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Purpose: Impaired memory performance is the most frequently reported cognitive problem in patients with chronic epilepsy. To examine memory deficits many studies have focused on the role of the mesiotemporal lobe, mostly with hippocampal abnormalities. However, the role of the prefrontal brain remains unresolved. To investigate the neuronal correlates of working memory dysfunction in patients without structural lesions, a combined study of neurocognitive assessment, hippocampal and cerebral volumetry, and functional magnetic resonance imaging of temporal and frontal memory networks was performed.
Methods: Thirty-six patients with cryptogenic localization-related epilepsy and 21 healthy controls underwent neuropsychological assessment of intelligence (IQ) and memory. On T1-weighted images obtained by 3-Tesla magnetic resonance imaging (MRI), volumetry of the hippocampi and the cerebrum was performed. Functional MRI (fMRI) was performed with a novel picture encoding and Sternberg paradigm that activated different memory-mediating brain regions. Functional connectivity analysis comprised cross-correlation of signal time-series of the most strongly activated regions involved in working memory function.
Key Findings: Patients with epilepsy displayed lower IQ values; impaired transient aspects of information processing, as indicated by lower scores on the digit-symbol substitution test (DSST); and decreased short-term memory performance relative to healthy controls, as measured with the Wechsler Adult Intelligence Scale subtests for working memory, and word and figure recognition. This could not be related to any hippocampal volume changes. No group differences were found regarding volumetry or fMRI–derived functional activation. In the Sternberg paradigm, a network involving the anterior cingulate and the middle and inferior frontal gyrus was activated. A reduced strength of four connections in this prefrontal network was associated with the DSST and word recognition performance in the patient group.
Significance: Deficits in the processes involved in transient working memory, and to a lesser extent in short-term memory, in patients with localization-related epilepsy of both temporal and extratemporal origin cannot be attributed to hippocampal atrophy or function only, but are also related to reduced functional connectivity in the prefrontal brain. Because patients with symptomatic lesions or mesiotemporal sclerosis were excluded from this study, the results cannot be explained by structural lesions. Therefore, the current findings highlight the influence of epilepsy on the prefrontal network integrity as a possible underlying problem of memory impairment.
Patients with chronic epilepsy commonly develop comorbid cognitive problems, ranging from memory deficits and mental slowing, to global cognitive deterioration (Oyegbile et al., 2004). Several aspects of memory can be disturbed, including verbal and figural encoding, working memory, and long-term memory (Helmstaedter, 2002).
Different clinical factors contribute to cognitive impairment in epilepsy, such as antiepileptic drugs (AEDs) (Jokeit et al., 2005), interictal epileptic discharges (Aldenkamp & Arends, 2004), and severity of seizures (Dodrill, 2002; Thompson & Duncan, 2005). However, the impact on cognition of these factors can be highly variable. A comprehensible model for the development of memory impairment in epilepsy is still lacking.
A more rewarding approach may be the investigation of cerebral mechanisms that could be responsible for memory dysfunction. Such mechanisms may be the mediator between epilepsy factors and the development of memory impairment. Usually, this is studied by attempting to find an association with macrostructural abnormalities on magnetic resonance imaging (MRI), for example, by focusing on hippocampal sclerosis and atrophy, as these are related to memory impairment. Studies using functional MRI (fMRI) are often integrated in the workup procedure for epilepsy surgery and focused on patients with medically refractory temporal lobe epilepsy (TLE), generally with unilateral hippocampal or mesiotemporal abnormalities (Crane & Milner, 2005; Baxendale et al., 2008; Binder et al., 2008; Powell et al., 2008; Cheung et al., 2009).
In clinical practice though, memory problems are reported not only by patients with unilateral TLE, but also by those with extratemporal lobe epilepsy and by patients without any structural lesions. These observations suggest that (1) dysfunction of structures outside the mesiotemporal lobe may cause memory deficits and (2) memory problems are not solely attributable to structural cerebral lesions.
Based on the “model of working memory” proposed by Baddeley & Hitch (1974), the term working memory covers the very early, transient aspects of information processing. Central components of the working memory model are the “central executive,” referring to the supervisory system that controls the flow of information from and to its slave systems: the “phonological loop” (a transient verbal storage system), the “visuospatial sketchpad” (transient visuo-spatial storage system), and the “episodic buffer” (which links the working memory to more stable phases of the short-term memory system) (Fig. 1). Theoretically, the cerebral regions involved in the central executive function, may well be located outside the temporal lobe, most likely in the prefrontal regions. Impairment of the central executive can lead to deficits in short-term memory as well.
Conventional MRI is not suited for detection of early changes associated with cognitive decline. However, with newer MR techniques, more subtle cerebral changes can be investigated. With fMRI, for instance, functional activation patterns during a cognitive task can be localized. Most fMRI studies describe group differences in activation patterns in homogeneous populations with TLE. A disruption of the memory network, independently of whether the temporal or extratemporal nodes in this network are dysfunctional, might result in the same types of memory impairment. With functional connectivity analysis, the integrity of such networks can be investigated.
The aim of the study was to investigate memory performance in patients with cryptogenic epilepsy of both temporal and extratemporal origin as compared to controls, and to explore the relation with brain volume and function. To assess brain function, we have investigated the relation of memory performance and functional connectivity in the hippocampus and the prefrontal networks. This exploration might reveal a possible etiologic explanation for the development of memory deficits in patients with cryptogenic localization-related epilepsy.