Epilepsy & Behavior 35 (2014) 28–33
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Epilepsy & Behavior journal homepage: www.elsevier.com/locate/yebeh
Object location performance: Detection of functional impairment in right temporal lobe epilepsy Christian Frisch ⁎, Christoph Helmstaedter University of Bonn Medical Center, Department of Epileptology, Sigmund Freud-Straße 25, 53105 Bonn, Germany
a r t i c l e
i n f o
Article history: Received 14 January 2014 Revised 25 March 2014 Accepted 27 March 2014 Available online xxxx Keywords: Object location Lateralization Temporal lobe epilepsy Memory impairment
a b s t r a c t A prominent role of the right temporal lobe in nonverbal memory and visuospatial memory is widely accepted. A variety of neuropsychological tests have been shown to be sensitive to functional deficits related to right temporal lobe epilepsies mainly after surgical interventions, whereas preoperative deficits were seldom used to demonstrate test sensitivities. Furthermore, compensation processes or additional cognitive deficits related to left temporal or extratemporal dysfunctions are often not adequately taken into account. We used a modified object location task to demarcate preoperative visuospatial memory deficits of right temporal origin against such processes in patients with clinically verified right temporal, left temporal, or extratemporal lobe epilepsies. Healthy subjects served as controls. By using 8 “unnameable” objects, the positional memory accuracy of patients with right temporal lobe epilepsy was significantly lower than the positional memory performance of patients with left temporal and extratemporal lobe epilepsies, while object location memory performance differentiated patients with right temporal and extratemporal lobe epilepsies from patients with left temporal lobe epilepsy. Our version of a classical object location task might be a useful tool to detect mnestic deficits specifically related to right temporal lobe dysfunction. Future studies should focus on the refinement of testing conditions in order to detect differences induced by more distinct structural or functional deficits. © 2014 Published by Elsevier Inc.
1. Introduction The concept of memory lateralization, originally based on the work of Milner et al., has guided clinical and experimental research [1–3]. Clinical experience since then, however, only partially fits with this central construct. It is generally accepted that well-designed verbal memory tasks are sensitive to impairments of verbal memory in left temporal lobe epilepsies, but the relation between right temporal lobe lesions and measures of nonverbal memory is not clear [4,5]. While postoperative deficits in nonverbal learning and memory are often observed after right-sided resections [6–9], preoperative nonverbal performance was not found to be strongly related to focus laterality [10]. Many factors, as such as residual verbalization, nonverbal capacity reduction due to language and concomitant memory transfer, or high impact of executive demands, may be related to the relatively low sensitivity of commonly used testing procedures [11]. Besides adequate control of these factors, salient incorporation of a genuinely high instrumental spatial demand and the induction of elemental space impression [12] might be decisive in determining nonverbal memory deficits [9]. When
⁎ Corresponding author. Tel.: +49 228 28714436. E-mail address: [email protected] (C. Frisch).
http://dx.doi.org/10.1016/j.yebeh.2014.03.027 1525-5050/© 2014 Published by Elsevier Inc.
sufficiently operationalized, tests of spatial memory should significantly increase the sensitivity of routine general diagnostic procedures. Because of limited amount of suitable room space, settings demanding true space are seldom sized as described by [13], who arranged objects on several square meters in a separate room. Smith and Milner [14,15] used objects distributed on a table in order to investigate the relation between laterality of temporal lobe excisions in patients with temporal lobe epilepsy and postoperative spatial location deficits. Patients with right-sided but not with left-sided lobectomy were significantly impaired in the minute-delayed relocation of these objects. Object location performance can be subdivided into the association of the object to a location (object location memory) and into spatial (positional) memory for this location. Object location association was found to be impaired in patients with epilepsy with left-sided selective amygdalohippocampectomy (SAH), while patients with right-sided SAH were impaired in spatial positional memory [16]. A procedure which reliably detects preperative object location memory and positional memory deficits induced by right temporal lobe epilepsy has not, to our knowledge, been described. We show here that distinct object location memory and positional memory-based scores differentiate between groups of patients with right and left temporal epilepsies as well as between groups of patients with right temporal and extratemporal lobe epilepsies, thereby pointing to the potential feasibility of this procedure to detect functional deficits specifically induced by right temporal disturbances.
C. Frisch, C. Helmstaedter / Epilepsy & Behavior 35 (2014) 28–33
2. Methods 2.1. Study population 2.1.1. Student controls A group of 35 psychology and neuroscience students, their lecturers, and institutional collaborators of the Neuropsychological Division of the Bonn Department of Epileptology (median age = 25 years, range =20– 45, male = 14) participated in the pilot study to establish baseline parameters suitable to examine and estimate laterality-related object location memory and positional memory deficits in patients with epilepsy. 2.1.2. Patients Between September 2010 and May 2011, 46 inpatients and outpatients were examined at our center with the object location memory/ positional memory task in parallel to routine neuropsychological examination. Results of 29 patients with clearly defined lesions or malformations (sclerosis, dysplasias, and tumors) and related interictal EEG abnormalities (theta-dysrhythms, delta-dysrhythms, sharp waves, and sharp slow waves with or without spikes) primarily localizable as left temporal (n = 11), right temporal (n = 9), or extratemporal (n = 9; two with right frontal, two with left frontal, three with not clearly lateralizable, and two with left parietooccipital seizures) were selected for inclusion into the study. Patients with nonlesional epilepsy and patients without localized and lateralized interictal epileptiform EEG activity were excluded. Localization-related groups did not differ regarding age, verbal intelligence, sex, duration of disease, or number of seizures (MANOVA, respective p-values N 0.1, see Table 1). All patients included received detailed information and gave written informed consent for the present research. All procedures were in accordance with requirements of the ethics committee of the University of Bonn Medical Center. 