Magnetic Resonance Imaging 33 (2015) 544–550
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Abnormalities of the uncinate fasciculus correlate with executive dysfunction in patients with left temporal lobe epilepsy Limei Diao a, b, 1, Haichun Yu c, 1, Jinou Zheng a,⁎, Zirong Chen a, Donghong Huang a, Lu Yu a a b c
Department of Neurology, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, China Department of Neurology, The First Affiliated Hospital of Guangxi University of Chinese Medicine, Nanning 530023, China Guangxi Technological College of Machinery and Electricity, Nanning, 530007, China
a r t i c l e
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Article history: Received 2 September 2014 Revised 12 February 2015 Accepted 15 February 2015 Keywords: Temporal lobe epilepsy Cognition Uncinate fasciculus Diffusion tensor imaging
a b s t r a c t Objective: To evaluate executive deficits in patients with left temporal lobe epilepsy (TLE) and to analyze the association of executive deficits and diffusion tensor imaging (DTI) parameters of the uncinate fasciculus. Methods: This study included 14 adult left TLE patients and 15 healthy controls. Executive function was examined using neuropsychological tests, including the Stroop color–word, digit span, digit symbol, trail-making test, and verbal fluency tests. All subjects underwent brain DTI. Results: Compared with controls, TLE patients needed significantly more time (P = 0.036) and had more wrong answers (P b 0.001) in the Stroop test, and exhibited significantly lower scores in the digit span (P = 0.017), digit symbol (P = 0.009), and verbal fluency (P = 0.001) tests. Additionally, TLE patients took significantly longer to accomplish the trail-making test (P = 0.042). Fractional anisotropy (FA) of the left uncinate fasciculus in TLE patients was significantly lower compared to controls (P b 0.001). FA of the left uncinate fasciculus in TLE patients and controls positively correlated with verbal fluency (r = 0.565, P = 0.035; r = 0.561, P = 0.031) and digit span (r = 0.556, P = 0.039; r = 0.559, P = 0.030) test scores. Conclusions: Patients with left TLE exhibit wide ranges of executive deficits. Abnormal FA values in the left UF ipsilateral to the epileptogenic zone suggest that disrupted integrity in the left uncinate fasciculus is related to executive deficits in patients with left TLE. © 2015 Elsevier Inc. All rights reserved.
1. Introduction Temporal lobe epilepsy (TLE), a common type of epilepsy, accounts for approximately 25% of patients with epilepsy [1,2]. Several studies have shown that TLE patients exhibit executive function deficits, and that the epileptic locus was located in the left temporal lobe in patients with left TLE [3–8]. The uncinate fasciculus (UF) is a major white matter tract that connects the anterior temporal and frontal lobes [9]. It links the three anterior temporal convolutions and the amygdala with the gyrus rectus, medial retro orbital cortex, and subcallosal area [10], and plays an important role in executive function [11–14]. In addition, the UF is a pathway that allows seizure spread to the frontal lobe in TLE [15]. However, the role of the UF in executive dyfunction in patients with left TLE has not been established. The pathogenesis of executive dysfunction in patients with left TLE remains unclear. It is hypothesized that TLE-induced impairment may be caused by epileptic discharges originating from the left
⁎ Corresponding author: Tel.: +86 771 5356504; fax: +86 771 5352627. E-mail address: [email protected] (J. Zheng). 1 Contributed equally to this work. http://dx.doi.org/10.1016/j.mri.2015.02.011 0730-725X/© 2015 Elsevier Inc. All rights reserved.
temporal lobe that are preferentially propagated to the frontal lobe via the uncinate fasciculus [16–18]. However, this hypothesis has not been proven using radiological imaging techniques, such as diffusion tensor imaging (DTI). DTI is a noninvasive imaging technique that detects and constructs three-dimensional white matter fiber bundles by measuring the effective diffusion tensor [19]. Fractional anisotropy (FA) used in DTI is a measurement that reflects axonal diameter and myelination in white matter. It is generated by the eigenvalues λ1, λ2, and λ3 of the diffusion tensor. FA ranges from 0 to 1, with an FA value of 0 indicating worse integrity of white matter and an FA value of 1 indicating good white matter integrity [16]. These tensor measurements contain useful information for detection of the white matter microstructure and evaluation of the integrity of white matter pathways. DTI has been shown to be a useful and reliable method to measure white matter lesions in patients with TLE [20–22]. Recent DTI studies have shown that white matter integrity is abnormal in TLE patients. For example, TLE patients with impaired memory exhibit decreased fractional anisotropy (FA) in the bilateral uncinate fasciculus [16,23]. Patients with left TLE were reported to have extensively decreased FA in the ipsilateral white matter [24]. However, an association between executive function and the uncinate fasciculus has not been evaluated in patients with left TLE.
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In the present study, we investigated executive function as well as the DTI features of the bilateral uncinate fasciculus in patients with left TLE. The purpose of this study was to test the hypothesis that DTI can reveal structural abnormalities of the UF in left TLE, and that the degree of abnormality correlates with functional abnormality as shown by reduced executive function scores. 2. Materials and methods 2.1. Patients The Medical Ethics Committee of Guangxi Medical University approved this study, and all patients provided informed consent prior to inclusion. This study included 14 consecutive patients with left temporal lobe epilepsy (TLE) who were admitted to our hospital between January 2007 and July 2011. All patients were diagnosed with left TLE based on their medical history, as well as clinical, radiological, and electroencephalography (EEG) findings. Patients were included if two of the following three criteria were met [25]: 1) onset symptoms indicated that the epileptic locus was located (or originated) in the left temporal lobe; 2) radiological images showed that the lesion was located in the left temporal lobe with hippocampal sclerosis or atrophy, with no abnormalities observed in other brain regions; and 3) ictal and interictal EEG showed that the epileptogenic zone was located in the left temporal lobe. Other inclusion criteria were: 1) patients who were treated with standardized antiepileptic drugs (lamotrigine, carbamazepine, or phenytoin) according to the treatment guidelines set by the International League Against Epilepsy for epileptic seizure and epileptic symptoms [26]; 2) no changes in the use of antiepileptic drugs within the previous 6 months; and 3) patients had to be right-handed. Exclusion criteria were: 1) patients with right TLE, susceptible bilateral TLE, or an unclearly identified epileptic locus; 2) patients with unilateral or bilateral frontal lesions, such as infarction, demyelination, or tumors; 3) patients who did not follow the antiepileptic guidelines, or had changed antiepileptic drugs within the previous 6 months; 4) patients who took antipsychotic medicines or any other drugs that could impair cognitive or psychotic function; 5) patients with impaired vision, hearing, or language functions; 6) patients with serious somatic diseases; and 7) patients who did not cooperate. 2.2. Neuropsychological tests A set of brief neuropsychological tests was used to examine various aspects of executive function, including response inhibition, working memory, planning, task switching, and vocabulary fluency. The stroop test was used to evaluate response inhibition. Digit span task and digit symbol tests were used to evaluate working memory. Trail-making tests were used to evaluate task switching. Verbal fluency tests were used to evaluate vocabulary fluency. 2.2.1. Stroop task The test included four tasks, consisting of 30 words in 3 consecutive lines: 1) naming words that are printed in black ink on a card; 2) naming the color words that are printed in color ink; 3) naming the color words that are written in a different color (for example, naming "green" for the word "green" that is written in red ink); and 4) naming the color in which the color words are written (for example, name “red” for the word “green” written in red ink). The time taken to complete parts of the test was measured as reaction time, and the number of wrong words in 2 minutes was recorded on the fourth task. The response times were evaluated. Because the fourth test provides the interference, it was used to assess inhibition functioning. The first three tests have a priming effect on the degree of interference in the fourth task [27].
