Sleep, epilepsy and translational research: What can we learn from the laboratory bench?
Highlights
► Prevention of epilepsy must be the main goal of the health system. ► The sleep–epilepsy relationship is complex and of great clinical importance. ► The relationship between sleep and epilepsy is similar in humans and animals. ► Few studies have been conducted on this topic using a translational framework. ► Translating findings from laboratory bench is crucial in treating epilepsy.
Introduction
The relationship between sleep and epilepsy has been known since antiquity, when Aristotle and Hippocrates pointed out a close correlation between the disease and sleep (Broughton, 1984, Crespel et al., 2000). Many clinical studies have since investigated this association, which is dependent on seizure-type (for review, see Matos et al., 2010a, Scorza et al., 2010a). The majority of studies on the effects of sleep on epilepsy and vice versa have been conducted in human subjects (Bazil and Walczak, 1997, Crespel et al., 1998, Dinner, 2002, Eisensehr et al., 2001, Herman et al., 2001, Sato et al., 1973). It is important to mention that variables such as anticonvulsant medication, stress, fatigue, and caffeine consumption might influence findings in human studies (Barreto et al., 2002, Frucht et al., 2000, Matos et al., 2010a). On the other hand, preclinical studies on animals under well-controlled conditions have also indicated a close relationship between sleep and epilepsy (Matos et al., 2010b, Schilling et al., 2006, van Luijtelaar and Bikbaev, 2007).
Epilepsy is one of the most common chronic neurological disorders. It affects 1–3% of the population, and almost 10% of individuals will have at least one seizure at some point in their lives (Hauser et al., 1996). Epilepsy is characterized by spontaneous recurrent seizures (two or more unprovoked seizures), and a seizure is defined as an excessive electrical discharge in a group of brain cells. Symptoms of seizures can vary from brief lapses in attention or muscle jerks, to severe or continuous convulsive seizures (violent and involuntary muscle contractions). The seizure frequency of individual patients can vary from less than one seizure per year to several per day (WHO, 2010).
One of the most debilitating aspects of epileptic seizures is the unpredictability of their occurrence (Quigg, 2000). It has been suggested that seizures may be modulated in part by circadian rhythms, such as sleep–wake states (Quigg, 2000). The typical neuronal synchronization of non-rapid eye movement (NREM) sleep activates interictal epileptiform discharges and facilitates the onset of seizures in most clinical cases (Malow et al., 1998, Neiman et al., 2010).
In clinical studies, seizures arising from the frontal lobe, as well as secondary generalized seizures of temporal lobe epilepsy (TLE), occurred more frequently during sleep (Bazil and Walczak, 1997, Herman et al., 2001). In generalized epilepsy, sleep–wake states also influence the occurrence of paroxysmal phenomena. For example, absence seizures occurred preferentially during drowsiness and NREM sleep (Sato et al., 1973). Recently, an extensive clinical study showed a strong relationship between sleep–wake states and different types of generalized seizures in children (Zarowski et al., 2011). Tonic and tonic–clonic seizures occurred more frequently during sleep whereas other types of generalized seizures (atonic, myoclonic, and absence seizures, and epileptic spasms) occurred during the wake state with peaks of occurrence (Zarowski et al., 2011).
At the laboratory bench, spike-wave discharges (SWD) occurred mainly during light slow wave sleep (SWS) and relaxed wakefulness in rats with absence epilepsy (Drinkenburg et al., 1991). In addition, rodents with partial seizures displayed 43.5% of their seizures during SWS, and only 13% in the wake state (Bastlund et al., 2005). The remaining 43.5% of seizures occurred in unknown state characterized by low voltage and fast activity without movement. The authors suggested that unknown state could be relaxed wakefulness, rapid eye movement (REM) sleep or possible preictal activity (Bastlund et al., 2005).
