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Recognition memory for unfamiliar faces in Parkinson's disease: Behavioral and electrophysiologic measures
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Parkinsonism and Related Disorders 13 (2007) 157–164 www.elsevier.com/locate/parkreldis
Recognition memory for unfamiliar faces in Parkinson’s disease: Behavioral and electrophysiologic measures Yasunobu Kidaa, Hisao Tachibanaa,, Masanaka Takedaa, Hiroo Yoshikawaa, Tsunetaka Okitab a
Department of Internal Medicine, Division of Neurology and Stroke Care Unit, Hyogo College of Medicine, 1-1, Mukogawa-cho, Nishinomiya, Hyogo 663-8501, Japan b Department of Psychology and Communication, Aichi Chukutoku University, Aichi 480-1197, Japan Received 25 April 2006; received in revised form 24 July 2006; accepted 28 August 2006
Abstract We analyzed event-related potentials (ERPs) and behavioral measurements during a recognition memory task in 15 normal elderly subjects and 15 patients with Parkinson’s disease (PD). To elicit ERPs unfamiliar faces were repeated immediately after initial presentation (at lag 0), after one intervening face (at lag 1) or at lag 3. Compared to normal controls, PD patients showed decreased accuracy in recognizing new unfamiliar faces. P170 latency and amplitude were similar between both groups. ERP amplitude between 300 and 500 ms after the stimulus in control subjects showed a positive shift (ERP repetition effect) for lag 0 at all sites and for lag 1 and 3 repetitions at the Fz site, while effects in the PD group were not noted at any site, even for the lag 0 repetition. ERP waveforms for the first presentation of faces in PD patients showed a significant positive shift compared to normal controls. These data suggest intact perception but impaired recognition memory for unfamiliar faces in PD. In addition, recognition memory deficits in PD may result from impairment of comparison of structural representations of presented faces with stored representations of faces known to the observer. r 2006 Elsevier Ltd. All rights reserved. Keywords: Event-related potential (ERP); ERP repetition effect; Parkinson’s disease; Recognition memory; Face perception
1. Introduction Although Parkinson’s disease (PD) classically is defined as a movement disorder, persons with PD also manifest neuropsychological deficits. Memory disturbances are among the cognitive deficits most commonly experienced by PD patients [1–5]. Studies of memory function in patients with PD show uniformly poor performance when a subject is required to consciously recall items from memory, while results are inconsistent when memory is tested by recognition methods [5–10]. Flowers et al. [6] reported that PD patients performed similarly to controls in recognition memory for objects, histograms, abstract designs, words and numbers, both immediately and after a delay. Dewick et al. [7], however, observed that while PD Corresponding author. Tel.: +81 798 45 6866; fax: +81 798 45 6873.
E-mail address: [email protected] (H. Tachibana). 1353-8020/$ - see front matter r 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.parkreldis.2006.08.012
patients performed similarly to controls on recognition tests using words, phrases and numbers, they were impaired on a recognition memory test using unfamiliar faces. Some authors [11] report face perception deficits in PD patients as well as memory deficits [7,9,10]. Levin et al. [10] also reported that PD patients with duration of illness less than 3 years performed significantly less well than controls on the short form of Benton’s Facial Recognition Task, a test of face perception. Although perception and recognition memory in PD thus appear impaired for faces, it is unclear which process is more impaired. Event-related potentials (ERPs) measure cognitive processing independently of motor disability, providing information complementary to that inferred from behavioral response characteristics measured during the test phases of memory evaluations [12]. ERPs have been used extensively to examine recognition memory function [13], consistently finding that repeated (old) words
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or figures evoked more positive ERPs than unrepeated (new) stimuli. This modulation has been termed ‘‘ the ERP repetition effect’’ or ‘‘ERP old/new effect’’. These repetition effects begin at approximately 250 ms following a stimulus and persist for several hundred milliseconds. They have been found to be larger when repeated items are assigned correctly to their study context than when these items are assigned incorrectly [14]. Based on such findings, many authors have suggested that repetition effects are evoked when recognition is accompanied by retrieval of information formed at the initial presentation of the item, i.e. conscious recollection [15–17]. ERP repetition effects thus should be highly informative in examining the nature of recognition memory impairment [18] in PD. The purpose of the present study was to evaluate whether ERP methods showed recognition memory for faces to be affected by PD and then clarify which stage of facial information processing represents the locus of impairment. ERPs were recorded in a direct memory task using unfamiliar faces. These stimuli were chosen because unfamiliar faces require the episodic process by which a completely new and distinctive representation is formed [19,20]. The interval between repetitions of items in previous ERP studies on recognition memory was varied from 30 s [21] to several minutes [22]. To ensure that the patients were able to perform the recognition task, we decided to use shorter intervals (12 s) between repetitions of items. To our knowledge, ERP data for PD patients in a recognition memory paradigm for faces have not been reported.
2. Experimental procedures 2.1. Subjects Study participants included 15 patients with a clinical diagnosis of idiopathic PD (6 women, 9 men; mean age7S.D., 63.478.2 years; range, 49–75) as well as 15 normal control subjects with no neurologic illness or drug abuse (6 women, 9 men; age, 65.078.1; range, 55–83). Patients with PD presented with insidious onset of two or more of cardinal symptoms (bradykinesia, tremor, or rigidity). Treatment with antiparkinsonian drugs improved symptoms and signs in all patients. Patients with secondary parkinsonism or with evidence of more widespread neurologic disease were excluded. Patients with evidence of focal lesions on computed tomography (CT) or magnetic resonance imaging (MRI) likewise were excluded. In the patient group, neuroradiologic examinations were normal or demonstrated mild diffuse cerebral atrophy. All patients fulfilled Parkinson’s Disease Society Brain Bank clinical criteria for definite PD [23]. Parkinsonian motor disability was graded on the scale of Hoehn and Yahr [24]. Depression was evaluated by use of Zung’s self-rating depression scale (SDS). Clinical and demographic data concerning patients with PD are presented in Table 1. No patient was demented according to the criteria at the Diagnostic and Statistical Manual of Mental Disorders, Edition IV [25]. Normal subjects were healthy and intellectually active, and were found to be normal on neurologic examination. We evaluated each subject’s cognitive function with the Mini-Mental State Examination (MMSE) [26]. All procedures were carried out with the adequate understanding and written consent of the subjects.
Table 1 Clinical characteristics of 15 patients with Parkinson’s disease Characteristic Sex, M/F, number of patients Age, y, mean7S.D. (range) Duration of disease, y, mean7S.D. (range) Hoehn–Yahr stage, number of patients II III IV Zung’s self-rating depression scale, mean7S.D. (range) Mini-mental State Examination score, mean7S.D. (range) Antiparkinson therapy, number of patients L-DOPAa Trihexyphenidyl hydrochloride L-DOPA, dopamine agonistb L-DOPA, amantadine, dopamine agonist L-DOPA, trihexyphenidyl hydrochloride, dopamine agonist L-DOPA, trihexyphenidyl hydrochloride, dopamine agonist, amantadine a
9/6 63.478.2 (49–75) 7.274.5 (2–15) 3 10 2 42.5710.1 (28–64) 28.172.4 (24–30)
3 1 6 1 2 2
With dopa-decarboxylase inhibitor (carbidopa or benserazide). Bromocriptine or pergolide or cabergoline.
b
2.2. ERP measurement 2.2.1. Stimuli and apparatus Stimuli consisted of 341 black and white photographs representing faces of persons unknown to the subjects. All facial pictures were frontal views against a neutral background. The pictures were scanned into a computer, and the resulting images were edited to a height of 14.1 cm and a width of 15 cm on a 15-inch monitor screen. A combination of 31 items comprised each list and 11 (1 practice, 10 experimental) lists are presented. The stimulus duration was 1 s and the interstimulus interval was 3 s (onset to onset). Of the 31 faces, the first appearance of a face was a nontarget stimulus and subsequent 30 faces were targets. Five target appearances were presented twice separately by no intervening item (lag 0); five were presented twice with one intervening item (lag 1); five were presented twice with three intervening items (lag 3). The procedure employed pseudorandom ordering of the first and second presentations of lag 0, 1 and 3 repeats.
2.2.2. Procedure Subjects were seated comfortably in a dimly lit room and given a thumb-switch to hold in each hand. They were instructed to minimize head movement, eye movements and blinking. Subjects were informed that they would see a sequence of faces on the monitor screen, and that they should respond as quickly and accurately as possible by pushing the right thumb button for the first (new) presentation of a unfamiliar face and the left thumb button for repeated (old) faces. Once they understood the instructions, subjects were given practice trials of 31 items to allow them to familiarize themselves with the task; then the first of the 10 experimental lists was presented on the computer screen pseudorandomly in a continuous repetition task sequence. Rest periods of 30 s were allowed following every 31-item list.