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2.2.2. Digit span task The subject read a sequence of numbers and was asked to repeat it in forward or reverse order. The results of this test were assessed using the Chinese adaptation of the Wechsler Adult Intelligence Scale. 2.2.3. Digit symbol test In this test, each digit was ascribed a unique symbol according to the Chinese adaptation of the Wechsler Adult Intelligence Scale. Subjects were presented with a series of digits and a key of the digit– symbol pairing, and were asked to fill in the corresponding symbols. The subjects were trained 10 times, and were asked to fill in as many consecutive spaces as possible in 90 seconds. The correct number of digit–symbol pairings was recorded. 2.2.4. Trail-making test In this test, subjects were presented with numbered points scattered randomly on a sheet of paper. They were asked to draw a line to join numbered points in numerical order. The time taken to perform this test was evaluated. 2.2.5. Verbal fluency test Subjects were asked to say as many animal words as possible in 1 minute. 2.3. Diffusion tensor imaging (DTI) study MR imaging data were obtained with an Achieva 3.0-T MR imaging system (Phillips, The Netherlands). Each patient underwent spin-echo T1-weighted MRI (T1WI) scans. T1WI scans were performed as follows: repetition time (TR), 60 ms; and echo time (TE), 16 ms; slice thickness, 6 mm; interslice gap, 2 mm; and field of view (FOV), 220 mm × 220 mm. DTI was performed using diffusion-weighted echo-planar imaging sequences, and the ZOOM gradient. The DTI parameters were as follows: TR, 1000 ms; TE, 15 ms; slice thickness, 2 mm; interslice gap, 0.5 mm; FOV, 220 mm × 220 mm; matrix, 128 × 128; diffusion gradient encoding in 15 directions; two diffusion gradient fields (b = 0 and b = 1,000 mm2/s); total sections, 16; and total imaging time, 224 seconds. After image acquisition, data were transferred to a personal computer and processed using the analysis software DTI studio (http://cmrm.med.Jhmi.edu/). Tracking was performed from all pixels in the bilateral frontal and temporal lobe, and the uncinate fasciculus was obtained from each patient [28] (Fig. 1). Tracking was stopped when fractional anisotropy (FA) was less than 0.2 [29], or the curvature from one voxel to the next was greater than 41 degrees [28]. Fibers with lengths less than 20 mm were automatically removed [30]. Coronal T1-weighted MRI images are shown in Fig. 2. FA, and fiber lengths were calculated using the DTI studio software, and colored DTI images of the uncinate fasciculus are shown (Fig. 3). The region of interest (ROI) was placed in the last coronal slice that separated the frontal lobe and the temporal lobe. One ROI was selected in the temporal lobe, and the second ROI was located in the same coronal slice as the first ROI but was superior to the temporal lobe, medial to the insula, and adjacent to the putamen (Fig. 1). 2.4. Statistical analyses Analyses were performed using SPSS 12.0 software package (Chicago, IL, USA). All values are presented as median and interquartile range (IQR). Mann–Whitney–Wilcoxon tests were used to compare differences between TLE patients and controls. Spearman's correlation tests were used to analyze associations between FA of the uncinate fasciculus and neuropsychological test scores. Probability values less than 0.05 were considered statistically significant.
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Fig. 1. DTI graph of normal uncinate fasciculus. DTI images showing the uncinate fasciculus. Color DTI images showing the ROI locations for the uncinate fasciculus on a coronal slice (A, C) and a mid-sagittal slice (C, D). The coronal slice (A, C) was the last slice that separated the frontal and temporal lobes. The first ROI (1) included the entire temporal lobe. The second ROI (2) included all projections toward the frontal lobe. The mid-sagittal slice (C) shows the location of the entire fasciculus in the first ROI, and the mid-sagittal slice (D) shows the uncinate fasciculus. The “AND” operation was applied to the two ROIs.
3. Results 3.1. Clinical characteristics of patients This study included fourteen patients with left TLE. Seven patients were male, and seven were female. The median age of the patients was 34.00 ± 8.15 years (range, 19–46 years). The median number of education years was 9.50 ± 4.63 years (range, 3–17 years). Fifteen age-matched healthy subjects were also included as controls. All controls were right-handed. Seven controls were male and eight were female. The median age of controls was 32.00 ±
8.15 years (range, 18–48 years). The median number of education years was 12.00 ± 7.41 years (range, 3–19 years). There were no significant differences in patient age (Z = − 0.634, P = 0.526), gender (Z = − 0.554, P = 0.579), or education level (Z = − 0.856, P = 0.392) between TLE patients and controls. 3.2. Psychological test results Compared with controls, TLE patients showed significantly worse performances on nearly all tasks (Table 1). TLE patients needed significantly more time (Z = − 2.097, P = 0.036) and had more
Fig. 2. Coronal T1-weighted MRI images. Coronal T1-weighted MRI images in a healthy control (A) and patient with left TLE (B).
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Fig. 3. left and right uncinate fasciculus color map graph (control group and left TLE group). DTI color images on the left (A, B, C, G, H, I) and right (D, E, F, J, K, L) sides of a healthy control (A–F) and patient with left TLE (G–L).
wrong answers (Z = −4.134, P b 0.001) in the Stroop test compared to controls. In addition, TLE patients exhibited significantly lower scores in the digit span test (Z = − 2.386, P = 0.017) and digit symbol test (Z = − 2.598, P = 0.009). TLE patients needed significantly more time to accomplish the trail-making test compared to controls (Z = − 2.030, P = 0.042). Finally, verbal fluency test scores were significantly lower in the TLE group (Z = − 3.416, P = 0.001).
