Can Low-frequency Do Better than High-frequency Electrical Stimulation in Some Patients with Epilepsy?

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Sunday, May 22, 2016

Despite the plethora of newer anti-seizure medications, a fixed one-third of all individuals with epilepsy still do not respond to medical therapy. Approximately half of these are also ineligible for epilepsy surgery. Therefore, alternative interventions, such as deep brain stimulation, are much needed.

Deep brain stimulation (DBS) has been tried in epilepsy targeting a number of brain regions and achieving limited benefit. These trials have used high-frequency stimulation (in the order of 100 Hz), while low-frequency stimulation (LFS) of 10 Hz or less has been relatively under-investigated.

There is evidence that LFS has major anti-seizure properties. Moreover, LFS subjects the brain tissue to less current injection and does not consume the stimulation battery as fast.

Where to stimulate?

With the exception of one trial of high-frequency DBS of the seizure focus, all completed clinical trials thus far attempted stimulation of one brain structure in patients with medically-intractable epilepsy. When the seizure focus itself is stimulated, some factors are important in determining success.

First and foremost, accurate localization of the seizure focus is needed, which may be elusive in some subjects. Additionally, each brain region has individual characteristics related to stimulus-induced alteration of excitatory and inhibitory potentials.

These may be reasons why seizure-focus DBS does not seem to benefit all patients equally. In the case of stimulating one brain structure, such as a thalamic nucleus for example, it is possible that the variability of the seizure networks in different patients determines their response to the stimulation of that specific brain structure.

In attempts to control for these variables, the effect of DBS in a specific epilepsy syndrome, such as temporal lobe epilepsy, can be studied, and LFS can be tried. Also, instead of stimulating the seizure focus itself (which is commonly the hippocampus in temporal lobe epilepsy), a white matter tract connected with the hippocampus can be stimulated. The dorsal hippocampal commissure, a large fiber tract connecting both hippocampi was stimulated in a rat model of temporal lobe epilepsy.1 The results showed that seizures were reduced by 90%, a dramatic decrease compared with results of high frequency stimulation. Additionally, the therapeutic effect outlasted the stimulation suggesting that LFS probably modulates the seizure network itself.

What is fiber tract stimulation?

There are reasons why fiber tract stimulation can be more efficient than grey matter stimulation.

  • First, fiber tract stimulation selectively activates axons, instead of inhibitory dendrites, thus delivering higher net current to the grey matter target.2
  • Second, white matter tract stimulation requires less energy than the grey matter.3

As regards the mechanisms of LFS, there are a number of theories. These include, among others, potassium-mediated mechanisms, reduced synaptic excitatory response, and decreased neuronal excitability.4 A recent study found that LFS induces long-lasting-hyperpolarization mediated by GABAB inhibitory post-synaptic potentials and slow after-hyperpolarization.5

In humans, a proof-of-principle study used LFS of a fiber tract connected with the hippocampus in 4-hour sessions in patients monitored with depth electrodes during continuous video-EEG monitoring.6 With the anti-seizure medication regimens unaltered, LFS resulted in 92% reduction of seizure odds with no discernible adverse events, including cognitive or psychiatric ones. This has led to an ongoing phase II trial ( Identifier: NCT02383407).

If this trial succeeds, the principle of stimulating a fiber tract connected with the seizure focus may be applied to targets outside the medial temporal lobe. Despite the variable successes of DBS trials in epilepsy thus far, electrical stimulation continues to be an important promising modality to improve seizure control. Further explorations of new stimulation parameters and brain targets, of which LFS and fiber tracts are examples, may lead to remarkably improved seizure control.


  1. Rashid, S., Pho, G., Czigler, M., Werz, M. A. & Durand, D. M. Low frequency stimulation of ventral hippocampal commissures reduces seizures in a rat model of chronic temporal lobe epilepsy. Epilepsia 53, 147–156 (2012).
  2. Stephani, C. & Koubeissi, M. Differences of Intracranial Electrical Stimulation Thresholds in the Human Brain. Brain Stimulat. 8, 724–729 (2015).
  3. Khan, S. et al. High frequency stimulation of the mamillothalamic tract for the treatment of resistant seizures associated with hypothalamic hamartoma. Epilepsia 50, 1608–1611 (2009).
  4. Toprani, S. & Durand, D. M. Long-lasting hyperpolarization underlies seizure reduction by low frequency deep brain electrical stimulation. J. Physiol. 591, 5765–5790 (2013).
  5. Toprani, S. & Durand, D. M. Long-lasting hyperpolarization underlies seizure reduction by low frequency deep brain electrical stimulation. J Physiol 591, 5765–90 (2013).
  6. Koubeissi, M. Z., Kahriman, E., Syed, T. U., Miller, J. & Durand, D. M. Low-frequency electrical stimulation of a fiber tract in temporal lobe epilepsy. Ann Neurol (2013). doi:10.1002/ana.23915
Authored by: Mohamad Koubeissi MD on 5/2016

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