Wolk, 2013 Erp MCI Recognition

ORIGINAL RESEARCH ARTICLE
published: 11 December 2013

doi: 10.3389/fnagi.2013.00089
Recognition memory in amnestic-mild cognitive

impairment: insights from event-related potentials
David A. Wolk 1,2 *, Katharine Manning 1,2 , Daria Kliot 1,2 and Steven E. Arnold 1,2,3
1
Department of Neurology, University of Pennsylvania, Philadelphia, PA, USA
2
Penn Memory Center, University of Pennsylvania, Philadelphia, PA, USA
3
Department of Psychiatry, University of Pennsylvania, Philadelphia, PA, USA
Edited by: Episodic memory loss is the hallmark cognitive dysfunction associated with Alzheimer’s dis-
Hari S. Sharma, Uppsala University, ease (AD). Amnestic mild cognitive impairment (a-MCI) frequently represents a transitional
Sweden
stage between normal aging and early AD. A better understanding of the qualitative features
Reviewed by:
Mira Didic, Assistance
of memory loss in a-MCI may have important implications for predicting those most likely to
Publique-Hôpitaux de Marseille, harbor AD-related pathology and for disease monitoring. Dual process models of memory
INSERM, Aix-Marseille Université, argue that recognition memory is subserved by the dissociable processes of recollection
France and familiarity. Work studying recognition memory in a-MCI from this perspective has been
Brandon Ally, Vanderbilt University,
USA
controversial, particularly with regard to the integrity of familiarity. Event-related potentials
*Correspondence:
(ERPs) offer an alternative means for assessing these functions without the associated
David A. Wolk, Penn Memory Center, assumptions of behavioral estimation methods. ERPs were recorded while a-MCI patients
University of Pennsylvania, 3615 and cognitively normal (CN) age-matched adults performed a recognition memory task.
Chestnut Street, #212A, Philadelphia, When retrieval success was measured (hits versus correct rejections) in which performance
PA 19104, USA
e-mail: [email protected]
was matched by group, a-MCI patients displayed similar neural correlates to that of
the CN group, including modulation of the FN400 and the late positive complex (LPC)
which are thought to index familiarity and recollection, respectively. Alternatively, when
the integrity of these components was measured based on retrieval attempts (studied
versus unstudied items), a-MCI patients displayed a reduced FN400 and LPC. Furthermore,
modulation of the FN400 correlated with a behavioral estimate of familiarity and the LPC
with a behavioral estimate of recollection obtained in a separate experiment in the same
individuals, consistent with the proposed mappings of these indices. These results support
a global decline of recognition memory in a-MCI, which suggests that the memory loss of
prodromal AD may be qualitatively distinct from normal aging.
Keywords: memory, recollection, familiarity, event-related potentials, FN400, LPC, mild cognitive impairment,
Alzheimer’s disease
INTRODUCTION retrieval of contextual aspects of a prior event (e.g., when or

Qualitative aspects and neural correlates of memory impairment where the event occurred). While descriptive details differ across
in early Alzheimer’s disease (AD) remain to be fully elucidated. dual process proposals and controversy remains regarding these
Such characterization may have implications for accurate early models (Squire et al., 2007; Wixted et al., 2010), it has served as a
diagnosis, disease monitoring, and potential therapeutic strategies. useful framework to test memory function in impaired popula-
Amnestic mild cognitive impairment (a-MCI) is conceptualized as tions, which, in turn, provide additional insight into the validity
a transitional state between normal aging and the development of of this conceptualization.