3.3. FA values, uncinate fasciculus length, and eigenvalues Compared to controls, TLE patients exhibited significantly lower FA values in the left uncinate fasciculus (Z = − 3.402, P = 0.001, Table 2). There were no significant differences between TLE patients and controls in FA of the right uncinate fasciculus (P N 0.05). There were no significant differences in the length of the bilateral uncinate fasciculus between TLE patients and controls (P N 0.05, Table 2). Compared to controls, the left eigenvalue λ1 was significantly lower (P = 0.022), and the left (λ2 + λ3)/2 value was significantly greater in left TLE patients (P = 0.040) (Table 3).
3.4. Correlation between psychological test results and FA values of the uncinate fasciculus In patients with left TLE, FA of the left uncinate fasciculus positively correlated with scores on the verbal fluency (r = 0.565, P = 0.035) and digit span (r = 0.556, P = 0.039) tests (Fig. 4). In the controls, FA of the left uncinate fasciculus also positively correlated with scores on the verbal fluency (r = 0.561, P = 0.031) and digit span (r = 0.559, P = 0.030) tests. FA of the left uncinate fasciculus did not significantly Table 1 Results of neuropsychological tests in patients with left TLE compared to healthy controls. Test
Control (n = 15) median (IQR)
TLE patients (n = 14) median (IQR)
Response time of Stroop test Wrong number of Stroop test Digit span test Digit symbol test Trail-making test Verbal fluency (words/min)
16.23 2.00 17.95 66.00 41.05 19.00
23.86 7.00 12. 53 50.50 56.12 11.50
(6.67) (0.74) (2.22) (14.08) (20.02) (2.22)
⁎ P b 0.05 vs. control based on Mann–Whitney–Wilcoxon tests.
(16.55)⁎ (4.82)⁎ (8.15)⁎ (22.42)⁎ (27.80)⁎ (7.78)⁎
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Table 2 FA values and the length of the uncinate fasciculus in left TLE patients and healthy controls.
FA of the left uncinate fasciculus FA of the right uncinate fasciculus Length of the left uncinate fasciculus (mm) Length of the right uncinate fasciculus (mm)
Controls (n = 15) median (IQR)
Left TLE patients (n = 14) median (IQR)
0.38 (0.0148) 0.32 (0.0222) 29.38 (7.74)
0.335 (0.0556)⁎ 0.31 (0.0315) 29.55 (9.28)
31.92 (8.07)
32.56 (11.61)
⁎ P = 0.001 vs. controls based on Wilcoxon–Mann–Whitney test.
correlate with Stroop, digital symbol, and trail-making test scores. There were weak correlations between FA of the right uncinate fasciculus and the results of the verbal fluency and digit span tests. 4. Discussion Patients with left TLE had a wide range of cognitive deficits, including attention [3–8]. It is postulated that attention regulates information processing via three interactive brain modules: the alertness network, orientation network, and execution network [13]. We have previously reported that patients with left TLE exhibit abnormal alertness network and execution network function, and that executive dysfunction is the most common impairment in attentional networks [31]. Executive function refers to the cognitive function that regulates and controls multiple cognitive process to accomplish specific goals or complex tasks in flexible ways [32]. Executive dysfunction can lead to cognition, emotion, and social function abnormalities, and is closely associated with poor rehabilitation of cognitive function [33]. Therefore, executive function plays a critical role in cognition, and studying executive function is important for understanding cognitive impairment in patients with left TLE. In this study, we used neuropsychological tests to examine various aspects of executive function in patients with left TLE, including response inhibition, working memory, planning, task switching, and vocabulary fluency tests. We found that compared with controls, TLE patients needed significantly more time to accomplish the Stroop and trail-making tests, had more wrong answers in the Stroop test, and exhibited significantly lower scores in the digit span and digit symbol tests. These results suggest that patients with left TLE exhibit a wide range of impaired executive functions, including response inhibition, working memory, planning, task switching, and vocabulary fluency. Our findings are consistent with a previous study showing that these functions are frequently affected in TLE patients [34]. Here, we used the DTI technique to examine the microstructure of the white matter, as well as to analyze the association of FA and uncinate fasciculus length with executive function in TLE patients. Compared with controls, no abnormalities in coronal MRI images were found in patients with left TLE. However, in DTI color images, the bilateral uncinate fasciculus in patients with left TLE appeared to be thinner compared with controls (Fig. 3). In addition, TLE patients exhibited significantly lower FA values in the left uncinate fasciculus, but not in the right uncinate fasciculus. There were no significant differences in bilateral uncinate fasciculus length between TLE patients and controls. In right-handed people who have lefthemisphere-dominant brains, the left uncinate fasciculus in the frontal and temporal lobes contains the afferent and efferent fiber connections that control frontal lobe-mediated executive function. Our findings that FA was reduced in the left, but not right, uncinate fasciculus in patients with left TLE suggest that left epileptogenic lesions may cause microstructural injury to the left uncinate fasciculus. We found reduced FA in the uncinate fasciculus in the ipsilateral, but
Table 3 The eigenvalues in TLE patients and healthy controls.