2.2.3. ERP recording An electroencephalogram (EEG) was recorded using silver-silver chloride electrodes placed at scalp sites Fz, Cz and Pz according to the International 10–20 system, with the reference electrode positioned at the
ARTICLE IN PRESS Y. Kida et al. / Parkinsonism and Related Disorders 13 (2007) 157–164 left earlobe. Eye movements (electrooculogram or EOG) were monitored by electrodes placed below the left inferior orbital margin and on the left outer orbit. Electrode impedance was maintained below 5 kO. The electroencephalographic and ocular activities were amplified using a 0.05–30 Hz filter and stored together with event markers on a magnetoptical disk after analog–digital conversion for subsequent off-line analyses.
2.2.4. Data analysis ERP averages for each stimulus and condition (new and lags 0, 1 and 3) were computed for each subject. Grand averages were computed separately for normal subjects and patients with PD. Trials in which amplitudes exceeded 750 mV for EOG and 7100 mV for EEG were rejected automatically. ERP waveforms were quantified by meanamplitude measures in the time window (between 300 and 700 ms) relative to a 200 ms prestimulus baseline. Reaction time (RT) was defined as the interval from stimulus onset to button pressing. This interval was recorded by the computer and checked for new/old errors, omissions and premature responses.
2.3. Statistical analysis Behavioral and ERP data were analyzed for normal vs. PD patient groups. Group differences (normal vs. PD) in MMSE scores and behavioral measures were tested using the Mann–Whitney U-test. ERP amplitude data were divided into intervals 300–500 ms (early stage) and 500–700 ms (late stage) from the onset of the stimulus and subjected to a four-way analysis of variance (ANOVA) with two conditions of group (PD vs. normal) as the between-subject variable, three conditions of electrode site (Fz, Cz, Pz ) as a within-subject variable, and two conditions of presentation (first vs. second), and three conditions of lag (lag 0, lag 1 and lag 3) as within-subject repeated measures factors. Planned comparisons of ERP repetition effects for each group were performed using Wilcoxon’s signed-rank test. Spearman’s rank correlation coefficients (r’s) were calculated to determine correlations. A level of Po0.05 was accepted as indicating statistical significance. Data are expressed as the mean7S.D.
3. Results 3.1. General cognitive testing All PD patients scored at least 24 points on the MMSE (mean7S.D., 28.172.4 points; range, 24–30) and were considered to have PD without dementia. No significant difference in MMSE scores was seen between patients and normal control subjects (28.472.0 points).
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(Po0.05), but no RT differences were evident between normal subjects and patients with PD for all lag repetitions (Tables 2 and 3). Both the control group and patients with PD showed a significant RT priming effect at the lag 0 repetition (Po0.01 for controls and Po0.02 for the PD group), while in the normal group RT in the lag 3 repetition was delayed relative compared to new faces (Po0.01). No significant correlation was found between RT and accuracy of response for new faces in the PD group. 3.2.2. ERPs Grand average ERP waveforms for the normal group and the PD group at each electrode are shown in Fig. 1. In normal subjects, new unfamiliar faces elicited waveforms characterized by negativity with a latency of about 115 ms, followed by positivity at 180 ms (vertex positive peak or VPP; P170) [23] and an additional negative peak at about 300 ms. No significant differences were evident in the P170 component between the two groups (latency, 183.0714.0 ms for controls and 196.3724.9 ms for PD patients; amplitude, 6.9472.36 mV for controls and 8.4373.22 mV for PD patients). Waveforms following the first and second presentations were virtually identical for the first 300 ms post-stimulus, after which the ERP in response to the second presentation began to show a more positive distribution. In normal subjects, the ERPs for repeated faces (lag 0) began to diverge from the ERPs for new faces at approximately 300 ms, and effects persisted to 700–1000 ms at the Fz, Cz and Pz sites. Repeated faces at lags 1 and 3 also showed a positive shift of ERP waveforms, although the magnitude of positive shift was less prominent. The positive shift of ERP waveforms was found only at the Fz site. In patients with PD, similar ERP waveforms also were elicited for new faces, although the waveforms were shifted in a positive direction compared with those in normal controls. Four-way ANOVA for mean ERP amplitudes between 300 and 500 ms after stimulus onset disclosed main effects for group [F(1, 28) ¼ 5.98, Po0.05], electrode site [F(2, 56) ¼ 3.17, Po0.05], lag [F(2, 56) ¼ 10.42, Po0.001] and presentation [F(1, 28) ¼ 4.86, Po0.05]. Significant inter-
3.2. ERP task 3.2.1. Behavioral measures Response accuracy in PD patients was significantly decreased compared to the normal group for the first presentation (Po0.02 for new faces). No significant differences in response accuracy were noted between patients and normal controls for lag 0, 1 and 3 repetitions. Both the control group and patients with PD showed significant priming effects of response accuracy at lag 0 repetition (Po0.01 for controls and Po0.01 for the PD group). No priming effects were found at lag 1 or 3. Significant differences were seen in RTs for new faces
Table 2 Response accuracy (%) for new and repeated facesa
First presentation Lag 0 repetition Lag 1 repetition Lag 3 repetition a
Elderly normal
Parkinson’s disease
Mann–Whitney U-test, P-value elderly vs. Parkinson
90.179.4
80.0719.4
0.017
97.275.2 79.8717.8 64.1721.6
91.5714.8 77.1717.2 59.7717.1
Ns Ns Ns
Values are mean7S.D.
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actions of group presentation [F(1, 28) ¼ 4.86, Po0.05], electrode lag [F(4, 112) ¼ 2.70, Po0.05], electrode presentation [F(2, 56) ¼ 3.31, Po0.05] and group lag presentation [F(2, 56) ¼ 5.20, Po0.01] were evident. In the
Table 3 Reaction time (ms) for new and repeated facesa
First presentation Lag 0 repetition Lag 1 repetition Lag 3 repetition
Elderly normal
Parkinson’s disease
Mann–Whitney U-test, P-value elderly vs. Parkinson
8557144
9447200
0.018
7887187 8837225 9497218
8157132 9407157 9867206
Ns Ns Ns
a Values are mean7S.D. New: unfamiliar faces of first presentation. Repeated faces at lags 0, 1 and 3.
normal group, three-way ANOVA for mean amplitude between 300 and 500 ms after onset identified significant main effects of electrode site [F(2, 28) ¼ 3.57, Po0.05], presentation [F(1, 14) ¼ 9.86, Po0.01] and lag [F(2, 28) ¼ 3.42, Po0.05]. Significant interactions of lag presentation [F(2, 28) ¼ 4.08, Po0.05] and lag electrode site [F(4, 56) ¼ 2.87, Po0.05] were noted; no other interactions were found. Planned comparisons using the Wilcoxon signed-rank test indicated significant ERP repetition effects for 300–500 ms after the stimulus in the normal group at all sites (Po0.05 for all sites) for the lag 0 repetition, while repetition effects for lags 1 (Po0.05) and 3 (Po0.05) were found only at the Fz site. On the other hand, no repetition effect was noted in patients with PD at any repetition. In the PD patients three-way ANOVA showed no main effects for any variable including electrode site, presentation and lag. In addition, no significant interactions were noted. Four-way ANOVA for the mean ERP amplitudes between 500 and 700 ms after the stimulus onset identified
-10
-10
EOG
EOG 500
1000
10
10
-10
-10
Fz
500
1000
500
1000
500
1000
500
1000
Fz 500
1000
10
10
-10
-10
Cz
Cz 500
1000
10
10
-10
-10
Pz
Pz 500
1000
10
10 1st presentation 2nd presentation
Control subjects
lag 0 lag 1 lag 3
Parkinson’s disease
Fig. 1. Grand average ERP waveforms for the normal control group and the PD group. In normal control subjects, the ERPs for repeated faces at lag 0 showed positive shifts of ERP waveforms at the Fz, Cz and Pz sites, although the positive shifts at lag 1 and 3 were found only at the Fz site. In patients with PD, the ERP waveforms for new faces were shifted in a positive direction compared with those in normal controls and no positive shifts for repeated faces were evident.
