi-
tively correlate with prefrontal volume in other,
partially overlapping, regions (45, 91). Some of
these apparent inconsistencies may be related to
variations in the age of the sample, mood state,
history of substance use, or treatment. In the
anterior cingulate cortex, for instance, age at onset
was negatively correlated with volumes on the right
only in patients receiving lithium. No significant
Neuroprogression in bipolar disorder
359
findings were observed in unmedicated patients
(88). It may also be significant that subjects in the
studies by Li et al. (45) and Lopez-Larson et al.
(91), which reported positive associations, were
somewhat younger; several investigators suggested
that the VLPFC may be characterized by an initial
increase in volume early in the course of illness,
only later followed by longer-term atrophic
changes (92). Recent efforts to connect neurostruc-
tural changes to specific genetic polymorphisms
(93) may help to elucidate the underlying patho-
physiology associated with these changes.
Studies of cortical development represent the
largest body of longitudinal structural data in
individuals with bipolar disorder, including multi-
ple longitudinal studies of cortical development in
child, adolescent, and young adult bipolar disorder
samples. However, as with cross-sectional studies,
interpretation of the results of these studies in a
developmental context remains a challenge. Typi-
cal cortical development is distinctly non-linear,
particularly during adolescence, and has been
characterized as an inverted U-shape, with the
timing of peak volume varying across cortical lobes
and even subregions within each lobe, and occur-
ring later in boys than in girls. This volume peak is
followed by regional volume reductions in typically
developing individuals (37). The implication is that
even typically developing individuals within an
adolescent patient population would be expected to
show a wide range of cortical volume changes over
time. Nonetheless, longitudinal studies represent
some of the best resources for understanding
progressive changes in bipolar disorder patients
across the course of the illness.
One important longitudinal study that scanned
patients both before and after the onset of bipolar
disorder specifically considered cortical develop-
ment by using dynamic cortical mapping (36). This
study identified children and adolescents present-
ing with symptoms of mood lability and attention-
deficit hyperactivity disorder (ADHD), but who
did not meet criteria for either bipolar disorder or
schizophrenia. These patients were labeled as
multi-dimensionally impaired, and followed with
repeated structural magnetic resonance imaging
(MRI) scans. Several of the patients went on to
develop bipolar disorder, and those patients
showed a pattern of cortical development distinct
from that of healthy adolescents, including
increases in left cortical gray matter in the VLPFC
and orbitofrontal cortex (OFC), as well as bilateral
loss of anterior and subgenual cingulate volume.
Results were clearer when the scans were aligned
with respect to the first manic episode, suggesting
that this pattern was associated with the onset of
bipolar illness. However, a similar pattern was seen
in patients who were initially impaired but did not
develop bipolar disorder, suggesting that these
findings may be associated with mood lability
generally as opposed to bipolar disorder specifi-
cally. However, this study does support suggestions
that prefrontal volume increases may be associated
with the early period of bipolar illness.
A study by Kalmar and colleagues (94) exploring
cortical development in children and adolescents
with bipolar disorder found that over two years,
adolescents with bipolar disorder showed greater
volume decreases than healthy subjects in the
prefrontal cortex bilaterally, including left BAs 10
and 11, the rostralACC, and the rightmedial frontal
gyrus. In this study, participants had a mean
duration of illness of more than five years at the first
scan, supporting suggestions that cortical volume
increases may precede longer-term cortical atrophy.
Similarly, Lisy andcolleagues (95) reported that,
while adolescents and adults with bipolar disorder
showed smaller volumes compared to healthy sub-
jects in several prefrontal regions at baseline, sub-
jects with bipolar disorder demonstrated increases
over time in several regions. Parsing the sample by
age, they found areas of increased left superior and
right medial frontal volumes only in adolescents.
Temporal cortex
The temporal cortex in general, and medial tem-
poral structures in particular, have been widely
implicated in the pathophysiology of bipolar dis-
order. Structures in this region, including the
superior temporal gyrus, amygdala, and hippo-
campus, have been particularly well studied in both
at-risk samples and patients with bipolar disorder.
In youth with bipolar disorder, overall temporal
cortical findings have been mixed; one study failed
to detect any difference in temporal lobe volume
between healthy adolescents and those with bipolar
disorder (56), while others reported both decreased
(78) and increased (82) temporal lobe volumes. No
association between total temporal cortical volume
and the duration of illness was reported for young
bipolar disorder patients (78). Overall temporal
cortical findings in adult patients have also been
inconsistent; those reporting a change in volume
associated with bipolar disorder exposure have
separately identified both positive and negative
correlations (42, 96, 97).
Superior temporal gyrus. Several studies reported
decreased superior temporal gyrus volume in
children and adolescents with bipolar disor-
der (78, 80, 81). However, those that examined
Schneider et al.
