Brain reward system dysfunction in adolescence: Current, cumulative, and developmental periods of depression

Abstract

Objective:

Reward system dysfunction is a well-known correlate and predictor of depression in adults and adolescents, with depressed individuals showing blunted (hyporeactive) striatal response to monetary rewards. Furthermore, studies of remitted depression suggest network wide hyporeactivity of striatal (caudate, putamen, nucleus accumbens) and cortical regions (insula, anterior cingulate cortex (ACC)) even in the absence of current symptoms. Thus, it remains unclear which patterns of hyporeactivity represent a trait-like indicator of depression, and which represent a current depressed state.

Methods:

Using a fMRI monetary reward task, we measured brain response to monetary gains and losses in a longitudinal sample of adolescents (N=131) that had been annually assessed for psychiatric symptoms since age 3–5 years.

Results:

Results indicate that current depression severity is associated with hyporeactivity exclusively in the nucleus accumbens in response to the anticipation of a reward, while cumulative depression severity is associated with blunted response to anticipation across a cortico-striatal circuit (i.e. striatum, ACC, insula). Follow-up analyses investigating the effects of depression on reward processing at different developmental stages reveal a similar pattern: recent depression severity during adolescence is associated with more focal hyporeactivity in the nucleus accumbens, while depression severity during early childhood (i.e. preschool) is associated with more global hyporeactivity across the cortico-striatal circuit.

Conclusions:

Findings indicate important distinctions between disruptions in reward system neural circuitry associated with a history of depression, particularly early-onset, versus current depression. These results have implications for understanding the etiology and treatment of hedonic (i.e., reward) processing deficits in depression.

Introduction

Reward system dysfunction (i.e. deficits in reward learning and reduced response to gains in the reward network of the brain) appears to be concurrently and prospectively related to depression among adults, with recent replications in adolescents. Blunted responses in the striatum (caudate, putamen, nucleus accumbens) to rewarding stimuli are found among depressed individuals (1,2), predict later onset of a depressive episode (3–5), and are found in the offspring and first-degree relatives of depressed individuals (6,7). This suggests that reward system dysfunction may serve as a candidate neural correlate or even risk factor for depression. The goal of the current study is to examine the relationships between regions of a cortico-striatal circuit supporting reward processing and both current depression and cumulative depression history in a sample of adolescents who have been participating in a longitudinal study of early onset depression since preschool.

In addition to being present in currently depressed individuals, studies of patients in remission from depression also show blunted reward responses behaviorally (8) and in the ventral striatum (9). However, brain responses to reward occur in regions beyond the striatum, engaging a broader cortico-striatal circuit. Individuals in remission show blunted neural responses to reward in this broader circuit, including the anterior cingulate cortex (ACC) (10–12) and insula (13). Such findings suggest the possibility that hyporeactivity of a broader set of regions within the cortico-striatal circuit persists beyond the depressive episode, potentially putting patients at risk of recurrence, particularly with early onset depression. Specifically, subcortical striatal function may be disrupted concurrently with depression. If so, such striatal disruption in early-onset depression may in turn contribute to disruption in the development of cortical regions and their functions. In later-onset depression, these cortical areas are more developed and thus their function may be less disrupted by depression. Few studies have been able to simultaneously examine both current depression severity and past history of depression (particularly using prospective data) to provide data relevant to test this hypothesis. Thus, the current study presents a unique opportunity to test the prediction that current depression is associated with a more focal blunted response to rewards in the striatum, while previous or cumulative depression (especially early-onset depression) is associated with a more global blunted response across the cortico-striatal circuit.

Further, there is evidence that depression can be related to dysfunction in both reward anticipation and receipt. Blunted reactivity to rewarding cues (anticipation) and outcomes (receipt) have been associated with depression in adolescents (1,2,6,14–16), suggesting deficits in the experience of rewards or hedonic tone. However, other studies have only observed blunted responsivity to reward anticipation (5,7,17,18). Therefore, determining whether depression is more strongly related to reward anticipation or receipt will help inform the neural and behavioral mechanisms that contribute to reward processing dysfunction related to depression.

