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Multimodal neuroimaging investigations of alterations to consciousness: The relationship between absence epilepsy and sleep
Epilepsy & Behavior 30 (2014) 33–37
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Review
Multimodal neuroimaging investigations of alterations to consciousness: The relationship between absence epilepsy and sleep Andrew P. Bagshaw a,⁎, David T. Rollings a,b, Sakh Khalsa a,c, Andrea E. Cavanna c a b c
School of Psychology and Birmingham University Imaging Centre, University of Birmingham, Edgbaston, Birmingham, UK Neuroscience Department, Queen Elizabeth Hospital, Edgbaston, Birmingham, UK Department of Neuropsychiatry, The Barberry National Centre for Mental Health, Birmingham, UK
a r t i c l e
i n f o
Article history: Accepted 16 September 2013 Available online 17 October 2013 Keywords: Epilepsy Sleep Consciousness Multimodal neuroimaging
a b s t r a c t The link between epilepsy and sleep is well established on many levels. The focus of the current review is on recent neuroimaging investigations into the alterations of consciousness that are observed during absence seizures and the descent into sleep. Functional neuroimaging provides simultaneous cortical and subcortical recording of activity throughout the brain, allowing a detailed definition and characterization of large-scale brain networks and the interactions between them. This has led to the identification of a set of regions which collectively form the consciousness system, which includes contributions from the default mode network (DMN), ascending arousal systems, and the thalamus. Electrophysiological and neuroimaging investigations have also clearly demonstrated the importance of thalamocortical and corticothalamic networks in the evolution of sleep and absence epilepsy, two phenomena in which the subject experiences an alteration to the conscious state and a disconnection from external input. However, the precise relationship between the consciousness system, thalamocortical networks, and consciousness itself remains to be clarified. One of the fundamental challenges is to understand how distributed brain networks coordinate their activity in order to maintain and implement complex behaviors such as consciousness and how modifications to this network activity lead to alterations in consciousness. By taking into account not only the level of activation of individual brain regions but also their connectivity within specific networks and the activity and connectivity of other relevant networks, a more specific quantification of brain states can be achieved. This, in turn, may provide a more fundamental understanding of the alterations to consciousness experienced in sleep and epilepsy. This article is part of a Special Issue entitled Epilepsy and Consciousness. © 2013 Elsevier Inc. All rights reserved.
1. Introduction There is a long history of basic and clinical research indicating a bidirectional link between many aspects of epilepsy and sleep (for reviews, see [1–4]). In this review, we will briefly recapitulate some of these links before focussing on recent neuroimaging investigations that relate to the alterations of consciousness and awareness that are observed during epileptic seizures and the descent into sleep. We will concentrate on absence seizures as perhaps the most obvious example of a modification to the conscious state in epilepsy. Absence seizures affect the level and the contents of consciousness [5], although they are not accompanied by complex experiential phenomena and are characterized by abrupt cessation of responsiveness associated with staring. They may also be accompanied by myoclonic movements, atonia, or automatisms. Electrophysiologically, they demonstrate spike–wave discharges (SWD) with durations of around 10 s and abrupt onset and offset. Shorter ⁎ Corresponding author at: School of Psychology, University of Birmingham, Birmingham B15 2TT, UK. E-mail address: [email protected] (A.P. Bagshaw). 1525-5050/$ – see front matter © 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.yebeh.2013.09.027
bursts of SWD do not result in the overt loss of awareness that is observed in absence seizures, although the reason for this is not clear, given that they are presumably generated by the same networks. While in vitro and in vivo electrophysiology studies allied with clinical studies are able to identify and characterize the basic links between sleep and epilepsy, they are less well suited to addressing the questions of how and why consciousness is altered. To investigate whether similar mechanisms are involved in the alterations to consciousness experienced in normal sleep and absence seizures, whole-brain functional recordings are needed which can provide a system-level characterization of the neural substrates underpinning such complex behaviors. The major neuroimaging techniques of functional MRI (fMRI), positron emission tomography (PET), and single photon emission computed tomography (SPECT) have all been extensively used to delineate the regions involved in the maintenance of the conscious state in patients with epilepsy and in sleeping subjects. A consistent picture generally emerges of a network of cortical and subcortical regions which comprise a ‘consciousness system’ [6,7]. Cortically, this involves the default mode network (DMN) and other regions such as the lateral frontal association cortices, with subcortical structures including the thalamus, hypothalamus, basal forebrain, and regions in the
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upper brainstem which are involved in arousal. How these distributed regions, which consist of contributions from several specific networks, interact to maintain the conscious state is an unresolved question. In particular, the relationship between the DMN and the thalamocortical (TC) and corticothalamic (CT) networks that generate the paroxsymal discharges of sleep and generalized epilepsy is not clear. In the following, we will review the evidence from functional neuroimaging that there are shared mechanisms responsible for the alterations to consciousness observed in sleep and absence seizures, with particular attention paid to the relationship between TC interactions and the DMN. Firstly, however, we will briefly discuss some of the electrophysiological links between epilepsy and sleep. Epilepsy is inherently an electrophysiological disorder, and there are a number of indications that specific electrophysiological markers of epileptogenicity are linked with the neurobiological processes underlying sleep. 