Associative Learning Impairments in Patients with Frontal Lobe Damage

Brain and Cognition 41, 213–230 (1999) Article ID brcg.1999.1121, available online at http://www.idealibrary.com on

Associative Learning Impairments in Patients with Frontal Lobe Damage Mariana Dimitrov, Joy Granetz, Matthew Peterson, Caroline Hollnagel, Gene Alexander, and Jordan Grafman Cognitive Neuroscience Section, National Institute of Neurological Disorders and Stroke, and Laboratory of Neurosciences, National Institute of Aging, National Institutes of Health The performance of 18 frontal lobe lesion (FL) and 10 frontal lobe dementia (FLD) patients on an associative memory test was compared with the performance of their matched normal controls. The FL group was severely impaired on cued and free recall and was moderately impaired on a recognition condition. Left FL patients performed the poorest on the cued and free recall conditions. The FLD patients were moderately impaired on the free recall condition only but there was a subgroup of FLD patients with additional left temporal atrophy who appeared severely impaired on both cued and free recall. These findings indicate that both left frontal and temporal lobe damage can impair associative learning and that this impairment is more strikingly seen with free rather than cued recall.  1999 Academic Press

INTRODUCTION

Damage to the prefrontal cortex can selectively impair certain memory processes. Patients with frontal lobe lesions typically demonstrate deficits on tests on which they are required to freely recall information presented during an earlier study period and appear unable to strategically organize the information to facilitate their recall (Eslinger & Grattan, 1994; Gershberg & Shimamura, 1995; Incisa della Rocchetta & Milner, 1993; Janowsky, Shimamura, Kritchevsky, & Squire, 1989; Janowsky, Shimamura, & Squire, 1989; Jetter, Poser, Freeman, & Markowitsch, 1986; Stuss, Alexander, Palumbo, Buckle, Sayer, & Pogue, 1994; Walker, 1986). Frontal lesion (FL) patients, however, have a relatively preserved recognition memory and their recall can improve if they are given appropriate cues (Jetter et al., 1986; McAndrews & Milner, 1991; Milner, Corsi, & Leonard, 1991). A review of the literature The authors thank Dr. Mark Shapiro for the medical screening of some of the frontal lobe dementia patients. Address correspondence and reprint requests to Jordan Grafman at Cognitive Neuroscience Section NIH/NINDS/MNB, Building 10, Room 5C205, 10 Center Drive, MSC 1440, Bethesda, MD 20892-1440. Fax: (301) 480-2909. E-mail: [email protected]. 213 0278-2626/99 $30.00

Copyright  1999 by Academic Press All rights of reproduction in any form reserved.

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on the performance of FL patients on tests of recognition, cued recall, and free recall shows strong evidence that frontal damage disrupts performance on all three types of test, with the greatest impairment in free recall, a moderate impairment in cued recall, and little or no impairment in recognition (Moscovitch & Winocur, 1995; Wheeler, Stuss, & Tulving, 1995). Deficits in temporal order memory are also prominent in FL patients (Fabiani & Friedman, 1997; Fuster, 1985; Kesner, Hopkins, & Fineman, 1994; Milner et al., 1991; Milner, Petrides, & Smith, 1985; Shimamura, 1995; Shimamura, Janowsky, & Squire, 1990) and can be partially attributed to their impaired strategic retrieval (Mangels, 1997; Vriezen & Moscovitch, 1990). Memory for the source of learned facts (i.e., where and when the facts were learned) is also documented to be impaired after frontal lobe lesions and attributed to the special role played by the frontal lobes in associating facts to the context in which they were learned (Dywan, Segalowitz, Henderson, & Jacoby, 1993; Janowsky et al., 1989; Johnson, 1997; Johnson, Kounios, & Nolde, 1997; Johnson, O’Connor, & Cantor, 1997; Shimamura & Squire, 1987). It has been suggested that frontal lobe dysfunction causes a disconnection between fact memory and context memory rather than causing amnesia for the context itself (Shimamura & Squire, 1987). Moscovitch and Winocur (1995) link the concept of source amnesia to the phenomenon of confabulation, a problem in the strategic aspects of retrieval and not in the particular kind of memory, while others (Dywan & Jacoby, 1990) argue that source errors represent an attributional problem resulting from disordered attention. Distractibility and difficulty in holding information in working memory is also found in FL patients (Fuster, 1985; Kapur, 1988; Stuss, Kaplan, Benson, Weir, Chiulli, & Sarazin, 1982; Vilkki & Holst, 1988). Impaired performance on tests of associative learning and memory is also seen in patients with damage to the frontal cortex (Gershberg, 1997; Owen, Sahakian, Semple, Polkey, & Robbins, 1995; Petrides, 1985a, 1990, 1997; Shimamura, Jurica, Mangels, Gershberg, & Knight, 1995; Vriezen & Moscovitch, 1990). Petrides and co-workers have extensively studied the performance of monkeys, nonhuman primates, and patients with frontal lobe damage on conditional associative tasks, which require learning arbitrary associations between a set of stimuli and a set of alternative responses (Petrides, 1985a, 1985b, 1987, 1990, 1997; Petrides & Milner, 1982). On the basis of their studies, Petrides and co-workers concluded that the impairment mainly reflects a specific difficulty in learning to select among competing responses and not a general deficit secondary to inadequate strategy development/retrieval (Petrides, 1997). The involvement of the frontal lobes in associative learning and memory processes has also been confirmed by a number of event-related potentials and neuroimaging studies in normal subjects (Buckner, Raichle, Miezin, & Petersen, 1996; Dolan & Fletcher, 1997; Petrides, 1995; Tendolkar, Doyle, & Rugg, 1997; Weyerts, Tendolkar,

