Incipient preoperative reorganization processes of verbal memory functions in patients with left temporal lobe epilepsy

Epilepsy & Behavior 42 (2015) 78–85

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Incipient preoperative reorganization processes of verbal memory functions in patients with left temporal lobe epilepsy Monika Milian a, Lena Zeltner b, Michael Erb c, Uwe Klose d, Kathrin Wagner e, Lars Frings f, Cornelia Veil c, Sabine Rona a, Holger Lerche g, Silke Klamer g,⁎ a

Department of Neurosurgery, University of Tuebingen, Tuebingen, Germany Department of Vascular Neurology, University of Tuebingen, Tuebingen, Germany Department of Biomedical Magnetic Resonance, University of Tuebingen, Tuebingen, Germany d Department of Neuroradiology, University of Tuebingen, Tuebingen, Germany e Epilepsy Center, University Hospital Freiburg, Germany f Center of Geriatrics and Gerontology Freiburg, University Hospital Freiburg, Germany g Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tuebingen, Tuebingen, Germany b c

a r t i c l e

i n f o

Article history: Received 14 October 2014 Accepted 21 November 2014 Available online xxxx Keywords: Memory fMRI Hippocampus Chronic mesial temporal lobe epilepsy Preoperative reorganization Nonlinear correlations

a b s t r a c t We previously reported nonlinear correlations between verbal episodic memory performance and BOLD signal in memory fMRI in healthy subjects. The purpose of the present study was to examine this observation in patients with left mesial temporal lobe epilepsy (mTLE) who often experience memory decline and need reliable prediction tools before epilepsy surgery with hippocampectomy. Fifteen patients with left mTLE (18–57 years, nine females) underwent a verbal memory fMRI paradigm. Correlations between BOLD activity and neuropsychological data were calculated for the i) hippocampus (HC) as well as ii) extrahippocampal mTL structures. Memory performance was systematically associated with activations within the right HC as well as with activations within the left extrahippocampal mTL regions (amygdala and parahippocampal gyrus). As hypothesized, the analyses revealed cubic relationships, with one peak in patients with marginal memory performance and another peak in patients with very good performance. The nonlinear correlations between memory performance and activations might reflect the compensatory recruitment of neural resources to maintain memory performance in patients with ongoing memory deterioration. The present data suggest an already incipient preoperative reorganization process of verbal memory in non-amnesic patients with left mTLE by simultaneously tapping the resources of the right HC and left extrahippocampal mTL regions. Thus, in the preoperative assessment, both neuropsychological performance and memory fMRI should be considered together. © 2014 Elsevier Inc. All rights reserved.

1. Introduction Surgery within the mesial temporal lobe (mTL) bears the risk of relevant episodic memory decline, typically of verbal memory following left and of nonverbal memory following right anterior temporal lobe resection (ATLR) [1,2]. The prediction of potential postoperative memory decline is, therefore, of great importance in the clinical setting and the goal of various memory functional MRI (fMRI) studies [3–7]. There is agreement that patients with epilepsy with good memory abilities prior to surgery [2,8,9] and patients whose memory functions are lateralized to the side of surgery [10] are more likely to have memory decline.

⁎ Corresponding author at: Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tuebingen, Hoppe-Seyler-Strasse 3, 72076 Tuebingen, Germany. Tel.: +49 7071 29 87707; fax: +49 7071 29 4488. E-mail address: [email protected] (S. Klamer).

http://dx.doi.org/10.1016/j.yebeh.2014.11.026 1525-5050/© 2014 Elsevier Inc. All rights reserved.

Several fMRI paradigms have been developed with regard to the prediction of postoperative memory outcome in operated patients with mesial temporal lobe epilepsy (mTLE) [3,6,7,11]. To date, only linear correlations between preoperative fMRI activations and preoperative memory performance [3] or postoperative memory changes [11, 12] were taken into account. In a recently published work, we investigated the nature of correlations between memory performance levels and fMRI activations within the mTL in healthy subjects [13]. Instead of linear correlations, we found u-shaped correlations between subjects' verbal memory performance and mTL activations. The observed hyperactivation among subjects with marginal memory performance might reflect a compensatory recruitment of neural resources to maintain memory performance, as previously reported for patients with mild cognitive impairment and Alzheimer's disease [14–16]. The purpose of the present study was to investigate the presence of nonlinear correlations in patients with left mTLE. We used a verbal memory paradigm, first published by Wagner and colleagues [17], that has been shown to produce strong left lateralized activation