2. Electrophysiological links between epilepsy and sleep One example of the link between sleep and epilepsy that has a long history and has received a considerable amount of attention is the hypothesis that the TC networks that generate sleep spindles are pathologically utilized to generate SWD (see [8–10] for reviews). Sleep spindles are one of the defining characteristics of non rapid-eye movement stage 2 sleep (N2, [11]) and are generated by reciprocal connections and interplay between the cortex, thalamic reticular nucleus (TRN), and TC neurons located in the dorsal thalamic nuclei. They originate in the thalamus as a result of hyperpolarization of TC neurons mediated by γ-aminobutyric acid (GABA), released through the firing of TRN neurons. Thalamocortical neurons, through low threshold calcium currents, experience a postinhibitory rebound, causing excitatory input into the TRN neurons. It is this cyclic alternation that results in rhythmic sleep spindles, which are then transferred to the cortex through TC neurons and become evident on scalp EEG [12–15]. Abnormal overexpression of these low threshold calcium currents has been implicated in the generation of SWD in rodent studies [16–18]. The relative importance of the thalamus and cortex in the generation of SWD is an ongoing debate [10], with the recent evidence pointing towards an initiating site in the cortex [19], rather than the thalamic origin of sleep spindles. Differences in time–frequency characteristics have also highlighted a less-thanstraightforward relationship between sleep spindles and SWD (for a review, see [20]). It is not only in absence seizures that the electrophysiological markers of epileptogenicity have been associated with sleep. Recently, it has been suggested that high frequency oscillations (HFO) represent one of the most specific markers of the epileptogenic zone in focal epilepsies, particularly in the fast ripple (N 250 Hz) range [21,22]. At lower frequencies, ripples (N 80 Hz) are considered to be one of the mechanisms of memory consolidation, whereby hippocampal traces acquired during wakefulness are transferred for long-term storage to the cortex [23]. Hippocampal ripples are temporally coincident with cortical sleep spindles [24], supporting the view that sleep spindles are an important part of the memory consolidation process [25]. The rate of occurrence of ripples and pathological fast ripples is strongly dependent on sleep stage, peaking in non-REM (NREM) sleep and minimal in both wakefulness and REM sleep [26]. This link between sleep stage and manifestations of epilepsy is also seen for interictal epileptiform discharges as well as overt seizures [2–4,27]. Seizures also tend to become more likely following sleep deprivation, potentially because of changes in cortical excitability that occur with prolonged wakefulness [28]. These observations, as well as others which are reviewed in detail elsewhere [1–4], cement the concept of a strong link between various types of epilepsy and sleep. In some cases, such as the link between spindles and SWD, hypotheses are very specific, and the putative neurobiological mechanisms are well developed. In other cases, the observed relationship may be more related to the profound changes in the electrophysiological and neuromodulatory environments that occur during
sleep, which consequently affect epileptogenic processes. Clearly, continued efforts are needed to clarify how and why epileptogenic processes are facilitated by sleep. However, with regard to the question of alterations to consciousness, functional neuroimaging has the advantage that it records the activity and interactions of regions distributed throughout the brain, allowing them to be linked with overt behaviors. This has facilitated some important observations regarding the disruptions to consciousness experienced in sleep and seizures. 3. Neuroimaging of alterations to consciousness in absence epilepsy and sleep There is a reasonable body of work which has examined the cortical and subcortical regions involved in SWD and absence seizures. From a practical point of view, this activity is amenable to investigation with functional magnetic resonance imaging (fMRI) since it does not necessarily result in motor activity which would have safety implications and degrade data quality. This has led to the application of EEG-fMRI in several studies, and reduced activity in the nodes of the DMN and increased thalamic activity, with less consistent alterations elsewhere in cortical and subcortical regions [29–40], have been consistently observed. The DMN includes the precuneus, posterior cingulate cortex, and bilateral inferior parietal and medial prefrontal cortices [41]. It is one of a series of resting state networks (RSNs) that can be reliably extracted from neuroimaging data which have become an increasingly important method of investigating the brain's functional architecture [42]. Activity in the DMN increases when the subject is not engaged in cognitively demanding activity [41,43], and it was originally identified as a set of regions which were consistently deactivated across a range of tasks [44]. It is considered to be particularly important for intrinsic thought processing and representing one's self in relation to the external environment [5]. Reduced DMN activity during SWD would imply a cessation of the self-monitoring that occurs during normal consciousness in the absence of an overt task and could be considered to be consistent with the observed clinical correlates of SWD. Besides reduced DMN activity during SWD, disruptions to the DMN have also been observed in patients with focal epilepsy, suggesting an inherent ability of epileptic activity to disrupt ongoing brain processes including the DMN and consciousness system [6,45]. However, bearing in mind that the DMN routinely deactivates during normal sensory and cognitive processing without leading to the loss of consciousness observed in absence seizures, it is perhaps not completely clear how to interpret the deactivation seen during SWD. Even in the simpler case of task responses, the interpretation of reductions in hemodynamic activity is still a matter of ongoing debate within the neuroimaging community, and it has been suggested that the physiological origin of negative responses may be dependent on task type and brain region [46]. This suggests that some caution is needed when considering the interpretation of deactivations in networks of ongoing brain activity in response to internally generated, pathological paroxysmal discharges. Alterations to DMN activity have also been implicated in the alterations to consciousness that are seen in the descent into sleep, often in terms of the connectivity between regions, which will be discussed below. When considering the regions activated or deactivated by sleep spindles, which have been more widely studied than K-complexes or vertex sharp waves and which are of particular relevance to the foregoing discussion, it is notable that they are not immediately comparable to those linked with SWD, and deactivation of the DMN is not observed [47–49]. While this would not preclude the same networks being involved in the generation of the two types of activity, it would require a more complex interpretation of the relationship between electrophysiology and hemodynamic neuroimaging. For example, if the same TC circuit is driven by very different modes of neuronal firing, it is conceivable that the downstream expression of that activity on the cortex, as well as the regional metabolic demands that drive hemodynamic
