The Neural Correlates of Transdiagnostic Dimensions of Psychopathology.

Psychopathology researchers have come to recognize that the boundaries between putatively distinct psychiatric disorders do not cleanly map to the more complex configurations of human experience that manifest as mental illness. This complexity stems from the fact that many putatively different psychiatric disorders share what appears at least on the surface to be common symptom features. This recognition has given rise to the Research Domain Criteria initiative, which is focused on identifying core brain-behavior relationships that may cut across traditional diagnostic boundaries. However, there are many open questions regarding such dimensions, including what the “brain” side of the brainbehavior equation entails and whether the same neural mechanisms are associated with seemingly similar behavioral dimensions across diagnostic boundaries. Three articles in this issue of the Journal report important new data that begin to help address these questions in different domains: McTeague et al., on cognitive control (1); Sharma et al., on reward processing (2); and Johnston et al., on suicidality (3). McTeague et al. (1) present an intriguing meta-analysis on alterations in task-related functional activation during cognitive control paradigms across many different forms of psychopathology, including both psychotic and nonpsychotic disorders. The context for this meta-analysis was twofold. The first was the recognition that 1) there is a heritable common component of cognitive function in humans that may reflect cognitive control (4); 2) many, if not all, forms of psychopathology are associated with impairment in cognitive control, albeit with graded severity (5); 3) there is a shared heritable dimension of general psychopathology (6); and 4) this general psychopathology dimension predicts poor cognitivecontrol and function ineveryday life (6).Thesecond contextual element was previous work identifying a set of regions that showed gray matter volume reductions across bothpsychotic andnonpsychotic disorders (7). These regions include the left and right anterior insula and dorsal anterior cingulate, a network referred to as both the “multiple cognitive demand” network and the cingulo-opercular network. This group of regions is thought to be critically involved in task control and conflict detection during performance of a wide variety of tasks (8). McTeague et al. once again found evidence for transdiagnostic alterations in the dorsal anterior cingulate and the right insula (Figure 1A) that overlapped with the regions found in their gray matter analysis. These results support the hypothesis that cognitive control impairments are a shared feature of many forms of psychopathology, and the results extend the literature by showing that such impairments are associated with shared structural and functional alterations in a circuit known to be important for cognitivecontrol.At thesametime, theresults also suggest that there may be diagnostically specific neural mechanisms that also contribute to cognitive control impairment. Specifically, McTeague et al. found that individuals with nonpsychotic disorders showed greater evidence of hyperactivation in a midcingulate/presupplementary motor area, while individuals with psychotic disorders showed greater evidence of reduced activation in the left dorsolateral prefrontal cortex, consistent with previous work (9). Sharma et al. (2) tackle a different dimension of behavior that may also be altered in many forms of psychopathology—reward responsiveness. In illnesses such as depression and psychosis, this often manifests as a reduction in reward sensitivity or motivation, a symptom typically referred to as anhedonia, although whether this involves alterations in responsiveness to reward or use of rewards to guide behavior may differ across depression and psychosis (10). Such alterations have frequently been associated with abnormalities in brain circuits suchas theventral striatum(e.g., thenucleusaccumbens), thought to be central to incentive processing, as well as cognitive control systems, thought to be important for goaldirected behavior (10). Sharma et al. examined the functional connectivity correlates of self-reports on a reward responsivity subscale of the Behavioral Activation Scale in a large sample of individuals with depression, bipolar disorder, and schizophrenia, aswell as individuals at clinical orgenetichigh risk for psychosis, along with healthy control subjects. The investigators employed a novel data-driven analytic technique to identify brain regionswhose functional connectivity varied as a function of the level of reward responsiveness. They found that reduced reward responsivity across diagnostic categories was related to 1) decreased functional These studies illustrate important ways to identify the neural and psychological mechanisms that may give rise to core behavioral dimensions of psychopathology that may cut across putatively different diagnostic entities.