clinical AD (Petersen, 2004; Winblad et al., 2004). While a some- Somewhat inconsistent findings have been reported for the
what heterogeneous population, a-MCI is enriched in patients relative impairment of familiarity and recollection in a-MCI
with AD pathology and high likelihood of developing clinical AD (Westerberg et al., 2006; Anderson et al., 2008; Wolk et al., 2008,
(Petersen et al., 2009). 2013; Algarabel et al., 2009, 2012; Ally et al., 2009a; Serra et al.,
Work that has investigated memory impairment in this popu- 2010). While almost all work suggests that recollection is sig-
lation has previously been framed from the perspective of the dual nificantly impaired in this population, studies have reported a
process model (Mandler, 1980; Jacoby, 1991; Yonelinas, 2002). range of effects on familiarity, from complete sparing (Wester-
These models generally argue that recognition memory is sub- berg et al., 2006; Anderson et al., 2008; Serra et al., 2010) to a level
served by the dissociable processes of familiarity and recollection. of impairment similar to that of recollection (Wolk et al., 2008,
Familiarity is conceptualized as being a strength-based process, 2013). The relative effect of early AD on these memory processes
best described by signal detection theory, and phenomenologically has considerable implications for dual process models that have
associated with an acontextual sense of prior encounter. Recollec- specified anatomical substrates within the medial temporal lobe
tion is a more lucid, associative form of memory that involves (MTL) that dissociably support these memory states (Aggleton
Frontiers in Aging Neuroscience www.frontiersin.org December 2013 | Volume 5 | Article 89 | 1
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Wolk et al. Recognition memory in MCI
and Brown, 2006; Eichenbaum et al., 2007; Ranganath, 2010). The In particular, do these groups differ in the degree to which ERP
hippocampal formation has generally been argued to be critical correlates of recollection and familiarity support accurate mem-
to the contextual memory of recollection, and its impairment in ory decisions or is there evidence of compensatory recruitment of
early AD is consistent with the relatively early pathological involve- alternative neural activity in a-MCI? As prior studies in a-MCI have
ment in this structure. Alternatively, familiarity has been argued been confounded by group differences in overall performance,
to be dependent on extrahippocampal MTL structures, particu- which could, for example, differentially dilute correct responses
larly perirhinal cortex (Aggleton and Brown, 2006; Eichenbaum with “lucky guesses,” the current study was designed to better
et al., 2007; Ranganath, 2010). This region is the earliest associated match recognition discrimination between the groups.
with the neurofibrillary pathology (neurofibrillary tangles, NFTs) 2. Are a-MCI patients less effective or efficient in retrieving
of AD (Braak and Braak, 1991; Delacourte et al., 1999). Thus, the familiarity- or recollection-based memories? This question more
integrity of familiarity-based memory in this population provides directly addresses the integrity of recollection and familiarity by
important data to evaluate these anatomic mappings. comparing their putative ERP correlates for studied versus unstud-
Event-related potentials (ERPs) have provided some of the ied items, regardless of the accuracy of memory decisions for these
strongest support for the dual process model, by providing evi- items (“retrieval attempt” as opposed to “retrieval success”). To
dence of a temporal dissociation of the neural correlates of some extent, this comparison is akin to behavioral measures of
recollection and familiarity (for review, see Rugg and Curran, familiarity and recollection in which a proportional estimate of
2007). In general, ERPs are more positive for correctly recognized success of these memory processes is calculated in the context of
items (“hits”) on a memory task than for correct responses to a given study and test condition. Most prior studies have sim-
novel items (“correct rejections”) beginning approximately 300 ms ply examined retrieval success effects to make claims about the
after stimulus onset. An early component of this “old/new” effect, integrity of these processes, but we feel that such analyses speak
often referred to as the “early old/new effect” or FN400, has been more to the processes supporting successful memory rather than
associated with familiarity-based responses. For example, items the effectiveness by which these memory traces are instantiated.
