Functional imaging of semantic memory predicts postoperative episodic memory functions in chronic temporal lobe epilepsy

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a v a i l a b l e a t w w w. s c i e n c e d i r e c t . c o m

w w w. e l s e v i e r. c o m / l o c a t e / b r a i n r e s

Research Report

Functional imaging of semantic memory predicts postoperative episodic memory functions in chronic temporal lobe epilepsy Bülent Köylü a , Gerald Walser a , Anja Ischebeck a , Martin Ortler b , Thomas Benke a,⁎ a b

Clinic of Neurology, Medical University Innsbruck, Austria Clinic of Neurosurgery, Medical University Innsbruck, Austria

A R T I C LE I N FO

AB S T R A C T

Article history:

Medial temporal (MTL) structures have crucial functions in episodic (EM), but also in

Accepted 28 May 2008

semantic memory (SM) processing. Preoperative functional magnetic resonance imaging

Available online 7 June 2008

(fMRI) activity within the MTL is increasingly used to predict post-surgical memory capacities. Based on the hypothesis that EM and SM memory functions are both hosted by

Keywords:

the MTL the present study wanted to explore the relationship between SM related

Episodic memory

activations in the MTL as assessed before and the capacity of EM functions after surgery.

Semantic memory

Patients with chronic unilateral left (n = 14) and right (n = 12) temporal lobe epilepsy (TLE)

Parallel distributed processing

performed a standard word list learning test pre- and postoperatively, and a fMRI procedure

Medial temporal lobe

before the operation using a semantic decision task. SM processing caused significant

Temporal lobe epilepsy

bilateral MTL activations in both patient groups. While right TLE patients showed

fMRI

asymmetry of fMRI activation with more activation in the left MTL, left TLE patients had almost equal activation in both MTL regions. Contrasting left TLE versus right TLE patients revealed greater activity within the right MTL, whereas no significant difference was observed for the reverse contrast. Greater effect size in the MTL region ipsilateral to the seizure focus was significantly and positively correlated with preoperative EM abilities. Greater effect size in the contralateral MTL was correlated with better postoperative verbal EM, especially in left TLE patients. These results suggest that functional imaging of SM tasks may be useful to predict postoperative verbal memory in TLE. They also advocate a common neuroanatomical basis for SM and EM processes in the MTL. © 2008 Elsevier B.V. All rights reserved.

1.

Introduction

Episodic memory (EM) has been defined as the ability to consciously store and recollect episodes of prior encounter (Baddeley, 2001). Contrastively, semantic memory (SM) comprises stored knowledge about concepts, facts and attributes which are acquired from, but no longer defined by particular episodes (Tulving, 1972). Classic theories of memory function

such as, e.g., the levels of processing approach (Craik and Lockhart., 1972) postulate that EM and SM are separate, independently working functional systems (Moscovitch et al., 2005). This model also assumes that both memory systems are organized in discrete units in the brain, with EM having an important representation in the medial temporal lobe (MTL) (Squire et al., 2004), whereas SM is located predominantly in anterior, lateral and ventral temporal, as well as other neo-

⁎ Corresponding author. E-mail address: [email protected] (T. Benke). 0006-8993/$ – see front matter © 2008 Elsevier B.V. All rights reserved. doi:10.1016/j.brainres.2008.05.075