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Smid, & Heinze, 1997). Gershberg and Shimamura administered organized lists of words to patients with FL lesions and reported that they were impaired on free and associate-cued recall of related and unrelated items (Gershberg, 1997; Gershberg & Shimamura, 1995). They argued that the FL patient deficit could not be explained by impaired semantic processing but rather by a problem in the use of organizational encoding and strategic retrieval processes. On the other hand, Shimamura, Jurica, Mangels, Gershberg, and Knight (1995), in agreement with Petrides, argued that the impaired performance of FL patients on paired-associate learning of related material resulted from their disrupted on-line control of irrelevant or competing memory associations. The goal of the present study was to further evaluate associative learning and memory processes in patients with frontal lobe dysfunction. Although many investigators have examined associative memory in FL patients, their findings are based on different baseline conditions, different levels of difficulty, dissimilar scales, and nonhomogeneous patient groups (Moscovitch & Winocur, 1995). In our study, we used a relatively homogeneous group of patients with circumscribed frontal lesions, as well as a second group of patients with frontal dementia. Furthermore, we used the same sets of stimuli for the tests of recognition and cued and free recall. Thus, the present study is designed to replicate and extend the previous findings using a well-studied task. To achieve this goal, we employed an experimental paired associates test (EPAT) (Grafman, Rao, Bernardin, & Leo, 1991; Grafman, Weingartner, Lawlor, Mellow, Thompsen-Putnam, & Sunderland, 1990; Weingartner, Burns, Diebel, & LeWitt, 1984; Weingartner, Kaye, Smallberg, Ebert, Gillin, & Sitaram, 1981) which contains three conditions for the evaluation of recognition, free and cued recall of both semantically related and semantically unrelated pictures and words. We then tried to identify anatomic correlates of any observed memory impairments. We studied patients with focal frontal lesions and a group of patients with frontal lobe dementia (FLD). FLD is a progressive bilateral frontotemporal cortical degenerative disease in which cognitive deficits, including diminished memory, accompany personality and behavioral changes (Alexander, Prohovnik, Sackeim, Stern, & Mayeux, 1995; Elfgren, Ryding, & Passant, 1996; Filley, Kleinschmidt-De Masters, & Gross, 1994; Frisoni, Pizzolato, Geroldi, Rossato, Bianchetti, & Trabucchi, 1995; Gregory & Hodges, 1996; Miller, Ikonte, Ponton, Levy, Boone, Darby, Berman, Mena, & Cummings, 1997; Moss, Albert, & Kemper, 1992; Talbot, 1996). Although patients with FLD demonstrate personality and social cognition problems, memory deficits are typically not prominent in the initial stages of FLD. While FL patients with selective lesions may demonstrate selective memory deficits, we expected the FLD patients to show a more global impairment in the cognitive processes required for associative learning and recall.

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METHODS

NC Subjects Thirty-eight normal subjects (92% right-handed, 17 male, 21 female), between the age of 22 and 85 years (M ⫽ 52.6 years, SD ⫽ 18.0 years) with between 10 and 22 years of education (M ⫽ 15.9 years, SD ⫽ 2.7 years) were recruited for this study. None of the subjects reported any history of alcohol or drug abuse or neurologic or psychiatric illness. All subjects were administered the EPAT and their scores on the different measures of the test were analyzed for the effects of age, education, handedness, and gender.

