Quantitative MRI of the prefrontal cortex and executive function in patients with temporal lobe epilepsy

Epilepsy & Behavior 15 (2009) 186–195

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Quantitative MRI of the prefrontal cortex and executive function in patients with temporal lobe epilepsy Simon Sean Keller a,*, Gus Baker b, Joseph John Downes c, Neil Roberts d a

Magnetic Resonance and Image Analysis Research Centre (MARIARC), University of Liverpool, Pembroke Place, Liverpool L69 3BX, UK Walton Centre for Neurology and Neurosurgery, Liverpool, UK c Department of Psychology, University of Liverpool, Liverpool, UK d Clinical Research Imaging Centre (CRIC), Queen’s Medical Research Institute (QMRI), University of Edinburgh, Edinburgh, UK b

a r t i c l e

i n f o

Article history: Received 21 November 2008 Revised 4 March 2009 Accepted 5 March 2009 Available online 11 April 2009 Keywords: Epilepsy Executive function Hippocampus Prefrontal cortex Quantitative MRI

a b s t r a c t We investigated the relationship between prefrontal cortex (PFC) and hippocampal volume and executive functioning in patients with temporal lobe epilepsy (TLE). Prefrontal volume and hippocampal volume were studied using stereology in conjunction with point counting and voxel-based morphometry on MR images. Executive functioning was assessed using tests routinely incorporated into presurgical neuropsychological evaluation. Relative to 30 healthy controls, 43 patients (26 left, 17 right) with TLE had volume atrophy of the ipsilateral hippocampus and bilateral dorsal PFC. Performance on the working memory index of the Wechsler Memory Scale was positively correlated with the volume of all prefrontal regions, and the Controlled Oral Word Association Test with the left dorsal PFC, whole left PFC, and left hippocampus. Stroop Color–Word Interference performance was not related to volume of dorsal PFC. The ‘‘extratemporal neuropsychological profile” frequently observed in patients with TLE may be due to extended damage to brain regions remote from the epileptogenic focus. In particular, volume atrophy of the dorsal PFC may account for deficits in executive functioning. Ó 2009 Elsevier Inc. All rights reserved.

1. Introduction Many patients with temporal lobe epilepsy (TLE) experience neurocognitive disturbances classically not associated with temporal lobe function. Some patients are impaired on tasks that require frontal lobe processing in a similar way to patients with frontal lobe epilepsy [1]. As hippocampal sclerosis is the most common neuropathological correlate of TLE, it has been suggested that hippocampal pathology may be the primary cause of executive dysfunction in this patient group. For example, Giovagnoli [1] reported deficits on the Wisconsin Card Sorting Test (WCST), which relies largely on frontal lobe processing, in patients with medial TLE and hippocampal sclerosis, but not in patients with lateral TLE and no hippocampal abnormalities. This is supported by an earlier study that found that patients with TLE with unilateral hippocampal sclerosis performed more poorly than patients with frontal lobe or temporal lobe neocortical lesions on the same task [2]. However, other studies have failed to find a relationship between hippocampal sclerosis and measures of frontal lobe function in patients with TLE [3–6]. Although recent MRI studies have demonstrated that patients with TLE may have atrophy of prefrontal cortex relative to healthy controls [7–9], no work to date has pro* Corresponding author. Fax: 0151 7945635. E-mail address: [email protected] (S.S. Keller). 1525-5050/$ - see front matter Ó 2009 Elsevier Inc. All rights reserved. doi:10.1016/j.yebeh.2009.03.005

spectively examined the relationship between prefrontal volume and executive functioning in patients with TLE. During presurgical evaluation for medically intractable TLE, all patients undergo baseline neuropsychological assessment to determine their current cognitive and affective status and to predict postsurgical neurocognitive outcome. The neuropsychological battery used at the Walton Centre for Neurology and Neurosurgery (WCNN) in Liverpool includes assessment of executive functioning using a combination of the Stroop Color–Word Interference task [10], the Controlled Oral Word Association Test (COWAT) [11], and the working memory index of the Wechsler Memory Scale Third Edition (WMS-III) [12]. The present study sought to investigate whether performance on the aforementioned neuropsychological tasks of executive functioning are preferentially related to the structure of the PFC or hippocampus in patients with TLE. The present study used two complementary quantitative magnetic resonance (MR) image analysis techniques to investigate the neuroanatomical correlates of executive function in patients with TLE: stereological region-of-interest analysis and whole-brain voxel-based morphometry (VBM). Stereological analysis provided unbiased volume estimation of the left and right dorsal and ventral PFC, hippocampus, and cerebral hemispheres, and VBM quantified gray matter concentration (GMC) over the entire brain. There were two primary objectives of the present study. First, we sought to investigate whether patients with unilateral TLE have volume