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neuroimaging signals, may well be very different. Similarly, when considering the lack of DMN deactivation, since the analysis is asking how activity changes at the time of paroxysmal discharges, this is inherently dependent on the nature of the baseline activity. Sleep certainly modifies DMN activity and the additional, transient modifications resulting from spindles may well be lost in this more fundamental alteration. Much of the focus in relation to the DMN in sleep has been around the extent to which the individual regions comprising the DMN are functionally connected and how that connectivity is altered at different sleep stages [50–53], following sleep deprivation [54,55] or as a function of nocturnal sleep duration [56]. In the simplest case, analysis of functional connectivity (FC) involves pairwise correlation analysis between regions of interest. One of the more consistent observations in relation to the DMN during sleep has been decoupling of frontal and posterior regions in stage N2 and deeper [51,53]. As with the reductions in DMN activity from baseline observed during SWD, this reduction in connectivity is consistent with the suggestion that a coherent DMN is important in the maintenance of awareness and, in a general sense, with the alterations to behavior and consciousness that occur with deepening sleep. However, moving beyond this general consistency to a more precise understanding of how tonic activity levels and integrity of network connectivity link with each other and with behavior is challenging. As an immediate step, it is important to understand how eventrelated changes in hemodynamic activity and alterations to the strength of connectivity are related. While the majority of neuroimaging investigations employ one or more of these strategies, there are some indications that examining both aspects may be a fruitful line of enquiry. For example, intrinsic resting and dynamic changes in network connectivity can explain inter- and intrasubject variability in the magnitude of behavioral and hemodynamic responses to a painful stimulus [57]. A more coherent understanding of the extent to which neuroimaging signatures can explain individual differences in behavior, in the current case in terms of alterations to consciousness in epilepsy and sleep, is vital if the imaging data are to be fully interpreted and exploited. Regional cerebral blood flow (CBF) studies using PET have also demonstrated a decrease in blood flow to the precuneus and posterior cingulate cortex in the deeper stages of sleep accompanied by an increase in blood flow to the thalamus which may be instigated by the prefrontal cortex [58,59]. EEG-fMRI also consistently demonstrates thalamic involvement at the time of spindles [47–49], as well as at the time of vertex sharp waves and K-complexes, the other electrophysiological transients of sleep [49,60,61]. Interestingly, Spoormaker et al. [62] noted a reduction in thalamocortical connectivity from wakefulness to light (N1) sleep, whereas corticocortical connectivity increased, though again the relationship between increases in blood flow and changes in connectivity is not obvious. The increased blood flow in the thalamus and the thalamic activation observed in response to SWD again highlights the idea that widespread TC and CT networks play an important role in the evolution of sleep and SWD. However, the precise relationship between the DMN, thalamocortical networks, and consciousness remains to be clarified. 4. Thalamocortical oscillations, the default mode network, and maintenance of consciousness Differentiating brain states and their behavioral correlates, taking into account not only their level of activation (i.e., activity observed on EEG or with neuroimaging methods) but also the status and connectivity of the arousal systems and other relevant networks like the DMN plus the overall neurochemical environment determined by phase within the sleep cycle, may allow a more fundamental understanding of alterations to consciousness in sleep and epilepsy. This forms the basis of the AIM state space model [63], which highlights the importance of three orthogonal features in defining behavioral state: activation (A), input–output gating (I), and modulation (M). While this model has been suggested as a way of understanding the alterations to conscious state observed in different sleep stages and in sleep
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disorders, it may also have relevance to the characterization of the altered states of consciousness observed in epilepsy. Access to sensory input via TC loops and, in a more general sense, the activity and integrity of TC networks may be particularly important. A full characterization of the physiological parameters that would be relevant to the AIM model remains difficult to achieve with existing methods of investigating the human brain, but some understanding of how TC and CT networks are linked to changes in the DMN can be gained from more detailed analyses of fMRI data. One interesting observation is the involvement of DMN regions prior to the development of absence seizures on the EEG. Bai et al. [39] demonstrated significant fMRI signal increases in the orbitofrontal, lateral parietal, and precuneus regions more than 5 s before any EEG changes were noted. These regions developed later decreases in the fMRI response, while late thalamic increases in activity were also seen at the time of widespread DMN deactivation. These observations suggest that cortical–subcortical interactions may be involved in the observed decreases in the DMN. One hypothesis that has been developed primarily in relation to generalized tonic–clonic seizures relates to the observation that there is an increase in cerebellar Purkinje cell firing in the late ictal and postictal phases of generalized seizures in cats [64]. It has been suggested that since Purkinje cells send inhibitory outputs to influence TC circuits, the increased cerebellar activity may play a role in seizure termination and possibly postictal suppression [7]. These inhibitory outputs cause depression of subcortical activating systems which leads to the attenuation of activity in the frontoparietal association cortex and to loss of consciousness. Intracranial EEG recordings from these regions during temporal lobe epileptic seizures have demonstrated