introspectively endorsed as “old,” but without contextual retrieval, 3. Do the neural correlates of familiarity and recollection based
are associated with modulation of this component (Duzel et al., on study status correlate with behaviorally measured estimates
1997; Curran, 2004; Azimian-Faridani and Wilding, 2006; Wolk of these processes? This question most directly tests the relation-
et al., 2006; Woodruff et al., 2006). This effect tends to occur ship between these ERP correlates and the memory processes they
between 300 and 500 ms with a fronto-central scalp distribution. are thought to index. While a number of studies have supported
A later component, sometimes referred to as the “parietal old/new the relationship between the early and late old/new effects with
effect,” or late positive complex (LPC), occurs between 500 and familiarity and recollection, respectively, there remains contro-
800 ms and is associated with contextual or associative retrieval, versy in these mappings and, more generally, the dual process
consistent with recollection (Wilding and Rugg, 1996; Duzel et al., model (Squire et al., 2007; Voss et al., 2008, 2010a; Wixted et al.,
1997; Curran et al., 2001; Vilberg et al., 2006; Woodruff et al., 2006; 2010). As cognitively normal (CN) older controls, who have been
Wolk et al., 2006). This old/new effect tends to have a predomi- reported to have variable recollection, but spared familiarity rel-
nance over left parietal scalp sites. Finally, a number of studies have ative to young adults (Parkin and Walter, 1992; Davidson and
described a slow wave, sometimes referred to as the late frontal Glisky, 2002; Howard et al., 2006; Wolk et al., 2013), and patients
effect (LFE), which occurs at approximately 800 ms, lasts up to with MCI likely represent a range of integrity for these memory
1000 ms, and is often maximal at right hemisphere scalp sites. processes (Wolk et al., 2008; Algarabel et al., 2009; Ally et al., 2009a;
Modulation of this effect has been argued to be associated with Hoppstadter et al., 2013), this is an ideal cohort for determining
retrieval monitoring or other aspects of executive control during the relationship between behavioral estimates and the underlying
memory retrieval (Wilding and Rugg, 1997; Allan et al., 2000; Ran- neural substrates. In particular, a dissociation of these ERP com-
ganath and Paller, 2000; Curran et al., 2001; Ally et al., 2008). An ponents with their respective behavioral correlates would provide
enhanced LFE has previously been associated with compensatory additional support for these mappings and, in turn, the general
neural activity in older adults and patients with MCI (Ally et al., notion of the dual process model.
2009b; Wolk et al., 2009).
Surprisingly, very few studies have examined recognition mem- MATERIALS AND METHODS
ory in a-MCI with ERPs and those have reported somewhat SUBJECTS
mixed results regarding the integrity of the above old/new effects Thirty-three CN older adults [mean age: 72.1 ± 8.9 (SD) years;
(Olichney et al., 2008; Ally et al., 2009b; Schefter et al., 2012; Hopp- mean education 16.8 ± 3.0 (SD) years] and 24 adults with a diag-
stadter et al., 2013). The current experiment measured ERPs of nosis of a-MCI [mean age: 70.0 ± 8.3 (SD) years; mean education
recognition memory during a task in which participants were first 17.1 ± 2.8 (SD) years] participated in the study (one additional CN
asked to decide whether a word was previously studied and then to adult and two a-MCI patients were excluded due to poor quality
determine the color font at study for those items endorsed as “old.” ERP data). Subjects were recruited from the Alzheimer’s Disease
The latter was instituted to encourage retrieval of both familiarity Research Center (ADRC) of the University of Pittsburgh and the
and recollection. In this context, we addressed the following issues: Alzheimer’s Disease Core Center (ADCC) of the University of
1. Does the neural signature of accurate memory performance, Pennsylvania. As part of their enrollment in their respective cen-
that is “retrieval success” (operationalized as “hits” versus “correct ters, each patient underwent an extensive evaluation, including
rejections”), differ between a-MCI and healthy older controls? medical history and physical examination, neurological history
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and examination, and psychometric testing, usually including “buffers” to reduce primacy and recency effects. Each word was
all elements of the National Alzheimer’s Coordinating Center’s preceded by a 1000 ms fixation (“+”). When the word was pre-
(NACC) Uniform Data Set (Morris et al., 2006; Beekly et al., 2007; sented, subjects were instructed to decide if the referent was an
Weintraub et al., 2009). Clinical diagnosis was determined by object that was “animate” or “inanimate” to insure deep, seman-
review of the above data, in addition to relevant blood work and tic encoding. Subjects indicated their animate/inanimate choice
brain imaging, at a consensus conference attended by neurologists, by button press. The words “animate” and “inanimate” along with
neuropsychologists, and/or psychiatrists. the button press mappings were displayed on the screen simultane-
Diagnosis of a-MCI was made essentially following the crite- ously with stimulus presentation. The study phase was self-paced
ria of Peterson and others (Petersen, 2004; Winblad et al., 2004). with the word remaining on the screen until a response was made.