M. Milian et al. / Epilepsy & Behavior 42 (2015) 78–85

patterns in healthy subjects [17,18]. We hypothesized there would be a nonlinear correlation between neuropsychological test scores and fMRI activations in mesial temporal structures due to compensatory hyperactivation in patients with marginal memory performance. 2. Materials and methods 2.1. Subjects We examined 15 German-speaking patients with chronic left-sided mTLE with clear mesiotemporal spikes on EEG and typical temporal lobe seizure semiology before left ATLR, 12 of them with clear signs of hippocampal sclerosis (HS) on MRI and 1 with mild and 2 without clear signs of HS. None of the patients had any extrahippocampal lesions. All patients were right-handed (Mhandedness quotient = 0.95, SD = 0.08; [19]) with normal or corrected-to-normal vision (9 females, 6 males, Mage = 36.3 years, SD = 11.7 years, range = 18–57 years, Meducation = 12.3 years, SD = 2.9 years) and showed left-sided language dominance as confirmed by fMRI. The study was approved by the ethics committee of the University of Tuebingen and is in accordance with the Declaration of Helsinki. All patients gave written informed consent. 2.2. Neuropsychological tests As memory performance level decreases with age [20,21], the use of raw scores in memory assessments appears to be, in our view, not entirely adequate when investigating a sample with a large variance of participants' age. For our analyses, we therefore considered the standardized memory performance compared to an age-matched reference population in the form of percentile ranks as determined by the manual instead of absolute values (i.e., raw scores). 2.2.1. Verbal memory test A verbal memory test was performed outside the scanner in which subjects had to memorize a list of 15 words (Verbaler Lern- und Merkfähigkeitstest, VLMT, [22]). We assessed three verbal memory scores: (i) ‘immediate recall’, i.e., the sum of words correctly reproduced during five learning trials (max. of 75); (ii) ‘delayed recall’, i.e., the number of correctly remembered words after a 30-minute delay (max. of 15); and (iii) ‘delayed recognition’ using a recognition condition after the delayed recall condition (max. of 15). 2.2.2. Nonverbal memory test To assess the functionality of the right mesial temporal lobe regions, a nonverbal learning and memory performance test, the DCS (Diagnostikum für Cerebralschädigung [23]), was applied where subjects had to learn 9 geometrical figures. The ‘immediate recall’ score, i.e., the sum of correctly reproduced figures during five learning trials (max. of 45), was assessed. Scores were correlated with the VLMT to assess the ability of the nondominant mTL to maintain verbal memory functions. 2.2.3. Intelligence level The level of verbal crystallized intelligence in each patient was assessed using the German multiple-choice vocabulary test to exclude patients with abnormal neuropsychological performance due to mental retardation (MWT-B, Mehrfachwahl-Wortschatz-Intelligenztest [24]).