Left λ1 Left (λ2 + λ3)/2 Right λ1 Right (λ2 + λ3)/2
Controls (10−4) (mm2/s)
Left TLE patients (10−4) (mm2/s)
t
P
11.781 5.891 11.688 5.844
11.400 6.033 11.567 5.950
2.338 2.078 0.820 1.390
0.022 0.040 0.411 0.169
± ± ± ±
0.608 0.210 0.592 0.236
± ± ± ±
0.675 0.320 0.568 0.356
not the contralateral, hemisphere of TLE patients. These data are not consistent with a meta-analysis study reporting that FA is reduced in the white matter of both hemispheres in TLE patients [35]. The discrepancy between the two studies is likely due to different patient populations. Of the 13 studies included in the meta-analysis report [35], only two papers investigated patients with left TLE, whereas the others studied patients with both left and right TLE. In addition, of the two studies that reported on patients with left TLE, one only included pediatric patients, whose white matter is clearly different from that of adult patients. In addition, despite no significant differences in FA between TLE patients and controls, we found that TLE patients tended to have reduced FA in the right uncinate fasciculus. Our findings that there were no significant differences in FA between TLE patients and controls may be explained by the small sample size of our study. Alternatively, there may be mild injury to the contralateral side of the uncinate fasciculus. We also found that the bilateral uncinate correlated with verbal fluency and digit span in left TLE and control subjects to a similar degree. However, the FA of the right uncinate had only weak correlation in the TLE and controls. Therefore, we speculate that part of executive function is associated with left uncinate fasciculus integrity. The verbal fluency and digit span tests reflect two essential components of executive function: vocabulary fluency and working memory, respectively. The positive correlation between FA in the left uncinate fasciculus and verbal fluency and digit span test scores suggests that the left uncinate fasciculus may be the brain structure that mediates verbal fluency and working memory. In addition, in all patients with left TLE, DTI showed reduced FA and eigenvalues in the left uncinate fasciculus, suggesting that TLE patients have microstructural abnormalities, such as demyelination and axonal loss. The eigenvalue λ1 reflects axonal changes, and the (λ2 + λ3)/2 value reflects demyelination changes. In the present study, we found that the left eigenvalue λ1 was significantly lower (P = 0.022), whereas the left (λ2 + λ3)/2 value was significantly greater, in the left TLE patients. We believe that axonal and myelination loss occurs in the left uncinate fasciculus of the left TLE patients, and myelination regeneration leads to a higher (λ2 + λ3)/2 value. This study found that TLE patients had substantial recognition deficits, and that the left uncinate was related to verbal fluency and digit span in TLE patients. The microstructural integrity changes in the left uncinate fasciculus may be the result of pathologic mechanisms of TLE. These diffusion abnormalities likely reflect a loss of both myelin and axon, resulting in lower membrane density and higher extracellular volume [36]. This may be caused by Wallerian degeneration of axons due to atrophy and gliosis of the uncinate fasciculus. Therefore, left uncinate abnormalities may partially explain executive function deficits in TLE patients. The prefrontal cortex is known to mediate executive function [32]. However, in the present study, we did not find any frontal lobe abnormalities in TLE patients with executive deficits. Therefore, the pathogenesis of executive deficits in patients with left TLE remains unclear. It may be caused by epileptic discharges originating in the left temporal lobe spreading to the frontal lobe via fiber connections between the temporal and frontal lobes. Epileptic discharges in the
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Fig. 4. Scatter plots and regression lines graph about FA of the left uncinate fasciculus in left TLE and the verbal fluency and digit span. FA of the left uncinate fasciculus positively correlated with scores on the verbal fluency (B) (r = 0.565, P = 0.035) and digit span (A) (r = 0.556, P = 0.039).
left temporal lobe may preferentially propagate via the ipsilateral fornix, stria terminalis, amygdala fibers, and uncinate fasciculus. Because the uncinate fasciculus is the only fiber bundle that connects the temporal and frontal lobes, we speculate that executive deficit is associated with uncinate fasciculus abnormalities in patients with left TLE. Our findings that FA in the left uncinate fasciculus was positively associated with verbal fluency and digit span test scores support this speculation. The average length of the fiber bundle reflects the macroscopic architecture of the uncinate fasciculus. Large, long fiber bundles conduct nerve impulses quickly with shorter response times. In the present study, we did not find any significant differences in bilateral uncinate fasciculus length between TLE patients and controls. These results suggest that TLE patients exhibit no obvious macroscopic abnormalities in the bilateral uncinate fasciculus. However, we cannot exclude the possibility that uncinate fasciculus abnormalities were not measured under our experimental conditions. For example, abnormalities may not be detected when tracking was stopped if the curvature was greater than 41 degrees and fiber lengths were less than 20 mm. This study only included TLE patients who were administered with lamotrigine, carbamazepine, or phenytoin, but not valproate. Valproate has been linked to neuronal preservation by increasing levels of brain-derived neurotrophic factor (BDNF) [37]. Valproateinduced neuronal preservation may protect the integrity of white matter, and thus may interfere with our ability to evaluate the damage in white matter. In addition, Kimford et al. reported that valproate exposure adversely affected cognitive development whereas lamotrigine, carbamazepine, and phenytoin do not [38]. Therefore, patients who had taken valproate were excluded from this study. Further studies are required to confirm our findings in TLE patients receiving valproate treatment. In summary, we examined the executive function of patients with left TLE using a set of neuropsychological tests. Microstructural abnormalities in the left uncinate fasciculus may contribute to executive deficits in TLE patients. In addition, we further found that FA of the left uncinate fasciculus positively correlated with verbal fluency and digit span test scores, suggesting that abnormalities in the uncinate fasciculus may underlie executive deficit pathogenesis in patients with left TLE. Using DTI techniques, we identified microstructural abnormalities in the uncinate fasciculus prior to morphological and signal changes in T1WI MRI, suggesting that microstructural abnormalities in the uncinate fasciculus occur early in TLE. Furthermore, the uncinate fasciculus is likely the major fiber that controls frontal lobemediated executive function.
5. Conclusions Patients with left TLE exhibit wide ranges of executive deficits. Abnormal FA values in the left uncinate fasciculus ipsilateral to the epileptogenic zone suggest that disrupted integrity in this region is related to executive deficits in patients with left TLE. Conflict of Interest There are no ethical/legal conflicts involved in the article. Contributors Limei Diao carried out the cases collection, tested the neuropsychological tests and drafted the manuscript. Haichun Yu carried out the data post-processing about diffusion tensor imaging (DTI) study, participated in the design of the study and performed the statistical analysis. Jinou Zheng conceived of the study, coordination and helped to draft the manuscript. Zirong Chen, Donghong Huang, and Lu Yu carried out some cases collection. All authors have approved the final article should be true and included in the disclosure. All authors read and approved the final manuscript. Acknowledgements This work was supported by grants from China National Natural Sciences Foundation (81360202). We thank Dr. Ye Wei for the help of imaging magnetic resonance from the First Affiliated Hospital of Guangxi Medical University. References [1] Semah F, Picot MC, Adam C, Broglin D, Arzimanoglou A, Bazin B, et al. Is the underlying cause of epilepsy a major prognostic factor for recurrence? Neurology 1998;51:1256–62. [2] Tellez-Zenteno JF, Hernandez-Ronquillo L. A review of the epidemiology of temporal lobe epilepsy. Epilepsy Res Treat 2012;2012:630853. [3] Rzezak P, Guimaraes CA, Fuentes D, Guerreiro MM, Valente KD. Memory in children with temporal lobe epilepsy is at least partially explained by executive dysfunction. Epilepsy Behav 2012;25:577–84. [4] Rusnakova S, Daniel P, Chladek J, Jurák P, Rektor I. The executive functions in frontal and temporal lobes: a flanker task intracerebral recording study. J Clin Neurophysiol 2011;28:30–5. [5] Stretton J, Thompson PJ. Frontal lobe function in temporal lobe epilepsy. Epilepsy Res 2012;98:1–13. [6] Lopes AF, Simoes MM, Robalo CN, Fineza I, Gonçalves OB. Neuropsychological evaluation in children with epilepsy: attention and executive functions in temporal lobe epilepsy. Rev Neurol 2010;50:265–72. [7] Wang WH, Liou HH, Chen CC, Chiu MJ, Chen TF, Cheng TW, et al. Neuropsychological performance and seizure-related risk factors in patients with temporal
