Using TMS to Reveal Neurophysiological Biomarkers in Parkinson’s Disease

Why TMS is Becoming Essential in Phase I Parkinson’s Trials 

With over 10 million people living with Parkinson’s disease (PD) worldwide, and with the condition representing the fastest-growing neurological disorder, there has never been a more urgent need to improve how we develop new therapies (Parkinson’s Foundation, 2026). With World Parkinson’s Awareness Day highlighting the growing global burden of the disease, a key challenge facing researchers and drug developers is clear: how can meaningful biological signals be identified early in a slow, heterogeneous disease? 

Transcranial magnetic stimulation (TMS) is increasingly positioned to address this gap. 

By enabling objective measurement of brain circuit function, TMS offers something traditional clinical scales cannot: direct, quantifiable evidence of central target engagement. In early-phase trials, this can fundamentally change how decisions are made, and the outcomes achieved. 

The Problem with Traditional Measures 

Parkinson’s disease is a complex neurodegenerative disorder characterised by degeneration of the substantia nigra pars compacta and disruption of basal ganglia–thalamo–cortical circuits (Dickson, 2018). However, the pathology extends well beyond these regions, with structural and functional changes observed across widespread cortical networks (Xu and Pu, 2016). 

The disease is also inherently multifactorial, arising from the interaction of genetic, environmental, and behavioural factors over time (Balestrino and Schapira, 2020). 

Despite this complexity, clinical trials continue to rely heavily on rating scales such as Hoehn and Yahr (H&Y) and the Unified Parkinson’s Disease Rating Scale/Movement Disorder Society–Sponsored Revision of the UPDRS (UPDRS/MDS-UPDRS). While these tools are valuable for assessing clinical severity, they present important limitations in early-phase research: 

From a protocol design perspective, this creates a critical issue: clinical endpoints may not reflect whether a therapy is engaging its intended target, particularly in Phase I studies. 

TMS: Measuring What Matters 

TMS provides a non-invasive method for probing human cortical physiology in vivo and is increasingly recognised as a translational tool in Parkinson’s disease research (Cantone et al., 2026; Pascuzzi et al., 2026). 

Crucially, TMS enables the integration of mechanistic biomarkers directly into early-phase trial design. Rather than relying solely on downstream clinical outcomes, you can measure circuit-level responses to pharmacological intervention in real time. 

When embedded into a Phase I protocol, TMS can support: 

This represents a shift from observational to mechanism-driven early development. 

Understanding the Circuits Behind Parkinson’s

The value of TMS lies in its ability to probe the neural circuits underlying Parkinson’s disease. 

Beyond dopaminergic depletion, PD involves widespread dysfunction in inhibitory and excitatory pathways, particularly within the primary motor cortex (M1). These circuits regulate corticospinal output and are critical for motor control (Pascuzzi et al., 2026). 

Paired-pulse TMS paradigms provide a structured way to interrogate these systems. By delivering two stimuli at defined interstimulus intervals, specific neurotransmitter-mediated processes can be isolated and quantified. 

For clinical trials, this enables standardised, reproducible measures of circuit function that can be incorporated into study endpoints. 

Targeting GABA-A: The Power of SICI 

Short-Interval Intracortical Inhibition (SICI) is one of the most robust and clinically informative TMS measures in Parkinson’s disease. 

SICI reflects fast GABA-A–mediated inhibition within the motor cortex (Interstimulus Interval (ISI) ~1–5 ms) and is consistently reduced in PD. 

Within PD populations: 

Within the drug development of a clinical trial setting, this makes SICI a highly sensitive biomarker. It provides a direct readout of inhibitory circuit dysfunction and a powerful way to assess how therapies modulate cortical activity. 

Beyond Dopamine: Probing Other Pathways 

Long-Interval Intracortical Inhibition (LICI) 

LICI reflects slower GABA-B–mediated inhibition (ISI ~50–200 ms). Although the findings of LICI in PD are more variable, LICI provides insight into longer-duration inhibitory processes and can complement SICI in characterising circuit-level changes. 

Probing Cholinergic Systems with Short-Latency Afferent Inhibition (SAI) 

Short-Latency Afferent Inhibition (SAI) measures sensorimotor integration and is closely linked to cholinergic function. By combining peripheral nerve stimulation with TMS (ISI ~20 ms), SAI provides a window into non-dopaminergic dysfunction. 

This is particularly relevant for therapies targeting mechanisms beyond dopamine, enabling a broader assessment of mechanistic engagement across multiple pathways. 

From Biomarkers to Better Decisions 

Integrating these TMS paradigms into early-phase trials transforms how data can be used. 

Through pharmaco-TMS approaches, measuring responses before and after drug administration, you can: 

TMS also complements clinical endpoints by providing neurophysiological context, strengthening interpretation of outcomes (Goodwill et al., 2017). 

Bridging the Gap to the Real World 

A persistent challenge in early-phase trials is balancing controlled study design with real-world relevance. 

Combining TMS with Electroencephalography (EEG) - A non-invasive technique that records electrical activity of the brain, using electrodes placed on the scalp - extends analysis beyond local cortical measurements to whole-brain network dynamics(Cantone et al., 2026). This allows for a more comprehensive understanding of how therapies influence distributed neural systems.  

From a translational perspective, this supports: 

Why This Matters Now 

Parkinson’s disease continues to represent a significant and growing global burden (Parkinson’s Foundation, 2026), while the development of disease-modifying therapies remains a major unmet need. 

At the same time, expectations for early-phase trials are evolving. There is increasing demand for objective, mechanistic evidence of biological activity, alongside faster and more confident decision-making. 

TMS directly addresses these needs by embedding quantitative neurophysiological biomarkers into early development programmes. 

A Smarter Approach to Phase I Trials 

Integrating TMS into Phase I protocol design enables a more informative and efficient approach to early clinical development. 

Specifically, it allows you to: 

When combined with adaptive trial designs, TMS further enables: 

What Should You Do Next? 

As you plan upcoming clinical trial programmes, the focus is shifting from whether to use mechanistic biomarkers to how best to integrate them into protocol design. 

Key considerations include: 

In a field where early signals are difficult to detect, integrating TMS offers a practical route to generating more meaningful, decision-driving data—earlier in development.