www.elsevier.com/locate/psychresns

Psychiatry Research: Neuroim

Subgenual prefrontal cortex of child and adolescent bipolar

patients: a morphometric magnetic resonance imaging study

Marsal Sanchesa,b,c, Roberto B. Sassid, David Axelsone, Mark Nicolettia,b,

Paolo Brambillaf, John P. Hatcha, Matcheri S. Keshavane, Neal D. Ryane,

Boris Birmahere, Jair C. Soaresa,b,*

aDivision of Mood and Anxiety Disorders, Department of Psychiatry, The University of Texas Health Science Center at San Antonio,

San Antonio, TX, USAbSouth Texas Veterans Health Care System, Audie L. Murphy Division, San Antonio, TX, USA

cDepartment of Psychiatry, Federal University of Sao Paulo, Sao Paulo, BrazildDepartment of Psychiatry, University of Sao Paulo School of Medicine, Sao Paulo, Brazil

eDepartment of Psychiatry, Western Psychiatric Institute and Clinic, University of Pittsburgh Medical Center, Pittsburgh, PA, USAfDepartment of Pathology and Experimental and Clinical Medicine, Section of Psychiatry, University of Udine, Udine, Italy

Received 18 March 2004; received in revised form 26 November 2004; accepted 27 November 2004

Abstract

The subgenual prefrontal cortex (SGPFC) plays an important role in emotional processing. We carried out a magnetic

resonance imaging (MRI) study comparing the volume of the SGPFC in child and adolescent bipolar patients and healthy

controls. The sample consisted of 15 children and adolescents who met DSM-IV criteria for bipolar disorder (mean

ageFS.D.=15.5F3.5 years) and 21 healthy adolescents (mean ageFS.D.=16.9F3.8 years). MR images were obtained with a

1.5 T GE Signa Imaging System with Signa 5.4.3 software. SGPFC volumes were measured with the semi-automated software

MedX (Sensor Systems, Sterling, VA, USA). ANCOVA was performed to compare SGPFC volumes between groups, using

age, gender and intra-cranial volume (ICV) as covariates. The volumes (meanFS.D.) of the right and left SGPFC for bipolar

patients were 291.27F88.70 mm3 and 284.86F83.98 mm3, respectively. For healthy controls, the right and left SGPFC

volumes were 284.95F73.33 mm3 and 307.55F73.67 mm3, respectively. There were no statistically significant differences

between groups regarding right or left SGPFC volumes. We found no evidence of volumetric abnormalities in the SGPFC of

bipolar children and adolescents.

D 2004 Elsevier Ireland Ltd. All rights reserved.

Keywords: Neuroimaging; Prefrontal cortex; Bipolar disorder; Adolescents

0925-4927/$ - s

doi:10.1016/j.ps

* Correspon

Center at San A

E-mail addr

aging 138 (2005) 43–49

ee front matter D 2004 Elsevier Ireland Ltd. All rights reserved.

cychresns.2004.11.004

ding author. Division of Mood and Anxiety Disorders, Department of Psychiatry, The University of Texas Health Science

ntonio, 7703 Floyd Curl Drive, San Antonio, TX 78229, USA. Tel.: +1 210 5675492; fax: +1 210 5673759.

ess: soares@uthscsa.edu (J.C. Soares).

Table 1

Demographic characteristics, handedness and pubertal status of

bipolar patients and healthy controls

Variable Bipolar patients

(n=15)

Healthy controls

(n=21)

P

Age (years)a 15.5F3.5 16.9F3.8 0.277

Gender

Male 8 12

Female 7 9 0.821

Race

White 14 18

Black 1 3 0.473

Handedness

Left 3 1

Right 12 20 0.151

Pubertal statusb 3.7F1.4 3.9F0.9 0.748

Right SGPFC

(meanFS.D.)

291.44F91.81

mm3

284.95F73.33

mm3

0.59c

Left SGPFC

(meanFS.D.)

287.59F86.19

mm3

307.55F73.67

mm3

0.77c

ICV

(meanFS.D.)

