Multimodal Imaging Approaches to Tackle Brain Excitability

Anna-Lisa Schuler Organizer
Max Planck Institute for Human Cognitive and Brain Sciences
Leipzig, Saxony 
Martin Tik Co Organizer
High Field MR Center, Center for Medical Physics and Biomedical Engineering, Medical University of V
Thursday, Jun 27: 9:00 AM - 10:15 AM
Room: Grand Ballroom 104-105 
This symposium is dedicated to taking a deep dive into mapping approaches to estimate cortical excitability. Brain excitability is a multifaceted concept that has been approached in various ways using extrinsic measures, i.e., observing responses to an external stimulus (commonly magnetic or electrical stimulation) or intrinsically by investigating ongoing patterns of neuronal electrical activity (M/EEG, ECoG) or BOLD response.
In clinical and neuroscientific research, mapping brain excitability is commonly approached by measuring muscle responses while applying transcranial magnetic stimulation (TMS) to the primary motor cortex (M1). Although this procedure is common practice in many experiments to evaluate implicit "global excitability", we have to date neither a good command of factors influencing M1 excitability nor of factors underlying excitability patterns in areas beyond M1. In the recent literature involving non-invasive brain stimulation, factors such as state-dependency, network-specific inhibitory and excitatory dynamics and region-specific excitability patterns are mostly neglected.
This results in an oversimplification of measures commonly used in neuroscientific research, i.e., motor evoked potentials (MEPs), and does not account for region-specific effects of excitability, questioning recent applications of NIBS in clinical and basic research.
A way to approach these issues is to combine brain stimulation with other techniques, such as M/EEG and fMRI to identify neural correlates of brain excitability states. Addressing these topics in a symposium will enable us to provide a leveled overview of the current state-of-the-science, combining a set of speakers with multi-professional backgrounds:
- Elisa Kallioniemi: TMS-EEG/EMG integration to study the excitability of M1
- John Coetzee: Heart-Brain Coupling Factor as a Correlate of iTBS Target Engagement, Clinical Effectiveness, and Cortical Excitability
- Martin Tik: TMS-induced BOLD changes to assess inter- and intraindividual differences in brain excitability: An interleaved TMS-fMRI approach
- Anna-Lisa Schuler: Intrinsic and Extrinsic Measures of Excitability: a synthesis


The audience will learn about the issues in recent approaches to evaluating brain excitability.
Furthermore, possibilities of combining imaging methods (M/EEG, fMRI, ECG etc.) that contribute to improved assessment of brain excitability via TMS or without TMS are presented.
Finally, challenges measuring brain excitability that have to be addressed in the future will be discussed.  

Target Audience

The target audience is all basic researchers working or wanting to work with NIBS. Moreover, all clinical practitioners (psychologists, neurologists, psychiatrists) using non-invasive brain stimulation in clinical practice, e.g., for evaluation or treatment of epilepsy, stroke, migraine, or depression. 


1. TMS-EEG/EMG integration to study the excitability of M1

Transcranial magnetic stimulation (TMS) is a non-invasive brain stimulation method that can activate cortical neurons. The TMS power needed to activate the neurons varies between cortical areas and individuals. This enables the use of TMS to study cortical excitability. However, the applicability of TMS is limited as it can only provide activation but not outcome measures. When combined with simultaneous electroencephalography (EEG) or electromyography (EMG), TMS evolves into a sophisticated neurophysiological method capable of studying cortical excitability and its dynamics. While TMS-EMG responses reflect the excitability of a limited population of neurons directly connected to pyramidal tract neurons, TMS-EEG responses reflect the activity of larger populations of neurons in the stimulated and connected areas. The advantage of the TMS-EEG/EMG methods is that TMS activates the cortical excitatory (glutamatergic) and inhibitory (gamma-aminobutyric acid-ergic, GABAergic) neurotransmitter systems at different time scales for EEG/EMG to measure them, allowing the investigation of both the excitatory and inhibitory excitability with these methods. Since the pathophysiology of several neuropsychiatric disorders is often associated with excitatory and/or inhibitory neurotransmitter systems, TMS-EEG/EMG methods offer potential biomarkers to study the presence or trajectory of a disease or response to a therapeutic intervention. Though promising findings, TMS-EEG/EMG methods still lack an understanding of which factors influence the outcome measures. This talk will provide an overview of the current state of TMS-EEG/EMG applications studying neuronal excitability and their limitations and possibilities, focusing on applications targeting M1. Data is presented on TMS-EEG/EMG excitability findings across the motor homunculus. 