2.1.3. Apparatus and objects Sets of self-constructed objects made of fine-planed spruce wood or sets of selected common household objects were used for pilot and patient studies. All household objects used were instantaneously named with at least one generally known denotation by all pilot study participants. Objects were presented on a black plastic sheet sized 60 × 40 cm placed on a table in the neuropsychological examination room. A digital photo camera was mounted 150 cm above the sheet. Photograph of the object arrangements shot before and after each trial were overlayed and analyzed by public domain software (GIMP, see Fig. 1D for an exemplary overlay). Variations of object number (8 or 12) and object qualities (sets of well-known household objects easily nameable, see Fig. 1A; wooden objects, see Fig. 1B; and identical wooden sticks, see Fig. 1C) were used during the initial pilot and the subsequent patient study. 2.1.4. Procedure Subjects took place in front of the table with the black sheet and the objects on it in front of them. They were told to study and memorize the object placement as detailed as possible for a duration of 120 s in order to replicate the arrangement as exact as possible after a delay. After the
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presentation, the objects were removed from the sheet, and a delay of 4 min was filled with a written word fluency task performed at another table in the same room. After the delay, subjects again took their places at the object table and replaced the objects during a time period of maximally 2 min. 2.1.5. Scores For the object location memory (OLM) score, mean distances of the replaced figures to the initial placements during presentation were measured in millimeters with the GIMP-based tool on the respective overlay (see Fig. 1D). To obtain the positional memory (PM) score, the lowest mean of the distances between the positions of replaced objects and object locations during presentation, regardless of object identity, was found by repeated quasi-algorhythmic calculation (see [18] for an automatized procedure). With this procedure, all PM calculations of patients and students used in the present study were unambiguous. Additionally, we obtained an object displacement error (ODE) score by counting every object displaced more than 5 cm away from its initial position [1]. Furthermore, we obtained reference values for figural memory (DCS-R), a test routinely used at the Bonn epileptological department relatively sensitive for nonverbal visuospatial memory deficits [19]. In this test, nine abstract figures are repeatedly presented to probands. Dependent variables are as follows: sum of correctly reproduced figures over 5 learning trials, correctly reproduced figures during the fifth trial, and the difference between correctly and falsely recognized figures in a recognition trial after a delay. These measures were related to the OLM and PM scores. 2.2. Statistics Analysis of variance (ANOVA) with post hoc between group comparisons (Bonferroni) and t-tests were performed both for pilot and main study data. Pearson's correlation was used for bivariate analyses of patient data. 3. Results 3.1. Pilot study In the student control cohort, the OLM score was significantly impaired with the wooden object conditions but was not affected by the number of objects presented (object location, two-factorial ANOVA, object number, F(1,27) = 3.21, p = 0.085; object quality, F(1,27) = 10.78, p = 0.003, object number × object quality, F(1,27) = 1.54, p = 0.226, see Fig. 2). By contrast, the PM score was higher for 12 objects, as related to the 8 object conditions, while there was no effect of object quality (location, two-factorial ANOVA, object number, F(1,37) = 7.37, p = 0.010; object quality, F(2,37) = 1.33, p = 0.277, object number × object quality, F(2,37) = 2.76, p = 0.076, see Fig. 2). Among the household object conditions, the ODE score ((displacement errors N 5 cm/number of objects) × 100) was 13.9% both for 8 and 12 objects. With 8 wooden objects, the ODE score was 22.3% and increased to 52.4% with 12 wooden objects (ODE score, two-factorial ANOVA, object number, F(1,27) = 3.21, p = 0.085; object quality, F(1,27) = 10.57, p = 0.003, object number ×
Table 1 Demographical and cognitive data of patients with left temporal, extratemporal, and right temporal lobe epilepsies. Group
N
Male
Mean age (years) (SD)
Mean disease duration (years) (SD)
Seizure frequency per month (SD)
Verbal intelligence (MWT-B [17])
Left temporal
11
5
Extratemporal
9
6
Right temporal
9
6
33.4 (9.8) 34.3 (14.2) 39.3 (12.3)
14.3 (11.8) 14.9 (10.4) 22.5 (18.1)
4.3 (3.3) 2.7 (3.0) 6.0 (6.2)
105.8 (7.4) 102.3 (7.1) 101.3 (5.0)
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C. Frisch, C. Helmstaedter / Epilepsy & Behavior 35 (2014) 28–33
Fig. 1. Object qualities and location displacement measures. A) “Nameable” household objects. B) “Nameless” wooden objects. C) Similar wooden sticks. D) Positional memory (PM) displacement (upper left, yellow) and object location memory (OLM) displacement (orange). (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)
object quality, F(1,27) = 3.22, p = 0.084, data not shown). Additional analysis on the single group level points to a higher deviation of the OLM score with 12 wooden objects, as related to the respective PM score (t-test for dependent measures, p = 0.033), or to OLM with 12 household objects (t-test for independent measures, p = 0.012, see Fig. 2B). Accordingly, in order to have a high probability for a wide data variance in the patient trials, we selected the 8 wooden and the 8 household object conditions for patients' trials. 3.2. Patient study The 8 household objects task was solved without errors by all patients participating in this task (data not shown). Therefore, it was excluded because of putatively insufficient discriminative power, and object location with 8 wooden objects was determined as the sole procedure of choice. Patients with right temporal pathology showed an impaired OLM score as related to patients with left temporal pathology (OLM score, ANOVA, F(2,26) = 4.5, p = 0.021; Bonferroni post hoc, right temporal (RT) vs. left temporal (LT), p = 0.024; extratemporal (ET) vs. LT, p = 0.094; RT vs. ET, p = 1.000, see Fig. 3B). Related to student controls, patients with extratemporal and right temporal but not with left temporal lobe epilepsies showed impaired OLM (t-test for independent measures, ET vs. student control (SC), p = 0.002; RT vs. SC, p = 0.004; LT vs. SC, p = 0.435). The ODE score also differed between groups, with patients with right temporal lobe epilepsy showing more displaced objects compared with patients with left temporal lobe epilepsy, while there were differences neither between patients with frontal and left temporal lobe epilepsies nor between patients with frontal and right temporal lobe epilepsies (ODE score, ANOVA F(2,26) = 4.1, p = 0.028; Bonferroni post hoc, RT vs. LT, p = 0.024; RT vs. ET, p = 0.726; ET vs. LT, p = 0.366, data not shown). Related to student controls, again, patients with extratemporal and right temporal but not with left temporal lobe epilepsies had impaired ODE scores (t-test