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alterations of prefrontal cortical subfields relative to healthy controls, and whether particular volume alterations are dependent on the hemispheric side of seizure onset. Previous VBM studies had shown that patients with unilateral left or right TLE have GMC reduction of right [7] or bilateral [8] dorsal PFC relative to healthy controls. These findings have not been replicated using quantitative MRI region-of-interest analyses. Second, we sought to investigate the relationship between executive functioning using three neuropsychological tasks, and prefrontal and hippocampal volume using stereological analysis and VBM, in patients with TLE. We hypothesized that dorsal prefrontal volume, and not hippocampal volume, would be associated with executive functioning in patients with TLE, based on previous work demonstrating the importance of dorsal prefrontal cortex for executive functions [13–17]. 2. Methods 2.1. Participants Thirty neurologically and psychiatrically healthy individuals were studied as a control population (see Table 1 for information). Forty-three nonconsecutive patients with medically intractable unilateral TLE undergoing presurgical evaluation were retrospectively selected from a large clinical database of patients. Each patient had complete archives of demographic information; clinical history; electroclinical information; volumetric data on the hippocampus, amygdala, temporal lobe, and cerebral hemisphere; hippocampal relaxometry; and an accessible three-dimensional T1weighted MR image for quantitative analysis of the prefrontal cortex. Temporal lobe seizure onset was determined using noninvasive electroencephalogram (EEG) recordings and invasive foramen ovale recordings in conjunction with video telemetry when EEG recordings were nonlocalizing, together with other routine presurgical evaluation techniques (baseline neuropsychological evaluation, diagnostic MRI, and Wada testing). Of the 43 patients, 26 had unilateral left TLE and 17 had unilateral right TLE (Table 1).

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for 23 patients (7 with right TLE), and the COWAT for 22 patients (6 with right TLE). The Stroop task was administered as described in the Stroop Neuropsychological Screening Test Manual [19]. Both stages of the Stroop task were administered using standardized applications, but only data from the second (color–word) interference task was used for analysis. For both tasks, performance was measured either as the time taken to complete the parts of the test or as the number of words read (or colors reported) in 2 minutes. Any errors were subtracted from the total score. Scoring on the second (color–word) task was used to assess frontal lobe functioning, as it is this test that provides the interference. Although only the color– word task is used for interpretation, both tasks should always be administered, as the first (color task) has a priming effect on the degree of interference in the second task [19]. The WMS-III [12] provides measures of numerous components of memory function, including visual and auditory immediate and delayed recall and recognition. In the present study, only data from the working memory component, which are obtained from two particular subtests (letter number sequencing and spatial span), were analyzed. For the former, participants were orally presented with an intermixed set of letters and numbers, and were instructed to overtly recall each number and letter in ascending sequential order (e.g., ‘‘2 B 4 F 7 J”). For the spatial span task, participants first observed the examiner tap a sequence of numbered blocks, and were then required to tap the same sequence, which increased in length with each trial. Scoring was based on the number of correct trials. Further information on the exact scoring method is available in Wechsler [12]. The COWAT is an overt verbal fluency task that required each participant to orally generate as many words as possible beginning with the letters F, A, and S. A response time of 1 minute was given for each letter, and participants were instructed not to generate nouns (e.g., France or Adam) or repeat words with alternative endings (e.g., eat and eating). The scoring system was based on the total number of words correctly generated. Further information on the scoring system is available in Spreen and Strauss [20]. 2.3. MRI

2.2. Neuropsychological evaluation All patients underwent full neuropsychological assessment as part of their consideration for the epilepsy surgery program at WCNN, which included tests of intellectual functioning, memory functioning, attention and concentration, language, executive functioning, and mood [18]. For the present study, data from the Stroop Color–Word interference test, WMS-III, and COWAT were analyzed. In the present investigation, Stroop scores were available for all 43 patients, the working memory component of WMS-III

2.3.1. Acquisition T1-weighted images were obtained for all subjects using a 1.5-T SIGNA whole-body MRI system (GE Medical Systems, Milwaukee, WI, USA). A spoiled gradient echo (SPGR) pulse sequence (TE = 9 ms, TR = 34 ms, flip angle = 30°) produced 124 coronal T1weighted images with a FOV of 20 cm. Acquired images were of voxel size 0.781  0.781  1.6 mm. Acquisition time was 13 min 56 s for a 1 NEX scan. 2.4. Stereology

Table 1 Demographic information for all participants and clinical information for patients studied in the present investigation.

N Age Gender (%) Male Female Handedness (%) Right Left Age at onset of epilepsy Duration of epilepsy (years)

Controls

Left TLE

Right TLE

30 43.8 (11.7)

26 32.0 (8.7)

17 33.4 (9.4)

36.7 63.3

46.2 53.8

23.5 76.5

100 0 — —

92.3 7.7 8.8 (8.3) 24.2 (12.7)

100 0 11.56 (8.6) 23.2 (12.0)

Note. Values are means (SD), unless otherwise indicated.

The Cavalieri method of modern design stereology in conjunction with point counting [21] was used to estimate the volume of the prefrontal cortical subfields, hippocampi, and cerebral hemispheres of all subjects. In the Cavalieri method, volume is directly estimated from equidistant and parallel MR images of the brain with a uniform random starting position. A second level of sampling is required to estimate the section area from each image by applying point counting. The mathematical justification and implementation of the methodology are simple, and it can be applied to structures of arbitrary shape [22]. This technique has been widely applied to reliably estimate brain compartment volume in a timeeffective manner [7,8,22–30]. Stereology has been shown to be at least as precise as tracing and thresholding volumetry techniques and substantially more time efficient [25].