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main effects of group [F(1, 28) ¼ 4.25, Po0.05], presentation [F(1, 28) ¼ 6.01, Po0.05] and lag [F(2, 56) ¼ 4.36, Po0.05], while no main effect was found for electrode site. Significant interactions were found for lag presentation [F(2, 56) ¼ 3.31, Po0.05] and lag presentation group [F(2, 56) ¼ 4.02, Po0.05]. In the control group, a threeway ANOVA for the mean amplitude revealed a main effect of presentation [F(1, 14) ¼ 5.79, Po0.05], while no effects were noted for electrode site and lag. A significant interaction was found for lag presentation [F(2, 28) ¼ 4.08, Po0.05]. Planned comparisons using the Wilcoxon signed-rank test showed that ERP repetition effects were found only at lag 0 (Po0.05). In PD patients, a three-way ANOVA showed neither main effects nor interactions. To clarify whether the mean amplitude of ERP waveforms between 300 and 500 ms from the onset of stimuli in the PD patients could be attributed to differences in clinical status or other patient characteristics, we evaluated possible relationships of the ERP amplitude for new unfamiliar faces to the following variables: antiparkinsonian medication (daily dose of L-DOPA or trihexyphenidyl hydrochloride), duration of illness, motor disability as evaluated by Hoehn and Yahr scale [21], age and MMSE score [17]. Mean ERP amplitude was not correlated with any of these clinical variables. 4. Discussion Accuracy of new/old responses was similar for lags 0, 1 and 3 repetitions between the two groups, but a significant decrease in accuracy was seen for new unfamiliar faces in the PD group. The results of this study were consistent with previous findings of a deficit in recognition memory for unfamiliar faces in PD [7,9]. The difference in accuracy between responses for new and old faces may suggest that PD patients were selectively impaired in correct-rejection (judging new faces as ‘new’) responses, not in hit (judging old faces as ‘old’). RT for repeated faces did not differ consistently between the two groups at any three lags (0, 1, or 3), suggesting that the PD patients still could recruit the attention-demanding process that facilitates reaction performance. On the other hand, responses for correctly categorized new faces were slower in the PD group. RT is a cumulative measure of stimulus processing, formation of response set, initiation of motor response, and in this study, movement time. The delay in RT for new faces in PD patients may primarily reflect a delay in response initiation and execution processes or in decision processes. Absence of a difference in RT for old faces did not indicate a delay in response initiation or execution processes in PD patients. Instead, the delayed RT for new faces may reflect decision-related processes. Main question in this study is whether recognition memory in PD is impaired at the moment of face perception or after perception of faces. Although many studies have investigated the function of high-level visual
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information processing from an electrophysiologic viewpoint, results have been inconsistent. Investigating the basis of impaired performance of PD patients in unfamiliar face recognition tasks, Cousins et al. [9] found that PD patients performed significantly less well than controls in a recognition memory test for faces. In addition, they found PD patients to be significantly impaired relative to controls in Mooney’s facial closure test, which is used to measure configural processing. On the other hand, no difference was evident between their two groups in a test of componential processing ability. They concluded that configural processing ability was an important predictor of unfamiliar face recognition memory in PD. In the present study, no significant differences in P170 (VPP) latency and amplitude were noted between PD and control groups. The P170 (VPP) reflects one stage of a processing system designed to respond selectively and rapidly to suddenly presented fixed images of single objects, especially faces [27]. Response properties of the VPP and those of a similar face evoked potential recorded from the cortical surface further suggest that this processing stage is located in inferior temporal areas corresponding to the anterior inferior temporal cortex in monkeys, which represents a component of the occipital–temporal functional pathways [28]. The VPP properties also suggest correspondence with the structural encoding component of Bruce and Young’s functional model of face processing [29]. The present results suggest that perception of unfamiliar faces in PD is relatively preserved. As described in the Introduction, some researchers [10,11] reported face perception deficits in PD. The discrepancy between our and their results may partly be due to the differences in parameters used, or anti-parkinsonian medication, or other clinical variables. In the present study, significant ERP repetition effects were seen for 300–500 ms after the stimulus in the normal group at all sites in the lag 0 repetition, while at lag 1 and 3 a repetition effect was found only at the Fz site. On the other hand, no repetition effect was noted in patients with PD at any lag repetition. The ERP old/new effect is considered to receive contributions from associative as well as episodic factors [18,19]. One effect known to provide a major contribution to the overall ERP repetition effect is elicited between 300 and 500 ms over posterior sites. This effect is not specific to the materials to be memorized [30]. Temporally and topographically overlapping the N400 component, it will be referred to here as the ‘‘N400 effect’’. Taken together, the present results suggest that absence of a repetition effect in the PD group might be explained by deficits of the N400 effect or reduction of N400 component per se. The PD patients showed a more positive ERP amplitude than control subjects between 300 and 500 after the onset of the first presentation of faces, suggesting that the N400 component per se was markedly reduced in our patients with PD. According to a hypothesis linking N400 to a context integrative process [13], the present result would suggest that contextual integration is impaired in the
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PD patients. Although many studies have suggested a retrieval difficulty of some sort as responsible for observed memory deficits in PD, available data have not led to a consensus regarding the status of the encoding mechanism [1,5]. Our data indicating reduced N400 amplitude suggest that PD patients fail to generate a full memory representation of the first presentation of unfamiliar faces. Although no ERP repetition effect suggests the involvement of retrieval mechanism in recognition memory deficits in PD, the ERP repetition effect could be largely influenced by reduced N400 amplitudes, as mentioned above. Rather, the reduced amplitude of N400 supports the view indicating that PD patients have difficulties in generating a sufficiently strong memory trace at the time of first presentation, in agreement with previous reports that PD patients exhibit deficits in encoding of information [31,32]. In a direct test with unfamiliar faces, some authors [19] have described ERP repetition effects including a frontocentral (FC) effect, an fronto-polar (FP) effect, and a late posterior effect (the usual P600 effect) in addition to parietal effect (the usual N400 effect). Donaldson and Rugg [33] and Curren [34] have dissociated a FC effect and an early bilateral FP effect. The FC effect is elicited between 300 and 500 ms and can persist even until 1400 ms in certain tasks. This effect appears to have a specific role in memory since it is not observed for incorrect judgments [35,36]. The FC effect reflects the activity of the dorsolateral prefrontal cortex [19]. Numerous studies of patients with prefrontal lobe damage indicate that the functional integrity of this region is necessary for monitoring of information retrieved from memory [37]. The FP effect has been less consistently described; some studies [30,34,38] have described a FP effect as elicited by unfamiliar stimuli (i.e., unfamiliar faces) only in direct tests. This effect is elicited in an identity-matching task (i.e., recognition test) [39,40]. Although the FP effect is elicited by stimuli and tasks that favor episodic processes, a functional interpretation remains to be established. The FP distribution of the effect is compatible with a central frontal origin (i.e., the inferior and orbital frontal cortices), a brain region known to play a major role in maintenance of novel information despite interference and in specifying retrieval cues [41,42]. Since the topographic distribution of the ERP repetition effect between 300 and 500 ms was frontal-dominant, particularly for lags 1 and 3, these FP and FC effects may be involved in the repetition effect observed in the normal group in the present study. Many investigations [4] have shown apparent effects on frontal lobe function from disturbed basal ganglionic outflow that could affect cognition in PD. Prefrontal involvement in PD has been suggested by both neuropsychologic studies [43,44] and cerebral blood flow studies [3,45]. Deficits of FC and FP effects evident at the Fz site may reflect prefrontal involvement in PD patients. These findings appear to support the view that a decline of recognition memory may result from working memory impairment, since working memory is associated with the prefrontal cortex.
The later effect underling the ERP repetition effect was elicited at 400–800 ms, showing a widespread distribution with maximal intensity at centro-parietal sites; and considerable agreement prevails that this effect is related to the modulation of the well-documented P600 (or P3b) [18]. The P600 increases in amplitude upon the second presentation of an item. Studies indicate that in a direct memory task the P600 effect is sensitive to the level of processing at encoding [21,46,47] and is modulated by conscious retrieval [18,46,48]. In the present study, the P600 effect was evident at lag 0 in normal controls, but was not evident at lags 1 and 3. In patients with PD, the P600 effect was not found at any lag repetition. The P600 effect elicited in direct memory tests receives a major contribution from mid-temporal lobe structures [49,50], not involved in the early stage of PD. The P600 reflects the endpoint for information extracted at earlier processing stages reflected in the N400, FP and FC effects converging to form a unitary representation of the stimulus that is consciously conceivable. In our study earlier processing stages were not evident at lag 1 or 3, which can explain why no P600 effect was evident in either groups. In summary, an ERP repetition effect was found in normal subjects. The ERP repetition effect seen between 300 and 500 ms after presentation of stimuli represented mainly the N400 effect, FC effect and FP effect. Effects between 500 and 700 ms may largely represent the P600 effect. In patients with PD, no ERP repetition effect could be seen between 300 and 700 ms. These results may indicate deficits of recognition memory for unfamiliar faces in PD patients. Temporal stability, i.e. lack of any repetition effect in the P170 component, indicates a difference of effect involving processes following structural encoding of faces. Additional findings in this study were that RTs to repeated faces at lag 0 were shorter than at first presentation, a facilitation taken to be an indirect performance measure of memory. Although RT at lag 3 was slower than at the first presentation, an ERP repetition effect was found in the control group. In addition, while patients with PD showed RT shortening at lag 0, no ERP repetition effect was found at lag 0. This discrepancy between ERP and behavioral measures suggested differing correlates of distinct psychological processes. Our PD patients continued to take antiparkinsonian medication during the study. Although some investigators have reported memory impairment as an effect of anticholinergic drugs, no significant correlation between medication (dose of L-DOPA or trihexyphenidy1) and ERP amplitude between 300 and 700 after stimulus onset was noted in this study. In addition, pharmacologic sensitivity of the repetition effect in the word-recognition paradigm has been investigated concerning anticholinergic medication, indicating no influence of medication on the repetition effect [15]. These findings suggest that any effects of antiparkinsonian drugs upon our results most likely were minimal or nonexistent.