for independent measures, ET vs. SC, p = 0.001; RT vs. SC, p b 0.001; LT vs. SC, p = 0.112). Analysis of the PM score revealed that patients with right temporal lobe epilepsy showed inferior performance, both related to patients with extratemporal and left temporal lobe epilepsies (PM score, ANOVA, F(2,26) = 6.0, p = 0.007; Bonferroni post hoc, RT vs. LT, p = 0.010; RT vs. ET, p = 0.045; ET vs. LT, p = 1.000, see Fig. 3A). Related to student controls, all patient subgroups showed impaired PM performance (t-test for independent measures, ET vs. SC, p = 0.001; RT vs. SC, p b 0.001; LT vs. SC, p = 0.003). According to the main parameters of the DCS-R, patients with right temporal lobe epilepsy were impaired in relation to the group with left temporal lobe epilepsy in terms of figural learning (ANOVA, sum of all figures correctly reproduced during learning trials 1–5, F(2,25) = 3.9, p = 0.034; Bonferroni post hoc, RT vs. LT, p = 0.030, data not shown) and maximal learning capacity (ANOVA, figures reproduced during the last learning trial, F(2,25) = 5.9, p = 0.008; Bonferroni post hoc, RT vs. LT, p = 0.006) and showed a tendency for a reduced recognition capacity (ANOVA, correctly recognized — wrongly recognized figures, F(2,25) = 3.9, p = 0.034; Bonferroni post hoc, RT vs. LT, p = 0.062) but were not impaired in relation to the group of patients with extratemporal lobe epilepsy (learning trials 1–5, trial 5, recognition, all p-values N 0.1). Furthermore, the DCS parameters did not differentiate between patients with left temporal and those with extratemporal lobe epilepsies (all p-values N 0.1). Correlational analysis revealed that figural memory and object location memory parameters were related in a group-dependent manner. While in patients with left temporal and extratemporal lobe epilepsies no significant correlation between PM scores and figural learning parameters was found (Pearson correlation coefficients ranging from −0.002 to 0.579, with p-values ranging from 0.133 to 0.996), in patients with right temporal lobe epilepsy, the DCS-R parameters were significantly correlated with the OLM and PM scores (correlation coefficients ranging from 0.681 to 0.823, with
C. Frisch, C. Helmstaedter / Epilepsy & Behavior 35 (2014) 28–33
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4. Discussion
Fig. 2. Positional memory (gray) and object location memory (dark gray) performance of healthy controls with similar, household, and constructed wooden objects: A) 8 objects; B) 12 objects. *: p b 0.05 vs. object location score with 12 household objects; +: p b 0.05 vs. location score with 12 wooden objects (t-tests for independent and dependent measures).
p-values ranging from 0.021 to 0.002, see Fig. 4). Furthermore, qualitative inspection did not reveal any relation between seizure lateralization and neuropsychological data in the group of patients with extratemporal lobe epilepsy.
Several neuropsychological tests are sensitive to functional impairments related to right temporal dysfunctions, mostly demonstrated in cases of postoperative right mesiotemporal epilepsies [5,9,15]. Preoperative deficits, playing an important role in the context of focus and lesion localization during presurgical evaluation, are much more difficult to assess [10]. Choice of test material, compensational verbalization, and deficits in extratemporally mediated executive functions or general intellectual capacities constitute factors often contaminating test results [11,12,20]. In order to minimize such confounding influence on the detection of visuospatial memory deficits with primary right temporal origin, we adapted an object location task described by Smith and Milner [14]. In a pilot study, we identified a sensitive setup with 8 “unnameable” objects, whose use induced a difference between object location memory (OLM) and positional memory (PM). While the OLM score differentiates patients with right temporal and extratemporal lobe epilepsies from patients with left temporal lobe epilepsy, the PM performance of patients with right temporal lobe epilepsy was significantly impaired in relation to the performance of patients with left temporal and extratemporal epilepsies. This differentiation was not found with the figural nonverbal memory task, which consists of the visuoconstructional reproduction of two-dimensional geometrical figures in a serial learning and memory task (DCS-R, [19]). The high differential power of the object location/positional memory procedure, as observed in the present study, might be related to two main factors. First, its lower cognitive demands in terms of sensorimotor, executive, and general intellectual effort, as compared with the figural memory task, might be related to a reduced load on extratemporal capacities and thereby helps to unmask and to identify spatial deficits primarily due to right temporal dysfunctions. Indeed, while a subpopulation of patients with extratemporal lobe epilepsy was impaired in figural memory scores but not in the OLM and PM scores, which were on the level of the patients with left temporal lobe epilepsy, patients with right temporal lobe epilepsy showed deficits to the same degree in both tasks, as indicated by the high correlations between their respective figural and OLM and PM scores. Second, the low nameability of the “artificial” wooden objects might decrease the compensability of spatial deficits by putative activation of left temporal capacities [20,21]. This assumption is further supported by the observations that OLM was less exact than PM in patients and in the student control group, and that usage of easily nameable household objects does not induce a difference between the OLM and PM scores. In relation to the study of Kessels et al. [16] who found that postoperatively investigated patients with right temporal lobe epilepsy were impaired in object
Fig. 3. Patients' performance with 8 wooden objects. A) Positional memory score; B) object location memory score. +, (+): p b 0.05, b0.1 vs. student control; *: p b 0.05 vs. left temporal, #: p b 0.05 vs. extratemporal (Bonferroni post hoc).
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Fig. 4. Correlations of patients' positional memory score with final nonverbal learning performance (DCS trial 5). A) Left temporal, B) extratemporal, C) right temporal group. Insets: Pearson correlation coefficient with respective p-value.
location memory but not in positional memory, while patients with left-sided temporal lobe epilepsy were impaired in positional but not in object location memory, some possible reasons for the sensitivity of our task to detect preoperative deficits might appear. First, our task captured object location memory and positional memory simultaneously, while Kessels et al. used different trials; second, demands in terms of three-dimensional elemental space (see [11]) might be higher in our task due to performance in “true” space on a table top. The combination of these factors might be important in the detection of functional deficits with possibly additive properties.
