Thalamic Stimulation Improves Postictal Cortical Arousal and Behavior

Abstract

The postictal state following seizures is characterized by impaired consciousness and has a major negative impact on individuals with epilepsy. Previous work in disorders of consciousness including the postictal state suggests that bilateral deep brain stimulation (DBS) of the thalamic intralaminar central lateral nucleus (CL) may improve level of arousal. We tested the effects of postictal thalamic CL DBS in a rat model of secondarily generalized seizures elicited by electrical hippocampal stimulation. Thalamic CL DBS was delivered at 100 Hz during the postictal period in 21 female rats while measuring cortical electrophysiology and behavior. The postictal period was characterized by frontal cortical slow waves, like other states of depressed consciousness. In addition, rats exhibited severely impaired responses on two different behavioral tasks in the postictal state. Thalamic CL stimulation prevented postictal cortical slow wave activity but produced only modest behavioral improvement on a spontaneous licking sucrose reward task. We therefore also tested responses using a lever-press shock escape/avoidance (E/A) task. Rats achieved high success rates responding to the sound warning on the E/A task even during natural slow wave sleep but were severely impaired in the postictal state. Unlike the spontaneous licking task, thalamic CL DBS during the E/A task produced a marked improvement in behavior, with significant increases in lever-press shock avoidance with DBS compared with sham controls. These findings support the idea that DBS of subcortical arousal structures may be a novel therapeutic strategy benefitting patients with medically and surgically refractory epilepsy.

Cortical low‐frequency power correlates with behavioral impairment in animal model of focal limbic seizures

“…Subcortical disruption may be important causally for the aberrant cortical oscillations we have associated with behavioral impairment 4 . Multiple pathologies and animal model studies have suggested the importance of the intralaminar thalamic nuclei 16,49,50 ; therefore, subcortical targeting of this circuit to improve behavior in a physiologically relevant way may have significant clinical implications 26,28,29,51 (see also https://braininitiative.nih.gov/funded-awards/thalamic-stimulation-prevent-impaired-consciousness-epilepsy). New therapeutic strategies to improve level of consciousness in epilepsy and traumatic brain injury have emerged 52,53 .…”

“…Once training was completed, electrophysiological recordings were performed in the shielded behavioral chambers (Figure 1B), as previously described 28 . Animals were connected from the head‐mounted pedestals to a commutator (Plastics One), headstages (×10 gain), and amplifiers (A‐M Systems, Model 1800, ×1000 gain), and local field potential (LFP) recordings were obtained at 1–500 Hz, with 60‐Hz notch filter.…”

“…We used an electrically shielded and sound‐attenuated chamber (Med Associates, ENV‐018MD‐EMS) containing a plexiglass behavioral operant chamber (Med Associates, ENV‐008‐CT) equipped with a camera, light, fan, speaker, and spout for sucrose reward delivery affixed to a photobeam lickometer (Med Associates, CT‐ENV‐251L‐X4) as previously described (Figure 1A). 28 A syringe pump delivered 60 μl of 10% sucrose solution reward. Sound stimuli were 2‐s, 100‐Hz trains of 3‐ms clicks at 75 dB, produced by an audio generator (Med Associates, ANL‐926) using a customized script in MED‐PC.…”

Thalamic Stimulation to Stay Stimulated After a Seizure

“…Xu et al, set out to test this in freely behaving female rats following focal limbic seizures with secondary generalization induced by hippocampal stimulation. 9 …”

A novel mouse model of focal limbic seizures that reproduces behavioral impairment associated with cortical slow wave activity

“…Due to a broader availability of genetic and molecular tools and the ease to manipulate mice in an awake head-fixed condition, we developed an awake, behaving head-fixed mouse model of TLE to measure electrophysiological and behavioral effects of focal limbic seizure. This mouse model will provide new opportunities to identify neuronal mechanisms crucial for maintaining consciousness during focal limbic seizures and explore the possibility to restore cortical function and behavior (Gummadavelli et al 2015; Furman et al 2015; Kundishora et al 2017; Xu et al 2020), providing hope for new treatment approaches to restore arousal in human epilepsy. This novel animal model of focal limbic seizures has been described recently by our group in abstract form and is presented here in greater detail (Sieu et al 2020; Sieu et al 2018; Sieu et al 2019).…”