We tested these predictions using fMRI responses in regions of the brain’s reward system (e.g., cortico-striatal network) to monetary rewards and losses in a longitudinal sample of adolescents that have been annually assessed for psychiatric symptoms since early childhood. We examined neural responses related to current depression severity versus cumulative depression severity since early childhood. Because participants were followed longitudinally, we had measures of depression severity prospectively acquired at annual waves using clinical interviews rather than based on retrospective report. Furthermore, while prior studies have typically compared healthy controls with depressed patients as a group (1,2,14,16), the current study used continuous measures of depression severity which are more reliable than categorical measures of psychopathology (19) and are in line with the Research Domain Criteria framework (20,21). We also tested the hypotheses that early onset of depression would be associated with blunting in a broader network of reward responsive regions as compared to only current depression, by comparing the relationship between cortico-striatal activation and depression symptoms reported at assessment waves during three different developmental periods: preschool, school age, and adolescence.

Methods

Participants

A total of 306 children ages 3–6 years at baseline, oversampled for symptoms of depression, were recruited in the St. Louis metropolitan area for participation in a study of preschool-onset depression. Details of recruitment have been previously reported (22,23). An imaging phase of the study started when the sample reached school age (8–14) at which time 216 children were eligible. An additional 42 children ages 9–14 years were recruited (no history of psychopathology at the time of recruitment) into the study to increase the sample size starting at the first imaging wave (Supplemental Materials for further information). Of these 258 children, 148 participated in the current, fourth wave of imaging. Of those, 131 had usable data (7 excluded for unusable fMRI data, 8 for excessive motion, 2 for too few trials with responses). See Table 1 for demographic descriptive statistics and Supplemental Materials for study timeline. Because some participants were recruited at later waves, results are described for the full sample consisting of 131 youth, and a subsample of 109 participants with initial preschool-age assessments (“subsample followed since preschool”). Parental written consent and child assent were obtained before participation and the local Institutional Review Board approved all procedures.

Table 1.

Demographic statistics for the full sample and subsample followed since preschool

Full sample (N=131)	N	%
Female	67	51.1
Race
Caucasian	73	55.7
African American	51	38.9
Other	7	5.3
Psychotropic medication use in past 48 hours	15	11.5
	Mean ± SD	Range	95% CI for mean
Age at scan	16.39 ± 1.11	13.3–19.43	(16.2, 16.58)
Income to Needs a	3.36 ± 2.17	0.13–8.25	(2.99, 3.74)
Cumulative depression symptoms	1.90 ± 1.24	0–5.68	(1.68, 2.11)
CDI T-score b	48.48 ± 8.27	37.5–90	(47.04, 49.93)
Preschool depression symptoms	2.32 ± 1.62	0–7	(2.02, 2.63)
School age depression symptoms	2.19 ± 1.44	0–7	(1.94, 2.45)
Adolescent depression symptoms	1.62 ± 1.45	0–6.62	(1.37, 1.87)
Subsample followed since preschool (N=109)	N	%
Female	57	51.8
Race
Caucasian	62	55.5
African American	42	38.2
Other	6	5.5
Psychotropic medication use in past 48 hours	15	13.6
	M0ean ± SD	Range	95% CI for mean
Age at scan	16.48 ± 1.00	14.18–19.43	(16.29, 16.67)
Income to Needs a	3.4 ± 2.22	0.13–8.25	(2.98, 3.82)
Cumulative depression symptoms	2.07 ± 1.21	0.13–5.68	(1.85, 2.30)
CDI T-score	49.05 ± 8.54	37.5–90	(47.42, 50.68)
Preschool depression symptoms	2.34 ± 1.62	0–7	(2.03, 2.65)
School age depression symptoms	2.29 ± 1.43	0.19–7	(2.02, 2.56)
Adolescent depression symptoms	1.77 ± 1.47	0–6.62	(1.49, 2.05)

SD: standard deviation, CI: confidence interval,

^a- Income to Needs is defined as the ratio of family income to the appropriate poverty threshold,