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2.4.1. Prefrontal cortex Volume estimation of the left and right dorsal and ventral prefrontal cortical subfields using stereology was based on the principles of a previous study [23]. All three-dimensional T1-weighted images were realigned perpendicular to the bicommissural plane using BrainVoyager software (R. Goebel, Brain Innovation, www.BrainVoyager.com) running on a PC workstation (Dell Dimension, Pentium II 400, Windows XP), and the 256  256  124 acquired voxels of side 0.781  0.781  1.6 mm were interpolated to cubic voxels of side 1.0 mm. The left and right dorsal and ventral prefrontal cortical subfields were manually demarcated using BrainVoyager. Two demarcations were marked on each image: First, to demarcate dorsal prefrontal cortex (DPFC) from ventral prefrontal cortex (VPFC), a marker was placed on the axial section where the anterior commissure and posterior commissure could be simultaneously visualized. Second, a marker was placed on a coronal image at the level of the genu of the corpus callosum, which served as the caudal border of the DPFC. Most of the point counting was guided by the markers placed using BrainVoyager. This is particularly true for the DPFC. Posterior regions of the VPFC are not demarcated by the markers, and require visualization of anatomy to delineate VPFC from adjacent subcortical anatomy. At midline, a boundary between medial prefrontal brain tissue and cerebrospinal fluid (CSF) is clearly visible for the majority of cases. When the cortical border with the CSF is obscured in the midline slices of the image, the anteroventral-most tip of the corpus callosum guided the posterior cortical boundary. Laterally, the boundary followed the anteriormost portion of the caudate nucleus. More laterally, the boundary was demarcated by the anterior branch of the Sylvian fissure. These anatomical features were visualized by the rater during point counting. Fig. 1 illustrates point counting for volume estimation of DPFC and VPFC. Volume estimation of the left and right DFPC and VPFC was achieved through sampling a series of equally spaced sagittal MR images, beginning with a random starting position, using Easymea-

sure software [24]. Each image was overlain with a test system comprising a regular array of test points, and the number of points lying within the transect through each prefrontal region was recorded. Separation between test points on the square grid used for point counting was 0.8 cm (i.e., 8 pixels) for the DPFC and 0.7 cm (i.e., 7 pixels) for the VPFC. Slice interval was 0.4 cm (every four MR sections). Unbiased estimates of transect area were obtained by multiplying the total number of points recorded by the area corresponding to each test point (e.g., 0.8  0.4 = 0.32 cm2 for DPFC). An unbiased estimate of volume was obtained as the sum of the estimated areas of the structure transects on consecutive systematic sections multiplied by the distance between sections. Approximately 150–200 points were recorded on 10 to 15 systematic random sections per structure (left/right/DPFC/VPFC). Sectioning and point counting intensities were optimized to achieve a coefficient of error on the Cavalieri volume estimates of below 5% [21]. An inter-/intrarater reliability study was carried out by three raters who estimated prefrontal volumes. Intraclass correlation coefficients were calculated and were greater than 0.9. 2.4.2. Hippocampus Quantitative MRI measures of the volume of the hippocampus using the Cavalieri method of modern design stereology in combination with point counting were available in the context of the presurgical evaluation program, and the methods of hippocampal stereology have been described in detail elsewhere [7,8,25–27]. For analysis, the three-dimensional T1-weighted MR images were transferred to ANALYZE (Mayo Foundation, Rochester, MN, USA) on a SPARC 10 workstation (SUN Microsystems, Santa Clara, CA, USA), and the 256  256  124 acquired voxels of side 0.781  0.781  1.6 mm were linearly interpolated to 256  256  256 cubic voxels of side 0.781 mm. Image sections were reformatted perpendicular to the long axis of the hippocampus to provide optimal visualization of medial temporal lobe structures. The direction of reformatting was adjusted so that the brain

Fig. 1. Point counting for stereology in medial (left) to lateral (right) regions of the dorsal (top) and ventral (bottom) prefrontal cortex.