After right temporal resections, residual object location memory capacities might further decline, putatively exceeding left temporal or extratemporal compensatory capacities. Accordingly, sensitivity of object location tasks based on nameable objects and figural twodimensional tasks is sufficient to detect the postoperatively more pronounced spatial memory deficits [10,14,15]. Importantly, results of tasks including simultaneous variation of object location, object nameability, and object functionality should be interpreted cautiously here, since putatively concurrent activation of brain areas primarily involved in the respective functions might interfere with the intended selective analysis of related locally distinctable functional impairments (e.g., [22]). The assumption of functional lateralization along the verbal–nonverbal/spatial division is supported by fMRI studies: detection of changes in image content was associated with left mediotemporal temporal lobe activation, while detection of changes in image location was associated with right mediotemporal lobe activation [2]. Furthermore, stronger left-sided activation during object identification contrasts with stronger right-sided activation during object location in the extrahippocampal MTL [3]. Besides that, structural (e.g., [21]) and hemodynamic data [22] are in accordance with the functional lateralization concept. The deficits of patients with left temporal lobe epilepsy in positional memory in the present study might be related to residual object identification capacities [2] still sufficient to perform object location memory on the level of controls, while the positional memory deficits cannot be compensated by object identification. For a more detailed analysis regarding lateralization of putatively compensatory capacities or relevant processes, comparison of patient results with the results of a matched control group appears to be necessary here. In relation to other paradigms developed to detect functional disturbances related to right hemisphere dysfunctions, procedural advantages of the setting presented here should not be underestimated. While the practicability of tasks portable in a pocket, as the DCS figural memory test, is probably unmatchable, in relation to other true threedimensional tasks [13,23], procedural or spatial advantages are obvious. Moreover, the object location and positional memory task presented here takes about 5 min to be completed and can easily be integrated into any neuropsychological examination. Another advantage can be seen in that patients with nonverbal memory impairments might probably perceive object location testing less aversive than other spatial or figural tests due to its short duration and the lower obviousness of performance deficits. Several points await further elaboration. First, the present small sample size should be increased in order to differentiate the effects of distinct anatomical malformations (such as dysplasias) or of electrophysiological irregularities in patients with nonlesional right temporal lobe epilepsy which were actually subsumed under broad localizational aspects or were not included in the study. Second, the detection of relations between left temporal and extratemporal lesions and spatial memory impairments, as indicated by moderate to strong correlations not reaching statistical significance in the present study, might be possible with an increased sample size. Furthermore, differences between controls and patients with left temporal lobe epilepsy in object location memory not observed in the present study might appear. Third, the object encoding effort could be analyzed by including positional memory trials with identical objects. Since it was shown in working memory paradigms that object identification primarily activates left-hemispheric areas, while object location association and pure location performance with similar objects induced right-hemispheric activity increases [24, 25], it seems possible that, by subsequent additional variation of object number and object qualities, further differentiation between more subtle clinical entities might succeed. Fourth, effects of relocation delay length should also be examined, although Smith and Milner [15] did not report a difference between 1-minute and 24-hour recall in their object location paradigm. Fifth, as mentioned above, information
C. Frisch, C. Helmstaedter / Epilepsy & Behavior 35 (2014) 28–33
regarding general population parameters by adequately matching control subjects should be acquired. In parallel, in order to investigate spatial memory as part of the clinical routine, implementation of automated analysis of positional memory accuracy by a semiautomatic algorithm [18] will be necessary. Taken together, our modified version of the classical object location task might be a useful clinical approach to detect mnestic deficits which are specifically related to impairments of right temporal lobe-associated capacities. Future studies might focus on the refinement of testing conditions in order to detect potential differences induced by more distinct structural or functional deficits. Conflict of interest None of the authors has any biomedical financial interest or any other potential conflict of interest to disclose. References [1] Crane J, Milner B. What went where? Impaired object-location learning in patients with right hippocampal lesions. Hippocampus 2005;15:216–31. [2] Treyer V, Buck A, Schnider A. Processing content or location: distinct brain activation in a memory task. Hippocampus 2005;15:684–9. [3] Bellgowan PS, Buffalo EA, Bodurka J, Martin A. Lateralized spatial and object memory encoding in entorhinal and perirhinal cortices. Learn Mem 2009;24:433–8. [4] Saling MM. Verbal memory in mesial temporal lobe epilepsy: beyond material specificity. Brain 2009;132:570–82. [5] Hampstead BM, Lacey S, Ali S, Phillips PA, Stringer AY, Sathian K. Use of complex threedimensional objects to assess visuospatial memory in healthy individuals and patients with unilateral amygdalohippocampectomy. Epilepsy Behav 2009;18:54–60. [6] Pillon B, Bazin B, Deweer B, Ehrlé N, Baulac M, Dubois B. Specificity of memory deficits after right or left temporal lobectomy. Cortex 1999;35:561–71. [7] Nunn JA, Graydon FJ, Polkey CE, Morris RG. Differential spatial memory impairment after right temporal lobectomy demonstrated using temporal titration. Brain 1999;122:47–59. [8] Feigenbaum JD, Morris RG. Allocentric versus egocentric spatial memory after unilateral temporal lobectomy in humans. Neuropsychology 2004;18:462–72. [9] Diaz-Asper CM, Dopkins S, Potolicchio SJ, Caputy A. Spatial memory following temporal lobe resection. J Clin Exp Neuropsychol 2006;28:1462–81.
