Noninvasive profiling of input-output excitability curves in human prefrontal cortex

Background

The human prefrontal cortex plays a critical role in cognitive control and behavior, and its dysfunction has been linked to numerous psychiatric and neurological disorders. However, noninvasive measurement of prefrontal activity remains challenging, limiting our understanding of how to optimize prefrontal treatments. Input-output relationships reveal how neural circuits respond to different inputs and are essential for determining optimal treatment parameters and understanding individual variability in treatment response, yet systematic investigation of prefrontal input-output relationships has been lacking.

Objective

To characterize human prefrontal excitability with input-output (I/O) curves.

Methods

We employed transcranial magnetic stimulation (TMS) with electroencephalography in a randomized mixed-block design with 28 healthy participants receiving single-pulse TMS to left dorsolateral prefrontal cortex (dlPFC) across 12 stimulation intensities (60-140% of resting motor threshold). We quantified prefrontal excitability using early local TMS-evoked potentials (EL-TEPs), local cortical responses measured locally 20-60 ms post-stimulus.

Results

We observed a strong effect of TMS intensity on prefrontal EL-TEPs. Sigmoidal EL-TEP I/O curves were observed in 57% of participants, with the sigmoidality partially explained by the signal quality of the EL-TEP. Correlations were observed between EL-TEP and motor-evoked potential curve parameters, but intensity parameterization approaches did not significantly differ in explaining inter-individual EL-TEP response variability. Reliable EL-TEPs could be obtained using fewer TMS pulses at higher intensities, and test-retest assessments revealed robust I/O curve profiles.

Conclusions

These findings provide a systematic noninvasive characterization of prefrontal input-output physiology in humans, establishing a validated framework for estimating prefrontal excitability. The comparison of various intensity parameterizations motivates the need for enhanced models and individualized measurement of stimulation responses.

Highlights

• We present noninvasive input-output curves for prefrontal TMS.

• EL-TEPs exhibit robust dose-dependent responses to TMS intensity.

• Sigmoidal I/O curves observed in 57% of participants, with a strong dependence on signal quality.

• Correlations observed between MEP and prefrontal EL-TEP curve parameters.

• High test-retest reliability and rapid protocols at ≥110% rMT