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Original Article |

Prefrontal Cortical Volume in Childhood-Onset Major Depression:  Preliminary Findings FREE

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
[+] Author Affiliations

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.


Arch Gen Psychiatry. 2002;59(2):173-179. doi:10.1001/archpsyc.59.2.173.
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Published online

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.

Figures in this Article

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.24 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.68 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.1215

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,1719 particularly those with underlying cerebrovascular disease originating from atherosclerotic disease.18,2023 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 least1 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.3247 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.4850 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

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 was12.18 ± 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,5312 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 × 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.61,6466 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.

Place holder to copy figure label and caption

Representative multislice composite series of coronal images demonstrating the boundaries delineating measurement of prefrontal cortical volume.

Graphic Jump Location

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.

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.

Table Graphic Jump LocationTable 1. Volumetric Results for Treatment-Naive Patients With MDD and Healthy Control Subjects*
Table Graphic Jump LocationTable 2. Volumetric Results for Patients With Familial and Nonfamilial MDD and Healthy Comparison Subjects*

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).

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.1619 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.7375 Alterations in hippocampal volumes have been reported in adults with MDD.7678

Many brain regions have been implicated in the neuroanatomy of MDD.68 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.1315 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.68 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,8183 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

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@med.wayne.edu).

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Chakos  MHLieberman  JABilder  RM Increase in caudate nuclei volumes of first-episode schizophrenic patients taking antipsychotic drugs. Am J Psychiatry. 1994;1511430- 1436
Gilbert  ARMoore  GJKeshavan  MSPaulson  LANarula  VMac Master  FPStewart  CMRosenberg  DR Decrease in thalamic volumes of pediatric patients with obsessive-compulsive disorder taking paroxetine. Arch Gen Psychiatry. 2000;57449- 456
Link to Article
Kaufman  JBirmaher  BBrent  DRao  UFlynn  CMoreci  PWilliamson  DRyan  N Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime Version (K-SADS-PL): initial reliability and validity data. J Am Acad Child Adolesc Psychiatry. 1997;36980- 988
Link to Article
American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition.  Washington, DC American Psychiatric Association1994;
Andreasen  NEndicott  JSpitzer  RLWinokur  G The family history method using diagnostic criteria: reliability and validity. Arch Gen Psychiatry. 1977;341229- 1335
Link to Article
Poznanski  EOFreman  LNMokros  HB Childhood Depression Rating Scale-Revised. Psychopharmacol Rev. 1985;21979- 989
Hamilton  M The assessment of anxiety states by rating. Br J Med Psychol. 1959;3250- 55
Link to Article
Kobak  KAReynolds  WMGreist  JH Development and validation of a computer-administered version of the Hamilton Anxiety Scale. Psychol Assess. 1993;5487- 492
Link to Article
Ammons  RBAmmons  CH Ammons Quick I.Q. Test.  New York, NY Psychological Test Specialists1962;
Knights  RMNorwood  J Revised Smoothed Normative Data on the Neuropsychological Test Battery for Children.  Ottawa, Ontario Carleton University1980;
Wechsler  D Wechsler Intelligence Scale for Children. 3rd New York, NY Psychological Corp1991;
