Lack of Ventral Striatal Response to Positive Stimuli in Depressed Versus Normal Subjects

Participants were 10 unmedicated subjects with DSM-IV major depression (nine women and one man; mean age=35.6 years, range=26–49; eight right-handed, two left-handed) and 12 healthy comparison subjects (seven women and five men; mean age=32.0 years, range=23–53; all right-handed). All subjects completed at least some education beyond high school, with level of education matched across subject groups. Apart from depression in the patient group, all participants were free of major psychiatric diagnoses, substance abuse, and significant neurological or medical disorders. After full explanation of the study to the participants, written informed consent was obtained. Hamilton Rating Scale for Depression (33) scores were obtained on the same day as the scan, before (but not immediately prior to) the imaging session.

Stimuli consisted of 24 positive words, 24 negative words, and 24 neutral words (adjectives, nouns, and verbs) balanced across categories for frequency, length and part of speech, with the exception that within the neutral list, verbs were substituted for adjectives. This was done because adjectives, which are important components of the valenced categories, are by nature generally not free of valence. Verbs were substituted rather than nouns, since their imageability is more similar to that of adjectives. Stimuli were designed to be relevant to depressive and counter-depressive themes, as defined by the literature and clinical experience, and were rated for suitability by a panel of three experienced clinicians. They were based on a similar list of words that were piloted on 34 healthy subjects who rated the three word types as significantly different in valence (p<0.001) and rated positive and negative words as not significantly different in intensity (p=0.26). Examples of such words are as follows: success, admired, heroic (positive words); worthless, bleak, burden (negative words); transfer, trunks, fasten (neutral words).

The three word types were visually presented on an MRI compatible Sharp LCD screen within a block design (six words per block, four blocks per valence), with blocks pseudorandomly balanced to control for order and time effects. Each word appeared for 2 seconds, followed by an interstimulus interval uniformly jittered around an average of 2.8 seconds for a total of 28.8 seconds per block. Each block was followed by 24 seconds of rest, with the paradigm as a whole preceded and followed by two additional 12-second rest periods. Stimulus presentation and response collection were performed within the Integrated Functional Imaging System SA/E-Prime environment (MRI Devices Corporation, Waukesha, Wisc.; Psychology Software Tools, Inc., Pittsburgh, Pa.). Subjects were instructed to read each word silently and then immediately press a button under their right index finger. During rest periods, they were instructed to look at a dash at the center of the screen, with their minds either blank or floating freely.

Immediately after imaging was completed and subjects were removed from the scanner, they were given a list of words consisting of the 72 stimuli seen during scanning (targets) and 36 other words (distractors), with which the targets were randomly interspersed. Distractor words were divided equally into positive, negative, and neutral categories and balanced for the same qualities as the target words. The subjects were instructed to read each word and to circle those words that they believed they had seen in the scanner. Following completion of this particular task, subjects were asked to rate the emotional valence and intensity of each word on a scale of –3 to +3.

All image data were acquired with a GE Signa 3 Tesla MRI scanner (max gradient strength 40mT/m, max gradient slew rate 150T/m/s, General Electric Company, Waukesha, Wisc.) using blood-oxygen-level-dependent fMRI, which measures hemodynamic and oxygenation changes associated with localized neuronal activity in the brain (34) . After shimming to maximize homogeneity, a series of fMRI scans was collected using gradient echo-planar imaging (TR=1200; TE=30; flip angle=70°; field of view=240 mm;15 slices; 5 mm thickness with 1 mm interslice space; matrix=64x64), with a single-shot version of a z-shimming algorithm to reduce susceptibility artifact at the base of the brain (35) . Echoplanar images were acquired in the axial plane parallel with the anterior commissure-posterior commissure (AC-PC) plane. The first five volumes of each session were discarded. A reference T1-weighted anatomical image with the same slice placement and thickness and a matrix of 256x256 was acquired immediately preceding the echo-planar imaging acquisition. A high-resolution T1-weighted anatomical image using a spoiled-gradient sequence with a resolution of 0.9375x0.9375x1.5 mm ³ was also acquired.

SPM99 software (Wellcome Department of Imaging Neuroscience) was used for processing the data (36), which included manual AC-PC reorientation of all anatomical and echo-planar images; realignment of functional echo-planar images based on intracranial voxels to correct for slight head movement between scans; coregistration of functional echo-planar images to the corresponding high-resolution anatomical image based on the transformation of the reference anatomical image to the latter for each individual subject; stereotactic normalization to the standardized coordinate space of Talairach and Tournoux (Montreal Neurological Institute [MNI] average of 152 T1 brain scans) based on the high-resolution anatomical image; and spatial smoothing of the normalized echo-planar images with an isotropic Gaussian kernel (7.5 mm, full width at half maximum). To perform image data analyses, a whole-brain voxel-by-voxel multiple linear regression model was employed at the individual subject level (37) . The temporal global fluctuation estimated as the mean intensity of intracranial voxels of each volume was removed through proportional scaling. The individual model comprised the regressor of interest (which consisted of the stimulus onset times convolved with a prototypical hemodynamic response function) and the covariates of no interest (which consisted of the first-order temporal derivative of the regressor of interest, global and physiological fluctuations [38], realignment parameters, and scanning periods [39] ). An autoregressive model was also incorporated to accommodate the intrasubject temporal correlation pattern in residual. Effects at every brain voxel were estimated by a restricted maximum likelihood estimator using an expectation maximization algorithm, and regionally specific effects were then compared using linear contrasts. The resulting set of contrast-effect images and their corresponding standard deviation images was then entered into a set of second-stage group-level models.

