Transcranial brain stimulation: closing the loop between brain and stimulation

Abstract

Purpose of review: To discuss recent strategies for boosting the efficacy of noninvasive transcranial brain stimulation to improve human brain function.

Recent findings: Recent research exposed substantial intra- and inter-individual variability in response to plasticity-inducing transcranial brain stimulation. Trait-related and state-related determinants contribute to this variability, challenging the standard approach to apply stimulation in a rigid, one-size-fits-all fashion. Several strategies have been identified to reduce variability and maximize the plasticity-inducing effects of noninvasive transcranial brain stimulation. Priming interventions or paired associative stimulation can be used to 'standardize' the brain-state and hereby, homogenize the group response to stimulation. Neuroanatomical and neurochemical profiling based on magnetic resonance imaging and spectroscopy can capture trait-related and state-related variability. Fluctuations in brain-states can be traced online with functional brain imaging and inform the timing or other settings of transcranial brain stimulation. State-informed open-loop stimulation is aligned to the expression of a predefined brain state, according to prespecified rules. In contrast, adaptive closed-loop stimulation dynamically adjusts stimulation settings based on the occurrence of stimulation-induced state changes.

Summary: Approaches that take into account trait-related and state-related determinants of stimulation-induced plasticity bear considerable potential to establish noninvasive transcranial brain stimulation as interventional therapeutic tool.

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FIGURE 1

Towards closed-loop NTBS. (a1) Standard application of NTBS. The protocol is selected based on its known average impact on physiological or behavioral variables. It is applied stereotypically in all patients or participants. (a2) The best protocol among some alternatives is selected based on prior measurements of markers, which have been demonstrated to be predictive of individual outcome. (a3) A combination of protocols is used to stabilize outcome. Initially, a protocol is applied which is known to ‘set’ the brain in a state that renders it sensitive to the main NTBS protocol. (b) Markers of a preselected brain state are continuously read out and used to align the application of the NTBS protocol. Electroencephalography (EEG) band activity is a feasible marker with good temporal resolution. This approach cannot only be applied during rest, but also to align the NTBS protocol with task-related activity. (c) Full closed-loop application of an adaptable NTBS protocol. In this setting, neuroimaging (or another readout) is used to assess markers of the immediate effects of the NTBS protocol on brain activity. These markers are then used for on-the-fly adaptations of the protocol.

FIGURE 2

Timescales of changes in neuroanatomy, neurochemistry and neurophysiology determining the ability of NTBS to induce long-term potentiation (LTP)-like or long term depression (LTD)-like plasticity. Neuroanatomical changes on the microscopic level (such as myelination) and the macroscopic level (such as cortical thickness or folding pattern) are slow and it can be assumed that neuroanatomical features remain constant for the duration of a brain stimulation protocol. Neurochemical changes can be faster and can be influenced by the time of the day (which is an easily controllable factor), but also faster acting factors such as motivation. Neurochemical features can undergo changes during the administration of NTBS. Neurophysiological changes can occur on the sub-second time scale. For example, attentional changes or changes of the involvement of the stimulated area in the time course of a behavioral task can be very fast. They lend themselves best for the usage in online control settings based on central and peripheral markers of brain state. NTBS, noninvasive transcranial brain stimulation.