This article examines contemporary efforts to integrate transactional analysis with neuroscience achievements and clinical psychiatry. Drawing on the ideas of Zefiro Mellacqua, recipient of the Eric Berne Memorial Award, it explores the development of a research programme aimed at identifying the neurobiological foundations of Eric Berne’s classical concepts. The article demonstrates the succession between Berne’s later works, the publications of James Allen, and modern concepts of the functioning of distributed neural networks in the brain. Particular attention is given to the concept of psychic organs, the contemporary understanding of ego states as dynamic functional processes, neural networks and neuroplasticity, and the mechanisms that influence personality development and, consequently, the possibility of psychotherapeutic change. The article analyses hypotheses concerning the potential neurobiological correlates of psychic organs and their significance for the further development of transactional analysis theory, as well as for understanding the structure of ego states across different modes of brain functioning. Differences between pharmacological treatment and psychotherapy are discussed solely as one of the contexts of contemporary scientific debate that encourages a reconsideration of Berne’s ideas in light of neuroscientific evidence. The article concludes that interdisciplinary dialogue is becoming increasingly important for the development of transactional analysis as a scientifically grounded psychotherapeutic approach.