Functional neuroimaging of the human lateral septum: a systematic review of behavioral correlates and anatomical localization

Abstract

Abstract The lateral septum (LS) is a basal forebrain structure extensively studied in rodents, where it regulates social behavior, stress, and motivation. In humans, its subtle anatomy and poor delineation limit systematic investigation with non-invasive imaging. We present the first systematic review of functional neuroimaging studies reporting LS activation in humans. Following PRISMA guidelines and a preregistered protocol, we found 3728 records. After screening, 26 studies met inclusion criteria. LS activations were categorized by behavioral domain, and spatial coordinates mapped for convergence. Reported LS/septal area activation was associated with prosocial processes including empathy, caregiving, trust, cooperation, and charitable decisions. LS activation was also associated with affiliative reward, sexual arousal, and affective states like guilt and gratitude, with alterations noted in depression. Coordinate-based mapping (where available) showed a tentative tendency toward left/anterior localization for social cognition-related activations in the left anterior septal area, though localization varied across studies due to anatomical and methodological challenges. Overall, the literature suggests the LS/septal area may contribute to multiple social-affective and motivational processes, but anatomical specificity remains uncertain. Despite challenges to measure LS function in humans, new neuroimaging techniques may elucidate LS function. This review highlights the LS as an underexplored but potentially critical structure for human socio-emotional and motivational processes, with clinical relevance for psychiatric conditions.