Directory UMM :Data Elmu:jurnal:B:Biological Psichatry:Vol48.Issue11.2000:

Increased Anterior Cingulate and Caudate Activity in
Bipolar Mania
Hilary P. Blumberg, Emily Stern, Diana Martinez, Sally Ricketts, Jose de Asis,
Thomas White, Jane Epstein, P. Anne McBride, David Eidelberg, James H. Kocsis,
and David A. Silbersweig
Background: Executive control of cognition, emotion,
and behavior are disrupted in the manic state of bipolar
disorder. Whereas frontal systems are implicated in such
dysfunction, the localization of functional brain abnormalities in the manic state is not well understood.
Methods: We utilized a high-sensitivity H2150 positron
emission tomography technique to investigate regions of
increased brain activity in mania, compared to euthymia,
in bipolar disorder.
Results: The principal findings were manic state-related
increased activity in left dorsal anterior cingulate, and left
head of caudate.
Conclusions: The findings suggest that the manic state of
bipolar disorder may be associated with heightened activity in a frontal cortical–subcortical neural system that
includes the anterior cingulate and caudate. Biol Psychiatry 2000;48:1045–1052 © 2000 Society of Biological
Psychiatry
Key Words: Bipolar disorder, mania, affective disorders,

tomography emission-computed, gyrus cinguli, caudate
nucleus

Introduction

C

lassic manic symptoms include sustained heightened
mood, as well as associated abnormalities in attentional and executive functions, such as distractibility and
excessive maladaptive behaviors. There are a number of
nonimaging studies suggesting that manic states are associated with greater right than left hemisphere prefrontal
and subcortical impairment, and greater ventral than dorsal
cortical impairment (reviewed in Bear 1986; Sackeim et al
1982; Starkstein and Robinson 1997; Wexler 1980). Al-

From the Functional Neuroimaging Laboratory, Department of Psychiatry, The
Weill Medical College of Cornell University, New York (HPB, ES, DM, SR,
JdA, TW, JE, PAM, DE, JHK, DAS) and the Department of Neurology, North
Shore University Hospital–New York University School of Medicine, Manhassett (DE).
Address reprint requests to Hilary P. Blumberg, M.D., Veterans Administration

Connecticut Healthcare System, Department of Psychiatry 116A, 950 Campbell Avenue, West Haven CT 06516.
Received November 24, 1999; revised May 23, 2000; accepted June 14, 2000.

© 2000 Society of Biological Psychiatry

though human brain lesion studies can help to localize
regions of decreased functioning, post-lesion compensation and reorganization can complicate the interpretation
of findings. Furthermore, the elucidation of dysregulated
or heightened activity in associated brain regions, which
might also underlie manic symptoms, has been limited by
available experimental methods. Functional neuroimaging
techniques allow for the investigation, in vivo, of such
possible manic state-related abnormalities in regional
brain function.
Functional neuroimaging techniques have been applied
to a greater extent to the study of depression, than of
mania, in mood disorders. Positron emission tomography
(PET) studies of depression have demonstrated abnormalities in ventral, rostral and dorsal anterior cingulate cortex
(AC), dorsolateral prefrontal cortex, as well as caudate,
which receives significant projections from these cortical

structures (Baxter et al 1989; Bench et al 1993; DeAsis et
al 1999; Drevets et al 1997; George et al 1997; Mayberg
et al 1997).
The regional brain involvement in mania is less clear.
There are findings that support possible frontal lobe,
temporal lobe, and basal ganglia involvement in primary
mania, although the associated studies differ in the imaging techniques and normalization procedures used, the
delineation of the frontal lobe regions examined, and
whether increases or decreases were found in these regions
(Table 1).
Decreased anterior–posterior gradients and general
frontal activity have been reported in mania (al-Mousawi
et al 1996; O’Connell et al 1995; Rubin et al 1995). More
specifically, mania-associated increased activity has been
reported in dorsal and ventral AC (Drevets et al 1995,
1997; Goodwin et al 1997), and increased activity has
been reported in more lateral prefrontal cortices (Baxter et
al 1989).
There has been evidence to suggest possible involvement of the temporal polar cortex in mania; however; there
have been conflicting findings in this area. Decreased right

basotemporal activity has been reported, with a trend
toward a negative correlation between mania ratings and
0006-3223/00/$20.00
PII S0006-3223(00)00962-8

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2000;48:1045–1052

Table 1. Results of Regional Functional Neuroimaging Studies of Primary Mania in Resting States
Group

