A Preliminary fMRI Study of Sustained Attention in Euthymic,
Unmedicated Bipolar Disorder
Stephen M Strakowski*,1,2, Caleb M Adler1,2, Scott K Holland3, Neil Mills1and Melissa P DelBello1
1Bipolar and Psychotic Disorders Research Program, University of Cincinnati College of Medicine, USA;2Center for Imaging Research, University of
Cincinnati College of Medicine, USA;3Imaging Research Center, Children’s Hospital Research Foundation, USA
The symptoms of bipolar disorder suggest dysfunction of anterior limbic networks that modulate emotional behavior and that
reciprocally interact with dorsal attentional systems. Bipolar patients maintain a constant vulnerability to mood episodes even during
euthymia, when symptoms are minimal. Consequently, we predicted that, compared with healthy subjects, bipolar patients would exhibit
abnormal activation of regions of the anterior limbic network with corresponding abnormal activation of other cortical areas involved in
attentional processing. In all, 10 unmedicated euthymic bipolar patients and 10 group-matched healthy subjects were studied with fMRI
while performing the Continuous Performance Task-Identical Pairs version (CPT-IP). fMRI scans were obtained on a 3.0T Bruker system
using an echo planar imaging (EPI) pulse sequence, while subjects performed the CPT-IP and a control condition to contrast group
differences in regional brain activation. The euthymic bipolar and healthy subjects performed similarly on the CPT-IP, yet showed
significantly different patterns of brain activation. Specifically, bipolar patients exhibited increased activation of limbic, paralimbic, and
ventrolateral prefrontal areas, as well as visual associational cortices. Healthy subjects exhibited relatively increased activation in fusiform
gyrus and medial prefrontal cortex. In conclusion, these differences suggest that bipolar patients exhibit overactivation of anterior limbic
areas with corresponding abnormal activation in visual associational cortical areas, permitting successful performance of an attentional
task. Since the differences occurred in euthymia, they may represent trait, rather than state, abnormalities of brain function in bipolar
Neuropsychopharmacology (2004) 29, 1734–1740, advance online publication, 2 June 2004; doi:10.1038/sj.npp.1300492
Keywords: bipolar disorder; fMRI; attention; anterior limbic network
Bipolar disorder is a dynamic illness characterized by
fluctuations among emotional extremes (ie mania and
depression), and even within extremes (ie mixed states),
that are accompanied by similarly extreme oscillations in
psychomotor and neurovegetative behaviors. The dynamic
expression of bipolar disorder suggests that its neuropatho-
physiology involves dysfunction of brain networks that
maintain emotional homeostasis. The orbitofrontal division
of the limbic forebrain provides these networks (Mega et al,
1997). This ‘anterior limbic network’ consists of linked
cortical and subcortical areas with common phylogenetic
and cytoarchitectural features that modulate complex
emotional and social behaviors (Mega et al, 1997; Ongu ¨r
and Price, 2000). Specifically, medial orbitofrontal and
ventrolateral prefrontal areas receive processed sensory
information through extensive reciprocal connections with
basal amygdala, anterior temporal regions, rostral insula,
and subgenual and anterior cingulate (Mega et al, 1997;
Ongu ¨r and Price, 2000). These prefrontal areas form
feedback loops with the ventromedial striatum and
thalamus that provide effector mechanisms for psycho-
hypothalamus and autonomic nervous system produce
visceromotor outputs to create bodily sensations (ie
‘feelings’) (Mega et al, 1997; Ongu ¨r and Price, 2000). Several
investigators have suggested that the symptoms of bipolar
disorder arise from dysfunction within this anterior limbic
network (Blumberg et al, 2003; Ketter et al, 2001; Phillips
et al, 2003; Strakowski, 2002; Strakowski et al, 2002).
In addition to mood and neurovegetative disturbances,
impaired attention is a defining symptom of both mania
and depression. Neuropsychological studies of bipolar
patients consistently report decrements in sustained atten-
tion during affective episodes (reviewed in Bearden et al,
2001). These observations are not particularly surprising
since both experiential and experimental evidence support
the notion that strong emotional states interfere with
attention (Mayberg et al, 1999; Yamasaki et al, 2002).