Beyond the influence of sleep on seizures, investigations conducted in animals and humans have highlighted the possibility that there may be cyclical variations in the temporal distribution of seizure occurrence. For instance, Quigg et al. (1998) demonstrated this phenomenon in both humans and rats with chronic epilepsy. Patients with spontaneous recurrent partial seizures were distributed into subgroups according to the seizure focus. Both rats and humans with mesial TLE showed a higher prevalence of seizures during the day (Quigg et al., 1998), whereas humans with lesional and extratemporal lobe seizures showed no correlation between seizures and the light-dark cycle. Thus, rats and humans with TLE presented a similar temporal distribution of seizures, regardless of species differences in the sleep–wake cycle (Quigg et al., 1998). Rats with absence epilepsy also displayed circadian modulation of seizure susceptibility, with a peak in SWD occurrence around the fourth and fifth hour of the night, and the smallest number of SWD at the beginning of light phase (van Luijtelaar and Coenen, 1988). Like in humans (Sato et al., 1973) there was a striking correlation between sleep–wake states and SWD and this relationship was maintained even in the absence of the most important Zeitgeber: the light-dark cycle (Smyk et al., 2011).
Endogenous timing systems could control the cyclicity of seizures in some kinds of epilepsy. Preclinical research has showed that the distribution pattern of seizures around the light-dark cycle persisted when rats were subjected to constant dark conditions (Quigg et al., 2000). Rats with absence epilepsy subjected to constant light conditions showed changes in motor activity, whereas the circadian rhythm of seizures was maintained (Sayk et al., 2010), suggesting that different control systems were involved. The suprachiasmatic nuclei (SCN) may have an important role in the circadian distribution of seizures, because SCN is the major biological clock in mammals and controls circadian rhythms and many physiological variables (Hofstra and de Weerd, 2008). In addition, other endogenous factors such as melatonin and noradrenaline have been suggested as risk factors of seizures (Quigg et al., 2000).
Many findings in preclinical and clinical studies have thus suggested an important role of endogenous factors and sleep–wake states in the temporal distribution of seizures, and it is unlikely that seizures occur in a random pattern. Clinical trials have provided considerable information about the relationship between sleep and epilepsy since the 20th century, particularly after the advent of the EEG. However, few translational studies have been performed, resulting in limited knowledge about the physiological mechanisms underlying this association.
Section snippets
The physiology of sleep
Pioneering physiologists and neurologists did not have the instruments to assess sleep in depth (Lesku et al., 2009), so the first sleep studies were observational, analyzing the phenomenon of sleep in a contemplative way. In the 19th century, physiological studies of sleep began with the discovery of fluctuations of some variables during sleep, in particular respiratory rate and blood glucose (Kleitman, 1963). The discovery of potential oscillations in the human nervous system by Hans Berger
The intriguing role of sleep in epilepsy
The modulating influence of sleep on epilepsy does not only occur in adults. Studies have also demonstrated sleep disturbances and interictal spikes-waves complexes during sleep in children (Chan et al., 2011, Maganti et al., 2006, Siniatchkin et al., 2010). Interestingly, benign neonatal sleep myoclonus, a non-epileptic syndrome, is characterized by myoclonic jerks that occur exclusively during sleep (Cohen et al., 2007, Coulter and Allen, 1982).
The initial phases of NREM sleep facilitate
Animal models of epilepsy: a translational overview
Animal models are crucial in the study of detailed aspects of epilepsy, and in the translation of findings into better therapeutic approaches for epileptic individuals (Buckmaster, 2004). Several animal models of epilepsy have been developed to investigate TLE. Temporal lobe seizures are often drug resistant and TLE is the most common type of epilepsy in humans (Sloviter, 2005). There is also an impressive number of preclinical investigations of absence epilepsy. Genetic models of absence
Considerations of preclinical sleep research
Many approaches can be used to understand the functions of sleep. Depriving animals of sleep and observing the behavioral and physiological consequences is a common procedure (Tufik et al., 2009). Preclinical research has contributed a great deal to our knowledge of the neurobiology of sleep and the consequences of sleep deprivation.