360
correlation with age (81) and duration of illness
(78) did not detect an association. In adult patients,
studies of the superior temporal gyrus have also
been generally unrevealing. Investigators observed
only an inverse correlation between volume and
age, which did not carry over into associations with
the duration or number of affective episodes (43,
98). Interestingly, a longitudinal study including
both adolescent and adult patients with bipolar
disorder reported increased volume in the superior
temporal gyrus over time in patients but not
controls (95). Overall, the interpretation of findings
in the superior temporal gyrus is complicated by
the observation of different developmental trajec-
tories in anterior and posterior subregions, and late
maturation in healthy individuals, with expected
decreases in volume extending into early adulthood
(99). To our knowledge, no study has specifically
examined this temporal structure in at-risk popu-
lations.
Amygdala. Volumetric and functional alterations
in the amygdala are common findings in patients
with bipolar disorder, although the findings in
adult and pediatric samples are inconsistent.
Amygdala volume has been often found to be
increased in adults with bipolar disorder, but the
effect of bipolar symptomatology on amygdala
structure is not entirely clear. Although some
studies have failed to identify any effects of bipolar
disorder course of illness on amygdala volumes
(42, 89, 98, 100, 101), other findings suggest that
illness course characteristics are associated with
morphological changes. Altshuler and colleagues
(97), for instance, found that amygdala volumes in
patients with bipolar disorder inversely correlated
with the number of previous manic episodes, while
others noted smaller amygdala volumes in older
patients (102). In contrast, at least one longitudinal
study and some meta-analyses have noted amyg-
dala enlargement over time in adult patients (103–
105). These findings, however, may be distorted by
developmental differences in amygdala volume and
trajectory between children ⁄adolescents and
adults, or differences in illness duration or medi-
cation exposure between samples (95, 103–105); in
particular, lithium exposure may lead to increased
amygdala volumes in adults (101).
In contrast to adults, reduction in amygdala
volume is the most frequently replicated structural
finding in children and adolescents with bipolar
disorder (55, 56, 62, 77, 100, 106), although such
differences have not been universally detected (63–
65, 107). Two different meta-analyses found that
amygdala volume is consistently smaller in children
and adolescents with bipolar disorder, compared to
psychiatrically healthy comparison groups (104,
105). Two studies suggest that amygdala volume
decreases over time. Geller and colleagues (107)
found decreasing amygdala volume with age in
bipolar disorder and increases in these volumes with
age in healthy subjects. In a second paper, DelBello
and colleagues (62) reported no association with
age, but noted a negative correlation between
amygdala volume and the duration of illness in
patients with bipolar disorder. These findings are
not, however, entirely consistent; Chen and col-
leagues (56) found a direct correlation between age
and amygdala volume in bipolar disorder and an
inverse relationship in healthy adolescents.
Nonetheless, recent findings from a longitudinal
study of adolescents following their first episode of
mania lend support to the hypothesis that a
decrease in volume occurs following the onset of
symptoms. Bitter and colleagues (108) recruited
patients who were initially scanned during their
first manic or mixed episode and then again
approximately one year later. At baseline, the
first-episode patients did not differ in amygdala
volumes from either healthy adolescents or ado-
lescents with ADHD. However, over a one-year
follow-up, there were significant differences in
developmental trajectories, such that at endpoint,
bipolar disorder patients had significantly smaller
amygdala volumes bilaterally. Consistent with
these findings, a second longitudinal study of
amygdala volume in multi-episode adolescents
with bipolar disorder found that patients had
smaller amygdala volumes at index assessment. In
this study, differences remained stable over a
follow-up period of approximately two years, with
no effects of time on amygdala volumes in either
the patients or healthy subjects (109).
Studies in multiple at-risk populations failed to
detect amygdala abnormalities in either family
members of bipolar disorder patients or youth at
risk for the disease. Hajek and colleagues (110)
reported no differences in amygdala volume be-
tween affected and non-affected high-risk partici-
pants from families affected with bipolar disorder
(i.e., having a first- or second-degree relative with
bipolar I disorder or a first-degree relative with
bipolar II disorder) and healthy subjects. Singh
and colleagues (75) also found no differences in
amygdala volume in 8- to 12- year-old children
with a familial risk for mania compared to children
of parents without psychopathology, and
Karchemskiy and colleagues (111) reported no
differences in amygdala volumes of children and
adolescents with ADHD and non-bipolar mood
symptoms and who were offspring of parents with
bipolar disorder compared to healthy controls.
Neuroprogression in bipolar disorder
361
Together, this evidence suggests that structural
abnormalities of the amygdala likely develop
following the onset of illness, rather than repre-
senting a risk factor or endophenotype associated
with bipolar disorder.
Taken together, these findings suggest that
decreased amygdala volumes associated with bipo-
lar disorder in adolescents may be neurodevelop-
mental, begin with the onset of the illness, and be
limited to a relatively short period close to the
appearance of mania. This pattern, combined with
the high variability in amygdala volumes in
healthy youth, and the observation that correla-
tions between amygdala volume and age are
sexually dimorphic (112), may explain the contra-
dictory correlational findings in cross-sectional
studies of amygdala volumes in youth with bipolar
disorder. The underlying mechanism of these
volumetric abnormalities remains unknown. How-
ever, it has been shown that amygdala volume
inversely correlates with activity duringthe view-
ing of emotional facial stimuli in adolescents with
bipolar disorder (106), suggesting either excitotox-
icity or the selective loss of inhibitory neurons as
potential mechanisms that could be associated
with both hyperactivity and decreased volumes in
this region. Findings in children and adolescents
with bipolar disorder are distinctly different than
the majority of findings in adults. It is possible that
early-onset bipolar disorder is associated with
different amygdala pathology than bipolar disor-
der in adults. Alternatively, the initial decrease in
volume observed in adolescence may be followed
by an increase over a longer timescale. Further
research is needed to distinguish between these
possibilities.
