Cross-frequency coupling analysis in amyotrophic lateral sclerosis as potential biomarker and therapeutic target

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Amyotrophic lateral sclerosis (ALS) is characterized by the degeneration of upper and lower motor neurons (UMN & LMN), located in the cerebral cortex, and the brainstem/spinal cord, respectively. ALS diagnosis mostly relies on LMN signs, which are also common to other diseases. In addition, the gold standard to assess therapy efficacy remains primarily based on LMN evaluation, excluding UMN assessment. This is partly because LMN degeneration can mask UMN signs, making it more difficult to faithfully detect UMN dysfunction, which delays treatment initiation and limits early inclusion in clinical trials. To circumvent this limitation, we here propose to evaluate cortical dysfunction (Ct Dysf) to improve ALS diagnosis. Methods relying on transcranial magnetic stimulation (TMS) and magnetic resonance imaging (MRI) revealed early cortical dysfunction in ALS, that precedes the onset of LMN signs, negatively correlates with survival and is not present in diseases that solely target LMN. Thus, in combination with LMN signs, Ct Dysf could help ensure diagnosis and prognosis of ALS. While TMS and MRI are limited in their routine clinical application, electroencephalogram (EEG) has the potential to meet the need for a quantitative and reliable biomarker of Ct Dysf thanks to its high time resolution and recent methodological advances, including source imaging and the assessment of cross-frequency coupling (CFC). Importantly, EEG can be easily implemented in both patients and animal models, thereby facilitating translational multicentric research, paving the way for the assessment of new therapies with a greater chance of success. Based on our preliminary data, we hypothesize that altered CFC can serve as an early and quantitative biomarker of Ct Dysf in ALS. We have thus gathered German and French preclinical and clinical teams with well-known expertise in ALS to 1) test whether altered CFC may represent a novel and early biomarker of Ct Dysf in patients with ALS and presymptomatic gene mutation carriers; 2) determine the temporal, spatial and cellular origins of altered CFC and Ct Dysf in mouse models of ALS and 3) generate computational models of cellular and synaptic origins of Ct Dysf in ALS mouse models and patients. We anticipate finding a significant impairment of CFC in ALS patients and presymptomatic mutation carriers, which will worsen over the course of the disease, particularly in sensorimotor areas, which are the first to be affected in ALS. In parallel, we expect to unravel the cellular and circuit basis of altered CFC in ALS and to generate a whole-brain oscillatory dynamics model, in order to facilitate therapeutic studies by targeting identified cell types in the future. Building on previously established, strong collaborations between our preclinical and clinical teams, FrequALS is thus providing groundwork for a strongly improved ALS diagnostic pipeline and will unravel novel circuit-based therapeutic targets.