Annett  M The binomial distribution of right, mixed and left handedness. Q J Exp Psychol. 1967;19327- 333
Link to Article
Rosenberg  DRKeshavan  MSO'Hearn  KMDick  ELBagwell  WWSeymour  ABMontrose  DMPierri  JNBirmaher  B Frontostriatal measurement of treatment-naive pediatric obsessive-compulsive disorder. Arch Gen Psychiatry. 1997;54824- 830
Link to Article
Daniels  DLHaughton  VMNaidich  TP Cranial and Spinal Magnetic Resonance Imaging: An Atlas and Guide.  New York, NY Raven Press1987;
Talairach  JTournoux  P Co-Planar Stereotaxic Atlas of the Human Brain.  New York, NY Thieme-Stratton Inc1988;
Hirayasu  YShenton  MESalisbury  DFKwon  JSWible  CGFischer  IAYurgelun-Todd  DZarate  CKikinis  RJolesz  FAMcCarley  RW Subgenual cingulate cortex volume in first-episode psychosis. Am J Psychiatry. 1999;1561091- 1093
Giedd  JNSnell  JWLange  NRajapakse  JCCasey  BJKozuch  PLVaituzis  ACVauss  YCHamburger  SDKaysen  DRapoport  JL Quantitative magnetic resonance imaging of human brain development: ages 4-18. Cereb Cortex. 1996;6551- 560
Link to Article
Kumra  SGiedd  JNVaituzis  ACJacobsen  LKMcKenna  KBedwell  JHamburger  SNelson  JELenane  MRapoport  JL Childhood-onset psychotic disorders: magnetic resonance imaging of volumetric differences in brain structure. Am J Psychiatry. 2000;1571467- 1474
Link to Article
Rasband  W NIH Image Manual.  Bethesda, Md National Institutes of Health1996;
Keshavan  MSBeckwith  CBagwell  WPettegrew  JKrishnan  KRR An objective method for edge detection in MRI morphometry. Eur Psychiatry. 1994;9205- 207
Keshavan  MSAnderson  SBeckwith  CNash  KPettegrew  JWKrishnan  KR A comparison of stereology and segmentation techniques for volumetric measurements of lateral ventricles in magnetic resonance imaging. Psychiatry Res. 1995;6153- 60
Link to Article
Cavalieri  B Geomerta degli indivisibli.  Torino, Italy Unione Tipografico Editrice1966;
 SPSS Base 10.0 for Windows.  Chicago, Ill SPSS Inc2000;
Drevets  WCOngur  DPrice  JL Neuroimaging abnormalities in the subgenual prefrontal cortex: implications for the pathophysiology of familial mood disorders. Mol Psychiatry. 1998;3220- 226190- 191
Link to Article
Papez  JW A proposed mechanism of emotion. Arch Neurol Psychiatry. 1937;38725- 743
Link to Article
Halgren  EWalter  RDCherlow  DGCrandall  PH Mental phenomena evoked by electrical stimulation of the human hippocampal formation and amygdala. Brain. 1978;10183- 117
Link to Article
Nolte  J Olfactory and Limbic Systems.  St Louis, Mo Mosby–Year Book Inc1993;
Bremner  JDNarayan  MAnderson  ERStaib  LHMiller  HLCharney  DS Hippocampal volume reduction in major depression. Am J Psychiatry. 2000;157115- 118
Link to Article
Sheline  YIWang  PWGado  MHCsernansky  JGVannier  MW Hippocampal atrophy in recurrent major depression. Proc Natl Acad Sci U S A. 1996;933908- 3913
Link to Article
Sheline  YISanghavi  MMintun  MAGado  MH Depression duration but not age predicts hippocampal volume loss in medically healthy women with recurrent major depression. J Neurosci. 1999;195034- 5043
Auer  DPPutz  BKraft  ELipinski  BSchill  JHolsboer  F Reduced glutamate in the anterior cingulate cortex in depression: an in vivo proton magnetic resonance spectroscopy study. Biol Psychiatry. 2000;47305- 313
Link to Article
Winsberg  MESachs  NTate  DLAdalsteinsson  ESpielman  DKetter  TA Decreased dorsolateral prefrontal N-acetyl aspartate in bipolar disorder. Biol Psychiatry. 2000;47475- 481
Link to Article
Goldman-Rakic  PSBrown  RM Postnatal development of monoamine content and synthesis in the cerebral cortex of rhesus monkeys. Brain Res. 1982;256339- 349
Link to Article
Huttenlocher  PR Synaptic density in human frontal cortex: developmental changes and effects of aging. Brain Res. 1979;163195- 205
Link to Article
Rosenberg  DRLewis  DA Postnatal maturation of the dopaminergic innervation of monkey prefrontal and motor cortices: a tyrosine hydroxylase immunohistochemical analysis. J Comp Neurol. 1995;358383- 400
Link to Article
Birmaher  BDahl  REWilliamson  DEPerel  JMBrent  DAAxelson  DAKaufman  JDorn  LDStull  SRao  URyan  ND Growth hormone secretion in children and adolescents at high risk for major depressive disorder. Arch Gen Psychiatry. 2000;57867- 872
Link to Article

Figures

Place holder to copy figure label and caption

Representative multislice composite series of coronal images demonstrating the boundaries delineating measurement of prefrontal cortical volume.

