A total of 26 adolescents participated in this study. 13 adolescents (mean ± SD, 16.0 ± 1.5 years; range, 13-17 years; 7 girls, 6 boys) with a DSM-IV diagnosis of major depressive disorder were compared with a matched group of 13 healthy adolescents (mean ± SD, 15.8 ± 1.5 years; range, 13-17 years; 7 girls, 6 boys). All adolescents were right-handed. The depressed and healthy adolescents did not significantly differ in estimated IQ [t(24) = -.1.21, p = 0.273], socioeconomic status (Х2(8, n = 26) = 7.33, p = 0.501), pubertal developmental stage (Tanner Stage) (Х2(6, n = 26) = 4.200, p = 0.650), age [t(24)= 4.59, p = 0.650], gender (Х2(1, n = 26)= 0.000, p = 1.00), ethnicity (Х2(3, n = 26) = 0.000, p = 1.000), and anxiety [t(24)= 1.618, p= 0.119]. Relative to the healthy controls, the depressed adolescents were significantly higher on the Children’s Depression Rating Scale-Revised (CDRS-R) [t(24) = 11.401, p = 0.00] and lower on the Children’s Global Assessment Scale (CGAS) [t(24) = -13.984, p = 0.00].
Healthy adolescents were recruited from all regions of San Diego through the use of posted flyers, e-mail, and the internet. Depressed adolescents were recruited from clinics in San Diego when they sought treatment.
Healthy adolescents were screened using the Computerized Diagnostic Interview Schedule for Children (DISC) version 4.0 [8
] and the Diagnostic Predictive Scale (DPS) [9
] to assess for the presence of any Axis I diagnoses.
For the potentially depressed adolescents, psychiatric diagnosis was determined through the administration of the Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime Version (K-SADS-PL) [10
] to both the adolescent and parent(s) by an experienced child and adolescent psychiatrist. Using the KSADS-PL, all adolescents met criteria for current major depressive disorder. None of the depressed adolescents had psychotic features.
All participants were administered the following items: (1) Wechsler Abbreviated Scale of Intelligence (WASI) [11
], (2) Customary Drinking and Drug Use Record (CDDR) [12
], (3) Standard Snellen Eye Chart, (4) Ishihara Color Plates Test (8 plate, 2005 edition), (5) Family Interview for Genetics Studies (FIGS) [13
], (6) Edinburgh Handedness Inventory [14
], (7) Children’s Depression Rating Scale-Revised (CDRS-R) [15
], and Children’s Global Assessment Scale (CGAS) [16
]. The CDRS-R and CGAS were administered by an experienced child and adolescent psychiatrist. In addition, each participant completed the following self-administered questionnaires: (1) Tanner Stage [17
], (2) demographics questionnaire, (3) medical and developmental history form, and (4) Multidimensional Anxiety Scale for Children (MASC) [18
Adolescents ages 13 to 17 years with major depressive disorder from all ethnicities and both genders were allowed to participate. All patients were medication-free and symptomatic. Exclusionary criteria for the depressed adolescents included: (1) having a full IQ score of less than 80 on the WASI; (2) being color blind or having less than 20/40 correctable vision as determined by the Ishihara color plates and Snellen eye chart: (3) any contraindication to MRI imaging (ferometallic implants, braces, claustrophobia); (4) any history of neurological disorder (e.g., meningitis, migraine, HIV), head trauma with loss of consciousness >2 minutes, learning disability, serious physical health problem, or a complicated or premature birth <33 weeks of gestation (exclusionary due to potentially abnormal neurodevelopment); (5) being pregnant or suspect being pregnant: (6) any evidence of illicit drug use, misuse of prescription drugs, or more than 2 alcohol drinks per week either currently or within the past 6 months as determined by the CDDR; (7) left-handedness; (8) prepubertal status (Tanner stages 1 or 2); (9) inability to fully understand and cooperate with the study procedures; (10) a current diagnosis of PTSD; (11) present or past diagnosis of anorexia nervosa, bipolar disorder, autism, or schizophrenia; (12) use of medication with central nervous system effects within the past 2 weeks prior to scanning; (13) CDRS-R score less than 55.
Healthy adolescents were excluded from the study for any of the items listed for the depressed adolescents and for any of these additional reasons: (1) any current or lifetime DSM-IV Axis I psychiatric disorders as determined by the DISC and DPS; (2) any family history of mood or psychotic disorders in first- or second-degree relatives as assessed by the FIGS.
This study was approved by the University of California at San Diego (UCSD) and Children’s Hospital and Health Center (CHHC) Institutional Review Boards. All subjects provided written assent, and their parent/legal guardians provided written informed consent to participate. All subjects were financially compensated.
