Abstract
In the same way that beauty lies in the eye of the beholder, what a stimulus does to the brain is determined not simply by the nature of the stimulus but by the nature of the brain that is receiving the stimulus at that instant in time. Over the past decades, therapeutic brain stimulation has typically applied open-loop fixed protocols and has largely ignored this principle. Only recent neurotechnological advancements have enabled us to predict the nature of the brain (i.e., the electrophysiological brain state in the next instance in time) with sufficient temporal precision in the range of milliseconds using feedforward algorithms applied to electroencephalography time-series data. This allows stimulation exclusively whenever the targeted brain area is in a prespecified excitability or connectivity state. Preclinical studies have shown that repetitive stimulation during a particular brain state (e.g., high-excitability state), but not during other states, results in lasting modification (e.g., long-term potentiation) of the stimulated circuits. Here, we survey the evidence that this is also possible at the systems level of the human cortex using electroencephalography-informed transcranial magnetic stimulation. We critically discuss opportunities and difficulties in developing brain state-dependent stimulation for more effective long-term modification of pathological brain networks (e.g., in major depressive disorder) than is achievable with conventional fixed protocols. The same real-time electroencephalography-informed transcranial magnetic stimulation technology will allow closing of the loop by recording the effects of stimulation. This information may enable stimulation protocol adaptation that maximizes treatment response. This way, brain states control brain stimulation, thereby introducing a paradigm shift from open-loop to closed-loop stimulation.