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brain, a sagittal T1-weighted 3D-MPRAGE sequence was used (TR/TI/ TE = 1300/660/3.19 ms, flip angle = 15°, field of view = 256 ∗ 256 mm2, matrix = 256 ∗ 256, 176 slices, voxel size = 1 ∗ 1 ∗ 1 mm3). Additionally, a field map was recorded for later correction of distortions in the functional images caused by magnetic field inhomogeneity. For the fMRI tasks, gradient-echo planar T2*-weighted images covering the whole brain were acquired (TR = 4000 ms, TE = 64 ms, field of view = 192 ∗ 192 mm2, matrix = 64 ∗ 64, voxel size = 3 ∗ 3 ∗ 3 mm3, gap = 0.3 mm, 38 interleaved slices). The task was performed in block design and consisted of 175 acquisitions. The first two images were discarded in order to reach equilibrium of magnetization. The stimuli were visually projected on a translucent screen positioned at the end of the scanner table using a video projector outside the magnet room. Subjects saw the presentation via a mirror attached to the head coil. Outside the scanner room, a Windows laptop using the software ‘Presentation 0.6’ (http://www.neurobehaviouralsystems. com) was connected to the video projector. Responses were recorded by use of a fiber optic button box where patients had to press the correct one of two buttons with the thumb of the right hand. 2.4. Stimuli and fMRI task design To investigate verbal memory, patients were presented with 24 word pairs and instructed to memorize and recognize them as described previously [17] (Fig. 1). During the blocks of the encoding condition, patients were shown four neither semantically nor phonematically related word pairs for 7 s (plus 1 s of black screen) and were asked to memorize them, e.g., “Ananas + Schraube” (“pineapple + screw”). This was alternated with a block of the control condition in which the names of two weekdays were presented [e.g., “Montag + Mittwoch” (“Monday + Wednesday”)] for 5 s (plus 1 s of black screen), and patients had to indicate by button press whether they were identical or not. During the recognition condition, patients performed a twoalternative forced-choice test in which one word was presented above two alternatives (the correct associate and one distractor) for 7 s (plus 1 s of black screen) and patients were asked to select by button press the memorized associate. Both alternatives had been seen during the encoding phase, so patients were not able to distinguish between them on the basis of familiarity alone. Moreover, items were presented in randomized order, alternating with a block of the control condition. The fMRI behavioral results obtained in the recognition condition were not considered as a measure of performance, and the button presses during the recognition task were used mainly to ensure cooperation. 2.5. Image processing and fMRI data analysis Imaging data were analyzed in MATLAB (http://www.mathworks. com) using Statistical Parametric Mapping (SPM 8) (Wellcome Trust Centre for Imaging Neuroscience; http://www.fil.ion.ucl.ac.uk/spm). Functional images were converted into NIFTI-1 format. The imaging time series of each patient underwent a slice-timing procedure, was realigned and unwarped based on the estimated field map data, and then was coregistered to the anatomical reference image and normalized to the MNI (Montreal Neurologic Institute Atlas, MNI) space [25]. The normalized data were smoothed with an isotropic Gaussian kernel (8-mm full width at half maximum) and temporally filtered with a high-pass filter with a cutoff time of 128 s.

2.3. Magnetic resonance data acquisition 2.6. Statistics Magnetic resonance imaging (MRI) studies were performed on a Siemens Magnetom Sonata [Maestro Class] 1.5 T scanner (Siemens AG, Erlangen, Germany). All data were acquired using an 8-channel array head coil for reception and the body coil for transmission. In order to obtain a high-resolution anatomical image of each subject's

2.6.1. fMRI single-level statistics For single-subject analyses, experimental task and control blocks were convolved with the hemodynamic response function (hrf) in order to evaluate individual main effects for the (i) encoding vs. control

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Fig. 1. The verbal memory paradigm: one of two experimental cycles showing examples for encoding, recognition, and control conditions. Examples: “Ananas + Schraube” (“pineapple + screw”), “Montag” and “Mittwoch” (“Monday” and “Wednesday”), and “Melone” (“melon”).

condition and (ii) recognition vs. control condition. To investigate activations within the mesial temporal lobe (mTL), four regions of interest were defined using an anatomic atlas: the right hippocampus and left hippocampus (HC) and right and left extrahippocampal mTL (mTL–HC, consisting of the parahippocampal gyrus and amygdala) regions [26]. The abbreviations HCR and mTLR–HCR stand for the right and HCL and mTLL–HCL for the left ROIs. The masks were applied to the normalized images of each patient. We report activations within these ROIs at a threshold of p b 0.05 (small volume corrected) with an extent threshold of 5 voxels.

intensity of the activation in the analysis. This is based on the method described in the study by Cheung et al. [27] that correlated the amount of total activated voxels in the mTL with the subjects' neuropsychological memory performance. To optimize this quantification method, we decided to also consider the intensity of activation, i.e., the t-values, with the aim of obtaining the spatial dimension weighted by the intensity. It did not seem to be adequate to take only the peak t-value in a region of interest because there could also be a higher peak t-value in a cluster of, for example, 5 voxels, that in itself does not necessarily represent a valid activation.