FL Patients Eighteen patients (16 male, 2 female) with nonprogressive frontal lesions confined to the frontal lobes (eight unilateral left, five unilateral right, and five bilateral) participated in the study. Eleven patients were veterans who received penetrating missile or shrapnel wounds during the Vietnam war, and 7 patients had undergone surgery due to tumors (n ⫽ 2), aneurysms (n ⫽ 2), or hematomas (n ⫽ 3). The 7 surgical patients were tested from 1 to 8 years postoperatively (M ⫽ 3.3). At the time of their evaluation, the patients age ranged between 20 and 62 years (M ⫽ 46.0 years, SD ⫽ 11.7 years) and their education ranged between 11 and 22 years (M ⫽ 15 years, SD ⫽ 3.0 years). All FL patients were administered the EPAT and their performance on all measures was compared with the performance of 18 age- (M ⫽ 45.8 years, SD ⫽ 17.5 years) and education(M⫽ 15.7 years, SD ⫽ 3.0 years) matched normal controls (NC) selected from the larger NC group described above. The demographic characteristics of the FL patients and the matched controls, as well as the patients’ general cognitive tests and EPAT scores, are given in Table 1. The EPAT results of the FL patients were compared with their results from the Wechsler Adult Intelligence Scale-Revised (WAIS-R) (Wechsler, 1981), the Wechsler Memory Scale (WMS) (Wechsler, 1974), the Wisconsin Card Sorting Test (WCST) (Berg, 1948; Grant & Berg, 1948), the National Adult Reading Test (NART) (Nelson, 1982), and the Beck Depression Inventory (BDI) (Beck, 1987). Precise individual charts of damaged frontal brain regions were drawn based on individual head CT or MRI scans available for 16 of the patients (Damasio & Damasio, 1989). Each individual lesion chart was represented as a vector of zeros and ones, indicating absence or presence of damage for all frontal Brodmann areas. The FL patients’ EPAT performance was analyzed for an effect of lateralization of lesion or specific lesion sites (Table 2).

FLD Patients Ten patients (4 male, 6 female), clinically diagnosed with FLD, aged between 52 and 85 years (M ⫽ 66.0 years, SD ⫽ 11.5 years) and educated between 12 and 18 years (M ⫽ 15.1 years, SD ⫽ 2.2 years), were included in the study. The clinical diagnoses were made according to the core diagnostic and exclusion research criteria based on the Lund and Manchester consensus statement (The Lund and Manchester Groups, 1994; Neary, Snowden, Gustafson, Passant, Stuss, Black, Freedman, Kertesz, Robert, Albert, Boone, Miller, Cummings, & Benson, 1998). The FLD patients’ results on all EPAT measures were compared to those of 10 normal control subjects selected from the larger NC group described above who were matched for age (M ⫽ 64.7 years, SD ⫽ 12.3 years) and education (M⫽ 15.3 years, SD ⫽ 2.0 years) with the FLD patients. The EPAT performance of the FLD group alone was compared with their performance on the WAIS-R (three patients were administered the WAIS), WMS, WCST, Mattis Dementia Rating Scale (MDRS) (Mattis, 1988), and the reading subtest of the Wide

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TABLE 1 Demographic Data, Basic Cognitive and EPAT Scores, and ANOVA Results for the FL and NC groups (Means (SD))

N Age (years) Education (years) Paired recall—total pairs Free recall Total correct items Total correct pairs Semantic intrusions Acoustic intrusions Random intrusions Recognition Pictures Words Total WAIS-R Vocabulary VIQ FSIQ WMS Verbal paired assoc. imm. Verbal paired assoc. del. Verbal memory Non-verbal memory BNT WCST Categories % Perseveration NART BDI

FL

NC

ANOVA results

18 46.0 (11.7) 15.0 (3.0) 11.8 (3.0)

18 45.8 (17.5) 15.7 (3.0) 16.2 (5.4)

NS NS F(1, 34) ⫽ 5.6, p ⬍ .05

15.9 3.9 0.7 0 0.3

(7.0) (3.0) (0.9) (0) (0.5)

29.7 (10.8) 10.7 (5.3) 0.8 (0.9) 0 (0) 0.2 (0.4)

F(1, 34) ⫽ 20.7, p ⬍ .0001 F(1, 34) ⫽ 22.3, p ⬍ .0001 NS NS NS

26.8 24.8 51.4

(3.4) (6.0) (7.0)

27.3 28.3 55.6

(2.7) (2.7) (4.3)

NS F(1, 34) ⫽ 5.0, p ⬍ .05 F(1, 34) ⫽ 4.8, p ⬍ .05

9.3 (2.8) 98.2 (12.5) 97.9 (12.0) 17.6 (4.5) 6.2 (1.8) 98.9 (17.6) 100.1 (17.9) 53.5 (4.9) 4.0 (2.4) 18.7 (18.0) 105.8 (10.5) 13.4 (7.9)

Range Achievement Test (WRAT) (Jastak & Wilkinson, 1984). The demographic and basic cognitive data, as well as the EPAT scores for the FLD patients and their matched NCs, are given in Table 3. This study was approved by the Institutional Review Board. All participating subjects understood the test instructions and gave their written informed consent to participate in the study.

