Table 1 Future Directions.

Methodologies

Build multiscale and multimodality E/I biomarkers that bridge micro -> meso -> macro

Same animal or tightly matched cross-modal/multimodal studies (e.g., calcium imaging with rs-fMRI, extracellular field recordings with MRS, fMRI with SV2A PET)

Standardize and benchmark between E/I analytical methods

Open community challenges with shared multi-site datasets. Publish Community consensus metrics for trial use

Leverage emerging acquisition techniques (e.g., improved field of view, spatial resolution, temporal resolution)

Whole-brain MRS; functional/time-resolved MRS (fMRS); glutamate chemical exchange saturation transfer MRI (GluCEST); electrocorticography (ECoG); wearable at home EEG and on-scalp OPM-MEG; high density Neuropixels/laminar probes

Clinical Research

Create longitudinal E/I trajectories (preclinical -> MCI - > AD)

Multi-year multimodal cohorts with quarterly home EEG + annual MEG/fMRI/MRS

Task vs rest context dependence of E/I

Within-subject task fMRI/MEG paradigms (e.g., pattern separation; inhibitory control) + resting measures

Equity by design: sex and APOE

Encourage and soft mandate/incentivize sex/APOE4 stratification and interaction reporting in all E/I studies and trials

Spatial influence of Aβ /tau

Co-register PET and fMRI/MRS/EEG/MEG and use spatially informed algorithms (e.g., gaussian kernels)

Clinical Trials

Electrophysiology-guided stratification for trials

Screen with 24-72 h EEG/MEG to identify E/I homeostatic phenotype; use eligibility or stratified randomization based on that phenotype

Dose-finding and responder profiling for levetiracetam

Bayesian, multi-arm adaptive RCT testing low-dose windows with EEG-titrated targets

Data collection of E/I metrics for anti-amyloid therapy

Recruitment and tracking of participants on anti-amyloid therapy with electrophysiology at regular intervals (EEG, fMRI, MEG).

Basic Science/Preclinical Studies

Map tau-amyloid tug-of-war on E/I and vice-versa at micro, meso, and macroscale

Longitudinal structural equation modeling (SEM) with ≥3 waves of measured amyloid tau and an E/I composite metric (e.g., Aβ-PET, tau-PET, fMRI global network coupling) to test bidirectional, lagged pathways (Aβ ↔ E/I↔tau), with time-varying confounders

Interneuron subtype mechanistic studies

Targeted interneuron subtype interventions (e.g., optogenetics/chemogenetics) in models to detect interneuron specific E/I biomarkers (e.g., gamma band power); translate to human EEG/MEG biomarker validation studies

Home & wearable electrophysiology for screening

Use at home EEG + MEG/fMRI on broad aging cohorts with differing cognitive status (CN, MCI, AD), sex, APOE, and/or amyloid and tau pathology