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Prefrontal Cortical Volume in Childhood-Onset Major Depression
Preliminary Findings
Carla L. Nolan;
Gregory J. Moore, PhD;
Rachel Madden;
Tiffany Farchione;
Marla Bartoi, PhD;
Elisa Lorch, MA;
Carol M. Stewart, RNC;
David R. Rosenberg, MD
Arch Gen Psychiatry. 2002;59:173-179.
ABSTRACT
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Background Abnormalities in the prefrontal cortex have been implicated in the pathogenesis
of major depressive disorder (MDD). To our knowledge, no prior study has examined
prefrontal cortical anatomy in pediatric patients with MDD near the onset
of illness before receiving treatment.
Methods Volumetric magnetic resonance imaging studies were conducted in 22 psychotropic-naive
patients with MDD, aged 9 to 17 years (10 males and 12 females), and 22 case-matched
healthy comparison control subjects. Twelve of the 22 patients with MDD had
at least 1 first-degree relative with MDD (familial MDD), whereas 10 had no
clear family history of MDD (nonfamilial MDD).
Results Patients with nonfamilial MDD had significantly larger left-sided but
not right-sided prefrontal cortical volumes than patients with familial MDD
(17% larger) and controls (11% larger). Left-sided and right-sided prefrontal
cortical volumes did not differ significantly between patients with familial
MDD and controls.
Conclusions These results provide new evidence of prefrontal cortical alterations
in pediatric MDD that may differ in familial and nonfamilial subtypes of MDD.
Our findings must be considered preliminary, however, in view of the small
sample size.
INTRODUCTION
MAJOR depressive disorder (MDD) is a severe, prevalent, and often chronically
disabling illness that is continuous with adult MDD.1
The lifetime prevalence of pediatric MDD is 15% to 20% consistent with reported
rates in adult patients with MDD.2-4
Investigations of younger patients with MDD can minimize potentially confounding
factors such as illness duration and treatment intervention and may begin
to clarify the contribution of neurodevelopmental abnormalities to the pathogenesis
of MDD.
The prefrontal cortex plays a critical role in mood regulation (see
Byrum et al5 for review). Abnormalities in
the prefrontal cortex have, therefore, been hypothesized to be involved in
causing depressive symptoms.6-8
The positive correlation between increased severity of depression in patients
with strokes and closeness of the lesion to the frontal pole9-10
combined with increased rates of MDD in patients with frontal lobe lesions11 provide indirect support for this hypothesis. More
direct evidence comes from functional neuroimaging studies in adult patients
with MDD who demonstrate prefrontal cortical (PFC) abnormalities associated
with severity of depression and treatment response.12-15
Dolan et al16 observed increased magnetic
resonance imaging (MRI) T1-weighted values in the frontal white matter of
patients with MDD but not bipolar disorder. Increased frontal lobe white matter
hyperintensities may be especially prominent in elderly patients with late-onset
MDD,17-19 particularly
those with underlying cerebrovascular disease originating from atherosclerotic
disease.18, 20-23
Krishnan et al24 noted decreased frontal brain
width in elderly patients with MDD vs control subjects. Coffey et al25 subsequently found a 7% reduction in the total frontal
lobe volume in 44 elderly patients with MDD referred for electroconvulsive
therapy vs controls. More recently, Kumar et al26-27
reported an overall decrease in frontal lobe volume and an increased number
of frontal lesions in elderly patients with depression. In contrast, Bremner
et al28 found no significant differences in
frontal lobe volumes in younger adult patients with MDD (mean age, 43 years)
in remission from antidepressant treatment compared with controls. Steingard
et al,29 however, observed decreased frontal
lobe– cerebral volume ratios in adolescent patients with MDD compared
with healthy controls.
Postmortem investigation of the prefrontal cortex30
has identified reduced neuronal and glial densities in the prefrontal cortex
of patients with MDD compared with controls. In vivo neuroimaging studies
in adult patients with MDD and bipolar disorder have identified reductions
in left-sided PFC gray matter volumes associated with reduced cerebral blood
flow in this region.14 These abnormalities
were most prominent in patients with MDD and bipolar disorder with at least
1 first-degree relative with MDD or bipolar disorder but were not observed
in patients with MDD and bipolar disorder without at least 1 first-degree
relative with MDD or bipolar disorder. In a related postmortem histological
study, Ongur et al31 observed a reduction in
glial number in the prefrontal cortex in familial but not nonfamilial MDD
and bipolar disorder.