Procedure There were two sets of stimuli in the EPAT. The first set of stimuli consisted of 32 cards with pairs of pictures and words on them. Eight of the cards had two pictures, 8 had two words, 8 cards had a word on the left and a picture on the right side, and 8 cards had a picture on the left and a word on the right side. Half of the pairs of each of the four types had unrelated items, and the other half had related items. The second set of stimuli, used for cued recall, consisted of 32 cards with single words or pictures on them, which contained only the first item of the 32 pairs. There were a total of 64 different items to be remembered, 32 of them

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TABLE 2 Individual Lesion Sites and Lateralization Patient Lateralization BA4L BA4R BA44L BA44R BA45L BA45R BA47L BA47R BA6L BA6R BA10L BA10R BA9L BA9R BA8L BA8R BA46L BA46R BA32L BA32R BA11,12L BA11,12R BA25L BA25R BA24L BA24R

1 L 1 0 0 0 1 0 0 0 1 0 1 0 1 0 1 0 1 0 1 0 1 0 0 0 1 0

2 B 0 0 1 0 0 1 0 0 0 0 1 1 0 1 0 0 0 1 1 1 1 1 0 0 1 1

3 B 0 0 0 0 0 0 0 0 1 1 0 0 0 1 1 1 0 0 0 0 0 0 0 0 0 0

4 L 0 0 0 0 0 0 0 0 0 0 1 0 0 0 0 0 1 0 1 0 1 0 0 0 0 0

5 L na na na na na na na na na na na na na na na na na na na na na na na na na na

6 R 0 1 0 1 0 1 0 0 0 1 0 1 0 0 0 0 0 1 0 0 0 0 0 0 0 1

7 B 1 1 0 1 0 0 0 0 1 1 0 0 1 0 1 1 1 0 1 1 0 0 0 0 0 0

8 R 0 0 0 0 0 0 0 0 0 0 0 1 0 0 0 0 0 0 0 0 0 1 0 0 0 1

9 B 0 0 0 0 0 1 0 0 0 0 1 1 1 1 1 1 1 1 1 1 1 1 0 0 0 1

10 R 0 0 1 1 0 1 0 0 0 1 0 0 0 0 0 1 0 1 0 1 0 0 0 0 0 1

11 B 0 0 1 0 0 0 0 0 1 1 0 1 1 1 1 1 0 1 1 1 1 1 0 0 1 1

12 L 0 0 0 0 1 0 0 0 0 0 1 0 0 0 0 0 1 0 1 0 1 0 0 0 1 0

13 R na na na na na na na na na na na na na na na na na na na na na na na na na na

14 L 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 1 0 0 0 0 0 0 0 0 0

15 L 0 0 0 0 1 0 0 0 1 0 1 0 1 0 0 0 1 0 1 0 1 0 0 0 1 0

16 R 0 0 0 0 0 1 0 0 0 1 0 0 0 0 0 0 0 1 0 1 0 0 0 0 0 1

17 L 1 0 1 0 1 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0

18 L 0 0 0 0 0 0 0 0 0 0 1 0 0 0 0 0 1 0 1 0 1 0 1 0 0 0

Note. BA, Brodmann area; L, left; R, right; B, bilateral; na, not available.

were pictures and 32 of them were words. All items were common, concrete, and easily imaginable even for young children. Each of the 32 cards was presented for 4–5 s, in random order, one at a time, with the examiner verbally pronouncing the names of the item pairs during presentation. During the cued recall part of the test, subjects were shown the cards with one-half of each item pair on them, one at a time, and were asked to recall the missing item. Subjects were informed whether their response was correct. If subjects did not answer or answered incorrectly, they were then told the correct response. The dependent variables were the numbers of correct pairings (four modalities, two levels of relatedness), the composite numbers for the four modalities, the composite numbers for the two levels of relatedness, and the total number of correct pairings. The cued recall condition was followed by the free recall condition. Subjects were asked to name as many of the individual items from the item pairs as they could in any order they wished. Answers were recorded in the exact order they were given by the subjects. From this list were counted the total number of correct responses; the numbers of semantic, acoustic, and random intrusions; the numbers of items originally presented as pictures or words, in related or unrelated pairs; and the number of items recalled as pairs, i.e., temporally adjacent to each other in free recall. Next there was an approximately 20-min filled delay which was followed by the format recognition condition. On this occasion, the examiner read aloud, one at a time, the names of the 64 items shown earlier as item pairs and asked the subject to tell if they remembered seeing each item as a picture or word. The dependent variables were the total numbers of correctly identified pictures and words.

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TABLE 3 Demographic Data, Basic Cognitive and EPAT Scores, and ANOVA Results for the FLD and NC Groups (Means (SD))

N Age (years) Education (years) Paired recall—total pairs Free recall Total correct items Total correct pairs Semantic intrusions Acoustic intrusions Random intrusions Recognition Pictures Words Total WAIS-R Vocabulary VIQ FSIQ WMS Verbal paired assoc. imm. Verbal paired assoc. del. Verbal memory Nonverbal memory BNT WCST Categories % Perseveration WRAT MDRS Memory Total

FLD

NC

ANOVA results

10 66.0 (11.5) 15.1 (2.2) 8.4 (6.2)

10 64.7 (12.3) 15.3 (2.0) 12.3 (4.5)

NS NS NS

11.7 2.7 2.8 0.1 0.2

(5.9) (2.9) (3.9) (0.3) (0.7)

24.8 (10.2) 7.5 (6.0) 0.8 (0.8) 0 (0) 0.2 (0.4)

