Research PaperComorbidities of early-onset temporal epilepsy: Cognitive, social, emotional, and morphologic dimensions
Introduction
Epilepsy is the most common neurologic disorder in childhood and is often associated with neurobehavioral abnormalities, including cognitive and emotional dysfunction (e.g., anxiety and depression), and social interaction and communication deficits (Berg et al., 2008; Caplan, 2017; Holmes, 2015; Holmes, 2016; Holmes et al., 2015; Jones et al., 2016; Mohanraj and Brodie, 2013). In early childhood and adolescence, the peak periods for epileptic seizure onset, the prevalence of intellectual disabilities is highest and is associated with structural brain lesions (Amiet et al., 2008; Nishimura et al., 2011). Data from epidemiologic studies suggest a bidirectional relationship between several psychiatric disorders and epilepsy, highlighting common pathogenic mechanisms in both conditions (for review, see Ekinci et al., 2009; Verrotti et al., 2014). Moreover, a number of studies support a bidirectional relationship between early-life seizures (ELS) and an early neurodevelopmental syndrome, autism spectrum disorder (ASD), with an increased prevalence of ASD in children with epilepsy and of epilepsy in children with ASD (Amiet et al., 2008; Berg and Plioplys, 2012; Bernard and Benke, 2015; Brooks-Kayal, 2010; Holmes, 2015). The newly-proposed definition of epilepsy recognizes psychiatric comorbidities in epilepsy as a part of the seizure disorder that should be treated together with the seizures (for review, see Kanner, 2016). Available data suggest a higher incidence of psychiatric comorbidity in children with temporal lobe epilepsy (TLE) than in adults, but the relationship of psychopathology to TLE has been less examined in children and adolescents (for review, see Ekinci et al., 2009). Children with TLE show impaired development of emotion recognition, perceptual deficits, abnormal social-behavioral traits, and disrupted cognition with or without intellectual deficiency. In addition, high levels of anxiety, depression, and seizure frequency are risk factors for impaired cognitive function (Laurent et al., 2014; Martinos et al., 2018).
In recent years, the extensive and complex comorbidities of ELS received significant attention as an important area of research in epilepsy (for review, see Brooks-Kayal et al., 2013; Danzer, 2012; Holmes et al., 2015; Stafstrom and Benke, 2015). Experimental studies conducted in commonly used rat models of epilepsy acquired because of ELS demonstrate an increased incidence of behavioral abnormalities. These include cognitive deficits, anxiety- and depression-like behavior, and profound deficits in social domains that mimic, to a certain extent, symptoms of neuropsychiatric comorbidities often present in humans (for review, see Bernard and Benke, 2015; Brooks-Kayal et al., 2013; Casanova et al., 2014). The majority of studies demonstrating cognitive impairment mainly examined spatial cognition (for review, see Barry et al., 2016; Casanova et al., 2014; Holmes, 2005; Holmes, 2015; Karnam et al., 2009; Kubová et al., 2004; Lugo et al., 2014; Rutten et al., 2002). ELS can also lead to alterations in social behavior, however, that in some models resemble the autistic features observed in humans (Castelhano et al., 2013; Hernan et al., 2014; Holmes et al., 2015; Lippman-Bell et al., 2013; Talos et al., 2012). The social tests were mainly interpreted in terms of pure socialization, but more sensitive tests of preference for a novel versus a familiar conspecific may also reflect abnormalities in socio-cognition (Sandi and Haller, 2015; Yang et al., 2011). Animal models of epilepsy, such as the pilocarpine model of acquired TLE are useful for studying the relationship between epilepsy and behavioral dysfunction. The temporal lobe and amygdala, in particular, play crucial roles in processing the appropriate cognitive and behavioral responses to emotionally-relevant stimuli (Twining et al., 2017). Dysregulation of the amygdala-hippocampal complex and entorhinal cortex function caused by neuronal hyperexcitability may lead to psychiatric comorbidities (Adolphs, 2010). Our data from immature rats with LiCl-pilocarpine–induced SE (Li-Pilo SE) suggest mild retardation of psychomotor development and persistent learning deficits in the hippocampal-dependent Morris water maze (MWM) task. In addition, continuous video-electroencephalographic monitoring indicates that the incidence of spontaneous non-convulsive seizures tends to progress over time (Kubová and Mareš, 2013; Kubová et al., 2004).
In the present study, we evaluated an integrative set of behavioral responses, including cognitive/socio-cognitive and emotional dimensions, using a number of behavioral paradigms in the Li-Pilo model of SE induced in immature rats at various developmental stages. The aims of the study were to examine whether ELS affect later 1) non-associative learning (habituation of exploratory behavior in an open-field arena); 2) investigatory response to an indifferent stimulus object; 3) sociability/social novelty preference; 4) social recognition or discrimination; 4) short- and long-term memory in the MWM. The final aim was to investigate the key brain structures involved in the examined behavioral dysfunctions.
The animals were tested repeatedly across multiple developmental time-points. Selected behavioral paradigms covered tasks of ethologic relevance to animals that differ in terms of the type of behavior they mediate. These behaviors involve neural circuits of interacting structures such as the hippocampus, perirhinal cortex, medial prefrontal cortex, medial dorsal thalamus, striatum, and amygdala. This neural circuitry plays a critical role in acquisition, discrimination learning, storage and retrieval of various memory processes, programming of social behavior, and mediation of behaviors with motivation/incentive and affective properties (Brown and Banks, 2015; Gasbarri et al., 2014; Hitti and Siegelbaum, 2014; Ouhaz et al., 2017; Ouhaz et al., 2015; Parnaudeau et al., 2018; van den Bos, 2015).
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Materials and methods
Male outbred Wistar albino rats (Institute of Physiology of the Czech Academy of Sciences, Prague, n = 59 for behavioral study, and n = 11 animals for neuropathological examination) were used in the experiments. Animals were maintained under controlled temperature (22 ± 1 °C) and humidity (50 to 60%) with a 12/12 h light/dark cycle (lights on at 6:00 AM). Food and water were provided ad libitum (with the exception of the testing period). On day 5, (birth was defined as day 0), the pups were
Effects of early-life SE on between-session habituation
Early SE had no effect on the development of between-session habituation. The distance moved was decreased between the 1st and the 4th session in both controls and SE groups at P25 and P32 (Fig. 2A, F(1,20) = 24.98, p < .001; F(1,20) = 34.63, p < .001, respectively). No habituation with repeated exposure to the open-field arena was observed at P18 (Fig. 2A, F(1,20) = 0.71, p = .40), suggesting a lack of habituation in both control and SE animals at this age. No age differences were found in the
Discussion
The results of the present study support the growing body of literature showing that early-life SE result in long-term behavioral alterations. Here we provide evidence that early-life SE decreases the responsiveness of animals to indifferent or social cues, process them, and elicit the appropriate behavioral response. Especially, the decreased social investigation and social discrimination by animals exposed to SE indicate disruption of the social motivation/incentive state essential for normal
Acknowledgments
We gratefully acknowledge the expert technical help by Mrs. Blanka Čejková and Mrs. Irinka Nešev. This study was supported by grant 16-04726S of the Czech Science Foundation and by the Czech Health Research Council (AZV) grant 16-29857A and support for long-term conceptual development of research organization RVO: 67985823. Ales Stuchlík was supported by the Czech Science Foundation grant 17-04047S. Institutional support was provided by Research Project RVO: 67985823.
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