^b- CDI T-scores unavailable for 2 participants from the full sample

Depression severity measures

Cumulative depression was measured as the area under the curve of symptoms of depression endorsed in a clinical interview over all available assessment waves. The area under the curve was calculated for each child by graphing the depression symptoms on the y-axis and days since initial assessment on the x-axis, yielding a trajectory depicting the number of depression symptoms endorsed by time in the study. The area below this curve was calculated and divided by the total number of days between the first and most recent assessment to account for individual differences in duration in the study. When children were between the ages of 3 years and 7 years 11 months, the Preschool Age Psychiatric Assessment was administered to caregivers (24–26). When children were 8.0 years or older, both child and caregiver reports of psychiatric symptoms were collected using the Child and Adolescent Psychiatric Assessment (27–29), then the Kiddie Schedule for Affective Disorders and Schizophrenia (30)) was used at the current wave. There were up to fourteen possible assessment waves for participants recruited in preschool and up to four possible assessment waves for participants recruited at ages 9–14 years. See Supplemental Materials for reliability. Current depression was measured as the average of the T-scores of child and parent-reported symptoms on the Childhood Depression Inventory (CDI) (31) at time of scan. Raw scores were converted into T-scores, which reflect standardized scores based on the child’s gender and age, thereby providing a more easily interpretable measure of depression severity since they have a mean of 50 and standard deviation of 10. The CDI was used instead of number of symptoms reported on the KSADS at the current assessment wave to increase inter-subject variability and thus power to detect meaningful individual differences. The CDI was not administered at the waves prior to imaging, and thus was not used to measure cumulative depression severity. Area under the curve of depression symptoms endorsed in a clinical interview during three mutually exclusive developmental periods were calculated: preschool <6.0 years old, school age 6.0 years old to 10 years old and 11 months, adolescence ≥11 years old.

Procedure

An event-related card-guessing task was used to assess neural reactivity to anticipation and receipt of reward feedback (7,14,15,32), allowing us to estimate responses to cues indicating they were likely to win (Win cue), lose (Lose cue), either win or lose (Mixed cue), or likely to get neutral feedback indicating no change (Neutral cue) (2000ms) as well as feedback that they either won (Reward outcome), lost (Loss outcome), or neither won nor lost (None outcome). See Supplemental Materials for details.

FMRI Analyses

FMRI data were run though the Human Connectome Project minimal preprocessing pipelines (33–37). See Supplemental Materials for details. Individual-subject generalized linear models (GLMs) included eight regressors: a) presentation of each type of cue (Win, Lose, Mixed, Neutral), b) presentation of each possible outcome (Reward, Loss, None), and c) onset of each trial/prompt to guess whether the card will be greater than or less than five. The GLM assumed a hemodynamic response shape lasting 12 seconds using a gamma variate basis function convolved with the hemodynamic response function provided in AFNI, where beta weights represent the peak height of the hemodynamic curve.

Regions of interest analyses

A priori regions of interest (ROIs) were selected based on previous literature showing reactivity in the cortico-striatal circuit to monetary rewards in adulthood and adolescence (38). Six ROIs were used: the caudate (defined as the caudate head), putamen, and nucleus accumbens (NAcc) from the TT Daemon atlas and the insula, dorsal anterior cingulate cortex (dACC), and rostral anterior cingulate cortex (rACC) from the Destrieux atlas (39) (Supplemental Materials). Mean beta estimates were extracted across each ROI for the a priori selected Win > Lose cue contrast and Reward > Loss outcome contrast, along with a composite average measure of activation across all ROIs reflecting activation across the cortico-striatal circuit (a mean of means). When referring to activation across the cortico-striatal circuit, we mean task-related BOLD signal from the six ROIs (i.e. a mean computed across all ROIs, with each ROI defined as mean response across the anatomically defined region). This measure does not refer to connectivity.

First, using multiple regression models, mean activation across the cortico-striatal network was regressed onto measures of current and cumulative depression severity simultaneously (i.e. in the same model), as well as covariates including sex, race, age at scan, and income-to-needs ratio. These covariates were selected because they have been shown to be related to either depression severity or functioning of the brain’s reward system (40,41). These covariates were controlled for in all analyses. Next, mean activation in each ROI was regressed onto measures of current and cumulative depression severity. Second, activation in each ROI was regressed onto each measure of depression during three distinct developmental periods. Third, these analyses were followed up with multiple regressions that included all three developmental periods as regressors, to test which developmental period accounted for the greatest variance in ROI activity. Additional analyses covaried for psychotropic medication use in the past 48 hours using a dichotomous variable (Supplemental Materials). Finally, complimentary analyses testing Cue type x Current and Cumulative depression interactions are presented in Supplemental Materials.