Hippocampus. Hippocampal findings in adult bipo-
lar disorder patients have been somewhat contra-
dictory. Some studies have failed to identify any
effects of bipolar illness course on hippocampal
volumes (89, 98, 100), while others are suggestive of
decreases in volume with illness exposure (49, 113),
and longitudinal data suggest hippocampus vol-
umes increase over time (95). These latter findings
are further supported by a study in which Strakow-
ski and colleagues (48) observed hippocampi to be
larger in multi- versus first-episode patients,
although multi-episode patients did not differ from
healthy subjects.
Similarly, studies in children and adolescents
with bipolar disorder have either failed to detect
alterations in hippocampal morphometry (55, 56,
64, 77, 107) or found reductions in volume (52, 63,
65, 100). Isolated abnormalities in hippocampal
subregions may help to explain these discrepancies.
A recent study using three-dimensional modeling
found significant volume reductions in hippocampal
volume in adolescents with bipolar disorder, with
localized deficits in the head and tail on the left,
most pronounced in the auricular region (52). This
same study found alterations in the volumetric
changes associated with age; adolescents with
bipolar disorder showed an increase in hippocam-
pal volumes over time, specifically in the anterior
and posterior CA1 subfields, while healthy adoles-
cents showed volume decreases associated with
age, specifically in the subiculum and anterior CA1
regions. This increase in volume over time in
patients seems difficult to reconcile with the general
findings of decreased volume, although it may be
related to alterations in the timing of normal
hippocampal development in youth with bipolar
disorder.
Interpretation of correlational findings in the
hippocampus is further complicated by evidence
that changes in hippocampal volumes during
adolescence are sexually dimorphic both in healthy
and in bipolar disorder subjects. Women and girls
with bipolar disorder have been found to have
smaller hippocampi in several studies (63–65), and
in one study of healthy adolescents, a significant
correlation between volume and age was reported
only for girls (112). Therefore, these detected
differences in hippocampal volumes may be due
to alterations in developmental processes, leading
to differences that become increasingly apparent as
healthy girls show expected increases in hippocam-
pal volume; whereas, girls with bipolar disorder
have altered timing or trajectory of hippocampal
development. Further research is needed to deter-
mine if sex differences in structural correlates are
associated with clinical or functional differences
between young men and women with bipolar
disorder.
Combined with evidence from adult popula-
tions, these results suggest that individuals with
bipolar disorder may show later development of
hippocampal structures with continued increases
over time, either with age or with illness exposure.
It remains possible that there are heterogeneous
alterations across multiple subregions of the hip-
pocampus, and future research should explore this
possibility. Thus far, there have been no reports of
altered hippocampus volumes in relatives of
patients with bipolar disorder or in at-risk samples
(75, 110, 111). One study, examining at-risk youth
who were free of any psychiatric disorder, identi-
fied significantly increased gray matter volumes in
the left parahippocampal ⁄hippocampal gyrus in
healthy offspring of parents with bipolar disorder.
Given that the lack of any psychiatric symptom-
Schneider et al.
362
atology in such a high-risk group is unusual, this
finding may represent a resiliency factor (76).
Nucleus accumbens
The volume of the nucleus accumbens has been
reported to be increased (61, 64, 65, 77), decreased
(77), and unchanged (107) in youth with bipolar
disorder. While these mixed results make it difficult
to draw definitive conclusions, there is some
evidence that there may be developmental expla-
nations for these varied findings. In one study,
larger right nucleus accumbens volumes were
found only in a prepubertal subgroup of patients
with bipolar disorder, while there was no relation-
ship between volumes and puberty status in
healthy adolescents (61). Consistent with these
findings, Geller and colleagues (107) reported a
decrease in nucleus accumbens volume associated
with age in boys with bipolar disorder, with no age-
related change in healthy subjects. Recent studies
in adult patients have similarly reported decreased
volumes in this region (114, 115).
Basal ganglia ⁄ striatum
Some of the most consistently reported structural
findings associated with genetic risk for bipolar
disorder involve striatal volume. Nonetheless, even
these data have been mixed, with reports of both
increased and decreased striatal volumes in at-risk
samples. Both unaffected and affected twins of
probands with bipolar disorder show larger left
caudate volumes than healthy subjects (71, 116),
while other studies of unaffected siblings of adults
with bipolar disorder identified an association
between genetic risk for bipolar disorder and gray
matter deficits in the ventral striatum (73). Simi-
larly, Hajek and colleagues (117) also reported
finding differences between caudate volumes in
affected and unaffected at-risk subjects, although
the finding was not significant after controlling for
the non-independence of observations in multiple
subjects per family. Further, neither affected nor
unaffected high-risk participants from families
with bipolar disorder exhibited differences in
putamen volumes compared to healthy subjects
(117).
