Psychiatry Research: Neuroimaging 193 (2011) 107112

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Psychiatry Research: Neuroimaging

j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / p s yc h r e s n s

Neurochemical alteration in the caudate: Implications for the pathophysiology of

bipolar disorder
Nasrin Shahana a, Melissa DelBello a, Wen-Jang Chu b, Kelly Jarvis a, David Fleck a,b, Jeffrey Welge a,
Stephen Strakowski a,b, Caleb Adler a,b,
a
b

Division of Bipolar Disorders Research, Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati College of Medicine, Cincinnati, OH 45267, United States
Center for Imaging Research, University of Cincinnati, OH 45237, United States

a r t i c l e

i n f o

Article history:
Received 28 September 2010
Received in revised form 19 January 2011
Accepted 20 January 2011
Keywords:
Bipolar disorder
Caudate
Magnetic resonance spectroscopy
Imaging

a b s t r a c t
Several lines of evidence suggest that the neuropathophysiology of bipolar disorder is marked by structural
and functional abnormalities in the caudate. We used magnetic resonance spectroscopy imaging (MRSI) to
examine potential neurochemical changes in the caudate of adult bipolar patients (BP). 2D-MRSI scans
including the caudate were obtained from 25 BP and 9 healthy subjects (HS). BP patients were further divided
into medicated (n = 14) and unmedicated (n = 11) groups; the majority of medicated patients received
atypical antipsychotics (AAP). Ratios of Cr/Cho, Cho/NAA and Cr/NAA in the caudate were compared between
groups, controlling for age, gender and gray/white ratio. BP and HS did not signicantly differ on any ratios.
The Cr/Cho ratio, however, was signicantly greater in medicated BP compared to HS. Conversely, the Cho/
NAA ratio was non-signicantly lower in medicated BP vs. HS. Medicated BP also showed signicantly greater
Cr/Cho and signicantly smaller Cho/NAA ratios than unmedicated BP. Although we did not observe
signicant overall differences between BP and HS, our ndings suggest the presence of reduced choline levels
in the caudate of medicated BP receiving AAP. While speculative, these results suggest that AAP do not cause
oxidative injury to neuronal membranes.
2011 Elsevier Ireland Ltd. All rights reserved.

1. Introduction
Bipolar disorder is a major source of psychiatric morbidity and
mortality that affects approximately 1.53.0% of the population
(Regier et al., 1990). Although the neuropathophysiology of bipolar
disorder remains unclear, several lines of evidence suggest that structural and functional abnormalities in bipolar patients are centered
within the anterior limbic network (ALN), including the basal ganglia.
Basal ganglia structures are particularly closely networked with both
cortical and sub-cortical regions involved in mood expression and
regulation, including the amygdala and ventral prefrontal cortex
(VPFC), and appear to be integral to affective regulation (Alexander
et al., 1986; Krishnan and Figiel 1989; Alexander et al., 1990; Mega
and Cummings 1994).
Several studies report structural and functional abnormalities in
the basal ganglia of bipolar patients, and particularly in the caudate.
Increased caudate volume has been widely observed in patients with
bipolar disorder, compared with matched groups of healthy subjects
(Aylward et al., 1994; Strakowski et al., 1999; DelBello et al., 2004).

Corresponding author at: University of Cincinnati College of Medicine, Department

of Psychiatry and Behavioral Neuroscience, 260 Stetson St., Suite 3200, Cincinnati, OH
45219-0516, United States. Tel.: +1 513 558 3362; fax: +1 513 558 3399.
E-mail address: cal.adler@uc.edu (C. Adler).
0925-4927/$ see front matter 2011 Elsevier Ireland Ltd. All rights reserved.
doi:10.1016/j.pscychresns.2011.01.014