F(1, 18) ⫽ 12.3; p ⬍ .01 F(1, 18) ⫽ 5.1; p ⬍ 0.05 NS NS NS

27.1 26.8 50.1

(4.1) (8.7) (8.2)

26.8 27.7 54.5

(3.7) (2.8) (5.3)

NS NS NS

6.6 (3.7) 81.2 (17.5) 83.3 (14.4) 8.9 (8.6) 3.3 (2.9) 75.1 (26.9) 88.4 (24.4) 38.7 (23.1) 3.3 (2.6) 39.6 (23.1) 38.0 (11.0) 17.3 (5.2) 102.3 (31.0)

Statistical Analysis The data were analyzed by MANOVA, repeated measures ANOVA, Pearson productmoment correlations, and cluster analysis, using the program Statistica (StatSoft, Tulsa, OK).

RESULTS

NC Group The performance of the normal subjects on all EPAT measures was analyzed for demographic and task-specific effects. No significant main effects of age, education, handedness, or gender were observed. For cued recall, a repeated measures ANOVA revealed a significant effect

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(F(3, 78) ⫽ 5.5; p ⬍ .01) of format (picture–picture, word–word, word– picture, picture–word) and relatedness (F(1, 26) ⫽ 204.2; p ⬍ .0001), a significant interaction of education and gender (F(1, 26) ⫽ 5.6; p ⬍ .05), and a significant format by relatedness interaction (F(3, 78) ⫽ 8.6; p ⬍ .0001). Significant post hoc tests revealed that picture–picture pairs were recalled better than the other types of item pairs, that related pairs were recalled better than unrelated pairs, and that educated women recalled more pairs than other NC subjects. For free recall of single items, there were significant effects of item format (F(1, 26) ⫽ 43.0; p ⬍ .0001) and item pair relatedness (F(1, 26) ⫽ 15.0; p ⬍ .001) and a significant interaction of format and relatedness (F(1, 26) ⫽ 7.8; p ⬍ .01). Significant post hoc tests revealed that more pictures than words and more items from related than from unrelated pairs were recalled, and therefore pictures from related pairs were significantly better recalled than words from unrelated pairs. For free recall of item pairs, there was no effect of format but there was a significant effect of relatedness (F(1, 26) ⫽ 36.8; p ⬍ .0001). For format recognition, there was no significant difference in the number of items recalled as words or pictures. FL Patients The analysis of the performance of the FL group and their respective NC group yielded significant effects of format and relatedness, identical to the ones observed for the larger normal control group. In addition, there were significant effects of group on cued recall (F(1, 34) ⫽ 5.6; p ⬍ .05) and for total correct items (F(1, 34) ⫽ 20.7; p ⬍ .0001) and total correct pairs (F(1, 34) ⫽ 22.3; p ⬍ .0001) generated during the free recall condition. There were no significant differences between the FL and NC groups in the generation of semantic, acoustic, or random intrusions during free recall. On the format recognition condition of the EPAT, the FL patients demonstrated a bias for remembering items as being presented as pictures during encoding although their scores for recall of pictures were not significantly different from the scores of the NC subjects. They did recall significantly fewer items as words than the NC group (F(1, 34) ⫽ 5.0; p ⬍ .05) and their total recognition (F(1, 34) ⫽ 4.8; p ⬍ .05) was impaired compared to the NC group. The overall results from the comparison of the performance of the FL and NC groups on the EPAT measures of free and cued recall and recognition are given in Table 1 (see above). Since there were no interactions between group and format or group and relatedness, only the means and ANOVA results for the composite cued and free recall EPAT measures are presented. An effect of lateralization of lesion in the FL patient group was observed for cued recall (F(2, 15) ⫽ 7.1; p ⬍ .01), on the number of random intrusions during free recall (F(2, 15) ⫽ 6.9; p ⬍ .01), and on the total number of pairs

