Profiling cortical excitability in ALS using threshold tracking transcranial magnetic stimulation and multimodal biomarkers

In the intricate network of the brain and spinal cord, neurons communicate with one another via specialized chemicals known as neurotransmitters. When this signaling network functions properly, a delicate balance is maintained between excitatory and inhibitory chemicals. A hallmark feature of ALS, thought to occur even before symptoms appear, is that motor neurons in the brain become overexcited (or hyperexcitable). This change occurs at the cellular level and can’t be noticed by people who experience it, but researchers have found evidence of hyperexcitability in both electrical recordings from the brain and markers in the cerebrospinal fluid of people with ALS. The relationship between hyperexcitability and clinical symptoms, however, remains unclear.

With this award, Liane will explore the link between hyperexcitability in ALS and various clinical and neuroimaging parameters, in addition to a fluid-based biomarker. Excitability circuits of the brain will be assessed using threshold-tracking transcranial magnetic stimulation (TT-TMS), a non-invasive technique that uses a magnetic field to stimulate nerve cells. In the first aim, Liane will analyze data from a group of 100 healthy controls to establish “normal” values for various TT-TMS parameters. She will then assess the reliability of these different TT-TMS measurements in a smaller group of 20 individuals living with ALS over a three-day period. Finally, she will seek to identify specific clinical profiles associated with hyperexcitability by comparing TT-TMS measurements from 30 individuals with ALS with demographic, neuroimaging, and clinical data (such as ALSFRS-R scores and blood neurofilament light levels – a biomarker for neurodegeneration).

This research could help to validate TT-TMS as a method to detect non-invasive biomarkers for ALS, aiding in diagnosis and potentially leading to more personalized treatment options in the future. Efforts to identify specific disease profiles, or subgroups, based on hyperexcitability may also help to improve clinical trial design, as the ability to enroll participants by specific ALS subtypes would reduce heterogeneity and therefore enhance the likelihood of detecting treatment effects.