Functional abnormalities in the basal ganglia, and particularly

caudate, of bipolar patients have been widely observed using both
positron emission tomography (PET) and functional magnetic
resonance imaging (fMRI). While Buchsbaum et al. (1986) found
uptake of uorodeoxyglucose (18FDG) to be decreased in response to
painful stimuli, Blumberg et al. (2000) observed increased basal left
caudate activity in manic bipolar patients. Findings of fMRI studies also
suggest increased caudate activity in bipolar patients during emotional
stimulation (Chang et al., 2004; Wessa et al., 2007).
Magnetic resonance spectroscopy (MRS) is a noninvasive neuroimaging technique that provides in vivo measurement of specic
biochemicals in localized brain regions (Glitz et al., 2002). Using MRS,
neurochemical changes have been identied in bipolar patients across
several brain regions making up the ALN, including prefrontal,
temporal, and limbic structures (Soares et al., 1996; Strakowski
et al., 2000; Wu et al., 2004; Silverstone et al., 2005; Frye et al., 2007;
Molina et al., 2007; Patel et al., 2008; Senaratne et al., 2009). MRS
ndings in the basal ganglia, however, remain ambiguous. Elevated
choline/creatine (Cho/Cr) and choline/N-acetylacetate (Cho/NAA)
ratios have been widely observed in the basal ganglia of euthymic
bipolar patients, as have elevated absolute choline (Cho) values (Kato
et al., 1996; Hamakawa et al., 1998; Dager et al., 2004). At least one
study however, failed to replicate these ndings (Ohara et al., 1998).
N-acetylacetate (NAA) ndings have been more mixed, with
investigators reporting increased N-acetylacetate/creatine (NAA/Cr)

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ratios (Sharma et al., 1992), decreased ratios (Frye et al., 2007) and no
differences between bipolar and healthy subjects (Ohara et al., 1998).
Absolute NAA concentration ndings have been similarly unclear
(Hamakawa et al., 1998; Dager et al., 2004; Frye et al., 2007). Patients
in these studies have typically been receiving medications, but Cho
concentrations were also found to be elevated in an unmedicated
sample of bipolar I and II patients (Dager et al., 2004), and in a
comparison between bipolar patients with and without lithium
treatment no differences were found (Kato et al., 1996). In this
study we utilized a multi-voxel MRS technique, two-dimensional
magnetic resonance spectroscopy imaging (2-D MRSI), to measure
metabolite ratios of creatine/choline (Cr/Cho), Cho/NAA, and creatine/
N-acetylacetate (Cr/NAA) in both medicated and unmedicated bipolar
patients, and a matched group of healthy subjects. Based on the bulk
of previous ndings, we hypothesized that both medicated and
unmedicated patients with bipolar disorder would demonstrate
evidence of neurochemical changes within the caudate nucleus
reective of abnormalities in neuronal structure and metabolism,
including decreased NAA and elevated Cho.
2. Methods
2.1. Subjects
Twenty-ve adult patients with bipolar disorder, type I (18 men/7
women) and nine healthy subjects (5 men/4 women) were recruited
to participate in proton 2-D MRSI scans that included the caudate.
Patient ages ranged from 16 to 42 years (mean S.D.: 26 9 years)
and healthy subject ages ranged from 18 to 44 years (mean S.D.:
26 10 years). Subjects with bipolar disorder were free of concurrent
axis I psychiatric or medical illnesses including substance abuse or
dependence, except for nicotine use disorders. Healthy subjects were
free of all medical and axis I psychiatric conditions except for nicotine
dependence, and were taking no medications at the time of scan.
Diagnoses were made and excluded using the Structured Clinical
Interview for DSM-IV (SCID). Mood symptoms were evaluated using
the Young Mania Rating Scale (YMRS) and Hamilton Depression
Rating Scale (HDRS) administered by trained, reliable raters (intraclass correlation coefcient N 0.9). No subjects had a history of head
trauma resulting in loss of consciousness for longer than 10 min.
Eighteen patients were euthymic, and seven patients were in a mixed
mood state at the time of their scan. Eleven patients were unmedicated
at the time of the scan. The remaining 14 bipolar subjects were receiving standard pharmacotherapy including lithium, valproate, atypical antipsychotic and antidepressant medications.
2.2. Magnetic resonance and magnetic resonance spectroscopy imaging
All magnetic resonance imaging (MRI) and MRSI were acquired
with a 4T Varian INOVA whole-body MR system using a volume TEM
(Transverse ElectroMagnetic) head coil. A sagittal scout slice (Fig. 1)
including anterior commissure (AC) and posterior commissure (PC)
was acquired and used for dening the AC-PC line (red dashed line,
Fig. 1). Another line at 25 mm above the AC-PC line (yellow dashed
line, Fig. 1) was dened and the oblique axial scout images along the
yellow dashed line were acquired for a 2-D MRSI acquisition (Fig. 1).
MRSI of the brain were acquired using a modied LASER (Localized
by Adiabatic SElective Refocusing) sequence with 10 mm slab
thickness (green lines, Fig. 1) (Garwood and DelaBarre 2001). Two
dimensions of 24 24 phase encodes were acquired over a eld of
view (FOV) of 192 mm 192 mm. To exclude the large lipid resonances from the extra-cranial fat, the acquired volume was restricted
to a 100 mm 80 mm rectangle within the 192 mm 192 mm FOV by
using adiabatic refocusing pulses (green box, Fig. 2). Magnetic eld
homogeneity was optimized by automatic B0 mapping (Miyasaka
et al., 2006). Water suppression was provided by an initial broad-