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generated during free recall (F(2, 15) ⫽ 4.2; p ⬍ .05). Post hoc analysis showed that patients with left frontal lesions made significantly more random intrusions during free recall and generated significantly less pairs after being cued and during free recall than patients with right or bilateral frontal lesions. We subsequently analyzed the matrix of all patients’ lesion sites (see Table 2) for possible dependencies between the location of lesion and the performance of the FL group on the EPAT. Significant negative correlations (the more Brodmann areas that were damaged in the frontal lobe, the poorer the performance) were found between all left frontal areas and most EPAT-related and total cued and free recall measures. The left frontal areas with the higher number of significant correlations were the dorsolateral and mesial prefrontal cortex, the frontal operculum, and the anterior cingulate gyrus (Brodmann areas 46, 10, 45 and 24). Only the vector representing damage to Brodmann area 8 was significantly correlated with the total measure of recognition. Paradoxically, there were significant positive correlations (the greater the damage, the better the performance) between all right frontal areas and the related, unrelated, and total cued and free recall EPAT measures. The right frontal area with the highest number of significant correlations was the orbital region (Brodmann area 11/12), followed by the dorsolateral and mesial prefrontal regions and the anterior cingulate gyrus (Brodmann areas 10, 24, 9, and 8). When the five patients with bilateral lesions were excluded from the analysis, we obtained an absolutely identical pattern of right frontal significant correlations. Exact overlap of significant negative correlations was observed for left Brodmann areas 46, 10, and 24. Left frontal areas 8 and 45 fell below the level of significance but there were additional significant negative correlations of left orbital gyri and association and primary motor cortical regions (Brodmann areas 11/12, 32, 9, 25, and 4) with the cued and free recall-related and total EPAT measures, and of left area 25 with all recognition measures. Next, the performance of the FL patients on the EPAT was compared with their performance on the tests of general cognitive abilities. Consistent patterns of significant positive correlations were observed between the WAIS-R verbal IQ and vocabulary subtest scores and the cued and free recall measures from the EPAT. In addition, the WAIS-R verbal IQ was also significantly correlated with the total recognition score. As expected, the WMS verbal paired associates subtest delayed score and WMS verbal memory index score were significantly positively correlated with the EPAT total measures of recognition, cued and free recall. There were also some other scattered significant correlations between several WMS index scores and EPAT measures. The number of correct responses on the BNT was highly positively correlated with the numbers of related and total pairs generated by the FL patients during the cued and free recall conditions. There were also positive significant correlations between the number of achieved categories on the WCST

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and most free recall EPAT measures. There were no statistically significant correlations between the EPAT and the NART or BDI total scores. FLD Patients The analysis of the EPAT performance of the FLD group and their matched NC group revealed significant effects of relatedness on the cued and free recall measures and item format on the free recall item distribution measures, which were identical to the ones observed in the larger normal group. However, there was no significant effect of pair format. There was no effect of group on all cued recall measures. For the free recall condition, there were significant effects of group on the total correct items (F(1, 18) ⫽ 12.3; p ⬍ .01) and total correct pairs (F(1, 18) ⫽ 5.0; p ⬍ .05) measures with the FLD patients performing more poorly. There were no group effects on the recognition measures. The ANOVA results from the performance of the FLD and NC groups on the total recognition and free and cued recall EPAT measures are presented in Table 3 (see above). The computation of the correlation coefficients among the general cognitive abilities scores and EPAT measures resulted in a matrix with just a few scattered significant correlations, much fewer and less consistent than the ones observed in the FL group. The WMS immediate and delayed verbal paired associates scores were significantly positively correlated with the EPAT measures of total cued and free recall. The MDRS memory and the WRAT reading measures were positively significantly correlated with the number of total items correctly identified during recognition. The distribution of FLD patient scores on the EPAT indicated that there were two subgroups of FLD patients (each composed of five patients) which was confirmed by cluster analysis. The EPAT performance of one of the two formed FLD subgroups did not differ significantly from the performance of the NC group on any of the general measures of recognition or cued or free recall. The other FLD subgroup, however, appeared impaired in comparison with the NC group on the cued recall measures (F(1, 13) ⫽ 16.0; p ⬍ .01), on the free recall measures of correctly recalled items (F(1, 13) ⫽ 11.9; p ⬍ .01) and pairs (F(1, 13) ⫽ 6.3; p ⬍ .05), and on the total number of items correctly identified during recognition (F(1, 11) ⫽ 8.3; p ⬍ .05). The FLD subgroup impaired on the EPAT performed significantly worse than the other FLD subgroup on the MDRS memory subtest (F(1, 6) ⫽ 18.1; p ⬍ .01) and on the WMS verbal memory measures. The impaired FLD subgroup consisted of patients who were older and had a later disease onset and demonstrated additional left or bilateral anterior temporal lobe atrophy as determined by a blinded reading of their CT or MRI brain scans. FL vs FLD Patients There were no significant between-group (FLD vs FL) differences for any EPAT measure even though the FLD group was significantly older than the

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TABLE 4 EPAT Total Scores for All Groups (Mean (SD)) NC n ⫽ 38 Paired recall Free recall—items Free recall—pairs Recognition

14.9 26.2 8.9 55.8

(5.2) (9.5) (5.0) (3.9)

Right FL n⫽5

Bilat. FL n⫽5

15.2 14.0 4.2 54.6

15.2 19.8 6.4 49.0

(6.1) (7.4) (3.6) (4.9)

(2.8) (3.7) (1.8) (4.6)

Left FL n⫽8 7.6 14.6 2.3 50.9

(3.5) (8.0) (2.1) (8.9)

Low FLD n⫽5

High FLD n⫽5

3.2 6.6 0.2 47.5

13.6 15.2 4.8 54.6

(3.1) (4.7) (0.4) (6.4)

(2.9) (5.6) (2.8) (2.3)