The visual stimuli, an “X” or an “O”, in white capital letters appeared on a black background back-projected to the MRI room subtending a visual angle of approximately 6°. Subjects were told to press as quickly as possible the right button whenever an “O” appeared and the left button when an “X” appeared. Additional details of this task have been published elsewhere [6
]. Subjects were also told that when they heard a tone delivered through headphones during a trial, they were not to press either button. Stimuli appeared at the beginning of each of the trials. Each trial lasted 1300 ms or until the subject responded. Trials were separated by 200 ms interstimulus intervals (blank screen). The individual response latency was used to denote the period of inhibitory processing and provided a naturally jittered reference function. Subjects performed seventy-two total stop trials which were pseudo-randomized throughout the task and counterbalanced. Six blocks were performed, each containing 48 total trials (12 stop and 36 non-stop trials in each block). Task instructions were presented for 12 seconds between blocks.
Just prior to scanning, each subject performed the stop task in a behavioral testing session to determine their mean reaction time (RT). Based upon this data, 6 different trial types were designed based on the amount of time after the beginning of the trial (when an “X” or “O” stimuli first appeared) when the stop signal was delivered: those when the stop signal was delivered at the subject’s mean RT, and those when the stop signal was delivered at 100 (RT-100), 200 (RT-200), 300 (RT-300), 400 (RT-400), or 500 (RT-500) ms less than the mean RT after the beginning of the trial. Behavioral response data were collected on all subjects during the scan.
A fast event-related fMRI design was employed. Images were acquired on a 3-T GE scanner (General Electric, Milwaukee, WI) with Twin Speed gradients using a GE 8-channel head coil. Each session consisted of a three-plane scout scan, high-resolution anatomical scan, T2*-weighted echo-planar imaging (EPI) scan to measure the blood oxygen-level dependent (BOLD) response, and EPI-based field maps to correct for susceptibility-induced geometric distortions. Functional scans covering the entire brain were acquired parallel to the anterior and posterior commissure (T2*-weighted EPI, TR = 2000 ms, TE = 32 ms, FOV = 23 × 23 cm, 64 × 64 matrix, thirty 2.6 mm oblique slices parallel with the ac-pc axial plane with a 1.4 mm gap, 256 repetitions, 512 seconds). During the same experimental session, a T1-weighted image with an inversion time of TI = 450 ms to null the CSF (FSPGR, TR = 8.0 ms, TE = 3.1 ms, flip angle = 12°, FOV = 25 cm, matrix = 256 × 256, 0.98 × 0.98 × 1.0 mm3 voxels) was collected in the sagittal plane for anatomical reference.
Statistical Analysis of Imaging Data
All functional and structural image processing and analyses were conducted with the Analysis of Functional NeuroImages (AFNI) software [19
]. Details of the image analysis pathway have been published elsewhere [6
]. To minimize motion artifact, an AFNI 3D-coregistration algorithm (3dvolreg) was used to realign all echoplanar images. Data were time-corrected for slice acquisition order, and the time series data for each individual were analyzed using a multiple regression model (3dDeconvolve).
For the analysis of task difficulty, three task regressors of interest: “easy” (MRT-400ms and MRT-500ms), “medium” (MRT-200ms and MRT-300ms), and “hard” (MRT and MRT-100ms), and five nuisance regressors: roll, pitch, yaw (to account for residual motion), baseline (which included block instructions), and linear trend (to eliminate slow signal drifts) were entered into a linear multiple regression. Prior to inclusion in the regression model, the task-related regressors were convolved with a modified gamma variate function to account for the hemodynamic delay and the slow rise and fall of the hemodynamic response. Activation in each voxel during each specific task condition was divided by the baseline activation to obtain the percent signal difference for each task condition.
A 4-mm full width half maximum Gaussian filter was applied to the voxel-wise percent signal difference data to account for individual variations in anatomical landmarks. After smoothing, each subject’s data were normalized to Talairach coordinates and a whole-brain mask screened out non-brain voxels.
The ANFI program 3dttest was used to examine differences in brain activation between the depressed and non-depressed adolescents for the all-stop minus non-stop condition.
A threshold/cluster method was then applied. This threshold adjustment method was based on Monte-Carlo simulations and was utilized to guard against identifying false positive areas of activation using a 4 mm FWHM Gaussian filter. Based on these simulations, it was determined that a minimum volume of 704 μl and a connectivity radius of 4.0 mm was necessary to ensure that a voxel-wise a-priori probability of 0.05 would result in a corrected cluster-wise activation probability of 0.05. Percent signal change values for the contrasts were extracted from significant brain clusters for further analysis.
Statistical Analyses of Behavioral and Clinical Scales Data
All behavioral and correlational statistical analyses were carried out with SPSS 14.0 [21
]. Correlational analyses of the task-related activation in the subgenual anterior cingulate cortex and bilateral medial frontal gyrus with the Children’s Depression Rating Scale-Revised and Children’s Global Assessment Scale were conducted for both groups combined.