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Abnormalities of the uncinate fasciculus correlate with executive dysfunction in patients with left temporal lobe epilepsy Limei Diao a, b, 1, Haichun Yu c, 1, Jinou Zheng a,⁎, Zirong Chen a, Donghong Huang a, Lu Yu a a b c
Department of Neurology, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, China Department of Neurology, The First Affiliated Hospital of Guangxi University of Chinese Medicine, Nanning 530023, China Guangxi Technological College of Machinery and Electricity, Nanning, 530007, China
a r t i c l e
i n f o
Article history: Received 2 September 2014 Revised 12 February 2015 Accepted 15 February 2015 Keywords: Temporal lobe epilepsy Cognition Uncinate fasciculus Diffusion tensor imaging
a b s t r a c t Objective: To evaluate executive deficits in patients with left temporal lobe epilepsy (TLE) and to analyze the association of executive deficits and diffusion tensor imaging (DTI) parameters of the uncinate fasciculus. Methods: This study included 14 adult left TLE patients and 15 healthy controls. Executive function was examined using neuropsychological tests, including the Stroop color–word, digit span, digit symbol, trail-making test, and verbal fluency tests. All subjects underwent brain DTI. Results: Compared with controls, TLE patients needed significantly more time (P = 0.036) and had more wrong answers (P b 0.001) in the Stroop test, and exhibited significantly lower scores in the digit span (P = 0.017), digit symbol (P = 0.009), and verbal fluency (P = 0.001) tests. Additionally, TLE patients took significantly longer to accomplish the trail-making test (P = 0.042). Fractional anisotropy (FA) of the left uncinate fasciculus in TLE patients was significantly lower compared to controls (P b 0.001). FA of the left uncinate fasciculus in TLE patients and controls positively correlated with verbal fluency (r = 0.565, P = 0.035; r = 0.561, P = 0.031) and digit span (r = 0.556, P = 0.039; r = 0.559, P = 0.030) test scores. Conclusions: Patients with left TLE exhibit wide ranges of executive deficits. Abnormal FA values in the left UF ipsilateral to the epileptogenic zone suggest that disrupted integrity in the left uncinate fasciculus is related to executive deficits in patients with left TLE. © 2015 Elsevier Inc. All rights reserved.
1. Introduction Temporal lobe epilepsy (TLE), a common type of epilepsy, accounts for approximately 25% of patients with epilepsy [1,2]. Several studies have shown that TLE patients exhibit executive function deficits, and that the epileptic locus was located in the left temporal lobe in patients with left TLE [3–8]. The uncinate fasciculus (UF) is a major white matter tract that connects the anterior temporal and frontal lobes [9]. It links the three anterior temporal convolutions and the amygdala with the gyrus rectus, medial retro orbital cortex, and subcallosal area [10], and plays an important role in executive function [11–14]. In addition, the UF is a pathway that allows seizure spread to the frontal lobe in TLE [15]. However, the role of the UF in executive dyfunction in patients with left TLE has not been established. The pathogenesis of executive dysfunction in patients with left TLE remains unclear. It is hypothesized that TLE-induced impairment may be caused by epileptic discharges originating from the left
⁎ Corresponding author: Tel.: +86 771 5356504; fax: +86 771 5352627. E-mail address: [email protected] (J. Zheng). 1 Contributed equally to this work. http://dx.doi.org/10.1016/j.mri.2015.02.011 0730-725X/© 2015 Elsevier Inc. All rights reserved.
temporal lobe that are preferentially propagated to the frontal lobe via the uncinate fasciculus [16–18]. However, this hypothesis has not been proven using radiological imaging techniques, such as diffusion tensor imaging (DTI). DTI is a noninvasive imaging technique that detects and constructs three-dimensional white matter fiber bundles by measuring the effective diffusion tensor [19]. Fractional anisotropy (FA) used in DTI is a measurement that reflects axonal diameter and myelination in white matter. It is generated by the eigenvalues λ1, λ2, and λ3 of the diffusion tensor. FA ranges from 0 to 1, with an FA value of 0 indicating worse integrity of white matter and an FA value of 1 indicating good white matter integrity [16]. These tensor measurements contain useful information for detection of the white matter microstructure and evaluation of the integrity of white matter pathways. DTI has been shown to be a useful and reliable method to measure white matter lesions in patients with TLE [20–22]. Recent DTI studies have shown that white matter integrity is abnormal in TLE patients. For example, TLE patients with impaired memory exhibit decreased fractional anisotropy (FA) in the bilateral uncinate fasciculus [16,23]. Patients with left TLE were reported to have extensively decreased FA in the ipsilateral white matter [24]. However, an association between executive function and the uncinate fasciculus has not been evaluated in patients with left TLE.
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In the present study, we investigated executive function as well as the DTI features of the bilateral uncinate fasciculus in patients with left TLE. The purpose of this study was to test the hypothesis that DTI can reveal structural abnormalities of the UF in left TLE, and that the degree of abnormality correlates with functional abnormality as shown by reduced executive function scores. 2. Materials and methods 2.1. Patients The Medical Ethics Committee of Guangxi Medical University approved this study, and all patients provided informed consent prior to inclusion. This study included 14 consecutive patients with left temporal lobe epilepsy (TLE) who were admitted to our hospital between January 2007 and July 2011. All patients were diagnosed with left TLE based on their medical history, as well as clinical, radiological, and electroencephalography (EEG) findings. Patients were included if two of the following three criteria were met [25]: 1) onset symptoms indicated that the epileptic locus was located (or originated) in the left temporal lobe; 2) radiological images showed that the lesion was located in the left temporal lobe with hippocampal sclerosis or atrophy, with no abnormalities observed in other brain regions; and 3) ictal and interictal EEG showed that the epileptogenic zone was located in the left temporal lobe. Other inclusion criteria were: 1) patients who were treated with standardized antiepileptic drugs (lamotrigine, carbamazepine, or phenytoin) according to the treatment guidelines set by the International League Against Epilepsy for epileptic seizure and epileptic symptoms [26]; 2) no changes in the use of antiepileptic drugs within the previous 6 months; and 3) patients had to be right-handed. Exclusion criteria were: 1) patients with right TLE, susceptible bilateral TLE, or an unclearly identified epileptic locus; 2) patients with unilateral or bilateral frontal lesions, such as infarction, demyelination, or tumors; 3) patients who did not follow the antiepileptic guidelines, or had changed antiepileptic drugs within the previous 6 months; 4) patients who took antipsychotic medicines or any other drugs that could impair cognitive or psychotic function; 5) patients with impaired vision, hearing, or language functions; 6) patients with serious somatic diseases; and 7) patients who did not cooperate. 2.2. Neuropsychological tests A set of brief neuropsychological tests was used to examine various aspects of executive function, including response inhibition, working memory, planning, task switching, and vocabulary fluency. The stroop test was used to evaluate response inhibition. Digit span task and digit symbol tests were used to evaluate working memory. Trail-making tests were used to evaluate task switching. Verbal fluency tests were used to evaluate vocabulary fluency. 2.2.1. Stroop task The test included four tasks, consisting of 30 words in 3 consecutive lines: 1) naming words that are printed in black ink on a card; 2) naming the color words that are printed in color ink; 3) naming the color words that are written in a different color (for example, naming "green" for the word "green" that is written in red ink); and 4) naming the color in which the color words are written (for example, name “red” for the word “green” written in red ink). The time taken to complete parts of the test was measured as reaction time, and the number of wrong words in 2 minutes was recorded on the fourth task. The response times were evaluated. Because the fourth test provides the interference, it was used to assess inhibition functioning. The first three tests have a priming effect on the degree of interference in the fourth task [27].
