Abstract
Vrinda M, Sasidharan A, Aparna S, Srikumar BN, Kutty BM, Rao BSS. Epilepsia 2017;58:1148–1158
Temporal lobe epilepsy (TLE) is commonly associated with depression, anxiety, and cognitive impairment. Despite significant progress in our understanding of the pathophysiology of TLE, it remains the most common form of refractory epilepsy. Enriched environment (EE) has a beneficial effect in many neuropsychiatric disorders. However, the effect of EE on cognitive changes in chronic TLE has not been evaluated. Accordingly, the present study evaluated the effects of EE on chronic epilepsy–induced alterations in cognitive functions, electrophysiology, and cellular changes in the hippocampus. Status epilepticus (SE) was induced in 2-month-old male Wistar rats with lithium and pilocarpine. Six weeks’ post SE, epileptic rats were either housed in their respective home cages or in an enrichment cage (6 h/day) for 14 days. Seizure behaviour was video-monitored 2 weeks before and during exposure to EE. Depression-like behavior, anxiety-like behavior, and spatial learning and memory were assessed using the sucrose preference test (SPT), elevated plus maze (EPM), and Morris water maze (MWM), respectively. Delta and theta power in the CA1 region of hippocampus was assessed from recordings of local field potentials (LFPs). Cellular changes in hippocampus were assessed by histo-chemistry followed by unbiased stereologic analysis. EE significantly reduced seizure episodes and seizure duration in epileptic rats. In addition, EE alleviated depression and hyperactivity, and restored delta and theta power of LFP in the hippocampal CA1 region. However, EE neither ameliorated epilepsy-induced spatial learning and memory deficits nor restored cell density in hippocampus. This is the first study that evaluates the role of EE in a chronic TLE model, where rats were exposed to EE after occurrence of spontaneous recurrent seizures (SRS). Given that 30% of TLE patients are refractory to drug treatment, therapeutic strategies that utilize components of EE could be designed to alleviate seizures and psychiatric comorbidities associated with TLE.
Commentary
In laboratory studies, environmental enrichment (EE) refers to altered housing conditions designed to enhance sensory, motor, social, and cognitive stimulation, not to mention improved animal welfare. This may include larger housing containers, enhanced novelty and complexity of toys, exercise equipment, and increased number of occupants, relative to control conditions. EE has repeatedly been demonstrated improved outcomes across many different animal models of neurological disease (1), delaying disease onset and limiting symptom severity in both genetic and acquired diseases. These improvements are likely driven by experience-dependent synaptic plasticity of neuronal circuits, which can counteract the progression of disease, although specific mechanisms are elusive and possibly disease-specific. Epilepsy is no exception, and there exists strong rationale to anticipate beneficial effects of EE (2): Early work showed that rats raised in EE conditions are protected against excitotoxic seizures and seizure-related cell death (3), and exhibit delayed epileptogenesis in the amygdala kindling model (4, 5). The recent article by Vrinda and colleagues extends this work by introducing EE to epileptic rats, and report a range of epilepsy-, behavior-, and physiology-related improvements.
One of the primary strengths of the article by Vrinda et al. relates to the study design. In the vast majority of research looking for anti-epileptogenic or disease-modifying therapies, interventions are almost exclusively given in the immediate hours after the precipitating insult, such as status epilepticus. But without biomarkers to identify patients likely to develop epilepsy, this is not a clinically appropriate timepoint since patients only present when they are diagnosed with epilepsy, sometimes years or decades following the causal insult. A more practical and translatable approach is to randomize treatment to patients already experiencing seizures—an approach adopted by Vrinda and colleagues. Epilepsy was triggered by pilocarpine-induced status epilepticus; after 6 weeks’ monitoring for spontaneous seizures, animals entered into their respective housing programs: The EE groups were introduced into enriched cages for 6 h/day for 2 weeks, while the control rats were in standard housing. They found that the rats exposed to the enriched environment exhibited fewer seizures compared to the baseline period of monitoring as well as the control housing group. While there have been several reports demonstrating anti-epileptogenic and antiseizure effects through environmental enrichment in models of acquired epilepsy, this study utilizes a model that exhibits spontaneous recurrent seizures, thereby improving face validity for these impressive effects.