Graphic Jump Location

Tables

Table Graphic Jump LocationTable 1. Volumetric Results for Treatment-Naive Patients With MDD and Healthy Control Subjects*
Table Graphic Jump LocationTable 2. Volumetric Results for Patients With Familial and Nonfamilial MDD and Healthy Comparison Subjects*

References

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Bremner  JDRandall  PVermetten  EStaib  LBronen  RAMazure  CCapelli  SMcCarthy  GInnis  RBCharney  DS Magnetic resonance imaging-based measurement of hippocampal volume in posttraumatic stress disorder related to childhood physical and sexual abuse: a preliminary report. Biol Psychiatry. 1997;4123- 32
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Steingard  RJRenshaw  PFYurgelun-Todd  DAppelmans  KELyoo  IKShorrock  KLBucci  JPCesena  MAbebe  DZurakowski  DPoussaint  TYBarnes  P Structural abnormalities in brain magnetic resonance images of depressed children. J Am Acad Child Adolesc Psychiatry. 1996;35307- 311
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Rajkowska  GMiguel-Hidalgo  JJWei  JDilley  GPittman  SDMeltzer  HYOverholser  JCRoth  BLStockmeier  CA Morphometric evidence for neuronal and glial prefrontal cell pathology in major depression. Biol Psychiatry. 1999;451085- 1098
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Birmaher  BRyan  NDWilliamson  DEBrent  DAKaufman  JDahl  REPerel  JNelson  B Childhood and adolescent depression, I: a review of the past 10 years. J Am Acad Child Adolesc Psychiatry. 1996;351427- 1439
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Birmaher  BRyan  NDWilliamson  DEBrent  DAKaufman  J Childhood and adolescent depression, II: a review of the past 10 years. J Am Acad Child Adolesc Psychiatry. 1996;351575- 1583
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Kutcher  SPMarton  P Affective disorders in first-degree relatives of adolescent onset bipolar, unipolar, and normal controls. J Am Acad Child Adolesc Psychiatry. 1991;3075- 78
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Livingston  RNugent  HRader  LSmith  GR Family histories of depressed and severely anxious children. Am J Psychiatry. 1985;1421497- 1499
Mitchell  JMcCauley  EBurke  PCalderon  RSchloredt  K Psychopathology in parents of depressed children and adolescents. J Am Acad Child Adolesc Psychiatry. 1989;28352- 357
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Puig-Antich  JGoetz  DDavies  MKaplan  TDavies  SOstrow  LAsnis  LTwomey  JIyengar  SRyan  ND A controlled family history study of prepubertal major depressive disorder[review]. Arch Gen Psychiatry. 1989;46406- 418
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Strober  M Familial aspects of depressive disorders in early adolescence.  Washington, DC American Psychiatric Press1984;
Todd  RDNeuman  RGeller  BFox  LWHickok  J Genetic studies of affective disorders: should we be starting with childhood onset probands? J Am Acad Child Adolesc Psychiatry. 1993;321164- 1171
Link to Article
Williamson  DERyan  NDBirmaher  BDahl  REKaufman  JRao  UPuig-Antich  J A case-control family history study of depression in adolescents. J Am Acad Child Adolesc Psychiatry. 1995;341596- 1607
Link to Article
Gershon  ESHamovit  JGuroff  JJDibble  ELeckman  JFSceery  WTargum  SDNurnberger  JI  JrGoldin  LRBunney  WE  Jr A family study of schizoaffective, bipolar I, bipolar II, unipolar, and normal control probands. Arch Gen Psychiatry. 1982;391157- 1167