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In conclusion, PD is associated with impaired recognition memory for unfamiliar faces. Facial recognition memory deficits in PD may result from difficulty in integration of items with their priming context following structural encoding of a face. Acknowledgements This work was supported in part by a grant-in-aid for scientific research (B15330158) from the Japan Ministry of Education, Science, Sports and Culture to T.O. References [1] Beatty WW. Memory disturbances in Parkinson’s disease. In: Huber SJ, Cummings JL, editors. Parkinson’s disease. Neurobehavioral aspects. New York: Oxford University Press; 1992. p. 49–58. [2] Dubois B, Pillon B. Cognitive deficits in Parkinson’s disease. J Neurol 1997;244:2–8. [3] Tachibana H, Kawabata K, Shibuya N, Okuda B, Sugita M, Fukuchi M. Cerebral blood flow and episodic memory in patients with Parkinson’s disease. J Cereb Blood FIow Meteb 1999;19(Suppl. 1):S102. [4] Taylor AE, Saint-Cyr JA. The neuropsychology of Parkinson’s disease. Brain Cogn 1995;28:281–96. [5] Tweedy JR, Langer KG, McDowell FH. The effect of semantic relations on the memory deficit associated with Parkinson’s disease. J Clin Neuropsychol 1982;4:235–47. [6] Flowers KA, Pearce I, Pearce JMS. Recognition memory in Parkinson’s disease. J Neurol Neurosurg Psychiatry 1984;47:1174–81. [7] Dewick HC, Hanley JR, Davies AD, Playfer JR, Turnbull CJ. Perception and memory for faces in Parkinson’s disease. Neuropsychologia 1991;29:785–802. [8] Lees AJ, Smith E. Cognitive deficits in the early stages of Parkinson’s disease. Brain 1983;106:257–70. [9] Cousins R, Hanley JR, Davies ADM, Turnbull CJ, Playfer JR. Understanding memory for faces in Parkinson’s disease: the role of configural processing. Neuropsychologia 2000;38:837–47. [10] Levin BE, Llabre MM, Weiner WJ. Cognitive impairments associated with early Parkinson’s disease. Neurology 1989;39:557–61. [11] Cumming JL, Huber SJ. Visuospatial abnormalities in Parkinson’s disease. In: Huber SJ, Cummings JL, editors. Parkinson’s disease. Neurobehavioral aspects. New York: Oxford University Press; 1992. p. 59–73. [12] Rugg MD, Mark RE, Gilchrist J, Roberts RC. ERP repetition effects in indirect and direct tasks: effects of age and interitem lag. Psychophysiology 1997;34:572–86. [13] Rugg MD, Doyle MC. Event-related potentials and stimulus repetition in direct and indirect tests of memory. In: Heinze H-J, Munte TF, Mangun GR, editors. Cognitive electrophysiology. Boston: Birkhauser; 1994. p. 124–48. [14] Wilding EL, Doyle MC, Rugg MD. Recognition memory with and without retrieval of context: an event-related potential study. Neuropsychologia 1995;33:743–67. [15] Pfuts E-M, Sommer W, Schweinberger SR. Age-related slowing in face and name recognition: evidence from event-related potentials. Psychol Aging 2002;17:140–60. [16] Potter DD, Pickles CD, Roberts RC, Rugg MD. The effects of scopolamine on event-related potentials in a continuous recognition memory task. Psychophysiology 1992;29:29–37. [17] Smith ME, Halgren E. Dissociation of recognition memory components following temporal lobe lesions. J Exp Psychol (Learn Mem Cogn) 1989;15:50–60. [18] Wilding EL, Rugg MD. An event-related potential study of recognition memory with and without retrieval of source. Brain 1996;119:889–905.
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[19] Guillem F, Bicu M, Debruille JB. Dissociating memory processes involved in direct and indirect tests with ERPs to unfamiliar faces. Cogn Brain Res 2001;11:113–25. [20] Tachibana H, Kida Y, Takeda M, Yoshikawa H, Okita T. Eventrelated potentials to unfamiliar faces in a recognition memory task. In: Nakagawa M, Hirata K, Koga Y, Nagata K, editors. Frontiers in human brain topography. Amsterdam: Elsevier; 2004. p. 287–90. [21] Rugg MD, Roberts RC, Potter DD, Pickles CD, Nagy ME. Eventrelated potentials related to recognition memory. Brain 1991;114:2313–32. [22] Paller KA, Kutas M, Mayes A. Neural correlates of encoding in an incidental learning paradigm. Electroenceph Clin Neurophysiol 1987;67:360–71. [23] Hughes AJ, Daniel SE, Kilford L, Lees AJ. Accuracy of clinical diagnosis of idiopathic Parkinson’s disease: a clinico-pathological study of 100 cases. J Neurol Neurosurg Psychiatry 1992; 55:181–4. [24] Hoehn MM, Yahr MD. Parkinsonism: onset, progression and mortality. Neurology 1967;17:427–42. [25] American Psychiatric Association. Diagnostic and statistical manual of mental disorders, 4th Edition. Washington DC: American Psychiatric Association; 1994. [26] Folstein MF, Folstein SE, McHugh PR. ‘Mini-Mental State’: a practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975;12:189–98. [27] Jeffregs DA. Evoked potential studies of face and abject processing. Visual Cognition 1996;3:1–38. [28] Desimone R, Ungerleider LG. Neural mechanisms of visual processing in monkeys. In: Boller F, Grafman J, editors. Handbook of Neuropsychology, vol. 2. Amsterdam: Elsevier; 1989. p. 267–99. [29] Bruce V, Young A. Understanding face recognition. Br J Psychol 1986;77:305–27. [30] Munte TF, Brack M, Grootheer O, Wieringa BM, Matzke M, Johannes S. Event-related brain potentials to unfamiliar faces in explicit and implicit memory tasks. Neurosci Res 1997;28:223–33. [31] Cooper JA, Sagar HJ. Encoding deficits in untreated Parkinson’s disease. Cortex 1993;29:251–65. [32] Pillon B, Deweer B, Agid Y, Dubois B. Explicit memory in Alzheimer’s, Huntington’s, and Parkinson’s diseases. Arch Neurol 1993;50:374–9. [33] Donaldson DI, Rugg MD. Event-related potential studies of associative recognition and recall: electrophysiological evidence for context dependent retrieval processes. Cogn Brain Res 1999;8:1–16. [34] Curran T. The electrophysiology of incidental and intentional retrieval: ERP old/new effects in lexical decision and recognition memory. Neuropsychologia 1999;37:771–85. [35] Senkfor AJ, VanPetten C. Who said what: an event-related potential investigation of source memory. J Exp Psychol Lear Mem Cogn 1998;24:1005–25. [36] Wilding EL. Separating retrieval strategies from retrieval success: an event-related potential study of source memory. Neuropsychologia 1999;37:441–54. [37] Shallice T. From neuropsychology to mental structure. London: Cambridge University Press; 1988. [38] Guillem F, Bicu M, Debruille JB. Spatial and temporal organisation of episodic and semantic processes revealed by event-related potentials to unfamiliar faces. Brain Cogn 1999;41:338–44. [39] Barrett SE, Rugg MD, Perrett DI. Event-related potentials and the semantic matching of faces. Neuropsychologia 1988;26: 105–17. [40] Barrett SE, Rugg MD. Event-related potentials and the semantic matching of faces. Neuropsychologia 1989;27:913–22. [41] D’Esposito M, Postle BR, Jonides J, Smith SE. The neural substrate and temporal dynamics of interference effects in working memory as revealed by event-related functional fMRI. Proc Natl Acad Sci USA 1999;96:7514–9. [42] Fuster JM. The prefrontal cortex. Anatomy, physiology and neuropsychology of the frontal lobe. New York: Raven Press; 1980.
ARTICLE IN PRESS 164
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[43] Owen AM, James M, Leigh PN, Summers BA, Marsden CD, Quinn NP. Front-striatal cognitive deficits at different stages of Parkinson’s disease. Brain 1992;115:1727–51. [44] Piccirilli M, D’Alessandro P, Finali GL, Piccinin L, Agostini L. Frontal lobe dysfunction in Parkinson’s disease: prognostic value for dementia? Eur Neurol 1989;29:71–6. [45] Bes A, Guell A, Fable N, Dupui P, Victor G, Geraud G. Cerebral blood flow studied by xenon-133 inhalation technique in parkinsonism: loss of hyperfrontal pattern. J Cereb Blood Flow Metab 1983;3:33–7. [46] Rugg MD, Mark RE, Walla P, Schloerscheidt AM, Birch CS, Allan K. Dissociation of the neural correlates of implicit and explicit memory. Nature 1998;392:595–8.
[47] Sanquist TF, Rohrbaugh JW, Syndulko K, Lindsley DB. Electrocortical signs of levels of processing: perceptual analysis and recognition memory. Psychophysiology 1980;17:568–76. [48] Smith ME. Neurophysiological manifestations of recollective experience during recognition memory judgments. J Cogn Neurosci 1993;5:1–13. [49] Eichenbaum H, Bunsey M. On the binding of associations in memory: clues from studies on the role of the hippocampal region in paired-associate learning. Cur Dir Psychol Sci 1995;4: 19–23. [50] Squire LR. Memory and the hippocampus: a synthesis from findings with rats, monkeys, and humans. Psychol Rev 1992;99:195–231.
