Elsevier

NeuroImage

Volume 46, Issue 1, 15 May 2009, Pages 327-337
NeuroImage

The role of the nucleus accumbens and rostral anterior cingulate cortex in anhedonia: Integration of resting EEG, fMRI, and volumetric techniques

https://doi.org/10.1016/j.neuroimage.2009.01.058Get rights and content

Abstract

Anhedonia, the reduced propensity to experience pleasure, is a promising endophenotype and vulnerability factor for several psychiatric disorders, including depression and schizophrenia. In the present study, we used resting electroencephalography, functional magnetic resonance imaging, and volumetric analyses to probe putative associations between anhedonia and individual differences in key nodes of the brain's reward system in a non-clinical sample. We found that anhedonia, but not other symptoms of depression or anxiety, was correlated with reduced nucleus accumbens (NAcc) responses to rewards (gains in a monetary incentive delay task), reduced NAcc volume, and increased resting delta current density (i.e., decreased resting activity) in the rostral anterior cingulate cortex (rACC), an area previously implicated in positive subjective experience. In addition, NAcc reward responses were inversely associated with rACC resting delta activity, supporting the hypothesis that delta might be lawfully related to activity within the brain's reward circuit. Taken together, these results help elucidate the neural basis of anhedonia and strengthen the argument for anhedonia as an endophenotype for depression.

Introduction

Early theorists suggested that anhedonia, the reduced propensity to experience pleasure, might constitute a vulnerability factor for psychiatric disorders, including Major Depressive Disorder (MDD) and schizophrenia (e.g., Meehl, 1975, Rado, 1956). Consistent with this view, anhedonia is currently considered a promising endophenotype of MDD, because it is a cardinal symptom of the disorder but is considerably more homogeneous, more easily quantified, and tied to dysfunction in the neural circuitry of reward, which is increasingly well-understood (Hasler et al., 2004, Pizzagalli et al., 2005). Therefore, information on the neural correlates of anhedonia may provide valuable insights into the pathophysiology and etiology of psychiatric disorders and may ultimately allow for early identification of high-risk individuals.

The neural systems underlying reward and pleasure have long been the object of scientific scrutiny (for a recent review, see Berridge and Kringelbach, 2008). Starting from early self-stimulation studies in rodents performed by Olds and Milner (1954), a large body of animal work has emphasized the role of mesocorticolimbic pathways in incentive motivation and the experience of pleasure. Even before the advent of modern neuroimaging techniques, Heath (1972) demonstrated that activation of these areas has powerful, positive motivational effects in humans by documenting fervent self-stimulation in a patient implanted with electrodes into the dopamine-rich mesolimbic septum/nucleus accumbens (NAcc) region. More recently, functional magnetic resonance imaging (fMRI) and positron emission tomography (PET) studies have described increased activation in the basal ganglia, including the ventral striatum, in response to various appetitive cues (see Phan et al., 2002, for a review). Furthermore, PET studies using dopaminergic tracers have shown that the positive subjective effects of amphetamine are correlated with receptor binding in the ventral striatum (e.g., Drevets et al., 2001, Leyton et al., 2002, Oswald et al., 2005). Thus, the role of the ventral striatum in reward processing has been firmly established using multiple methods.

Neuroimaging studies have also linked the experience of pleasure to neural activity in the medial prefrontal cortex (Berridge and Kringelbach, 2008, Phan et al., 2002). In particular, Rolls and colleagues (de Araujo et al., 2003, Grabenhorst et al., 2008, Rolls et al., 2003, Rolls et al., 2008) have described an association between subjective ratings of pleasantness for a wide variety of stimuli from different modalities and responses to these stimuli in ventromedial prefrontal cortex (vmPFC) and rostral anterior cingulate cortex (rACC) regions (Fig. 1). These cortical areas receive dense dopaminergic inputs (Gaspar et al., 1989), project to the striatum (in particular the NAcc) and the ventral tegmental area (Haber et al., 2006, Öngür and Price, 2000, Sesack and Pickel, 1992), show activity increases in response to dopamine-inducing drugs (Udo de Haes et al., 2007, Völlm et al., 2004), and have been implicated in preference judgments (e.g., Paulus and Frank, 2003), consistent with a role in reward-guided decision making (Rushworth et al., 2007).