1529.65F138.68

cm3

1479.81F162.51

cm3

0.25d

a Age is reported as meanFS.D.b Pubertal status was described according to the scores

(meanFS.D.) in the Pubertal Development Scale (Petersen et al.,

1988).c ANCOVA, with age, gender and ICV as covariates: F=0.291,

df=1/31 (right SGPFC) and F=0.085 (left SGPFC).d ANCOVA, with age and gender as covariates: F=1.369,

df=1/32.

M. Sanches et al. / Psychiatry Research: Neuroimaging 138 (2005) 43–4944

1. Introduction

Evidence from neuroimaging studies indicates that

the frontal lobe plays an important role in the

processing of emotions, as part of the neuronal

circuits involved in mood regulation (Soares and

Mann, 1997). The subgenual prefrontal cortex

(SGPFC) corresponds to the agranular anterior cingu-

late cortex immediately ventral to the genu of the

corpus callosum (Brodmann area 24). This sub-region

of the frontal lobe is connected to several structures of

the limbic system such as the amygdala, striatum and

specific thalamic nuclei (Drevets et al., 1998). Clinical

reports suggest that lesions in the SGPFC may bring

about behavioral abnormalities and mood dysregula-

tion in previously normal individuals (Damasio,

1997).

Recently, the SGPFC has been implicated in the

pathophysiology of mood disorders. Neuroimaging

and post-mortem studies demonstrated smaller gray

matter content in the SGPFC of adult familial cases of

unipolar depression and bipolar disorder compared

with healthy controls (Drevets et al., 1997; Ongur et

al., 1998). These results suggested that decreased

SGPFC volume may correspond to a biological

marker for familial mood disorder (Drevets et al.,

1997; Hirayasu et al., 1999; Ongur et al., 1998), even

though other studies were not able to replicate such

findings (Brambilla et al., 2002; Bremner et al., 2002).

It is not clear whether similar findings are present

in children and adolescents with mood disorders. A

single study (Botteron et al., 2002) reported decreased

left SGPFC volumes in female adolescents with

unipolar depression. Given the controversy regarding

the characterization of the clinical phenotypes of

bipolar disorder in young patients (Leibenluft et al.,

2003; Weckerly, 2002), the identification of consistent

neuroimaging findings could possibly have relevance

for the diagnosis and treatment of this illness. In

addition, the detection of prefrontal cortex volumetric

abnormalities among young patients could contribute

to a better understanding of the pathophysiology of

bipolar disorder, supporting a role for neurodevelop-

mental disruptions, since brain maturation processes

are particularly pronounced during adolescence

(Keshavan and Rosenberg, 1999).

We carried out a morphometric magnetic resonance

imaging (MRI) study of the SGPFC of children and

adolescents with bipolar disorder. We hypothesized

that the mean SGPFC volumes of bipolar patients

would be smaller than those of healthy controls.

2. Methods

2.1. Subjects

The sample consisted of 15 children and adoles-

cents who met DSM-IV criteria for bipolar disorder

(mean ageFSD=15.5F3.5 years; age range: 10–21

years; 8 males, 7 females; 11 bipolar type I, 3 bipolar

type II, 1 bipolar NOS) and 21 healthy controls (mean

ageFSD=16.9F3.8 years; age range: 11–21 years; 12

males, 9 females). There were no statistically signifi-

cant differences between patients and controls regard-

ing demographic characteristics, handedness and

pubertal status (Table 1).

The diagnosis of bipolar disorder in patients and

the absence of psychiatric disorders in healthy

M. Sanches et al. / Psychiatry Research: Neuroimaging 138 (2005) 43–49 45

controls was established through the Schedule for

Affective Disorders and Schizophrenia for School-

Age Children—Present and Lifetime Version (Kauf-

man et al., 1997); the Structured Clinical Interview for

DSM-IV (Spitzer et al., 1994) was used instead

subjects were 18 or older. Trained postdoctoral

fellows and study coordinators administered the

diagnostic instruments to the subjects and their

parents, and the results were reviewed by a senior

study psychiatrist. The information obtained was

supplemented by review of the patients’ medical

charts.