Parkinsonism and Related Disorders 13 (2007) 157–164 www.elsevier.com/locate/parkreldis
Recognition memory for unfamiliar faces in Parkinson’s disease: Behavioral and electrophysiologic measures Yasunobu Kidaa, Hisao Tachibanaa,, Masanaka Takedaa, Hiroo Yoshikawaa, Tsunetaka Okitab a
Department of Internal Medicine, Division of Neurology and Stroke Care Unit, Hyogo College of Medicine, 1-1, Mukogawa-cho, Nishinomiya, Hyogo 663-8501, Japan b Department of Psychology and Communication, Aichi Chukutoku University, Aichi 480-1197, Japan Received 25 April 2006; received in revised form 24 July 2006; accepted 28 August 2006
Abstract We analyzed event-related potentials (ERPs) and behavioral measurements during a recognition memory task in 15 normal elderly subjects and 15 patients with Parkinson’s disease (PD). To elicit ERPs unfamiliar faces were repeated immediately after initial presentation (at lag 0), after one intervening face (at lag 1) or at lag 3. Compared to normal controls, PD patients showed decreased accuracy in recognizing new unfamiliar faces. P170 latency and amplitude were similar between both groups. ERP amplitude between 300 and 500 ms after the stimulus in control subjects showed a positive shift (ERP repetition effect) for lag 0 at all sites and for lag 1 and 3 repetitions at the Fz site, while effects in the PD group were not noted at any site, even for the lag 0 repetition. ERP waveforms for the first presentation of faces in PD patients showed a significant positive shift compared to normal controls. These data suggest intact perception but impaired recognition memory for unfamiliar faces in PD. In addition, recognition memory deficits in PD may result from impairment of comparison of structural representations of presented faces with stored representations of faces known to the observer. r 2006 Elsevier Ltd. All rights reserved. Keywords: Event-related potential (ERP); ERP repetition effect; Parkinson’s disease; Recognition memory; Face perception
1. Introduction Although Parkinson’s disease (PD) classically is defined as a movement disorder, persons with PD also manifest neuropsychological deficits. Memory disturbances are among the cognitive deficits most commonly experienced by PD patients [1–5]. Studies of memory function in patients with PD show uniformly poor performance when a subject is required to consciously recall items from memory, while results are inconsistent when memory is tested by recognition methods [5–10]. Flowers et al. [6] reported that PD patients performed similarly to controls in recognition memory for objects, histograms, abstract designs, words and numbers, both immediately and after a delay. Dewick et al. [7], however, observed that while PD Corresponding author. Tel.: +81 798 45 6866; fax: +81 798 45 6873.
E-mail address: [email protected] (H. Tachibana). 1353-8020/$ - see front matter r 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.parkreldis.2006.08.012
patients performed similarly to controls on recognition tests using words, phrases and numbers, they were impaired on a recognition memory test using unfamiliar faces. Some authors [11] report face perception deficits in PD patients as well as memory deficits [7,9,10]. Levin et al. [10] also reported that PD patients with duration of illness less than 3 years performed significantly less well than controls on the short form of Benton’s Facial Recognition Task, a test of face perception. Although perception and recognition memory in PD thus appear impaired for faces, it is unclear which process is more impaired. Event-related potentials (ERPs) measure cognitive processing independently of motor disability, providing information complementary to that inferred from behavioral response characteristics measured during the test phases of memory evaluations [12]. ERPs have been used extensively to examine recognition memory function [13], consistently finding that repeated (old) words
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or figures evoked more positive ERPs than unrepeated (new) stimuli. This modulation has been termed ‘‘ the ERP repetition effect’’ or ‘‘ERP old/new effect’’. These repetition effects begin at approximately 250 ms following a stimulus and persist for several hundred milliseconds. They have been found to be larger when repeated items are assigned correctly to their study context than when these items are assigned incorrectly [14]. Based on such findings, many authors have suggested that repetition effects are evoked when recognition is accompanied by retrieval of information formed at the initial presentation of the item, i.e. conscious recollection [15–17]. ERP repetition effects thus should be highly informative in examining the nature of recognition memory impairment [18] in PD. The purpose of the present study was to evaluate whether ERP methods showed recognition memory for faces to be affected by PD and then clarify which stage of facial information processing represents the locus of impairment. ERPs were recorded in a direct memory task using unfamiliar faces. These stimuli were chosen because unfamiliar faces require the episodic process by which a completely new and distinctive representation is formed [19,20]. The interval between repetitions of items in previous ERP studies on recognition memory was varied from 30 s [21] to several minutes [22]. To ensure that the patients were able to perform the recognition task, we decided to use shorter intervals (12 s) between repetitions of items. To our knowledge, ERP data for PD patients in a recognition memory paradigm for faces have not been reported.
2. Experimental procedures 2.1. Subjects Study participants included 15 patients with a clinical diagnosis of idiopathic PD (6 women, 9 men; mean age7S.D., 63.478.2 years; range, 49–75) as well as 15 normal control subjects with no neurologic illness or drug abuse (6 women, 9 men; age, 65.078.1; range, 55–83). Patients with PD presented with insidious onset of two or more of cardinal symptoms (bradykinesia, tremor, or rigidity). Treatment with antiparkinsonian drugs improved symptoms and signs in all patients. Patients with secondary parkinsonism or with evidence of more widespread neurologic disease were excluded. Patients with evidence of focal lesions on computed tomography (CT) or magnetic resonance imaging (MRI) likewise were excluded. In the patient group, neuroradiologic examinations were normal or demonstrated mild diffuse cerebral atrophy. All patients fulfilled Parkinson’s Disease Society Brain Bank clinical criteria for definite PD [23]. Parkinsonian motor disability was graded on the scale of Hoehn and Yahr [24]. Depression was evaluated by use of Zung’s self-rating depression scale (SDS). Clinical and demographic data concerning patients with PD are presented in Table 1. No patient was demented according to the criteria at the Diagnostic and Statistical Manual of Mental Disorders, Edition IV [25]. Normal subjects were healthy and intellectually active, and were found to be normal on neurologic examination. We evaluated each subject’s cognitive function with the Mini-Mental State Examination (MMSE) [26]. All procedures were carried out with the adequate understanding and written consent of the subjects.
Table 1 Clinical characteristics of 15 patients with Parkinson’s disease Characteristic Sex, M/F, number of patients Age, y, mean7S.D. (range) Duration of disease, y, mean7S.D. (range) Hoehn–Yahr stage, number of patients II III IV Zung’s self-rating depression scale, mean7S.D. (range) Mini-mental State Examination score, mean7S.D. (range) Antiparkinson therapy, number of patients L-DOPAa Trihexyphenidyl hydrochloride L-DOPA, dopamine agonistb L-DOPA, amantadine, dopamine agonist L-DOPA, trihexyphenidyl hydrochloride, dopamine agonist L-DOPA, trihexyphenidyl hydrochloride, dopamine agonist, amantadine a
9/6 63.478.2 (49–75) 7.274.5 (2–15) 3 10 2 42.5710.1 (28–64) 28.172.4 (24–30)
3 1 6 1 2 2
With dopa-decarboxylase inhibitor (carbidopa or benserazide). Bromocriptine or pergolide or cabergoline.
b
2.2. ERP measurement 2.2.1. Stimuli and apparatus Stimuli consisted of 341 black and white photographs representing faces of persons unknown to the subjects. All facial pictures were frontal views against a neutral background. The pictures were scanned into a computer, and the resulting images were edited to a height of 14.1 cm and a width of 15 cm on a 15-inch monitor screen. A combination of 31 items comprised each list and 11 (1 practice, 10 experimental) lists are presented. The stimulus duration was 1 s and the interstimulus interval was 3 s (onset to onset). Of the 31 faces, the first appearance of a face was a nontarget stimulus and subsequent 30 faces were targets. Five target appearances were presented twice separately by no intervening item (lag 0); five were presented twice with one intervening item (lag 1); five were presented twice with three intervening items (lag 3). The procedure employed pseudorandom ordering of the first and second presentations of lag 0, 1 and 3 repeats.
2.2.2. Procedure Subjects were seated comfortably in a dimly lit room and given a thumb-switch to hold in each hand. They were instructed to minimize head movement, eye movements and blinking. Subjects were informed that they would see a sequence of faces on the monitor screen, and that they should respond as quickly and accurately as possible by pushing the right thumb button for the first (new) presentation of a unfamiliar face and the left thumb button for repeated (old) faces. Once they understood the instructions, subjects were given practice trials of 31 items to allow them to familiarize themselves with the task; then the first of the 10 experimental lists was presented on the computer screen pseudorandomly in a continuous repetition task sequence. Rest periods of 30 s were allowed following every 31-item list.
2.2.3. ERP recording An electroencephalogram (EEG) was recorded using silver-silver chloride electrodes placed at scalp sites Fz, Cz and Pz according to the International 10–20 system, with the reference electrode positioned at the
ARTICLE IN PRESS Y. Kida et al. / Parkinsonism and Related Disorders 13 (2007) 157–164 left earlobe. Eye movements (electrooculogram or EOG) were monitored by electrodes placed below the left inferior orbital margin and on the left outer orbit. Electrode impedance was maintained below 5 kO. The electroencephalographic and ocular activities were amplified using a 0.05–30 Hz filter and stored together with event markers on a magnetoptical disk after analog–digital conversion for subsequent off-line analyses.