increased slow-wave activity during complex partial compared with simple partial seizures [65], while EEG-fMRI consistently demonstrates cerebellar activation in response to SWD [32]. Further investigation of these large-scale cortical and subcortical networks is needed. It is particularly important to include an assessment of how the integrity of functional networks changes dynamically, since networks are often defined based on temporal correlation over several minutes of data. While this leads to consistent and robust results, it is clearly suboptimal from the point of view of understanding transient alterations in consciousness. Similarly, it is important to understand how different networks interact and how this links with behavior, especially in light of the contribution of the arousal, thalamocortical, and DMN regions to the maintenance of consciousness. Some recent studies examining the alpha rhythm have provided some methodological insights into how this could be accomplished [66–68]. This may be particularly relevant to the discussion of epileptic and sleep activity since the alpha rhythm is also thalamocortically generated and provides a dynamic marker of thalamic gating of sensory input that is linked with levels of attention and vigilance [69–71]. Finally, despite the fact that short bursts of SWD do not lead to the overt loss of awareness that is characteristic of an absence seizure, the pattern of thalamic activation and primarily cortical deactivation during SWD and absence seizures is remarkably similar. This would suggest that even SWD of shorter duration would lead to transient alterations in awareness or have some impact on cognitive function. This does indeed seem to be the case. One of the earliest studies investigating the clinical effect of interictal SWD on cognitive function noted a reduction in task performance during a simple reaction-time paradigm [72]. Further studies have supported this observation and supported the hypothesis of a transient impairment of cognition associated with interictal SWD [73–76]. The question of whether these cognitive effects are actually the result of a transient disruption of the consciousness system remains to be determined. 5. Conclusions Sleep and absence seizures result in altered consciousness that disconnects the subject from the environment. Recent neuroimaging studies
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imply that changes in and interactions between large-scale brain networks including thalamocortical loops, the ascending arousal system, and the DMN may be implicated in the observed alterations to consciousness. This approach might help in understanding why absence seizures result in impaired consciousness, as well as shedding light on the systems and networks responsible for maintenance of the conscious state. Challenges remain at every stage of this work. More detail is needed about the significance and physiological interpretation of reductions in hemodynamic signals in response to paroxysmal discharges and how they relate to alterations in the FC of distributed networks. More precise analytical tools are needed to characterize and quantify the activity of these networks, including the dynamic changes that are fundamental to an understanding of rapidly changing behavior. The fundamental understanding of how neuroimaging signatures represent and link with behavioral changes also needs to improve. While this is a general point, this lack of understanding, perhaps, becomes most apparent when trying to understand particularly complex behaviors such as the maintenance of and alterations to consciousness. The work that has been done so far does not clearly point to equivalent mechanisms underlying the alterations to consciousness experienced in absence seizures and sleep, but certainly, there is overlap. This is particularly apparent at the level of the DMN. The links in terms of TC networks that have been suggested by invasive electrophysiology also show signs of being supported by neuroimaging data. How these observations are related is not clear, although the suggestion that the DMN forms one aspect of the consciousness system that also includes the thalamus and ascending arousal systems provides a framework to integrate these data. From a clinical point of view, it is interesting that overt loss of consciousness, which represents possibly the major burden of this kind of seizure to the patient, only seems to occur with seizure durations of 5–10 s. This raises the possibility that if the mechanisms responsible for maintenance of consciousness and for the termination of SWD were understood, a considerable clinical impact could be achieved by focussing on terminating the discharges quickly rather than preventing their occurrence. Conflict of interest The authors declare that there are no conflicts of interest. References [1] Steriade M. Sleep, epilepsy and thalamic reticular inhibitory neurons. Trends Neurosci 2005;28(6):317–24. [2] Kotagal P, Yardi N. The relationship between sleep and epilepsy. Semin Pediatr Neurol 2008;15(2):42–9. [3] Eriksson SH. Epilepsy and sleep. Curr Opin Neurol 2011;24(2):171–6. [4] Sinha SR. Basic mechanisms of sleep and epilepsy. J Clin Neurophysiol 2011;28(2):103–10. [5] Cavanna AE, Monaco F. Brain mechanisms of altered conscious states during epileptic seizures. Nat Rev Neurol 2009;5(5):267–76. [6] Danielson NB, Guo JN, Blumenfeld H. The default mode network and altered consciousness in epilepsy. Behav Neurol 2011;24(1):55–65. [7] Blumenfeld H. Impaired consciousness in epilepsy. Lancet Neurol 2012;11(9):814–26. [8] Kostopoulos GK. Spike-and-wave discharges of absence seizures as a transformation of sleep spindles: the continuing development of a hypothesis. Clin Neurophysiol 2000;111(Suppl. 2):S27–38. [9] Kostopoulos GK. Involvement of the thalamocortical system in epileptic loss of consciousness. Epilepsia 2001;42(Suppl. 3):13–9. [10] Avoli M. A brief history on the oscillating roles of thalamus and cortex in absence seizures. Epilepsia 2011;53(5):779–89. [11] Iber C, Ancoli-Israel S, Chesson AL, Quan SF. The AASM manual for the scoring of sleep and associated events. Rules, terminology and technical specifications. Westchester, IL: American Association of Sleep Medicine; 2007. [12] Steriade M, Contreras R, Curró Dossi R, Nuňez A. The slow (b1 Hz) oscillation in reticular thalamic and thalamocortical neurons: scenario of sleep rhythm generation in interacting thalamic and neocortical networks. J Neurosci 1993;13:3284–99. [13] Huguenard JR. Low-threshold calcium currents in central nervous system neurons. Annu Rev Physiol 1996;58:329–48. [14] Steriade M, Timofeev I. Neuronal plasticity in thalamocortical networks during sleep and waking oscillations. Neuron 2003;37:563–76. [15] Steriade M. Grouping of brain rhythms in corticothalamic systems. Neuroscience 2006;137:1087–106.