Twenty percent to 46% of the patients with MDD have a first-degree relative
with MDD with an inverse relationship between age of onset of MDD and density
of familial loading of MDD.32-47
Although MDD commonly emerges during childhood and adolescence, to our knowledge,
no prior brain imaging study has examined patients with MDD near-illness onset,
before exposure to psychotropic medication. Studying this population helps
minimize potential confounders of illness duration and medication treatment.48-50 The prefrontal cortex,
a primary site of metabolic abnormality in MDD,12, 14-15
undergoes substantial developmental changes during childhood and adolescence.
Therefore, we performed a volumetric MRI study in pediatric patients with
MDD, focusing on the prefrontal cortex. We hypothesized reduced left-sided
but not right-sided PFC volumes in familial patients with MDD compared with
both nonfamilial patients with MDD and healthy comparison subjects.
SUBJECTS AND METHODS
SUBJECTS
Twenty-two right hand–dominant, psychotropic-naive patients with
MDD, aged 9 to 17 years (10 males and 12 females), and 22 healthy controls
matched pairwise for age, sex, weight, and height were recruited. Mean (±SD)
age of onset of the first clinical presentation in the patients with MDD was
12.18 ± 2.68 years. Patients and controls were matched within a maximum
of 12.96 months of each other (mean age, 5.58 ± 3.7 months). Patients
were recruited after being referred to the Wayne State University Child Psychiatry
outpatient clinic, Detroit, Mich. Controls were referred by pediatricians
and school and community groups. Both patients and controls were paid an honorarium
for their participation in this clinical research study. The Schedule for
Affective Disorders and Schizophrenia for School-Age Children–Present
and Lifetime Version (K-SADS-PL)51 was administered
to all subjects and their parent(s). A board-certified pediatric psychiatrist
(D.R.R.) reviewed all clinical information and confirmed DSM-IV52 diagnostic criteria as well
as associated medical or neurologic conditions. Exclusion criteria included
lifetime history of psychosis, bipolar disorder, obsessive-compulsive disorder,
anorexia or bulimia nervosa, posttraumatic stress disorder, substance abuse
or dependence, Tourette syndrome or other tic-related conditions, autism,
mental retardation or learning disabilities, or significant medical or neurologic
conditions. Of the 22 patients, 7 had comorbid anxiety disorders, 4 had oppositional
defiant disorder, 2 had attention-deficit disorder without hyperactivity,
1 had dysthymia, and 9 had MDD as their sole diagnosis. As determined by Family
History–Research Diagnostic Criteria,53
12 patients had at least 1 first-degree relative with MDD. No patients had
a first-degree relative with bipolar disorder. Controls had no history of
psychiatric illness and no family history of a DSM-IV52 Axis I disorder. Written informed consent was obtained
from all parents or legal guardians and written assent was obtained from all
children prior to initiating the study in compliance with the regulations
of the Wayne State University Pediatric Human Investigation Committee.
ASSESSMENTS
Depression symptom severity was measured by the Childhood Depression
Rating Scale-Revised54 (mean ± SD score,
57.27 ± 8.64). All patients had a Childhood Depression Rating Scale-Revised
score of at least 42, indicative of significant dysfunction. Severity of anxiety
was also assessed with the Hamilton Anxiety Rating Scale55
(mean ± SD score, 12.41 ± 8.07). A score of 14 or higher is
considered clinically significant.56 A screening
neuropsychological examination revealed no abnormalities and no significant
differences between patients with MDD and controls in general intelligence
as measured by the Ammons Quick IQ Test,57
motor coordination assessed with the Grooved Pegboard Test,58
attention measured with the Digit Span scaled score from the Wechsler Intelligence
Scale for Children59 or handedness measured
by the Annett Behavioral Handedness Index.60
One patient with MDD was unable to complete the neuropsychological screening
because of severity of illness.
MRI ACQUISITION AND ANALYSIS
The MRI studies were conducted with a 1.5-T (version 5.7; GE Signa;
General Electric, Milwaukee, Wis) magnetic resonance system (General Electric).
