간질 환자의 뇌 흥분을 연결 관련 평가하는 멀티 모달 Imaging- 및 자극 기반 방법

Executive Industry Relevance

This multimodal imaging and stimulation method enables biopharma R&D to assess cortical hyperexcitability in epilepsy models, supporting target validation by linking functional connectivity abnormalities to electrophysiological phenotypes. It provides a mechanistic de-risking tool for evaluating circuit-level excitability changes in preclinical and translational studies, particularly for neuropsychiatric indications where network hyperexcitability is a putative driver of disease. The approach enhances predictive confidence in target selection by demonstrating causal relevance of connectivity alterations to pathophysiological states.

Strategic Applications in Biopharma R&D

Early Discovery & Target Validation

• Scientific Value: Interrogates therapeutic hypotheses by testing whether regions with abnormal resting-state connectivity exhibit causal hyperexcitability via TMS-EEG perturbation.
• Operational Value: Enables biological de-risking of targets by establishing whether connectivity changes correlate with measurable electrophysiological dysfunction in disease-relevant systems.

Screening & Assay Development

• Scientific Value: Prepares validated biological systems with quantified TMS-evoked EEG responses as a standardized assay for screening compounds that modulate cortical excitability.
• Operational Value: Supports assay reproducibility through MRI-guided targeting and ICA-based artifact removal, enabling reliable longitudinal or cross-condition comparisons.

Translational & Preclinical Research

• Scientific Value: Demonstrates disease relevance by showing that abnormal TMS-evoked activity co-localizes with seizure-onset zones, supporting continuity from connectivity biomarkers to pathophysiological circuits.
• Operational Value: Facilitates risk-adjusted advancement decisions by providing a translatable readout of circuit hyperexcitability that can be monitored across discovery to preclinical stages.

Pipeline & Workflow Integration

The method integrates into the discovery continuum by first identifying aberrant networks via rs-fcMRI, then probing their causal excitability using TMS-EEG, and finally validating target engagement through normalization of abnormal late components in evoked potentials.

• Discovery Biology: Supports hypothesis testing by determining whether functionally connected regions exhibit pathogenic hyperexcitability, clarifying network-level mechanisms in epilepsy models.
• Screening: Enables assay readiness through standardized TMS pulse application and ERP quantification, allowing assessment of compound effects on cortical reactivity.
• Analytics: Generates quantitative dependent variable measurements (e.g., latency and amplitude of late TMS-evoked potential components) that enable statistical comparison between disease and control states.
• Translational Research: Connects to preclinical continuity by demonstrating spatial colocalization of abnormal TMS-evoked activity with epileptogenic zones, supporting biomarker-aligned target validation.
• Enterprise Reuse: Represents a reusable platform for probing circuit excitability across neuropsychiatric indications, not limited to single-use experimental validation.

Operational & Enterprise Impact

• Scientific Value: Provides predictive confidence in target validation by linking connectivity abnormalities to causal electrophysiological phenotypes, reducing mechanistic ambiguity in neuropsychiatric target selection.
• Operational Value: Ensures standardization and reproducibility through neuronavigation-guided TMS, fixed inter-pulse intervals, and multi-stage ICA artifact correction.
• Strategic Value: Improves go/no-go decisions by enabling early detection of circuit hyperexcitability, even when routine EEG is normal, thereby reducing late-stage biological risk in CNS programs.
• Portfolio Impact: Supports risk-adjusted prioritization by identifying targets whose modulation normalizes pathological excitability, informing capital allocation toward mechanistically de-risked candidates.

Implementation Considerations

• Requires expertise in neurophysiology, TMS safety protocols, EEG acquisition, and multimodal image coregistration.
• Depends on neuronavigation systems, TMS coils compatible with simultaneous EEG, and high-density EEG caps to minimize artifacts.
• Necessitates cross-team standardization between imaging, stimulation, and electrophysiology teams to ensure consistent target selection and data interpretation.
• Involves adaptation considerations when applying to different model systems, as head size, coil positioning, and ICA parameters may require optimization across species or strain.
• Includes practical limitations such as susceptibility to movement artifacts, inter-individual variability in skull conductivity, and the need for careful subject screening to exclude contraindications to TMS.

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