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appeared symmetrical on the reformatted sections. The hippocampus as defined in the present study comprised hippocampus proper, dentate gyrus, ambient gyrus, subiculum, fimbria, alveus, and hippocampal vertical digitations. We excluded the uncus and choroid plexus. The posteriormost section of the hippocampus was defined as the section on which the lateral ventricles divide into frontal and temporal horns. On the anteriormost section, the hippocampus was differentiated from the amygdala by visualization of the alveus and typically additionally by a region of CSF superior to the alveus. Volume estimation was achieved by sampling a series of equally spaced MR images, beginning with a random starting position. Each image was overlain with a test system comprising a regular array of test points, and the number of points lying within each transect through the hippocampus was recorded. Separation between test points on the square grid used for point counting was 0.234 cm (i.e., 3 pixels) and slice interval was also 0.234 cm for the hippocampus. Unbiased estimates of transect area were obtained by multiplying the total number of points recorded by the area corresponding to each test point (i.e., 0.234  0.234 = 0.0548 cm2). An unbiased estimate of structure volume was obtained as the sum of the estimated areas of the structure transects on consecutive systematic sections multiplied by the distance between sections. Approximately 150 points were recorded on 10 to 15 systematic random sections. Intraclass correlation coefficients were calculated and were greater than 0.9 in intraand interrater reliability studies, as previously reported [7,8,26,27].

trols. Pearson’s coefficient was used for the within-group analysis of association between neuropsychological performance and volume of neuroanatomical structures. Because of the relatively small sample size, we did not incorporate a stringent correction for multiple comparisons given that such a correction may have obscured subtle but significant effects.

2.4.3. Cerebral hemispheres As neuropsychological–prefrontal correlations could potentially be due to larger brains in general, we additionally measured the volume of the left and right cerebral hemispheres to control for the effects of brain size. The application of stereological methods to estimate the volume of the cerebral hemispheres has been detailed previously [26,27]. Briefly, after image interpolation and reformatting identical to that for hippocampal volume measurements, the left and right hemispheres were sampled separately on every 15th MR section (i.e., 1.17 cm) using a square grid of 15 pixels (i.e., 1.2 cm). Measurements excluded the brainstem and cerebellum. All supratentorial gray matter and white matter was sampled.

3.1. Neuroanatomical comparisons

2.5. Voxel-based morphometry Prior to voxel-based statistical analysis, MR images were spatially processed using SPM5 (Wellcome Department of Cognitive Neurology, www.fil.ion.ucl.ac.uk), running in Matlab 5.3 (The Mathworks, Natick, MA, USA) on a PC workstation (Dell Dimension, Pentium II 400, Windows XP). Optimized VBM techniques were performed as described in our previous studies (automatic segmentation, linear and nonlinear (7  8  7 basis functions) normalization, 10-mm smoothing) [9,31,32]. We have previously reported that VBM analyses incorporating the modulation step are less sensitive in detecting frontal lobe effects in patients with TLE [7–9,31,32]. We therefore performed analyses without inclusion of the modulation step, and compared findings of GMC with changes in prefrontal volume estimates obtained using stereology.

2.6.2. Voxel-based morphometry The spatially processed images were compared between patients with left TLE, patients with right TLE, and controls on a voxel-by-voxel basis using the general linear model. Contrasts were defined to detect whether each voxel of tissue had a greater or lesser probability of being gray matter between groups. For neuroanatomical–cognitive relationships, the spatially processed images of patients with left TLE and those with right TLE were entered into a multiple regression model with Stroop, COWAT, and working memory performance as covariates of interest. The output for each comparison is a statistical parametric map of the t statistic (SPM{t}), which was transformed to a normal distribution (SPM{z}) and thresholded at P < 0.05 (corrected for multiple comparisons). To increase the sensitivity of detecting neuroanatomical–cognitive relationships, we used a small volume correction (SVC) on the brain regions of interest, thresholding at P < 0.05. Spherical SVCs of 20 and 10 mm were used on prefrontal cortex and hippocampus, respectively. 3. Results

3.1.1. Stereology In controls, mean left and right hippocampal volumes were found to be 2.5 ml (SD = 0.4) and 2.6 ml (SD = 0.4), respectively. Mean left and right hippocampal volumes in patients with left TLE were 1.5 ml (SD = 0.3) and 2.5 ml (SD = 0.5), and in patients with right TLE, 2.4 ml (SD = 0.4) and 1.8 ml (SD = 0.6). A 3  2 mixed ANOVA revealed a significant main effect of group (F(1, 69) = 12.551, P < 0.001), a significant effect of side of hippocampus (F(1, 69) = 33.749, P < 0.001), and a significant group  side interaction (F(2, 69) = 151.088, P < 0.001). Further investigation of the group  side interaction using a one-way ANOVA revealed significant differences in left (F(2, 71) = 47.93, P < 0.001) and right (F(2, 71) = 13.65, P < 0.001) hippocampal volume between groups, with patients with left TLE having reduced left hippocampal volumes (Tukey’s HSD, 0.9732, P < 0.001) and patients with right TLE having reduced right hippocampal volumes (Tukey’s HSD, 0.7257, P < 0.001) compared to controls. There were no significant differences in hippocampal volume contralateral to the side of seizure onset between patient groups and controls (P = 0.692 in patients with left TLE, and P = 0.822 in patients with right TLE). Table 2 summarizes the descriptive statistics of prefrontal cortical subfield volume in controls and patients. Two 3  2 ANOVAs

Table 2 Mean volumes of left and right ventral and dorsal prefrontal cortex in controls, patients with left TLE, and patients with right TLE. Volume (ml)

2.6. Statistical analysis 2.6.1. Stereology Statistical analyses were administered using SPSS Version 11 for Windows (SPSS Inc., Chicago, IL, USA). A combination of 3  2 mixed ANOVAs, one-way ANOVAs, and t tests, in addition to Tukey’s HSD post hoc testing, were used for comparison of prefrontal and hippocampal morphology between patient groups and con-

Left VPFC Right VPFC Left DPFC Right DPFC

Controls

Left TLE

Right TLE

10.5 10.4 23.6 23.7

9.2 (2.7) 9.4 (2.3) 21.1 (3.9)a 21.6 (3.8)a

10.4 10.8 22.1 21.0

(2.8) (2.5) (4.6) (3.7)

Note. Values are means (SD). VPFC (DPFC), ventral (dorsal) prefrontal cortex. a Significantly different from controls (see main text).