Image acquisition and analysis are described in detail in our prior reports.50, 61 Briefly, a sagittal scout series
was obtained to test image quality and clarity. A 3-dimensional spoiled gradient
echo-pulse sequence obtained one hundred twenty-four 1.5-mm-thick coronal
contiguous slices through the entire brain, perpendicular to the anterior
commisure–posterior commisure line (echo time, 5 milliseconds; repetition
time, 25 milliseconds; acquisition matrix, 256 x 256 pixels; field of
view, 24 cm; and flip angle, 10°). Positioning was done by the magnetic
resonance technologist under the supervision of an expert in these procedures
(G.J.M.). Measurement of the "tilt" in the axial plane (relative to the long
axis of the magnet) was conducted to determine whether the degree of tilt
in patients with MDD and controls differed. No significant differences were
observed between the 2 groups. All MRI scans were reviewed to rule out clinically
significant abnormalities. Scans with motion artifact (n = 1) were excluded
from analysis. Thus, 22 case-control pairs were analyzed. Images were exported
from the MRI unit to a computer workstation (MacIntosh Personal Computer;
Apple Computer, Cupertino, Calif).
Anatomical boundaries (detailed definitions are available on request)
were determined from neuroanatomical atlases62-63
and adapted from previously published psychiatric neuroimaging studies of
the prefrontal cortex.61, 64-66
Measurement of intracranial volume is described elsewhere.61
Anatomical data were measured with National Institute of Health image software
(version 1.61),67 a semiautomated segmentation
algorithm for obtaining reliable quantitative neuroanatomical measurements.68-69 This semiautomated segmentation algorithm
measured regions of interest from coronal scans using 3-dimensional, spoiled
gradient, recalled acquisitions in the steady state. Mathematical cutoffs
for gray matter–white matter–cerebrospinal fluid divisions were
determined with histograms of signal intensity. Validation of this method
by a point-counting stereological approach based on the Cavalieri theorem
of systematic sampling70 has been achieved.
Both methods have documented validity and sensitivity with high correlations
(r = 0.96).69
Left and right PFC regions were measured separately. The most anterior
coronal slice containing gray matter served as the anterior boundary, while
the genu of the corpus callosum marked the posterior boundary (Figure 1). Separate measurements for gray and white matter were
obtained from each slice. Total gray and white matter combined represented
total PFC volume.
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Representative multislice composite series of coronal images demonstrating
the boundaries delineating measurement of prefrontal cortical volume.
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Measurements of prefrontal cortex and intracranial volume were made
in a single batch by a single well-trained and reliable rater (R.M.) blind
to any identifying clinical information. Interrater and intrarater reliability
(C.N. and R.M.) for PFC (0.99) and intracranial volume (0.97-0.99) were high.
DATA ANALYSIS
We conducted analyses of covariance (ANCOVAs) with age and intracranial
volume as covariates, and the Scheffé post hoc tests to examine for
significant differences among diagnostic groups. We also examined for differences
in left-sided and right-sided PFC volumes testing for the interaction of laterality
with group. The ANCOVAs with age as a covariate were used to test for differences
in intracranial volume between patients with MDD and controls. Independent t tests were used to compare patients with MDD and controls
on neuropsychologic screening measures, head tilt, age, height, and weight.
All analyses were conducted using SPSS software.71
Two-tailed significance is reported throughout, with statistical significance
defined as P<.05.
RESULTS
Intracranial volume and left- and right-sided PFC volumes did not differ
significantly between the 22 MDD case-control pairs (Table 1). The ANCOVA with age and intracranial volume as covariates
revealed significant intergroup differences in left-sided but not right-sided
total PFC volume or prefrontal gray and white matter volumes (Table 2). Post hoc tests revealed that patients with nonfamilial
MDD had larger left-sided but not right-sided total PFC volumes and prefrontal
white matter volumes than both patients with familial MDD and controls. Left-
and right-sided total PFC white matter and gray matter volumes did not differ
between patients with familial MDD and controls. Left-sided PFC gray matter
volumes were smaller in patients with familial MDD than in patients with nonfamilial
MDD. Intracranial volume did not differ among patients with familial MDD,
patients with nonfamilial MDD, and controls. Significant inverse correlations
were observed in patients with familial MDD between severity of MDD as measured
by the Childhood Depression Rating Scale-Revised and total left-sided PFC
volume (r = -0.66, P
= .03), left-sided prefrontal gray matter (r = -
0.67, P = .023) but not left-sided prefrontal white
matter volume. Although not statistically significant, longer illness duration
tended to be inversely correlated with reduced total left-sided PFC volume
(r = -0.57, P = .07),
left-sided prefrontal gray matter (r = -0.58, P = .06) but not left-sided PFC white matter. Illness duration
and severity were not associated with PFC volumes in patients with nonfamilial
MDD. Comparable ages were observed in male (13.43 ± 2.70 years) and
female patients (13.90 ± 2.26 years) with MDD. No sex-related differences
were noted in PFC and intracranial volumes between patients with MDD and controls.
