Elsevier

Neurobiology of Disease

Volume 52, April 2013, Pages 66-74
Neurobiology of Disease

Neural response to reward as a predictor of increases in depressive symptoms in adolescence

https://doi.org/10.1016/j.nbd.2012.03.039Get rights and content

Abstract

Adolescence is a developmental period characterized by significant increases in the onset of depression, but also by increases in depressive symptoms, even among psychiatrically healthy youth. Disrupted reward function has been postulated as a critical factor in the development of depression, but it is still unclear which adolescents are particularly at risk for rising depressive symptoms. We provide a conceptual stance on gender, pubertal development, and reward type as potential moderators of the association between neural response to reward and rises in depressive symptoms. In addition, we describe preliminary findings that support claims of this conceptual stance. We propose that (1) status-related rewards may be particularly salient for eliciting neural response relevant to depressive symptoms in boys, whereas social rewards may be more salient for eliciting neural response relevant to depressive symptoms in girls and (2) the pattern of reduced striatal response and enhanced medial prefrontal response to reward may be particularly predictive of depressive symptoms in pubertal adolescents. We found that greater vmPFC activation when winning rewards predicted greater increases in depressive symptoms over 2 years, for boys only, and less striatal activation when anticipating rewards predicted greater increases in depressive symptoms over 2 years, for adolescents in mid to late pubertal stages but not those in pre to early puberty. We also propose directions for future studies, including the investigation of social vs. monetary reward directly and the longitudinal assessment of parallel changes in pubertal development, neural response to reward, and depressive symptoms.

Introduction

Rates of depressive episodes rise significantly during adolescence with age 15 found to be the peak age of onset (Lewinsohn et al., 1994). Not only do many adolescents experience their first depressive episode during this time period, many additional adolescents experience subthreshold rises in depressive symptoms that are nevertheless distressing and interfere with adolescent development (Lewinsohn et al., 2000). This increase in depressive symptoms during adolescence appears normative in some ways (Sawyer et al., 2009) but there are also individual differences in the increase.

Much research has been conducted to delineate risk factors that may contribute to risk for onset of clinical depression during adolescence (Cicchetti and Toth, 1998, Davey et al., 2008, Forbes and Dahl, 2005). Depression is characterized by a number of symptoms including elevated negative affect and disturbances in sleep and appetite, but it is consistently distinguished from other affective disorders by dysregulation in positive affect and low reward responding (for review, see Forbes and Dahl, 2005). Accordingly, adolescents with Major Depressive Disorder (MDD) have less striatal response and more ventral medial prefrontal cortex (vmPFC) response to monetary reward (Forbes et al., 2006, Forbes et al., 2009). Similarly, adolescents at risk for MDD (via familial history) also have less striatal response to pleasant stimuli (Monk et al., 2008) and monetary reward (Gotlib et al., 2010). These findings suggest that reward-related changes may be related to rises in depressive symptoms in youth during adolescence prior to onset of clinical levels of depression.

According to Davey et al.'s (2008) developmental model of depression, social (e.g., greater peer affliation) and neural (e.g., reward circuitry maturation) developmental changes in adolescence result in reward-related changes that may increase risk for depression during this time period. These concurrent neural and social changes during adolescence make pursuit of rewards not only more valued but also more purposeful, leading to increased use of executive function to set and work toward abstract goals involving social rewards (Davey et al., 2008). As a result, challenges or failures in obtaining dearly-valued social goals (e.g., becoming romantically involved with someone, joining a high-status peer group) can put vulnerable adolescents on a trajectory toward disrupted reward responding and, eventually, depression. Feedback to the developing dopamine system at this sensitive time in development might then lead to disrupted neural reward function and, then, depressive symptoms (Davey et al., 2008).