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[10] Helmstaedter C, Richter S, Röske S, Oltmanns F, Schramm J, Lehmann TN. Differential effects of temporal pole resection with amygdalohippocampectomy versus selective amygdalohippocampectomy on material-specific memory in patients with mesial temporal lobe epilepsy. Epilepsia 2008;49:88–97. [11] McConley R, Martin R, Palmer CA, Kuzniecky R, Knowlton R, Faught E. Rey Osterrieth complex figure test spatial and figural scoring: relations to seizure focus and hippocampal pathology in patients with temporal lobe epilepsy. Epilepsy Behav 2008;13: 174–7. [12] Zeidman P, Mullally SL, Schwarzkopf DS, Maguire E. Exploring the parahippocampal cortex response to high and low spatial frequency spaces. Neuroreport 2012;23: 503–7. [13] Stepankova K, Fenton AA, Pastalkova E, Kalina M, Bohbot VD. Object-location memory impairment in patients with thermal lesions to the right or left hippocampus. Neuropsychologia 2008;42:1017–28. [14] Smith ML, Milner B. The role of the right hippocampus in the recall of spatial location. Neuropsychologia 1981;19:781–93. [15] Smith ML, Milner B. Right hippocampal impairment in the recall of spatial location: encoding deficit or rapid forgetting? Neuropsychologia 1989;27:71–81. [16] Kessels RPC, Hendriks MPH, Schouten J, van Asselen M, Postma A. Spatial memory deficits in patients after unilateral selective amygdalohippocampectomy. J Int Neuropsychol Soc 2004;10:907–12. [17] Lehrl S, Triebig G, Fischer B. Multiple choice vocabulary test MWT as a valid and short test to estimate premorbid intelligence. Acta Neurol Scand 1995;5:335–45. [18] Kessels RPC, Postma A, De Haan EHF. Object relocation: a program for setting up, running, and analyzing experiments on memory for object locations. Behav Res Methods Instrum Comput 1999;31:423–8. [19] Helmstaedter C, Pohl C, Hufnagel A, Elger CE. Visual learning deficits in nonresected patients with right temporal lobe epilepsy. Cortex 1991;27:547–55. [20] Helmstaedter C, Pohl C, Elger CE. Relations between verbal and nonverbal memory performance: evidence of confounding effects particularly in patients with right temporal lobe epilepsy. Cortex 1995;31:345–55. [21] Hamberger MJ, Seidel WT, McKhann GM, Goodman RR. Hippocampal removal affects visual but not auditory naming. Neurology 2010;74:1488–93. [22] Glikmann-Johnston Y, Saling MM, Chen J, Cooper KA, Beare RJ, Reutens DC. Structural and functional correlates of unilateral mesial temporal lobe spatial memory impairment. Brain 2008;131:3006–18. [23] Abrahams S, Pickering A, Polkey CE, Morris RG. Spatial memory deficits in patients with unilateral damage to the right hippocampal formation. Neuropsychologia 1997;35:11–24. [24] Smith EE, Jonides J, Koeppe RA, Awh E, Schumacher EH, Minoshima S. Spatial versus object working memory: PET investigations. J Cogn Neurosci 1995;7:337–56. [25] Piekema C, Kessels RPC, Mars RB, Petersson KM, Fernández G. The right hippocampus participates in short-term memory maintenance of object–location associations. Neuroimage 2006;33:374–82.
Contents lists available at ScienceDirect
Epilepsy & Behavior journal homepage: www.elsevier.com/locate/yebeh
Object location performance: Detection of functional impairment in right temporal lobe epilepsy Christian Frisch ⁎, Christoph Helmstaedter University of Bonn Medical Center, Department of Epileptology, Sigmund Freud-Straße 25, 53105 Bonn, Germany
a r t i c l e
i n f o
Article history: Received 14 January 2014 Revised 25 March 2014 Accepted 27 March 2014 Available online xxxx Keywords: Object location Lateralization Temporal lobe epilepsy Memory impairment
a b s t r a c t A prominent role of the right temporal lobe in nonverbal memory and visuospatial memory is widely accepted. A variety of neuropsychological tests have been shown to be sensitive to functional deficits related to right temporal lobe epilepsies mainly after surgical interventions, whereas preoperative deficits were seldom used to demonstrate test sensitivities. Furthermore, compensation processes or additional cognitive deficits related to left temporal or extratemporal dysfunctions are often not adequately taken into account. We used a modified object location task to demarcate preoperative visuospatial memory deficits of right temporal origin against such processes in patients with clinically verified right temporal, left temporal, or extratemporal lobe epilepsies. Healthy subjects served as controls. By using 8 “unnameable” objects, the positional memory accuracy of patients with right temporal lobe epilepsy was significantly lower than the positional memory performance of patients with left temporal and extratemporal lobe epilepsies, while object location memory performance differentiated patients with right temporal and extratemporal lobe epilepsies from patients with left temporal lobe epilepsy. Our version of a classical object location task might be a useful tool to detect mnestic deficits specifically related to right temporal lobe dysfunction. Future studies should focus on the refinement of testing conditions in order to detect differences induced by more distinct structural or functional deficits. © 2014 Published by Elsevier Inc.
1. Introduction The concept of memory lateralization, originally based on the work of Milner et al., has guided clinical and experimental research [1–3]. Clinical experience since then, however, only partially fits with this central construct. It is generally accepted that well-designed verbal memory tasks are sensitive to impairments of verbal memory in left temporal lobe epilepsies, but the relation between right temporal lobe lesions and measures of nonverbal memory is not clear [4,5]. While postoperative deficits in nonverbal learning and memory are often observed after right-sided resections [6–9], preoperative nonverbal performance was not found to be strongly related to focus laterality [10]. Many factors, as such as residual verbalization, nonverbal capacity reduction due to language and concomitant memory transfer, or high impact of executive demands, may be related to the relatively low sensitivity of commonly used testing procedures [11]. Besides adequate control of these factors, salient incorporation of a genuinely high instrumental spatial demand and the induction of elemental space impression [12] might be decisive in determining nonverbal memory deficits [9]. When
⁎ Corresponding author. Tel.: +49 228 28714436. E-mail address: [email protected] (C. Frisch).
http://dx.doi.org/10.1016/j.yebeh.2014.03.027 1525-5050/© 2014 Published by Elsevier Inc.
sufficiently operationalized, tests of spatial memory should significantly increase the sensitivity of routine general diagnostic procedures. Because of limited amount of suitable room space, settings demanding true space are seldom sized as described by [13], who arranged objects on several square meters in a separate room. Smith and Milner [14,15] used objects distributed on a table in order to investigate the relation between laterality of temporal lobe excisions in patients with temporal lobe epilepsy and postoperative spatial location deficits. Patients with right-sided but not with left-sided lobectomy were significantly impaired in the minute-delayed relocation of these objects. Object location performance can be subdivided into the association of the object to a location (object location memory) and into spatial (positional) memory for this location. Object location association was found to be impaired in patients with epilepsy with left-sided selective amygdalohippocampectomy (SAH), while patients with right-sided SAH were impaired in spatial positional memory [16]. A procedure which reliably detects preperative object location memory and positional memory deficits induced by right temporal lobe epilepsy has not, to our knowledge, been described. We show here that distinct object location memory and positional memory-based scores differentiate between groups of patients with right and left temporal epilepsies as well as between groups of patients with right temporal and extratemporal lobe epilepsies, thereby pointing to the potential feasibility of this procedure to detect functional deficits specifically induced by right temporal disturbances.
