Rationale: Neuromodulation is a treatment for patients with drug resistant epilepsy and those ineligible for surgical intervention. While the majority of invasive approaches stimulate grey matter, research has shown that white matter stimulation, specifically of the corpus callosum (CC), is also an effective target for seizure suppression (1). Although beneficial to patients, invasive stimulation is nonideal due to surgical risks. Transcranial focused ultrasound stimulation (tFUS) is a non-invasive alternative uniquely positioned to treat patients with epilepsy due to its great spatial precision (2). The aim of this study is to address whether tFUS stimulation of white matter can suppress seizures non-invasively.
References:
- N. H. Couturier and D. M. Durand, 2018. Corpus callosum low-frequency stimulation suppresses seizures in an acute rat model of focal cortical seizures. Epilepsia, 59(12): 2219–2230.
- K. Yu, X. Niu, E. Krook-Magnuson, and B. He, 2021. Intrinsic functional neuron-type selectivity of transcranial focused ultrasound neuromodulation. Nat Commun, 12: 2519.
Methods: Repeated injections of 4-Aminopyridine (4-AP) cocktail administered to the right somatosensory cortex (S1) induced cortical seizures in rats (N=9) under anesthesia (Fig.1A). An intracranial recording electrode was inserted into the contralateral S1, and EEG signals were collected from the skull surface. For each experimental condition, 1 hour of stimulation was applied to either the right S1 or the CC using a 128-element random-array transducer with a fundamental frequency of 1.5MHz. The pulse duration, pulse repetition frequency, ultrasound duration, and inter-stimulation-interval were set to 200us, 40Hz, 1s, and 2.5s (10% jitter), respectively. Two pressure levels were tested: ~105 kPa and ~127 kPa, measured ex vivo at the CC.Another hour without stimulation was used to analyze post-stimulation effects. Seizures were manually labeled by increases in band power. The percent time in seizure, average seizure duration, and average inter-seizure-interval were calculated, baseline-normalized, and averaged among rats to quantify efficacy.
Results: The ~105kPa conditions reduced percent time in seizure (Fig.1B) and increased inter-seizure-interval (Fig.1C) while the ~127kPa conditions generally had the opposite effect. All conditions except one decreased average seizure duration (Fig.1D). Stimulation at the CC with ~105kPa was the most effective parameter.
Conclusions: Applying tFUS to a 4-AP model of epilepsy can reduce the amount of time in seizure and average seizure duration, as well as increase the average inter-seizure-interval. Based on these results, the CC may be a more effective target than the seizure onset site. Additionally, tFUS demonstrated lasting effects in the post-stimulation period that would be essential for clinical translation. Overall, these results indicate that tFUS is a promising treatment for epilepsy.
Funding: NIH NS131069, NS124564, NS096761, NS127849-01A1, and EB029365.