In addition to a subjective memory complaint, patients needed The test phase immediately followed study. For each block, 20
to have objective evidence of memory impairment for age. Strict test items (10 studied; 10 unstudied) were presented. As with the
cutoffs to denote impairment were not used, but generally patients study phase, each word followed presentation of a 1000 ms fixation
performed greater than 1.5 SDs below age and education adjusted (“+”). Subjects were asked to identify which words were “OLD”
norms. Patients with a-MCI included those with isolated mem- or “NEW” by button press with the mappings displayed under
ory impairment (i.e., single-domain) and those with involvement each word. Test items remained on the screen until a response was
of other aspects of cognition (i.e., multiple-domain). Consis- given. For words endorsed as “OLD,” a “GREEN or RED” prompt
tent with the a-MCI designation, patients had to have minimal immediately followed in which subjects were instructed to recall
impairment in instrumental activities of daily living and not the font color of each word and indicate with a corresponding
qualify for a diagnosis of dementia. Inclusion criteria were age button press. All aspects of the test phase were self-paced. For both
between 50 and 85 years, >7 years of education, and English the study and test phase, subjects were encouraged to respond as
speaking from an early age. Participants were excluded if they quickly as possible, but without sacrificing accuracy.
had a history of clinical stroke, traumatic brain injury, alcohol,
or drug abuse/dependence, prior electroconvulsive therapy, and Behavioral paradigm
any significant disease or medical/psychiatric condition that was An additional behavioral paradigm was performed in a sepa-
felt to impact neuropsychological performance. The study was rate session to estimate recollection and familiarity. This task
approved by the Institutional Review Boards of the University of is a variant of the “process dissociation procedure (PDP)” and
Pennsylvania and the University of Pittsburgh. was previously described in prior reports involving some of the
For the purposes of this study, each subject completed the current cohort (Wolk et al., 2008, 2011). In brief, subjects stud-
following psychometric battery within three months of the ERP ied words in either red or green font, analogous to the ERP
recording: mini-mental status exam (MMSE; Folstein et al., 1975); paradigm. Test items consisted of previously studied words pre-
digit span subtest of the Wechsler Adult Intelligence Scale III sented in white font and unstudied items. Participants were told
(Wechsler, 1987); category fluency (animals; Spreen and Strauss, to endorse only items studied in one of the two colors as “Old”
1998); Consortium to Establish a Registry for Alzheimer’s Disease (e.g., “Only endorse items that were previously studied in green
(CERAD) word list memory (WLM) test (Morris et al., 1989); trail as Old. Call all other items New.”). Using the language of the
making test (TMT) A and B (Reitan, 1958); and a 15- or 30-item PDP, these are considered the “included” items. Words studied in
version of the Boston Naming Test (BNT; Kaplan et al., 1983). the other font color, or the “excluded” items, produced a con-
dition in which recollection opposes familiarity. As these words
EXPERIMENTAL MATERIALS AND METHODS were previously studied, they may be associated with familiar-
We selected 480 nouns between five and eight letters (mean ity, potentially driving the subject to incorrectly endorse them as
Kucera–Francis written frequency: 46.3) from the MRC Psy- “Old.” However, the contextual retrieval of recollection would
cholinguistic database1 . Eight study and test lists were created, allow the subject to recall that the word had been studied in
counterbalanced by study status (half studied; half unstudied). the other font color and correctly endorse it as “New.” Based
Studied words were further counterbalanced by color (half red on the rate of “Old” endorsements to these classes of items,
font; half green font) and number of study presentations [half one can calculate estimates of recollection (R) and familiarity
once (1×); half thrice (3×)]. Words were presented on a com- (F) based on the following: R = p(included) – p(excluded);
puter screen in capital letters in red or green font during the F = p(excluded)/(1 − R). To account for differences in base rates
study phase and white font in the test phase against a black of false alarms (“Old” responses to novel words), familiarity was
background. calculated using a measure of discrimination (d ) derived from sig-
nal detection theory (Yonelinas et al., 1995; Davidson et al., 2006).