Exclusion criteria included mental retardation,

previous head trauma with loss of consciousness for

more than 1 h, and report of substance abuse during

the 6 months that preceded the interview.

Among the bipolar patients, 13 were euthymic

(Hamilton Depression Rating Scale score b8 and

Young Mania Rating Scale score b6) and 2 were

mildly depressed (Hamilton Depression Rating Scale

scores between 8 and 13). All reported a familial

history of mood disorders, defined as having a first-

degree relative who ever received a diagnosis of

unipolar or bipolar disorder. Thirteen patients were

receiving mood-stabilizing treatment for bipolar dis-

order (six on lithium, three on valproate and four on

lithium plus valproate). The doses of lithium ranged

from 675 to 1350 mg/day, and the blood levels from

0.4 to1.26 mEq/l. The doses of valproate ranged from

500 to 2000 mg/day, and the blood levels ranged from

10 to 150 Ag/ml. Ten patients reported previous use of

antipsychotic drugs.

The mean duration of the disease was 3.8 (S.D.=2.4,

median 4.5) years. Comorbid mental disorders were

found in seven patients and consisted of attention-

deficit/hypeactivity disorder (five subjects), opposi-

tional defiant disorder (one subject) and conduct

disorder (one subject). This study was approved by

the University of Pittsburgh Institutional Review

Board, and informed consent was obtained from all

subjects and their parents or legal representatives.

2.2. MRI procedure

MR images were obtained with a 1.5 T GE Signa

Imaging System running the program Signa 5.4.3

(General Electric Medical Systems, Milwaukee, WI)

at the University of Pittsburgh. Images were acquired

using 3D-gradient echo imaging (Spoiled Gradient

Recalled Acquisition) in the coronal plane (TR=25

ms, TE=5 ms, nutation angle=408, FOV=24 cm, slice

thickness=1.5 mm, NEX=1, matrix size=256�192). A

sagittal scout series was first obtained to verify the

position of the subject and to locate a midline sagittal

slice. A T1-weighted sagittal scout image was

obtained for graphic prescription of the coronal

images. To screen for neuroradiological abnormalities,

T2 and proton density images were obtained in the

axial plane. The 3D SPGR images were realigned to

the AC-PC line before volumetric measurements of

the SGPFC were performed.

2.3. SGPFC measurement

SGPFC measurements were obtained using the

semi-automated software MedX version 3.2 (Sensor

System, Sterling, VA). Manual tracing was performed

by a trained evaluator (intra-class correlation coef-

ficient r=0.92 for the right SGPFC and r=0.94 for the

left SGPFC), according to methods proposed by

Drevets et al. (1997). Likewise, intra-cranial volumes

(ICV) were obtained by another trained evaluator

(ICC=0.98) using the semi-automated software Scion

Image Beta-4.0.2 for Windows (Scion, Frederick,

MD, USA). The evaluators were blind to subjectsTdiagnosis and identity.

2.4. Anatomical landmarks

2.4.1. SGPFC

The gray matter of the gyrus immediately below

the corpus callosum was traced in the coronal plane,

after realigning the images along the anterior–poste-

rior commissure line (Fig. 1). Tracing started at the

most rostral slice where the corpus callosum could be

seen and continued to the slice anterior to the one

where the internal capsule no longer divided the

striatum. The tracing procedure was exactly as

previously reported (Brambilla et al., 2002).

2.4.2. ICV

The outer border of the brain was traced in the

coronal plane from the most anterior to the most

posterior slice that contained brain matter. Total

cerebral gray and white matter, cerebro-spinal fluid,

dura matter and sinuses were included in the tracing.

Fig. 1. Subgenual prefrontal cortex tracing. The SGPFC was

manually traced from the most rostral slice where corpus callosum

could be seen to the slice anterior to the one where the internal

capsule no longer divided the striatum.

M. Sanches et al. / Psychiatry Research: Neuroimaging 138 (2005) 43–4946

The brain stem and the left and right lobes of the

cerebellum were excluded.