2.2.4. Data analysis ERP averages for each stimulus and condition (new and lags 0, 1 and 3) were computed for each subject. Grand averages were computed separately for normal subjects and patients with PD. Trials in which amplitudes exceeded 750 mV for EOG and 7100 mV for EEG were rejected automatically. ERP waveforms were quantified by meanamplitude measures in the time window (between 300 and 700 ms) relative to a 200 ms prestimulus baseline. Reaction time (RT) was defined as the interval from stimulus onset to button pressing. This interval was recorded by the computer and checked for new/old errors, omissions and premature responses.
2.3. Statistical analysis Behavioral and ERP data were analyzed for normal vs. PD patient groups. Group differences (normal vs. PD) in MMSE scores and behavioral measures were tested using the Mann–Whitney U-test. ERP amplitude data were divided into intervals 300–500 ms (early stage) and 500–700 ms (late stage) from the onset of the stimulus and subjected to a four-way analysis of variance (ANOVA) with two conditions of group (PD vs. normal) as the between-subject variable, three conditions of electrode site (Fz, Cz, Pz ) as a within-subject variable, and two conditions of presentation (first vs. second), and three conditions of lag (lag 0, lag 1 and lag 3) as within-subject repeated measures factors. Planned comparisons of ERP repetition effects for each group were performed using Wilcoxon’s signed-rank test. Spearman’s rank correlation coefficients (r’s) were calculated to determine correlations. A level of Po0.05 was accepted as indicating statistical significance. Data are expressed as the mean7S.D.
3. Results 3.1. General cognitive testing All PD patients scored at least 24 points on the MMSE (mean7S.D., 28.172.4 points; range, 24–30) and were considered to have PD without dementia. No significant difference in MMSE scores was seen between patients and normal control subjects (28.472.0 points).
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(Po0.05), but no RT differences were evident between normal subjects and patients with PD for all lag repetitions (Tables 2 and 3). Both the control group and patients with PD showed a significant RT priming effect at the lag 0 repetition (Po0.01 for controls and Po0.02 for the PD group), while in the normal group RT in the lag 3 repetition was delayed relative compared to new faces (Po0.01). No significant correlation was found between RT and accuracy of response for new faces in the PD group. 3.2.2. ERPs Grand average ERP waveforms for the normal group and the PD group at each electrode are shown in Fig. 1. In normal subjects, new unfamiliar faces elicited waveforms characterized by negativity with a latency of about 115 ms, followed by positivity at 180 ms (vertex positive peak or VPP; P170) [23] and an additional negative peak at about 300 ms. No significant differences were evident in the P170 component between the two groups (latency, 183.0714.0 ms for controls and 196.3724.9 ms for PD patients; amplitude, 6.9472.36 mV for controls and 8.4373.22 mV for PD patients). Waveforms following the first and second presentations were virtually identical for the first 300 ms post-stimulus, after which the ERP in response to the second presentation began to show a more positive distribution. In normal subjects, the ERPs for repeated faces (lag 0) began to diverge from the ERPs for new faces at approximately 300 ms, and effects persisted to 700–1000 ms at the Fz, Cz and Pz sites. Repeated faces at lags 1 and 3 also showed a positive shift of ERP waveforms, although the magnitude of positive shift was less prominent. The positive shift of ERP waveforms was found only at the Fz site. In patients with PD, similar ERP waveforms also were elicited for new faces, although the waveforms were shifted in a positive direction compared with those in normal controls. Four-way ANOVA for mean ERP amplitudes between 300 and 500 ms after stimulus onset disclosed main effects for group [F(1, 28) ¼ 5.98, Po0.05], electrode site [F(2, 56) ¼ 3.17, Po0.05], lag [F(2, 56) ¼ 10.42, Po0.001] and presentation [F(1, 28) ¼ 4.86, Po0.05]. Significant inter-
3.2. ERP task 3.2.1. Behavioral measures Response accuracy in PD patients was significantly decreased compared to the normal group for the first presentation (Po0.02 for new faces). No significant differences in response accuracy were noted between patients and normal controls for lag 0, 1 and 3 repetitions. Both the control group and patients with PD showed significant priming effects of response accuracy at lag 0 repetition (Po0.01 for controls and Po0.01 for the PD group). No priming effects were found at lag 1 or 3. Significant differences were seen in RTs for new faces
Table 2 Response accuracy (%) for new and repeated facesa
First presentation Lag 0 repetition Lag 1 repetition Lag 3 repetition a
Elderly normal
Parkinson’s disease
Mann–Whitney U-test, P-value elderly vs. Parkinson
90.179.4
80.0719.4
0.017
97.275.2 79.8717.8 64.1721.6
91.5714.8 77.1717.2 59.7717.1
Ns Ns Ns
Values are mean7S.D.
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actions of group presentation [F(1, 28) ¼ 4.86, Po0.05], electrode lag [F(4, 112) ¼ 2.70, Po0.05], electrode presentation [F(2, 56) ¼ 3.31, Po0.05] and group lag presentation [F(2, 56) ¼ 5.20, Po0.01] were evident. In the
Table 3 Reaction time (ms) for new and repeated facesa
First presentation Lag 0 repetition Lag 1 repetition Lag 3 repetition
Elderly normal
Parkinson’s disease
Mann–Whitney U-test, P-value elderly vs. Parkinson
8557144
9447200
0.018
7887187 8837225 9497218
8157132 9407157 9867206
Ns Ns Ns
a Values are mean7S.D. New: unfamiliar faces of first presentation. Repeated faces at lags 0, 1 and 3.
normal group, three-way ANOVA for mean amplitude between 300 and 500 ms after onset identified significant main effects of electrode site [F(2, 28) ¼ 3.57, Po0.05], presentation [F(1, 14) ¼ 9.86, Po0.01] and lag [F(2, 28) ¼ 3.42, Po0.05]. Significant interactions of lag presentation [F(2, 28) ¼ 4.08, Po0.05] and lag electrode site [F(4, 56) ¼ 2.87, Po0.05] were noted; no other interactions were found. Planned comparisons using the Wilcoxon signed-rank test indicated significant ERP repetition effects for 300–500 ms after the stimulus in the normal group at all sites (Po0.05 for all sites) for the lag 0 repetition, while repetition effects for lags 1 (Po0.05) and 3 (Po0.05) were found only at the Fz site. On the other hand, no repetition effect was noted in patients with PD at any repetition. In the PD patients three-way ANOVA showed no main effects for any variable including electrode site, presentation and lag. In addition, no significant interactions were noted. Four-way ANOVA for the mean ERP amplitudes between 500 and 700 ms after the stimulus onset identified
-10
-10
EOG
EOG 500
1000
10
10
-10
-10
Fz
500
1000
500
1000
500
1000
500
1000
Fz 500
1000
10
10
-10
-10
Cz
Cz 500
1000
10
10
-10
-10
Pz
Pz 500
1000
10
10 1st presentation 2nd presentation
Control subjects
lag 0 lag 1 lag 3
Parkinson’s disease
Fig. 1. Grand average ERP waveforms for the normal control group and the PD group. In normal control subjects, the ERPs for repeated faces at lag 0 showed positive shifts of ERP waveforms at the Fz, Cz and Pz sites, although the positive shifts at lag 1 and 3 were found only at the Fz site. In patients with PD, the ERP waveforms for new faces were shifted in a positive direction compared with those in normal controls and no positive shifts for repeated faces were evident.