Fig. 1. Spectra, axial scout images and T1-based images were obtained in the same
angulated axial plane 25 mm (yellow dashed line) above the line of the anteriorposterior
commissure (AC-PC) (red dashed line). The slab thickness was 10 mm (green line).

band semi-selective excitation pulse and frequency selective DANTE

(Delays Alternating with Nutation for Tailored Excitation) pulse
applied to the water resonance. To determine the gray matter (GM)
and white matter (WM) content in each MRSI voxel, quantitative
T1 (spin-lattice relaxation time) maps along the MRSI slab were
generated using a 15-slice, 7-point inversion recovery imaging
sequence with TR of 4 s, 1.5-mm-thick planes (without gap). The T1
from each pixel was determined by tting the time course of the
magnetization using a simplex algorithm with T1, and each voxel was
further classied into GM, WM, or cerebrospinal uid (CSF) based on
its T1 value (Hetherington et al., 1996). Tissue content in each MRSI
voxel (e.g. percentage of gray matter and percentage of white matter)
was used for the correction of brain metabolite data (Chu et al., 2000).
Precautions were taken to minimize subjects' motion during the MRI
study by instructing subjects to remain still and packing the area
under their heads with foam padding. The MRSI data were processed
with 2 Hz of Gaussian line broadening, co-registered with scout
image, displayed and curve tted using software written at the Center
for Imaging Research in MATLAB (Fig. 2).
Scout images, MRSI and tissue segmentation images (GM, WM and
CSF) were co-registered to facilitate localization of the spectroscopic
data with tissue segmentation data (Fig. 3). Voxels from both the left
and right caudate were averaged across each individual; four voxels
on average were selected for each subject (two from each side).
One subject had only 3 appropriate voxels and one subject had 5
appropriate voxels. Control subject voxels had mean gray and white
percentages (standard deviation) of 26 9 and 74 9, respectively.
Bipolar subjects had respective mean gray and white voxel percentages of 27 11 and 72 11.
2.3. Statistics
Data were expressed as mean S.D.. Demographic differences
between bipolar and healthy subjects, and differences in rating scores
between medicated and unmedicated bipolar patients were analyzed
using unpaired Student t-tests and 2 tests. Analyses of covariance
were used to separately identify effects of group on each ratio of
neurochemicals in the caudate, controlling for age, sex, and gray/
white ratio. Post-hoc comparisons were made between medicated

N. Shahana et al. / Psychiatry Research: Neuroimaging 193 (2011) 107112

109

Fig. 2. Two dimensions of 24 24 phase encodes were acquired over a eld of view of 192 mm 192 mm. The acquired volume was restricted to a 100 mm 80 mm rectangle within
the 192 mm 192 mm FOV by using adiabatic refocusing pulses (green box). Included are representative spectra from the bipolar and healthy control groups.

patients with bipolar disorder, unmedicated patients, and healthy

subjects when P 0.15. Signicance was dened as P 0.05.
3. Results
Bipolar patients and healthy subjects did not signicantly differ
with regard to age, gender ratio or handedness (Table 1). Medicated
and unmedicated bipolar and healthy subjects similarly did not differ
in age, gender, handedness, or rating scale scores (Table 2). After
adjusting for age, gender, and percent white matter, ratios of Cr/Cho
(1.08 0.23 vs. 1.17 0.18) (F = 1.39, df = 1,29, P = 0.25), Cho/NAA
(0.61 0.06 vs. 0.58 0.10) (F = 0.67, df = 1,29, P = 0.42), and Cr/
NAA (0.65 0.09 vs. 0.67 0.09) (F = 0.25, df = 1,29, P = 0.62) did
not signicantly differ between healthy controls and bipolar patients.
Signicant and near signicant group differences among medicated,
unmedicated, and healthy subjects were observed in Cr/Cho (F = 3.72,
df = 2,28, P = 0.03) and Cho/NAA (F = 2.41, df = 2,28, P = 0.11) ratios,
respectively. Between-group differences in Cr/NAA were not significant (F = 0.48, df = 2,28, P = 0.49) (Table 3).
Post-hoc comparisons between unmedicated bipolar patients and
healthy subjects adjusted for age, gender and gray/white ratio failed
to nd signicant differences in Cr/Cho (1.08 0.23 vs. 1.07 0.17,
P = 0.91), Cho/NAA (0.61 0.60 vs. 0.62 0.12, P = 0.81) or Cr/NAA
(0.65 0.09 vs. 0.65 0.08, P = 0.93) ratios. The Cr/Cho ratio was
signicantly greater in medicated bipolar patients compared with
healthy controls (1.08 0.23 vs. 1.24 0.15, P = 0.04), however, and
the Cho/NAA ratio lower in medicated bipolar patients vs. healthy
subjects (0.61 0.06 vs. 0.55 0.07, P = 0.11) (Fig. 4). The Cr/NAA
ratio did not signicantly differ between the two groups (0.65 0.09
vs. 0.65 0.09, P = 0.93).