C. Frisch, C. Helmstaedter / Epilepsy & Behavior 35 (2014) 28–33
2. Methods 2.1. Study population 2.1.1. Student controls A group of 35 psychology and neuroscience students, their lecturers, and institutional collaborators of the Neuropsychological Division of the Bonn Department of Epileptology (median age = 25 years, range =20– 45, male = 14) participated in the pilot study to establish baseline parameters suitable to examine and estimate laterality-related object location memory and positional memory deficits in patients with epilepsy. 2.1.2. Patients Between September 2010 and May 2011, 46 inpatients and outpatients were examined at our center with the object location memory/ positional memory task in parallel to routine neuropsychological examination. Results of 29 patients with clearly defined lesions or malformations (sclerosis, dysplasias, and tumors) and related interictal EEG abnormalities (theta-dysrhythms, delta-dysrhythms, sharp waves, and sharp slow waves with or without spikes) primarily localizable as left temporal (n = 11), right temporal (n = 9), or extratemporal (n = 9; two with right frontal, two with left frontal, three with not clearly lateralizable, and two with left parietooccipital seizures) were selected for inclusion into the study. Patients with nonlesional epilepsy and patients without localized and lateralized interictal epileptiform EEG activity were excluded. Localization-related groups did not differ regarding age, verbal intelligence, sex, duration of disease, or number of seizures (MANOVA, respective p-values N 0.1, see Table 1). All patients included received detailed information and gave written informed consent for the present research. All procedures were in accordance with requirements of the ethics committee of the University of Bonn Medical Center. 2.1.3. Apparatus and objects Sets of self-constructed objects made of fine-planed spruce wood or sets of selected common household objects were used for pilot and patient studies. All household objects used were instantaneously named with at least one generally known denotation by all pilot study participants. Objects were presented on a black plastic sheet sized 60 × 40 cm placed on a table in the neuropsychological examination room. A digital photo camera was mounted 150 cm above the sheet. Photograph of the object arrangements shot before and after each trial were overlayed and analyzed by public domain software (GIMP, see Fig. 1D for an exemplary overlay). Variations of object number (8 or 12) and object qualities (sets of well-known household objects easily nameable, see Fig. 1A; wooden objects, see Fig. 1B; and identical wooden sticks, see Fig. 1C) were used during the initial pilot and the subsequent patient study. 2.1.4. Procedure Subjects took place in front of the table with the black sheet and the objects on it in front of them. They were told to study and memorize the object placement as detailed as possible for a duration of 120 s in order to replicate the arrangement as exact as possible after a delay. After the
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presentation, the objects were removed from the sheet, and a delay of 4 min was filled with a written word fluency task performed at another table in the same room. After the delay, subjects again took their places at the object table and replaced the objects during a time period of maximally 2 min. 2.1.5. Scores For the object location memory (OLM) score, mean distances of the replaced figures to the initial placements during presentation were measured in millimeters with the GIMP-based tool on the respective overlay (see Fig. 1D). To obtain the positional memory (PM) score, the lowest mean of the distances between the positions of replaced objects and object locations during presentation, regardless of object identity, was found by repeated quasi-algorhythmic calculation (see [18] for an automatized procedure). With this procedure, all PM calculations of patients and students used in the present study were unambiguous. Additionally, we obtained an object displacement error (ODE) score by counting every object displaced more than 5 cm away from its initial position [1]. Furthermore, we obtained reference values for figural memory (DCS-R), a test routinely used at the Bonn epileptological department relatively sensitive for nonverbal visuospatial memory deficits [19]. In this test, nine abstract figures are repeatedly presented to probands. Dependent variables are as follows: sum of correctly reproduced figures over 5 learning trials, correctly reproduced figures during the fifth trial, and the difference between correctly and falsely recognized figures in a recognition trial after a delay. These measures were related to the OLM and PM scores. 2.2. Statistics Analysis of variance (ANOVA) with post hoc between group comparisons (Bonferroni) and t-tests were performed both for pilot and main study data. Pearson's correlation was used for bivariate analyses of patient data. 3. Results 3.1. Pilot study In the student control cohort, the OLM score was significantly impaired with the wooden object conditions but was not affected by the number of objects presented (object location, two-factorial ANOVA, object number, F(1,27) = 3.21, p = 0.085; object quality, F(1,27) = 10.78, p = 0.003, object number × object quality, F(1,27) = 1.54, p = 0.226, see Fig. 2). By contrast, the PM score was higher for 12 objects, as related to the 8 object conditions, while there was no effect of object quality (location, two-factorial ANOVA, object number, F(1,37) = 7.37, p = 0.010; object quality, F(2,37) = 1.33, p = 0.277, object number × object quality, F(2,37) = 2.76, p = 0.076, see Fig. 2). Among the household object conditions, the ODE score ((displacement errors N 5 cm/number of objects) × 100) was 13.9% both for 8 and 12 objects. With 8 wooden objects, the ODE score was 22.3% and increased to 52.4% with 12 wooden objects (ODE score, two-factorial ANOVA, object number, F(1,27) = 3.21, p = 0.085; object quality, F(1,27) = 10.57, p = 0.003, object number ×
Table 1 Demographical and cognitive data of patients with left temporal, extratemporal, and right temporal lobe epilepsies. Group
N
Male
Mean age (years) (SD)
Mean disease duration (years) (SD)
Seizure frequency per month (SD)
Verbal intelligence (MWT-B [17])
Left temporal
11
5
Extratemporal
9
6
Right temporal
9
6
33.4 (9.8) 34.3 (14.2) 39.3 (12.3)
14.3 (11.8) 14.9 (10.4) 22.5 (18.1)
4.3 (3.3) 2.7 (3.0) 6.0 (6.2)
105.8 (7.4) 102.3 (7.1) 101.3 (5.0)
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Fig. 1. Object qualities and location displacement measures. A) “Nameable” household objects. B) “Nameless” wooden objects. C) Similar wooden sticks. D) Positional memory (PM) displacement (upper left, yellow) and object location memory (OLM) displacement (orange). (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)
