Reliability and Validity of Transcranial Magnetic Stimulation-Electroencephalography Biomarkers

Abstract

Noninvasive brain stimulation and neuroimaging have revolutionized human neuroscience with a multitude of applications, including diagnostic subtyping, treatment optimization, and relapse prediction. It is therefore particularly relevant to identify robust and clinically valuable brain biomarkers linking symptoms to their underlying neural mechanisms. Brain biomarkers must be reproducible (i.e., have internal reliability) across similar experiments within a laboratory and be generalizable (i.e., have external reliability) across experimental setups, laboratories, brain regions, and disease states. However, reliability (internal and external) is not alone sufficient; biomarkers also must have validity. Validity describes closeness to a true measure of the underlying neural signal or disease state. We propose that these metrics, reliability and validity, should be evaluated and optimized before any biomarker is used to inform treatment decisions. Here, we discuss these metrics with respect to causal brain connectivity biomarkers from coupling transcranial magnetic stimulation (TMS) with electroencephalography (EEG). We discuss controversies around TMS-EEG stemming from the multiple large off-target components (noise) and relatively weak genuine brain responses (signal), as is unfortunately often the case in noninvasive human neuroscience. We review the current state of TMS-EEG recordings, which consist of a mix of reliable noise and unreliable signal. We describe methods for evaluating TMS-EEG biomarkers, including how to assess internal and external reliability across facilities, cognitive states, brain networks, and disorders and how to validate these biomarkers using invasive neural recordings or treatment response. We provide recommendations to increase reliability and validity, discuss lessons learned, and suggest future directions for the field.

Keywords: Electroencephalography (EEG); Reliability; TMS-EEG; Transcranial magnetic stimulation (TMS); Transcranial magnetic stimulation–evoked potentials (TEP); Validity.

Figure 1 -. Reliability and validity of neuroimaging biomarkers.

A biomarker should be scrutinized for both reliability and validity because it is possible to have high reliability but low validity or high validity but low reliability.

Figure 2 -. High internal reliability of TEPs.

In each of these two studies (30,86), TEPs after single pulse TMS to M1 were internally consistent across time (one week between experiments). A adapted from (30), where blue line represents the first and red line the second recording one week later. B adapted from (86), where the dashed line represents the first and solid line the second recording one week later.

Figure 3 -. Low external reliability of the TEP.

Comparison of TEPs from different laboratories. Local TEP responses after stimulation of A,B) parietal cortex and C,D) frontal cortex. A and C are from (42), and B and D are from (6). The figure is adapted from (50).