What is not explained by Davey et al.'s (2008) model is why some adolescents show clinically significant increases in depressive symptoms during adolescence, whereas others do not, despite these normative social and neural developmental changes. The current paper postulates that individual differences in reward function early in adolescence could predict increases in depressive symptoms—placing some adolescents at greater risk for developing clinical levels of the disorder in the future—and that the association between reward function and depression may be moderated by gender, pubertal development, and reward type. Specifically, we postulate that less striatal response and more vmPFC response to anticipation and gain of rewards during adolescence increases adolescents’ risk for depression during this developmental time period. Moreover, we hypothesize that this brain-behavior association unfolds in the context of pubertal development and the combination of gender and reward type, with status rewards as more salient to boys and affiliative rewards as more salient to girls.

Our goal is to put forward a more detailed conceptual model of reward function in the development of adolescent depression, rather than to offer a definitive explanation for the emerging gender difference in the prevalence rate of adolescent depression or the increase in depression with pubertal changes. Therefore, addressing other important etiological issues such as the role of stressful life events or cognitive bias toward negative information on depression is beyond the scope of this paper. We offer a conceptual model for putative differing mechanisms of risk—based on disrupted reward systems in differing contexts—for depression depending on adolescent characteristics (e.g., gender, pubertal stage). We outline previous literature on reward-related regions, the striatum and vmPFC, and their association with the development of depression. In addition, to provide proof of concept for our model that could inspire future research, we describe preliminary empirical support for the role of gender and pubertal development as moderating factors of reward-depression associations, and we raise questions that may be tested empirically in future research.

The striatum is a region of the brain typically associated with positive affect and reward (Forbes, 2009, Haber and Knutson, 2009). Function of the striatum appears to be relatively specific, with activation in the striatum found in response to reward win but not reward loss in many studies (for review, see Knutson and Greer, 2008). In adolescents without diagnoses of depression, striatal response is positively associated with subjective positive affect and inversely associated with depressive symptoms (Forbes et al., 2009, Forbes et al., 2010). Previous research has demonstrated that, similar to adults with depression (Epstein et al., 2006, Smoski et al., 2009), adolescents with clinical diagnoses of depression show less striatal activation during a reward decision-making task compared to healthy adolescents (Forbes et al., 2006, Forbes et al., 2009). Indeed, a recent meta-analysis conducted by our group indicates that low striatal response to monetary reward is consistent across studies of adult and adolescent depression (Olino and Forbes, in preparation).

Adolescents may be showing reward-related differences in striatal reactivity prior to onset of depression, and these patterns of neural response, especially during periods of developmental sensitivity, may even be predictive of depression. While previous findings (Forbes et al., 2006, Forbes et al., 2009, Forbes et al., 2010) indicate associations between depression and neural response to reward, they do not provide us with information about when reward-related developmental changes occur in relation to rise of depressive symptoms. Studies of adolescents at risk for depression (Gotlib et al., 2010, Monk et al., 2008) have reported less response to reward in the striatum compared to low risk adolescents, suggesting that alterations in reward function could precede the onset of clinical levels of depression. However, because these studies did not examine changes in depressive symptoms in their samples, more research examining adolescents' striatal reactivity is needed to clarify whether these neural differences in reward function subsequently predict later increases in depressive symptoms.

The vmPFC plays an important role in the regulation of affect and may foster the formation of and pursuit of abstract social and emotional goals (e.g., establishing social status, initiating a romantic relationship; Davey et al., 2008). In addition to abstract reward processing, many subregions of the vmPFC (i.e., the Anterior Cingulate (ACC), Brodmann area (BA) 32, and medial BA 10) have been associated with the processing of self-performance and self-mastery in relation to others (Amodio and Frith, 2006, Haber and Knutson, 2009, Masten et al., 2011). The ACC, in particular, plays a role in reward decision making and self-evaluation in social contexts and is highly interconnected with the ventral striatum, among other brain regions (Haber and Knutson, 2009). Greater activation in the ACC during social peer-rejection fMRI paradigms has been associated with depressive symptoms (Masten et al., 2011).