FL group (F(1, 26) ⫽ 19.1; p ⬍ .001). Analysis of the EPAT performance of five patient subgroups—left FL, right FL, bilateral FL, more impaired FLD, and less impaired FLD—indicated an effect of group for the cued recall measures (F(5, 60) ⫽ 8.0; p ⬍ .0001) and for the free recall measures of items (F(5, 60) ⫽ 7.9; p ⬍ .0001) and pairs (F(5, 60) ⫽ 6.9; p ⬍ .0001) but not for the recognition measures. Planned comparisons revealed that the left FL and the impaired FLD groups’ performance was much worse than the performance of the NC, right FL, bilateral FL, and unimpaired FLD groups. There was also an effect of age (p ⬍ .01), with the left FL group being the youngest and the impaired FLD group being the oldest but no interaction between age and the other measures. The EPAT score distributions for all groups are given in Table 4. The cued and free recall total measures group differences are illustrated in Fig. 1. DISCUSSION

The FL patients appeared impaired in comparison with their matched NC subjects on all three EPAT conditions. They were especially compromised on the free recall condition and recalled significantly less single items and significantly less members of pairs in adjacent order for all types of picture– word modalities and for both related and unrelated pairs. The FL patients also appeared modestly but significantly impaired on the cued recall of associated items across format and relatedness variables. FL patients appeared picture biased during recognition. The FL and NC groups had a similar number of semantic, acoustic, and random intrusions (which was surprising considering the usual interference effect demonstrated by FL patients on recall). However, when lateralization of lesion was used as a grouping variable for the analysis of the EPAT performance of the FL group, patients with left frontal lesions had a significantly higher number of random intrusions compared to FL patients with bilateral and right frontal lesions. Patients with left frontal lesions also did significantly worse than the patients with bilateral and right frontal lesions on the cued and free recall conditions of the EPAT. No effect of lateralization was observed for format recognition of pictures and words. This marked effect of left frontal lobe lesions was confirmed by our finding that damage to most left frontal regions (and predominantly the dorsolateral

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FIG. 1.

(a) Cued recall—group means. (b) Free recall—group means.

prefrontal cortex) was significantly negatively correlated with the patients’ performance on the cued and free recall EPAT measures. This finding regarding the relationship between left frontal damage and poorer performance on the cued and free recall parts of the EPAT is in concordance with the neuroimaging findings of Petrides (1995) and Dolan and Fletcher (1977) of left frontal activation during performance of normal subjects on verbal free recall and paired associate tasks. Our seemingly paradoxical finding of better cued and free recall performance being associated with right frontal damage

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might be due to the imprecision of our lesion analysis method. Another possibility is that the left frontal cortex is so specialized for the kind of precise episodic verbal recall we demanded of subjects in our task that the additional contribution of right frontal cortex processing could only have diminished performance on this task. Right frontal lesions, therefore, would release the left frontal cortex to accomplish the task efficiently. This admittedly speculative interpretation would also suggest that if our encoding or recall conditions were designed in such a way as to have required such processes as temporal order judgment, then a right frontal lesion might have led to an equally impaired performance. Our findings are compatible with previous studies indicating that FL patients have difficulty in selecting from a set of competing responses the appropriate response during conditional associative learning and recall of unrelated (Petrides, 1997) and semantically related (Shimamura, 1995) items. Our findings also confirm the conclusion of Wheeler et al. (1995), based on metaanalysis of numerous reports on the relation between frontal lobes and memory, that frontal lobe damage disrupts performance on tests of recognition, cued recall, and free recall, with the greatest impairment in free recall and the smallest in recognition. Memory for the source of learned facts (i.e., when and where the facts were learned and whether they were inferred or imagined, suggested or seen) is different from the memory for the format in which the stimuli were presented (i.e., picture or word) and for this reason the performance of the frontal group on the format recognition condition is only mildly impaired (and not severely impaired, as would be expected on a source memory test as described by several authors (Dywan et al., 1993; Janowsky et al., 1989; Johnson, 1997; Johnson et al., 1997, 1997; Shimamura & Squire, 1987)). Because of the compactness of the EPAT which uses same sets of stimuli for all three conditions, there is a possibility that the cued recall serves as an additional learning session for the free recall condition, which comes immediately after it, and that the NC subjects benefited more from this additional learning than the FL patients. However, FL patients have been found to be severely impaired on tests of free recall alone in many other studies (Wheeler et al., 1995). The EPAT stimuli, which are composed of imageable words and pictures, probably require dual encoding and retrieval strategies with a significant verbal component consistent with the significant correlations of the EPAT measures with the WMS, WAIS-R, and BNT verbal measures. The bias for recognition of visual stimuli could be accounted for by the possibility that the FL patients rely more on posterior visual surface feature processing for encoding and retrieval. We can exclude depression as a possible cause for the impaired EPAT performance of the FL group since the total BDI score was not associated with any EPAT measure. We expected that the FLD patients in our study would show a more global decline in the cognitive processes required for associative recall. Our FLD

