Alexander T. Sack, Jasmina Paneva, Tara Küthe, Eva Dijkstra, Lauren Zwienenberg, Martijn Arns, and Teresa Schuhmann
ABSTRACT
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 ef cacy 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.
CONCLUSIONS AND IMPLICATIONS FOR CLINICAL PRACTICE
It has been demonstrated that TMS has state-dependent effects in the human brain, whereby both the immediate and long-term effects of TMS, including plasticity, are contingent upon the cognitive, emotional, and/or perceptual state of the individual at the time of stimulation, as well as on the spontaneously fluctuating oscillatory brain state. Additionally, the efficacy of TMS therapy can be further influenced by the previous history of neural activity prior to stimulation, potentially leading to a reversal in polarity of the intended effects. This means nothing less than that the target engagement of our TMS intervention cannot be controlled reliably without systematically considering and co-controlling the different brain state dependencies of our TMS therapy. Surprisingly, however, clinical TMS protocols are largely ignoring this fundamental principle, which may explain the large variability and often still limited efficacy of TMS treatments.
We argue here that it is time to change this practice and replace standard clinical TMS by personalized state-dependent TMS protocols. There are several approaches available to this end, including the combination of TMS with a simultaneously applied cognitive intervention (e.g., cognitive engagement) (24–26,54). Li et al. (81), for example, combined TMS over the DLPFC for the treatment of depression, with a computerized rostral ACC–engaging cognitive task. They revealed that this manipulation of patients’ cognitive brain state augmented the antidepressant effects to rTMS treatment with more reduction in total depression scores, more responders, and more remitters as compared with standard rTMS (81). Donse et al. (82) demonstrated high response and remission rates when simultaneously combining rTMS over right DLPFC with psychotherapy.
In addition to cognitive state–dependent interventions, EEG-informed or even EEG-triggered closed-loop TMS protocols are now available, capable of stimulating at particular amplitudes or phases of simultaneously recorded and analyzed EEG-indexed oscillatory states (83–85). Zrenner et al. (86) showed in 2020 that oscillatory state–dependent rTMS of the left DLPFC is feasible and capable of inducing fast neuromodulatory effects in patients with antidepressant-resistant depression. Our own group has also developed a user-friendly, hardware-software system for oscillatory state–dependent TMS neuromodulation (84), which allows the user to bring oscillatory state under experimental control using transcranial alternating current stimulation, and to then apply the TMS pulse at predetermined oscillatory parameters (phase or power) of the endogenous brain oscillations (84,85).
Finally, priming or preconditioning TMS with a preceding tDCS (or rTMS) session could be a clinically powerful means to capitalize on the described processes of homeostatic plasticity, leading to more stable and consistent rTMS-induced neuroplastic changes within and between patients. In a meta-analysis, Brunoni et al. (87) indeed already concluded 5 years ago that the estimated relative ranking of effective TMS depression treatments suggests that priming rTMS may be among the most efficacious of all current rTMS strategies.
Still, none of these state-dependent TMS approaches listed above are widely accepted and/or adopted in clinical practice today. In fact, many clinicians focus solely on the best TMS protocol or the best parameters for stimulation, assuming that the state of the brain of their patients during TMS plays no role for the efficacy of the treatment. Clinicians even often introduce various ways of making patients most comfortable during the TMS sessions, allowing them to listen to music, watch a movie, or even fall asleep during TMS. It is vital to be aware that all of these different states could also affect the efficacy of TMS therapy. We cannot yet recommend which exact state is desired or should be avoided for a given TMS therapy (e.g., depression) in a given patient, but this will hopefully change in the next 5 years.