(3.8) (3.3) (3.3)a (3.5)a

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were used to analyze VPFC and DPFC volume separately. Results indicated no significant group difference (F(1, 70) = 1.72, P = 0.19), left–right asymmetry (F(1, 70) = 0.78, P = 0.38), or group  side interaction (F(2, 70) = 0.56, P = 0.57) in VPFC volume. Analysis of DPFC volumes revealed that there was a significant main effect of group (F(1, 70) = 3.28, P = 0.04), but no significant left–right asymmetry (F(1, 70) = 0.33, P = 0.57) or side  group interaction (F(2, 70) = 1.45, P = 0.24). Further investigation of the significant main effect of group on DPFC volume using a one-way ANOVA revealed that significant group differences were restricted to the right DPFC (F(2, 70) = 3.455, P = 0.03), with possibly a trend in the left DPFC (F(2, 70) = 2.615, P = 0.08). Post hoc investigation using Tukey’s HSD revealed that right DPFC volumes were reduced in both patient groups relative to controls, and that left DPFC volume was significantly reduced when patients with left and those with right TLE were combined relative to controls (F(2, 70) = 3.28, P = 0.04). 3.1.2. Voxel-based morphometry GMC reduction and increase in patients with left and right TLE relative to controls is illustrated in Fig. 2 (reduction = red-orange, increase = purple-blue). Peak coordinates and statistical significance levels of all effects are provided in Table 3. In patients with left TLE, GMC reduction was identified in left hippocampus, left dorsolateral prefrontal cortex, bilateral dorsomedial prefrontal cor-

tex, and left occipitoparietal cortex. In patients with right TLE, GMC reduction was identified in right hippocampus, right dorsolateral prefrontal cortex, bilateral dorsomedial prefrontal cortex, and medial parietal cortex (including posterior cingulate gyrus and precuneus). Areas of GMC increase were identified in bilateral parahippocampal gyrus in patients with left and right TLE relative to controls. Further areas of GMC increase were identified in right insula and left cerebellum in patients with left TLE and in medioventral prefrontal cortex in patients with right TLE. 3.2. Neuroanatomical–cognitive relationships One-way ANOVAs revealed that there was no difference in Stroop (F(1, 41) = 0.323, P = 0.573) or WMS III (F(1, 21) = 0.649, P = 0.429) performance between patients with left and right TLE. However, patients with left TLE performed significantly worse on the COWAT relative to patients with right TLE (F(1, 20) = 9.139, P = 0.007). The only significant correlation found between the three tasks was between performance on the WMS-III and performance on COWAT in patients with left TLE only (r = 0.551, P = 0.027). 3.2.1. Stereology When all patients were pooled, several significant correlations emerged. First, performance on the working memory component of the WMS-III was positively correlated with volume of left DPFC

Fig. 2. Results from voxel-based morphometry for group comparison analyses of patients with left and patients with right TLE and controls. Red-orange regions indicate gray matter concentration reduction and blue-purple regions indicate gray matter concentration increase in patients relative to controls. The top rows for each group indicate effects in prefrontal cortex (PFC), and the bottom rows indicate effects in the medial temporal lobe (MTL). Images are in neurological convention (R = R/L = L). (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

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S.S. Keller et al. / Epilepsy & Behavior 15 (2009) 186–195 Table 3 Results from voxel-based morphometry. Analysis Patients with left TLE vs controls

Contrast GMC reduction

GMC increase

Patients with right TLE vs controls

GMC reduction

GMC increase

Region

Voxel cluster

Bilateral medial PFC, left dorsolateral PFC Left occipitoparietal cortex Left hippocampus Left PHG Right PHG Right cerebellum, PHG Left insula Medial parietal cortex Bilateral medial PFC Right hippocampus Left dorsal PFC Right dorsolateral PFC Right parietal cortex Bilateral medioventral PFC Bilateral medial PFC Right PHG Left PHG, amygdala, hippocampus

8554 7428 1509 2645 2999 2734 1635 3452 3038 643 1905 877 731 2410 1739 1437 1568

SPM{z} b

5.29 5.11a 5.04a 5.87c 5.48b 4.95a 4.93a 5.12a 5.11a 5.04a 5.00a 4.95a 4.93a 5.45b 5.33b 5.04a 4.92a

Peak coordinates 17 27 59 55 63 33 32 15 18 26 27 21 23 49 4 23 53 23 39 1 10 -1 60 37 8 45 42 36 20 14 8 9 65 32 32 43 45 57 51 4 29 16 10 47 9 29 19 28 –26 18 -20

Note. Region, voxel cluster size (spatial extent), significance (SPM{z}), and coordinates of peak effect are indicated. All results are reported at P < 0.05, corrected for multiple comparisons. GMC, gray matter concentration; PFC, prefrontal cortex; PHG, parahippocampal gyrus. a Significant at the P < 0.05 level, when corrected for multiple global comparisons. b Significant at the P < 0.025 level, when corrected for multiple global comparisons. c Significant at the P < 0.01 level, when corrected for multiple global comparisons.

