Consciousness and epilepsy: why are complex-partial seizures complex?

Abstract

Why do complex-partial seizures in temporal lobe epilepsy (TLE) cause a loss of consciousness? Abnormal function of the medial temporal lobe is expected to cause memory loss, but it is unclear why profoundly impaired consciousness is so common in temporal lobe seizures. Recent exciting advances in behavioral, electrophysiological, and neuroimaging techniques spanning both human patients and animal models may allow new insights into this old question. While behavioral automatisms are often associated with diminished consciousness during temporal lobe seizures, impaired consciousness without ictal motor activity has also been described. Some have argued that electrographic lateralization of seizure activity to the left temporal lobe is most likely to cause impaired consciousness, but the evidence remains equivocal. Other data correlates ictal consciousness in TLE with bilateral temporal lobe involvement of seizure spiking. Nevertheless, it remains unclear why bilateral temporal seizures should impair responsiveness. Recent evidence has shown that impaired consciousness during temporal lobe seizures is correlated with large-amplitude slow EEG activity and neuroimaging signal decreases in the frontal and parietal association cortices. This abnormal decreased function in the neocortex contrasts with fast polyspike activity and elevated cerebral blood flow in limbic and other subcortical structures ictally. Our laboratory has thus proposed the "network inhibition hypothesis," in which seizure activity propagates to subcortical regions necessary for cortical activation, allowing the cortex to descend into an inhibited state of unconsciousness during complex-partial temporal lobe seizures. Supporting this hypothesis, recent rat studies during partial limbic seizures have shown that behavioral arrest is associated with frontal cortical slow waves, decreased neuronal firing, and hypometabolism. Animal studies further demonstrate that cortical deactivation and behavioral changes depend on seizure spread to subcortical structures including the lateral septum. Understanding the contributions of network inhibition to impaired consciousness in TLE is an important goal, as recurrent limbic seizures often result in cortical dysfunction during and between epileptic events that adversely affects patients' quality of life.

Fig. 1

Network inhibition hypothesis for loss of consciousness in complex-partial seizures. (A) Under normal conditions, the upper brainstem-diencephalic activating systems interact with the cerebral cortex to maintain normal consciousness. (B) A focal seizure involving the mesial temporal lobe unilaterally. (C) Propagation of seizure activity from the mesial temporal lobe to midline subcortical structures. (D) Disruption of the normal activating functions of the midline subcortical structures, together with the resulting depressed activity in bilateral regions of the frontoparietal association cortex, leads to loss of consciousness. Adapted with permission from Blumenfeld and Taylor (2003). Please see online version of this article for full color figure.

Fig. 2

Example of intracranial EEG recording during a mesial temporal seizure. (A) Seizure onset with low-voltage fast activity emerging from periodic spiking in the mesial temporal contacts. Later in this interval (0–30 s after seizure onset) spike-and-slow activity later appeared in the mesial as well as the lateral temporal contacts (not shown). (B) Sample from 30 to 60 s after seizure onset. Rhythmic spike and sharp wave activity continues in the temporal lobe, while the frontal and parietal contacts show large amplitude irregular slow-wave activity. (C) Sample from 60 to 90 s after seizure onset. Spike and polyspike-and-wave activity is present in the temporal lobe, with ongoing slow waves in the neocortex. (D) Postictal suppression is seen in temporal lobe contacts, with continued irregular slowing in the frontoparietal neocortex. Ipsilateral contacts only are shown. Bars along left margin indicate electrode contacts from different strips, rows, or depth electrodes in the indicated brain regions. Calibration bar on right is 1000 μV. Montage is referential to mastoid. Mes T, mesial temporal; Lat T, lateral temporal; OF, orbital frontal; Lat F, lateral frontal; Med F, medial frontal; Lat P, lateral parietal; C, perirolandic (pre- and post-central gyri); O, occipital. Adapted with permission from Blumenfeld et al. (2004b).

Fig. 3

Complex-partial, but not simple-partial, temporal lobe seizures are associated with significant CBF decreases in frontoparietal neocortical regions. Statistical parametric maps depict CBF increases in red and decreases in green. Changes ipsilateral to seizure onset are shown on the left side of the brain, and contralateral changes on the right side of the brain (combining patients with left and right onset seizures). (A) Complex-partial seizures arising from the temporal lobe are associated with significant CBF increases and decreases in widespread brain regions. Sixty to ninety seconds after seizure onset, increases occur mainly in the ipsilateral temporal lobe, while decreases occur in the ipsilateral > contralateral frontal and parietal association cortex (n = ). (B) Simple-partial seizures arising from the temporal lobe are not associated with widespread CBF changes (n = ). For (A) and (B), extent threshold, k = voxels (voxel size = × 2 × 2 mm). Height threshold, P = . Equivalently, only voxel clusters greater than 1 cm³ in volume and with Z scores greater than 2.33 are displayed. Adapted with permission from Blumenfeld et al. (2004a). Please see online version of this article for full color figure.