Complementing these findings, emerging evidence from neuroimaging studies in clinical samples indicates that anhedonic symptoms are linked to reward responses in key nodes of the reward system (Epstein et al., 2006, Juckel et al., 2006a, Juckel et al., 2006b, Keedwell et al., 2005, Mitterschiffthaler et al., 2003, Tremblay et al., 2005). For example, Epstein et al. (2006) reported that depressed subjects were characterized by reduced ventral striatal responses to positive pictures, and the strength of these responses was negatively correlated with self-reported anhedonia. Similarly, in a sample of twelve patients with MDD, Keedwell et al. (2005) found a negative correlation between anhedonia (but not depression severity) and ventral striatal responses to positive stimuli. Interestingly, these authors also found a positive correlation between anhedonia and responses in the vmPFC (BA10) and rACC (BA24/32). In what seems to be the only neuroimaging study on the brain correlates of anhedonia in healthy subjects, Harvey et al. (2007) did not observe a significant correlation between anhedonia and ventral striatal responses to positive pictures. They did, however, replicate Keedwell et al.'s (2005) observation of a positive correlation between anhedonia and responses to positive stimuli in a region in the vmPFC, again extending into the rACC. In addition, Harvey et al. (2007) found that anhedonia was associated with reduced volume in caudate regions extending into the NAcc.

Taken together, these previous findings suggest that anhedonia may be associated with weaker responses to positive stimuli and reduced volume in the striatum, as well as with increased responses to positive stimuli in vmPFC/rACC. The latter association is surprising, given that activity in vmPFC/rACC is also positively related to ratings of pleasure as detailed above (e.g., de Araujo et al., 2003, Grabenhorst et al., 2008, Rolls et al., 2008, Rolls et al., 2003). Importantly, the vmPFC/rACC figures prominently in the brain's default network, which is activated during resting, task-free states and becomes deactivated when participants engage in a task (Buckner et al., 2008). Indeed, converging lines of evidence raise the possibility that associations between anhedonia and task-related activation in medial frontal regions may reflect individual differences in resting state activity.

First, depression has been associated with dysfunctional resting activity in vmPFC/rACC, with some studies reporting decreased (e.g., Drevets et al., 1997, Ito et al., 1996, Mayberg et al., 1994) and others increased (e.g., Kennedy et al., 2001, Videbech et al., 2002) activity, and decreased resting rACC activity has been found to predict a poor response to treatment (Mayberg et al., 1997, Mülert et al., 2007, Pizzagalli et al., 2001). Second, using both PET and measurements of electroencephalographic (EEG) activity, Pizzagalli et al. (2004) reported decreased resting activity (i.e., reduced glucose metabolism and increased delta activity) in the subgenual ACC (BA 25) in patients with melancholia — a depressive subtype characterized by psychomotor disturbances and pervasive anhedonia. Finally, various conditions and diseases characterized by reduced resting medial PFC activity are associated with reduced task-induced medial PFC deactivation (Fletcher et al., 1998, Kennedy et al., 2006, Lustig et al., 2003), and recent findings by Grimm et al. (2009) indicate that this may also apply to depression. Specifically, these authors observed smaller task-induced deactivations in depressed individuals versus controls in several areas of the default network, including an area closely matching the ones implicated by Keedwell et al., 2005, Harvey et al., 2007. Collectively, these observations suggest that the seemingly paradoxical positive association between anhedonia and vmPFC/rACC activation to positive stimuli might be due to an association between reduced baseline activity in this area and anhedonia, resulting in smaller deactivations during stimulus-processing. To our knowledge the hypothesis of an association between lower resting vmPFC/rACC activity and anhedonia has not been tested previously.