Technique

na

Frontal findings
Increased left
anterolateral compared
to depression

Baxter et al 1989

FDG PET

6 (6)

Migliorelli et al 1993

HMPAO SPECT

5 (5)

Drevets et al 1995

FDG PET

3 (3)

O’Connell et al 1995

IMP SPECT

11

Rubin et al 1995

rCBF

11

al-Mousawi et al 1996

FDG PET

Drevets et al 1997
Goodwin et al 1997

Temporal findings

Basal ganglia
findings

Decreased right
basotemporal
Increased right ventral
AC
Decreased frontal (in four
of 11 subjects)

Increased temporal
(in 11/11)

Decreased anterior
cortical rCBF in
depression and mania

15 (2)

Decreased anteriorposterior gradient

FDG PET
EMZ SPECT

4 (3)
7 (7)

Increased ventral AC
Increased dorsal AC

Gyulai et al 1997

IMP SPECT

3

Blumberg et al 1999

H2150 PET

5

Increased right
temporal and
decreased left
amygdala

Correlation to
mania scores

Negative trend
with right
basotemporal
Increased right ventral
striatum
Increased right . left
basal ganglia (in
5/11)

Positive with

right temporal

Comments
Differences may be accounted
for by the metabolic
reduction in the depressed
phase
All subjects female, normalized
to cerebellum

Abnormalities on visual
inspection
Preliminary suggestion of left
. right rCBF in mania
compared to depression in
inferior prefrontal cortex
Normalized to the areaweighted mean of all regions
of interest

Subjects manic after lithium

discontinuation
Increased right .
left anterior
temporal (in 2/3)

Decreased orbitofrontal

H.P. Blumberg et al

FDG, 18 fluorodeoxyglucose; PET, positron emission tomography; HMPAO, 99mTchexamethylpropyleneamine oxime; SPECT, single photon emission computed tomography; AC, anterior cingulate; IMP,
isopropyliodoamphetamine; rCBF, regional cerebral blood flow; EMZ, 99mTc-exametazime.
a
Numbers in parentheses represent the number of unmedicated subjects.

Cingulate and Caudate Activity in Mania

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1047

Table 2. Brain Regions of Increased Activity in the Manic State of Bipolar Disorder
Brain area (Brodmann area)
Left, dorsal AC (24/32)
Left caudate head
Right, dorsal AC (24/32)
Right ventral AC (32)

x
218
216
24
10

y
12
20
6
26

z

Z
a

34
0
38
28

4.69
4.20a
3.32
3.13

Mania rCBF

Euthymia rCBF

60.54 6 0.33
75.76 6 1.32
60.49 6 0.89
77.29 6 0.63

54.61 6 0.66
67.52 6 0.66
57.10 6 0.49
74.22 6 0.76

The brain areas represent regions of increased activity in the manic state, compared to the euthymic state, above significance thresholds of p , .001, uncorrected for
multiple comparisons. Coordinates of the maxima within a region of increased regional cerebral blood flow (rCBF) are in millimeters relative to the anterior commissure
in standardized stereotactic space (Talairach and Tournoux 1988); x is the lateral distance from the midline (positive, right), y is the anteroposterior distance from the anterior
commissure (positive, anterior), and z is the height relative to the anterior commissure–posterior commissure plane (positive, dorsal). Z is the significance level converted
to the unit normal distribution. rCBF, mean adjusted rCBF 6 SD in mL/100 g/min. AC, anterior cingulate.
a
p , .05, corrected for multiple comparisons.

right basotemporal cerebral blood flow (CBF) (Migliorelli
et al 1993); however, increased right temporal activity
(al-Mousawi et al 1996; Gyulai et al 1997; O’Connell et al
1995) and decreased left amygdala activity (al-Mousawi et
al 1996) have also been reported, and right temporal
increases have been shown to positively correlate with
mania scores (O’Connell et al 1995).
Abnormalities have been reported in bipolar mania in
the basal ganglia. There was a report of increased uptake
in the basal ganglia, greater in the right hemisphere
(O’Connell et al 1995). Another preliminary report suggests that there may be increased right ventral striatal
activity (Drevets et al 1995).
We previously reported manic state-related decreased
orbitofrontal activity (Blumberg et al 1999). We suggested
that dysfunction in ventral cortices might be associated
with increased activity in associated cortical and subcortical structures with significant connectivity to these regions. As noted above, the nonimaging literature suggests
that an imbalance with right more than left, and ventral
more than dorsal, frontal lesions are associated with
mania. It is plausible that, conversely, increased left dorsal
frontal activity may contribute to a similar regional imbalance, in the absence of gross lesions. The small functional
neuroimaging literature of mania to date has not resolved
these issues. In this article we describe analyses performed
to examine increases in brain activity in mania compared
to euthymia with particular interest in lateralized frontal
systems.