Studies using paradoxical sleep deprivation (PSD) have provided essential information on the possible functions of sleep and the potentially harmful consequences of
The effects of epilepsy on sleep in animal models: a neuroscience-of-sleep approach
As described in Section 4, we have a considerable number of preclinical animal models that could contribute to our knowledge of epilepsy. Unfortunately, few studies have been conducted within a strong translational framework. The lack of information from laboratory benches is even more evident when the focus is on the physiology of sleep in epilepsy. In this section, we will describe some preclinical studies of the effects of epilepsy and/or seizures on sleep.
Final considerations
The main objective of investigating sleep and epilepsy from a translational science perspective is to transfer knowledge published in the literature to the medical clinic. Translational research puts together results from the laboratory bench (animal models, tissue culture, molecular analysis), and tries to apply them in clinical practice. In human oncology, for example, many molecular markers were initially tested in animals, and the medications available on the market were developed through
Acknowledgments
This work was supported by Associação Fundo de Incentivo à Pesquisa (AFIP), Conselho Nacional de Desenvolvimento Científico e Tecnológico, Ministério da Ciência e Tecnologia (2008/57904 to EAC and FAS) and Fundação de Amparo à Pesquisa do Estado de São Paulo (CEPID #98/14303-3 to ST, #10/15110-8 to GM). MLA, ST, FAS and EAC are recipients of the CNPq fellowship.
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2021, Neuroscience and Biobehavioral ReviewsSleep tight, wake up bright. Should sleep deprivation be included as a potential risk factor for SUDEP?
2014, Epilepsy and BehaviorThe effects of sleep deprivation on microRNA expression in rats submitted to pilocarpine-induced status epilepticus
2014, Progress in Neuro-Psychopharmacology and Biological PsychiatryCitation Excerpt :Sleep deprivation protocols also modulated the majority of miRNA analyzed in the current study. The role of sleep deprivation on seizures occurrence has well been accepted (Badawy et al., 2006; Matos et al., 2011, 2013b). Interestingly, even with the established consensus regarding this dangerous condition, the studies performed in this area were conducted with electrophysiological approaches, which in turn, did not provide significant advances regarding the neurobiological mechanisms involved in this relationship.
Sleep and epilepsy: Exploring an intriguing relationship with a translational approach
2013, Epilepsy and BehaviorCitation Excerpt :In this context, animal models with face, predictive, constructive, and ethological validity are important tools. One reason why these models are valuable is that the sleep pattern of rodents is similar to humans, including tonic (i.e., suppression of rhythmic muscular activity) and phasic (i.e., rapid eye movements and cardiac changes) events of REM sleep [23]. It is very important in preclinical research to use animal models that have characteristics of clinical epilepsy because this increases the likelihood of translation from basic science to clinical trials.
A strength exercise program in rats with epilepsy is protective against seizures
2012, Epilepsy and BehaviorCitation Excerpt :Although information about the light/dark cycle is well documented ([32,42–45]), one study has demonstrated that the seizure frequency in pilocarpine-treated rats was not related to the circadian rhythm [46]. Accordingly, a literature search has demonstrated that the seizure threshold is reduced during sleep (for a review, see Matos et al. [47]). In our investigation, the animals subjected to the strength exercise exhibited the same pattern of seizure frequency as the control and SHAM groups over the light/dark cycle, which is in accordance with previous experimental studies reporting an increase in seizure frequency during the diurnal period compared with the nocturnal period [7,48,49].
Impairment of Sexual Function in Rats with Epilepsy
2012, Journal of Sexual MedicineCitation Excerpt :Taken together, the pilocarpine‐induced temporal lobe epilepsy may be a suitable preclinical approach for evaluating future therapies for sexual dysfunctions in individuals with epilepsy. The aim of translational research is to apply advancements in basic science to clinical practice, taking basic research from “bench to bedside”[32,33]. This approach in future should improve health care and, in so doing, increase knowledge of some chronic diseases, such as epilepsy.