Effects and mechanisms of anterior thalamus nucleus deep brain stimulation for epilepsy: A scoping review of preclinical studies

Deep brain stimulation (DBS) of the anterior nucleus of the thalamus (ANT) is a safe and effective intervention for the treatment of certain forms of epilepsy. In preclinical models, electrical stimulation of the ANT has antiepileptogenic effects but its underlying mechanisms remain unclear. In this review, we searched multiple databases for studies that described the effects and mechanisms of ANT low or high frequency stimulation (LFS or HFS) in models of epilepsy. Out of 289 articles identified, 83 were pooled for analysis and 34 were included. Overall, ANT DBS was most commonly delivered at high frequency to rodents injected with kainic acid, pilocarpine, or pentylenetetrazole. In most studies, this therapy increased the latency to the first spontaneous seizure and reduced the frequency of seizures by 20%-80%. Electrophysiology data suggested that DBS reduces the severity of electrographic seizures, decreases the duration and increases the threshold of afterdischarges, reduces the power of low-frequency and increase the power high-frequency bands. Mechanistic studies revealed that ANT DBS leads to a series of short- and long-term changes at multiple levels. Some of its anticonvulsant effects were proposed to occur via the modulation of serotonergic and adenosinergic transmission. The latter seems to be derived from the downregulation of adenosine kinase (ADK). ANT DBS was also shown to increase hippocampal levels of lactate, alter the expression of genes involved in calcium signaling, synaptic glutamate, and the NOD- like receptor signaling pathway. When delivered during status epilepticus or following the injection of convulsant agents, DBS was found to reduce the expression of proinflammatory cytokines and apoptosis. When administered chronically, ANT DBS increased the expression of proteins involved in axonal guidance, changed functional connectivity in limbic circuits, and increased the number of hippocampal cells in epileptic animals, suggesting a neuroprotective effect.