EXPERIMENTAL PROCEDURE The delay between this task and the ERP paradigm was 44.2 ± 68.9
Event-related potential paradigm (SD) days.
A source memory task was used to ensure that participants
consciously attempted to recollect the prior study episode. The ELECTROPHYSIOLOGIC RECORDING
paradigm was divided into 20 study-test blocks. Each study block Subjects were fitted with an active two electrode cap (Behav-
consisted of 14 words. The first and last two words served as ioral Brain Sciences Center, Birmingham, UK). One hundred and
twenty-eight Ag–AgCl BioSemi (Amsterdam, The Netherlands)
1 http://websites.psychology.uwa.edu.au/school/MRCDatabase/uwa_mrc.htm “active” electrodes were connected to the cap in a pre-configured
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array placing each electrode in equidistant concentric circles from RESULTS

10 to 20 system Cz position. In addition to the 128 scalp electrodes, DEMOGRAPHIC AND PSYCHOMETRIC DATA
electrodes were placed below and on the outer canthus of the left Demographic and psychometric data are presented in Table 1.
and right eye to measure vertical and horizontal electrooculogra- The groups did not differ with regard to age or education. The
phy (EOG) activity. Electrical offsets were verified to be between overall cognitive impairment of the a-MCI group was relatively
−20 and 20 μV for every channel prior to data collection. Con- mild based on the MMSE (27.8), but significantly worse than that
tinuous electroencephalography (EEG) data were amplified and of the CN group (29.5) [t (55) = 4.8; p < 0.01]. As a point of
digitized with a sampling rate of 512 Hz and a default low-pass, reference, the mean MMSE from the Alzheimer’s Disease Neu-
anti-aliasing filter at one-fifth of the sampling rate2 . roimaging Initiative (ADNI) a-MCI cohort was 27.0 (Petersen
et al., 2010). Consistent with their amnestic status, the a-MCI
EVENT-RELATED POTENTIAL PRE-PROCESSING AND STATISTICAL group displayed significant impairments in tests of memory rel-
ANALYSIS ative to the CN participants. As anticipated in light of including
Data were processed off-line using the EMSE Software Suite both single and multiple domain patients, the a-MCI group was
(Source Signal Imaging, San Diego, CA, USA). A common aver- also significantly impaired on several non-memory tests. However,
age reference and 0.1–40 Hz bandwidth filter were applied. Trials mean performance in these was generally within one standard
were corrected for excessive EOG activity using the EMSE Ocu- deviation of the control group. Finally, the a-MCI group had
lar Artifact Correction Tool. After manual designation of artifact a greater proportion of individuals who were carriers of the
and artifact-free segments, a covariance technique models these apolipoprotein E (ApoE) ε4 allele, the major genetic risk factor
segments, subtracting the contribution of the artifact from the for AD (Mayeux et al., 1993), but this did not reach statistical
recording when detected. Individual bad channels were corrected significance (p > 0.1).