(r = 0.415, P = 0.049), left VPFC (r = 0.600, P = 0.002), right VPFC (r = 0.507, P = 0.013), whole (i.e., dorsal and ventral) left PFC (r = 0.561, P = 0.005), whole right PFC (r = 0.433, P = 0.039), and total (i.e., left and right) PFC (r = 0.533, P = 0.009). These correlations are illustrated in Fig. 3. WMS-III performance was not correlated with left (P = 0.204) or right (P = 0.915) hippocampal volume. Second, performance on the COWAT was positively correlated with volume of the left hippocampus (r = 0.524, P = 0.012), left DPFC (r = 0.426, P = 0.048), and whole left PFC (r = 0.463, P = 0.030). The relationships between COWAT performance and neuroanatomical volume are illustrated in Fig. 4. Finally, Stroop performance was correlated only with volume of the left VPFC (r = 0.357,

P = 0.019). All other effects were nonsignificant (P > 0.055). There were no correlations between left or right hemisphere volume and neuropsychological performance when all patients were analyzed together, although there was a trend for relationships between left hemisphere volume and COWAT performance (r = 0.301, P = 0.174) and working memory performance on the WMS-III (r = 0.371, P = 0.081). When patients were separated according to the side of seizure onset, significant correlations were observed only for the right TLE group. This was surprising given that neuropsychological scores were available for only 17 (Stroop), 7 (WMS-III), and 6 (COWAT) patients with right TLE. In these patients, the working memory

Fig. 3. Significant positive correlations between performance on the working memory index of the WMS-III (raw scores) and (A) left DPFC, (B) left VPFC, (C) right VPFC, (D) whole left PFC, (E) whole right PFC, and (F) entire PFC in all patients. All significant correlations stand when the outlier is removed from analyses.

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Fig. 4. Significant positive correlations between performance on the COWAT (raw scores) and (A) left DPFC, (B) whole left PFC, and (C) left hippocampus in all patients.

component of the WMS-III was positively correlated with the volume of the left VPFC (r = 0.790, P = 0.035), whole right PFC (r = 0.786, P = 0.036), and total PFC (r = 0.786, P = 0.036); COWAT performance was correlated with volume of the left DPFC (r = 0.840, P = 0.036) and whole right PFC (r = 0.839, P = 0.037); and Stroop performance was correlated with volume of the left VPFC (r = 0.495, P = 0.043). No hippocampal volume–neuropsychological performance correlations existed. There were no correlations between left or right hemisphere volume and neuropsychological performance when patients were analyzed separately according to the side of seizure onset. 3.2.2. Voxel-based morphometry No GMC–cognitive relationships were observed using wholebrain correction for multiple comparisons or small volume corrections on the prefrontal cortex or hippocampus when patient groups were analyzed separately or together. Fig. 5 schematically illustrates the significant findings of the present study. 4. Discussion There were two primary objectives of the present study. First, we sought to investigate whether patients with unilateral TLE have volume alterations of prefrontal cortical subfields relative to healthy controls, and whether particular volume alterations are dependent on the side of seizure onset. We found that patients with unilateral left and right TLE had significant volume reduction of right DPFC relative to controls, and significant volume reduction of left DPFC was obtained only when patients with left and those with right TLE were pooled in a single analysis. No differences were

observed in VPFC. These results were obtained using both stereology and VBM, as was volume reduction of the hippocampus ipsilateral to the side of seizure onset. Second, we sought to investigate the relationships between the volumes of prefrontal cortical subfields and hippocampus and neuropsychological performance on the executive measures. We found that performance on (1) the working memory index of WMS-III was positively correlated with the volume of all prefrontal cortical regions other than right DPFC, (2) COWAT performance was positively correlated with left DPFC, whole left PFC, and left hippocampal volumes, and (3) Stroop performance was positively correlated with left VPFC volume. No significant correlations were observed between neuropsychological performance and whole cerebral hemisphere volume, and with hippocampal volume when patients were separated according to the side of seizure onset. We discuss the neurocognitive implications of these results after highlighting pertinent methodological issues. 4.1. Methodological issues There are few studies that have assessed the morphology of the prefrontal cortex in patients with TLE. Those that have analyzed prefrontal structure have employed VBM techniques to study whole-brain morphology (see Keller and Roberts [9] for a review). Some of these studies have reported prefrontal gray matter reduction in patients with TLE relative to controls. Discrepancies between studies may relate to differences in VBM technique employed or the sample of patients with TLE studied (e.g., whether patients were classified according to electroclinical information, hippocampal volume, or psychometric information). To our knowledge, the present study is the first to prospectively focus on the

