Research approaches for the RDoC project will differ from current practice, which typically constrains study designs not only to a single DSM/ICD patient group but also to particular clinical features. The primary focus for RDoC is on neural circuitry, with levels of analysis progressing in one of two directions: upwards from measures of circuitry function to clinically relevant variation, or downwards to the genetic and molecular/cellular factors that ultimately influence such function. From this perspective, research for RDoC can be conceived as a matrix in which the rows represent various constructs grouped hierarchically into broad domains of function (e.g., negative emotionality, cognition). The columns of the matrix denote different levels of analysis, from genetic, molecular, and cellular levels, proceeding to the circuit-level (which, as suggested above, is the focal element of the RDoC organization), and on to the level of the individual, family environment, and social context. Importantly, all of these levels are seen as affecting both the biology and psychology of mental illness. With the RDoC approach, independent variables for classification might be specified from any of these levels of analysis, with dependent variables chosen from one or more other columns. Notably, samples might include patients spanning multiple DSM diagnoses. For instance, a study of working memory might recruit patients from a psychotic disorders clinic, with the independent variable a genetic polymorphism and dependent variables comprising cognitive performance and neuroimaging of dorsolateral prefrontal cortex activation. A study of fear circuitry might include all patients presenting at an anxiety clinic, with an independent variable of defense-system reactivity (e.g., fear-potentiated startle) and dependent variables comprising scores on fear, distress, and symptom measures. While maintaining a clear focus on overt psychopathology, investigators will be encouraged to explicate the full range of a given dimension to develop thresholds for different types of interventions and identify early opportunities for preventive interventions.