Methods and Materials
Subjects with Bipolar I Disorder, non–rapid-cycling, established
by Structured Clinical Interview (First et al 1995) included five
manic subjects (M; four female, one male; mean age 34.2 years,
SD 5 12.2), and six euthymic subjects (E; four female, two male;
32.5 years, SD 5 11.0). Manic subjects met DSM-IV criteria for
a current manic episode. Euthymic subjects did not meet
DSM-IV criteria for a current manic or depressive episode and
had a score of ,6 on the 29-item Hamilton Depression Rating
Scale (Hamilton 1960). Subjects were without comorbid Axis I

or II Disorders, except distant substance abuse (.5 years in 3 M,
3 E). All subjects were right-handed (Oldfield 1971), spoke
English as a first language, and were without neurologic or
medical illness. Patient groups did not differ significantly in
estimated premorbid verbal intelligence quotient (Grober and
Sliwinski 1991): M 5 111.6 6 6.0, E 5 118.7 6 7.6. The manic
and euthymic groups also did not differ significantly in illness
duration: M 5 14.2 years 6 14.9, E 5 12.0 6 5.6. Subjects
denied family history of psychotic or anxiety disorder. Medications included mood stabilizers (lithium [4 M, 5 E], valproic acid
[2 M, 2 E], and carbamazepine [1 M, 2 E]), antipsychotic agents
(3 M), benzodiazepines (4 M, 1 E), and antidepressants (2 E). No
subject required acute sedation for scanning. After complete
description of the study to the subjects, written informed consent
was obtained in accordance with hospital institutional review
board protocols.
A General Electric ADVANCE Positron Emission Tomograph
was operated in three-dimensional mode (Lewellen et al 1996).
Four scans, in one study session, were performed in the resting
condition with eyes closed, lights dimmed, and low levels of
ambient noise. Regional cerebral blood flow (rCBF) was measured as an index of local neuronal activity (Raichle 1987). H2150
delivery and data acquisition were performed according to a
previously published technique (Silbersweig et al 1993). Realignment of images across runs within subject was performed to
correct for slight head movement, and spatial smoothing (15 mm
full-width-at-half-maximum) was performed. Head movement
was significantly less than the resolution of smoothing for all
subjects. Regional CBF was normalized to a mean of 50 mL/100
gm/min. Group effects were identified with multiple linear
regression analysis. Image processing and analyses were performed with statistical parametric mapping (SPM ’96, Wellcome
Department of Cognitive Neurology, University College London, UK) according to the General Linear Model, and probability
estimates were determined according to the Theory of Random
Fields (Friston et al 1995).

Results
Mean mania scores (Altman et al 1994) for the manic
group and the euthymic group were 21.8 6 SD 6.7 and
2.5 6 4.5, respectively. The groups differed significantly
on 7 of the 10 mania items (p , .05; Student’s t test, two

1048

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2000;48:1045–1052

Figure 1. Sagittal section 16 mm left of the midsagittal plane
demonstrating increased activity in the head of the caudate, and
in left dorsal anterior cingulate in mania, compared to euthymia.
Regional cerebral blood flow functional results (p , .001) are
displayed in color and superimposed on a structural T1-weighted
magnetic resonance imaging template.

H.P. Blumberg et al

tailed), including measures of mood elevation, irritability,
pressured speech, racing thoughts, distractibility, grandiosity, and sleep disturbance. Although there were trends
toward increases in mania, there were no significant
differences on measures of hyperactivity, increased energy, and impaired judgment. The lack of difference
between groups on these items may reflect a bias in
selecting manic subjects without psychomotor agitation
that would render them unable to complete scanning, and
in choosing only those subjects judged by an attending
physician to have capacity to make an informed decision
to participate in the study.
Increased mania-associated rCBF was detected in the
bilateral dorsal AC, the right ventral AC, and in the left
head of the caudate at a threshold of p , .001,
uncorrected (Table 2). Applying correction for multiple
comparisons, significant findings were restricted to the left
dorsal AC and left head of caudate (p , .05, corrected
for multiple comparisons; Figures 1 and 2).

