Mapping Disease Course Across the Mood Disorder Spectrum Through a Research Domain Criteria Framework

Abstract

Background: The National Institute of Mental Health Research Domain Criteria (RDoC) initiative aims to establish a neurobiologically valid framework for classifying mental illness. Here, we examined whether the RDoC construct of reward learning and three aspects of its underlying neurocircuitry predicted symptom trajectories in individuals with mood pathology.

Methods: Aligning with the RDoC approach, we recruited individuals (n = 80 with mood disorders [58 unipolar and 22 bipolar] and n = 32 control subjects; 63.4% female) based on their performance on a laboratory-based reward learning task rather than clinical diagnosis. We then assessed 1) anterior cingulate cortex prediction errors using electroencephalography, 2) striatal reward prediction errors using functional magnetic resonance imaging, and 3) medial prefrontal cortex glutamatergic function (mPFC Gln/Glu) using ¹H magnetic resonance spectroscopy. Severity of anhedonia, (hypo)mania, and impulsivity were measured at baseline, 3 months, and 6 months.

Results: Greater homogeneity in aspects of brain function (mPFC Gln/Glu) was observed when individuals were classified according to reward learning ability rather than diagnosis. Furthermore, mPFC Gln/Glu levels predicted more severe (hypo)manic symptoms cross-sectionally, predicted worsening (hypo)manic symptoms longitudinally, and explained greater variance in future (hypo)manic symptoms than diagnostic information. However, rather than being transdiagnostic, this effect was specific to individuals with bipolar disorder. Prediction error indices were unrelated to symptom severity.

Conclusions: Although findings are preliminary and require replication, they suggest that heightened mPFC Gln/Glu warrants further consideration as a predictor of future (hypo)mania. Importantly, this work highlights the value of an RDoC approach that works in tandem with, rather than independent of, traditional diagnostic frameworks.

Keywords: Bipolar disorder; Depression; Dopamine; Glutamate; Reward learning; Reward prediction error.

Figure 1.

Study methods overview Panel A shows a summary of the study flow. Participants were screened on a Probabilistic Reward Task (PRT) and the patient group was recruited so that their scores on the PRT spanned the entire range of possible scores on a pre-existing normative distribution. If eligible, a clinical assessment was conducted, then participants returned for two baseline neuroimaging visits (EEG and fMRI/MRS sessions), as well as 3- and 6-month follow-up assessments. Panel B displays source localization analyses demonstrating that scalp-recorded RewP amplitude correlated with current source density in the dorsal ACC (p<0.005 uncorrected; x=−3), validating RewP amplitude as a marker of ACC-mediated activation. Panel C shows the bilateral NAc region-of-interest (y=10) from which striatal RPEs were extracted. Panel D shows the 2 × 2 × 2cm voxel placed in the mPFC (x=0), from which Gln/Glu metabolites were extracted.

Figure 2.

Recruitment based on behavioral reward learning Panel A shows the number of participants with mood pathology whose PRT performance fell in each quintile of reward learning performance according to the normative distribution (the normative distribution was based on a separate existing sample of N=572 healthy controls). The dotted line indicates the a priori target of n=16 per quintile that was set to ensure that we recruited individuals who spanned the entire range of reward learning performance. This target was met in all but the lowest quintile, however, this quintile was still adequately represented with a sample of n=13. Panel B shows frequency histograms of reward learning performance across the control, unipolar and bipolar groups.

Figure 3.

Group × mPFC Gln/Glu interaction for longitudinal (hypo)manic symptom severity Residualized scatter plots showing the relationship between mPFC Gln/Glu and (hypo)manic symptom severity (BISS-mania subscale scores) at baseline (A, B) and at the 3-month follow-up assessment (C, D) in the unipolar and bipolar mood disorder groups. Residualized values on each axis control for the other variables in the model, which were: age, sex, baseline BISS-mania subscale scores, ΔRewP amplitude, NAc RPE beta weights.