The interpretation of these findings is further
complicated by the limited evidence for volumet-
ric differences in the basal ganglia of adolescents
with bipolar disorder. A majority of studies have
found no differences between bipolar disorder and
healthy adolescents in caudate (55, 60–62, 64, 65,
118), putamen (60, 61, 64, 65), or globus pallidus
volumes (61, 62, 64, 65). In contrast, there has
been only one report of increased volume in the
putamen of youth with bipolar disorder (62),
while one voxel-based morphometry study found
areas of increased volume in subregions of the
basal ganglia that include the anterior putamen
and the head of the caudate (82). The inconsis-
tency in the findings in youth with bipolar
disorder may be due in part to the high levels
of ADHD comorbidity in this population. Striatal
volume reduction and abnormal trajectory of
striatal development is an often replicated finding
in youth with ADHD (119). A recent study
looking at the differential effects of ADHD and
bipolar disorder diagnosis on striatal volumes
found that bipolar disorder was associated with
increases in the volume of the caudate, putamen,
and globus pallidis, while ADHD was associated
with decreases in these regions (120). These
findings are in contrast with an earlier study that
found that bipolar disorder patients with and
without ADHD did not differ from each other or
from healthy subjects (65), although both studies
reported reductions in striatal volumes in patients
with ADHD alone.
In one cross-sectional study, bipolar disorder
adolescents exhibited an inverse correlation be-
tween age and volume ofthe left and right caudate,
and the left putamen, while there was no relation-
ship between striatal volumes and age in healthy
youth (60). While, to our knowledge, no longitu-
dinal studies have been published exploring the
development of, or progressive changes in, the
basal ganglia of adolescents with bipolar disorder,
a single longitudinal study in relatively young
adults with bipolar disorder reported increases in
basal ganglia volume over several years (95).
Subcortical volumes in adults have not, for the
most part, been otherwise found to correlate with
age, age at onset, illness duration or number of
affective episodes (43, 48, 89, 121). Only Brambilla
and colleagues (122) noted an inverse correlation
between duration of illness and left putamen size,
as well as evidence of increasing globus pallidus
volume.
Thalamus
To our knowledge, there have been no descriptions
of thalamic volume changes specific to relatives of
patients with bipolar disorder. However, a com-
parison of MRI findings among unaffected rela-
tives of patients with bipolar disorder or
schizophrenia, unaffected individuals from families
with both schizophrenia and bipolar disorder,
patients with bipolar disorder or schizophrenia,
and healthy subjects identified reduced anterior
Neuroprogression in bipolar disorder
363
thalamic gray matter in both patient groups and
unaffected relatives, compared with healthy sub-
jects, suggesting that thalamic volume changes may
represent a general marker of psychosis (123). This
suggestion is supported by the findings from an
early study in adolescents with either bipolar
disorder or schizophrenia, which found that the
combined patient group had a smaller thalamic
area than healthy adolescents (124). In contrast,
thalamic findings in groups of both young and
adult bipolar disorder patients are quite sparse.
The majority of studies in children and adolescents
have found no differences in thalamic volumes (55,
62–65, 125) and associations have not been
reported between thalamic volume and age or
measures of illness burden in either young or adult
patients.
Cerebellum and subtentorial structures
One of the earliest, computerized tomography
studies of bipolar brains found no correlation
between patients� age and measures of cerebellar
atrophy (41). Another early study using structural
MRI similarly failed to observe any relationship
between either duration of illness or number of
affective episodes and cerebellar volume (89). Since
that time, however, other investigators have noted
negative correlations between age and cerebellar
size (43), and at least one longitudinal study found
progressive loss of cerebellar gray matter (126). It
may be that portions of the cerebellum are dispa-
rately affected; three studies found an association
between the number of affective episodes and a
specific portion of the cerebellar vermis, including
lobules VIII through X (V3), and one study found
an association for lobules IV through VII (V2)
(127–129).
In children with bipolar disorder, a single study
found no statistically significant differences in
volume of the total cerebellum, or in any cerebellar
subregion, compared with healthy subjects,
although there was a trend toward a smaller V2
area in the bipolar group (130). In this sample,
however, age was inversely correlated with the V3
area in patients but not healthy subjects, and there
was a trend toward an inverse correlation between
the V2 area and the number of previous episodes,
largely driven by the male patients. Kempton and
colleagues (131) observed that greater left cerebel-
lar volumes may be associated with the absence of
a clinical diagnosis in adult relatives of patients
with bipolar disorder, suggesting preserved cere-
bellar volume may represent a protective factor in
individuals at risk for bipolar illness.
White matter findings
The observation that greater numbers of white
matter hyperintensities (WMH) are present in
older bipolar disorder patients dates back almost
two decades (132). The earliest MRI studies in
youth with bipolar disorder specifically explored
white matter pathology, with recently replicated
reports of WMH in a case study and small sample
of youth with bipolar disorder (68, 133–135). Some
more recent studies report finding similarly high
rates of WMH in family members of bipolar
disorder patients (136). However, this finding has
not been replicated; another study failed to identify
any differences in the number of WMH among
healthy relatives of bipolar probands, relatives of
bipolar probands who met criteria for an Axis I
mood disorder, or healthy subjects, but also failed
to replicate earlier findings of increased WMH in
bipolar disorder patients (137).