Whole brain analysis

To identify significance thresholds, we conducted a non-parametric permutation test using the Clustsim option within 3dttest++ in AFNI, using a group-level brain mask where at least 70% of the participants had signal. The updated version of Clustsim generates cluster thresholds based on voxel-wise threshold and FWE p-value. Results indicated voxel-wise threshold of p<.005 with a minimum cluster of 448 voxels for cumulative depression severity and 520 voxels for current depression severity corresponding with a whole brain FWE of p=.05. Because such a large spatial extent may not be realistic for subcortical regions such as the striatum, whole brain analyses were also conducted with a newer equitable thresholding and clustering method, using the ETAC option within 3dttest++ in AFNI. ETAC has the “potential to detect both small, intense clusters (found using small p-value thresholds and small blurring) and large, weak clusters (found using large p-value thresholds and perhaps more blurring) within a single execution” (42). ETAC has recently been lauded as “eliminat[ing] the need for selection of a primary cluster-defining threshold by combining information from multiple simulations at a range of primary voxelwise thresholds, and then adjusting for multiple tests to control the overall false positive rate” (43).

To test whether the subsample followed since preschool showed a similar pattern of activation within the same clusters, clusters from the full sample were extracted and used as a mask in follow-up analyses. At the group level, we examined neural activity to the Win > Lose cue and Reward > Loss outcome contrasts. We used multiple regression models to examine the relationship between individual-level current depression and cumulative depression and activation to the Win > Lose cue and the Reward > Loss outcome contrasts while accounting for the same covariates as specified above.

We refer to the nucleus accumbens when discussing the results of the ROI analyses as it is an ROI distinct from the caudate and putamen. We refer to the ventral striatum when discussing whole brain results because it is more difficult to determine whether the activity in these analyses is localized to the nucleus accumbens (or is also present in ventral portions of the caudate and putamen).

Results

Group-level response to reward anticipation and receipt

Participants showed significant BOLD response to reward anticipation and receipt across regions of the cortico-striatal circuit including the dorsal and ventral striatum, dorsal and rostral anterior cingulate cortex (dACC and rACC, respectively), and insula, among other regions (p<.01 corrected; Supplemental Materials Figure S2).

Depression severity and neural response to reward receipt

Neither cumulative nor current depression were related to mean activation across the cortico-striatal circuit or to specific individual ROIs to reward receipt (see Table S1). Furthermore, whole brain analyses did not reveal any significant clusters of activation during reward receipt that were correlated with cumulative depression severity. Some clusters were correlated with current depression severity, though none in the dorsal or ventral striatum (see Table S3).

Depression severity and neural response to reward anticipation

Multiple regression analyses that included both current and cumulative depression as simultaneous regressors showed that cumulative depression was related to mean activation in the cortico-striatal circuit (Table 2; Figure 1B), as well as the caudate, putamen, insula, dACC, and rACC. Current depression was related to activation in the nucleus accumbens and dACC (Table 2; Figure 1A). The relationship with the nucleus accumbens was nominally significant but not after FDR correction; though this relationship was significant when cumulative depression was excluded from the model and FDR corrected (see Table S3). The association with the dACC did not hold when cumulative depression severity was excluded from the model (see Table S3). Regressions with current and cumulative depression as separate regressors showed a similar pattern of results (see Table S3). Findings were consistent when accounting for psychotropic medication use and for the subsample followed since preschool (see Table S5, S7, S9, and S10). See Supplemental Materials for complementary analyses using MANCOVAs with all four cue type conditions.

Table 2.

Association between current and cumulative depression severity and BOLD response in a priori ROIs to reward anticipation in the full sample

ROIs	Depression severity	β	95% CI	p (nominal)	p (FDR corrected)
Cortico-Striatal Circuit	Current	0.026	−0.176, 0.228	0.803
	Cumulative	−0.300	−0.501, −0.099	0.004
Nucleus accumbens	Current	−0.219	−0.424, −0.014	0.037	0.111
	Cumulative	−0.144	−0.348, 0.06	0.164	0.164
Caudate	Current	−0.063	−0.266, 0.141	0.544	0.653
	Cumulative	−0.220	−0.422, −0.018	0.033	0.042
Putamen	Current	0.039	−0.165, 0.243	0.704	0.704
	Cumulative	−0.249	−0.452, −0.046	0.016	0.038
Insula	Current	0.120	−0.092, 0.332	0.263	0.526
	Cumulative	−0.228	−0.439, −0.017	0.035	0.042
Dorsal ACC	Current	0.232	0.027, 0.437	0.027	0.111
	Cumulative	−0.371	−0.574, −0.167	0.001	0.001
Rostral ACC	Current	0.093	−0.12, 0.306	0.389	0.584
	Cumulative	−0.253	−0.465, −0.042	0.019	0.038

Associations at p < .05 bolded. FDR corrected p values were corrected separately for current and cumulative depression severity.

