A pharmacodynamic readout of cortical activity
Pharmaco-TMS
Transcranial Magnetic Stimulation (TMS) is a non-invasive neurostimulation technique that uses a magnetic field to stimulate nerve cells in the brain. TMS can be used in pharmaceutical clinical trials to help study the effects of the drug on the brain, by obtaining measurements of cortical excitability and using these as biological markers. These biological markers of the acute or chronic drug effects allow for the understanding of the drugs mechanisms and its ability to treat conditions (TMS and Drugs, Zeimann, 2004).
TMS-EDM
Transcranial Magnetic Stimulation – Electro Diagnostic Markers (TMS-EDMs) offer new avenues of investigating novel CNS therapeutics by providing:
- in-vivo markers for pharmacological activity
- in-vivo markers for specific biological processes
Offering a better signal to noise ratio compared to EEG resting state recordings and thanks to a ‘perturbation and measure’ approach, it does not require subject involvement in a specific task.
Case Study
Applications
The observation of TMS-EDMs before and after the administration of drugs with well-known mechanisms of action contributed to the development of markers of cortical inhibitory and excitatory processes. For this reason, TMS-EDMs are particularly useful in early phase clinical trials for new therapeutics to obtain pharmacodynamic readouts.
The use of TMS to provide pharmacodynamic endpoints of newly developed drugs acting in the human brain is a reliable, reproducible, non-invasive and comparatively cost-effective way of identifying cortical and cortico-spinal excitability markers and demonstrating specific neurophysiological correlates and neural inhibition/excitation. It is particularly useful in several neurological and neuropsychiatric conditions including Epilepsy, Amyotrophic Lateral Sclerosis (ALS), Parkinson’s Disease, Multiple Sclerosis, Autism and Schizophrenia.
These neuro biomarkers play a pivotal role in shaping clinical trial strategies and achieving study objectives. However, integrating them into trials requires careful consideration and coordination among stakeholders.
Advantages of Pharmaco-TMS
There are several advantages to including TMS measures into a Phase I clinical trial.
Objective measures of brain activity or neural excitability in response to a drug.
Provides further understanding and confirmation of the drug’s mechanism of action.
Contributes to understanding of the PK/PD relationship.
Obtain non-invasive neuro biomarkers.
Can provide early indicators of efficacy.
TMS-EEG
Electroencephalography (EEG) sensors are applied over the subjects head and TMS is delivered over the EEG. The main parameters are the TMS evoked potentials (TEPs).
TEPs are a reliable and reproducible alternating sequence of positive (P) and negative (N) peaks at a 25 (P25), 45 (N45), 100 (N100) and 180 (P180) milliseconds after stimulation.
Measurement of TEP amplitude allows a direct investigation of cortical excitability and connectivity in a highly time-resolved manner.
TMS-EMG
Electromyography (EMG) is applied at the contralateral hand muscle with TMS delivered over the cortex. The main parameter for simgle pulse TMS-EMG is the resting motor threshold (RMT) which reflects cortico-spinal excitability. RMT is the minimum stimulation intensity required to elicit a small motor evoked potential (MEP).
Paired Pulse TME-EMG protocols consist of a conditioning stimulus which precedes a test stimulus. The key parameters here are the inter stimulus intervals (ISI).
Neurotransmitters Commonly Targeted by TMS
| Drug Example | Drug Effect on MEP | TMS-induced PD Effect |
|---|---|---|
| D-Cycloserine | Enhanced facilitatory effect of MEP | Increased glutamatergic neurotransmission in motor cortex |
| Lorazepam | Decrease in MEP amplitude | Increased in GABAergic neurotransmission in motor cortex |
| L-Dopa | Increased in MEP amplitude | Increase dopamine transmission |
| Fluoxetine | Increased in MEP amplitude | Increase serotinergic neurotransmission |
Glutamate plays a key role in learning and memory, with excessive glutamate activity being linked to various neurological disorders, including stroke and neurodegenerative diseases such as Alzheimer’s Disease.
GABA regulates anxiety and stress, with disruptions in GABAergic signalling being linked to various mood disorders and Epilepsy.
Dopamine plays a key role in the brain’s reward system, which helps to reinforce certain behaviours and motivate us to seek out pleasurable experiences, The dysregulation of dopamine signalling has been implicated in a range of psychiatric disorders, including Addiction, Depression and Schizophrenia.
Serotonin helps to regulate mood, appetite and sleep. Dysregulation of serotonin has been linked to various psychiatric disorders including Depression, Anxiety and Obsessive-Compulsive Disorder.
Frequently Asked Questions
TMS can reliably and reproducibly measure cortical and cortico-spinal excitability markers. These pharmacodynamic endpoints help demonstrate the drug’s neurophysiological effects, aiding in understanding its mechanism of action, PK/PD relationship, and providing early indicators of efficacy. This is especially useful for conditions like Epilepsy, ALS, Parkinson’s Disease, Multiple Sclerosis, Autism, and Schizophrenia.
TMS-EEG involves applying EEG sensors on the subject’s head and delivering TMS to measure TMS-evoked potentials (TEPs). TEPs, characterised by specific positive and negative peaks after stimulation, allow direct investigation of cortical excitability and connectivity in a highly time-resolved manner.
TMS-EMG involves applying electromyography to a muscle, typically in the contralateral hand, and delivering TMS over the cortex. The main parameter measured is the resting motor threshold (RMT), which reflects cortico-spinal excitability. Paired-pulse TMS-EMG protocols, involving a conditioning stimulus followed by a test stimulus, help investigate neurotransmitter effects and cortical inhibition/excitation.
To incorporate Pharmaco-TMS into your clinical trial, please contact us. Our team of experts will assist you in designing and implementing TMS protocols tailored to your study’s needs, ensuring precise and reliable assessment of cortical activity.
Useful Resources
Research papers
TMS and Drugs Revisited – Ziemann et al 2014
Clinical Utility and Prospective of TMS-EEG – Tremblay et al 2019
TMS Studies of Motor Excitability – Zeimann et al 2013
Want to Know More?
To learn more about how your Phase I clinical trial could benefit from the application of Pharmaco contact us. Our team of experts is ready to provide detailed information and assist you in designing the most effective and comprehensive assessment plan for your study.