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Table 1. Volumetric Results for Treatment-Naive Patients With MDD and
Healthy Control Subjects*
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Table 2. Volumetric Results for Patients With Familial and Nonfamilial
MDD and Healthy Comparison Subjects*
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Assessment of group by side (left-right) interactions for PFC volume
revealed a significant group effect (F2,87 = 4.35, P = .02) and a significant interaction with side (F1,87
= 11.06, P = .001). Although there was a significant
hemisphere difference in mean PFC volume, the magnitude of difference varied
across group so that the interaction, while present, was a weak interaction
given no crossover of the mean PFC values (F2,87 = 0.84, P = .44).
COMMENT
Alterations in left-sided PFC volume were most prominent in patients
with nonfamilial MDD who had larger left-sided PFC volumes than both patients
with familial MDD (17%) and controls (11%). This hypothesis-driven, preliminary
investigation failed to replicate in vivo neuroimaging14
and postmortem investigation31 in adult patients
with MDD and bipolar disorder that found reductions in left-sided prefrontal
gray matter volumes, cerebral blood flow, and glial number in patients with
at least 1 first-degree relative with MDD compared with both controls and
patients without at least 1 first-degree relative with MDD or bipolar disorder.
Our study provides new data about distinct differences in PFC anatomy in patients
with familial and nonfamilial MDD without the confounders of central nervous
system–active medications and with less potential influence of disease
progression. Specifically, abnormalities in PFC anatomy may be associated
with the clinical presentation of MDD, and this pathological involvement may
be an early and central neurobiological deficit in the illness.
The association of reduced left-sided PFC volume with increased depressive
symptom severity in patients with familial MDD but not nonfamilial MDD may
reflect a continuum of illness in which reduction of left-sided PFC volume
increases with increased severity of illness and duration of illness. The
results of this study, as well as studies in adult patients with MDD demonstrating
that PFC abnormalities are most prominent in patients with a clear family
history of MDD or bipolar disorder14, 31, 72
suggest that prefrontal volume reduction in patients with familial MDD may
reflect left-sided PFC degeneration. Increased left-sided PFC volume in treatment-naive
pediatric patients with nonfamilial MDD may, in contrast, reflect abnormal
PFC maturation. These arguments must be considered speculative, however. Our
division of patients with MDD into familial and nonfamilial MDD was arbitrary
and does not consider patients with several relatives (eg, grandparents) who
have MDD. Future studies with more precise delineation of familial and nonfamilial
subtypes of MDD are clearly warranted.
It is possible that comorbid disorders associated with familial and
nonfamilial patients with MDD might have a differential influence on brain
anatomy and potentially confound results in this study. Seven of the 12 patients
with familial MDD had comorbid DSM-IV Axis I psychiatric
disorders, while 7 of the 10 patients with nonfamilial MDD had comorbid disorders.
Comorbid anxiety disorders were also comparable in both groups (5 patients
with familial MDD and 3 patients with nonfamilial MDD). However, all 3 patients
with oppositional defiant disorder were patients with nonfamilial MDD. Patients
with nonfamilial MDD had significantly larger left-sided PFC volumes compared
with both patients with familial MDD and controls. Major depressive disorder
with comorbid oppositional defiant disorder could, therefore, represent a
discrete subtype of MDD with a differential influence on brain anatomy. The
small sample size in the present study precludes more definitive conclusions
but merits further investigation since MDD is commonly associated with comorbid
psychiatric conditions.32-33
Consistent with neuroimaging studies in adult patients with MDD,14 we observed greater alterations in left than right-sided
PFC volumes in treatment-naive pediatric patients with MDD. Although definitive
conclusions regarding laterality and depression cannot be made at this time,
a recent review of the literature8 found that
left hemisphere lesions were more frequently associated with depression, while
right hemisphere lesions were more commonly associated with mania.
