Temporal lobe epilepsy (TLE) is an often debilitating condition that has known associations with changes in regional brain structure and function, as well as cognition. Most studies relating these factors focus on memory function in TLE where the seizures generally originate from the hippocampus, a structure known for its role in memory. However, it has been reported that there are declines in other cognitive functions in TLE outside the temporal lobe [1]. In these patients, the mechanism of cognitive decline is less understood. The goal of this study was to investigate the relationship between brain structure and extratemporal cognitive function in patients with right TLE.

In compliance with the Vanderbilt University Institutional Review Board, 23 patients with TLE were recruited for participation in the study, which consisted of both MR imaging and neuropsychological evaluations. Control patients were recruited to individually match patients by both sex and age +/-2 years. Of these subjects, 15 patients with right TLE completed imaging and 14 completed both neuropsychological evaluations and imaging. This patient subset and their matched controls are considered in the following analysis.

Neuropsychological evaluations were conducted using the Wechsler Adult Intelligence Scale, versions III and IV (WAIS)-III/IV which provides scores for Full Scale Intelligence Quotient (FSIQ), Verbal Comprehension Index (VCI), and the Perceptual Organization/Reasoning Index (POI/PRI). Here we focused on the VCI for two reasons: VCI is reduced in some patients with TLE in relation to age of onset, seizure frequency and number of anti-epileptic drugs used [1], and it is associated with function in the inferior frontal lobe [2] (outside the expected primary area of impairment in TLE).

MRI scanning was performed at 3T with a 32 channel head coil using T1-weighted turbo fast-field echo MRI (matrix = 256 x 256 x 150, 1 mm³) and diffusion weighted MRI (b=1600 s/mm², 92 directions, 2.5 x. 2.5 x 2.5 mm³, 3 averages). Gray matter volumes were calculated from the T1-weighted images using the Freesurfer image analysis suite [3]. White matter tracts were reconstructed and diffusion parameters estimated using the TRActs Constrained by UnderLying Anatomy (TRACULA) tool [4] within Freesurfer using the diffusion MRI.

Two separate analyses were performed to investigate the relationship between known right hippocampal volume (HV) decreases in right TLE (p<0.0002 compared to the healthy controls) and VCI score. Analysis 1: The direct relationship was evaluated using a Pearson partial correlation between HV and VCI, adjusting for age (p<0.05 considered significant). Analysis 2: The indirect relationship was evaluated by two steps. Step 1 involved the computation of the Pearson partial correlations between white matter TRACULA parameters and HV, with subject age as a covariate. Since 18 TRACULA tracts were investigated, a Bonferroni correction requires p<0.002 to determine significance. Step 2 was to compute the Pearson partial correlation between the TRACULA parameters found in step 1 and VCI scores, with age as a covariate (p<0.05 considered significant, 1 test).

Using the direct relationship analysis no significant correlation was detected between HV and VCI scores. The results from the indirect analyses yielded the following results. Step 1: The only TRACULA parameter that showed a significant correlation with HV was an inverse correlation between the right uncinate fasciculus (RUF) axial diffusivity (AD) and the HV (p<0.001) (Figure 1a). Step 2: VCI was found to be negatively correlated with both RUF AD (p=0.0201) (Figure 1b) and RUF fractional anisotropy (FA; p=0.0498). In addition, RUF AD (p=0.0243), radial diffusivity (RD; p=0.0313), and mean diffusivity (MD; p=0.0035) were significantly greater in patients than in controls. This study demonstrates an indirect link between known right hippocampal volume reductions in right TLE and extratemporal cognition. As the hippocampal volume decreases, the RUF AD increases. In fact, the right HV decrease and the RUF AD (and RD and MD) increase in the patients were significant compared to the controls. This increase in RUF white matter AD was also significantly correlated with decreased VCI score. Considering that VCI deficits have been found to be associated with inferior frontal cortex lesions, these results taken together imply that the RUF, which structurally connects the hippocampus and other limbic structures to the frontal lobe (Figure 2), is the mediator of impairment between the seizure focus in the hippocampus and VCI deficits in right TLE.