Theta burst stimulation in humans: a need for better understanding effects of brain stimulation in health and disease.

Repetitive transcranial stimulation (rTMS) paradigms have been used to induce lasting changes in brain activity and excitability. Previous methods of stimulation were long, often ineffective and produced short-lived and variable results. A new non-invasive brain stimulation technique was developed in John Rothwell's laboratory in the early 2000s, which was named 'theta burst stimulation' (TBS). This used rTMS applied in burst patterns of newly acquired 50 Hz rTMS machines, which emulated long-term potentiation/depression-like effects in brain slices. This stimulation paradigm created long-lasting changes in brain excitability, using efficient, very rapid stimulation, which would affect behaviour, with the aim to influence neurological diseases in humans. We describe the development of this technique, including findings and limitations identified since then. We discuss how pitfalls facing TBS reflect those involving both older and newer, non-invasive stimulation techniques, with suggestions of how to overcome these, using personalised, 'closed loop' stimulation methods. The challenge in most non-invasive stimulation techniques remains in identifying their exact mechanisms of action in the context of neurological disease models. The development of TBS provides the backdrop for describing John's contribution to the field, inspiring our own scientific endeavour thanks to his unconditional support, and unfailing kindness.