Reward mechanism of depressive episodes in bipolar disorder: Enhanced theta power in feedback-related negativity

Highlights

• Patients with bipolar disorder (BD) depression did report anhedonia in everyday life.

• A deepened feedback-related negativity (FRN) in response to negative outcomes was observed in the classic gambling paradigm in BD depression.

• The FRN was composed by increased theta power.

Abstract

Introduction

This study aimed to explore the reward-related neural mechanism in patients with depressive mood in bipolar disorder (BD) using event-related potentials. It remains unknown whether or not different neurobiological markers underlying depression symptoms in BD depression and major depression disorder (MDD).

Methods

24 patients with BD depression and 20 healthy controls were included. Participants underwent evaluation with the Temporal Experience of Pleasure Scale (TEPS), followed by the classical gambling paradigm, while undergoing 64-channel electroencephalography. The waveform of feedback-related negativity (FRN) was extracted from the 250–350 ms time-window after participants received feedback regarding loss or gain. Event-related potential datasets were obtained using time-frequency analysis.

Results

(1) The TEPS scores of the patients were significantly lower than those of the controls [t ₍₄₂₎ = 5.16, p < 0.01]. (2) The event of loss elicited a deeper FRN in patients than that in controls [t ₍₄₂₎ = 2.19, p < 0.05], while no difference was observed in the event of gains (t ₍₄₂₎ = 1.12, p > 0.05). (3) Theta power rooted in FRN in patients was significantly higher in loss than in gain [F _(1,42) = 30.32, p < 0.01]. (4) Analysis of Variance (ANOVA) illustrated the interaction effect of theta power in gain/loss between two groups [F _(1,42) = 3.59, p = 0.06].

Limitation

Our study did not analyze the effect of different drugs which might affect our results.

Conclusion

The enhanced reflection of negative feedback was consistent with the negative bias, impulse control impairment, and emotional dysregulation observed in the bipolar disorder spectrum. We suggested that the extreme theta power generated from the anterior cingulate gyrus (ACC) might be the main component of abnormal FRN.

Introduction

Bipolar Disorder (BD), the sixth most disability with a global prevalence rate above 1% (Lúcia et al., 2017), is a chronic disease characterized by alternation between the depressive and manic states. As depressive episodes are more common than manic episodes in BD, patients with BD depression are 60% more likely to be misdiagnosed with unipolar depression, owing to the perceived uniformity in clinical symptoms (Hirschfeldet al., 2003; Koichiro et al., 2016). It would be of great interest to dissociate biological mechanism of depressive symptoms of BD depression from MDD.

The reward processing abnormalities persist in BD spectrum, including in hypomania-prone, manic, and euthymic patients. Patients often exhibit high drive and expectations (for goals) during manic episodes, while depressive episodes are characterized by a lack of interest in positive stimulation, known as anhedonia, which is also observed in major depression disorder (MDD) (Guha, 2009). According to the Behavioral Approach System (BAS) model, patients with BD exhibit high expectations and approach motivation for goals throughout the disease independent of the emotional state (mania or depression) (Lauren et al., 2010). Furthermore, the neural mechanism underlying reward-related behavior in BD may be consistent for both depressive and manic episodes, while being distinct from that of MDD, even though the same clinical symptoms are all observed in BD depression and MDD. This phenomenon is defined as "state-independent"(Chase et al., 2013). More evidence is urgently required to prove this phenomenon.

Feedback-related negativity (FRN), a mature reward-related neural biomarker, is an induced negative deflection within 250-350 ms after experiencing gain or loss during the gambling task (Hajcak et al., 2006). It appeared to induce greater negative bias when participants suffered a loss instead of gaining a reward, which led to a positive difference between the waves elicited by gain and loss. The amplitude bias of FRN in monetary loss or unfavorable results was initially interpreted to reflect the reaction to undesirable events (Holroyd et al., 2003; Marcus et al., 2008; Nusslock et al., 2014). While another reward-related event has been observed to introduce an increased positive deflection over the past 10 years. For example, patients with MDD showed a blunted FRN amplitude in response to reward, instead of an increased change in response to unfavorable outcomes (Dan and Greg, 2009; Liu et al., 2014; Carlson et al., 2011; Mueller et al., 2015), which corresponded to the concept mentioned above.

Previous studies demonstrated a more negative FRN bias in patients with BD in response to unfavorable outcomes (Mason et al., 2012; Ryu et al., 2017), which indicated that these patients were more sensitive to the gap between expectations and results. In line with the classic BAS, some studies found that individuals in remission from BD exhibited enhanced FRN in both winning and losing scenarios (Mason et al., 2016). Further exploration was needed to explain the cause of impaired reward processing in the bipolar spectrum. Current studies on the FRN of BD depression are still insufficient. The probable consistency in the neurological mechanism underlying depressive and manic episodes, and the remission period of BD are still being debated. Research is also needed to determine whether the BD depression can be distinguished from the blunted trend due to the lack of enjoyment of reward (anhedonia) observed in previous studies on MDD (Liu et al., 2014; Min et al., 2019; Wu et al., 2017).

Time-frequency analysis, which was conducted to explore the mechanism of FRN, found that FRN was composed of two waves, i.e., the delta wave (<3 Hz), which was more sensitive to reward, and the theta wave (4-7 Hz), which was sensitive to loss (Foti, 2015). The theta wave could be more active when an individual suffers a loss compared to reward (Bernat et al., 2015; Foti et al., 2015). Researchers conducted an FRN study on adolescents with depression and verified that anomalies of the theta wave were the main component of loss-related FRN (Webb et al., 2017). The study also verified the changes of theta power changes in FRN are more flexible and sensitive than the amplitude itself, which renders time-frequency analysis as the new path to be explored to elucidate the FRN mechanism.

This study included patients with BD depression and healthy controls to explore the reward-related neural mechanism underlying BD depression. We sought to inspect the characteristics of time-frequency outcomes responsible for abnormal FRN. First, this study used the Temporal Experience of Pleasure Scale (TEPS) for evaluating clinical symptoms of anhedonia (Liu et al., 2014). Second, the classic gambling paradigm was used to induce FRN waves on accepting monetary feedback. The results of TEPS and FRN would be correlated to help verifying some reasons for the reward impairment of BD depression. Third, this study tended to find more evidence for the reward-related neural mechanism by deconstructing theta activity.

The hypotheses of this study were as follows.

• Patients with BD-related depression would report a lack of pleasure while receiving rewards, as per the TEPS scale, which would be consistent with the clinical manifestations of the onset of depression.

• BD depression would exhibit a higher amplitude than that of healthy controls on the time domain analysis, reflecting the hypersensitivity to monetary circumstances.

• FRN of BD depression may be composed of abnormal theta power on frequency domain analysis as the results of previous studies.