Therefore, activation of emotional (anterior limbic) net-
works may disrupt function of attentional brain regions.
Online publication: 21 April 2004 at http://www.acnp.org/citations/
Received 4 February 2004; revised 24 March 2004; accepted 20
*Correspondence: Dr SM Strakowski, Center for Imaging Research,
University of Cincinnati College of Medicine, Cincinnati, OH 45267-
0583, USA, Tel: þ1 513 558 4489, Fax: þ1 513 558 3399,
Neuropsychopharmacology (2004) 29, 1734–1740
& 2004 Nature Publishing GroupAll rights reserved 0893-133X/04 $30.00
Indeed, attentional and emotional networks intersect within
the anterior cingulate, providing a neuroanatomic basis
for interactions between these circuits (Mega et al, 1997;
Mayberg et al, 1999; Yamasaki et al, 2002). Consequently
during mood episodes, dysregulation of the anterior limbic
network may inhibit cognitive brain regions, thereby
producing both the affective and attentional impairments
of bipolar disorder. Moreover, because of these reciprocal
interactions, studying attentional function in bipolar dis-
order provides one approach towards identifying inappro-
priately activated anterior limbic areas that might not be
possible to identify by direct emotional probes; that is,
this approach may identify inappropriate activation of
emotional areas during a nonemotional task.
During euthymia, bipolar patients exhibit minimal
symptoms by definition, although a persistent vulnerability
for mood dysregulation is always present. This persistent
vulnerability has been hypothesized to result from over-
reactive emotional (ie anterior limbic) brain networks
(Ketter et al, 2001; Phillips et al, 2003; Strakowski, 2002;
Strakowski et al, 2002). If correct, this hypothesis suggests
that, even during euthymia, dysfunction within the anterior
limbic network persists, leaving patients at risk for mood
and cognitive disturbances. The goal of this study was to
determine whether abnormal anterior limbic activation
during an attentional task was present during euthymia, to
specifically identify this persistent dysfunction.
Several challenges face imaging studies that compare
healthy and bipolar subjects, which have limited previous
investigations (Strakowski, 2002). First, bipolar patients are
typically taking psychotropic medications, which may alter
patterns of brain activation in unpredictable ways. Second,
if patients perform a cognitive task significantly worse than
comparison subjects, interpreting differences in brain
activation is confounded. Specifically, if task performance
differs, then differences in brain activation may simply
reflect the inability of the patients to complete the task,
rather than differences in how they process information.
Finally, if bipolar patients are studied while in a mood
episode, then differences in brain activation from healthy
subjects might simply represent epiphenomena of that
mood state, rather than representing a trait of bipolar
disorder per se. To address these limitations, we studied
brain activation using functional magnetic resonance
imaging (fMRI) in unmedicated, euthymic bipolar and
healthy subjects while they performed the Continuous
Performance Task-Identical Pairs version (CPT-IP), an
established measure of sustained attention (Adler et al,
2001a; Cornblatt et al, 1988; Ha ¨ger et al, 1998). From these
and previous considerations (Ketter et al, 2001; Phillips et al,
2003; Strakowski, 2002; Strakowski et al, 2002; Mayberg
et al, 1999; Yamasaki et al, 2002), we hypothesized that,
compared with healthy subjects, bipolar patients would
exhibit abnormal activation of regions of the anterior limbic
network during a nonemotional attentional task.
Patients with DSM-IV type I bipolar disorder were recruited
from the University of Cincinnati First-Episode Mania
Study (Strakowski et al, 2000a,b,c). From ongoing ratings
obtained for this study, patients (N¼10) were identified
who had discontinued medication for at least 1 month and
were euthymic. Euthymia was defined as at least 4 weeks of
Young Mania Rating Scale (YMRS; Young et al, 1978) total
scores p5 and Hamilton Depression Rating Scale (HDRS;
Hamilton, 1960) total scores p7. Since this study is
naturalistic, the study investigators do not control treat-
ment prescription. Therefore, a number of patients had
discontinued medications in conjunction with their perso-
nal psychiatrist or on their own (despite encouragement by
investigators not to do so). Subjects were subsequently
followed to ensure that they remained euthymic for at least
1 month after the MRI exam as well.