Depressive symptoms may putatively be associated with distorted self-perception of the ability to obtain rewards successfully, with excessive focus on the loss of status or on difficulties obtaining reward. Indeed, increased mPFC response to reward has been associated with depression in adults (Knutson et al., 2008) and adolescents (Forbes, 2009), possibly reflecting difficulty regulating striatal response or disengaging from self-focused cognition during rewarding experiences (Forbes and Dahl, 2012). The vmPFC has reciprocal connections with the striatum, and, given the inverse relation of cortical and striatal dopamine function (Grace, 1993), is thought to serve a regulatory role for the striatum (Price and Drevets, 2010). In terms of development of symptoms, some adolescents may be at greater risk for rises in depressive symptoms because of increased activation in these self-processing areas (Forbes et al., 2010).

Other regions have also been implicated in reward processing, including the amygdala and orbitofrontal cortex (OFC; Haber & Knutson, 2009). Whereas our conceptual framework focuses on the ventral striatum (due to its role in affective experience in pleasant and rewarding stimuli) and the vmPFC (due its cognitive and regulatory role in reward seeking and attainment), research has also found that monetary and social rewards are associated with activation in the amygdala and OFC (e.g., Davey et al., 2010, Monk et al., 2008). Imaging studies that examine the association between reward-related differences and risk for depression should consider these regions as well.

In order to provide a more comprehensive conceptual model of reward function in adolescent risk for depression, we postulate that the association of reward-related changes and depressive symptoms is moderated by (1) gender differences in response to specific types of reward and (2) pubertal development. We provide more detail on these hypotheses below.

Although girls are at greater risk for depressive symptoms than boys starting at adolescence (Essau et al., 2010), boys also experience an increase in depressive symptoms during this time period (Cicchetti and Toth, 1998), and depression disrupts the academic and social functioning of both male and female adolescents (Lewinsohn et al., 2000). Many conceptual models have studied the impact of negative life events and stressors in girls in order to explain the emergence of depression (Hankin et al., 2007). However, this research has originated from models of stress in the etiology of depression. From a reward function perspective, it is not only important to examine whether neural response to reward is related to depression but to elaborate on how different types of reward may be relevant to depression (Forbes, 2009), and furthermore, whether these types of reward are similarly important to the development of depression in boys and girls.

The salience of different types of rewarding goals may differ for boys and girls. Conceptual perspectives have emphasized the importance of social reward in the development of adolescent depression (Davey et al., 2008, Forbes, 2009), and more affiliative social stressors (loss of a friend, end of a romantic relationship) are postulated to be more problematic for girls, whereas more power-oriented social stressors (threat to social status, reputation) may be more critical for boys (Guyer et al., 2009, Oldehinkel et al., 2007, Stroud et al., 2002). For instance, Conger et al. (1993) found that adult men showed greater sensitivity to financial stress, while women showed greater sensitivity to familial social stressors (Conger et al., 1993). Similarly, Stroud et al. (2002) found that adult men showed greater cortisol reactivity to achievement related stress, whereas adult women showed greater cortisol reactivity to social rejection stress. Similar differences in reward type based on gender have also been found with adolescents. Based on a meta-analytic review of literature on adolescent peer relationships, Rose and Rudolph (2006) suggest that adolescent boys and girls also differ in how they value and respond to social rewards, with boys valuing status-related rewards associated with social groups and girls placing greater value on deeper social connections within the group. Based on this previous literature, we are postulating about mean differences, and we note that both boys and girls value each of these social rewards (affliative bonds and social status) and that individual differences may indicate that some boys value affliative social rewards more than social status (and vice versa).

From a threat-reduction model of depression, girls and boys may minimize reward-seeking behavior in forming affiliative bonds and establishing social status, respectively, in order to decrease the risk for disappointment. Less reward-seeking behavior may increase likelihood for depressive symptoms for both genders, but in differing ways. In other words, both boys and girls may both be experiencing social changes in adolescence that explain a general increase in depressive symptoms but the types of social changes that occur may be different. It is possible that the social rewards that girls seek (e.g. affliative social bonds) may be more tenuous and easily thwarted (Hankin et al., 2007) than those sought by boys (e.g., social status).

Few researchers have explicitly examined gender differences in neural responses to different types of rewarding stimuli as predictors of depressive symptoms across adolescence. However, many researchers have suggested the need for such evaluation (Gotlib et al., 2010, Masten et al., 2011). At any rate, studies evaluating reward-related differences and depression in both male and female adolescents are needed to examine neural response to ecologically valid and valued rewards for both genders (both affiliative and status-related rewards).