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Fig. 5. Schematic illustration of the main results of the present study. Colors correspond to side of hemisphere and subregion: left dorsal PFC (light blue), left ventral PFC (dark blue), left hippocampus (purple), right dorsal PFC (light yellow), right ventral PFC (dark yellow), right hippocampus (orange). The significant differences/correlations for these regions are provided in the text underneath highlighted in the corresponding brain region. Nonitalicized text indicates neuroanatomical comparisons between patients and controls. Italicized text indicates neuroanatomical–cognitive correlations in patients. Finding replicated using stereology and voxel-based morphometry. Note the lack of hippocampal–cognitive correlations. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

structure of the prefrontal cortex in patients with TLE. Prefrontal volumetry is not routinely performed during presurgical MRI evaluation for patients being considered for temporal lobe resection, as multimodal invasive (e.g., ictal foramen ovale or depth electrode recordings in combination with video telemetry) and noninvasive (e.g., interictal surface EEG recordings) investigations specifically indicate a temporal lobe seizure focus. However, quantitative analysis of prefrontal volume may be important in understanding why many patients with TLE show evidence of an ‘‘extratemporal lobe” neuropsychological profile. The findings obtained in the present study are consistent with our previous work indicating volume loss of right DPFC regardless of the side of TLE [7], and volume loss of the left and right DPFC when patients with left and those with right TLE are combined [8]. However, interpretations of extratemporal TLE effects in combined samples of patients with left and right TLE should be treated with caution, given that previous work has shown that such effects may be different according to the side of seizure onset [7–9,29]. Furthermore, we are reluctant to speculate on the differences in cognitive–neuroanatomical relationships between patients with left and those with right TLE based on the data presented in this article, given the relatively small sample of patients with right TLE in particular. Our finding that patients with left TLE scored significantly more poorly on the COWAT relative to those with right TLE is consistent with the well-known language deficits observed in left-sided patients due to damage to the language-dominant hemisphere. Stereological analysis of prefrontal cortical subfields and VBM analysis of GMC were consistent in the identification of prefrontal changes in patients with TLE. A discrepancy may have been expected between results as there were fundamental differences in the regions of brain morphology being assessed between the two

techniques. Analysis of prefrontal structure using stereology quantifies regional compartment volume of gray and white matter together, whereas VBM analyzes regional distribution of only gray matter. Nevertheless, both techniques indicated that (1) DPFC is preferentially reduced in volume in patients with TLE, (2) the morphology of VPFC does not differ from healthy controls, and (3) hippocampal volume reduction is observed only on the side ipsilateral to seizure onset, thus providing further evidence for the consistency between hippocampal stereology and hippocampal GMC using VBM [7,8]. It is, however, important to note that although VBM and stereology revealed excellent agreement when comparisons were made between patients and controls, the correlations observed between stereologically derived volumes and neuropsychological performance were not replicated using VBM. Although we advocate the potential significance of subtle frontal lobe abnormalities causing executive dysfunction in patients with TLE, we are cautious in the interpretation of the results presented in this study for two reasons. First, we did not obtain neuropsychology performance in controls, as this was beyond the scope of the original investigation for which the control MR images were acquired, unlike patient neuropsychological performance, which is routinely assessed during presurgical evaluation. We were therefore unable to compare control and patient neuropsychological performance in this study. However, the neuropsychological profiles of patients were consistent with previously published cohorts of surgical patients with reduced functioning across a number of key domains including learning and memory, attention and concentration, and higher executive functioning [18]. We were unable to confidently ascribe cognitive–neuroanatomical correlations to the pathology associated with TLE, given that the same relationships were not assessed in our controls. Previous work