Studies involving twins discordant for bipolar
disorder report volumetric abnormalities in the
white matter of unaffected siblings of bipolar
disorder patients, including decreased left hemi-
spheric white matter volume, suggesting that
reduced white matter connectivity may represent
an endophenotype for bipolar illness (71, 116). In
youth with bipolar disorder, several studies have
focused on the corpus callosum structure, and
have detected several abnormalities, including
decreased volume overall (138), decreased signal
intensity (139), and lower measures of splenium
circularity (140). Abnormal correlations were
observed between age and both signal intensity
(139) and volume (138). These findings may be
due to alterations in myelination, which is occur-
ring during this developmental period, abnormal
tract development, or a combination of these and
other factors. Age also appears to affect the shape
of the corpus callosum in adult patients with
bipolar disorder, as does duration of bipolar
illness (141).
Newer studies have utilized a range of MRI
techniques to expand on previous findings of
progressive white matter changes in patients with
bipolar disorder. Using diffusion tensor imaging
(DTI), several investigators found decreased frac-
tional anisotropy (FA) in the corpus callosum,
prefrontal regions, the cingulate-paracingulate
white matter, fornix, and superior longitudinal
fasciculus (79, 142–146) in youth with bipolar
diorder. These tracts are known to provide con-
nections between regions involved in emotional
regulation, and white matter changes in these
regions may have functional correlates (79, 143).
Schneider et al.
364
Some cross-sectional findings suggest that alter-
ations in white matter tracts may represent aber-
rant developmental patterns associated with
bipolar disorder. In a cross-sectional DTI study
of at-risk youth, Versace and colleagues (147)
reported a linear increase with age in FA in
healthy subjects in the left corpus callosum and the
right inferior longitudinal fasciculus. In contrast,
high-risk offspring showed a linear decrease in FA
with age in the left corpus callosum and no
relationship in the right inferior longitudinal fas-
ciculus, suggesting that abnormalities in these
white matter tracts may represent endophenotypic
markers of risk. In another study involving both
high-risk youth (with one affected first-degree
relative) and youth with bipolar disorder, only
the latter exhibited reduced FA relative to healthy
subjects in the cingulate-paracingulate white mat-
ter, while both the bipolar and high-risk groups
exhibited decreased FA in the bilateral superior
longitudinal fasciculus I, although the high-risk
subjects exhibited greater FA values even than
those with bipolar disorder (142). Another study of
first-episode manic patients detected significant
alterations early in the illness course (146).
Together these findings suggest that some white
matter abnormalities may represent risk factors
while others represent early disease markers. It is
possible that abnormal connectivity between re-
gions contributes to developmental alterations of
key neural structures in bipolar disorder. Longi-
tudinal studies assessing the correlation between
white matter development and other structural
volumetric alterations areneeded to evaluate this
possibility.
DTI studies in adults have also noted age- and
illness-related decreases in FA, suggestive of white
matter changes in networks linking prefrontal,
medial temporal, and subcortical structures (148,
149). Furthermore, white matter volume has been
observed to increase over time in portions of the
posterior frontal ⁄parietal cortex, temporo-parietal
junction, and portions of the parietal lobe and
cerebellum (150). These findings are balanced,
however, by the larger number of studies that
failed to observe any effect of age, age of onset,
illness duration, or number of affective episodes on
total white matter volume or FA—even in regions
previously implicated in the pathophysiology of
bipolar disorder, including the corpus callosum,
uncinate fasciculus, and anterior thalamic radia-
tions (43, 44, 47, 151, 152). Overall, the evidence
supports the conclusion that white matter altera-
tions may be more stable than other structural
abnormalities, and that they may represent risk
and early disease markers.
Functional findings
Bipolar disorder has been associated with a large
number of behavioral and cognitive abnormalities
across the disease spectrum, and numerous func-
tional MRI (fMRI) studies have attempted to
correlate these behavioral findings with abnormal
brain activation patterns. These studies have found
functional alterations associated with bipolar dis-
order across widely distributed brain regions,
including frontal and limbic systems thought to
be involved in emotion expression and regulation.
However, to date, relatively little research has
explored the developmental or progressive nature
of these findings, and few longitudinal fMRI
studies have been performed in patients with
bipolar disorder or those at risk for the illness.
Functional neuroimaging studies of individuals
at risk for bipolar disorder have been generally
consistent with findings of structural abnormalities
(153–160). An fMRI study comparing remitted
bipolar I disorder patients, their unaffected first-
degree relatives, and healthy subjects during an
N-back working memory task reported that there
was significantly greater activation in left frontal
polar ⁄VLPFC in unaffected relatives compared
with controls during the 2-back task (160).