2.6.2. fMRI group-level statistics In order to test for task-related whole brain activations across patients, second-level analyses were performed. We tested for the main effects of encoding and recognition on the word paradigm using one-sample t-tests. Results are reported at a threshold of p b 0.05 (uncorrected) also with an extent threshold of 5 voxels. A lower threshold or a correction would have led to a lack of activity within the ROIs. As in the single-subject analyses, the same four ROIs were used.

3. Results

2.6.3. Behavioral data and correlation analyses Data were analyzed using SPSS (Statistical Package for Social Sciences) version 21 for Windows. Descriptive statistics were used to analyze sociodemographic and neuropsychological characteristics using minimum, maximum, mean, and standard deviations (SDs) for parametric data. The percentage of correct answers was calculated for the fMRI control task and the recognition task. To test for normal distribution, we used Kolmogorov–Smirnov tests. When data showed non-normal distribution, comparisons between two related groups were performed with the Wilcoxon signed-rank test. Linear correlations between nonparametric data are expressed as Spearman's rank correlation coefficients. To avoid a high number of comparisons, we used a hypothesisdriven approach by testing for nonlinear (i.e., quadratic and cubic) correlations between the percentile ranks of the VLMT and the sum of the t-values of suprathreshold voxels within the ROIs based on our previous study [13]. The significance level was set at p b 0.05.

3.1. Neuropsychological memory performance The patients' neuropsychological data are presented in Table 1. According to their percentile ranks in the VLMT immediate recall condition, they were assigned to three groups: (i) 6 patients showed severe impairments (percentile rank ≤ 5); (ii) 3 patients showed marginal verbal immediate recall scores (percentile rank around 16, i.e., between 10 and 20); and (iii) 6 patients showed normal immediate recall scores (percentile rank N 20). A percentile rank of 16 in the Gaussian normal distribution represents exactly one standard deviation below the mean and is, therefore, the critical threshold for the classification of average or below average. Thus, a result around the percentile rank of 16 indicates a marginal performance. Patients' mean IQ according to the MWT-B was 96.9 ± 11.8 (mean ± SD). The Kolmogorov–Smirnov tests revealed non-normal distributions for the VLMT immediate and delayed recall conditions as well as the DCS immediate recall condition (each p b 0.05) and normal distribution for the VLMT delayed recognition task (p = 0.119). There was a significant correlation between the figural learning in the DCS and the delayed recognition parameter of the VLMT (delayed recognition: r = 0.523, p b 0.050) and a clear trend towards a significant correlation between the DCS and the VLMT immediate recall (r = 0.485, p = 0.067) and delayed recall (r = 0.480, p = 0.070) conditions. 3.2. fMRI behavioral data

2.6.4. Measure of BOLD activation We chose the sum of the t-values of suprathreshold voxels as the activation parameter to integrate not only the extension but also the

Patients' fMRI behavioral data are presented in Table 1. The Kolmogorov–Smirnov tests revealed non-normal distributions for the

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Table 1 Demographic, neuropsychological, and fMRI data of the subjects (N = 15). No.