Medicated bipolar patients also showed signicantly greater Cr/

Cho (1.25 0.15 vs. 1.07 0.17, P = 0.02) and lower Cho/NAA (0.55
0.07 vs. 0.62 0.12, P = 0.05) ratios than unmedicated bipolar patients
after adjusting for age, gender and gray/white ratio (Fig. 4). The Cr/
NAA ratio was similar across medicated and unmedicated patients
(0.68 0.09 vs. 0.65 0.08, P = 0.49).
4. Discussion
In this study, MRSI was used to measure ratios of choline, creatine
and NAA in the caudate of patients with bipolar disorder and healthy
subjects. Although ratios rather than absolute concentrations were
obtained, our ndings suggest that while bipolar patients overall
did not differ from healthy subjects, choline is decreased (based on
elevated Cr/Cho and decreased Cho/NAA ratios) in the caudate of
medicated bipolar patients. The combination of decreased Cho/NAA
ratios with unchanged NAA/Cr ratios suggests that NAA concentrations did not differ between bipolar and healthy subjects. These data
are consistent with other MRS studies that included at least a portion
of the caudate (Kato et al., 1996; Ohara et al., 1998; Dager et al., 2004).
Our results are not, however, entirely consistent with previous
choline ndings. With few exceptions (Ohara et al., 1998) the
majority of investigators have reported evidence of increased choline
in the basal ganglia of bipolar patients (Sharma et al., 1992; Kato et al.,
1996; Hamakawa et al., 1998; Dager et al., 2004). Voxels-of-interest
were typically comprised only partially of the caudate and in some
cases included portions of a variety of structures including the
thalamus and insula (Sharma et al., 1992; Kato et al., 1996; Hamakawa
et al., 1998). In addition, several studies combined bipolar I and
bipolar II or NOS patients (Kato et al., 1996; Hamakawa et al., 1998;

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N. Shahana et al. / Psychiatry Research: Neuroimaging 193 (2011) 107112

Fig. 3. Images including scout images, MRSI and tissue segmentation images (GM, WM, and CSF) were acquired over the same region and co-registered to allow localization of the
spectroscopic data and segmentation correction.

Dager et al., 2004). It is also of potential signicance that the majority

of studies that found evidence of increased choline involved bipolar
patients who were receiving therapeutic lithium when scanned
(Sharma et al., 1992; Hamakawa et al., 1998); a single study of the
effects of neuroleptics on choline concentrations did not observe an
effect (Kato et al., 1996). Medicated patients in this study were for the
most part receiving atypical antipsychotics, with one patient also
taking adjunctive lithium and another receiving adjunctive oxcarbamazepam and sertraline. Only one patient was not taking an atypical
antipsychotic; the ndings were not affected by excluding the patient
receiving divalproex alone. Although somewhat speculative given the
limited sample size of this study, our ndings raised the possibility
that treatment with atypical antipsychotics may be associated with
decreased concentrations of choline in the caudate of bipolar patients.
The choline resonance is primarily composed of phosphorylcholine (PC) and glycerophosphocholine (GPC), phosphatidylcholine, and
acetylcholine, as well as free choline, (Miller et al., 1996) and may be
linked to membrane phospholipid metabolism (Moore and Galloway
2002). Our ndings suggest that medicated bipolar patients may show
less membrane turnover than both healthy controls and unmedicated
patients. Several other studies examining a wide range of psychiatric

Table 1
Characteristics of bipolar patients and healthy controls.