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2.2.2. Digit span task The subject read a sequence of numbers and was asked to repeat it in forward or reverse order. The results of this test were assessed using the Chinese adaptation of the Wechsler Adult Intelligence Scale. 2.2.3. Digit symbol test In this test, each digit was ascribed a unique symbol according to the Chinese adaptation of the Wechsler Adult Intelligence Scale. Subjects were presented with a series of digits and a key of the digit– symbol pairing, and were asked to fill in the corresponding symbols. The subjects were trained 10 times, and were asked to fill in as many consecutive spaces as possible in 90 seconds. The correct number of digit–symbol pairings was recorded. 2.2.4. Trail-making test In this test, subjects were presented with numbered points scattered randomly on a sheet of paper. They were asked to draw a line to join numbered points in numerical order. The time taken to perform this test was evaluated. 2.2.5. Verbal fluency test Subjects were asked to say as many animal words as possible in 1 minute. 2.3. Diffusion tensor imaging (DTI) study MR imaging data were obtained with an Achieva 3.0-T MR imaging system (Phillips, The Netherlands). Each patient underwent spin-echo T1-weighted MRI (T1WI) scans. T1WI scans were performed as follows: repetition time (TR), 60 ms; and echo time (TE), 16 ms; slice thickness, 6 mm; interslice gap, 2 mm; and field of view (FOV), 220 mm × 220 mm. DTI was performed using diffusion-weighted echo-planar imaging sequences, and the ZOOM gradient. The DTI parameters were as follows: TR, 1000 ms; TE, 15 ms; slice thickness, 2 mm; interslice gap, 0.5 mm; FOV, 220 mm × 220 mm; matrix, 128 × 128; diffusion gradient encoding in 15 directions; two diffusion gradient fields (b = 0 and b = 1,000 mm2/s); total sections, 16; and total imaging time, 224 seconds. After image acquisition, data were transferred to a personal computer and processed using the analysis software DTI studio (http://cmrm.med.Jhmi.edu/). Tracking was performed from all pixels in the bilateral frontal and temporal lobe, and the uncinate fasciculus was obtained from each patient [28] (Fig. 1). Tracking was stopped when fractional anisotropy (FA) was less than 0.2 [29], or the curvature from one voxel to the next was greater than 41 degrees [28]. Fibers with lengths less than 20 mm were automatically removed [30]. Coronal T1-weighted MRI images are shown in Fig. 2. FA, and fiber lengths were calculated using the DTI studio software, and colored DTI images of the uncinate fasciculus are shown (Fig. 3). The region of interest (ROI) was placed in the last coronal slice that separated the frontal lobe and the temporal lobe. One ROI was selected in the temporal lobe, and the second ROI was located in the same coronal slice as the first ROI but was superior to the temporal lobe, medial to the insula, and adjacent to the putamen (Fig. 1). 2.4. Statistical analyses Analyses were performed using SPSS 12.0 software package (Chicago, IL, USA). All values are presented as median and interquartile range (IQR). Mann–Whitney–Wilcoxon tests were used to compare differences between TLE patients and controls. Spearman's correlation tests were used to analyze associations between FA of the uncinate fasciculus and neuropsychological test scores. Probability values less than 0.05 were considered statistically significant.
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Fig. 1. DTI graph of normal uncinate fasciculus. DTI images showing the uncinate fasciculus. Color DTI images showing the ROI locations for the uncinate fasciculus on a coronal slice (A, C) and a mid-sagittal slice (C, D). The coronal slice (A, C) was the last slice that separated the frontal and temporal lobes. The first ROI (1) included the entire temporal lobe. The second ROI (2) included all projections toward the frontal lobe. The mid-sagittal slice (C) shows the location of the entire fasciculus in the first ROI, and the mid-sagittal slice (D) shows the uncinate fasciculus. The “AND” operation was applied to the two ROIs.
3. Results 3.1. Clinical characteristics of patients This study included fourteen patients with left TLE. Seven patients were male, and seven were female. The median age of the patients was 34.00 ± 8.15 years (range, 19–46 years). The median number of education years was 9.50 ± 4.63 years (range, 3–17 years). Fifteen age-matched healthy subjects were also included as controls. All controls were right-handed. Seven controls were male and eight were female. The median age of controls was 32.00 ±
8.15 years (range, 18–48 years). The median number of education years was 12.00 ± 7.41 years (range, 3–19 years). There were no significant differences in patient age (Z = − 0.634, P = 0.526), gender (Z = − 0.554, P = 0.579), or education level (Z = − 0.856, P = 0.392) between TLE patients and controls. 3.2. Psychological test results Compared with controls, TLE patients showed significantly worse performances on nearly all tasks (Table 1). TLE patients needed significantly more time (Z = − 2.097, P = 0.036) and had more
Fig. 2. Coronal T1-weighted MRI images. Coronal T1-weighted MRI images in a healthy control (A) and patient with left TLE (B).
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Fig. 3. left and right uncinate fasciculus color map graph (control group and left TLE group). DTI color images on the left (A, B, C, G, H, I) and right (D, E, F, J, K, L) sides of a healthy control (A–F) and patient with left TLE (G–L).
wrong answers (Z = −4.134, P b 0.001) in the Stroop test compared to controls. In addition, TLE patients exhibited significantly lower scores in the digit span test (Z = − 2.386, P = 0.017) and digit symbol test (Z = − 2.598, P = 0.009). TLE patients needed significantly more time to accomplish the trail-making test compared to controls (Z = − 2.030, P = 0.042). Finally, verbal fluency test scores were significantly lower in the TLE group (Z = − 3.416, P = 0.001).