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main effects of group [F(1, 28) ¼ 4.25, Po0.05], presentation [F(1, 28) ¼ 6.01, Po0.05] and lag [F(2, 56) ¼ 4.36, Po0.05], while no main effect was found for electrode site. Significant interactions were found for lag presentation [F(2, 56) ¼ 3.31, Po0.05] and lag presentation group [F(2, 56) ¼ 4.02, Po0.05]. In the control group, a threeway ANOVA for the mean amplitude revealed a main effect of presentation [F(1, 14) ¼ 5.79, Po0.05], while no effects were noted for electrode site and lag. A significant interaction was found for lag presentation [F(2, 28) ¼ 4.08, Po0.05]. Planned comparisons using the Wilcoxon signed-rank test showed that ERP repetition effects were found only at lag 0 (Po0.05). In PD patients, a three-way ANOVA showed neither main effects nor interactions. To clarify whether the mean amplitude of ERP waveforms between 300 and 500 ms from the onset of stimuli in the PD patients could be attributed to differences in clinical status or other patient characteristics, we evaluated possible relationships of the ERP amplitude for new unfamiliar faces to the following variables: antiparkinsonian medication (daily dose of L-DOPA or trihexyphenidyl hydrochloride), duration of illness, motor disability as evaluated by Hoehn and Yahr scale [21], age and MMSE score [17]. Mean ERP amplitude was not correlated with any of these clinical variables. 4. Discussion Accuracy of new/old responses was similar for lags 0, 1 and 3 repetitions between the two groups, but a significant decrease in accuracy was seen for new unfamiliar faces in the PD group. The results of this study were consistent with previous findings of a deficit in recognition memory for unfamiliar faces in PD [7,9]. The difference in accuracy between responses for new and old faces may suggest that PD patients were selectively impaired in correct-rejection (judging new faces as ‘new’) responses, not in hit (judging old faces as ‘old’). RT for repeated faces did not differ consistently between the two groups at any three lags (0, 1, or 3), suggesting that the PD patients still could recruit the attention-demanding process that facilitates reaction performance. On the other hand, responses for correctly categorized new faces were slower in the PD group. RT is a cumulative measure of stimulus processing, formation of response set, initiation of motor response, and in this study, movement time. The delay in RT for new faces in PD patients may primarily reflect a delay in response initiation and execution processes or in decision processes. Absence of a difference in RT for old faces did not indicate a delay in response initiation or execution processes in PD patients. Instead, the delayed RT for new faces may reflect decision-related processes. Main question in this study is whether recognition memory in PD is impaired at the moment of face perception or after perception of faces. Although many studies have investigated the function of high-level visual
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information processing from an electrophysiologic viewpoint, results have been inconsistent. Investigating the basis of impaired performance of PD patients in unfamiliar face recognition tasks, Cousins et al. [9] found that PD patients performed significantly less well than controls in a recognition memory test for faces. In addition, they found PD patients to be significantly impaired relative to controls in Mooney’s facial closure test, which is used to measure configural processing. On the other hand, no difference was evident between their two groups in a test of componential processing ability. They concluded that configural processing ability was an important predictor of unfamiliar face recognition memory in PD. In the present study, no significant differences in P170 (VPP) latency and amplitude were noted between PD and control groups. The P170 (VPP) reflects one stage of a processing system designed to respond selectively and rapidly to suddenly presented fixed images of single objects, especially faces [27]. Response properties of the VPP and those of a similar face evoked potential recorded from the cortical surface further suggest that this processing stage is located in inferior temporal areas corresponding to the anterior inferior temporal cortex in monkeys, which represents a component of the occipital–temporal functional pathways [28]. The VPP properties also suggest correspondence with the structural encoding component of Bruce and Young’s functional model of face processing [29]. The present results suggest that perception of unfamiliar faces in PD is relatively preserved. As described in the Introduction, some researchers [10,11] reported face perception deficits in PD. The discrepancy between our and their results may partly be due to the differences in parameters used, or anti-parkinsonian medication, or other clinical variables. In the present study, significant ERP repetition effects were seen for 300–500 ms after the stimulus in the normal group at all sites in the lag 0 repetition, while at lag 1 and 3 a repetition effect was found only at the Fz site. On the other hand, no repetition effect was noted in patients with PD at any lag repetition. The ERP old/new effect is considered to receive contributions from associative as well as episodic factors [18,19]. One effect known to provide a major contribution to the overall ERP repetition effect is elicited between 300 and 500 ms over posterior sites. This effect is not specific to the materials to be memorized [30]. Temporally and topographically overlapping the N400 component, it will be referred to here as the ‘‘N400 effect’’. Taken together, the present results suggest that absence of a repetition effect in the PD group might be explained by deficits of the N400 effect or reduction of N400 component per se. The PD patients showed a more positive ERP amplitude than control subjects between 300 and 500 after the onset of the first presentation of faces, suggesting that the N400 component per se was markedly reduced in our patients with PD. According to a hypothesis linking N400 to a context integrative process [13], the present result would suggest that contextual integration is impaired in the
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PD patients. Although many studies have suggested a retrieval difficulty of some sort as responsible for observed memory deficits in PD, available data have not led to a consensus regarding the status of the encoding mechanism [1,5]. Our data indicating reduced N400 amplitude suggest that PD patients fail to generate a full memory representation of the first presentation of unfamiliar faces. Although no ERP repetition effect suggests the involvement of retrieval mechanism in recognition memory deficits in PD, the ERP repetition effect could be largely influenced by reduced N400 amplitudes, as mentioned above. Rather, the reduced amplitude of N400 supports the view indicating that PD patients have difficulties in generating a sufficiently strong memory trace at the time of first presentation, in agreement with previous reports that PD patients exhibit deficits in encoding of information [31,32]. In a direct test with unfamiliar faces, some authors [19] have described ERP repetition effects including a frontocentral (FC) effect, an fronto-polar (FP) effect, and a late posterior effect (the usual P600 effect) in addition to parietal effect (the usual N400 effect). Donaldson and Rugg [33] and Curren [34] have dissociated a FC effect and an early bilateral FP effect. The FC effect is elicited between 300 and 500 ms and can persist even until 1400 ms in certain tasks. This effect appears to have a specific role in memory since it is not observed for incorrect judgments [35,36]. The FC effect reflects the activity of the dorsolateral prefrontal cortex [19]. Numerous studies of patients with prefrontal lobe damage indicate that the functional integrity of this region is necessary for monitoring of information retrieved from memory [37]. The FP effect has been less consistently described; some studies [30,34,38] have described a FP effect as elicited by unfamiliar stimuli (i.e., unfamiliar faces) only in direct tests. This effect is elicited in an identity-matching task (i.e., recognition test) [39,40]. Although the FP effect is elicited by stimuli and tasks that favor episodic processes, a functional interpretation remains to be established. The FP distribution of the effect is compatible with a central frontal origin (i.e., the inferior and orbital frontal cortices), a brain region known to play a major role in maintenance of novel information despite interference and in specifying retrieval cues [41,42]. Since the topographic distribution of the ERP repetition effect between 300 and 500 ms was frontal-dominant, particularly for lags 1 and 3, these FP and FC effects may be involved in the repetition effect observed in the normal group in the present study. Many investigations [4] have shown apparent effects on frontal lobe function from disturbed basal ganglionic outflow that could affect cognition in PD. Prefrontal involvement in PD has been suggested by both neuropsychologic studies [43,44] and cerebral blood flow studies [3,45]. Deficits of FC and FP effects evident at the Fz site may reflect prefrontal involvement in PD patients. These findings appear to support the view that a decline of recognition memory may result from working memory impairment, since working memory is associated with the prefrontal cortex.
The later effect underling the ERP repetition effect was elicited at 400–800 ms, showing a widespread distribution with maximal intensity at centro-parietal sites; and considerable agreement prevails that this effect is related to the modulation of the well-documented P600 (or P3b) [18]. The P600 increases in amplitude upon the second presentation of an item. Studies indicate that in a direct memory task the P600 effect is sensitive to the level of processing at encoding [21,46,47] and is modulated by conscious retrieval [18,46,48]. In the present study, the P600 effect was evident at lag 0 in normal controls, but was not evident at lags 1 and 3. In patients with PD, the P600 effect was not found at any lag repetition. The P600 effect elicited in direct memory tests receives a major contribution from mid-temporal lobe structures [49,50], not involved in the early stage of PD. The P600 reflects the endpoint for information extracted at earlier processing stages reflected in the N400, FP and FC effects converging to form a unitary representation of the stimulus that is consciously conceivable. In our study earlier processing stages were not evident at lag 1 or 3, which can explain why no P600 effect was evident in either groups. In summary, an ERP repetition effect was found in normal subjects. The ERP repetition effect seen between 300 and 500 ms after presentation of stimuli represented mainly the N400 effect, FC effect and FP effect. Effects between 500 and 700 ms may largely represent the P600 effect. In patients with PD, no ERP repetition effect could be seen between 300 and 700 ms. These results may indicate deficits of recognition memory for unfamiliar faces in PD patients. Temporal stability, i.e. lack of any repetition effect in the P170 component, indicates a difference of effect involving processes following structural encoding of faces. Additional findings in this study were that RTs to repeated faces at lag 0 were shorter than at first presentation, a facilitation taken to be an indirect performance measure of memory. Although RT at lag 3 was slower than at the first presentation, an ERP repetition effect was found in the control group. In addition, while patients with PD showed RT shortening at lag 0, no ERP repetition effect was found at lag 0. This discrepancy between ERP and behavioral measures suggested differing correlates of distinct psychological processes. Our PD patients continued to take antiparkinsonian medication during the study. Although some investigators have reported memory impairment as an effect of anticholinergic drugs, no significant correlation between medication (dose of L-DOPA or trihexyphenidy1) and ERP amplitude between 300 and 700 after stimulus onset was noted in this study. In addition, pharmacologic sensitivity of the repetition effect in the word-recognition paradigm has been investigated concerning anticholinergic medication, indicating no influence of medication on the repetition effect [15]. These findings suggest that any effects of antiparkinsonian drugs upon our results most likely were minimal or nonexistent.