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Review
Multimodal neuroimaging investigations of alterations to consciousness: The relationship between absence epilepsy and sleep Andrew P. Bagshaw a,⁎, David T. Rollings a,b, Sakh Khalsa a,c, Andrea E. Cavanna c a b c
School of Psychology and Birmingham University Imaging Centre, University of Birmingham, Edgbaston, Birmingham, UK Neuroscience Department, Queen Elizabeth Hospital, Edgbaston, Birmingham, UK Department of Neuropsychiatry, The Barberry National Centre for Mental Health, Birmingham, UK
a r t i c l e
i n f o
Article history: Accepted 16 September 2013 Available online 17 October 2013 Keywords: Epilepsy Sleep Consciousness Multimodal neuroimaging
a b s t r a c t The link between epilepsy and sleep is well established on many levels. The focus of the current review is on recent neuroimaging investigations into the alterations of consciousness that are observed during absence seizures and the descent into sleep. Functional neuroimaging provides simultaneous cortical and subcortical recording of activity throughout the brain, allowing a detailed definition and characterization of large-scale brain networks and the interactions between them. This has led to the identification of a set of regions which collectively form the consciousness system, which includes contributions from the default mode network (DMN), ascending arousal systems, and the thalamus. Electrophysiological and neuroimaging investigations have also clearly demonstrated the importance of thalamocortical and corticothalamic networks in the evolution of sleep and absence epilepsy, two phenomena in which the subject experiences an alteration to the conscious state and a disconnection from external input. However, the precise relationship between the consciousness system, thalamocortical networks, and consciousness itself remains to be clarified. One of the fundamental challenges is to understand how distributed brain networks coordinate their activity in order to maintain and implement complex behaviors such as consciousness and how modifications to this network activity lead to alterations in consciousness. By taking into account not only the level of activation of individual brain regions but also their connectivity within specific networks and the activity and connectivity of other relevant networks, a more specific quantification of brain states can be achieved. This, in turn, may provide a more fundamental understanding of the alterations to consciousness experienced in sleep and epilepsy. This article is part of a Special Issue entitled Epilepsy and Consciousness. © 2013 Elsevier Inc. All rights reserved.
1. Introduction There is a long history of basic and clinical research indicating a bidirectional link between many aspects of epilepsy and sleep (for reviews, see [1–4]). In this review, we will briefly recapitulate some of these links before focussing on recent neuroimaging investigations that relate to the alterations of consciousness and awareness that are observed during epileptic seizures and the descent into sleep. We will concentrate on absence seizures as perhaps the most obvious example of a modification to the conscious state in epilepsy. Absence seizures affect the level and the contents of consciousness [5], although they are not accompanied by complex experiential phenomena and are characterized by abrupt cessation of responsiveness associated with staring. They may also be accompanied by myoclonic movements, atonia, or automatisms. Electrophysiologically, they demonstrate spike–wave discharges (SWD) with durations of around 10 s and abrupt onset and offset. Shorter ⁎ Corresponding author at: School of Psychology, University of Birmingham, Birmingham B15 2TT, UK. E-mail address: [email protected] (A.P. Bagshaw). 1525-5050/$ – see front matter © 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.yebeh.2013.09.027
bursts of SWD do not result in the overt loss of awareness that is observed in absence seizures, although the reason for this is not clear, given that they are presumably generated by the same networks. While in vitro and in vivo electrophysiology studies allied with clinical studies are able to identify and characterize the basic links between sleep and epilepsy, they are less well suited to addressing the questions of how and why consciousness is altered. To investigate whether similar mechanisms are involved in the alterations to consciousness experienced in normal sleep and absence seizures, whole-brain functional recordings are needed which can provide a system-level characterization of the neural substrates underpinning such complex behaviors. The major neuroimaging techniques of functional MRI (fMRI), positron emission tomography (PET), and single photon emission computed tomography (SPECT) have all been extensively used to delineate the regions involved in the maintenance of the conscious state in patients with epilepsy and in sleeping subjects. A consistent picture generally emerges of a network of cortical and subcortical regions which comprise a ‘consciousness system’ [6,7]. Cortically, this involves the default mode network (DMN) and other regions such as the lateral frontal association cortices, with subcortical structures including the thalamus, hypothalamus, basal forebrain, and regions in the
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upper brainstem which are involved in arousal. How these distributed regions, which consist of contributions from several specific networks, interact to maintain the conscious state is an unresolved question. In particular, the relationship between the DMN and the thalamocortical (TC) and corticothalamic (CT) networks that generate the paroxsymal discharges of sleep and generalized epilepsy is not clear. In the following, we will review the evidence from functional neuroimaging that there are shared mechanisms responsible for the alterations to consciousness observed in sleep and absence seizures, with particular attention paid to the relationship between TC interactions and the DMN. Firstly, however, we will briefly discuss some of the electrophysiological links between epilepsy and sleep. Epilepsy is inherently an electrophysiological disorder, and there are a number of indications that specific electrophysiological markers of epileptogenicity are linked with the neurobiological processes underlying sleep. 