For decades, the field searched for a universal cause of major depressive disorder (MDD). It is now clear that MDD follows the process of equifinality, whereby it is the common outcome of a wide range of genetic, physiological, and environmental factors (1). Yet for any one individual, it is not clear what unique combination of factors causes MDD to develop. Mapping specific pathways to MDD is necessary for tailored prevention efforts and intervention targets that will optimize public health outcomes. One promising approach for isolating such pathways is to focus on genetically homogenous subtypes that are likely characterized by unique pathophysiological processes (2). A recent genome-wide association study of 135,458 cases yielded 19 functionally distinct genetic pathways that confer MDD risk, each of which is a unique starting point for mapping MDD etiology (3).
Critically, one such genetic pathway is regulated by the fragile X mental retardation 1 gene (FMR1). The fragile X premutation is a 55–199 CGG repeat expansion in the FMR1 promotor region, and it occurs in approximately 1:200 women in the USA (4). Women with the Fragile X premutation (PMC) are at high risk for adult-onset MDD, with 54% developing depression by age 50, independent of parental status (5). The pathophysiological processes through which the FMR1 premutation confers increased risk for depression, however, are unknown.
One recent behavioral study found that MDD symptom severity in PMC was associated with impaired executive function (6), which is broadly consistent with MDD findings in the general population (7). This association, however, was not clinically specific: impaired executive function in PMC was also associated with self-reported symptoms of anxiety and ADHD (6), leaving it unclear whether this cognitive deficit is indicative of MDD risk per se or is instead a more general marker of psychiatric vulnerability in PMC.
To clarify this association, we turn to the error-related negativity (ERN), a neurophysiological measure of executive function that has been widely applied in clinical research, including as a risk process for MDD (8). The ERN is an event related-potential (ERP) that occurs within 100 ms of an error on speeded reaction time tasks (9, 10), represents dopaminergic innervation of the anterior cingulate cortex (11), and reflects early, pre-conscious error detection (12, 13). Many studies have found an enhanced ERN in people with MDD (14, 15), including a recent meta-analysis (16). However, a blunted ERN has also been observed in MDD, particularly in cases with melancholic symptoms (17). Critically, among individuals with comorbid mood and anxiety disorders, decreased ERN amplitude uniquely relates to MDD symptom severity (18, 19). This is a particularly important issue in PMC given high rates of co-occurring disorders (5, 20, 21).
Another candidate process of depression risk in the general population is reduced neural sensitivity to rewards, as indicated by the reward positivity (RewP), an ERP that occurs within 300 ms following reward delivery (22). RewP amplitude captures the initial evaluation of reward outcomes (23), and it correlates with reward-related BOLD signal within the medial prefrontal cortex and ventral striatum (24, 25). In the general population, the RewP amplitude is reduced in nonclinical samples with MDD symptoms (26–29), as well as adults diagnosed with MDD (30, 31). Other studies show that the RewP reduced among at-risk individuals (32), prospectively predicts illness onset (33, 34), and persists into illness remission (35). Thus, the RewP can be understood as an indicator of neurophysiological vulnerability to depression (33, 34). The RewP specifically, and reward sensitivity more broadly, is thus far unexplored in PMC. Given these findings linking the RewP to MDD vulnerability in the general population, we expect that the RewP might also be blunted in PMC.
Moreover, there is utility in combining ERP measures to characterize the neurophysiological profile of MDD risk in PMC. Each ERP may reveal unique pathophysiological predictors of illness, and their combination may reveal points of overlap and divergence with MDD risk in the general population. With regard to the ERN and RewP specifically, previous research has shown the incremental utility in combining these ERPs in order to characterize candidate process of risk for psychopathology. For example, individuals with schizophrenia exhibit a blunted ERN but an intact RewP (36, 37), indicating a neurophysiological profile that is distinct from MDD despite the symptom of anhedonia being prominent in both illnesses (38). Furthermore, early childhood research has shown that the ERN and RewP are differentially affected by stress and environment (39), and that the ERN and RewP have been shown to be uniquely related to internalizing symptoms in children and adolescents (40).
Thus, in the current study, we evaluated ERN and RewP amplitude for the first time in PMC. Reductions in ERN and RewP amplitudes among premutation carriers would suggest candidate pathophysiological processes that are consistent with the known increased risk of MDD in this population, and that are shared with MDD vulnerability in the general population.