In all, 10 healthy comparison subjects were recruited from
the same communities as the patients and were individually
matched to the patients by age, sex, and ethnicity. Healthy
subjects had no history of any major psychiatric disorder in
themselves or first-degree family members. All bipolar and
healthy subjects met the following inclusion criteria: (1) age
18–45 years; (2) no history of alcohol or drug dependence;
(3) no alcohol or drug abuse for at least 3 months prior to
the scan; (4) no history of mental retardation or documen-
ted IQo70; (5) right-handed; (6) no history of major
medical or neurological disorders that were felt by the
investigators to influence fMRI results; (7) no contra-
indication for an MRI study; (8) ability to communicate in
English; and (9) a negative pregnancy test in women. All
subjects provided written informed consent for this study
after the procedures and risks were explained in full. Both
the University of Cincinnati and Children’s Hospital
Medical Center Institutional Review Boards approved this
A diagnosis of bipolar disorder (patients) or the absence of
a psychiatric condition (healthy subjects) was established
using the Structured Clinical Interview for DSM-IV (SCID-I/
P; First et al, 1997) administered by trained, experienced
clinicians (inter-rater kappa40.90; Strakowski et al, 2000a).
Assessment of euthymia during the previous 4 weeks was
obtained from the bipolar subjects’ participation in the
outcome study (Strakowski et al, 2000a, b, c). Additionally,
all subjects were administered the YMRS and HDRS at the
time of the MRI study. Treatment contacts and medications
prescribed and taken were also recorded. The patients were
relatively young (Table 1) with an average illness age at
onset of 23 (SD 9) years and average illness duration of 2.2
(SD 1.9) years.
The presence of substance use disorders was assessed
using the SCID-I/P and the Addiction Severity Index (ASI;
McClellan et al, 1992). Additionally, subjects provided a
sample for a urine toxicology screen at the time of the
MRI study (which had to be negative for participation).
A medical review of systems performed by a licensed
physician (CMA) identified any potentially exclusionary
medical problems. All of the subjects were medically healthy
and none had any history of significant medical or
neurological disorders. Demographic information was
obtained by direct interview. Finally, right-handedness
was verified using the Crovitz Handedness Scale (Crovitz
CPT in bipolar disorder
SM Strakowski et al
and Zener, 1962). Demographic and clinical variables are
listed in Table 1.
Although unmedicated at the time of the study, all
patients had previously received psychotropic medications.
Prior medication use is listed in Table 2. As can be seen,
most patients had discontinued medications for a number
of months prior to this fMRI study.
As noted, the CPT-IP version was the experimental
cognitive task of interest. Pilot data suggested that euthymic
bipolar and healthy subjects would perform this task
similarly (SM Strakowski et al, unpublished data), which
was one reason it was chosen. Subjects were presented with
a series of four-digit numbers and were asked to respond
with a button press when the same number occurred twice
sequentially. The control task consisted of the number
‘1234’ presented at the same rate and intervals as the CPT-IP
to the subjects. The subjects were asked to watch the control
presentation, but not to respond. This task was designed to
control for being in the MRI scanner and the simple visual
components of watching flashing numbers; therefore, a
response was not required, since to do so would have made
the control task a form of continuous performance task,
thereby potentially limiting ability to detect activations
associated with attention.
In the MRI scanner, subjects were presented stimuli using
nonferromagnetic goggles (Resonance Technologies Inc.)
that provided a 3000field-of-view (FOV) visual presentation
that mimics the presentation of a computer monitor and
obscures the peripheral FOV. The experimental and control
tasks were given in alternating blocks of 30s each with
numbers being presented for 700ms at 750ms intervals (ie
there was a 50ms gap between presentations, for a total of
40 numbers/block). Five blocks of each task were obtained
for analysis during each scan session. Subjects responded to
targets (ie two identical numbers presented sequentially) in
the CPT-IP task using a button box. The responses were
electronically recorded on a computer to permit calculation
of response parameters (ie discriminability and percent
correct and percent false-positive responses).