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cortical regions (Martin and Chao, 2001). An alternative hypothesis suggests that knowledge is processed in a parallel fashion and is distributed among several, interconnected neural structures (PDP, parallel distributed processing) (McClelland and Rogers, 2003). According to this concept, the MTL, neocortical regions and their rich reciprocal connections are viewed together as global processing sites for both, EM and SM. In line with this view, several recent studies using functional imaging have demonstrated that the MTL is not solely involved in EM processing, but also in verbal fluency, semantic decision making, or face and object recognition which all depend on the SM system (Binder et al., 1997; Pihlajamaki et al., 2000) as well as in other cognitive functions (Grunwald et al., 1998; Meyer et al., 2005). These findings suggest that the hippocampal system not only participates in EM, but also in SM processing. Chronic, medically intractable temporal lobe epilepsy (TLE) provides a good opportunity to study the processing mode, capacity and plasticity of temporal lobe memory systems. Impairments of verbal and nonverbal EM are a hallmark of the TLE syndrome (Hermann et al., 1997). Similarly, deficits of SM functions have also been found in TLE, including word fluency (N'Kaoua et al., 2001), object decision (Vannucci et al., 2003), processing of famous names and faces (Douville et al., 2005; Trautner et al., 2004), emotion recognition (Meletti et al., 2003), naming (Giovagnoli, 1999; Sawrie et al., 2000) or semantic decision making (Binder et al., 1997). Due to the chronicity of TLE and its frequent early onset, anatomical reorganization of memory related structures is often observed. A well known model of plasticity proposes that reorganization of memory may occur due to functional reserve, the ability of the nonepileptic, contralateral MTL to adopt and provide spare memory capacities (Chelune, 1995; Powell et al., 2007). Alternatively, functional adequacy, the memory capability of undamaged ipsilesional temporal lobe structures may substitute primary memory areas. Epilepsy surgery poses an effective treatment option for many patients suffering from pharmacologically intractable TLE. However, postoperative loss of memory functions is a significant side effect of temporal lobe surgery in a subgroup of patients. Thus, the identification of reliable prognostic factors is of great importance. In epilepsy surgery, significant correlations have been detected between postoperative memory loss, side of seizure origin, lesion type, age at onset and duration of epilepsy (Gleissner et al., 2002). Importantly, postoperative memory

impairment is more disabling when the dominant hippocampal formation is removed and no plasticity has been developed (Helmstaedter et al., 1994; Hertz-Pannier et al., 2002). Intracarotid amobarbital procedure (IAP) test results are often used to assess memory lateralization and to predict postoperative memory, however with variable efficiency (Lineweaver et al., 2006; Simkins-Bullock, 2000). More recently, functional magnetic resonance imaging (fMRI) has been proposed as a prognostic opportunity for the postoperative EM status (Dupont et al., 2000). Basically, activations in both MTL regions are compared to estimate the amount of functionality on the nonepileptic and epileptic side (Binder et al., 2005; Golby et al., 2002; Janszky et al., 2004; Jokeit et al., 2001). To evoke MTL activations, most studies used EM functions such as encoding of new words, scenes or patterns which are then employed to predict postoperative memory (Binder et al., 2005; Branco et al., 2006; Golby et al., 2002; Powell et al., 2007; Richardson et al., 2006). However, the MTL can also be activated by SM tasks (Binder et al., 1997), and MTL activations from SM tasks are highly prevalent in normals (Bartha et al., 2003) and patients (Bartha et al., 2005). Furthermore in a previous study by Bellgowan et al. (1998) a semantic decision task was used to activate MTL regions and determine memory lateralization. SM and EM functions are thus both served by a distributed neural network which includes the whole MTL, rather than by discrete areas with rigorous functional and anatomical segregation, an assumption well in line with other studies which have demonstrated the close interaction between both declarative memory systems (Menon et al., 2002; Dalla et al., 1998; Manns et al., 2003b; Squire et al., 2004; Tulving and Markowitsch, 1998). Accordingly, one may assume that the MTL accomplishes different types of memory — presumably in distinct but connected sections, such as the hippocampus proper functionally linked to EM, and the parahippocampal region and adjacent cortical areas dealing with SM functions (Davies et al., 2004; Hoenig et al., 2005; Tieleman et al., 2005; Venneri et al., 2008). The present study was undertaken to explore the relationship between MTL activation and postoperative EM. Different from previous studies using EM paradigms, we were interested to see whether activations in the MTL evoked by a semantic language task are associated with verbal EM functions. Since side of seizure focus is an important variable in postoperative memory, we furthermore wanted to explore how SM is lateralized in the MTL in patients with different

Table 1 – Verbal learning and memory performance of patient groups Left TLE

MGT — variable Sum of trials (1–5) Short delay free recall Long delay free recall Recognition memory score (corrected)

Right TLE

Preoperative

Postoperative

p-value

47.5 (13.9) 8.4 (4.2) 8.6 (4.4) 14.4 (1.9)

35.5 (11.4) 5.0 (2.7) 5.3 (3.3) 13.6 (1.8)

0.005 0.015 0.011 n.s.

Preoperative 54.7 10.8 11.8 15.3

(9.2) (3.0) (2.9) (1.1)

Postoperative

p-value

59.0 (10.1) 11.0 (3.9) 11.6 (4.0) 15.2 (1.2)

n.s. n.s. n.s n.s.