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Tsuang  MTFaraone  SVFleming  JA Familial transmission of major affective disorders: is there evidence supporting the distinction between unipolar and bipolar disorders? Br J Psychiatry. 1985;146268- 271
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Weissman  MMKidd  KKPrusoff  BA Variability in rates of affective disorders in relatives of depressed and normal probands. Arch Gen Psychiatry. 1982;391397- 1403
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Weissman  MMLeckman  JFMerikangas  KRGammon  GDPrusoff  BA Depression and anxiety disorders in parents and children: results from the Yale family study. Arch Gen Psychiatry. 1984;41845- 852
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Weissman  MMWickramaratne  PMerikangas  KRLeckman  JFPrusoff  BACaruso  KAKidd  KKGammon  GD Onset of major depression in early adulthood: increase in familial loading and specificity. Arch Gen Psychiatry. 1984;411136- 1143
Link to Article
Keshavan  MSBagwell  WWHaas  GLSweeney  JASchooler  NRPettegrew  JW Changes in caudate volume with neuroleptic treatment. Lancet. 1994;3441434
Link to Article
Chakos  MHLieberman  JABilder  RM Increase in caudate nuclei volumes of first-episode schizophrenic patients taking antipsychotic drugs. Am J Psychiatry. 1994;1511430- 1436
Gilbert  ARMoore  GJKeshavan  MSPaulson  LANarula  VMac Master  FPStewart  CMRosenberg  DR Decrease in thalamic volumes of pediatric patients with obsessive-compulsive disorder taking paroxetine. Arch Gen Psychiatry. 2000;57449- 456
Link to Article
Kaufman  JBirmaher  BBrent  DRao  UFlynn  CMoreci  PWilliamson  DRyan  N Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime Version (K-SADS-PL): initial reliability and validity data. J Am Acad Child Adolesc Psychiatry. 1997;36980- 988
Link to Article
American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition.  Washington, DC American Psychiatric Association1994;
Andreasen  NEndicott  JSpitzer  RLWinokur  G The family history method using diagnostic criteria: reliability and validity. Arch Gen Psychiatry. 1977;341229- 1335
Link to Article
Poznanski  EOFreman  LNMokros  HB Childhood Depression Rating Scale-Revised. Psychopharmacol Rev. 1985;21979- 989
Hamilton  M The assessment of anxiety states by rating. Br J Med Psychol. 1959;3250- 55
Link to Article
Kobak  KAReynolds  WMGreist  JH Development and validation of a computer-administered version of the Hamilton Anxiety Scale. Psychol Assess. 1993;5487- 492
Link to Article
Ammons  RBAmmons  CH Ammons Quick I.Q. Test.  New York, NY Psychological Test Specialists1962;
Knights  RMNorwood  J Revised Smoothed Normative Data on the Neuropsychological Test Battery for Children.  Ottawa, Ontario Carleton University1980;
Wechsler  D Wechsler Intelligence Scale for Children. 3rd New York, NY Psychological Corp1991;
Annett  M The binomial distribution of right, mixed and left handedness. Q J Exp Psychol. 1967;19327- 333
Link to Article
Rosenberg  DRKeshavan  MSO'Hearn  KMDick  ELBagwell  WWSeymour  ABMontrose  DMPierri  JNBirmaher  B Frontostriatal measurement of treatment-naive pediatric obsessive-compulsive disorder. Arch Gen Psychiatry. 1997;54824- 830
Link to Article
Daniels  DLHaughton  VMNaidich  TP Cranial and Spinal Magnetic Resonance Imaging: An Atlas and Guide.  New York, NY Raven Press1987;
Talairach  JTournoux  P Co-Planar Stereotaxic Atlas of the Human Brain.  New York, NY Thieme-Stratton Inc1988;
Hirayasu  YShenton  MESalisbury  DFKwon  JSWible  CGFischer  IAYurgelun-Todd  DZarate  CKikinis  RJolesz  FAMcCarley  RW Subgenual cingulate cortex volume in first-episode psychosis. Am J Psychiatry. 1999;1561091- 1093