To our knowledge, our study is the first to report increased left-sided
PFC white matter volumes in patients with nonfamilial MDD compared with both
patients with familial MDD and controls. Drevets et al14
did not report PFC white matter volumes in their sample of adult patients
with MDD and bipolar disorder. This may have important implications in the
pathogenesis of MDD since white matter plays a critical role in signal conduction
and neurotransmission. Prefrontal cortical white matter lesions and abnormalities
have been reported in adult patients with MDD and bipolar disorder.16-19 The
prefrontal cortex distributes terminal fibers through white matter to the
hippocampus, a component of the limbic system that plays a particularly critical
role in emotion.73-75
Alterations in hippocampal volumes have been reported in adults with MDD.76-78
Many brain regions have been implicated in the neuroanatomy of MDD.6-8 Our findings suggest
that the relevant brain circuits underlying the pathophysiology of pediatric
MDD likely include the prefrontal cortex with distinct patterns in pediatric
patients with familial vs nonfamilial MDD. However, it is likely that several
other regions and abnormalities in regional interaction are involved in the
pathogenesis of this heterogeneous and complex disorder. Our findings are
preliminary in view of the small sample size and require replication in a
separate, larger cohort before more definitive conclusions can be drawn. In
vivo neuroimaging14, 64 and postmortem
investigations31 in adult patients with MDD
have focused on specific subdivisions of the prefrontal cortex (eg, subgenual
region) where volumetric reductions as high as 40% have been observed.13-15 Such an approach
may identify subtle localized region-specific alterations in PFC volume. Thus,
future neuropathological as well as in vivo neuroimaging studies are critical
to examine subdivisions of the prefrontal cortex as well as other brain regions
including the amygdala, hippocampus, and basal ganglia that may also be involved
in the pathogenesis of pediatric MDD.6-8
Recent studies also suggest the feasibility of investigating PFC function
and chemistry in vivo using functional14 and
spectroscopic imaging techniques.79-80
These studies must control for potential neuroanatomical differences and subtypes
of illness (eg, familial vs nonfamilial) for appropriate data interpretation.
Given the evidence that PFC function continues to develop throughout adolescence
into early adulthood,81-83
studies of prefrontal cortex in MDD may help to identify critical windows
for treatment intervention. Studies in children at high risk for developing
MDD may also be helpful given recent neuroendocrine studies demonstrating
abnormalities in this population.84
AUTHOR INFORMATION
Accepted for publication August 13, 2001.
This work was supported in part by the National Alliance for Research
on Schizophrenia and Depression, Great Neck, NY (Dr Rosenberg); the Miriam
L. Hamburger Endowed Chair at Children's Hospital of Michigan, Detroit (Dr
Rosenberg) and Wayne State University, Detroit; the State of Michigan Joe
F. Young, Sr, Psychiatric Research and Training Program, Lansing, Mich; and
grants MH01372, MH59299, MH65122, and MH02037 from the National Institute
of Mental Health, Bethesda, Md (Dr Rosenberg).
We are grateful to Perry Renshaw, MD, PhD, Wayne Drevets, MD, Ranga
Krishan, MD, and David A. Lewis, MD, for their consultation on these data,
to Joel Ager, PhD, and Ronald Thomas, PhD, for statistical consultation, and
to Valerie Felder for assistance with manuscript production.
Reprints: David R. Rosenberg, MD, Psychiatry 9B, 4201 St Antoine
Blvd, Detroit, MI 48201, (e-mail: drosen{at}med.wayne.edu).
From the Departments of Psychiatry and Behavioral Neurosciences (Mss
Nolan, Madden, Farchione, Lorch, and Stewart and Drs Moore, Bartoi, and Rosenberg),
Radiology (Dr Moore), and Pediatrics (Dr Rosenberg), Wayne State University
School of Medicine, Detroit, Mich.
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