Despite a large body of research addressing impaired neural functioning in major depressive disorder (MDD), relatively little is known about the neurofunctional characteristics of individuals without MDD but with subclinical levels of depressive symptoms. Studies of individuals who do not meet criteria for MDD but with subclinical levels of depressive symptoms may yield a number of insights: first, they may suggest potential neurobiologic markers of those at risk for MDD [1, 2]; second, they may shed light on hereditary and environmental influences on depressive temperament ; and third, they may suggest avenues of inquiry regarding the neurobiology of MDD risk and resilience, and thereby inform treatment and preventative intervention approaches [4, 5]. The goal of the present pilot study was to investigate linkages between regional brain activation patterns and subclinical depressive symptoms while participants were engaged in emotion regulation, resting state, and reward processing paradigms that have previously been shown to differentiate MDD and nondepressed samples. Below we outline the rationale for selecting each of these three paradigms.
Deficits in emotion regulation (ER) are thought to be central to the core features of MDD . Human and preclinical studies suggest that the prefrontal cortex influences activity in the limbic system in a top-down manner [7, 8], and numerous investigations have demonstrated abnormal recruitment of prefrontal cortical regions while individuals with MDD actively regulate responses to emotional stimuli [9, 10]. For example, Johnstone and colleagues  reported that when instructed to reappraise negatively valenced images, individuals with MDD demonstrated impaired prefrontal cortical inhibition of limbic regions as well as a divergent pattern of covariation between ventromedial prefrontal cortex and amygdala activity. Similarly, Beauregard and colleagues  reported right anterior cingulate and insular cortex hyperactivation while individuals with MDD down-regulated their emotional responses to sad images. Finally, Kanske and colleagues  reported anterior cingulate and lateral orbitofrontal cortex hyperactivation during emotion regulation in individuals with remitted MDD , supporting the framework that altered neural mechanisms of emotion regulation may indeed represent not only a state marker of MDD illness, but potentially a trait marker of MDD risk as well.
Second, we investigated resting state functional brain connectivity. A mostly midline network of correlated intrinsic brain activity is active during rest and deactive during goal-directed tasks [13, 14]. This network has been called both the “baseline state” and the “default mode network (DMN)” [15, 16]. The DMN regulates self-referential activities, including evaluating the salience of internal and external cues, remembering the past, and planning the future [13, 17]. Individuals with MDD are characterized by altered patterns of DMN activity during emotion processing tasks as well as at rest. Sheline and colleagues  reported increased activity in MDD within DMN regions (i.e., ventromedial prefrontal cortex, anterior cingulate, and lateral parietal and temporal cortices), suggesting that MDD is characterized by a failure to down-regulate DMN activity during emotion processing. Another study by the same research group  reported increased intrinsic connectivity in MDD between a precuneus seed region and dorsolateral prefrontal cortex (the so-called “dorsal nexus” for overconnected brain regions in MDD) (see also  and ). Given the centrality of the DMN for self-referential activities, abnormal DMN activity in MDD has been suggested to reflect excessive self-focus accompanied by a decreased ability to attend to cognitive tasks .
Finally, we measured frontostriatal responses during a reward processing task because multiple studies have reported altered neural mechanisms of reward processing in MDD (for a review, see ). For example, Smoski and colleagues  reported that individuals with MDD demonstrated orbital frontal cortex hyperactivity during reward selection that predicted depressive symptom severity and caudate nucleus hypoactivation during reward anticipation. Pizzagalli and colleagues  found that individuals with MDD showed decreased putamen responses during reward anticipation and decreased nucleus accumbens and caudate nucleus responses to monetary gains. Finally, Knutson and colleagues  reported increased anterior cingulate activation during reward anticipation in MDD. Taken together, these studies highlight not only that MDD is characterized by altered neural activation patterns during reward processing, but that patterns of brain activation differences in MDD are contingent on the temporal phase of the reward response. For this reason, we used a task that allowed for the dissociation of responses during reward selection, reward anticipation, and reward outcome phases of reward responding.
In summary, the purpose of the present study was to extend the literature addressing altered neural mechanisms of emotion regulation, DMN connectivity, and reward processing in MDD by examining the covariation between levels of depressive symptoms and patterns of brain activation in individuals with subclinical levels of depressive symptoms but without MDD diagnoses. Predictions were informed by the extant MDD literature reviewed above [6, 19, 22]: we hypothesized relations between subclinical depressive symptom severity and (1) lateral prefrontal cortex activity during ER; (2) precuneus-dorsolateral prefrontal cortex connectivity during the resting state scan; (3) lateral prefrontal cortex activity during reward selection; (4) striatal activity during reward anticipation; and (5) medial prefrontal cortex activity during reward outcomes. Given the higher rates of MDD in women  and because gender moderates responses to emotional images [26, 27], this pilot study examined only females, a strategy that is consistent with other neuroimaging studies examining MDD , depression risk  and depressive traits .