Pre- and postoperative verbal learning and memory scores for left TLE and right TLE patients. Values (means, SD in parentheses) represent number of correctly recalled words as measured with the MGT. Effect of surgery was tested on the collected four neuropsychological measures using paired t-tests; p-values are presented for each comparison (significance level at p b 0.05, n.s. indicating no significant change).

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Table 2 – MNI coordinates of MTL activations for intra- and inter-group analysis Contrast

Left hemisphere

Right hemisphere

Cluster size

t-max.

x

y

z

Cluster size

t-max.

x

y

z

90 158

11.61 14.00

−28 −34

− 32 − 26

−4 −16

111 10

8.13 7.75

34 42

−28 −18

−8 − 16

11

3.81

32

−12

− 16

Intra-group analysis Left TLE Right TLE Inter-group analysis Left TLE N right TLE Right TLE N left TLE

n.s.

Values represent number of significantly activated voxel, maximum t-values, and coordinates in MNI-space for intra- and inter-group analysis for the contrast semantic decision vs. tone decision for left TLE and right TLE, respectively (second level one-sample t-test; p b 0.0001; two-sample t-test, p b 0.005; extent of cluster size (k) N 10).

seizure onset, and also if SM-derived activity in the MTL is related to EM. In other words, would left and right TLE patients show group specific activation patterns in the MTL, and would these patterns correspond to the functional reserve or the functional adequacy model?

2.

Results

2.1.

Seizure outcome

Eighteen (69.3%) patients were classified as seizure free (Engel Class I), and six patients (23.0%) had rare and non-disabling seizures (Class II). Two patients (7.6%) were categorised in Class III with a reduction of seizure frequency N75%. Histological examination of resected specimens revealed ammonshornsclerosis as the most common histopathological finding (73.0%), followed by cavernoma (2), ischemia (1), dysplasia (1),

Table 3 – Relation between memory performance measures and effect size within ROI Left TLE

MGT sum of trials (1–5) preoperative Short delay free recall, preoperative Long delay free recall, preoperative Recognition memory score, preoperative (corr.) Sum of trials (1–5), postoperative Short delay free recall, postoperative Long delay free recall, postoperative Recognition memory score, postoperative (corr.)

and a grade I oligodendroglioma (1).

2.2. Pre- and postoperative verbal memory performance (Table 1) The MANOVA with the four memory variables as dependent variables, test repetition as within-subject factor, and side of surgery as between-subject factor yielded a significant overall group effect for side of surgery (F = 3.76, p = 0.019), while no significant effects were seen for time of testing and the interaction between the two factors. Separate univariate repeated measures ANOVAs demonstrated a significant worsening in sum of learning trials (F = 11.8, p = 0.002), short delay free recall (F = 6.1, p = 0.02) and long delay free recall (F = 5.0, p = 0.033) only for patients with left-sided resections. Post hoc univariate F-test revealed, that before surgery, groups differed only in long delay free recall (F = 4.5, p = 0.43), while postoperative left TLE patients scored lower in all assessed memory scores (sum of learning trials: F = 30.18, p b 0.001; short delay free recall: F = 21.02; p b 0.001; long delay free recall: F = 19.06, p b 0.001; recognition memory score: F = 6.51, p = 0.017) (Table 1).

Right TLE

Left ROI

Right ROI

Left ROI

Right ROI

0.707 (0.005) 0.490 (0.075) 0.607 (0.021) 0.623 (0.017) 0.392 (0.166) 0.200 (0.494) 0.316 (0.271) 0.497 (0.071)

0.616 (0.019) 0.330 (0.249) 0.501 (0.068) 0.466 (0.093) 0.638 (0.014) 0.623 (0.017) 0.621 (0.018) 0.485 (0.079)

0.431 (0.162) 0.536 (0.072) 0.492 (0.104) 0.381 (0.222) 0.581 (0.048) 0.368 (0.240) 0.418 (0.277) 0.251 (0.431)

0.516 (0.086) 0.553 (0.062) 0.633 (0.027) 0.382 (0.221) 0.663 (0.019) 0.472 (0.122) 0.557 (0.060) 0.434 (0.159)

Values represent Pearson correlation coefficients between pre- and postoperative memory performance and effect size within ROI (corresponding p-values in parentheses; significances marked bold).