1 2 3 4 5 6 7 8 9 10 11 12 13a 14a 15a

Age/sex

47/M 49/F 25/F 21/M 46/M 28/F 36/M 57/F 46/M 36/F 30/F 18/F 25/M 35/F 46/F

Neuropsychology

fMRI behavioral data

fMRI encoding activation

VLMT PR

DCS PR

fMRI recognition

fMRI control

Left HC

Left mTL–HC

Right HC

Right mTL–HC

Left HC

fMRI recognition activation Left mTL–HC

Right HC

Right mTL-HC

0 0 0 5 0 0 10 20 20 30 70 85 70 85 70

5 12 5 5 30 14 75 47 70 5 92 85 68 9 35

33.3 47.6 75.0 79.2 54.2 75.0 83.3 60.0 87.5 75.0 83.3 100.0 100.0 91.7 87.5

83.0 72.7 89.6 100.0 85.1 95.8 97.9 65.0 100.0 100.0 87.2 100.0 100.0 97.6 100.0

0.0 0.0 0.0 0.0 203.4 116.6 80.3 0.0 0.0 0.0 69.0 147.6 33.8 125.4 10.0

0.0 0.0 0.0 0.0 169.1 76.3 94.9 0.0 0.0 0.0 131.6 146.7 0.7 4.5 23.5

0.0 0.0 0.0 0.0 156.2 252.7 72.9 33.6 0.0 0.0 91.3 94.4 0.0 37.7 35.3

10.6 0.0 0.0 0.0 299.4 260.4 152.2 39.0 0.0 0.0 126.5 110.5 0.0 4.1 78.1

0.0 31.7 0.0 27.1 0.0 0.0 9.8 86.10 8.0 0.0 0.0 33.8 0.0 15.9 0.0

10.1 31.7 0.0 3.0 13.6 0.0 18.0 29.9 58.0 28.0 0.0 17.2 61.7 90.2 20.0

0.0 0.0 0.0 22.7 0.0 29.6 13.4 0.0 8.0 15.1 0.0 82.9 0.0 22.9 0.0

51.2 0.0 0.0 0.0 0.0 10.6 108.6 0.0 40.0 59.3 0.0 1.9 38.6 16.3 0.0

VLMT: Verbaler Lern- und Merkfähigkeitstest (wordlist learning and memory test); DCS: Diagnostikum für Cerebralschädigung (figure learning and memory test); PR: percentile ranks; SD: standard deviation; fMRI activation: sum of the t-values of suprathreshold voxels; HC: hippocampus; mTL–HC: mesial temporal lobe–hippocampus. a Patients with mild or without clear signs of hippocampal sclerosis.

control condition and the recognition condition (each p b 0.05). Percent correct recognition performance in the fMRI tasks showed 75.5 ± 19.2 correctly recognized word pairs in the word recognition condition (Table 1). In the control condition, the mean percentage of correct responses was 91.6 ± 11.1, demonstrating the good feasibility of the task and compliance of the patients. Performance was significantly better in the control compared to the recognition condition (Z = −3.183, p b 0.01). There was a significant correlation between the fMRI recognition behavioral data and all parameters of the VLMT (immediate recall: r = 0.828, p b 0.001; delayed recall: r = 0.805, p b 0.001; and delayed recognition: r = 0.831, p b 0.001). 3.3. fMRI data The sums of the suprathreshold t-values for each ROI and condition are summarized in Table 1. Activations in the right extrahippocampal mesial temporal regions, i.e., mTL–HC, were stronger than activations within the right hippocampal mask (Z = − 2.073, p b 0.05) for the word-encoding condition. For the other calculations, extrahippocampal mTL activations were similarly strong as HC activations (each p N 0.05).

3.4. Correlation analyses Nonlinear correlation analyses were performed between fMRI recognition data (similar to [13]) and the percentile ranks of the VLMT parameters. Only the cubic correlation analyses produced statistically significant results. Correlations between the behavioral fMRI data and fMRI activations were not calculated, since for this parameter, no ageadjusted normative values are available.

3.4.1. Hippocampal (HC) ROI Significant cubic correlations between fMRI activations and neuropsychological memory scores (VLMT immediate recall: R2 = 0.568, p b 0.05; VLMT delayed recall: R2 = 0.577, p b 0.05; VLMT delayed recognition: R2 = 0.828, p b 0.0001) were only found within the right

3.3.1. Group analyses In the group analysis for the word-encoding condition, we found significant activation within the right HC mask (Fig. 2). The peak activation was observed in the right hippocampus (21, −39, 3). No significant activation was found in extrahippocampal mTL regions. The recognition condition produced no significant activations within both the HC and mTL–HC masks in the group analysis. 3.3.2. Single-subject analyses — comparison of patients with marginal and average memory performance Exemplarily, Fig. 3A shows significant clusters of fMRI activation in two patients with marginal memory performance during the recognition condition of the word paradigm. In the two illustrated patients with normal memory performance (Fig. 3B), activity within the ROI is less present. The coordinates of the activated clusters are different for all patients, pointing to a great variability in the anatomical distribution of activity within the ROI which results in the absence of significant clusters in the group analysis. 3.3.3. Lateralization Statistical comparisons between activations in the left and right ROIs (i.e., HC and mTL–HC) revealed no significant differences (each p N 0.05), indicating no lateralization of BOLD signal.