Another study examining brain activation during
a 2-back working memory task in adults (ages 32–
46 years) with bipolar disorder, first-degree rela-
tives of adults with bipolar disorder, and healthy
adults reported abnormal activation in the left
anterior insula in both adults with bipolar disorder
and their unaffected relatives, as well as alterations
in activation in the OFC and superior parietal
cortex (156). Similarly, Thermenos and colleagues
(155) reported alterations in frontopolar, cerebellar
vermal, amygdala ⁄parahippocampal, and insula
activation during a 2-back working memory task in
a younger sample of unaffected adolescents and
young adults with a first-degree relative with
bipolar disorder, compared to healthy subjects. In
contrast, Whalley and colleagues (153) compared
regional brain activation during a parametric
sentence completion paradigm in high-risk adole-
scents and young adults and found no group
differences from healthy subjects for the overall
task. However, the high-risk group exhibited
increased left amygdala activation during the
parametric contrast, compared with healthy sub-
jects. A positive association was found across the
groups between depression ratings and ventral
striatal activation, and a negative association was
identified between cyclothymic temperament and
ventral prefrontal activation. Similarly, Chang and
colleagues (159) explored relationships between
Neuroprogression in bipolar disorder
365
mood symptoms and brain activation in an at-risk
sample and reported that children with mood
dysregulation, but not full bipolar disorder, and a
parent with bipolar disorder exhibited decreases in
dorsolateral prefrontal activation during an Inter-
national Affective Picture System (IAPS) task that
was associated with improvement in depressive
symptom severity following treatment with divalp-
roex. Other functional abnormalities do not appear
to manifest until after the onset of symptoms. In an
fMRI study examining neural activation during a
cognitive flexibility task, both youth with bipolar
disorder and their at-risk counterparts exhibited
increased right VLPFC and inferior parietal activ-
ity on successful change trials, and increased
activation in the caudate during failed change
trials. In contrast, youth with bipolar disorder also
had increased activation in the subgenual ACC
compared with the healthy and at-risk groups
(154).
To our knowledge, only one study to date
examined functional connectivity changes in a
sample at risk for bipolar disorder (157). In order
to identify potential changes associated with risk
and resilience, Pompei and colleagues examined
functional connectivity during performance of a
Stroop task in patients with bipolar disorder, their
unaffected first-degree relatives with and without
depression, and healthy subjects. Findings from
this study suggest that there is a breakdown in
VLPFC–subcortical interactions that is associated
with risk and illness expression for mood disorders,
whereas increased functional coupling between
dorsal and ventral prefrontal regions may be
related to resilience (157). Together, these findings
suggest that functional impairments in at least
portions of the extended limbic network might
represent endophenotypic changes for bipolar dis-
order. Alternatively, these findings might mark
early functional abnormalities in the development
of bipolar symptoms (153).
Numerous functional imaging studies have been
performed in young bipolar disorder patients.
Collectively, these studies suggest that youth with
bipolar disorder display functional abnormalities
during performance of cognitive and emotional
tasks across multiple cognitive domains, including
emotional processing (161–165), working memory
(166), inhibitory control (167–170), and reward
processing (171, 172). Short-term longitudinal
studies have been performed, which suggest that
some functional alterations may normalize follow-
ing pharmacological treatment (173, 174) while
others, including amygdala over-activation, may
persist (175). However, there have been no pub-
lished longitudinal studies assessing the develop-
ment or long-term progression of these functional
abnormalities.
Similarly, there have been relatively few func-
tional neuroimaging studies examining the effects
of illness exposure in adult patients with bipolar
disorder. In these studies, patients are typically
scanned during disparate affective episodes, raising
issues with disentangling longitudinal effects from
changes in mood state. A study of 10 depressed
bipolar I disorder patients who were scanned an
average of 11 months later in a euthymic state
found no differences in activation during perfor-
mance of a Stroop or dominant-hand motor task.
Patients did, however, show increased activation in
the right medial frontal gyrus (BA 9 ⁄10) and ACC
(BA 24 ⁄32) on a non-dominant-hand motor task
during the second scan (176). Another study of nine
bipolar I disorder patients initially scanned during
a facial affect task while manic and again when
euthymic an average of six months later, showed a
significant group · time interaction (with a group
of healthy controls) in the amygdala; activity was
greater in the second scan. An effect of time was
also observed in the hippocampus; activation was
increased in the second scan (177). In a single study
of eight euthymic bipolar I disorder patients,
however, a frontal region differentially activated
in patients versus healthy subjects during a lan-
guage task did not show any association with either
patient age or duration of illness (178).
Overall, while there is very little direct evidence
for developmental or progressive alterations in
functional brain activation, very few studies have
addressedthis question. This area is ripe for
further research, and as it is the cognitive and
behavioral symptoms of bipolar disorder that most
directly relate to the disease burden experienced by
patients, further research to assess the develop-
mental underpinnings and progressive nature of
functional abnormalities associated with the disor-
der is urgently needed.
Conclusions
Over the last few decades, a significant body of
imaging research has demonstrated the presence of
neurostructural and functional abnormalities in
patients with bipolar disorder across a spectrum of
ages. Only recently, however, have studies begun to
reveal aspects of the neuroprogressive nature of the
illness. Structural, and to a lesser extent functional,
changes have been identified, but the nature of
those changes alters as the illness progresses and as
patients age. Further, at least some of these
abnormalities appear to predate the initial appear-
ance of overt bipolar symptomatology.