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In conclusion, PD is associated with impaired recognition memory for unfamiliar faces. Facial recognition memory deficits in PD may result from difficulty in integration of items with their priming context following structural encoding of a face. Acknowledgements This work was supported in part by a grant-in-aid for scientific research (B15330158) from the Japan Ministry of Education, Science, Sports and Culture to T.O. References [1] Beatty WW. Memory disturbances in Parkinson’s disease. In: Huber SJ, Cummings JL, editors. Parkinson’s disease. Neurobehavioral aspects. New York: Oxford University Press; 1992. p. 49–58. [2] Dubois B, Pillon B. Cognitive deficits in Parkinson’s disease. J Neurol 1997;244:2–8. [3] Tachibana H, Kawabata K, Shibuya N, Okuda B, Sugita M, Fukuchi M. Cerebral blood flow and episodic memory in patients with Parkinson’s disease. J Cereb Blood FIow Meteb 1999;19(Suppl. 1):S102. [4] Taylor AE, Saint-Cyr JA. The neuropsychology of Parkinson’s disease. Brain Cogn 1995;28:281–96. [5] Tweedy JR, Langer KG, McDowell FH. The effect of semantic relations on the memory deficit associated with Parkinson’s disease. J Clin Neuropsychol 1982;4:235–47. [6] Flowers KA, Pearce I, Pearce JMS. Recognition memory in Parkinson’s disease. J Neurol Neurosurg Psychiatry 1984;47:1174–81. [7] Dewick HC, Hanley JR, Davies AD, Playfer JR, Turnbull CJ. Perception and memory for faces in Parkinson’s disease. Neuropsychologia 1991;29:785–802. [8] Lees AJ, Smith E. Cognitive deficits in the early stages of Parkinson’s disease. Brain 1983;106:257–70. [9] Cousins R, Hanley JR, Davies ADM, Turnbull CJ, Playfer JR. Understanding memory for faces in Parkinson’s disease: the role of configural processing. Neuropsychologia 2000;38:837–47. [10] Levin BE, Llabre MM, Weiner WJ. Cognitive impairments associated with early Parkinson’s disease. Neurology 1989;39:557–61. [11] Cumming JL, Huber SJ. Visuospatial abnormalities in Parkinson’s disease. In: Huber SJ, Cummings JL, editors. Parkinson’s disease. Neurobehavioral aspects. New York: Oxford University Press; 1992. p. 59–73. [12] Rugg MD, Mark RE, Gilchrist J, Roberts RC. ERP repetition effects in indirect and direct tasks: effects of age and interitem lag. Psychophysiology 1997;34:572–86. [13] Rugg MD, Doyle MC. Event-related potentials and stimulus repetition in direct and indirect tests of memory. In: Heinze H-J, Munte TF, Mangun GR, editors. Cognitive electrophysiology. Boston: Birkhauser; 1994. p. 124–48. [14] Wilding EL, Doyle MC, Rugg MD. Recognition memory with and without retrieval of context: an event-related potential study. Neuropsychologia 1995;33:743–67. [15] Pfuts E-M, Sommer W, Schweinberger SR. Age-related slowing in face and name recognition: evidence from event-related potentials. Psychol Aging 2002;17:140–60. [16] Potter DD, Pickles CD, Roberts RC, Rugg MD. The effects of scopolamine on event-related potentials in a continuous recognition memory task. Psychophysiology 1992;29:29–37. [17] Smith ME, Halgren E. Dissociation of recognition memory components following temporal lobe lesions. J Exp Psychol (Learn Mem Cogn) 1989;15:50–60. [18] Wilding EL, Rugg MD. An event-related potential study of recognition memory with and without retrieval of source. Brain 1996;119:889–905.
163
[19] Guillem F, Bicu M, Debruille JB. Dissociating memory processes involved in direct and indirect tests with ERPs to unfamiliar faces. Cogn Brain Res 2001;11:113–25. [20] Tachibana H, Kida Y, Takeda M, Yoshikawa H, Okita T. Eventrelated potentials to unfamiliar faces in a recognition memory task. In: Nakagawa M, Hirata K, Koga Y, Nagata K, editors. Frontiers in human brain topography. Amsterdam: Elsevier; 2004. p. 287–90. [21] Rugg MD, Roberts RC, Potter DD, Pickles CD, Nagy ME. Eventrelated potentials related to recognition memory. Brain 1991;114:2313–32. [22] Paller KA, Kutas M, Mayes A. Neural correlates of encoding in an incidental learning paradigm. Electroenceph Clin Neurophysiol 1987;67:360–71. [23] Hughes AJ, Daniel SE, Kilford L, Lees AJ. Accuracy of clinical diagnosis of idiopathic Parkinson’s disease: a clinico-pathological study of 100 cases. J Neurol Neurosurg Psychiatry 1992; 55:181–4. [24] Hoehn MM, Yahr MD. Parkinsonism: onset, progression and mortality. Neurology 1967;17:427–42. [25] American Psychiatric Association. Diagnostic and statistical manual of mental disorders, 4th Edition. Washington DC: American Psychiatric Association; 1994. [26] Folstein MF, Folstein SE, McHugh PR. ‘Mini-Mental State’: a practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975;12:189–98. [27] Jeffregs DA. Evoked potential studies of face and abject processing. Visual Cognition 1996;3:1–38. [28] Desimone R, Ungerleider LG. Neural mechanisms of visual processing in monkeys. In: Boller F, Grafman J, editors. Handbook of Neuropsychology, vol. 2. Amsterdam: Elsevier; 1989. p. 267–99. [29] Bruce V, Young A. Understanding face recognition. Br J Psychol 1986;77:305–27. [30] Munte TF, Brack M, Grootheer O, Wieringa BM, Matzke M, Johannes S. Event-related brain potentials to unfamiliar faces in explicit and implicit memory tasks. Neurosci Res 1997;28:223–33. [31] Cooper JA, Sagar HJ. Encoding deficits in untreated Parkinson’s disease. Cortex 1993;29:251–65. [32] Pillon B, Deweer B, Agid Y, Dubois B. Explicit memory in Alzheimer’s, Huntington’s, and Parkinson’s diseases. Arch Neurol 1993;50:374–9. [33] Donaldson DI, Rugg MD. Event-related potential studies of associative recognition and recall: electrophysiological evidence for context dependent retrieval processes. Cogn Brain Res 1999;8:1–16. [34] Curran T. The electrophysiology of incidental and intentional retrieval: ERP old/new effects in lexical decision and recognition memory. Neuropsychologia 1999;37:771–85. [35] Senkfor AJ, VanPetten C. Who said what: an event-related potential investigation of source memory. J Exp Psychol Lear Mem Cogn 1998;24:1005–25. [36] Wilding EL. Separating retrieval strategies from retrieval success: an event-related potential study of source memory. Neuropsychologia 1999;37:441–54. [37] Shallice T. From neuropsychology to mental structure. London: Cambridge University Press; 1988. [38] Guillem F, Bicu M, Debruille JB. Spatial and temporal organisation of episodic and semantic processes revealed by event-related potentials to unfamiliar faces. Brain Cogn 1999;41:338–44. [39] Barrett SE, Rugg MD, Perrett DI. Event-related potentials and the semantic matching of faces. Neuropsychologia 1988;26: 105–17. [40] Barrett SE, Rugg MD. Event-related potentials and the semantic matching of faces. Neuropsychologia 1989;27:913–22. [41] D’Esposito M, Postle BR, Jonides J, Smith SE. The neural substrate and temporal dynamics of interference effects in working memory as revealed by event-related functional fMRI. Proc Natl Acad Sci USA 1999;96:7514–9. [42] Fuster JM. The prefrontal cortex. Anatomy, physiology and neuropsychology of the frontal lobe. New York: Raven Press; 1980.
ARTICLE IN PRESS 164
Y. Kida et al. / Parkinsonism and Related Disorders 13 (2007) 157–164
[43] Owen AM, James M, Leigh PN, Summers BA, Marsden CD, Quinn NP. Front-striatal cognitive deficits at different stages of Parkinson’s disease. Brain 1992;115:1727–51. [44] Piccirilli M, D’Alessandro P, Finali GL, Piccinin L, Agostini L. Frontal lobe dysfunction in Parkinson’s disease: prognostic value for dementia? Eur Neurol 1989;29:71–6. [45] Bes A, Guell A, Fable N, Dupui P, Victor G, Geraud G. Cerebral blood flow studied by xenon-133 inhalation technique in parkinsonism: loss of hyperfrontal pattern. J Cereb Blood Flow Metab 1983;3:33–7. [46] Rugg MD, Mark RE, Walla P, Schloerscheidt AM, Birch CS, Allan K. Dissociation of the neural correlates of implicit and explicit memory. Nature 1998;392:595–8.
[47] Sanquist TF, Rohrbaugh JW, Syndulko K, Lindsley DB. Electrocortical signs of levels of processing: perceptual analysis and recognition memory. Psychophysiology 1980;17:568–76. [48] Smith ME. Neurophysiological manifestations of recollective experience during recognition memory judgments. J Cogn Neurosci 1993;5:1–13. [49] Eichenbaum H, Bunsey M. On the binding of associations in memory: clues from studies on the role of the hippocampal region in paired-associate learning. Cur Dir Psychol Sci 1995;4: 19–23. [50] Squire LR. Memory and the hippocampus: a synthesis from findings with rats, monkeys, and humans. Psychol Rev 1992;99:195–231.