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patients as a group performed comparably to their NC controls on the measures of recognition and cued recall, and only their performance on the free recall condition was impaired. This result is in agreement with the observations of many researchers (Filley et al., 1994; Frisoni et al., 1995; Gregory & Hodges, 1996) that verbal memory deficits in FLD are not prominent early in the course of the disorder. However, the two subgroups we found within the FLD group differed significantly from each other on the EPAT measures of recognition and cued and free recall. The EPAT performance of one of the subgroups was not significantly different from the performance of the NC group, while the other subgroup appeared impaired on all total EPAT measures in comparison with the NC. We suspected that the impaired subgroup consisted of individuals with longer disease duration. However, no relationship between impaired cognitive function and age at onset or duration of disease was found in the FLD patients in our study or in the study of Elfgren et al. (1996). The impaired FLD patients were older and performed significantly worse than the patients in the less impaired FLD subgroup on the MDRS memory and WMS verbal paired associates measures—performance on both these tasks is associated with EPAT performance. The impaired FLD patients had additional left or bilateral temporal lobe atrophy based on their CT or MRI head scans. Although there was no effect of age observed on the EPAT performance of the larger NC group, it is possible that old age interacts with the changes caused by frontal lobe degeneration to cause decrements in memory performance or that temporal lobe atrophy contributes to some memory impairments by a mechanism that is different than the one observed in FL patients. Petrides (1997) found that subjects with temporal lobe excisions were not impaired on their conditional associative task unless they had extensive damage to the hippocampal system (which is present in most FLD patients). On the other hand, there are reports (Goldstein, Canavan, & Polkey, 1988; Ivnik, Sharbrough, & Laws, 1988) that left temporal lobe damage is associated with impaired performance on the WMS (including verbal paired associates) subtests. Direct comparison of the performance of all patient subgroups showed that the left FL group and the impaired FLD group performed similarly on the cued and free recall conditions and that their performance was significantly worse than the performance of the other patient groups or the larger NC group. Another interpretation of our results is possible on the basis of the distinction of levels of cognitive processing with respect to the amount of effort they require. The attentional requirements during encoding and recognition may be based on a more automatic cognitive process since it involves the retrieval of the surface features of the stimuli. On the other hand, free recall is a task demanding significant mental effort, because it depends on meaningfully encoding and then recalling of previously presented material. Cued recall, which could be placed between recognition and free recall in the contin-

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uum from automatic to effort-demanding cognitive processes, may allow a reduction in competing responses since each cue is associated with only one response (in our task). Since FL patients are usually impaired on the effortdemanding free recall tasks, but were able to perform better on the less effortdemanding cued recall tasks, then their automatic processing should be relatively intact. On the other hand, FL patients have problems functioning in complex everyday situations in which automatic processing is required in order to engage in highly overlearned behaviors while simultaneously managing other activities (Grafman, 1989, 1995). Versions of the EPAT were utilized in several other studies for the assessment of the cognitive processing in patients with different diagnoses mainly within the automatic vs effortful framework (Grafman et al., 1991, 1990; Weingartner et al., 1984). In these studies, patients with depression, Parkinson’s disease, and multiple sclerosis were found to be significantly impaired on the effort-demanding free recall condition, but performed normally on the less effort-demanding format recognition condition, while patients with dementia–Alzheimer’s type were significantly impaired on both free recall and recognition. The results of the present study indicate that both left frontal and temporal lobe involvement can impair associative learning and that this impairment is more strikingly seen with free rather than cued recall. REFERENCES Alexander, G. E., Prohovnik, I., Sackeim, H. A., Stern, Y., & Mayeux, R. 1995. Cortical perfusion and gray matter weight in frontal lobe dementia. Journal of Neuropsychiatry and Clinical Neuroscience, 7, 188–196. Beck, A. T. 1987. Beck Depression Inventory. San Antonio, TX: The Psychological Corporation. Berg, E. A. 1948. A simple objective technique for measuring flexibility in thinking. The Journal of General Psychology, 39, 15–22. Buckner, R. L., Raichle, M. E., Miezin, F. M., & Petersen, S. E. 1996. Functional anatomic studies of memory retrieval for auditory words and visual pictures. Journal of Neuroscience, 16, 6219–6235. Damasio, H., & Damasio, A. R. 1989. Lesion analysis in neuropsychology. New York: Oxford University Press. Dolan, R. J., & Fletcher, P. C. 1997. Dissociating prefrontal and hippocampal function in episodic memory encoding. Nature, 388, 582–585. Dywan, J., & Jacoby, L. 1990. Effects of aging on source monitoring: Differences in susceptibility to false fame. Psychology of Aging, 5, 379–387. Dywan, J., Segalowitz, S. J., Henderson, D., & Jacoby, L. 1993. Memory for source after traumatic brain injury. Brain and Cognition, 21, 20–43. Elfgren, C. I., Ryding, E., & Passant, U. 1996. Performance on neuropsychological tests related to single photon emission computerised tomography findings in frontotemporal dementia. British Journal of Psychiatry, 169, 416–422. Eslinger, P. J., & Grattan, L. M. 1994. Altered serial position learning after frontal lobe lesion. Neuropsychologia, 32, 729–739.

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