object quality, F(1,27) = 3.22, p = 0.084, data not shown). Additional analysis on the single group level points to a higher deviation of the OLM score with 12 wooden objects, as related to the respective PM score (t-test for dependent measures, p = 0.033), or to OLM with 12 household objects (t-test for independent measures, p = 0.012, see Fig. 2B). Accordingly, in order to have a high probability for a wide data variance in the patient trials, we selected the 8 wooden and the 8 household object conditions for patients' trials. 3.2. Patient study The 8 household objects task was solved without errors by all patients participating in this task (data not shown). Therefore, it was excluded because of putatively insufficient discriminative power, and object location with 8 wooden objects was determined as the sole procedure of choice. Patients with right temporal pathology showed an impaired OLM score as related to patients with left temporal pathology (OLM score, ANOVA, F(2,26) = 4.5, p = 0.021; Bonferroni post hoc, right temporal (RT) vs. left temporal (LT), p = 0.024; extratemporal (ET) vs. LT, p = 0.094; RT vs. ET, p = 1.000, see Fig. 3B). Related to student controls, patients with extratemporal and right temporal but not with left temporal lobe epilepsies showed impaired OLM (t-test for independent measures, ET vs. student control (SC), p = 0.002; RT vs. SC, p = 0.004; LT vs. SC, p = 0.435). The ODE score also differed between groups, with patients with right temporal lobe epilepsy showing more displaced objects compared with patients with left temporal lobe epilepsy, while there were differences neither between patients with frontal and left temporal lobe epilepsies nor between patients with frontal and right temporal lobe epilepsies (ODE score, ANOVA F(2,26) = 4.1, p = 0.028; Bonferroni post hoc, RT vs. LT, p = 0.024; RT vs. ET, p = 0.726; ET vs. LT, p = 0.366, data not shown). Related to student controls, again, patients with extratemporal and right temporal but not with left temporal lobe epilepsies had impaired ODE scores (t-test
for independent measures, ET vs. SC, p = 0.001; RT vs. SC, p b 0.001; LT vs. SC, p = 0.112). Analysis of the PM score revealed that patients with right temporal lobe epilepsy showed inferior performance, both related to patients with extratemporal and left temporal lobe epilepsies (PM score, ANOVA, F(2,26) = 6.0, p = 0.007; Bonferroni post hoc, RT vs. LT, p = 0.010; RT vs. ET, p = 0.045; ET vs. LT, p = 1.000, see Fig. 3A). Related to student controls, all patient subgroups showed impaired PM performance (t-test for independent measures, ET vs. SC, p = 0.001; RT vs. SC, p b 0.001; LT vs. SC, p = 0.003). According to the main parameters of the DCS-R, patients with right temporal lobe epilepsy were impaired in relation to the group with left temporal lobe epilepsy in terms of figural learning (ANOVA, sum of all figures correctly reproduced during learning trials 1–5, F(2,25) = 3.9, p = 0.034; Bonferroni post hoc, RT vs. LT, p = 0.030, data not shown) and maximal learning capacity (ANOVA, figures reproduced during the last learning trial, F(2,25) = 5.9, p = 0.008; Bonferroni post hoc, RT vs. LT, p = 0.006) and showed a tendency for a reduced recognition capacity (ANOVA, correctly recognized — wrongly recognized figures, F(2,25) = 3.9, p = 0.034; Bonferroni post hoc, RT vs. LT, p = 0.062) but were not impaired in relation to the group of patients with extratemporal lobe epilepsy (learning trials 1–5, trial 5, recognition, all p-values N 0.1). Furthermore, the DCS parameters did not differentiate between patients with left temporal and those with extratemporal lobe epilepsies (all p-values N 0.1). Correlational analysis revealed that figural memory and object location memory parameters were related in a group-dependent manner. While in patients with left temporal and extratemporal lobe epilepsies no significant correlation between PM scores and figural learning parameters was found (Pearson correlation coefficients ranging from −0.002 to 0.579, with p-values ranging from 0.133 to 0.996), in patients with right temporal lobe epilepsy, the DCS-R parameters were significantly correlated with the OLM and PM scores (correlation coefficients ranging from 0.681 to 0.823, with
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4. Discussion
Fig. 2. Positional memory (gray) and object location memory (dark gray) performance of healthy controls with similar, household, and constructed wooden objects: A) 8 objects; B) 12 objects. *: p b 0.05 vs. object location score with 12 household objects; +: p b 0.05 vs. location score with 12 wooden objects (t-tests for independent and dependent measures).
p-values ranging from 0.021 to 0.002, see Fig. 4). Furthermore, qualitative inspection did not reveal any relation between seizure lateralization and neuropsychological data in the group of patients with extratemporal lobe epilepsy.
Several neuropsychological tests are sensitive to functional impairments related to right temporal dysfunctions, mostly demonstrated in cases of postoperative right mesiotemporal epilepsies [5,9,15]. Preoperative deficits, playing an important role in the context of focus and lesion localization during presurgical evaluation, are much more difficult to assess [10]. Choice of test material, compensational verbalization, and deficits in extratemporally mediated executive functions or general intellectual capacities constitute factors often contaminating test results [11,12,20]. In order to minimize such confounding influence on the detection of visuospatial memory deficits with primary right temporal origin, we adapted an object location task described by Smith and Milner [14]. In a pilot study, we identified a sensitive setup with 8 “unnameable” objects, whose use induced a difference between object location memory (OLM) and positional memory (PM). While the OLM score differentiates patients with right temporal and extratemporal lobe epilepsies from patients with left temporal lobe epilepsy, the PM performance of patients with right temporal lobe epilepsy was significantly impaired in relation to the performance of patients with left temporal and extratemporal epilepsies. This differentiation was not found with the figural nonverbal memory task, which consists of the visuoconstructional reproduction of two-dimensional geometrical figures in a serial learning and memory task (DCS-R, [19]). The high differential power of the object location/positional memory procedure, as observed in the present study, might be related to two main factors. First, its lower cognitive demands in terms of sensorimotor, executive, and general intellectual effort, as compared with the figural memory task, might be related to a reduced load on extratemporal capacities and thereby helps to unmask and to identify spatial deficits primarily due to right temporal dysfunctions. Indeed, while a subpopulation of patients with extratemporal lobe epilepsy was impaired in figural memory scores but not in the OLM and PM scores, which were on the level of the patients with left temporal lobe epilepsy, patients with right temporal lobe epilepsy showed deficits to the same degree in both tasks, as indicated by the high correlations between their respective figural and OLM and PM scores. Second, the low nameability of the “artificial” wooden objects might decrease the compensability of spatial deficits by putative activation of left temporal capacities [20,21]. This assumption is further supported by the observations that OLM was less exact than PM in patients and in the student control group, and that usage of easily nameable household objects does not induce a difference between the OLM and PM scores. In relation to the study of Kessels et al. [16] who found that postoperatively investigated patients with right temporal lobe epilepsy were impaired in object
Fig. 3. Patients' performance with 8 wooden objects. A) Positional memory score; B) object location memory score. +, (+): p b 0.05, b0.1 vs. student control; *: p b 0.05 vs. left temporal, #: p b 0.05 vs. extratemporal (Bonferroni post hoc).
