Target engagement and brain state dependence of transcranial magnetic stimulation: implications for clinical practice

Transcranial magnetic stimulation (TMS) is capable of noninvasively inducing lasting neuroplastic changes when applied repetitively across multiple treatment sessions. In recent years, repetitive TMS has developed into an established evidence-based treatment for various neuropsychiatric disorders such as depression. Despite significant advancements in our understanding of the mechanisms of action of TMS, there is still much to learn about how these mechanisms relate to the clinical effects observed in patients. If there is one thing about TMS that we know for sure, it is that TMS effects are state dependent. In this review, we describe how the effects of TMS on brain networks depend on various factors, including cognitive brain state, oscillatory brain state, and recent brain state history. These states play a crucial role in determining the effects of TMS at the moment of stimulation and are therefore directly linked to what is referred to as target engagement in TMS therapy. There is no control over target engagement without considering the different brain state dependencies of our TMS intervention. Clinical TMS protocols are largely ignoring this fundamental principle, which may explain the large variability and often still limited efficacy of TMS treatments. We propose that after almost 30 years of research on state dependency of TMS, it is time to change standard clinical practice by taking advantage of this fundamental principle. Rather than ignoring TMS state dependency, we can use it to our clinical advantage to improve the effectiveness of TMS treatments.