Figure 1.

Associations of current and cumulative depression with BOLD response to reward anticipation in nucleus accumbens and cortico-striatal circuit ROIs

Panel A: Association between parent and child CDI T-scores at time of scan and difference in BOLD response to win versus lose cues within the nucleus accumbens ROI. Panel B: Association between cumulative core depression symptoms and BOLD response to Win > Lose cue across the cortico-striatal circuit (average mean activation across 12 a priori ROIs). Gray bands surrounding regression lines indicate 95% confidence interval.

In whole brain analyses, consistent with the ROI analyses, cumulative depression was negatively correlated with activity in the dorsal and ventral striatum, as well as cortical regions including the left insula and bilateral superior frontal gyrus (p<.005 uncorrected for spatial extent, see Figure 2b, Table 3). Results from ETAC analyses confirm the significance of striatal regions of activity (see Figure S7, Table S12). Findings did not meaningfully differ when accounting for psychotropic medication (see Figure S5b and Table S8). Among the subsample followed since preschool, a mask was applied using the clusters from the full sample and analyses tested whether activation within this mask correlated with cumulative depression. All eight clusters were negatively correlated with cumulative depression, including clusters in the dorsal and ventral striatum (see Figure S6b and Table S11).

Figure 2.

BOLD response to reward anticipation in striatum associated with current depression severity and cumulative depression severity from whole brain analyses in the full sample

Images in panel A are centered at x= 14, y= 14, z= −4, and images in panel B are centered at x= −12, y= 14, z= −8 (MNI coordinates).

Table 3.

Current and cumulative depression severity associations with BOLD response to reward anticipation in whole brain analyses

Brain region	Cluster Size (# of 2mm3 voxels)	MNI coordinates
		x	y	z
Current depression severity a
Right ventral striatum	46	14	14	−4
Left middle occipital gyrus c	37	−16	−104	16
Left middle frontal gyrus c	28	−16	−0	64
Left ventral striatum	19	−12	12	−8
Right inferior temporal gyrus c	18	58	−32	−22
Left medial frontal gyrus c	13	−18	−8	58
Left cerebellar tonsil	13	−6	−54	−56
Left pons	11	−8	−20	−44
Cumulative depression severity b
Left insula	405	−50	−26	20
Left parahippocampal gyrus	325	−12	−42	0
Left ventral striatum	274	−12	14	−8
Right putamen	263	18	20	−6
Right inferior frontal gyrus	246	52	38	−6
Left caudate	218	−10	6	16
Left superior frontal gyrus	210	−26	42	30
Right superior frontal gyrus	190	30	44	32
Right lingual gyrus	171	2	−74	−2

MNI coordinates correspond to peak activation within each cluster.

^a– current depression severity clusters significant at p < .005 (uncorrected) and at least 10 voxels;

^b– cumulative depression severity cluster significant at p < .005 (uncorrected) and at least 150 voxels;

^c– clusters showing positive correlations with depression severity.

In whole brain analyses, consistent with the ROI analyses, current depression was negatively correlated with activity in the ventral striatum among the full sample (p<.005 uncorrected for spatial extent, see Figure 2a, Table 3). Four cortical clusters located in the left middle occipital gyrus, left middle frontal gyrus, right inferior temporal gyrus, and left medial frontal gyrus were also positively correlated with current depression. Results from ETAC analyses confirm the significance of striatal regions of activity (see Figure S7, Table S11). Findings did not meaningfully differ when accounting for psychotropic medication (see Figure S5a and Table S8). In the subsample followed since preschool, three clusters were negatively correlated with current depression, two in the striatum: the left and right ventral striatum and one in the left ventral pons (see Figure S6a and Table S11).