Elisa Kallioniemi, New Jersey Institute of Technology
Biomedical Engineering
Newark, NJ 
United States

2. Heart-Brain Coupling Factor as a Correlate of iTBS Target Engagement, Clinical Effectiveness, and Cortical Excitability

Interoception refers to both the processing by the brain of afferent signals arising from bodily organs, as well as to the efferent signals the brain sends to modify their function. The interaction between the brain and heart, via the vagus nerve, is especially dynamic. We used the heart-brain coupling (HBC) factor, a measure of heart rate entrainment induced by repetitive transcranial magnetic stimulation (rTMS) applied to the left dorsolateral prefrontal cortex (L-DLPFC). It can be derived using Neuro-Cardiac-Guided (NCG) TMS-2.0, and reflects the spectral density of the 0.1 Hz frequency. This entrainment occurs during conventional rTMS, and also during intermittent theta burst stimulation (iTBS), which is used in Stanford Neuromodulation Therapy (SNT). In this talk, we discuss the use of HBC factor to as a measure of target engagement, clinical effectiveness, and cortical excitability.

15 participants were included in this study, 8 in the active and 7 in the sham condition, with participants and treaters blinded. There were 7 women and 8 men in the study, with 3 women in the sham and 4 women in the active condition. The mean age 50.1 yrs. Each participant underwent 10 iTBS sessions a day for 5 days, in accordance with SNT procedures. During treatment sessions, electrocardiogram (ECG) recordings were collected (NCG-ENGAGE, Neurocare). Recordings were visually inspected and artifact free sections of 300 seconds identified for analysis. These were then processed using a modified version of the script described in Dijkstra et al., 2023 in order to generate the HBC factor values. These were then analyzed using SPSS version 29. The resulting values were also categorized as being above or below a threshold of 2, a practice which had proven accurate in a prior study for categorizing recordings as coming from an active or sham condition.

Target engagement & clinical effectiveness

A linear mixed effects model was constructed with HBC factor as the dependent variable in which the model included Day, Session, and Active/Sham as fixed effects, while participants were included as a random effect. Age and sex were included as covariates. Only Active/Sham was significant (F=9.356, df=1,484, p<.01). Looking across participants, on each day, HBC factor for the active condition was numerically greater than HBC factor for the sham condition (although not significant). Negative Pearson’s correlations were found between the mean percent of HBC factors above 2 for each participant and the percent reduction from baseline in MADRS score at week 2 (r(12) = -.638, p = .025), week 4 (r(14) = -.670, p = .009), and week 5 (r(14) = -.577, p = .031) following SAINT treatment.

The HBC factor appears to have associations with meaningful clinical outcomes. More data is still needed to determine if it can function as a predictor of treatment outcome. It may have quantifiable relationships with cortical excitability.

Cortical excitability

Preliminary findings from a pilot study of HBC factor as a measure of cortical excitability will be discussed, as well as their relevance for thresholding during SAINT and other TMS applications. 


John Coetzee, PhD, Stanford
Psychiatry and Behavioral Science
San Francisco, CA 
United States

3. TMS-induced BOLD changes to assess inter- and intraindividual differences in brain excitability: An interleaved TMS-fMRI approach

New advancements in interleaved TMS-fMRI provides us with invaluable insights into excitability states of the brain due to TMS. In this talk a series of studies addressing variability in brain excitability due to internal states and subject-specific traits will be discussed. First, we will discuss differences in excitability between the primary motor cortex and the DLPFC on a local as well as a network level. Then sex-differences in DLPFC excitability for local and downstream brain areas will be highlighted. Further, we will show how brain state influences interactions between DLPFC and downstream areas by systematically manipulating brain states via a working memory task. Finally, we will show how task responses relate to the actual E-fields induced by stimulation to spot interactions between excitability-modulated areas and behavioural outcomes.
In sum the integration of fMRI with TMS presents a significant methodological benefit in examining the variability of TMS responses, i.e. specific excitability states. Especially, it allows us to understand brain excitability variability in different cortical areas as well as network effects of brain excitability states. With this knowledge stimulation intensities might be improved to apply person specific stimulation doses. Moreover, better timing might result in better interactions between excitability states and stimulation.
These insights have the potential to improve TMS treatment in neuropsychiatric populations moving a step forward to personalized interventions.


Martin Tik, High Field MR Center, Center for Medical Physics and Biomedical Engineering, Medical University of V Vienna

4. Intrinsic and Extrinsic Measures of Excitability: a synthesis

Cortical excitability has been defined as the reactivity of a cortical area to external stimulation (usually TMS). Commonly it is measured via motor-evoked potentials (MEPs) that are elicited due to TMS over the primary motor cortex. It is however debated how this measure translates to the excitability of other cortical areas, specifically association cortices. Different approaches have been suggested to evaluate the excitability of brain areas beyond M1, among these, the combination of TMS with: behavioural outcomes, M/EEG-responses, BOLD-response as well as stimulation-free measures using fMRI or M/EEG signals. In this talk an overview about these so-called ‘extrinsic’ and ‘intrinsic’ excitability measures is given. This is followed by an overview of our ongoing research investigating different approaches to measure cortical excitability including combinations of TMS with behavioural outcomes and M/EEG as well as pure ‘intrinsic’ excitability measures based on M/EEG. Finally, a conclusion is given on how these measures relate to each other and how they can be applied in a clinical context, e.g. diagnostics and treatment of epilepsy, migraine or stroke. 


Anna-Lisa Schuler, Max Planck Institute for Human Cognitive and Brain Sciences Leipzig, Saxony