2.5. Statistical analysis

Statistical analysis was done using Systat version

8.0 and SPSS for Windows, version 11.5 (SPSS,

Chicago). Analysis of covariance (ANCOVA) was

performed to compare the volumes of the SGPFC in

adolescents with bipolar disorder and healthy controls,

using age, gender and ICV as covariates. Subgroups

were compared using ANOVA or t-tests. The signifi-

cance level was set at 0.05.

3. Results

No statistically significant differences between

bipolar patients and healthy controls were found

regarding ICV and the mean volumes of right and left

SGPFC (Table 1). The differences between groups

remained non-significant after the untreated bipolar

patients and the patients with bipolar disorder type II

and NOS were excluded from the analysis (right

SGPFC: F=0.776, df=1/27, P=0.39; left SGPFC:

F=0.051, df=1/27, P=0.82; ICV: F=2.144, df=1/28,

P=0.15).

No patients reported use of antipsychotics during

the 2 weeks preceding the MRI. The SGPFC volumes

of bipolar patients who had ever received antipsy-

chotic medications were compared with volume of the

ones who had not. No statistically significant differ-

ences were found between these two groups (right

SGPFC: F=0.387, df=1/10, P=0.55; left SGPFC:

F=0.124, df=1/10, P=0.73). In addition, we compared

the SGPFC volumes of bipolar patients previously

treated with antipsychotics, not previously treated

with antipsychotics, and healthy controls. ANCOVA

did not reveal statistically significant differences (right

SGPFC: F=0.22, df=2/30, P=0.80; left SGPFC:

F=0.073, df=2/30, P=0.93).

Bipolar patients who were receiving treatment with

a mood stabilizer (lithium, valproate or both) were

also compared regarding their SGPFC volumes. No

differences were found among the three groups (right

SGPFC: F=0.86, df=2/7, P=0.46; left SGPFC:

F=1.47, df=2/7, P=0.29).

We also examined left to right asymmetry in

SGPFC measures in patients and controls, and there

were no significant differences (repeated measures

ANOVA: F=2.83, df=1/31, P=0.10).

4. Discussion

To our knowledge, this is the first study to focus on

the SGPFC volumes of pediatric bipolar patients. We

did not find statistically significant differences between

the SGPFC volumes of patients and healthy controls.

M. Sanches et al. / Psychiatry Research: Neuroimaging 138 (2005) 43–49 47

Few neuroimaging studies have examined children

and adolescents with bipolar disorder, and it is unclear

whether these patients present the same pattern of

morphometric differences found in adult ones. Our

results and prior literature in this area suggest that

bipolar disorder in childhood and adolescence may

represent a specific subtype with distinct neurobio-

logical mechanisms and clinical features compared

with adult-onset bipolar disorder (Weckerly, 2002).

Support for this hypothesis is provided by the clinical

atypicality of this disorder among children and

adolescents, as well as the high rates of comorbidity

of bipolar disorder and other mental disorders in

pediatric populations (Biederman et al., 2000).

Regarding MRI findings in adult patients, Drevets

et al. (1997) reported smaller left SGPFC volumes in

bipolar and unipolar patients compared with healthy

controls. The bipolar group included manic, depres-

sive and remitted patients, and all of them had a first

degree relative with bipolar disorder. These results

were partially replicated by Hirayasu et al. (1999),

who also described smaller left SGPFC volumes

among patients with first-episode affective psychosis

and a positive family history of mood disorders.

Significant differences were also found by Sharma et

al. (2003), who reported a significant reduction in the

right SGPFC of bipolar I patients compared with

healthy controls. On the other hand, our group

(Brambilla et al., 2002) compared the SGPFC

volumes of adult familial and non-familial bipolar

patients with those of healthy controls and found no

significant difference. Bremner et al. (2002) also did

not identify volumetric abnormalities in SGPFC in a

group of depressed unipolar patients.