All images were obtained using a 3.0T, Bruker Biospec
30/60 MRI scanner (Bruker Medizintechnik, Karlsruhe,
have been previously described (Adler et al, 2001a, b,
2004). Following a three-plane gradient echo scan for
alignment and brain localization, a shim procedure was
performed to generate a homogeneous magnetic field. To
provide anatomical localization for activation maps, a
obtained using a modified driven equilibrium Fourier
16.5ms, TE¼4.3ms, FOV¼25.6?19.2?14.4cm, matrix
256?128?96 pixels, flip angle¼201). After the anatomic
scan was obtained, subjects participated in an fMRI session
in which scans were acquired using a T2*-weighted
gradient-echo echo planar imaging (EPI) pulse sequence
(TR/TE¼3000/38ms, FOV¼25.6?25.6cm, matrix 64?64
pixels, slice-thickness¼5mm, flip angle¼901). Contiguous
5mm axial slices, 24 in number, which extended from the
inferior cerebellum to encompass most of the brain were
selected from a sagittal localizer scan.
During the fMRI sessions, subjects performed the CPT-IP
and control tasks in an alternating boxcar design. A boxcar
design was chosen to maximize signal-to-noise in this
relatively small sample. In all, 24 image slices were
acquired at each time point. Data from the first (control
task) interval were discarded during postprocessing to
avoid any nonequilibrium intensity modulation effects.
Following that first interval, five alternating blocks of each
Table 1 Clinical and Demographic Characteristics of 10
Unmedicated, Euthymic Patients with Bipolar Disorder, and 10
Healthy Subjects Studied Using fMRI
Bipolar patients Healthy subjects
Age, years 25.5 (8.1) 25.3 (7.3)
1.0 Sex, N (%) women6 (60) 6 (60)
Ethnicity, N (%) white8 (80) 8 (80)1.0
HDRS 3.1 (2.5)1.6 (1.8)
1.6 (1.8)0.4 (0.8)
Discriminability 5.9 (2.2)6.9 (2.5)
Percent correct94.3 (6.5) 95.6 (5.8)
Percent false positives4.0 (3.2) 2.0 (2.8)
Variables are listed as mean (SD) unless otherwise noted. HDRS¼Hamilton
Depression Rating Scale; YMRS¼Young Mania Rating Scale. Two-tailed p-
values calculated by Wilcoxon rank-sum test for continuous variables and w2-test
for dichotomous variables.
aThree patients’ CPT performance measures that were obtained in the scanner
were lost after the session due to a computer failure. These three patients
appeared to perform the task without difficulty, however.
Table 2 Medication Histories of 10 Euthymic Bipolar Patients
prior to MRI Scan Acquisition, Including Time since Last Medication
last use, mean
Divalproex8 26 (2–83)14 (3–39)
Risperidone3 27 (3–59)9 (8–11)
Olanzapine3 4 (2–6)21 (7–43)
Quetiapine2 14 (10–18) 9 (7–11)
Sertraline234 (2–66)10 (7–12)
CPT in bipolar disorder
SM Strakowski et al
task were obtained. High-frequency noise was removed in
preprocessing using a Hamming filter applied to the k-space
data prior to image reconstruction. Binary masking was
applied to each image to remove pixels outside the brain.
Linear and quadratic drift components in the temporal
baseline of each pixel were removed using a quadratic drift
correction algorithm (Adler et al, 2001a,b, 2000, 2004).
Subjects’ head movements were minimized by instructing
them to remain still and by packing foam padding around
their heads. Images were corrected for motion using a
pyramid coregistration technique without landmarks that
measures mean square differences in intensity between a
reference image and succeeding time point images (The ´venaz
and Unser, 1998). After realignment, all data sets were
reviewed as a cine loop for uncorrected movement and were
to be removed from the study if motion was detected. All
images had less than 2mm of movement.