Fig. 1 – Correlation between preoperative effect size within right ROI during the SM task and verbal memory outcome in long delay free recall as measured by MGT for left TLE patients.

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Fig. 2 – Correlation between preoperative effect size within right ROI during the SM task and performance in preoperative long delay free recall as measured by MGT for right TLE patients.

2.3.

ROIs for both patient groups. Also, no statistically significant relationship was observed between results of the IAP and the pre- and postoperative verbal memory performances. There were no between-group differences regarding the effect size within the left and right ROI and the resulting ratio (ratio left vs. right ROI in left TLE 1.19 +/− 1.43, in right TLE 1.11 +/− 1.29, two-sample t-test, p N 0.05). Correlational results for activation in the MTL and memory scores are summarized in Table 3. In the left TLE group greater effect size for SM contrast in the left MTL correlated with better preoperative performance in sum of learning trials, long delay free recall and recognition memory. Greater effect size in the right MTL was associated with higher scores in pre- and postoperative sum of learning trials and postoperative short and long delay free recall. For right TLE patients there was a significant positive correlation between the effect size within the right MTL and preoperative long delay free recall as well as postoperative sum of learning trials. A trend for greater effect size in the right MTL to correlate with better postoperative long delay free recall was also observed. Greater effect size in the left MTL predicted performance in postoperative sum of learning trials. Examples for correlation plots are given in Figs. 1 and 2.

fMRI activations in the MTL 2.5.

The ROI analysis revealed significant bilateral activation peaks in the MTL for the contrast semantic decision vs. tone decision in both patient groups. While MTL activations of left TLE patient group were almost symmetric (left ROI score 0.129 +/− 0.156, right ROI score 0.141 +/− 0.117), activations of right TLE patient group showed an asymmetry with strong left predominance (left ROI score 0.125 +/− 0.181, right ROI score 0.034 +/− 0.18). A direct comparison of left TLE versus right TLE patients revealed greater activity within the right ROI, whereas no significant differences were observed for the reverse contrast (Table 2).

Case reports

Examples for two left TLE patients displaying unchanged (patient 3) and worsened (patient 9) postoperative memory and different SM activation patterns in the MTL are given in Figs. 3 and 4. Activity during SM processing for patient 3 was exclusively located within right ROI and no postoperative memory change after left-sided selective amygdalohippocampectomy was observed (Engel Class I, hippocampal sclerosis). In contrast, patient 9 whose SM processing was exclusively located in the left MTL experienced a decline in all tests of verbal learning and memory after selective amygdalohippocampectomy (Engel Class II, dysplasia).

2.4. Correlations: clinical data, fMRI activity and episodic memory

3. A trend for an inverse correlation between epilepsy duration and effect size within the left MTL was detected (r = −0.55, p = 0.059) for right TLE patients, while no significant associations were found between education, IQ, confrontation naming, age at epilepsy onset and the resulting effect size within

Discussion

This study analyzed MTL activations evoked during semantic decision making in a group of chronic TLE patients and correlated SM related activations with EM performance. Side of seizure origin was determined according to standard

Fig. 3 – Coronar sections showing preoperative activations within right medial temporal region in a left TLE subject (patient 3) for the contrast semantic decision vs. tone decision (puncorr = 0.0001; extent of cluster size (k) N 10).

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Fig. 4 – Coronar sections showing preoperative activations within left medial temporal region in a left TLE subject (patient 9) for the contrast semantic decision vs. tone decision (puncorr = 0.0001; extent of cluster size (k) N 10).