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has indicated that prefrontal volume is related to performance on neuropsychological tasks of executive functioning [33–36]. In particular, normal age-related atrophy of the PFC is inversely correlated with increased errors on tasks of executive function [33– 35]. However, the patients in our study were younger than the controls, so we were confident that any prefrontal changes in morphology were not due to normal brain maturation. Second, we were studying a relatively small sample of patients with TLE (i.e., n < 100), and as such, we did not incorporate a correction for multiple correlations given that the stringent correction may have obscured subtle, but biologically significant, cognitive– neuroanatomical correlations. We therefore suggest that these analyses are replicated in large samples of patients with available psychometric and MRI data incorporating the stringent correction for multiple comparisons. 4.2. Neurocognitive Implications Previous work has speculated that volume changes in the PFC may be related to executive dysfunction in patients with TLE [7,8]. Abnormalities of frontostriatal cortex are the candidate etiology of executive dysfunction as these brain regions are intimately associated with executive functions [13–17]. Human lesion and functional neuroimaging studies provide evidence of a widespread network of cortical and subcortical regions involved in executive functions, including dorsolateral prefrontal cortex, medial prefrontal cortex, anterior cingulate gyrus, temporal neocortex, parietal cortex, and basal ganglia (e.g., [37–47]). It is conceivable that disruption to any region of this network could potentially cause impairments in executive functions. Although we have provided strong support for the theory that impaired executive functioning may be due to atrophy of the PFC in patients with TLE, it will be important to consider the relationship between neuropsychological performance and structure of the basal ganglia in particular, given how the PFC and basal ganglia interact in cognitive processing and the previous documentation of abnormalities of the basal ganglia in TLE [9,48]. Results observed in the present study are also in keeping with previous research suggesting that hippocampal sclerosis is not necessarily a predictor of executive dysfunction in patients with TLE [3– 6]. We failed to observe correlations between hippocampal volume and Stroop or working memory (WMS-III) performance in the entire group of patients or when patients were separated according to the side of seizure onset. There was also no relationship between COWAT performance and hippocampal volume when patients with left and those with right TLE were treated separately. However, there was a significant positive correlation between COWAT performance and left hippocampal volume when patients with left and those with right TLE were combined. This represented the only hippocampal– cognitive correlate in the present study, and is consistent with a previous study that reported a relationship between verbal fluency and left hippocampal volume in patients with TLE [49]. Even though data presented here support the hypothesis that prefrontal abnormalities are the likely cause of executive dysfunction, it is difficult to differentiate the impact of prefrontal and hippocampal abnormalities on executive function in patients with TLE, given that hippocampal epileptogenic tissue may adversely affect the function of frontal lobe regions [50], perhaps interictally mediated via medial temporal lobe–prefrontal cortical connections [17,51]. Invasive EEG investigations in patients with intractable epilepsy have demonstrated preferential propagation of interictal spikes from medial temporal lobe to medial and orbital frontal lobe regions [52,53], and ictal activity from the medial temporal lobe to ipsilateral frontal lobe regions [54]. Furthermore, previous work has demonstrated that frontal lobe cognitive impairment is associated with decreased prefrontal glucose metabolism in patients

with TLE using PET [55], and that neonatal lesions to the ventral hippocampus disrupt metabolic properties of pyramidal glutamate neurons in the rodent prefrontal cortex and associated cognition [56]. The suggestion that the effects of electrophysiological disruption to distal extratemporal regions may be a contributing factor to executive dysfunction in patients with TLE is supported by a previous study that reported a significant correlation between WCST performance and history of secondary generalization of temporal lobe seizures [5]. Therefore, it is likely that aberrant hippocampo-fronto-striatal neurophysiological processes account for at least part of the executive dysfunction observed in patients with TLE. Results from the present study suggest that neuroanatomical abnormalities of the PFC may accompany neurophysiological abnormalities of the same region in patients with TLE. If interictal discharges from the pathological medial temporal lobe to frontostriatal cortex are the sole cause of executive dysfunction in patients with TLE, then it would be expected that impaired presurgical executive functions would normalize after successful resective surgery for intractable temporal lobe seizures. Previous studies in this area have reported conflicting results. Hermann and Seidenberg [4] presented results consistent with this hypothesis. In addition to reporting no relationship between histopathological grading of hippocampal sclerosis and presurgical executive function, the authors found that complete cessation of seizures via resection of temporal lobe epileptogenic cortex leads to improvement of executive function in patients who were presurgically impaired on the WCST. However, Martin et al. [5] reported that card sorting ability was not significantly correlated with postsurgical seizure status in patients with left and those with right TLE, and Seidenberg et al. [57] reported that the number of WCST perseverative errors was not dependent on postsurgical seizure outcome in patients with left TLE without hippocampal sclerosis. The data presented in our study are consistent with those of Martin et al. [5] and Seidenberg et al. [57] given that we would not expect executive functions to normalize after successful surgery for seizure control due to the presence of an underlying structural pathology distal from the epileptogenic cortex (i.e., atrophy of PFC) that would continue to impair executive functions after temporal lobectomy. 5. Conclusions Using a stereological region-of-interest approach and wholebrain VBM, we have corroborated the findings from previous VBM studies indicating atrophy of the DPFC in patients with TLE. Importantly and for the first time, we provide evidence indicating that volume changes in the PFC are correlated with impaired executive functioning. These preliminary data may shed light on why many patients with focal TLE show evidence of an extratemporal neuropsychological profile. Acknowledgments We thank Helen Jones and James Thompson at the Department of Psychology, University of Liverpool, for assistance with data acquisition. We also thank the radiographers, nursing staff, and Dr. Enis Cezayirli at MARIARC for their roles in acquisition of patient and control MRI data sets. References [1] Giovagnoli A. Relation of sorting impairment to hippocampal damage in temporal lobe epilepsy. Neuropsychologia 2001;39:140–50. [2] Corcoran R, Upton D. A role for the hippocampus in card sorting? Cortex 1993;29:293–304. [3] Cowey C, Green S. The hippocampus: a ‘working memory’ structure? The effect of hippocampal sclerosis on working memory. Memory 1996;4:19–30.

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