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Fig. 4. Correlations of patients' positional memory score with final nonverbal learning performance (DCS trial 5). A) Left temporal, B) extratemporal, C) right temporal group. Insets: Pearson correlation coefficient with respective p-value.
location memory but not in positional memory, while patients with left-sided temporal lobe epilepsy were impaired in positional but not in object location memory, some possible reasons for the sensitivity of our task to detect preoperative deficits might appear. First, our task captured object location memory and positional memory simultaneously, while Kessels et al. used different trials; second, demands in terms of three-dimensional elemental space (see [11]) might be higher in our task due to performance in “true” space on a table top. The combination of these factors might be important in the detection of functional deficits with possibly additive properties.
After right temporal resections, residual object location memory capacities might further decline, putatively exceeding left temporal or extratemporal compensatory capacities. Accordingly, sensitivity of object location tasks based on nameable objects and figural twodimensional tasks is sufficient to detect the postoperatively more pronounced spatial memory deficits [10,14,15]. Importantly, results of tasks including simultaneous variation of object location, object nameability, and object functionality should be interpreted cautiously here, since putatively concurrent activation of brain areas primarily involved in the respective functions might interfere with the intended selective analysis of related locally distinctable functional impairments (e.g., [22]). The assumption of functional lateralization along the verbal–nonverbal/spatial division is supported by fMRI studies: detection of changes in image content was associated with left mediotemporal temporal lobe activation, while detection of changes in image location was associated with right mediotemporal lobe activation [2]. Furthermore, stronger left-sided activation during object identification contrasts with stronger right-sided activation during object location in the extrahippocampal MTL [3]. Besides that, structural (e.g., [21]) and hemodynamic data [22] are in accordance with the functional lateralization concept. The deficits of patients with left temporal lobe epilepsy in positional memory in the present study might be related to residual object identification capacities [2] still sufficient to perform object location memory on the level of controls, while the positional memory deficits cannot be compensated by object identification. For a more detailed analysis regarding lateralization of putatively compensatory capacities or relevant processes, comparison of patient results with the results of a matched control group appears to be necessary here. In relation to other paradigms developed to detect functional disturbances related to right hemisphere dysfunctions, procedural advantages of the setting presented here should not be underestimated. While the practicability of tasks portable in a pocket, as the DCS figural memory test, is probably unmatchable, in relation to other true threedimensional tasks [13,23], procedural or spatial advantages are obvious. Moreover, the object location and positional memory task presented here takes about 5 min to be completed and can easily be integrated into any neuropsychological examination. Another advantage can be seen in that patients with nonverbal memory impairments might probably perceive object location testing less aversive than other spatial or figural tests due to its short duration and the lower obviousness of performance deficits. Several points await further elaboration. First, the present small sample size should be increased in order to differentiate the effects of distinct anatomical malformations (such as dysplasias) or of electrophysiological irregularities in patients with nonlesional right temporal lobe epilepsy which were actually subsumed under broad localizational aspects or were not included in the study. Second, the detection of relations between left temporal and extratemporal lesions and spatial memory impairments, as indicated by moderate to strong correlations not reaching statistical significance in the present study, might be possible with an increased sample size. Furthermore, differences between controls and patients with left temporal lobe epilepsy in object location memory not observed in the present study might appear. Third, the object encoding effort could be analyzed by including positional memory trials with identical objects. Since it was shown in working memory paradigms that object identification primarily activates left-hemispheric areas, while object location association and pure location performance with similar objects induced right-hemispheric activity increases [24, 25], it seems possible that, by subsequent additional variation of object number and object qualities, further differentiation between more subtle clinical entities might succeed. Fourth, effects of relocation delay length should also be examined, although Smith and Milner [15] did not report a difference between 1-minute and 24-hour recall in their object location paradigm. Fifth, as mentioned above, information
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regarding general population parameters by adequately matching control subjects should be acquired. In parallel, in order to investigate spatial memory as part of the clinical routine, implementation of automated analysis of positional memory accuracy by a semiautomatic algorithm [18] will be necessary. Taken together, our modified version of the classical object location task might be a useful clinical approach to detect mnestic deficits which are specifically related to impairments of right temporal lobe-associated capacities. Future studies might focus on the refinement of testing conditions in order to detect potential differences induced by more distinct structural or functional deficits. Conflict of interest None of the authors has any biomedical financial interest or any other potential conflict of interest to disclose. References [1] Crane J, Milner B. What went where? Impaired object-location learning in patients with right hippocampal lesions. Hippocampus 2005;15:216–31. [2] Treyer V, Buck A, Schnider A. Processing content or location: distinct brain activation in a memory task. Hippocampus 2005;15:684–9. [3] Bellgowan PS, Buffalo EA, Bodurka J, Martin A. Lateralized spatial and object memory encoding in entorhinal and perirhinal cortices. Learn Mem 2009;24:433–8. [4] Saling MM. Verbal memory in mesial temporal lobe epilepsy: beyond material specificity. Brain 2009;132:570–82. [5] Hampstead BM, Lacey S, Ali S, Phillips PA, Stringer AY, Sathian K. Use of complex threedimensional objects to assess visuospatial memory in healthy individuals and patients with unilateral amygdalohippocampectomy. Epilepsy Behav 2009;18:54–60. [6] Pillon B, Bazin B, Deweer B, Ehrlé N, Baulac M, Dubois B. Specificity of memory deficits after right or left temporal lobectomy. Cortex 1999;35:561–71. [7] Nunn JA, Graydon FJ, Polkey CE, Morris RG. Differential spatial memory impairment after right temporal lobectomy demonstrated using temporal titration. Brain 1999;122:47–59. [8] Feigenbaum JD, Morris RG. Allocentric versus egocentric spatial memory after unilateral temporal lobectomy in humans. Neuropsychology 2004;18:462–72. [9] Diaz-Asper CM, Dopkins S, Potolicchio SJ, Caputy A. Spatial memory following temporal lobe resection. J Clin Exp Neuropsychol 2006;28:1462–81.
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