Age (years)
Gender (male: female)
Dominant hand (right: left)

Healthy controls
(N = 9)

Bipolar patients
(N = 25)

P-value

26 10
5: 4
7: 2

26 9
18:7
24: 1

0.89
0.37
0.12

Data are means standard deviation (S.D.).

pathology have also noted evidence of decreased choline in patients

receiving atypical antipsychotics. One study of chronic schizophrenic
patients largely receiving atypical antipsychotics found lower concentrations of choline vs. both healthy controls and a group of
unmedicated, albeit rst-episode patients (Ohrmann et al., 2007). A
second study in schizophrenia similarly found decreased Cho/Cr ratios
in patients receiving atypical antipsychotics (Ertugrul and Ulug,
2007). In patients with bipolar disorder, atypical antipsychotics were
associated with increased ratios of NAA/Cho in the hippocampus, also
consistent with decreased choline. NAA/Cho was increased vs. both
unmedicated patients and a group of patients receiving only valproate
(Atmaca et al., 2007). A single study by DelBello et al. (2006) that
reported increased choline in a group of bipolar adolescents treated
with olanzapine measured changes over only 7 days.
Choline levels have been correlated with evidence of neuropathology in patients treated with neuroleptics (Yamasue et al., 2003);
while speculative, our observation of decreased choline in patients
taking atypical antipsychotics could be consistent with preclinical
data suggesting that atypical antipsychotics do not cause signicant
oxidative injury to neuronal membranes, and might even be
protective (Parikh et al., 2003; Pillai et al., 2007). There are several
limitations to this study, however, most notably the fairly small
number of patients in each group and our inability to measure
absolute neurochemical concentrations. Because we have only ratio
data, it is possible that our ndings reect a combination of NAA and
Cr increases rather than decrements in Cho, though previous ndings
make this interpretation less likely. In addition, as in most MRS
studies, our voxels-of-interest include both caudate and some
surrounding white matter, requiring us to control for the gray/white
ratios. Furthermore, few patients in this study were taking antiseizure medications or lithium, making it impossible to compare our

N. Shahana et al. / Psychiatry Research: Neuroimaging 193 (2011) 107112

111

Table 3
Neurochemcial ratios in healthy controls, and in medicated and unmedicated bipolar
patients.

Cr/Cho
Cho/NAA
Cr/NAA

Healthy
controls
(N = 9)

Medicated
bipolar patients
(N = 14)

Unmedicated
bipolar patients
(N = 11)

P-value

1.08 0.23
0.61 0.06
0.65 0.03

1.25 0.05
0.55 0.07
0.68 0.02

1.07 0.17
0.62 0.12
0.65 0.03

0.03
0.11
0.49

Data are means standard deviation (S.D.).

in that group. Further studies, measuring absolute concentrations of

neurochemicals in larger groups of patients including treatment nave
and medicated bipolar patients, would be helpful to expand on our
preliminary ndings. Nonetheless, this study suggests that medications,
and particularly atypical antipsychotic medications, may decrease neuronal membrane turnover in bipolar patients. Although speculative, it is
possible that these effects may be related to the long-term benecial
effects of effective mood stabilization.
Acknowledgments
This study was funded by a grant from the NARSAD Young
Investigator Award program.
References

Fig. 4. Effects of medication on the ratios of Cr/Cho and Cho/NAA. Differences were
observed between medicated patients and both unmedicated patients and healthy
subjects. Error bars represent standard deviation.

ndings across medication groups. Our lack of data as to nicotine

exposure raises another potential issue while nicotine has not been
associated with choline changes in the basal ganglia, mild changes
have been reported elsewhere in the brain (Durazzo et al., 2004;
Gazdzinski et al., 2008; Azizian et al., 2009; Licata and Renshaw,
2010). Finally, none of the unmedicated bipolar patients were
treatment nave, raising the possibility of residual medication effects

Table 2
Characteristics of medicated and unmedicated bipolar patients and healthy controls.

Age (years)
Gender (male: female)
Dominant hand
(right: left)
Age of onset (years)
Hamilton Depression
Rating Scale
Young Mania Rating Scale

Healthy
controls
(N = 9)

Unmedicated
bipolar patients
(N = 11)

Medicated
bipolar patients
(N = 14)

P-value

26 10
5:4
7:2

24 8
9:2
11:0

30 9
9:5
13:1

0.28
0.43
0.21

21 7
8.91 8.63

20 7
6.64 10.02

0.85a
0.56a

8.91 9.40

4.29 4.34

0.12a

Medication summary:
Quetiapine
Risperidone
Aripiprazole
Ziprasidone
Divalproex sodium
Lithium
Sertraline
Oxcarbazepine
Data are means standard deviation (S.D.).
a
Unmedicated vs. Medicated bipolar patients.
b
Plus atypical anti-psychotic (AAP).

5
4
3
1
1
1b
1b
1b

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