It is now well-established that psychiatric conditions and cognitive deficits are present in a high proportion of epilepsy patients, much higher than observed in the general population (6). These are debilitating and can be stronger determinants to the quality of life of people with epilepsy than are seizures themselves. Therefore, appropriate diagnosis and management of these disorders is important, as is assessment of beneficial (or detrimental) effects of any newly developed therapies. Many animal models of epilepsy (including the commonly utilized post-SE model) exhibit anxiety- and depressive-like behaviors, as well as a range of cognitive deficits (7). This feature promotes these models as ideal tools to examine biological mechanisms that cause such behavioral abnormalities and test the effects of interventions. The current study examined EE effects not only on epilepsy outcomes but also on a variety of emotional and cognitive measures. EE successfully ameliorated depressive-like behaviors in epileptic rats (as measured using the sucrose-preference test of anhedonia) but did not influence spatial learning or memory deficits, suggesting that these comorbidities are differentially influenced by environmental exposure or generated via different biological mechanisms.
Identifying the relevant epigenetic/molecular/cellular/physiological drivers underpinning the beneficial effects of environmental exposures has proven elusive, perhaps because the experience-dependent plasticity triggered by these exposures encompasses a broad range of physiological endpoints. To gauge further understanding of the relevant pathophysiological mechanisms responsible for epileptic and behavioral improvements thought to be EE, a number of other hippocampal outcomes were assessed. The study found that deficits in hippocampal delta and theta oscillations improved with EE, but while these outcomes are associated with improvements in seizure frequency and behavior, further work is required to demonstrate a causal connection. The finding that the reduced CA3 cell density in epileptic rats not reversible by EE is not surprising since cell death occurs rapidly following SE (8) and would likely be realized when the intervention was introduced (6 weeks post-SE). Since neurogenesis is not observed in pyramidal cell layers, it is difficult to envisage a scenario where this cell loss could be restored. Enhanced spatial learning and memory function is the most widely replicated beneficial effect of EE, yet this was not realized in the current study. The hippocampus is known to regulate spatial learning and memory, but perhaps nonrecoverable loss of hippocampal neurons in epileptic rats was sufficiently severe to overcome any beneficial influence of EE on cognition.
While several strengths of this paper have been mentioned, some limitations should also be addressed. First, there is no mention of sample sizes in the treatment groups throughout the paper, which is a striking omission and should be mandatory for these types of studies. Also, seizures were quantified by behavioral analysis only, yet measuring seizures using EEG should be the minimum standard to accurately assess frequency. The Morris Water Maze was used to assess spatial learning and memory in epileptic rats. In the cued version, which incorporates a visible platform, the authors found clear deficits in epileptic rats. This infers that either the animals have marked vision impairment or display an inability to understand the goal of the task (i.e., reach the platform to escape the water). Therefore, results from the subsequently conducted acquisition phase of the task were compromised, and any conclusions drawn regarding spatial learning and memory should be viewed with caution.
While environmental enrichment is typically referred to as an experimental manipulation, translation of this intervention is achievable. For instance, clinical trials are ongoing for several brain disorders, such as autism and Huntington's disease. In the epilepsy realm, recent studies have highlighted the benefits of cognitive behavioral therapy and mindfulness in epilepsy (9), promoting these nonpharmacological interventions as potential avenues for adjunctive treatment. In addition, these interventions may also benefit psychiatric comorbidities of epilepsy. In an era where new anti-epileptic drugs are not markedly reducing the number of patients with poorly controlled epilepsy, alternative treatment approaches need to be investigated. The biological mechanisms underlying effects of environmental enrichment remain elusive; however, if identified, we could pave the way for new therapeutic strategies in epilepsy.