Comparisons in demographic variables were made using
Wilcoxon rank-sum tests for continuous variables and w2-
tests for dichotomous variables. Discriminability (d0) was
calculated to assess CPT-IP task performance in the
scanner. Discriminability is a well-recognized signal-detec-
tion measure that incorporates both false-positive and true
positive responses in its calculation (Coren and Ward,
1989). For completeness, we also report the more familiar
percent of true and false-positive responses in Table 1.
Comparisons between groups for these measures were made
using Wilcoxon rank-sum tests.
Image data were processed using the Children’s Hospital
Imaging Processing Software (CHIPSs) (Adler et al, 2000,
2001a, b, 2004; Holland et al, 1998a, b). Images were
analyzed as composites to determine activation differences
between groups. Smoothing was applied (6mm. FWHM)
and t-statistics calculated, contrasting voxels across the
experimental (CPT-IP) and control (repeating numbers)
tasks. The t-maps were transformed to Talairach space.
Then a t-statistic was determined for each voxel across
subjects to create group-specific composite images (Figures
1 and 2), using a significance threshold of po0.05 based on
a combination of voxel cluster size and activation threshold
to control for multiple comparisons following the recom-
mendations of Xiong et al (1995). Voxel-by-voxel com-
parisons were then made between subject groups. Only
differences in which positive activation relative to the
control task was observed in at least one group were
included (ie none of the differences in activation analyzed
involve differences in relative deactivation). In order to
control for multiple comparisons and protect against type I
error a clustering technique was employed. Specifically, a
minimum cluster size of 15 with a significance threshold of
po0.05 was used to identify activation, as previously
suggested (Adler et al, 2001a, 2004). Functional maps
were coregistered to a structural template of averaged
T1-weighted MDEFT structural images to aid interpretation.
In order to help interpret activation differences, we
examined correlations among brain regions of activation
that significantly differed between groups and CPT-IP
performance (using the signal detection measure d0).
Specifically, regions of interest were defined as those areas
showing significant group differences in activation, as
identified using the methods described in the previous
paragraph. We then identified correlations between d0and
activation at each voxel within those identified regions of
interest only, in order to increase power. We defined
significant correlations as r40.75 which corresponded to a
po0.05. For simplicity, the maximal r-value (for those
voxels with r40.75) for each region is reported.
Demographics and Task Performance
The patient and healthy subject groups were closely
matched on demographic and clinical variables (Table 1).
anatomic images in 10 healthy subjects performing the CPT-IP. Statistically
significant activation was defined as po0.05 using a combination of voxel
cluster size and activation threshold to control for multiple comparisons
following the recommendations of Xiong et al (1995).
Functional brain activation map overlaid on T1-weighted
anatomic images in 10 euthymic, unmedicated bipolar subjects performing
the CPT-IP. Statistically significant activation was defined as po0.05 using a
combination of voxel cluster size and activation threshold to control for
multiple comparisons following the recommendations of Xiong et al
Functional brain activation map overlaid on T1-weighted
CPT in bipolar disorder
SM Strakowski et al
Although differences in YMRS ratings approached signifi-
cance, the mean and range of values of this mania rating is
so low that this difference is clinically meaningless. The
groups also performed the CPT-IP similarly (Table 1).
Individual group activation maps are illustrated in Figures 1
fMRI Group Comparisons in Activation
Figure 3 illustrates areas of significant regional brain
activation differences in healthy vs bipolar subjects while
performing the CPT-IP as contrasted with the control task.
These regional differences are listed in Table 3, with
corresponding Brodmann areas and Talairach coordinates.
As illustrated, healthy subjects showed relative greater
activation in the fusiform gyrus and medial frontal cortex.
Bipolar patients showed relative greater activation in limbic
(hypothalamus, parahippocampus/amygdala), paralimbic
(insula) and prefrontal and visual associational regions.
Activation in other brain areas commonly associated with
attentional tasks, such as the anterior cingulate (see Figures
1 and 2) did not significantly differ between groups
Correlations in fMRI Activation and Task Performance
For the bipolar patients, significant positive correlations
were observed between task performance (d0) in the right
inferior frontal (r¼0.93, po0.003) and bilaterally in the
ventrolateral frontal (specifically BA 10; r¼0.85, po0.02
and r¼0.78, po0.04 on the left and right, respectively)
regions. In the healthy subjects, d0
negatively correlated with activation in the left mid-
occipital/temporal region (r¼?0.90, po0.0004).
