Introduction Motor neuron disease (MND) is characterised by progressive failure of upper (UMN) and lower motor neurons (LMN). UMN dysfunction remains difficult to detect clinically, and the influence of cortical change on disease progression and prognosis remains unclarified. This study quantitatively assessed cortical dysfunction in vivo using a novel combined structural and functional approach.

Methods Forty-one newly diagnosed MND patients and 30 controls prospectively underwent 3T diffusion tensor magnetic resonance imaging (DTI) to assess cerebral white matter structural integrity. DTI measures including apparent diffusion coefficient (ADC) and functional anisotropy (FA) were analysed using statistical parametric mapping. Threshold tracking transcranial magnetic stimulation (TT-TMS) studies were additionally performed across all four limbs to concurrently assess the functional integrity of the motor cortex. All patients underwent detailed clinical and cognitive assessment.

Results Cortical abnormalities were prominent, with FA significantly reduced (p<0.01) and ADC enhanced (p<0.03) along the primary motor tracts in all MND patients, suggestive of primary axonal degeneration. These changes correlated with clinical function and disease duration. TT-TMS revealed evidence of cortical hyper-excitability over the motor cortex corresponding with clinical site-of-onset (p<0.05). Structural (FA) and functional (cortical hyper-excitability) changes correlated across all extremities. Patients without clinical UMN signs also showed evidence of UMN dysfunction, identifying subclinical change. Subgroup analysis identified the greatest changes in bulbar-onset patients (p<0.03).

Conclusion This multimodal technique identified UMN dysfunction in patients prior to clinically detectable change, which may contribute to earlier diagnosis. More significant cortical involvement in bulbar-onset patients aligns with their poorer survival, highlighting the cortically driven determination of clinical progression and prognosis. Further clinical translation of such patterns may therefore lend insight into pathophysiological disease mechanisms and may influence stratification for clinical trials. Overall, this can serve as a robust biomarker for earlier diagnosis, disease progression and prognosis.