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

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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.

Introduction

Consciousness has been an exceeding difficult concept to define for researchers, clinicians, and philosophers alike. This is likely because consciousness is a complex phenomenon which encompasses various different processes. Plum and Posner (1980) have suggested that it is important to distinguish between the level of consciousness and the content of consciousness. The content of consciousness can be described as the substrate on which consciousness acts, and is composed of all other neural systems hierarchically organized into parallel sensory and motor systems that receive inputs, generate outputs, and perform internal processing on multiple levels (Blumenfeld, 2002). In turn, the level of consciousness also has multiple components, which can be summarized as the maintenance of three distinct but related processes: (i) the awake, alert state; (ii) attention; and (iii) awareness of self and environment (Blumenfeld (2002), Blumenfeld (2009)). To study the neurobiological mechanisms of the awake, alert state necessary for consciousness, previous investigators have utilized various models such as sleep, coma, deep anesthesia, brain lesions, and epilepsy.

Generalized seizure disorders in humans, such as absence (petite mal) and tonic-clonic (grand mal) epilepsy, involve a pathological pattern of synchronous neuronal discharges in extensive networks throughout the brain, resulting in a loss of consciousness (Blumenfeld, 2005). Absence seizures are a form of generalized epilepsy in children characterized by rhythmic 3–4 Hz “spike-wave” discharges on electroencephalogram (EEG) produced by pathophysiological corticothalamic interactions (Avoli and Gloor, 1982; Blumenfeld and McCormick, 2000). These events are associated with brief 5–10 s episodes of unresponsiveness that have significant effects on a child's attentional abilities both during and between events (Levav et al., 2002; Mirsky and Van Buren, 1965). Conversely, generalized tonic-clonic seizures are characterized by fast excitatory discharges synchronously affecting neuronal networks in numerous brain regions, producing several minutes of unconsciousness and abnormal convulsive activity of widespread muscle groups (Blumenfeld et al., 2009; Morrell, 1993; Zifkin and Dravet, 2007).

It is perhaps not surprising that generalized seizures, involving extensive dysfunction of cortical and subcortical brain regions, cause significant impairments of consciousness. In temporal lobe epilepsy (TLE), however, seizures often originate from focal structures within the mesial temporal lobe, and frequently do not secondarily generalize or propagate to distal cortical areas. Yet, despite confinement of epileptic discharges to the temporal lobe and related limbic structures, seizures in TLE often cause a loss of consciousness. Understanding the mechanisms of impaired consciousness and cortical dysfunction during temporal lobe seizures has important clinical implications, as impaired consciousness causes motor vehicle accidents, drownings, poor work and school performance, and social stigmatization resulting in a major negative impact on patient quality of life (Drazkowski, 2007; Jacoby et al., 2005; Kobau et al., 2008; Sperling, 2004). In addition, previous investigations of TLE patients have found neocortical deficits including gray matter atrophy (Bonilha et al., 2006) and hypometabolism between seizures (Diehl et al., 2003; Nelissen et al., 2006), which may be related to neuropsychological sequelae and chronic cognitive impairments frequently suffered by these individuals (Helmstaedter and Kockelmann, 2006; Hermann et al., 1997; Laurent and Arzimanoglou, 2006). An appreciation of the long-range network effects of temporal lobe seizures on the neocortex may lead to a better grasp of epileptic mechanisms and a further understanding of the brain region interactions that underlie the conscious state. In this review, we will summarize previous investigations of TLE in humans and animal models, discuss what they suggest about the mechanisms of impaired consciousness during temporal lobe seizures, and advocate directions to further our understanding of this important problem.

Section snippets

The network inhibition hypothesis in TLE

Epilepsy is a debilitating neurological disorder that affects approximately 1% of the population in developed countries such as the United States (Devinsky, 2004). TLE is one of the most common epileptic disorders, characterized by seizures that frequently originate in limbic structures of the medial temporal lobe, such as the hippocampus and the amygdala (Engel, 1987; Williamson et al., 1993). As the temporal lobe is the most common site of origin of focal epileptic discharges, it has been

Behavioral semiology of temporal lobe seizures

While simple-partial temporal lobe seizures are frequently characterized by autonomic and/or psychic symptoms and epigastric sensations, complex-partial seizures of the temporal lobe often begin with an inhibition of purposeful motor activity and elicitation of automatic behavioral manifestations that are associated with unresponsiveness (ILAE, 1989). These automaton-like behaviors, termed “automatisms,” are typically manifested as repetitive orofacial movements such as lip-smacking, chewing,

EEG correlates of impaired consciousness in human TLE

Limbic seizures originate from mesial temporal structures on either the left or right side of the brain. Lateralization of behavioral signs such as automatisms can provide insight into the side of seizure onset, albeit with some inconsistency (Saint-Hilaire and Lee, 2000). It has also been proposed that lateralization or bilaterality of temporal lobe seizures may be the predominant feature predicting either loss or preservation of consciousness ictally. Some have hypothesized that the left

Neuroimaging insights into impaired consciousness in human TLE

Why do complex-partial temporal lobe seizures cause unconsciousness even though EEG recordings typically show seizure activity confined to temporal cortex? As discussed previously, partial seizures in TLE often cause other functional deficits beyond those expected from local limbic impairment, such as repetitive automaton-like movements (Loddenkemper and Kotagal, 2005), dystonic posturing of the limbs (Marks and Laxer, 1998), and neuroendocrine changes (Bauer, 2001; Quigg et al., 2002). It has

Network effects of temporal lobe seizures in animal models

While human studies of neurological disease possess the greatest validity, animal models of TLE activity allow controlled mechanistic studies which can be valuable in understanding both network effects and behavioral manifestations associated with complex-partial seizures. Behavioral correlates of electrographic temporal lobe seizures have been extensively studied in rodent models of TLE. For instance, the classic scale created by Ronald Racine (1972) allows investigators to rate behavioral

The network inhibition hypothesis revisited

As proposed in our network inhibition hypothesis (Fig. 1), it is possible that ictal aberration of normal activity in subcortical arousal systems may contribute to unconsciousness during complex-partial temporal lobe seizures. Some attention has been directed toward the importance of thalamocortical interactions in this phenomenon, but the intense lateral septal involvement during partial limbic seizures in rats has led us to also consider a possible role for the septum in eliciting ictal

Future directions

The human and animal studies of TLE summarized here provide characterization and preliminary insight into the mechanistic underpinnings of impaired consciousness and ictal neocortical slow rhythms during complex-partial temporal lobe seizures. However, much remains unknown about how focal seizure activity in the temporal lobe leads to a loss of consciousness ictally, and additional investigations — including studies in animal models within which mechanistic interventions are feasible — are

Conclusions: the consciousness system and TLE

In the mid-20th century, Wilder Penfield and Herbert Jasper hypothesized that the brainstem and diencephalon play critical roles in integrating brain activity across both cerebral hemispheres (Jasper, 1991; Penfield, 1958). It was observed that most epileptic patients suffered little to no impairment of consciousness after wide resection of cerebral cortical structures or the corpus callosum, although applying pressure to the brainstem resulted in immediate and reversible loss of consciousness (

Acknowledgments

This work was supported by NIH R01 NS049307 (HB) and F30 NS59074 (DJE), a Donaghue Foundation Investigator Award (HB), and by the Betsy and Jonathan Blattmachr family.

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