Giedd  JNSnell  JWLange  NRajapakse  JCCasey  BJKozuch  PLVaituzis  ACVauss  YCHamburger  SDKaysen  DRapoport  JL Quantitative magnetic resonance imaging of human brain development: ages 4-18. Cereb Cortex. 1996;6551- 560
Link to Article
Kumra  SGiedd  JNVaituzis  ACJacobsen  LKMcKenna  KBedwell  JHamburger  SNelson  JELenane  MRapoport  JL Childhood-onset psychotic disorders: magnetic resonance imaging of volumetric differences in brain structure. Am J Psychiatry. 2000;1571467- 1474
Link to Article
Rasband  W NIH Image Manual.  Bethesda, Md National Institutes of Health1996;
Keshavan  MSBeckwith  CBagwell  WPettegrew  JKrishnan  KRR An objective method for edge detection in MRI morphometry. Eur Psychiatry. 1994;9205- 207
Keshavan  MSAnderson  SBeckwith  CNash  KPettegrew  JWKrishnan  KR A comparison of stereology and segmentation techniques for volumetric measurements of lateral ventricles in magnetic resonance imaging. Psychiatry Res. 1995;6153- 60
Link to Article
Cavalieri  B Geomerta degli indivisibli.  Torino, Italy Unione Tipografico Editrice1966;
 SPSS Base 10.0 for Windows.  Chicago, Ill SPSS Inc2000;
Drevets  WCOngur  DPrice  JL Neuroimaging abnormalities in the subgenual prefrontal cortex: implications for the pathophysiology of familial mood disorders. Mol Psychiatry. 1998;3220- 226190- 191
Link to Article
Papez  JW A proposed mechanism of emotion. Arch Neurol Psychiatry. 1937;38725- 743
Link to Article
Halgren  EWalter  RDCherlow  DGCrandall  PH Mental phenomena evoked by electrical stimulation of the human hippocampal formation and amygdala. Brain. 1978;10183- 117
Link to Article
Nolte  J Olfactory and Limbic Systems.  St Louis, Mo Mosby–Year Book Inc1993;
Bremner  JDNarayan  MAnderson  ERStaib  LHMiller  HLCharney  DS Hippocampal volume reduction in major depression. Am J Psychiatry. 2000;157115- 118
Link to Article
Sheline  YIWang  PWGado  MHCsernansky  JGVannier  MW Hippocampal atrophy in recurrent major depression. Proc Natl Acad Sci U S A. 1996;933908- 3913
Link to Article
Sheline  YISanghavi  MMintun  MAGado  MH Depression duration but not age predicts hippocampal volume loss in medically healthy women with recurrent major depression. J Neurosci. 1999;195034- 5043
Auer  DPPutz  BKraft  ELipinski  BSchill  JHolsboer  F Reduced glutamate in the anterior cingulate cortex in depression: an in vivo proton magnetic resonance spectroscopy study. Biol Psychiatry. 2000;47305- 313
Link to Article
Winsberg  MESachs  NTate  DLAdalsteinsson  ESpielman  DKetter  TA Decreased dorsolateral prefrontal N-acetyl aspartate in bipolar disorder. Biol Psychiatry. 2000;47475- 481
Link to Article
Goldman-Rakic  PSBrown  RM Postnatal development of monoamine content and synthesis in the cerebral cortex of rhesus monkeys. Brain Res. 1982;256339- 349
Link to Article
Huttenlocher  PR Synaptic density in human frontal cortex: developmental changes and effects of aging. Brain Res. 1979;163195- 205
Link to Article
Rosenberg  DRLewis  DA Postnatal maturation of the dopaminergic innervation of monkey prefrontal and motor cortices: a tyrosine hydroxylase immunohistochemical analysis. J Comp Neurol. 1995;358383- 400
Link to Article
Birmaher  BDahl  REWilliamson  DEPerel  JMBrent  DAAxelson  DAKaufman  JDorn  LDStull  SRao  URyan  ND Growth hormone secretion in children and adolescents at high risk for major depressive disorder. Arch Gen Psychiatry. 2000;57867- 872
Link to Article

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