Fig. 2. Significant clusters of fMRI activation in the group analysis (N = 15) in the wordencoding condition within the hippocampus mask (p b 0.05, uncorrected; HC = hippocampus). Colored voxels exceeded the statistical threshold and are superimposed on the corresponding anatomical image. The left side of each image corresponds to the left side of the brain. (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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Fig. 3. Significant clusters of fMRI activation on the single-subject level. (A) Patients with marginal memory performance during the recognition condition (p b 0.05, small volume corrected) and (B) patients with normal memory performance during the recognition condition (p b 0.05, small volume corrected). HC = hippocampus, left and right; mTL = mesial temporal lobe, left and right. The slice of the brain corresponds to the peak voxel within the ROI (presupposed significant activation). Colored voxels exceeded the statistical threshold and are superimposed on corresponding normalized anatomical images. The left side of each image corresponds to the left side of the brain. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

hippocampal ROI (Table 2, Fig. 4A). Activations in the left hippocampal region were not correlated with verbal memory performance (each p N 0.05).

3.4.2. Extrahippocampal mesial temporal lobe regions (mTL–HC) Activations in the left extrahippocampal mTL region (mTLL–HCL), including the left amygdala and left parahippocampal gyrus, were

M. Milian et al. / Epilepsy & Behavior 42 (2015) 78–85 Table 2 Cubic correlations between fMRI word recognition activation and VLMT immediate recall, delayed recall, and delayed recognition conditions (N = 15). Recognition paradigm

HC mTL–HC

HCR HCL mTLR–HCR mTLL–HCL

VLMT (percentile ranks) Immediate recall

Delayed recall

Delayed recognition

R2

p

R2

p

R2

p

0.568 0.279 0.205 0.441

0.022 0.289 0.452 0.084

0.577 0.111 0.206 0.476

0.020 0.718 0.450 0.060

0.828 0.113 0.057 0.541

b0.001 0.710 0.880 0.030

VLMT: Verbaler Lern- und Merkfähigkeitstest (wordlist learning and memory test); mTL: mesial temporal lobe; HC: hippocampus; R: right; L: left. p b 0.05, statistical significance. Significant results are in bold, while those marginally failed the significance level are in italics.

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significantly related to the percentile ranks of the VLMT delayed recognition condition (R2 = 0.541, p b 0.05), explaining a variance of 54.1%. Similarly, there was a clear trend towards a significant cubic correlation between the fMRI activation in the left extrahippocampal mTL region and the VLMT immediate recall (R2 = 0.441, p = 0.084) (Fig. 4B) and delayed recall (R2 = 0.476, p = 0.060) conditions (Table 2). Activations in the right extrahippocampal mTL region were not correlated with verbal memory performance (each p N 0.05). 4. Discussion The aim of the present work was to evaluate the nature of nonlinear correlations between memory performance levels and BOLD activity in a group of patients suffering from chronic left mTLE, a group that is well known to have memory problems and need reliable prediction tools for postoperative outcome. 4.1. Activation pattern and lateralization of activity The encoding condition produced stronger activations within mesial temporal lobe regions compared to the recognition condition, indicating that less effort was required to recognize information [28,29]. In the group analysis, the encoding condition produced significant right hippocampal activation. We assume that the absence of activated clusters in the group analysis during recognition was due to a large variability in the anatomical distribution of activity between patients within the mesial temporal lobe. Overall, activations appeared bilaterally within the ROIs, without the strong left lateralizations that have been observed in healthy controls. 4.2. Inefficient compensatory mTL activation may explain higher activations in subjects with marginal memory performance As hypothesized, nonlinear correlation models explained the relation between patients' verbal neuropsychological performance and activations in the fMRI word recognition task, with one peak in patients with marginal memory performance and another peak in very good performing patients. Schwarze et al. [30] already demonstrated in patients with right TLE that impaired memory performance showed increased functional activity compared to healthy controls. The authors interpreted this hyperactivation of the hippocampus as a compensatory but inefficient process. Also in patients with mild cognitive impairment, the preliminary phase of Alzheimer's disease, a mesial temporal hyperactivation was found, while in patients with Alzheimer's disease, a hypoactivation is present [14–16,31–33]. 4.3. Strong preoperative activation — great postoperative decline?