with the EMSE spatial interpolation filter, and trials with artifact Behavioral performance on the memory task performed during
exceeding approximately ± 90 μV were discarded. EEG recording is displayed in Table 2. In both the 1× and 3× con-
Continuous EEG data were divided into epochs beginning dition, the CN group displayed better discrimination and source
200 ms preceding test item presentation and ending 1500 ms memory. In an ANOVA of item memory discrimination with fac-
after test item presentation. ERPs were calculated for the fol- tors of study repetition (1×, 3×) and group, there was a main effect
lowing stimulus classes to assess retrieval success effects: 1× hits, of repetition [F (1,55) = 17.5, p < 0.001] and group [F (1,55) = 41.2,
3× hits, and correct rejections. In addition, ERPs of studied p < 0.001], reflecting better discrimination in the 3× than 1×
and unstudied items, regardless of response, were formed to condition and for the CN group relative to a-MCI group. In addi-
determine group differences in the neural correlates associated tion, an interaction between repetition and group was observed
with prior study. ERPs from individual electrodes were then [F (1,55) = 8.7, p < 0.01] as the CN group appeared to benefit more
averaged into 15 scalp locations divided into five anterior to from repetition than the a-MCI group; however, both groups dis-
posterior [prefrontal (Fp), frontal (F), central (I), parietal (P), played a significant repetition effect [CN: t (32) = 13.1, p < 0.001;
occipital (O)] and three left to right (left, midline, and right) a-MCI: t (23) = 9.3, p < 0.001]. A similar ANOVA was performed
regions of interest (Figure 1). Mean peak amplitudes, relative to for source memory accuracy (proportion source correct/hits).
a 200 ms prestimulus baseline, were calculated for four epochs Again, effects of repetition [F (1,55) = 20.7, p < 0.001], group
following stimulus presentation; 300–500, 600–800, 800–1200, [F (1,55) = 29.2, p < 0.001], and repetition × group [F (1,55) = 18.3,
and 1200–1500 ms. The first two intervals were chosen based p < 0.001] all reached significance, reflecting the better perfor-
on the established literature to differentially capture the early mance of the CN group and the benefit of repetition. Interestingly,
(FN400) and parietal (LPC) old/new effects. The 800–1200 ms the latter interaction was driven by the fact that only the CN
interval was analyzed based on inspection of the data reveal- group displayed improved source memory with study repetition
ing a sustained parietal effect into this time frame, and the [t (32) = 6.3, p < 0.001] while the a-MCI group did not [t (23) < 1.0].
1200–1500 ms interval was analyzed to address differences in the
LFE. RETRIEVAL SUCCESS EFFECTS
Statistical analyses were performed in a standard manner using In order to examine the neural correlates of successful retrieval, we
SPSS 20.0 (Chicago, IL, USA). In general, group differences were attempted to match the groups on item memory discrimination.
determined using analysis of variance (ANOVA). Selected elec- We achieved reasonably comparable performance in the 3× con-
trode clusters for these analyses were determined based upon dition for the a-MCI patients relative to the 1× condition for the
prior reports in the literature and visual inspection of the inter- CN group [t (55) = 1.59, p > 0.1]. ERPs of hits and correct rejec-
vals of interest. The Greenhouse–Geisser correction procedure was tions and the scalp topographies of the difference waves for both
used for repeated measures factors with greater than one numer- groups in these respective conditions are displayed in Figures 2
ator degree of freedom. Spearman correlation coefficients were and 3, respectively. As can be observed, both groups demonstrated
calculated for determining the relationship between measures of a relative positivity associated with hits compared to correct rejec-
recollection and familiarity determined in the separate behavioral tions beginning at around 300 ms. From ∼300 to 500 ms, this
task with their putative ERP correlates. effect was maximal at central, midline scalp sites extending some-
what more anterior. Subsequently, there was a clear shift to a more
posterior, left-hemisphere effect that slowly decreased throughout
2 http://www.biosemi.com/faq/adjust_samplerate.htm the remainder of the recording epoch. These hit/correct rejection
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FIGURE 1 | Electrode positions on the Bio-Semi ActiveTwo headcap with the 15 regions of interest displayed. Anterior-to-posterior: Fp, prefrontal;
F, frontal; C, central; P, parietal; O, occipital central; left-to-right, L, left; C, midline; R, right.
differences have the timing and topography of the “early” (FN400) visual source memory paradigms as the late posterior negativity
and “parietal” (LPC) old/new effects, with the exception of the (LPN; Cycowicz and Friedman, 2003; Li et al., 2004).