Figure 2. Mean normalized regional cerebral blood flow (rCBF) for the manic and the euthymic groups in the left dorsal anterior
cingulate and caudate. Regional cerebral blood flow values (the Y axis) were normalized to a mean of 50 mL/100 g/min for the manic
and euthymic subject groups. Each column corresponds to the mean (6SD) rCBF for a group of subjects. Results for subjects in the
manic state are represented in blue, and results for subjects in the euthymic state are represented in red. The two columns on the left
are values for the left dorsal anterior cingulate at the statistical parametric mapping (SPM) regional maximum. The two columns on
the right are values for the left head of caudate at the SPM regional maximum.

Cingulate and Caudate Activity in Mania

Discussion
DSM-IV criteria for a manic episode include a sustained
heightened emotional state, as well as accompanying
symptoms of distractibility, rapid loosely connected
thoughts, and behaviors associated with increased motivational drives (American Psychiatric Association 1994).
We report here greater manic, versus euthymic, staterelated activity in the AC and caudate. The greater activity
in these structures may relate to behavioral abnormalities
observed in mania.
The AC is associated with attentional, emotional, and
cognitive functions. The AC has significant reciprocal
connections to the amygdala (Vogt et al 1992), a brain
structure thought to be central to emotional processing.
Stimulation of AC can lead to euphoria and a sense of
well-being, as well as alterations in rate, volume, and
degree of perseveration in speech (reviewed in Devinsky
et al 1995). Cingulate seizures have been associated with
ictal emotional changes, and interictal irritability, emotional lability, and sexual behaviors (Devinsky et al 1995).
Rats will self-stimulate in this brain region in a manner
enhanced over time and thought to be associated with
kindling (Corbett and Stellar 1983), a process theorized to
develop in limbic brain regions in bipolar disorder. Anticonvulsant agents, also used as mood stabilizing agents in
bipolar disorder, have been demonstrated to interfere with
this process (Post et al 1982).
The principal finding of this study was in the dorsal
region of the AC. This region of the AC has relatively
organized and granular cytoarchitecture, and the related
behavioral functions are of higher order (Devinsky et al
1995), than the ventral AC. The dorsal AC has been
associated with cognitive functions, such as the appropriate directing of attention, conflict monitoring, and response selection (Botvinick et al 1999; Carter et al 1998;
Peterson et al 1999; Posner and Rothbart 1998). Decreased
activity in the left dorsal AC has been described in
association with depressive cognitive abnormalities
(Bench et al 1993; DeAsis et al 1999; George et al 1997).
The more ventral regions of the AC region have a more
agranular cytoarchitecture and the related functions are
more primitive. The ventral AC has efferent connections
to autonomic, endocrine, and visceral effectors (Nauta
1971), and is thought to regulate the associated functions.
The rostral AC has also been associated with the expression of internal states, including vocalizations and social
behaviors (Devinsky et al 1995). The ventral AC region
has been demonstrated to activate more to emotional
stimuli, in contrast to the dorsal AC, which may activate
more during cognitive tasks (Whalen et al 1998). One
region of increased activity in this study, the ventral AC,
is a region that overlaps that previously reported to have