Adolescents who have reached mid-to-late puberty and exhibit a pattern of low striatal or high mPFC response to reward might be particularly likely to experience an increase in depressive symptoms. With the marked rise of depressive symptoms occurring during adolescence, pubertal changes appear to be directly related to risk for depression. Peak age of onset for depression appears to coincide with average age of pubertal completion, and depressive symptoms increase with pubertal development (Angold and Worthman, 1993). Conceptual models propose that neural changes (e.g. striatal and mPFC development) that occur during adolescent pubertal development contribute greatly to rise in depressive symptoms during this time period (Davey et al., 2008). And, as mentioned above, the pattern of low striatal response and high mPFC response to reward receipt is associated both with pubertal development and depressive symptoms in adolescents (Forbes et al., 2010). Taken together, the association between reward response, pubertal changes, and adolescent depression suggests that pubertal maturation plays a key moderating role in the influence of reward function on rises in depressive symptoms across adolescence. However, as existing studies have been cross-sectional, it is not clear whether these reward-related changes that co-occur with pubertal development affect the development of depressive symptoms over time. As indicated by findings that the association between high cortisol reactivity and depression is moderated by pubertal development (Hankin et al., 2010) and that associations between striatal and mPFC response and depressive symptoms were much stronger in mid/late pubertal adolescents than in pre/early pubertal adolescents (Forbes et al., 2010), such a developmental stance is critical to elucidating neural mechanisms of depression.

In sum, we propose that developmental social changes and neural changes interact to increase risk for depression during adolescence. Neurally, adolescents undergo greater maturation of the vmPFC, changes in vmPFC function, and maturation of the dopamine system (Davey et al., 2008). These neural changes appear to be influenced by pubertal maturation, rather than age. And, while biological in nature, they may be reinforced by social behaviors that are also changing during this developmental period—adolescents spend more time with peers and engage in greater reward-seeking behaviors than during childhood (Steinberg, 2008). Together, these social and neural changes make experiencing social rewards more valued during this developmental period. Despite these developmental changes that occur on average among adolescents, individual differences greatly influence the kind of social rewards that are valued and the degree to which these rewards are pursued. We suggest that gender is associated with salience of reward type, and thus with the association between depression and neural response to reward type. We examine these relations in particular in our empirical findings below.

To illustrate our conceptual model of reward-related mechanisms of risk for depression in adolescents, we provide two case examples drawn from clinical cases. These cases highlight reward-related changes that may be associated with depressive symptoms and illustrate how they may be moderated by gender. The first case includes changes in seeking social rewards associated with affliative bonds in a female adolescent, whereas the second case demonstrates changes in seeking status based rewards in a male adolescent. Both cases illustrate the abstract and distal nature of rewards that are common in adolescence and may be both related to vmPFC and striatal activity.

Case 1

M. K. is a 14 year-old girl brought to an outpatient clinic by her mother, who was concerned about her recent social isolation and irritability. Her mother reports that although her daughter always had a very positive and enthusiastic attitude, she now seems flat and spends most of her time alone in her room. She also reports that she suspects this is related to trouble with a boy with whom M.K. has been romantically involved over the last year. M. K. confirms numerous ups and downs in her relationship with a boy at school with whom she recently had her first sexual experience. She reports that although she loves him, feels he is her “soulmate”, and plans to marry him, she recently learned that he has been unfaithful to her. She reports that this has hurt her very badly because she trusted him and imagined a future together. This experience has led her to question the “goodness” and loyalty of people around her. She reports spending most of her free time in her room by herself, because she has lost interest in spending time with others—even her best friend. She also reports that although she used to participate in dance and band, where she had several friendships, she no longer enjoys those activities, and has stopped participating in recent months.