Fig. 4

Partial limbic seizures in rats produce ictal neocortical slow waves in the orbitofrontal cortex (CTX). (A) Local field potentials (LFP) in the hippocampus and orbitofrontal cortex during a spontaneous partial seizure associated with behavioral arrest in an awake-behaving rat. Hippocampal recordings reveal large-amplitude, fast polyspike activity during the seizure, while frontal cortical recordings show large-amplitude 1–3 Hz slow waves during and after the seizure without considerable propagation of fast spike activity. Ictal neocortical slow activity resembles large-amplitude slow rhythms seen in the frontal cortex during an episode of natural sleep, recorded in the same animal at a different time (bottom, right). LFP recordings are filtered 0.3–100 Hz. (B) Example of LFP and multiunit activity (MUA) recordings during an electrically stimulated partial seizure in a lightly anesthetized rat. During baseline, recordings show a stable theta rhythm in hippocampal LFP and low-voltage beta activity with occasional slow waves in the orbitofrontal cortex (see also inset). MUA recordings reveal relatively stable neuronal firing in both areas. During the seizure, hippocampal LFP recordings show 9–10 Hz fast polyspike activity ictally associated with population spikes in MUA recordings. Population spikes are often up to 10 times larger in amplitude than individual baseline units and are thus shown truncated here. In the orbitofrontal cortex, 1–2 Hz large-amplitude slow waves are seen in LFP recordings, associated with Up and Down states (arrows) of neuronal firing in MUA recordings. No fast polyspike activity is present in the frontal cortex LFPs. After the seizure, hippocampal activity is depressed whereas frontal slow oscillations persist postictally. Recordings from the same rat under deep anesthesia at a different time are also shown (bottom right), during which slow activity is present in the frontal cortex. LFP recordings are filtered 0.1–100 Hz and MUA recordings are filtered 400 Hz–20 kHz. Adapted with permission from Englot et al. (2008).

Fig. 5

Example of BOLD increases and decreases during an electrically stimulated partial limbic seizure. During partial limbic seizures, BOLD fMRI signal increases are observed in the hippocampus, thalamus, and septal nuclei. Prominent BOLD decreases are seen in the orbitofrontal, anterior cingulate, and retrosplenial/posterior cingulate cortices. The arrow signifies the hippocampal electrode artifact. t-maps are shown for the first 30 s of seizure activity (10 consecutive fMRI images acquired every 3 s) versus 30 s baseline and are superimposed on high-resolution anatomical images. Slices are shown from anterior to posterior, with approximate coordinates relative to bregma (Englot et al., 2008). Color bars indicate t-values for increases (warm colors) and decreases (cold colors). The display threshold is t = Cg1, anterior cingulate cortex; HC, hippocampus; OFC, orbitofrontal cortex; RSC, retrosplenial/posterior cingulate cortex; Thal, thalamus. Adapted with permission from Englot et al. (2008). Please see online version of this article for full color figure.

Fig. 6

Schematic diagram illustrating possible network mechanisms of ictal neocortical slow activity. (A) A simplified schematic diagram, showing that excitation of the hippocampus during a seizure may activate the lateral septum via glutamatergic projections in the fornix. This leads in turn to GABAergic inhibition of the nucleus basalis, which then results in diminished acetylcholinergic activation of the frontal cortex by the nucleus basalis, and thus allows the cortex to enter a depressed state associated with ictal neocortical slow activity. (B) A more complex diagram based on (A), adding other network changes that may contribute to ictal neocortical slow oscillations during hippocampal seizure activity. These mechanisms include the inhibitory influence of the lateral septum and the thalamic reticular nucleus onto subcortical structures and the ascending reticular activation system. This in turn leads to decreased excitatory input to the frontal neocortex by various activating structures, such as the thalamus, hypothalamus, and the nucleus basalis — ultimately resulting in cortical depression. Anatomical structures are labeled with black lettering, while neurotransmitters are listed in green. Recordings in the hippocampus and frontal cortex show example LFPs in each region. 5-HT, serotonin; Ach, acetylcholine; AM, amygdala; ARAS, ascending reticular activation system; CTX, cortex; DA, dopamine; ERC, entorhinal cortex; FF, fimbria-fornix; FR, fasciculus retroflexus; GABA, gamma-aminobutyric acid; Glu, glutamate; Hb, habenula; HC, hippocampus; His, histamine; MFB, medial forebrain bundle; LS, lateral septum; MS, medial septum; NB, nucleus basalis; NE, norepinephrine; Rt, thalamic reticular nucleus; SM, stria medullaris, Thal, thalamus. Please see online version of this article for full color figure.