2. Electrophysiological links between epilepsy and sleep One example of the link between sleep and epilepsy that has a long history and has received a considerable amount of attention is the hypothesis that the TC networks that generate sleep spindles are pathologically utilized to generate SWD (see [8–10] for reviews). Sleep spindles are one of the defining characteristics of non rapid-eye movement stage 2 sleep (N2, [11]) and are generated by reciprocal connections and interplay between the cortex, thalamic reticular nucleus (TRN), and TC neurons located in the dorsal thalamic nuclei. They originate in the thalamus as a result of hyperpolarization of TC neurons mediated by γ-aminobutyric acid (GABA), released through the firing of TRN neurons. Thalamocortical neurons, through low threshold calcium currents, experience a postinhibitory rebound, causing excitatory input into the TRN neurons. It is this cyclic alternation that results in rhythmic sleep spindles, which are then transferred to the cortex through TC neurons and become evident on scalp EEG [12–15]. Abnormal overexpression of these low threshold calcium currents has been implicated in the generation of SWD in rodent studies [16–18]. The relative importance of the thalamus and cortex in the generation of SWD is an ongoing debate [10], with the recent evidence pointing towards an initiating site in the cortex [19], rather than the thalamic origin of sleep spindles. Differences in time–frequency characteristics have also highlighted a less-thanstraightforward relationship between sleep spindles and SWD (for a review, see [20]). It is not only in absence seizures that the electrophysiological markers of epileptogenicity have been associated with sleep. Recently, it has been suggested that high frequency oscillations (HFO) represent one of the most specific markers of the epileptogenic zone in focal epilepsies, particularly in the fast ripple (N 250 Hz) range [21,22]. At lower frequencies, ripples (N 80 Hz) are considered to be one of the mechanisms of memory consolidation, whereby hippocampal traces acquired during wakefulness are transferred for long-term storage to the cortex [23]. Hippocampal ripples are temporally coincident with cortical sleep spindles [24], supporting the view that sleep spindles are an important part of the memory consolidation process [25]. The rate of occurrence of ripples and pathological fast ripples is strongly dependent on sleep stage, peaking in non-REM (NREM) sleep and minimal in both wakefulness and REM sleep [26]. This link between sleep stage and manifestations of epilepsy is also seen for interictal epileptiform discharges as well as overt seizures [2–4,27]. Seizures also tend to become more likely following sleep deprivation, potentially because of changes in cortical excitability that occur with prolonged wakefulness [28]. These observations, as well as others which are reviewed in detail elsewhere [1–4], cement the concept of a strong link between various types of epilepsy and sleep. In some cases, such as the link between spindles and SWD, hypotheses are very specific, and the putative neurobiological mechanisms are well developed. In other cases, the observed relationship may be more related to the profound changes in the electrophysiological and neuromodulatory environments that occur during
sleep, which consequently affect epileptogenic processes. Clearly, continued efforts are needed to clarify how and why epileptogenic processes are facilitated by sleep. However, with regard to the question of alterations to consciousness, functional neuroimaging has the advantage that it records the activity and interactions of regions distributed throughout the brain, allowing them to be linked with overt behaviors. This has facilitated some important observations regarding the disruptions to consciousness experienced in sleep and seizures. 3. Neuroimaging of alterations to consciousness in absence epilepsy and sleep There is a reasonable body of work which has examined the cortical and subcortical regions involved in SWD and absence seizures. From a practical point of view, this activity is amenable to investigation with functional magnetic resonance imaging (fMRI) since it does not necessarily result in motor activity which would have safety implications and degrade data quality. This has led to the application of EEG-fMRI in several studies, and reduced activity in the nodes of the DMN and increased thalamic activity, with less consistent alterations elsewhere in cortical and subcortical regions [29–40], have been consistently observed. The DMN includes the precuneus, posterior cingulate cortex, and bilateral inferior parietal and medial prefrontal cortices [41]. It is one of a series of resting state networks (RSNs) that can be reliably extracted from neuroimaging data which have become an increasingly important method of investigating the brain's functional architecture [42]. Activity in the DMN increases when the subject is not engaged in cognitively demanding activity [41,43], and it was originally identified as a set of regions which were consistently deactivated across a range of tasks [44]. It is considered to be particularly important for intrinsic thought processing and representing one's self in relation to the external environment [5]. Reduced DMN activity during SWD would imply a cessation of the self-monitoring that occurs during normal consciousness in the absence of an overt task and could be considered to be consistent with the observed clinical correlates of SWD. Besides reduced DMN activity during SWD, disruptions to the DMN have also been observed in patients with focal epilepsy, suggesting an inherent ability of epileptic activity to disrupt ongoing brain processes including the DMN and consciousness system [6,45]. However, bearing in mind that the DMN routinely deactivates during normal sensory and cognitive processing without leading to the loss of consciousness observed in absence seizures, it is perhaps not completely clear how to interpret the deactivation seen during SWD. Even in the simpler case of task responses, the interpretation of reductions in hemodynamic activity is still a matter of ongoing debate within the neuroimaging community, and it has been suggested that the physiological origin of negative responses may be dependent on task type and brain region [46]. This suggests that some caution is needed when considering the interpretation of deactivations in networks of ongoing brain activity in response to internally generated, pathological paroxysmal discharges. Alterations to DMN activity have also been implicated in the alterations to consciousness that are seen in the descent into sleep, often in terms of the connectivity between regions, which will be discussed below. When considering the regions activated or deactivated by sleep spindles, which have been more widely studied than K-complexes or vertex sharp waves and which are of particular relevance to the foregoing discussion, it is notable that they are not immediately comparable to those linked with SWD, and deactivation of the DMN is not observed [47–49]. While this would not preclude the same networks being involved in the generation of the two types of activity, it would require a more complex interpretation of the relationship between electrophysiology and hemodynamic neuroimaging. For example, if the same TC circuit is driven by very different modes of neuronal firing, it is conceivable that the downstream expression of that activity on the cortex, as well as the regional metabolic demands that drive hemodynamic
