Arousal and Consciousness in Focal Seizures

Abstract

Impaired consciousness during seizures severely affects quality of life for people with epilepsy but the mechanisms are just beginning to be understood. Consciousness is thought to involve large-scale brain networks, so it is puzzling that focal seizures often impair consciousness. Recent work investigating focal temporal lobe or limbic seizures in human patients and experimental animal models suggests that impaired consciousness is caused by active inhibition of subcortical arousal mechanisms. Focal limbic seizures exhibit decreased neuronal firing in brainstem, basal forebrain, and thalamic arousal networks, and cortical arousal can be restored when subcortical arousal circuits are stimulated during seizures. These findings open the possibility of restoring arousal and consciousness therapeutically during and following seizures by thalamic neurostimulation. When seizures cannot be stopped by existing treatments, targeted subcortical stimulation may improve arousal and consciousness, leading to improved safety and better psychosocial function for people with epilepsy.

Keywords: Epilepsy; awareness; consciousness; deep brain stimulation; temporal lobe epilepsy; thalamus.

Figure 1.

Local and long-range network effects in temporal lobe seizures consistent with decreased cortical physiological arousal. (A and B) Group analysis of SPECT ictal–interictal difference imaging during temporal lobe seizures. CBF increases (red) are present in the temporal lobe (A) and in the medial thalamus and upper brainstem (B). Decreases (green) are seen in the lateral frontoparietal association cortex (A) and in the interhemispheric frontoparietal regions (B). (C, D) Intracranial EEG recordings from a patient during a temporal lobe seizure. High-frequency polyspike-and-wave seizure activity is seen in the temporal lobe (C). The orbital and medial frontal cortex (and other regions, EEG not shown) do not show polyspike activity, but instead large-amplitude, irregular slow rhythms resembling coma or sleep (D). Vertical lines in (C) and (D) denote 1-s intervals. Note that the EEG and SPECT data were from similar patients, but were not simultaneous, and are shown together here for illustrative purposes only ((A, B) Modified from Blumenfeld et al. with permission. (C, D) Modified from Englot et al. with permission).

Figure 2.

Hippocampal, cortical, and subcortical blood oxygen-level–dependent (BOLD) fMRI changes during focal limbic seizures in a rat model. T-map of ictal changes during focal seizures (vs 30 s pre-seizure baseline) reveals a complicated network of changes. Widespread cortical decreases are accompanied by mixed subcortical increases and decreases. Increases are seen in known areas of seizure propagation such as the hippocampus (HC) and lateral septum as well as in sleep-promoting regions such as the anterior hypothalamus (Ant Hyp). Decreases are seen in the cortex, most prominently in lateral and ventral orbital frontal cortex (LO/VO) and in medial regions including cingulate and retrosplenial cortex. Decreases are also seen in arousal-promoting regions such as the thalamic intralaminar nuclei including centrolateral nucleus (CL), as well as in the midbrain tegmentum (MT). The arrowheads at AP −3.4 mm signify the hippocampal electrode artifact. Warm colors represent fMRI increases, and cool colors, decreases, superimposed on coronal anatomical images from the template animal. AP coordinates in millimeters are relative to bregma. 10 animals, with FDR corrected threshold P < .05. Reproduced with permission from Motelow et al.

Figure 3.

Network inhibition hypothesis. A simplified model demonstrating propagation of excitatory seizure activity from hippocampus (HC) to subcortical inhibitory areas such as anterior hypothalamus (Hypothal) or lateral septum (LS). From there, parallel pathways of direct inhibition (GABA) and indirect de-excitation (e.g., reduced glutamate, Glu from paratenial nucleus, PT) cause subcortical arousal structures to have reduced activity. This leads to reduced subcortical arousal projections to the cortex, including reduced acetylcholine (Ach) and reduction of other neurotransmitter systems, leading to cortical slow-wave activity and impaired consciousness. Modified with permission from Motelow et al.