Impaired spatial pattern separation performance in temporal lobe epilepsy is associated with visuospatial memory deficits and hippocampal volume loss
Introduction
Temporal lobe epilepsy (TLE) is the most common treatment resistant partial epilepsy in adults (Engel, 1996). Hippocampal dysfunction is a hallmark feature of refractory TLE, and is often characterized by neuronal loss within the hippocampus and surrounding medial temporal lobe structures (de Lanerolle et al., 1989). Due to the role of the hippocampus in memory, the most common cognitive deficits observed in patients with TLE are in episodic memory (Hermann et al., 1997, Viskontas et al., 2000). These deficits can be quite debilitating and have been shown to increase with the extent of hippocampal damage or following surgical resection of an intact hippocampus (for review see Helmstaedter, 2013; Lee et al., 2002).
Converging evidence from animal and human studies indicates that pattern separation is a potential neural mechanism that might facilitate accurate memory encoding (for review see Kesner and Rolls, 2015; Yassa and Stark, 2011). Pattern separation is involved in the orthogonalization of partially overlapping neural representations and may allow for one pattern (or episode) to be retrieved separately from another similar pattern, increasing the potential for successful encoding and subsequent retrieval (O'Reilly and McClelland, 1994, O'Reilly and Norman, 2002). Based on animal models and human imaging studies, pattern separation may depend largely on the integrity of the hippocampus, and specifically, the dentate gyrus (Wesnes et al., 2014) and CA3 subfields (for review see Gilbert and Brushfield, 2009; Gilbert and Kesner, 2006; Kesner and Rolls, 2015; Yassa and Stark, 2011). Therefore, it is possible that disrupted pattern separation may contribute to episodic memory deficits in patients with known hippocampal dysfunction, including TLE.
To date, most studies of pattern separation have focused on impairments associated with normal or pathological aging (for review see Gilbert et al., 2016). In particular, several studies have demonstrated that pattern separation performance declines with typical aging (Holden et al., 2012, Stark et al., 2010) and that this age-related decline reflects hippocampal structural and functional changes (Doxey and Kirwan, 2015, Yassa et al., 2011a, Yassa et al., 2011b). Although spatial memory has been shown to decline with age across different species (Light and Zelinski, 1983, Park et al., 1982, Perlmutter et al., 1981), only a few studies have examined age-related declines in spatial pattern separation performance (Holden et al., 2012, Reagh et al., 2016, Reagh et al., 2014, Stark et al., 2010). Deficits in pattern separation performance have also been reported in patients with Alzheimer's disease (AD) and mild cognitive impairment (MCI) (Ally et al., 2013, Stark et al., 2013, Yassa et al., 2010) and these deficits have been linked directly to hippocampal dysfunction in both patient groups (Wesnes et al., 2014, Yassa et al., 2010). Overall, these studies demonstrate that disrupted pattern separation may contribute to visuospatial memory impairments, and that these deficits are likely associated with hippocampal dysfunction.
Despite increasing evidence that poor pattern separation contributes to episodic memory impairments in older adults and other patient populations with known hippocampal damage, and the high incidence of episodic memory impairment and hippocampal atrophy in TLE (de Lanerolle et al., 1989, Hermann et al., 1997), there are no current studies examining pattern separation performance in patients with TLE. In the present study, we examine the performance of patients with TLE on a previously published task hypothesized to place high demands upon spatial pattern separation (Holden et al., 2012, Sheppard et al., 2016). The test was based on a task developed in the mid 1990s for use in animal models (Gilbert et al., 1998, Gilbert et al., 2001). This was one of the first tests developed to assess pattern separation on a behavioral level. The test was found to be dependent on functioning of the hippocampus (Gilbert et al., 1998) and specifically the DG (Gilbert et al., 2001) and CA3 subregions (Gilbert and Kesner, 2006).
We compare the performance of patients with medically-refractory TLE to healthy, age- and education-matched adults on a delayed match-to sample task for spatial location, with graded levels of interference. We hypothesized that our patients would perform more poorly than healthy adults. In addition, we hypothesized that poorer performance on the task would be associated with hippocampal atrophy, particularly in task conditions that place greater demands on pattern separation (i.e., high spatial interference).
Section snippets
Participants
This study was approved by the Institutional Review Board at the University of California, San Diego (UC San Diego) and San Diego State University. Informed consent was collected from all participants in accordance to the Declaration of Helsinki. Twenty-two patients with medically-refractory TLE met inclusion/exclusion criteria for the study. Inclusion criterion included a TLE diagnosis, unilateral seizure onset, and age between 18 and 65 years of age. Patients were excluded if they had any
Participant demographic and neuropsychological data
There were no differences in age or education between TLE patients and healthy adults [Age: t (40) = 1.75, p = 0.088; Education: t (40) = − 1.05, p = 0.300] (See Table 1). There were no differences in the distribution of sex (χ2 = 0.287, Fisher's Exact p = 0.730). Impairment was defined using two clinically-relevant cut-offs 1.0 and 1.5 standard deviation below the normative mean. Based on the 1.5 standard deviation cut-off, seven TLE patients were impaired on the BVMT -R immediate recall and
Discussion
We present the first data on pattern separation performance in patients with TLE using a previously published behavioral spatial pattern separation task that has been linked to episodic memory decline in older adults (Holden et al., 2012, Sheppard et al., 2016). Our data revealed three novel findings: (1) individuals with TLE show impaired spatial pattern separation performance relative to healthy age- and education-matched adults (2) poor spatial pattern separation performance in TLE is
Conclusion
We demonstrate that patients with chronic, refractory TLE show impairments on a task hypothesized to measure spatial pattern separation, and that poor pattern separation may be associated with hippocampal pathology and contribute to spatial episodic memory impairments observed in many patients with TLE.
Acknowledgements
This work was supported by the National Institutes of Health [R01 NS065838 to C.R.M; 5R01AG034202 to P.E.G.; 5R25GM058906 to S.Y.D.].
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