procedures and confirmed by postoperative outcome. The core findings can be summarized as follows. First, depending on the side of seizure focus, fMRI evoked differential, group dependent activations in the MTL. Thus, SM processing in left TLE patients was associated with bilateral, almost symmetric MTL activations. In contrast, SM related activations in the right TLE group showed an asymmetric pattern with a prevalence of activations in the left MTL. Second, a significant relationship was observed between the effect size of the SM contrast in the MTL and the individual patient's performance on a test of word list learning. In general, we found that greater effect size of MTL ipsilateral to the seizure focus is correlated with better preoperative free recall of the word list in both groups; in left TLE patients greater ipsilateral effect size was also correlated with preoperative learning and recognition abilities. In addition, greater effect size in the right MTL of left TLE patients was predictive for better postoperative verbal learning and spontaneous verbal recall abilities, whereas for right TLE patients greater effect size within the left MTL is correlated with higher postoperative verbal learning performance. Finally, language IAP measures were not significantly related to pre- and postoperative verbal memory. This result is unexpected from a traditional standpoint, since EM and SM have been considered as interacting, but functionally and neurally separate memory systems (Tulving, 1972); accordingly, a semantic decision task would not allow predictions about episodic verbal memory. Given the nature of the chosen SM task which requires meaning based elaboration on verbal material the current findings could also be interpreted within the framework of the depth of processing effect (Craik and Lockhart, 1972), as well as incidential encoding (Kapur et al., 1994; Demb et al., 1995; Gabrieli et al., 1996). Retrieval of words learned during incidential encoding produces activity in left frontal (Rotte et al., 1998; Alkire et al., 1998; Brewer et al., 1998), and also in MTL regions (Buckner and Koutstaal, 1998; Buckner et al., 1999; Holdstock et al., 2002). Consistent with this hypothesis, it seems likely that incidential encoding has contributed to the observed MTL activation, and consequently also to the correlation between MTL activation and episodic memory measures. In fact, further investigations and a different setup would be required to separate MTL activations from those related to SM vs. EM. However, at large the present data strongly suggest that the processing of object attributes such as in our study is

functionally related to MTL activation, and further, to EM outcome in epilepsy surgery. However, this relationship was significant in two different patient groups with lesions in either temporal region, and in subjects with different fMRI activation patterns. Depending on the side of seizure onset (left, right) and the time point of memory assessment (before, after surgery) there was variation in the observed relationship between SM and EM functions. Generally speaking, preoperative verbal memory functions were associated with ipsilateral effect size, whereas memory after removal of the epileptogenic MTL was predicted by the amount of preoperative activation in the contralateral MTL. This pattern is more obvious in left TLE subjects, whereas in right TLE patients activity in both MTL regions seems equally related to postoperative memory outcome. Of note, SM evoked activation is not correlated with a single, but with several memory modalities, including learning, spontaneous recall and recognition, possibly due to a high intercorrelation of EM functions. The clinical consequence of this finding is that SM related activations in the MTL can be used to predict postoperative episodic memory outcome in TLE, especially in the left TLE group which is at higher risk for postoperative memory loss. Although these conclusions of course need further confirmation from future studies including larger patient samples, they rest on the finding of a significant association between SMderived activations in the MTL and episodic verbal memory functions. In terms of plasticity and memory reorganization our findings favour the reserve over the adequacy model (Chelune, 1995), particularly in the left TLE group. According to these observations, the reorganization of memory functions in the contralateral MTL region appears as the most important factor for postoperative memory performance. Of note, these claims are at variance with studies using EM-fMRI to predict postoperative memory outcome stating that reorganization in the damaged MTL is more efficient than to the contralateral MTL (Powell et al., 2007). However, one might also argue that SM related activation represents a different approach to the memory system and represents different equivalents of EM plasticity. These data also confirm that MTL structures are involved in SM functions, a finding for which a growing body of evidence exists from both, functional and lesion studies (Davies et al., 2004; Elfgren et al., 2006; Giovagnoli et al., 2005; Manns et al., 2003a; Pihlajamaki et al., 2000). Finally, the

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present findings support the model of distributed processing of neural representations. SM and EM functions are thus both served by a distributed neural network which includes the MTL among other regions, rather than by discrete areas with rigorous functional and anatomical segregation, an assumption well in line with other studies which have demonstrated the close interaction between both declarative memory systems (Menon et al., 2002; Dalla et al., 1998; Manns et al., 2003b; Squire et al., 2004; Tulving and Markowitsch, 1998). Accordingly, one may assume that the MTL accomplishes different types of memory — presumably in distinct but connected sections, such as the hippocampus proper functionally linked to EM, and the parahippocampal region and adjacent cortical areas dealing with SM functions (Davies et al., 2004; Hoenig et al., 2005; Tieleman et al., 2005; Venneri et al., 2008).

4.

Experimental procedures

4.1.

