One ring to rule them all? - Temporospatial specificity of deep brain stimulation for treatment-resistant depression

Abstract Deep brain stimulation (DBS) for intractable cases of depression has emerged as a valuable therapeutic option during the last decade. While several locations have been intensely investigated in recent years, the literature is lacking an all-encompassing perspective thereupon asking if and how these stimulation sites relate to each other and what this may imply for the underlying mechanisms of action of this treatment modality. We aim at proposing a model of DBS mechanism of action with particular focus on several puzzling aspects regarding an apparent temporo-spatial specificity of antidepressant action, i.e. the discrepancy between protracted response after initiation of stimulation and rapid relapse upon discontinuation, as well as differential effects on psychopathology. We suggest that the pre-treatment depressive state is determined by the interaction of individual traits with dysfunctional adaptive processes as responses to stress, resulting in a disease-associated, overtly dysfunctional, equilibrium. The antidepressant action of DBS is thought to modify and re-set this equilibrium in a temporospatially distinct manner by influencing the activity states of two different brain circuitries. The idea of sequential and temporospatially distinct mechanisms of action bears implications for the assessment of psychopathology and behavior in clinical and preclinical studies as well as investigations into brain circuit activity states.