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neuroimaging signals, may well be very different. Similarly, when considering the lack of DMN deactivation, since the analysis is asking how activity changes at the time of paroxysmal discharges, this is inherently dependent on the nature of the baseline activity. Sleep certainly modifies DMN activity and the additional, transient modifications resulting from spindles may well be lost in this more fundamental alteration. Much of the focus in relation to the DMN in sleep has been around the extent to which the individual regions comprising the DMN are functionally connected and how that connectivity is altered at different sleep stages [50–53], following sleep deprivation [54,55] or as a function of nocturnal sleep duration [56]. In the simplest case, analysis of functional connectivity (FC) involves pairwise correlation analysis between regions of interest. One of the more consistent observations in relation to the DMN during sleep has been decoupling of frontal and posterior regions in stage N2 and deeper [51,53]. As with the reductions in DMN activity from baseline observed during SWD, this reduction in connectivity is consistent with the suggestion that a coherent DMN is important in the maintenance of awareness and, in a general sense, with the alterations to behavior and consciousness that occur with deepening sleep. However, moving beyond this general consistency to a more precise understanding of how tonic activity levels and integrity of network connectivity link with each other and with behavior is challenging. As an immediate step, it is important to understand how eventrelated changes in hemodynamic activity and alterations to the strength of connectivity are related. While the majority of neuroimaging investigations employ one or more of these strategies, there are some indications that examining both aspects may be a fruitful line of enquiry. For example, intrinsic resting and dynamic changes in network connectivity can explain inter- and intrasubject variability in the magnitude of behavioral and hemodynamic responses to a painful stimulus [57]. A more coherent understanding of the extent to which neuroimaging signatures can explain individual differences in behavior, in the current case in terms of alterations to consciousness in epilepsy and sleep, is vital if the imaging data are to be fully interpreted and exploited. Regional cerebral blood flow (CBF) studies using PET have also demonstrated a decrease in blood flow to the precuneus and posterior cingulate cortex in the deeper stages of sleep accompanied by an increase in blood flow to the thalamus which may be instigated by the prefrontal cortex [58,59]. EEG-fMRI also consistently demonstrates thalamic involvement at the time of spindles [47–49], as well as at the time of vertex sharp waves and K-complexes, the other electrophysiological transients of sleep [49,60,61]. Interestingly, Spoormaker et al. [62] noted a reduction in thalamocortical connectivity from wakefulness to light (N1) sleep, whereas corticocortical connectivity increased, though again the relationship between increases in blood flow and changes in connectivity is not obvious. The increased blood flow in the thalamus and the thalamic activation observed in response to SWD again highlights the idea that widespread TC and CT networks play an important role in the evolution of sleep and SWD. However, the precise relationship between the DMN, thalamocortical networks, and consciousness remains to be clarified. 4. Thalamocortical oscillations, the default mode network, and maintenance of consciousness Differentiating brain states and their behavioral correlates, taking into account not only their level of activation (i.e., activity observed on EEG or with neuroimaging methods) but also the status and connectivity of the arousal systems and other relevant networks like the DMN plus the overall neurochemical environment determined by phase within the sleep cycle, may allow a more fundamental understanding of alterations to consciousness in sleep and epilepsy. This forms the basis of the AIM state space model [63], which highlights the importance of three orthogonal features in defining behavioral state: activation (A), input–output gating (I), and modulation (M). While this model has been suggested as a way of understanding the alterations to conscious state observed in different sleep stages and in sleep
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disorders, it may also have relevance to the characterization of the altered states of consciousness observed in epilepsy. Access to sensory input via TC loops and, in a more general sense, the activity and integrity of TC networks may be particularly important. A full characterization of the physiological parameters that would be relevant to the AIM model remains difficult to achieve with existing methods of investigating the human brain, but some understanding of how TC and CT networks are linked to changes in the DMN can be gained from more detailed analyses of fMRI data. One interesting observation is the involvement of DMN regions prior to the development of absence seizures on the EEG. Bai et al. [39] demonstrated significant fMRI signal increases in the orbitofrontal, lateral parietal, and precuneus regions more than 5 s before any EEG changes were noted. These regions developed later decreases in the fMRI response, while late thalamic increases in activity were also seen at the time of widespread DMN deactivation. These observations suggest that cortical–subcortical interactions may be involved in the observed decreases in the DMN. One hypothesis that has been developed primarily in relation to generalized tonic–clonic seizures relates to the observation that there is an increase in cerebellar Purkinje cell firing in the late ictal and postictal phases of generalized seizures in cats [64]. It has been suggested that since Purkinje cells send inhibitory outputs to influence TC circuits, the increased cerebellar activity may play a role in seizure termination and possibly postictal suppression [7]. These inhibitory outputs cause depression of subcortical activating systems which leads to the attenuation of activity in the frontoparietal association cortex and to loss of consciousness. Intracranial EEG recordings from these regions during temporal lobe epileptic seizures have demonstrated increased slow-wave activity during complex partial compared with simple partial seizures [65], while EEG-fMRI consistently demonstrates cerebellar activation in response to SWD [32]. Further investigation of these large-scale cortical and subcortical networks is needed. It is particularly important to include an assessment of how the integrity of functional networks changes dynamically, since networks are often defined based on temporal correlation over several minutes of data. While this leads to consistent and robust results, it is clearly suboptimal from the point of view of understanding transient alterations in consciousness. Similarly, it is important to understand how different networks interact and how this links with behavior, especially in light of the contribution of the arousal, thalamocortical, and DMN regions to the maintenance of consciousness. Some recent studies examining the alpha rhythm have provided some methodological insights into how this could be accomplished [66–68]. This may be particularly relevant to the discussion of epileptic and sleep activity since the alpha rhythm is also thalamocortically generated and provides a dynamic marker of thalamic gating of sensory input that is linked with levels of attention and vigilance [69–71]. Finally, despite the fact that short bursts of SWD do not lead to the overt loss of awareness that is characteristic of an absence seizure, the pattern of thalamic activation and primarily cortical deactivation during SWD and absence seizures is remarkably similar. This would suggest that even SWD of shorter duration would lead to transient alterations in awareness or have some impact on cognitive function. This does indeed seem to be the case. One of the earliest studies investigating the clinical effect of interictal SWD on cognitive function noted a reduction in task performance during a simple reaction-time paradigm [72]. Further studies have supported this observation and supported the hypothesis of a transient impairment of cognition associated with interictal SWD [73–76]. The question of whether these cognitive effects are actually the result of a transient disruption of the consciousness system remains to be determined. 5. Conclusions Sleep and absence seizures result in altered consciousness that disconnects the subject from the environment. Recent neuroimaging studies
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imply that changes in and interactions between large-scale brain networks including thalamocortical loops, the ascending arousal system, and the DMN may be implicated in the observed alterations to consciousness. This approach might help in understanding why absence seizures result in impaired consciousness, as well as shedding light on the systems and networks responsible for maintenance of the conscious state. Challenges remain at every stage of this work. More detail is needed about the significance and physiological interpretation of reductions in hemodynamic signals in response to paroxysmal discharges and how they relate to alterations in the FC of distributed networks. More precise analytical tools are needed to characterize and quantify the activity of these networks, including the dynamic changes that are fundamental to an understanding of rapidly changing behavior. The fundamental understanding of how neuroimaging signatures represent and link with behavioral changes also needs to improve. While this is a general point, this lack of understanding, perhaps, becomes most apparent when trying to understand particularly complex behaviors such as the maintenance of and alterations to consciousness. The work that has been done so far does not clearly point to equivalent mechanisms underlying the alterations to consciousness experienced in absence seizures and sleep, but certainly, there is overlap. This is particularly apparent at the level of the DMN. The links in terms of TC networks that have been suggested by invasive electrophysiology also show signs of being supported by neuroimaging data. How these observations are related is not clear, although the suggestion that the DMN forms one aspect of the consciousness system that also includes the thalamus and ascending arousal systems provides a framework to integrate these data. From a clinical point of view, it is interesting that overt loss of consciousness, which represents possibly the major burden of this kind of seizure to the patient, only seems to occur with seizure durations of 5–10 s. This raises the possibility that if the mechanisms responsible for maintenance of consciousness and for the termination of SWD were understood, a considerable clinical impact could be achieved by focussing on terminating the discharges quickly rather than preventing their occurrence. Conflict of interest The authors declare that there are no conflicts of interest. References [1] Steriade M. Sleep, epilepsy and thalamic reticular inhibitory neurons. Trends Neurosci 2005;28(6):317–24. [2] Kotagal P, Yardi N. The relationship between sleep and epilepsy. Semin Pediatr Neurol 2008;15(2):42–9. [3] Eriksson SH. Epilepsy and sleep. Curr Opin Neurol 2011;24(2):171–6. [4] Sinha SR. Basic mechanisms of sleep and epilepsy. J Clin Neurophysiol 2011;28(2):103–10. [5] Cavanna AE, Monaco F. Brain mechanisms of altered conscious states during epileptic seizures. Nat Rev Neurol 2009;5(5):267–76. [6] Danielson NB, Guo JN, Blumenfeld H. The default mode network and altered consciousness in epilepsy. Behav Neurol 2011;24(1):55–65. [7] Blumenfeld H. Impaired consciousness in epilepsy. Lancet Neurol 2012;11(9):814–26. [8] Kostopoulos GK. Spike-and-wave discharges of absence seizures as a transformation of sleep spindles: the continuing development of a hypothesis. Clin Neurophysiol 2000;111(Suppl. 2):S27–38. [9] Kostopoulos GK. Involvement of the thalamocortical system in epileptic loss of consciousness. Epilepsia 2001;42(Suppl. 3):13–9. [10] Avoli M. A brief history on the oscillating roles of thalamus and cortex in absence seizures. Epilepsia 2011;53(5):779–89. [11] Iber C, Ancoli-Israel S, Chesson AL, Quan SF. The AASM manual for the scoring of sleep and associated events. Rules, terminology and technical specifications. Westchester, IL: American Association of Sleep Medicine; 2007. [12] Steriade M, Contreras R, Curró Dossi R, Nuňez A. The slow (b1 Hz) oscillation in reticular thalamic and thalamocortical neurons: scenario of sleep rhythm generation in interacting thalamic and neocortical networks. J Neurosci 1993;13:3284–99. [13] Huguenard JR. Low-threshold calcium currents in central nervous system neurons. Annu Rev Physiol 1996;58:329–48. [14] Steriade M, Timofeev I. Neuronal plasticity in thalamocortical networks during sleep and waking oscillations. Neuron 2003;37:563–76. [15] Steriade M. Grouping of brain rhythms in corticothalamic systems. Neuroscience 2006;137:1087–106.
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