Patients

Twenty six consecutively admitted patients suffering from left or right temporal lobe epilepsy (left TLE, n = 14; right TLE, n = 12) were included in this study. Inclusion criteria were the diagnosis of a medically intractable, chronic, unilateral TLE with epileptogenic focus in the mesial or neocortical temporal region and left hemisphere speech dominance as revealed by the IAP. All but one left TLE patients had seizure foci in the mesial temporal region. Several patients had participated in previous studies of TLE and fMRI (Benke et al., 2006; Koylu et al., 2006) and were re-evaluated according to the aspects of this study. Subjects underwent selective amygdalo-hippocampectomy (12 left TLE; 9 right TLE), standard 2/3 temporal

Table 4 – Clinical and demographical data

Age (years) Age at epilepsy onset (years) Duration of epilepsy (years) Education (years) Handedness IQ Ratio mesial vs. extramesial seizure focus LQ-IAP Left IAP score Right IAP score Retest interval (months after operation) Type of surgical intervention Selective amygdalohippocampectomy Standard 2/3 temporal lobe resection Modified standard resection

Left TLE (n = 14)

Right TLE (n = 12)

43.2 (12.6) 16.1 (14.6) 25.1 (17.5) 9.9 (1.4) 99.2 (2.6) 97.2 (11.4) 13/1

36.0 (13.6) 17.5 (11.5) 19.1 (11.0) 11.1 (2.6) 97.5 (6.2) 103.4 (13.7) 12/0

0.77 (0.2) 14.7 (6.29) 0.67 (2.87) 5.92 (4.0)

0.92 (0.1) 18.9 (1.32) 0.16 (1.72) 6.58 (6.41)

12

9

1

3

1

–

Patient data (means, SD in parentheses). LQ-IAP = laterality quotient of intracarotid amobarbital procedure, left/right IAP score: IAP language score.

lobe resection (1 left TLE; 3 right TLE) and modified standard resection (1 left TLE) (see Table 4). Pre-surgical evaluation comprised detailed neurological examination, video EEG, high-resolution MRI and neuropsychological examination. No statistically significant differences were found between the left TLE and right TLE patients with regard to Edinburgh handedness laterality quotient (Mann–Whitney–U Test, p = 0.431), LQ-IAP-scores (Mann–Whitney–U Test, p = 0.076), age (t-test, p = 0.419), years of formal education (t-test, p = 0.141), age at epilepsy onset (t-test, p = 0.798), duration of epilepsy (t-test, p = 0.319), confrontation naming (t-test, p = 0.932), IQ (t-test, p = 0.227), or postoperative retest interval (t-test, p = 0.754). Patients were followed up 3–12 months after operation to evaluate seizure outcome and memory functions.

4.2.

Language lateralization and verbal memory

A slightly modified IAP version of Loring et al. (1994) was used to determine language dominance (Benke et al., 2006). A laterality quotient [LQ-IAP = (L − R) / (L + R) × (language score of side with superior performance) / 20] was calculated, with L and R defined as total language performance score after injection in the contralateral hemisphere, respectively. All patients scored N0.4 indicating left hemisphere language lateralization. Psychometric Testing and fMRI were part of the routine pre-surgical evaluation. Episodic verbal memory was assessed with the Münchner Gedächtnistest (MGT), a German version of the California Verbal Learning Test (Delis et al., 1988). Sum of learning trials, short delay free recall, long delay free recall and recognition memory scores of a 16 word list were examined before and, using a parallel test version, after surgery. Multivariate analyses of variance (MANOVA) with repeated measures and subsequent univariate analyses of variance (ANOVAs) were performed to test the effect of the surgical intervention on neuropsychological measures. For each of these measures, bivariate Pearson correlation coefficients for verbal memory scores and effect size within left/right ROI were calculated. Adjustment for multiple testing is especially relevant, if the study is interpreted with respect to the universal null hypothesis. However, the present study focused on a priori hypotheses regarding the functional association between left/right ROI (comprising hippocampus proper and parahippocampal gyrus) and separate measures of verbal learning and memory. In order to evaluate individual associations between the study variables, which is of vital importance in clinical practice, and the explorative nature of the current study design the use of a lenient threshold at p b 0.05 was chosen (Rothman, 1990; Perneger, 1998).

4.3.

