What's the science?
Patients with epilepsy demonstrate abnormally elevated neuron firing and synchronization which contributes to seizures. Developing treatments that can reduce this neuron excitability and synchrony is a promising area of research. Many patients do not respond to anti-epileptic drugs or are not good candidates for surgery (for removal of seizure-generating brain tissue). In particular, deep brain stimulation of the anterior nucleus of the thalamus has shown promising results, however, the mechanism through which it improves symptoms remains unclear. This week in Brain, Yu and colleagues investigate the mechanism by which deep brain stimulation of the thalamus alters activity in brain regions of seizure onset.
How did they do it?
Nine patients with drug-resistant epilepsy underwent surgery for deep brain stimulation where electrodes are implanted deep in the brain. Intermittent high frequency stimulation of the anterior thalamus (130 Hz) was applied 5 days after surgery on the same side of the brain as the seizure onset region and local field potentials (neuronal activity) were recorded simultaneously from the seizure onset site using stereoelectroencephalography (SEEG) to better understand the resulting changes in neuronal activity and synchrony. Stimulation was applied in a range of frequencies (5 Hz-130 Hz) to assess the effect of frequency on brain activity at the seizure onset site. The seizure onset site varied among patients, but was located either in the hippocampus (6 patients), frontal lobe (2 patients) or temporal lobe (1 patient). Activity was recorded for 7 to 10 days in the seizure onset zones to ensure that at least 3 seizures were captured. They also tested ‘cortico-cortical evoked potentials’ by stimulating the thalamus and measuring the response in the hippocampus and vice versa to understand how these two brain regions interact in response to an electrical stimulus.
What did they find?
For patients with seizure onset in the hippocampus, high frequency stimulation of the anterior nucleus of the thalamus resulted in immediate desynchronization and reduction of neuronal activity in the hippocampus. This effect lasted while stimulation was turned on, and neuronal activity returned to baseline levels once stimulation was turned off. This effect was specific to the anterior nucleus of the thalamus (i.e. there was no similar effect for stimulation on other regions of the thalamus). This effect was also specific to patients with seizures originating in the hippocampus, as no activity changes were seen for patients with other seizure onset zones (i.e. frontal cortex or temporal lobe). Seizure-associated spiking activity of neurons in the hippocampus (also known as interictal spikes) and high frequency oscillations were reduced during high frequency stimulation of the anterior nucleus of the thalamus, but not during stimulation of other thalamic regions or for other seizure onset zones. This indicates that seizure-related activity was reduced in the seizure onset zone. Low frequency stimulation of the thalamus resulted in increased synchrony of neuronal activity in the hippocampus, while frequencies higher than 45 Hz resulted in desynchronization. They then examined cortico-cortical evoked potentials between the thalamus and the hippocampus and demonstrated that these regions are directly and reciprocally connected, which helps to explain why thalamic stimulation reduced seizure activity in the hippocampus.
What's the impact?
This is the first study to demonstrate the mechanism underlying the effects of deep brain stimulation of the anterior nucleus of the thalamus on seizure activity in epilepsy. Deep brain stimulation of the anterior nucleus of the thalamus results in desynchronization and reduction of activity in the hippocampus which are reciprocally connected. These findings improve our understanding of epilepsy originating in the hippocampus and suggest that deep brain stimulation of the anterior nucleus of the thalamus may be a promising treatment for epilepsy patients.
Word of caution: As the number of patients was low and there were few patients with neocortical seizure onset areas, the specific seizure type and seizure areas that respond to deep brain stimulation need to be clarified in a larger patient group.
Yu et al., High-frequency stimulation of anterior nucleus of thalamus desynchronizes epileptic network in humans. Brain (2018). Access the original scientific publication here.