Depression severity during distinct developmental periods and response to reward anticipation

As shown in Supplemental Materials Table S3, after FDR correction, regression analyses with each developmental period as a separate regressor indicated that preschool depression severity was related to reduced activity in the cortico-striatal circuit, as well as in the caudate, putamen, insula, dACC, and rACC. School age depression severity was related to reduced activity in cortico-striatal circuit, caudate, and putamen. Adolescent depression severity was related to reduced activity in the cortico-striatal circuit and the nucleus accumbens. Findings were mostly consistent when accounting for psychotropic medication use and for the subsample followed since preschool (see Tables S7 and S10, respectively).

We then directly compared each developmental period by conducting multiple regression analyses that simultaneously included preschool, school age, and adolescent depression severity as regressors. Because these models exclude participants missing depression severity from any of the three developmental periods, only the subsample followed since preschool was used. As shown in Supplemental Materials Table S4, preschool depression severity was related to reduced activation in the cortico-striatal circuit, putamen, and the rACC. In contrast, adolescent depression severity was related to reduced activation only in the nucleus accumbens. Findings were consistent when accounting for psychotropic medication use (see Table S6).

Discussion

We replicated previous findings (5,18,44) that greater current level of depression severity was related to reduced activity in the nucleus accumbens (i.e. ventral striatum) to reward anticipation, but not receipt, in both a priori ROI and whole-brain analyses. A priori ROI analyses further revealed that cumulative depression severity was related to blunting to reward anticipation across the cortico-striatal circuit, with whole brain analyses also showing that cumulative depression severity was related to blunted activity in both the dorsal and ventral striatum. Of note, the whole brain associations did not survive very conservative whole brain correction, primarily due to the large spatial extent threshold mandated by such corrections. Supplementary analyses using equitable thresholding and clustering were used to assess for the presence of smaller, more intense clusters. The strongest results were directly consistent with the ROI based analyses in showing a relationship between current depression severity and ventral striatum activity, with broader relationships of cumulative depression across the ventral and dorsal striatum. Additional analyses demonstrated that preschool depression severity was related to blunted response to anticipation in regions including the dorsal striatum (i.e. putamen) and rostral ACC, while adolescent depression severity was related to activation in the ventral striatum (i.e. nucleus accumbens). Finally, we did not find support for any a priori relationships between depression severity and response to reward receipt.

Our finding that current depression severity was associated with focal dysfunction in the ventral striatum, while cumulative depression severity was associated with global dysfunction of the cortico-striatal circuit, has implications for future research seeking to identify risk-factors and consequences of depression. First, global blunting of the cortico-striatal circuit could represent a risk-factor for chronic or recurrent depression and might be associated with early onset and/or more severe forms of depression. This hypothesis is consistent with our finding that both cumulative depression severity and depression severity in the preschool period specifically were associated with reduced responsivity across the cortico-striatal network. This hypothesis would predict that children who go on to experience early onsets of depression or more severe or chronic depression histories should show more wide-spread dysfunction of a cortical-striatal network related to reward anticipation even prior to the onset of depression.

A second possibility is that blunting across a broad cortical-striatal network represents a scar of chronic depression. That is, with repeated exposure to depressive symptoms, particularly early in life, the cortico-striatal circuit may not develop properly, giving rise to deficits in reward processing. Further, our findings also demonstrated that current depression severity was associated with hyporeactivity of the ventral striatum to anticipation of reward. If such an association between current depressed mood state and ventral striatal hyporeactivity to reward anticipation is present across development, repeated experience of depression that starts early in childhood could lead to downstream hyporeactivity of the entire circuit. An early onset of depression may disrupt this network as the child is developing and have a cascading and broader impact. This could be tested by longitudinal studies concurrently measuring depression and neural responses to rewards from early childhood to adolescence.

One intriguing explanation for these findings is the possibility that over time blunting to rewards transitions from the ventral to the dorsal striatum, becoming a “habit” of reduced reward response. This is analogous to Everitt and Robbin’s hypotheses proposing stages of substance use. They proposed a shift in responsivity from the nucleus accumbens to the dorsolateral striatum as drug seeking behavior transitions from instrumental (i.e. controlled or voluntary) to habitual, via striato-nigro-striatal ascending anatomical connections (45,46), with ventral areas of the striatum innervating more dorsal areas via spiraling anatomical connections (47,48). The authors further posit that the striatum may interact with cortical regions to drive negatively reinforced behaviors, resulting in anhedonia (45). The current findings lend some evidence to this theory’s generalizability to depression—with a greater accumulation of depression symptoms associated with more blunted activity in the dorsal striatum and cortical regions, and acute depression more associated with blunting of the ventral striatum. If replicated, this hypothesis has implications for how we characterize and treat depression.

