First Stimulate, Then Listen

The glymphatic system is a macroscopic waste clearance network that utilizes perivascular channels created by astroglial cells to eliminate neurotoxic metabolites, such as amyloid-β, from the central nervous system. Because the brain lacks traditional lymphatic vessels, it relies on the continuous exchange between cerebrospinal fluid (CSF) and interstitial fluid (ISF) to maintain homeostasis.

According to the primary framework, the system operates through three segments: periarterial influx of CSF, parenchymal exchange facilitated by aquaporin-4 (AQP4) water channels on astrocyte endfeet, and perivenous efflux of waste-laden fluid.

The mechanical energy for this clearance system is provided by the cardiovascular system, which acts as the engine driving fluid through the brain.

The following references were used to create the podcast:

1. Hauglund, N. L., et al. (2025). Norepinephrine-mediated slow vasomotion drives glymphatic clearance during sleep. Cell, 188, 606–622.
2. Astara, K., et al. (2023). A novel conceptual framework for the functionality of the glymphatic system. Journal of Neurophysiology, 129, 1228–1236.
3. Jessen, N. A., et al. (2015). The Glymphatic System – A Beginner's Guide. Neurochemical Research, 40(12), 2583–2599.
4. Rasmussen, M. K., et al. (2022). Fluid transport in the brain. Physiological Reviews, 102, 1025–1151.
5. Soldozy, S., et al. (2022). Interplay between vascular hemodynamics and the glymphatic system in the pathogenesis of idiopathic normal pressure hydrocephalus, exploring novel neuroimaging diagnostics. Neurosurgical Review, 45, 1255–1261.
6. Hladky, S. B., & Barrand, M. A. (2022). The glymphatic hypothesis: the theory and the evidence. Fluids and Barriers of the CNS, 19:9.

This episode explores advanced methods for recording and analyzing EEG responses evoked by transcranial magnetic stimulation, with a focus on TMS-evoked potentials, or TEPs. Drawing on recent research by Zrenner and Ziemann (2024), Beck et al. (2024), Casarotto et al. (2022), Kabir et al. (2024), and Vasileiadi et al. (2026), the episode examines how scientists are improving the precision, reliability, and physiological interpretation of brain stimulation measurements.

The discussion highlights a major shift from traditional open-loop stimulation protocols toward state-dependent and closed-loop approaches, where TMS pulses are timed according to the brain’s ongoing electrophysiological activity. It covers real-time EEG-informed stimulation, immediate TEPs occurring within the first milliseconds after a pulse, real-time artifact monitoring, EEG microstate-dependent variability, and state-dependent network effects during speech production.

Together, these studies show that the brain’s response to stimulation depends strongly on its moment-to-moment state. By improving signal-to-noise ratio, temporal resolution, artifact control, and stimulation timing, these approaches help researchers better capture the brain’s earliest physiological responses to non-invasive stimulation. The podcast also considers how these developments may support more precise neuromodulation protocols for neuroscience research and clinical applications, including disorders such as major depressive disorder.

References

Zrenner, C., & Ziemann, U. (2024). Closed-Loop Brain Stimulation. Biological Psychiatry.

Beck, M. M., Christiansen, L., Madsen, M. A. J., et al. (2024). Transcranial magnetic stimulation of primary motor cortex elicits an immediate transcranial evoked potential. Brain Stimulation.

Casarotto, S., Fecchio, M., Rosanova, M., et al. (2022). The rt-TEP tool: real-time visualization of TMS-Evoked Potentials to maximize cortical activation and minimize artifacts. Journal of Neuroscience Methods.

Kabir, A., Dhami, P., Dussault Gomez, M.-A., et al. (2024). Influence of Large-Scale Brain State Dynamics on the Evoked Response to Brain Stimulation. The Journal of Neuroscience.

Vasileiadi, M., Schuler, A.-L., Woletz, M., et al. (2026). Chronometric interleaved TMS-fMRI shows state-dependent network effects underlying speech production. Brain Stimulation.