There are few methodological differences between

our study and the ones that obtained positive results

in adult bipolar patients. The SGPFC measurement

method we used was the same one described in all

previous studies. Our methodology to obtain infor-

mation about family history of mood disorders also

was the same (directly questioning subjects and their

parents plus chart review). Our sample was larger

than that of Sharma et al. (2003), and slightly

smaller than those of Drevets et al. (1997) and

Hirayasu et al. (1999). A post hoc power analysis,

based in one of those studies (Hirayasu et al., 1999),

revealed that our sample size provided a power of

78% to detect similar differences. Nonetheless, given

the age range of our subjects, it is possible our

sample was too small to detect significant differences

because of the wide variation of developmental

stages of the nervous system during childhood and

adolescence. However, our patients and controls

were matched for stage of pubertal development, as

determined by the Pubertal Development Scale

(Petersen et al., 1988).

On the other hand, Drevets et al. (1997) and

Hirayasu et al. (1999) included patients whose illness

symptoms at the time of the MRI procedure were

markedly more severe than those of our sample. All

of our subjects were outpatients, and 13 of 15 were

euthymic. This issue should be considered in the

interpretation of our results. Nonetheless, the study

demonstrating significant differences in the right

SGPFC of bipolar patients (Sharma et al., 2003)

included only euthymic patients.

Further, we analyzed a relatively heterogeneous

group of bipolar children and adolescents, including

bipolar type I, II and NOS, with variable treatment

histories, which may have influenced our results.

Lithium and possibly other mood stabilizers are

thought to have protective and neurotrophic effects

on the brain in mood disorder patients (Manji et al.,

2000). Most of our patients were receiving a mood-

stabilizing drug, which may have reversed or

prevented decreases in SGPFC volumes. Drevets et

al. (1997) included treated and untreated bipolar

patients in their sample. Brambilla et al. (2002) did

not find significant differences between drug-free

and lithium-treated bipolar patients. Our analysis

comparing bipolar patients who were receiving

lithium, valproate or both did not detect statistically

significant differences across these three groups.

Nonetheless, our sample size, when subdivided,

resulted in small groups, and because of that, the

findings for this specific comparison should be

viewed with caution.

The use of antipsychotics can also bring about

changes in the volumes of brain structures (Chakos

et al., 1994; Selemon et al., 1999). All patients in the

study of Hirayasu et al. (1999) were receiving

antipsychotic medication. None of our patients

reported use of antipsychotics during the 2 weeks

preceding the MRI procedure, but several of them

had previously received antipsychotic treatment. In

order to examine the possible influence of antipsy-

M. Sanches et al. / Psychiatry Research: Neuroimaging 138 (2005) 43–4948

chotic use on our findings, we compared bipolar

patients with and without previous antipsychotic

therapy. We found neither statistically significant

differences between treated and untreated groups of

bipolar patients, nor between patients and healthy

controls.

Because childhood and adolescence are important

transitional phases regarding maturation of the

nervous system (Bartzokis et al., 2001; Giedd et

al., 1999), studies involving young psychiatric

patients may provide valuable information about

the role of neurodevelopmental processes in the

pathophysiology of mental disorders, as well as

about the timing of some brain abnormalities found

in adults (Friedman et al., 1999; Keshavan and

Rosenberg, 1999). This may be especially important

when frontal lobe abnormalities are considered, since

this brain region seems to show particularly impor-

tant changes between adolescence and early adult-

hood (Sowell et al., 1999). Even though Botteron et

al. (2002) described the same finding of decreased

left SGPFC volume among adolescents and middle-

aged women with unipolar depression, no similar

studies were carried out among bipolar patients.

Therefore, an alternative explanation to our negative

findings is that SGPFC abnormalities in bipolar

disorder may be observed late in the course of the

illness and cannot be found in its earliest phases.

Nonetheless, findings by Brambilla et al. (2002)

suggest that such abnormalities are only present in

severely ill patient samples.

In conclusion, the results of our study suggest no

abnormalities in the SGPFC of children and adoles-

cents with bipolar disorder. Future studies should

examine untreated patients and involve longitudinal

designs to compare the volumes of the SGPFC before

and after psychotropic treatment and across various

phases of the illness.

Acknowledgments

This work was partly supported by grants MH

01736, MH 55123, MH 30915 and MH 59929 from

the National Institute of Mental Health, NARSAD, the

Krus Endowed Chair in Psychiatry (The University of

Texas Health Science Center at San Antonio) and

CAPES Foundation (Brazil).

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