Schneider et al.
366
A range of studies involving unaffected relatives
and twins discordant for bipolar disorder have
suggested the presence of structural abnormalities
that may represent bipolar endophenotypes and ⁄or
resilience factors. Many of the affected regions
correspond to structures involved in emotional
expression and regulation that have been previ-
ously implicated in bipolar disorder, including
portions of the prefrontal cortex, ACC, basal
ganglia, and thalamus. Some of these structural
abnormalities may represent risk factors for devel-
opment of mood symptoms, while others may be
epiphenomena, and at least some of these findings
may represent resiliency factors linked to the
absence of symptoms in these populations. In
contrast, the majority of studies involving partic-
ularly high-risk youth have not found the struc-
tural abnormalities seen in affected cohorts. Some
of this discrepancy may be related to the significant
subject heterogeneity among groups. It is possible,
however, that the lack of findings in this group
might be related to their relative youth; structural
changes may still evolve over time.
Unaffected relatives of patients with bipolar
disorder have also been shown to display abnormal
patterns of neurofunctional activation in many of
these same regions: the prefrontal cortex and amyg-
dala, as well as networked regions including the
cerebellar vermis. In contrast to much of the
neurostructural data, abnormalities in prefrontal,
medial temporal, and subcortical activation appear
to extend to high-risk youth. At least one study
suggests that a breakdown in VLPFC–subcortical
networking is associated with risk of developing
frankmood symptoms (157), potentially implicating
white matter abnormalities as well. Evidence of
white matter pathology is widely present in the
relatives of bipolar disorder patients, including their
high-risk offspring; in some cases the abnormality
was greater even than that observed in probands.
The observation of structural findings in chil-
dren and adolescents lends credibility to sugges-
tions that bipolar symptomatology involves
neurodevelopmental abnormalities that may appear
quite early. Bipolar mania often presents during
the developmental period in which both regressive
(synaptic pruning) and progressive (i.e., myelina-
tion) cellular events are prominent. The period
between childhood and early adolescence
(7–12 years) is associated with rapid expansion of
cortical gray matter density, while the period
between adolescence (13–18 years) and young
adulthood (‡ 18 years) is associated with progres-
sive loss of cortical gray matter density that
stabilizes only in the third decade of life (179–
181). These age-related changes in cortical volumes
are sexually dimorphic, peaking later in men than
women (182); are governed by both genetic and
environmental factors (183, 184); and are dysreg-
ulated in a variety of neurodevelopmental disor-
ders (185). Human postmortem and non-human
primate histological studies suggest that decreases
in cortical gray matter during adolescence are
primarily attributable to reductions in synaptic
density (i.e., synaptic pruning) (186–189). Frontal
gray matter density loss is associated with recipro-
cal increases in white matter density in fiber tracts
including frontotemporal pathways (190, 191), the
expansion of which is positively correlated with
cognitive development (i.e., performance on work-
ing memory tasks) (192). These normative data
therefore suggest that the onset of bipolar disorder
often occurs during a developmental period asso-
ciated with dynamic changes in cortical maturation
and connectivity, and that perturbations in these
processes may contribute to illness risk.
Studies in children and adolescents with bipolar
disorder further suggest that these neurodevelop-
mental abnormalities are not indiscriminate, but
rather, that they are confined to regions associated
with emotional expression and regulation. Young
patients demonstrated few global gray matter
abnormalities, but showed evidence of a possibly
accelerated volume loss in the prefrontal cortex
that is consistent with pathologic synaptic prun-
ing—particularly in late adolescents and young
adults with bipolar disorder (54). Studies correlat-
ing amygdala size with patient age were mixed, but
patients with a longer duration of illness also
appeared to have smaller amygdala volumes (62).
Further, at least one longitudinal study found that
amygdala volume failed to increase normally over
time (108). These changes may have functional
significance; amygdala activation during exposure
to emotional stimuli inversely correlated with size
(106). In contrast to these prefrontal and medial
temporal findings, there is relatively little evidence
for symptom-related changes in subcortical struc-
tures, including the basal ganglia and thalamus.
One exception to these findings occurs with the
nucleus accumbens, which might be affected spe-
cifically in very early-onset bipolar disorder (61).
A few studies in youth with bipolar disorder also
identified abnormal correlations between age and
both signal intensity and volume in some white
matter tracts, including the corpus callosum (138,
139). These findings may be due to alterations in
myelination, a process which occurs during this
period, abnormal white matter development, or a
combination of these and other factors. Other
white matter abnormalities, however, reflected in
changes in measures of DTI in the frontal white
Neuroprogression in bipolar disorder
367
matter tracts, appear to be present quite early in
the course of illness (146).
Interpreting the largely structural findings in
children and adolescents with bipolar disorder is
complicated by the non-linear nature of develop-
mental trajectories. Some prefrontal studies in a
more mixed-age population, for instance, suggest
that prefrontal volume increases in some patients,
supporting previous suggestions that prefrontal
volume follows an inverted U-shaped pattern (37).
