Perturbational complexity index detects subclinical cortical changes in early multiple sclerosis

Objective: Transcranial magnetic stimulation combined with EEG (TMS-EEG) can probe cortical excitability and synaptic function. Subtle cortical dysfunction in early Multiple Sclerosis (MS), however, may escape detection by standard clinical and evoked-potential measures. We investigated whether TMS-EEG–derived indices can reveal early cortical network alterations in minimally disabled relapsing MS. Methods: We prospectively recruited 28 persons with early relapsing MS (pwMS, disease duration < 3 years; Expanded Disability Status Scale < 2.0) and 25 matched healthy controls. All participants underwent single-pulse TMS over the left motor cortex with simultaneous 19-channel EEG recording. TMS-evoked potentials (TEPs), Global Field Power (GFP), and the Perturbational Complexity Index (PCI) were compared between groups. Clinical measures, Motor Evoked Potentials (MEPs), and brain MRI volumetrics were also collected and correlated with TMS-EEG metrics. Results: After preprocessing, 25 pwMS and 20 HCs were retained for TMS–EEG analysis. Conventional TEP component amplitudes, latencies, and GFP-derived measures did not differ significantly between groups after correction for multiple comparisons. PCIst was significantly reduced in pwMS and was associated with normalized grey-matter, white-matter, and thalamic volumes, as well as with right MEP latency. Conclusions: PCI is sensitive to subtle cortical network alterations in early MS, despite preserved conventional TEP and GFP measures. Significance: PCI provides a single quantitative index of reduced global spatiotemporal complexity, potentially reflecting early synaptic dysfunction related to demyelination and neuroinflammation.