3.3. FA values, uncinate fasciculus length, and eigenvalues Compared to controls, TLE patients exhibited significantly lower FA values in the left uncinate fasciculus (Z = − 3.402, P = 0.001, Table 2). There were no significant differences between TLE patients and controls in FA of the right uncinate fasciculus (P N 0.05). There were no significant differences in the length of the bilateral uncinate fasciculus between TLE patients and controls (P N 0.05, Table 2). Compared to controls, the left eigenvalue λ1 was significantly lower (P = 0.022), and the left (λ2 + λ3)/2 value was significantly greater in left TLE patients (P = 0.040) (Table 3).
3.4. Correlation between psychological test results and FA values of the uncinate fasciculus In patients with left TLE, FA of the left uncinate fasciculus positively correlated with scores on the verbal fluency (r = 0.565, P = 0.035) and digit span (r = 0.556, P = 0.039) tests (Fig. 4). In the controls, FA of the left uncinate fasciculus also positively correlated with scores on the verbal fluency (r = 0.561, P = 0.031) and digit span (r = 0.559, P = 0.030) tests. FA of the left uncinate fasciculus did not significantly Table 1 Results of neuropsychological tests in patients with left TLE compared to healthy controls. Test
Control (n = 15) median (IQR)
TLE patients (n = 14) median (IQR)
Response time of Stroop test Wrong number of Stroop test Digit span test Digit symbol test Trail-making test Verbal fluency (words/min)
16.23 2.00 17.95 66.00 41.05 19.00
23.86 7.00 12. 53 50.50 56.12 11.50
(6.67) (0.74) (2.22) (14.08) (20.02) (2.22)
⁎ P b 0.05 vs. control based on Mann–Whitney–Wilcoxon tests.
(16.55)⁎ (4.82)⁎ (8.15)⁎ (22.42)⁎ (27.80)⁎ (7.78)⁎
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Table 2 FA values and the length of the uncinate fasciculus in left TLE patients and healthy controls.
FA of the left uncinate fasciculus FA of the right uncinate fasciculus Length of the left uncinate fasciculus (mm) Length of the right uncinate fasciculus (mm)
Controls (n = 15) median (IQR)
Left TLE patients (n = 14) median (IQR)
0.38 (0.0148) 0.32 (0.0222) 29.38 (7.74)
0.335 (0.0556)⁎ 0.31 (0.0315) 29.55 (9.28)
31.92 (8.07)
32.56 (11.61)
⁎ P = 0.001 vs. controls based on Wilcoxon–Mann–Whitney test.
correlate with Stroop, digital symbol, and trail-making test scores. There were weak correlations between FA of the right uncinate fasciculus and the results of the verbal fluency and digit span tests. 4. Discussion Patients with left TLE had a wide range of cognitive deficits, including attention [3–8]. It is postulated that attention regulates information processing via three interactive brain modules: the alertness network, orientation network, and execution network [13]. We have previously reported that patients with left TLE exhibit abnormal alertness network and execution network function, and that executive dysfunction is the most common impairment in attentional networks [31]. Executive function refers to the cognitive function that regulates and controls multiple cognitive process to accomplish specific goals or complex tasks in flexible ways [32]. Executive dysfunction can lead to cognition, emotion, and social function abnormalities, and is closely associated with poor rehabilitation of cognitive function [33]. Therefore, executive function plays a critical role in cognition, and studying executive function is important for understanding cognitive impairment in patients with left TLE. In this study, we used neuropsychological tests to examine various aspects of executive function in patients with left TLE, including response inhibition, working memory, planning, task switching, and vocabulary fluency tests. We found that compared with controls, TLE patients needed significantly more time to accomplish the Stroop and trail-making tests, had more wrong answers in the Stroop test, and exhibited significantly lower scores in the digit span and digit symbol tests. These results suggest that patients with left TLE exhibit a wide range of impaired executive functions, including response inhibition, working memory, planning, task switching, and vocabulary fluency. Our findings are consistent with a previous study showing that these functions are frequently affected in TLE patients [34]. Here, we used the DTI technique to examine the microstructure of the white matter, as well as to analyze the association of FA and uncinate fasciculus length with executive function in TLE patients. Compared with controls, no abnormalities in coronal MRI images were found in patients with left TLE. However, in DTI color images, the bilateral uncinate fasciculus in patients with left TLE appeared to be thinner compared with controls (Fig. 3). In addition, TLE patients exhibited significantly lower FA values in the left uncinate fasciculus, but not in the right uncinate fasciculus. There were no significant differences in bilateral uncinate fasciculus length between TLE patients and controls. In right-handed people who have lefthemisphere-dominant brains, the left uncinate fasciculus in the frontal and temporal lobes contains the afferent and efferent fiber connections that control frontal lobe-mediated executive function. Our findings that FA was reduced in the left, but not right, uncinate fasciculus in patients with left TLE suggest that left epileptogenic lesions may cause microstructural injury to the left uncinate fasciculus. We found reduced FA in the uncinate fasciculus in the ipsilateral, but
Table 3 The eigenvalues in TLE patients and healthy controls.