Fig. 4. Scatterplots demonstrating the correlations between the behavioral data scores and activations in the ROIs in the 15 patients with left mTLE: (A) word paradigm recognition HCR; (B) word paradigm recognition mTLL–HCL. No linear correlations were observable between the neuropsychological data and the sum of the t-values of suprathreshold voxels. The solid lines show the cubic fits, and the R2 values illustrate the explained variance of the fits. The black dots represent the impaired group, the gray dots the patients with marginal memory performance, and the white dots the patients with normal memory performance.

The nonlinear relationship highlights that a strong activation does not necessarily go hand in hand with good memory performance. The assumption ‘the greater the mTL activation, the greater the memory decline after ATLR’ seems to apply only to a group of patients, i.e., patients with normal or very poor memory performance in the presurgical neuropsychological evaluation. In patients with marginal memory performance, the inefficient compensatory activity might lead to wrong conclusions. Since there is this gap in quantification of memory, fMRI is suitable for indicating the asymmetry of mTL activation rather than quantification. Asymmetry of memory functions was already shown to be more valid than absolute activity for the prediction of postoperative memory outcome [3,6,7,34,35]. 4.4. Incipient preoperative reorganization of episodic memory in patients with mTLE All parameters of the verbal learning memory test correlated significantly with the BOLD activity within the contralateral hippocampus

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during the recognition condition. On the other hand, when regarding the ipsilateral side, activities within the extrahippocampal mTL regions were related to memory performance. The found correlations with the contralateral hippocampus as well as the ipsilateral extrahippocampal mTL regions in this study indicate an already incipient preoperative reorganization process of memory functions in non-amnesic patients even before epilepsy surgery is performed. Similar to our observation, Richardson et al. [36] assume that the contralateral activation in nonamnesic patients with left hippocampal sclerosis represents adaptive functional reorganization of retained verbal memory function in the presence of left mTL pathology. This aspect is also supported by our finding that verbal memory was correlated with nonverbal memory. As nonverbal memory is usually processed by the nondominant, i.e., the contralateral hemisphere, good nonverbal memory functions point to the functionality of the contralateral hippocampus. As a consequence, the better verbal memory performance points to the capability of the nonaffected hippocampus to also maintain parts of verbal memory. Moreover, the integrity of the ipsilateral extrahippocampal mTL regions in this study is in accordance with the results of previous research, suggesting that patients with unilateral HS use adjacent mTL regions (e.g., parahippocampal gyrus) rather than the affected hippocampus to maintain memory functions [37,38]. In general, it is believed that patients with left HS show more widespread areas of activation than controls in terms of functional reorganization [39]. Based on our results, we propose to consider activations within the subregions of the mTL separately, especially the contralateral HC and the ipsilateral extrahippocampal mTL structures, to account for differential activation patterns in these regions during preoperative memory reorganization. 4.5. Methodological aspects and limitations This study's sample size was relatively small, but the cohort was homogeneous concerning the pathology, i.e., patients with chronic left mTLE with clear mesiotemporal spikes and no extrahippocampal pathology. Moreover, all possible memory performance levels were represented, although the number of patients with impaired and normal memory performance was overrepresented compared to those with marginal memory. 5. Conclusions Similar to the healthy subjects, patients with marginal memory performance demonstrated a stronger activity than patients with average memory scores, which we interpret as the effort of the patient to compensate during ongoing memory deterioration. Thus, when considering a whole continuum of all possible memory performances, the distribution of the BOLD activity along the continuum can be described by a cubic relationship. Further, we were able to demonstrate that in non-amnesic patients with chronic left mTLE but no extrahippocampal lesions, verbal memory shifts already preoperatively to ipsilateral extrahippocampal mTL structures as well as the contralateral HC. Thus, when interpreting memory fMRI in the preoperative assessment, it is indispensable to take into account firstly the neuropsychological performance and secondly activations in the contralateral HC and ipsilateral extrahippocampal mTL regions. Funding This work was supported by funding from the AKF Program of the University of Tuebingen with the project number 275-0-0. Conflict of interest statement None of the authors has any conflict of interest to disclose.

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