If such an association exists, it is likely to be evident in the delta frequency band of the EEG. As Knyazev (2007) recently noted in his review of the functional roles of different EEG oscillations, a number of observations support the idea that the delta rhythm is a signature of reward processing and salience detection. First, animal studies have identified generators of delta activity in key nodes of the brain reward system, such as the NAcc (Leung and Yim, 1993), ventral pallidum (Lavin and Grace, 1996), and dopaminergic neurons of the ventral tegmental area (Grace, 1995). Second, although electrical activity in the striatum cannot be measured noninvasively in humans, EEG source localization studies have implicated anterior medial frontal regions in the generation of delta activity (Michel et al., 1992, Michel et al., 1993). Critically, these sources overlap with regions reciprocally connected to the ventral tegmental area and emerging from fMRI studies as being associated with self-reported pleasure responses (see above). Third, the available animal data suggest that dopamine release in the NAcc is associated with decreased delta activity (Chang et al., 1995, Ferger et al., 1994, Kropf and Kuschinsky, 1993, Leung and Yim, 1993, Luoh et al., 1994). Fourth, opioid and cocaine administration have been associated with changes in delta activity in humans (Greenwald and Roehrs, 2005, Reid et al., 2006, Scott et al., 1991). However, in contrast to the animal data, increases instead of decreases in delta activity were observed (see also Heath, 1972). Whereas these apparent discrepancies between animal and human data currently cannot be resolved, the available evidence nonetheless suggests that EEG delta activity may be linked to reward processing. Therefore the present study aims to further elucidate the proposed link between delta and reward.

In sum, the major goals of the present investigation were: (1) to examine whether anhedonia is negatively and positively associated with reward response in the ventral striatum and the vmPFC/rACC, respectively, as assessed by fMRI in conjunction with a monetary incentive delay task known to recruit the brain's reward network (Dillon et al., 2008); (2) to replicate Harvey et al.'s (2007) observation of an inverse association between anhedonia and striatal volume; (3) to investigate whether anhedonia is associated with increased resting EEG delta current density (i.e., decreased resting activity) in vmPFC/rACC; and (4) to probe the suggested link between EEG delta activity and the brain's reward system (Knyazev, 2007) by assessing the correlation between striatal reward responses measured via fMRI and resting EEG delta current density in the vmPFC/rACC.

Section snippets

Participants

Data from the present report stem from a larger study that integrates behavioral, electrophysiological (resting EEG, event-related potentials), and neuroimaging (fMRI, structural MRI) measures as well as molecular genetics to investigate the neurobiology of reward processing and anhedonia in a non-clinical sample. A previous publication on this sample has focused on event-related potential data collected during a reinforcement task (Santesso et al., 2008), and a report on links between

Intercorrelations of MASQ and PANAS scales

As shown in Table 1, the MASQ scales were moderately to highly correlated with each other and with PANAS state negative affect in both sessions. However, mirroring prior observations (Watson and Clark, 1995), only MASQ AD displayed a significant negative correlation with PANAS state positive affect at both sessions. Mean and standard deviation of MASQ AD (weighted by gender) did not differ from the values reported by Watson et al. (1995, Table 1) for a large student sample, t(1112) = 1.28, p = .20,

Discussion

This study integrated resting EEG, structural MRI, and fMRI to identify neural correlates of anhedonia, an important endophenotype and vulnerability factor for psychiatric disorders (e.g., Gooding et al., 2005, Hasler et al., 2004, Loas, 1996, Pizzagalli et al., 2005). As hypothesized, we observed (1) a negative association between anhedonia and NAcc responses to reward feedback (i.e., monetary gains), (2) a negative association between anhedonia and NAcc volume, and (3) a positive association

Acknowledgments

This research was supported by grants from NIMH (R01 MH68376) and NCCAM (R21 AT002974) awarded to DAP. Its content is solely the responsibility of the authors and does not necessarily represent the official views of the NIMH, NCCAM, or the National Institutes of Health. Dr. Pizzagalli has received research support from Glaxo-SmithKline and Merck & Co., Inc. for projects unrelated to this research. Jan Wacker was supported by a grant from the G.-A.-Lienert-Stiftung zur Nachwuchsförderung in

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