The results of this preliminary study support the hypothesis
that dysfunctional anterior limbic networks are present in
between healthy subjects and euthymic bipolar patients while performing
an attentional task (CPT-IP). Areas in which healthy subjects exhibited
greater activation are in blue tones and include: (1) left fusiform gyrus (BA
20) and (2) left medial frontal cortex (BA 11). Areas in which bipolar
patients exhibited greater activation are in yellow/green/red hues and
include: (3) left parahippocampus/amygdala (BA 34), (4) right inferior
frontal cortex/insula (BA 13, 47), (5) hypothalamus, (6 and 7) bilateral
ventral prefrontal cortex (BA 10, 47), and (8 and 9) bilateral mid-occipital/
mid-temporal cortex (BA 18, 19, 39). Images are in radiological convention.
Difference images displaying differences in brain activation
Table 3 Brain Regions Exhibiting Significant Differences in Activation between Healthy and Unmedicated, Euthymic Bipolar Subjects While
Performing the CPT-IP (See Also Figure 1). Brodmann Areas Derived from Talairach Daemon are Provided Unless Otherwise Noted
RegionsBrodmann areaHemi-sphere Talairach coordinatesa
Increased in healthy subjects
Fusiform gyrus 20L
?50, ?29, ?25
?6, 47, ?15
?0.52 Medial frontal cortex11L 15
Increased in bipolar subjects
Inferior frontal cortex/insula13, 47R 26, 15, ?10
?38, 39, 0
34, 35, ?5
Ventral prefrontal cortex10, 47L 390.75
?10, ?1, ?15
2, ?5, ?5
Mid-occipital/mid-temporal cortex18, 19, 39R 38, ?77, 10
?30, ?85, 15
34, ?41, 45
26, ?53, 50
?62, ?5, 15
Inferior parietal cortexb
Superior parietal cortexb
40R 57 0.57
7, 40R39 0.60
43L 27 0.79
aTalairach coordinates of pixel within structure with maximal activation difference.
bThis region not shown in Figure 1.
cZ-score is for the point indicated by the Talairach coordinates.
CPT in bipolar disorder
SM Strakowski et al
euthymic bipolar patients. Specifically, compared with the
healthy subjects, patients showed increased activation in
limbic and paralimbic areas (parahippocampus/amygdala
and insula, BA 13) as well as ventrolateral prefrontal regions
(BA 10/47) that are components of this network (Mega et al,
1997; Ongu ¨r and Price, 2000; Yamasaki et al, 2002). The
bipolar patients in this study, then, activated these brain
regions, which are typically involved in emotional arousal,
yet they were performing a nonemotional attentional task.
This activation therefore suggests that the bipolar subjects
attached emotional valence to this task differently than
healthy subjects. This suggestion is supported by the
significant correlation between task performance (d0) and
ventrolateral prefrontal cortical activation in the bipolar
patients, which was not observed in healthy subjects. In the
absence of specific measures of emotional responses to this
task, these suggestions remain speculative, however. More-
over, alternatively, these differences may represent differ-
ences in levels of performance anxiety, concerns about the
MRI scanner experience, or simply differences in how
bipolar and healthy subjects process attentional informa-
tion. These alternatives require additional study to extend
the present preliminary work.
Healthy subjects demonstrated greater activation than
bipolar patients in left medial orbitofrontal (BA 11) and
fusiform areas. Previously, we demonstrated that fusiform
activation (bilaterally) was associated with CPT-IP perfor-
mance in healthy human subjects (Adler et al, 2001a).
Yamasaki et al (2002) also observed fusiform activation
during a CPT task with emotional and neutral distracters. In
their analysis, fusiform was more strongly activated in
response to distracters than targets and was greatest with
emotional distracters. Since the subjects in the Yamasaki
et al (2002) study performed the task despite the distracters,
the fusiform activation may have signaled inhibition of
emotional networks to permit attention to the task.