For whole-brain group analyses, we used a mixed-effects model, which accounted for intra- and intersubject variabilities and allowed population-based inferences to be drawn (37) . Age, gender, and handedness were used as covariates of no interest in an analysis of covariance setting. A voxel-wise inference at the group level was then drawn according to Gaussian random field theory, focusing on the ventral striatum, considered as those regions of the nucleus accumbens, head of the caudate, and putamen where z≤–3mm and y≥0mm in MNI space. For the contrast of interest, a region of interest analysis was performed for the bilateral ventral striatum using a mask of the region as defined above. For the a priori regions of interest, the comparisons based on one-tailed t tests were considered significant if their initial voxel-wise p values were less than 0.001 and p<0.05 corrected for multiple comparisons within the bilateral nucleus accumbens, with a search volume of 1.8 cm ³ . For regions outside the ventral striatum, the comparisons were considered significant if their initial voxel-wise p values were less than 0.001, with a spatial extent of at least 50 mm ³ .

A set of supplementary analyses, based on the group level models, was performed to aid in the interpretation of the primary finding. A correlation analysis was performed to determine the association between activity in the ventral striatum and the Hamilton depression scale measure that quantifies interest and pleasure in, and subsequent performance of, activities. Analyses of behavioral data were performed using Mann-Whitney tests.

Between-group contrasts revealed significantly less activation to positive stimuli in depressed patients relative to healthy subjects in bilateral ventral striatal regions, including ventral head of caudate and putamen and nucleus accumbens, with the left contrast maximum falling in the region of the nucleus accumbens (right:[15,6, –3], Z=–3.66, voxel-wise p=0.0001, p<0.05 [corrected]; left:[–15,15, –6], Z=–3.52,voxel-wise p=0.0002, p<0.05 [corrected]) ( Figure 1 A). Within-group analyses (reported at the statistical maxima of the between-group findings) revealed that these findings were due to a decrease in activation to positive stimuli in depressed subjects (right: [15, 6, –3], Z= –1.42, p=0.08; left: [–15, 15, –6], Z=–3.23, p=0.004), coupled with an increase in healthy comparison subjects (right:[15, 6, –3], Z=3.75, p<0.0001; left:[–15, 15, –6], z=1.82, p=0.04) ( Figure 1 B). Decreased activity in bilateral ventral striatum was also found in depressed patients relative to healthy comparison subjects in response to positive versus neutral stimuli (right:[15, 9, –3], Z=–2.43,voxel-wise p=0.008; left:[–18, 9, –6], Z=–3.23, voxel-wise p=0.0006, p<0.05 [corrected]). No significant between-group differences in ventral striatal activation were seen in any other contrast. The fMRI data are available as a supplement in the online version of this article.

In order to determine whether the differential response to positive stimuli might be occurring in the setting of differential regional baseline activity, a between-group comparison of regional (relative to global) activity during rest (at the statistical maxima of the between-group finding for the positive condition) was performed by sampling two different time points in the experiment before subjects were exposed to valenced stimuli. The two time points are as follows: 1) before the blood-oxygen-level-dependent response to the initial stimulus began to emerge and 2) at the end of the 24-second rest period following the first neutral presentation block. No significant between-group differences were seen for either comparison (Time point 1: right: [15, 6, –3], Z=–0.27, p=0.40; left: [–15, 15, –6], Z=–0.83, p=0.20. Time point 2: right: [15, 6, –3], Z=–0.40, p=0.35; left: [–15, 15, –6], Z=–0.83, p=0.20). While the analysis does not constitute an integrated measure of baseline activity, it represents a relevant sampling of baseline activity in these subjects before valenced stimuli were delivered, which is useful for interpreting the main finding.

To determine whether the differences displayed between depressed patients and comparison subjects in positive blocks represented prolonged processing of negative stimuli (27, 40) rather than a differential response to positive stimuli, we examined each block of positive stimuli individually to determine whether a lack of ventral striatal activation in depressed patients, compared with healthy subjects, was observed predominantly following blocks of negative stimuli. No such pattern was revealed. Similarly, because decreases in basal ganglia volumes have been reported in depressed patients (41), a voxel-based morphometric comparison (42) of depressed patients relative to comparison subjects was performed. This revealed no significant differences in gray matter volume in ventral striatal regions (right: 15, 6, –3 [Z=–1.01, p=0.16]; left: –15, 15, –6 [Z=–0.33, p=0.37]) that might account for our findings.

A correlation analysis was performed within the depressed group to investigate the association between the blood-oxygen-level-dependent activation levels in depressed subjects in the positive condition and their day-of-scan scores on question 7 of the Hamilton depression scale, which assesses interest and pleasure in and subsequent performance of activities. A significant negative correlation was observed, with those subjects who had higher scores (i.e., less interest/pleasure/performance of activities) showing less activation in bilateral ventral striatal regions (right: 27, 6, –9 [Z=–2.20, p=0.01]; left: –18, 0, –6 [Z= –1.84, p=0.03]). In areas outside the region of interest (at the level of p<0.001), negative correlations with question 7 of the Hamilton depression scale were also found in the left dorsolateral prefrontal cortex (–33, 60, 18) and right frontal operculum (60, 9, 12), while a positive correlation was found in the left posterior cerebellum (–24, –72, –45).

Between-group differences outside the ventral striatum for positive, negative, neutral, positive versus neutral and negative versus neutral contrasts are shown in the Table (available in the online version of this article as a data supplement) and will be commented upon in the discussion section.