Multimodal Imaging Approaches to Tackle Brain Excitability

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. 

Introduction:
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.

Methods:
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

Results:
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.

Discussion:
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. 

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.
 

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.