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2000;48:1045–1052

1049

increased activity in mania (Drevets et al 1997), representing a possible convergence of findings.
This study also demonstrated increased activity in the
left head of the caudate in mania, ipsilateral to the
increased activity in the dorsal AC. The AC has excitatory
efferent input to the head of the caudate (Eblen and
Graybiel 1995; Yeterian and van Hoesen 1978). The
modulatory caudate input back to the AC has intervening
connections via the globus pallidus and thalamus (Alexander et al 1986). The known structural connectivity
between the cingulate and caudate suggests that the
increased activity occurs within the context of this cortical–subcortical neural system. Increased activity has previously been reported in mania in the basal ganglia
(Drevets et al 1995; O’Connell et al 1995) and warrants
further investigation.
We speculate that increased AC activity could relate to
heightened, dysregulated attentive and cognitive processes, such as manic-type distractibility and maladaptive
excessive behaviors. An alternative possible interpretation
for increased left AC activity in the manic state relates to
the behavioral constraint required during scanning. The
scanning requirement of decreasing inappropriate behavioral outputs, such as psychomotor movements and speaking, may require additional efforts on the part of manic
subjects. Heightened AC and caudate activity could be
associated with this demand.
The findings here are preliminary and require replication, as this study is limited by the relatively small number
of subjects and their medication status. More manic
subjects were receiving both antipsychotic and benzodiazepine medications, and more euthymics were receiving
antidepressants. In each group all but one subject was on
lithium at the time of study. Goodwin et al (1997) reported
decreases in anterior cingulate and right caudate CBF after
lithium withdrawal, whereas development of mania on
lithium withdrawal was associated with increased AC
CBF. There have been reports of increased caudate activity and basal ganglia size associated with antipsychotic
medication (Buchsbaum et al 1987; Chakos et al 1994;
Holcomb et al 1996), and decreased rostral AC activity
with antidepressant treatment (Mayberg et al 1997); however, there is not clear evidence to suggest a contribution
to the lateralized effects seen in this study. Both antipsychotic and benzodiazepine medication have been reported
to be associated with decreased AC activity (Holcomb et
al 1996; Veselis et al 1997), which would have predicted
the opposite outcome in the AC in the manic group.
Findings in ventral AC and striatum have previously been
reported in three unmedicated manic subjects, although the
results were lateralized to the right hemisphere (Drevets et
al 1995).
Increased anterior cingulate activity is not specific to

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H.P. Blumberg et al

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2000;48:1045–1052

bipolar manic states. Elevated emotional states in healthy
subjects have been reported in association with increased
AC activity. For example, Ketter et al (1997) demonstrated increased rCBF in AC associated with procaineinduced euphoria in healthy subjects. In a study of
transient psychologically induced emotional states (via
emotional memory and face presentation) also in healthy
subjects, AC rCBF has been demonstrated to increase
significantly in sad states, and there was a trend toward an
increase in happy states (George et al 1995). Increased
anterior cingulate activity is also not specific to the bipolar
diagnosis, and has also been demonstrated in symptomatic
states of anxiety disorders, such as obsessive-compulsive
disorder and phobias (Rauch et al 1994, 1995). These and
our findings, seen in the light of the behavioral neuroscientific literature, suggest that the AC is a vulnerable part
of an important final common pathway of emotional
regulation.
As this study was designed to examine relative regional
changes in CBF, mean CBF measures were normalized for
each subject, and global changes were not assessed. There
has been a previous report to suggest possible global brain
changes in mania. Kishimoto et al (1987), reported generalized increases in 11C-glucose uptake in three medication-free manic patients compared to control subjects.
Other groups have not found an increase in global activity
(Rubin et al 1995; Schwartz et al 1987; Silfverskiold and
Risberg 1989).
Concurrent volumetric measurements were not performed in this study. A possible contribution of dorsal AC
volume change across mood states can be a subject for
further study. There have been reports of volumetric
differences in ventral AC grey matter (Drevets et al 1997),
and a conflicting literature on the possibility of caudate
volume abnormalities in mood disorders (Aylward et al
1994; Dupont et al 1995; Krishnan et al 1992; Lenze and
Sheline 1999). This literature suggests possible trait abnormalities; however, volumetric state abnormalities that
would have greater implications for the current work are
less clear.
The most significant areas of increased manic staterelated activity were in the left dorsal AC and head of
caudate. This finding, and our previously reported finding
of decreased orbitofrontal activity in mania (Blumberg et
al 1999), are consistent with theories that relative right
lower than left, and ventral less than dorsal, prefrontal
activity is associated with manic states (Bear 1986; Sackeim et al 1982; Starkstein and Robinson 1997; Wexler
1980). This has been theorized to extend to relative
impairment in activity in related right hemisphere subcortical structures, including caudate, thalamus, and medial
diencephalon (Mega et al 1997; Starkstein and Robinson
1997). Much of the reasoning for these theories is based

upon manic behavior described in association with brain
lesions. The data in this functional neuroimaging study
suggest that greater left dorsal AC and caudate activity
may contribute to an equivalent net imbalance in brain
function associated with the manic state in bipolar
disorder.
Supported by the DeWitt-Wallace Fund in the New York Community
Trust.
The authors thank the volunteers for their participation, and Vijay
Dhawan, PhD, Abdelfatihe Belakhlef, PhD, and Claude Marguleff, MA
for their expert technical assistance, and Hong Pan, PhD for his statistical
input.
The findings of this study were presented at the 53rd annual meeting
of the Society of Biological Psychiatry, May 27–31, 1998, Toronto.

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