Similarly, the medial prefrontal area (BA 11) is a component
of the anterior limbic network that modulates emotional
and social behavior (Mega et al, 1997). The increased
activation in the healthy vs bipolar subjects in these brain
areas may represent a failure in bipolar disorder to activate
regions that would inhibit other components of emotional
networks in order to focus brain resources on cognitive
activities, namely sustained attention. The activation
pattern observed in these healthy subjects was similar to
that we reported previously from a completely independent
set of healthy subjects (Adler et al, 2001a).
Importantly, despite different patterns of brain activation,
bipolar and healthy subjects exhibited similar performance
on the CPT-IP. This suggests that the patients used an
alternative neural ‘strategy’ to process attentional informa-
tion or that, despite potential interference from inappro-
priate emotional network activation, they were able to
compensate for the overactivation of emotional brain areas
in order to do the attentional task. In the healthy subjects,
discriminability was significantly inversely correlated with
activation in visual association areas (eg BA 18, 19, 39, 40,
and 43). The inverse correlation suggests that these areas
were recruited when subjects were having difficulty with the
task. These same areas exhibited increased activation in the
bipolar patients, perhaps as a means to maintain attention
despite disruption from overactivated anterior limbic
(emotional) brain networks. Alternatively, bipolar patients
may have a dysfunction of inhibitory cognitive networks
that leads to overactivated emotional circuits (Mayberg et al,
1999). Activation in these visual association areas is a
recognized part of the healthy response pattern during the
CPT-IP (Adler et al, 2001a).
Several limitations should be considered when interpret-
ing these results. Although the CPT-IP is a widely used
measure of sustained attention, it is not a pure attentional
task as it incorporates elements of working memory. This
confounds interpretation of the data somewhat as atten-
tional and memory neural systems, though sharing
components, are separate. In this study, differential
activation in areas commonly associated with working
memory (eg dorsolateral prefrontal cortex) were not
observed. Although this could be a result of no differences
in working memory function, the CPT-IP has only a modest
working memory component, so may simply not be able to
differentiate these subject groups. Future studies that
examine the specific separate aspects of this task would
clarify the contributions of each. However, as the aim of this
preliminary study was to identify whether anterior limbic
networks inappropriately activated during a cognitive task,
this limitation is secondary. Studying unmedicated patients
eliminates the uncertain effects of psychotropic medication
on brain activation. However, patients who are able to
discontinue medication and still remain well for extended
periods of time may not be representative of all bipolar
patients. Additionally, all patients had received psycho-
tropic medications at some point in their course of illness.
It is possible that residual effects from these medications
contributed to the differences observed. The comparison
task used did not have a response parameter, as we were
concerned that most responses require an attentional
component, which would defeat the role of a comparison
task. Therefore, differences in motor activation were
expected and observed in left postcentral gyrus in these
right-handed subjects (Table 2). However, the primary
regions of interest were not motor brain regions, suggesting
this task limitation is not likely to explain the other
activation differences reported. Finally, the number of
subjects in each group in this study is relatively small,
thereby increasing the risk of type II statistical error.
Therefore, these results should be viewed as preliminary
and interpreted cautiously. Nonetheless, we believe that
these limitations are obviated by the strengths and
uniqueness of our study design, which removed confounds
of medications, mood state, and poor task performance.
By studying unmedicated, euthymic patients, group
differences could not be attributed to the effects of affective
symptoms or medications. Additionally, since both groups
exhibited similar performance measures on the CPT-IP,
activation differences could not be attributed to bipolar
patients failing to perform the task. Therefore, the findings
may reflect core abnormalities in brain function present in
bipolar disorder even during periods of clinical stability.
Coupled with other studies that have reported structural
and functional brain abnormalities in bipolar disorder
(reviewed by Strakowski, 2002), these results help to define
specific regional brain abnormalities within the anterior
limbic network that may underlie the loss of emotional
homeostasis that defines this common mental illness.
CPT in bipolar disorder
SM Strakowski et al
Supported by a grants from the Stanley Medical Research
Institute and NIH Award MH58170 (SMS).
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