Older adult bipolar disorder patients appear to
show a different pattern of symptom-related neu-
rostructural and functional changes, most likely
involving a different set of neurobiological pro-
cesses that may be implicated in the progressive
clinical and cognitive effects observed in these
patients. Several studies identified evidence of more
widespread neuronal atrophy reflected in some
measures of cerebral volume and ventricular
enlargement (47, 48, 127, 193, 194). Prefrontal
findings also appear more consistently in both late-
adolescent and adult populations. The neurophys-
iology underlying these findings, however, appears
to differ, and the hypothesized atrophic changes
have been linked with the emergence and increas-
ing frequency of affective episodes.
Symptom exposure also appears to be associated
with smaller amygdala volumes in adults with
bipolar disorder (97, 102). While the data are not
entirely consistent, conflicting studies generally
included at least some younger bipolar disorder
patientswho may have obscured the overall
finding. The larger amygdala volumes generally
observed in younger adult bipolar disorder
patients, coupled with the decreases in volumes
seen in older patients, suggest another non-linear
trajectory, with early volume increases followed by
later atrophic changes. Increased functional acti-
vation observed in one study over roughly
six months in medial temporal structures may be
related to these anatomical changes, but may also
reflect changes in mood state (177). As with
younger patients, adults with bipolar disorder did
not generally demonstrate subcortical changes over
time. Two studies, however, did suggest that at
least portions of the basal ganglia may increase
with illness duration in a way not observed in
children and adolescents (95, 122), although this
finding may be related to medication exposure.
Other regions also appear to undergo neuropatho-
logic changes in bipolar disorder adults, including
portions of the cerebellum (127–129).
While not entirely consistent, several studies
suggest that illness-related effects on white matter
tracts are more extensive in older bipolar disorder
patients, comparedwith youthwith bipolar disorder
(141, 146, 149). These findings are concordant with
suggestions that bipolar symptomatology is linked
to the appearance of network abnormalities. In
addition to effects on the corpus callosum, adults
with bipolar disorder show evidence of age- and
illness-related changes in networks linking
prefrontal, medial temporal, and subcortical struc-
tures, as well as some posterior brain regions also
associated with bipolar symptomatology (146, 149).
While these findings are potentially quite pro-
vocative, there are several issues with much of the
data that must be addressed to better understand
these processes. Patients are often tested in varying
mood states and may be taking a variety of
medications over the course of their illness or
between scans of longitudinal studies. This latter
issue may be particularly relevant given the
emerging evidence that mood-stabilizer medica-
tions have neuroprotective and neurotrophic
effects, and the observation that lithium treatment
may be associated with increased cortical volumes
in adults. In addition, some data suggest that
clinical subsets of bipolar disorder patients may
differ substantially in their longer-term response to
bipolar symptomatology. Other findings suggest
that often ignored variations in sex, as well as other
factors including stressful life events and nutri-
tional deficiencies, may be important. Most prom-
inently, the majority of studies examining the effect
of illness progression on neurophysiology in bipo-
lar disorder are cross-sectional, and while a few use
track-back techniques, these generally rely heavily
on patient recollection, the recollection of family
members, and often scant medical records that
may have limited validity. The potential biases
introduced by retrospective recall are illustrated by
the frequent discrepancies between data from
retrospective studies and the limited prospective
data. Nonetheless, these studies suggest a pattern
of abnormalities in neural development early in the
appearance of bipolar disorder that gives way to
progressive neuropathic changes at least influenced
by the course of illness leading to an iterative
process in which structural and functional changes
drive clinical symptomatology and are in turn
exacerbated by the consequences of these symp-
toms. A better understanding of this process is
essential to create targeted treatments that may
intervene early in the disease process, and prevent
clinical deterioration later in the course of illness.
Acknowledgements
This work was supported by National Institute of Health (NIH)
grants R01MH078043, R01MH078043S1, P50MH077138,
R01MH080973, R34MH083924, and R01MH07193.
Schneider et al.
368
Disclosures
MPB has received research support from AstraZeneca, Bristol-
Myers Squibb, Eli Lilly & Co., Forrest, Amylin, Glaxo-
SmithKline, Pfizer, Janssen, Merck, Novartis, and Johnson &
Johnson; and has served on the speakers bureau or as a
consultant for Bristol-Myers Squibb, Pfizer, and Merck. RKM
has received research support from Martek Biosciences Inc.,
Inflammation Research Foundation, Ortho-McNeil Janssen,
AstraZeneca, Eli Lilly & Co., NARSAD, NIMH, and NIA;
and is a consultant for the Inflammation Research Foundation.
In the past year, SMS received research support from Eli Lilly
& Co., Janssen, Johnson & Johnson, AstraZeneca, Sumatomo,
Pfizer, NIDA, NIAAA, and NIMH; he also received fees for
directed discussions on WebMD. CMA has received research
support from AstraZeneca, Eli Lilly & Co., Pfizer, Otzuka,
Forrest, Sunovion, Novartis, GlaxoSmithKline, and Amylin;
and has served as a consultant and on the speakers bureau for
Merck. MRS has no relevant financial disclosures to report.
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