Finally, our findings only revealed associations between depression and reward anticipation, but not reward receipt, contrary to our hypotheses. While some studies have found blunted reactivity to both reward anticipation and receipt (1,2), others have similarly found stronger relationships between depression and reward anticipation, sometimes to the exclusion of reward receipt (7,17,18), including a study of 1576 adolescents (5). Moreover, anhedonia appears to be more strongly linked to blunted responses to reward anticipation than reward receipt (49). This dissociation has interesting implications. While blunted reactivity to reward receipts may be representative of hedonic pleasure, blunted reactivity to reward anticipation may represent deficits in learning about cues that predict reward or in being able to represent future reward experience or information. Our findings suggest the possibility that rather than failing to experience pleasure from rewards, chronic depression experienced over childhood affects motivation more than hedonic response in adolescence. One possible explanation is that reward anticipation is a developmental skill honed by learning and experience whereas hedonic response to rewards is more automatic. If so, repeated exposure to depression during development may disrupt this trajectory, resulting not in impairments to hedonic response to rewards per se, but rather in altered motivation and related aberrant reactivity of the striatum and broader regions. In fact, other studies have found that depression is related to reduced behavioral reward learning (50) and reward related decision making (51). Future studies assessing reward learning and responsivity to reward cues longitudinally will be necessary to further test this hypothesis.

A positive relationship between current depression and medial/middle prefrontal regions appeared in exploratory whole brain analyses, as has been observed in prior studies (2). One possible explanation is that depressed individuals use cognitive resources to compensate for insufficient striatal resources in order to represent the reward that follows the cue (i.e. learn the cue). This would suggest coordination between the cortico-striatal circuit and frontal regions in learning and anticipating rewards.

Limitations

First, a small sample of participants included in the full sample (n=20) were added at later waves to increase the sample size of healthy controls for the imaging waves, and therefore were missing depressive measures prior to age 9 years. The findings did not meaningfully change when this subset was excluded. Second, because rewards in the current task were based on chance, we were not able to compare neural response to reward with a behavioral measure of reward learning. At the same time, the current task avoids potential confounds that can occur with such behavioral measures, such as motor preparation between the anticipatory cue and action or task anxiety over one’s performance (52). Third, our whole brain results were significant at a p-value of .005 but did not meet the full spatial extent mandated by a conservative whole brain correction. However, for the striatum, such a large spatial extent may not be realistic. Whole brain results using equitable thresholding and clustering confirm the striatal results found in a priori ROI based results. Fourth, our a priori planned analyses focused on Win>Lose contrasts and complimentary MANCOVAs with additional cue type conditions were very consistent, but not every result replicated to the same significance level (see Supplemental Materials). Fifth, we used mean BOLD signal to measure cortico-striatal circuit activity. An interesting extension of these findings will be to test whether the functional connectivity of these regions is related to depression severity. Finally, it is often difficult to disentangle chronicity from developmental effects. Children with early-onset depression are at greater risk of experiencing more chronic depression throughout childhood, making it difficult to know whether associations between cumulative depression and cortico-striatal function is the result of early-onset depression, or a chronic course. However, our finding that nucleus accumbens activity was most associated with adolescent depression severity provides some evidence for developmental specificity. Future studies comparing youth with depression exclusively in early childhood with those who experience depression exclusively later in life could inform such questions.

Conclusions

Our findings demonstrate a relationship between cumulative depression throughout childhood and brain responses to rewards. The current study additionally distinguishes neural patterns of hyporeactivity associated with cumulative depression from those of current depression severity, and between distinct developmental periods, showing that early and cumulative experiences of depression disrupt the cortico-striatal circuit in optimally responding to rewarding cue, while acute experiences of depression occurring in adolescence exclusively disrupt the ventral striatum. Therefore, individuals with early and recent episodes of depression may both show blunted reactivity to rewards, but with differing neural contributions from concurrent versus cumulative depression history. These findings suggest that unique neurodevelopmental processes may be at play. Understanding the differences in these mechanisms is integral towards creating interventions aimed at alleviating depression.