Semantic decision task

An adapted version of the Binder et al. (1997) semantic decision paradigm was used which had been previously been employed in TLE (Benke et al., 2006; Koylu et al., 2006). The fMRI procedure was approved by the local ethic's committee. Stimuli in the activation condition were spoken German nouns with a duration of 750 ms designating common objects (e.g. spaghetti, violin, soap, sofa). Each stimulus was followed by an interstimulus interval (ISI) of 2250 ms. Subjects responded per button press ‘yes’ for objects they considered to be both

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available in a supermarket and to cost less than a certain amount of money (7 Euro); otherwise they had to press ‘no’. Both, the availability of items and their cost judgement are part of the general knowledge and estimation system which is strongly based on semantic object knowledge. A tone decision task was used as reference condition using digitally synthesized tones (500 and 750 Hz, duration 150 ms) which were presented in sequences of four to six tones. Again an ISI of 2250 ms was used. Subjects decided whether a sequence contained two 750 Hz (‘high’) tones and had to respond by button press ‘yes’ or ‘no’. This reference had been chosen to control to some degree for low-level processes not related to language such as activation due to auditory processing and motor preparation/execution. There was an equal number of ‘yes’ and ‘no’ answers for both types of stimuli in the experimental and the control condition. Stimuli were presented binaurally via non-magnetic, pneumatic headphones precisely during the silent intervals between scanner noise and periods using a computer playback system. Eight blocks of each paradigm were presented, with tone and semantic decision tasks alternating. During each block six nouns or tone sequences were presented, resulting in an overall number of 48 stimuli per condition. Patients received instructions and brief practice sessions before entering the scanner, and five practice items of each condition in the scanner. Response accuracy was recorded via button press.

4.4.

Image acquisition and analysis of fMRI data

MRI scanning was performed on a Siemens Vision (Erlangen, Germany) 1.5-T scanner with a circular polarized head coil (diameter ~25 cm). Functional images were collected by using a single-shot echoplanar imaging (EPI) sequence with echo-time TE 64 ms, repetition time TR 6000 ms and a flip angle of 90°. During fMRI session, 28 slices (slice thickness 3 mm; interslice gap, 0.75 mm; matrix 128 × 64; voxel size 3.4 × 1.7 × 3.0 mm) were scanned parallel to the intercommissural line. Anatomical images were acquired as a set of 134 contiguous sagittal slices by using T1-weighted 3D-MPRAGE sequences with the following parameters: TR 9.7 ms, TE 4 ms, TI 1000 ms, slice thickness of 1.23 mm, matrix size 256 × 256, FoV 230 mm; pixel size 0.9 × 0.9 × 1.23 mm. Data were processed using statistical parametric mapping (SPM99, Wellcome Department of Cognitive Neurology, London, UK). After discarding the first 3 functional sans to ensure signal stabilization, the scans of each individual were realigned to the first scan, coregistered to the anatomical image, and spatially normalized into approximate Talairach and Tournoux space (Talairach and Tournoux, 1997). For further analysis, images were smoothed with an isotropic Gaussian kernel of 6 × 6 × 12 FWHM in x, y, and z axes to increase signal to noise ratio. Statistical parametric maps (SPMs) were generated according to general linear model. A time shifted box-car design reference function was used to determine activation related to the difference between the alternating baseline and activation blocks. A fixed effects model was calculated for every subject. Contrast images of all subjects were then entered into a second level (random effects) analysis. For the between-task comparison (semantic decision N tone decision) the resultant statistical parameter map

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was thresholded at puncorr b 0.0001. For inter-group comparisons a threshold of puncorr b 0.005 was chosen, and only activations within the MTL involving cluster of more than 10 contiguous voxels were interpreted. Additionally, a region of interest (ROI) analysis was employed to further quantify the effect size within the medial temporal region for the chosen contrast (Brett et al., 2002). Anatomical ROIs from the AAL software package using combined templates of hippocampus proper and parahippocampal gyrus were chosen to estimate the activity in the left and right MTL (Tzourio-Mazoyer et al., 2002). ROI analyses were performed with the MarsBar toolbox in SPM99 (Wellcome Department of Cognitive Neurology, London, U.K.). The statistical model described above was reapplied to the average signal within the two ROIs using unsmoothed images to avoid signal distortions within the MTL. The effect size for left and right ROIs describing average signal within this region for the contrast semantic decision vs. tone decision for each patient as well as the resulting ratio score (left ROI/right ROI) was subjected to further statistical analysis in SPSS (SPSS Inc., Chicago, IL, USA).

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