Resting-state and task-related neurometabolite levels differentially relate to cortical excitability in the sensorimotor and prefrontal cortex

BackgroundNormal brain function requires a dynamic balance between inhibition and excitation. While magnetic resonance spectroscopy (MRS) quantifies the chief inhibitory and excitatory neurometabolites, GABA and glutamate-glutamine (Glx), the combination of transcranial magnetic stimulation and electroencephalography (TMS-EEG) provides a complementary measure of cortical inhibition-excitation dynamics via transcranial evoked potentials (TEPs). However, the relationship between neurometabolite concentrations and TEPs is unclear. ObjectiveTo characterize the relationship between neurometabolite concentrations and TEPs, as a function of TEP component, TMS pulse type, brain region, neurometabolite, and MRS brain state. MethodsTwenty-five young healthy adults completed a 4-day protocol. Sessions 1 and 2 involved screening, anatomical MRI, and functional MRI localization of DLPFC. In session 3, single- and paired-pulse TMS-EEG were applied over SM1 and DLPFC. Session 4 included resting-state and motor-task-related MRS of SM1 and DLPFC. ResultsIn SM1, task-related GABAergic tone strongly predicted early to mid-latency TEPs. In DLPFC, local early to mid-latency TEPs showed no relationship to neurometabolites, whereas late and global TEP outcomes revealed some links. The later N100 TEP was the only component consistently modulated by paired-pulse TMS. Task-related MRS measures consistently outperformed resting-state measures in predicting TEPs for SM1, while the opposite was true for DLPFC. ConclusionsSingle-pulse TEPs reliably index the local inhibitory tone in SM1, with limited added value from paired-pulse paradigms. These findings support the use of single-pulse TEPs as accessible markers of cortical inhibition, especially for SM1, and may inform biomarkers and strategies for individualized neuromodulation. Key point summaryO_LINormal brain function relies on a balance between inhibition and excitation, yet the relationship between local cortical neurometabolite levels and cortical excitability in humans remains poorly understood. C_LIO_LIWe measured inhibitory and excitatory neurometabolites using magnetic resonance spectroscopy and assessed cortical excitability responses to non-invasive stimulation using combined transcranial magnetic stimulation - electroencephalography (TMS-EEG). C_LIO_LIIn the primary sensorimotor cortex (SM1), local cortical responses to stimulation were best explained by inhibitory GABA levels during motor task performance. In the dorsolateral prefrontal cortex (DLPFC), global cortical responses were best predicted by resting-state neurometabolite levels. C_LIO_LIOverall, paired-pulse TMS paradigms offered little additional value over single-pulse paradigms for informing on neurometabolite levels. C_LIO_LIBy demonstrating region- and state-dependent links between neurometabolite levels and cortical excitability, our findings position TMS-EEG as an accessible biomarker of cortical inhibition, particularly in SM1. C_LI Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=79 SRC="FIGDIR/small/701225v1_ufig1.gif" ALT="Figure 1"> View larger version (37K): org.highwire.dtl.DTLVardef@132b3faorg.highwire.dtl.DTLVardef@1c5ebeeorg.highwire.dtl.DTLVardef@1048a75org.highwire.dtl.DTLVardef@11e1a4f_HPS_FORMAT_FIGEXP M_FIG C_FIG Abstract figure legendThe left panel provides a stepwise overview of the study protocol, including (i) participant screening, (ii) functional and anatomical magnetic resonance imaging (MRI) scanning for individualization purposes, (iii) single- and paired-pulse transcranial magnetic stimulation-electroencephalography (TMS-EEG), and (iv) magnetic resonance spectroscopy (MRS) acquired at rest and during a bimanual motor task. The middle and right panels show the grand-average EEG responses to single-pulse TMS over the sensorimotor cortex (SM1, red) and dorsolateral prefrontal cortex (DLPFC, blue), respectively. The topographical maps below each EEG response depict the averaged scalp distributions corresponding to each canonical transcranial evoked potential. Per region, the top left illustration shows the group-level MRS voxel placement, whereas the top right illustration shows the simulated TMS-induced electric fields. While early to mid-latency local cortical responses were best predicted by task-related GABAergic inhibition in SM1, global cortical responses following DLPFC stimulation were best predicted by resting-state neurometabolite levels.