Objective:

To synthesize findings on upper motor neuron (UMN) dysfunction in ALS and propose a novel experimental framework integrating transcranial focused ultrasound (tFUS) with transcranial magnetic stimulation (TMS) for further investigation.

Approach:

Key Findings:

• Cortical hyperexcitability is an early mechanism in ALS, potentially driving lower motor neuron degeneration.
• TMS-EMG and TMS-EEG studies indicate cortical disinhibition and excitatory-inhibitory imbalance in ALS.
• Current biomarkers lack sensitivity to capture subtle disease progression, highlighting the need for quantitative measures.

Interpretation:

The integration of TMS and tFUS may enhance understanding of UMN dysfunction in ALS, leading to improved biomarkers and therapeutic strategies.

Limitations:

• Clinical and biological heterogeneity in ALS complicates effective trial design.
• No single biomarker has achieved universal clinical adoption.

Conclusion:

Noninvasive neurophysiology, particularly through TMS and tFUS, offers a framework for elucidating UMN dysfunction in ALS.

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