Left λ1 Left (λ2 + λ3)/2 Right λ1 Right (λ2 + λ3)/2
Controls (10−4) (mm2/s)
Left TLE patients (10−4) (mm2/s)
t
P
11.781 5.891 11.688 5.844
11.400 6.033 11.567 5.950
2.338 2.078 0.820 1.390
0.022 0.040 0.411 0.169
± ± ± ±
0.608 0.210 0.592 0.236
± ± ± ±
0.675 0.320 0.568 0.356
not the contralateral, hemisphere of TLE patients. These data are not consistent with a meta-analysis study reporting that FA is reduced in the white matter of both hemispheres in TLE patients [35]. The discrepancy between the two studies is likely due to different patient populations. Of the 13 studies included in the meta-analysis report [35], only two papers investigated patients with left TLE, whereas the others studied patients with both left and right TLE. In addition, of the two studies that reported on patients with left TLE, one only included pediatric patients, whose white matter is clearly different from that of adult patients. In addition, despite no significant differences in FA between TLE patients and controls, we found that TLE patients tended to have reduced FA in the right uncinate fasciculus. Our findings that there were no significant differences in FA between TLE patients and controls may be explained by the small sample size of our study. Alternatively, there may be mild injury to the contralateral side of the uncinate fasciculus. We also found that the bilateral uncinate correlated with verbal fluency and digit span in left TLE and control subjects to a similar degree. However, the FA of the right uncinate had only weak correlation in the TLE and controls. Therefore, we speculate that part of executive function is associated with left uncinate fasciculus integrity. The verbal fluency and digit span tests reflect two essential components of executive function: vocabulary fluency and working memory, respectively. The positive correlation between FA in the left uncinate fasciculus and verbal fluency and digit span test scores suggests that the left uncinate fasciculus may be the brain structure that mediates verbal fluency and working memory. In addition, in all patients with left TLE, DTI showed reduced FA and eigenvalues in the left uncinate fasciculus, suggesting that TLE patients have microstructural abnormalities, such as demyelination and axonal loss. The eigenvalue λ1 reflects axonal changes, and the (λ2 + λ3)/2 value reflects demyelination changes. In the present study, we found that the left eigenvalue λ1 was significantly lower (P = 0.022), whereas the left (λ2 + λ3)/2 value was significantly greater, in the left TLE patients. We believe that axonal and myelination loss occurs in the left uncinate fasciculus of the left TLE patients, and myelination regeneration leads to a higher (λ2 + λ3)/2 value. This study found that TLE patients had substantial recognition deficits, and that the left uncinate was related to verbal fluency and digit span in TLE patients. The microstructural integrity changes in the left uncinate fasciculus may be the result of pathologic mechanisms of TLE. These diffusion abnormalities likely reflect a loss of both myelin and axon, resulting in lower membrane density and higher extracellular volume [36]. This may be caused by Wallerian degeneration of axons due to atrophy and gliosis of the uncinate fasciculus. Therefore, left uncinate abnormalities may partially explain executive function deficits in TLE patients. The prefrontal cortex is known to mediate executive function [32]. However, in the present study, we did not find any frontal lobe abnormalities in TLE patients with executive deficits. Therefore, the pathogenesis of executive deficits in patients with left TLE remains unclear. It may be caused by epileptic discharges originating in the left temporal lobe spreading to the frontal lobe via fiber connections between the temporal and frontal lobes. Epileptic discharges in the
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Fig. 4. Scatter plots and regression lines graph about FA of the left uncinate fasciculus in left TLE and the verbal fluency and digit span. FA of the left uncinate fasciculus positively correlated with scores on the verbal fluency (B) (r = 0.565, P = 0.035) and digit span (A) (r = 0.556, P = 0.039).
left temporal lobe may preferentially propagate via the ipsilateral fornix, stria terminalis, amygdala fibers, and uncinate fasciculus. Because the uncinate fasciculus is the only fiber bundle that connects the temporal and frontal lobes, we speculate that executive deficit is associated with uncinate fasciculus abnormalities in patients with left TLE. Our findings that FA in the left uncinate fasciculus was positively associated with verbal fluency and digit span test scores support this speculation. The average length of the fiber bundle reflects the macroscopic architecture of the uncinate fasciculus. Large, long fiber bundles conduct nerve impulses quickly with shorter response times. In the present study, we did not find any significant differences in bilateral uncinate fasciculus length between TLE patients and controls. These results suggest that TLE patients exhibit no obvious macroscopic abnormalities in the bilateral uncinate fasciculus. However, we cannot exclude the possibility that uncinate fasciculus abnormalities were not measured under our experimental conditions. For example, abnormalities may not be detected when tracking was stopped if the curvature was greater than 41 degrees and fiber lengths were less than 20 mm. This study only included TLE patients who were administered with lamotrigine, carbamazepine, or phenytoin, but not valproate. Valproate has been linked to neuronal preservation by increasing levels of brain-derived neurotrophic factor (BDNF) [37]. Valproateinduced neuronal preservation may protect the integrity of white matter, and thus may interfere with our ability to evaluate the damage in white matter. In addition, Kimford et al. reported that valproate exposure adversely affected cognitive development whereas lamotrigine, carbamazepine, and phenytoin do not [38]. Therefore, patients who had taken valproate were excluded from this study. Further studies are required to confirm our findings in TLE patients receiving valproate treatment. In summary, we examined the executive function of patients with left TLE using a set of neuropsychological tests. Microstructural abnormalities in the left uncinate fasciculus may contribute to executive deficits in TLE patients. In addition, we further found that FA of the left uncinate fasciculus positively correlated with verbal fluency and digit span test scores, suggesting that abnormalities in the uncinate fasciculus may underlie executive deficit pathogenesis in patients with left TLE. Using DTI techniques, we identified microstructural abnormalities in the uncinate fasciculus prior to morphological and signal changes in T1WI MRI, suggesting that microstructural abnormalities in the uncinate fasciculus occur early in TLE. Furthermore, the uncinate fasciculus is likely the major fiber that controls frontal lobemediated executive function.
5. Conclusions Patients with left TLE exhibit wide ranges of executive deficits. Abnormal FA values in the left uncinate fasciculus ipsilateral to the epileptogenic zone suggest that disrupted integrity in this region is related to executive deficits in patients with left TLE. Conflict of Interest There are no ethical/legal conflicts involved in the article. Contributors Limei Diao carried out the cases collection, tested the neuropsychological tests and drafted the manuscript. Haichun Yu carried out the data post-processing about diffusion tensor imaging (DTI) study, participated in the design of the study and performed the statistical analysis. Jinou Zheng conceived of the study, coordination and helped to draft the manuscript. Zirong Chen, Donghong Huang, and Lu Yu carried out some cases collection. All authors have approved the final article should be true and included in the disclosure. All authors read and approved the final manuscript. Acknowledgements This work was supported by grants from China National Natural Sciences Foundation (81360202). We thank Dr. Ye Wei for the help of imaging magnetic resonance from the First Affiliated Hospital of Guangxi Medical University. References [1] Semah F, Picot MC, Adam C, Broglin D, Arzimanoglou A, Bazin B, et al. Is the underlying cause of epilepsy a major prognostic factor for recurrence? Neurology 1998;51:1256–62. [2] Tellez-Zenteno JF, Hernandez-Ronquillo L. A review of the epidemiology of temporal lobe epilepsy. Epilepsy Res Treat 2012;2012:630853. [3] Rzezak P, Guimaraes CA, Fuentes D, Guerreiro MM, Valente KD. Memory in children with temporal lobe epilepsy is at least partially explained by executive dysfunction. Epilepsy Behav 2012;25:577–84. [4] Rusnakova S, Daniel P, Chladek J, Jurák P, Rektor I. The executive functions in frontal and temporal lobes: a flanker task intracerebral recording study. J Clin Neurophysiol 2011;28:30–5. [5] Stretton J, Thompson PJ. Frontal lobe function in temporal lobe epilepsy. Epilepsy Res 2012;98:1–13. [6] Lopes AF, Simoes MM, Robalo CN, Fineza I, Gonçalves OB. Neuropsychological evaluation in children with epilepsy: attention and executive functions in temporal lobe epilepsy. Rev Neurol 2010;50:265–72. [7] Wang WH, Liou HH, Chen CC, Chiu MJ, Chen TF, Cheng TW, et al. Neuropsychological performance and seizure-related risk factors in patients with temporal
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