Case 2

T. R. is a 16 year old boy who presented to the clinic after making suicidal statements to an older cousin. Upon presenting to the clinic, he stated that he had been a popular and well-liked teen in his school in past years. Recently, however, he had begun to withdraw from interactions with his peers. He noted that in addition to feeling sad and frustrated much of the time, he felt unmotivated to pursue many of his interests including writing and playing music. He indicated that he had enjoyed being known as a good rapper and musician among his peers and he had often been asked to perform some of his newest music. He had planned to pursue a professional career in music following graduating from high school. He mentioned liking many aspects of music culture, in particular hip hop culture. He wanted to achieve the recognition that many of his favorite artists had achieved. He had experienced a taste of that type of recognition in the past within his peer group. However, recently his parents had greatly limited the time he spent on music as they wanted him to pursue a different career path. As a result, there was much parent–child conflict over him attending college, and he found himself blocked from pursuing a dearly held goal. He stated that as a result of his parents’ influence, he was struggling with losing the reputation and status among his peers as being a good musician. He noted that he felt that he would not win in life: either he would lose the respect of his parents or of his friends.

Here, we provide empirical data that show initial support for our conceptual model that differences in reward-related functioning (both in anticipating and obtaining rewards) explain the increases in depressive symptoms observed during adolescence. This study serves as a starting point for more comprehensive measurement of reward-related risk for depression in adolescents.

Hypotheses

We evaluated the role of striatal and vmPFC activation during anticipation and win of monetary reward as predictors of increases in depressive symptoms across a 2-year period of adolescence in a sample of psychiatrically healthy adolescents. Adolescents in our sample were part of a larger study of reward function in normal adolescent brain development, and results on puberty and neural response to reward from this study have previously been reported (Forbes et al., 2010). However, the contribution of individual differences in reward function (as influenced by gender and pubertal maturation) to rises in depressive symptoms across adolescence—or the moderation of this association by gender or pubertal development—was not examined by Forbes et al. (2010), nor has it been studied by other researchers, to our knowledge. Thus, we evaluated the proposed hypotheses in this sample in order to examine the association of reward-related differences (moderated by gender and reward type and by puberty) with depressive symptoms in healthy adolescents. While this sample was not recruited for clinical-level depression, it is a typical community sample, which makes it suitable for evaluating changes in depressive symptoms occurring before the usual age of onset of depression. Depressive symptoms were measured longitudinally in this sample, providing an opportunity to examine these data as a preliminary test of our hypotheses.

Based on our conceptual model, we hypothesized that 1) less striatal activation and greater vmPFC activation during reward anticipation and reward win would predict greater increases in depressive symptoms; 2) because monetary reward reflects status (Izuma et al., 2008) the association between striatal and vmPFC activation and increases in depressive symptoms would be stronger for boys rather than girls; and 3) the association between striatal and vmPFC activation and increases in depressive symptoms would be stronger for adolescents in mid to late puberty rather than pre/early puberty.

Section snippets

Participants and procedure

The final sample included 72 adolescents—40 girls, 32 boys. Sixty-three of these adolescents provided pubertal stage data. Consistent with our previous approach to examining affective development (Forbes et al., 2006), we classified adolescents as pre/early pubertal if they were Tanner breast/genital stage 1 or 2 (n = 23) and as mid/late pubertal if they were stage 3, 4, or 5 (n = 40).

Adolescents were recruited from the community through advertisements, flyers, and demographically targeted phone

Depressive symptoms

The means and standard deviations for time 1, time 2, and residualized change in depressive symptoms are listed in Table 1. Girls had higher levels of depressive symptoms than boys at time 2 (F = 4.05, p < .05). Gender was unrelated to depressive symptoms at time 1 or change in symptoms from time 1 to time 2. Girls were more likely to be in pre/early puberty than boys at time 1 (χ2 = 8.05, p < .01). Pubertal development at time 1 was unassociated with depressive symptoms at time 1 or time 2 and with

Discussion

The current conceptual model provides a framework for understanding how reward-related differences in brain function during adolescence may increase the risk for depression for adolescents based on their gender and pubertal development. Previous conceptual models have focused on individual differences in environmental and social stressors and negative life events as predictors of risk (Hankin et al., 2004) or on reward-related differences that may increase risk for adolescents as a whole (Davey

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