The intervention, the patient and the illness - Personalizing non-invasive brain stimulation in psychiatry.

Current hypotheses on the therapeutic action of non-invasive brain stimulation (NIBS) in psychiatric disorders build on the abundant data from neuroimaging studies. This makes NIBS a very promising tool for developing personalized interventions within a precision medicine framework. NIBS methods fundamentally vary in their neurophysiological properties. They comprise repetitive transcranial magnetic stimulation (rTMS) and its variants (e.g. theta burst stimulation - TBS) as well as different types of transcranial electrical stimulation (tES), with the largest body of evidence for transcranial direct current stimulation (tDCS). In the last two decades, significant conceptual progress has been made in terms of NIBS targets, i.e. from single brain regions to neural circuits and to functional connectivity as well as their states, recently leading to brain state modulating closed-loop approaches. Regarding structural and functional brain anatomy, NIBS meets an individually unique constellation, which varies across normal and pathophysiological states. Thus, individual constitutions and signatures of disorders may be indistinguishable at a given time point, but can theoretically be parsed along course- and treatment-related trajectories. We address precision interventions on three levels: 1) the NIBS intervention, 2) the constitutional factors of a single patient, and 3) the phenotypes and pathophysiology of illness. With examples from research on depressive disorders, we propose solutions and discuss future perspectives, e.g. individual MRI-based electrical field strength as a proxy for NIBS dosage, and also symptoms, their clusters, or biotypes instead of disorder focused NIBS. In conclusion, we propose interleaved research on these three levels along a general track of reverse and forward translation including both clinically directed research in preclinical model systems, and biomarker guided controlled clinical trials. Besides driving the development of safe and efficacious interventions, this framework could also deepen our understanding of psychiatric disorders at their neurophysiological underpinnings.