Highly task-specific and distributed neural connectivity in working memory revealed by single-trial decoding in mice and humans

Working memory (WM), the capacity to briefly and intentionally maintain mental items, is key to successful goal-directed behaviour and impaired in a range of psychiatric disorders. To date, several brain regions, connections, and types of neural activity have been correlatively associated with WM performance. However, no unifying framework to integrate these findings exits, as the degree of their species- and task-specificity remains unclear. Here, we investigate WM correlates in three task paradigms each in mice and humans, with simultaneous multi-site electrophysiological recordings. We developed a machine learning-based approach to decode WM-mediated choices in individual trials across subjects from hundreds of electrophysiological measures of neural connectivity with up to 90% prediction accuracy. Relying on predictive power as indicator of correlates of psychological functions, we unveiled a large number of task phase-specific WM-related connectivity from analysis of predictor weights in an unbiased manner. Only a few common connectivity patterns emerged across tasks. In rodents, these were thalamus-prefrontal cortex delta- and beta-frequency connectivity during memory encoding and maintenance, respectively, and hippocampal-prefrontal delta- and theta-range coupling during retrieval, in rodents. In humans, task-independent WM correlates were exclusively in the gamma-band. Mostly, however, the predictive activity patterns were unexpectedly specific to each task and always widely distributed across brain regions. Our results suggest that individual tasks cannot be used to uncover generic physiological correlates of the psychological construct termed WM and call for a new conceptualization of this cognitive domain in translational psychiatry. ### Competing Interest Statement The authors have declared no competing interest.