early effect being less anterior than typically described. An addi-
tional right-hemisphere effect, most prominent in the CN group, Early (FN400) retrieval success effects
emerges and moves more anterior near the end of the recording For comparison of the early old/new effect, a condition (hits, cor-
epoch consistent with descriptions of the LFE. Finally a central rect rejections) × group (MCI, CN) ANOVA was performed at
negativity is observed most prominently in the older adults in the the central electrode cluster (CC) that best captured this effect in
later portion of the recording epoch, as has been described in other the 300–500 ms epoch. There was a significant effect of condition
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Table 1 | Demographic and psychometric data. effect was similar for both the CN and MCI groups (0.76 versus
0.58 μV, respectively). Given the apparent continuation of the left
CN (n = 33) MCI (n = 24)
parietal effect beyond 800 ms, the same analysis was performed
Age (years) 72.1 (8.9) 70.0 (8.3)
for the 800–1200 ms interval. Again, there was a significant effect
of condition [F (1,55) = 11.6, p < 0.01], but no interaction with
Education (years) 16.8 (3.0) 17.1 (2.8)
group [F (1,55) < 1.0]. Nonetheless, the magnitude of the effect
Gender (% Female) 66.7 41.7 was somewhat larger in the CN group (0.78 versus 0.51 μV).
ApoE4 carrier status (%) 36.6 59.1
MMSE 29.5 (0.9) 27.8 (1.6)**
Late posterior negativity and LFE retrieval success effects
Finally, given the apparent central negativity in the CN group
WLM immediate recall 24.0 (3.7) 16.8 (3.1)**
consistent with the LPN, we also examined the old/new effect
WLM delayed recall 8.2 (1.8) 2.6 (1.9)** at the central cluster of electrodes for the 800–1200 ms
WLM recognition 9.9 (0.3) 8.7 (1.4)** interval. In this case, there was a main effect of condi-
Digit span forwards 7.0 (1.1) 6.5 (0.9) tion [F (1,55) = 4.8, p < 0.05] and a marginally signif-
Digit span backwards 5.4 (1.3) 4.6 (0.9)* icant interaction with group [F (1,55) = 3.8, p < 0.06].
TMT A (s) 32.0 (12.2) 38.0 (14.8)
The interaction was driven by the presence of an LPN
old/new effect in the CN group (−0.61 μV), but not a-MCI
TMT B (s) 73.9 (28.7) 107.5 (54.8)**
(−0.04 μV).
Category fluency (animals) 22.0 (5.5) 16.6 (2.8)** Based on inspection of scalp topography, it appeared that the
BNT 28.6 (2.2) 27.9 (2.7) a-MCI group may have exhibited a stronger and more central LFE
than the CN group. To assess this potential difference, a condition
WLM immediate recall is the sum of the three immediate memory trials. WLM (hits, correct rejections) × group (a-MCI, CN) × electrode cluster
recognition is calculated as hits minus false alarms. Two CN did not complete
TMT and digit span. BNT comparison includes 23 CN and 18 MCI patients, as (LFp, CFp, RFp) ANOVA within the 1200–1500 ms interval was
the remainder performed a 15-item version of the task. ApoE genotype was not calculated. No main effect or interaction reached significance other
available in five individuals. *p < 0.05; **p < 0.01. than an effect of group [F (1,55) = 6.1, p < 0.05] due to the a-MCI
patients having generally more negative voltage in this time frame.
[F (1,55) = 13.3, p < 0.01] due to hits having a more positive voltage
than correct rejections. There was no condition × group interac- More rigorous matching of performance
tion [F (1,55) < 1.0] suggesting the magnitude of the effect did Despite the lack of statistical difference between the groups based
not differ between the two groups although it was of somewhat on item discrimination in the above analysis, it is worth point-
decreased magnitude in the a-MCI patients (0.22 versus 0.38 μV). ing out that in absolute terms, the MCI group still performed
more poorly. To address this possible confound, we removed the
Parietal (LPC) retrieval success effects five highest performing CN participants and the three lowest MCI
To assess the parietal old/new effect, the analogous ANOVA was patients to achieve groups very closely matched in discrimination
performed on the left parietal cluster in the 600–800 ms interval. A [d : 2.40 versus 2.41 in CN versus MCI, respectively; t (47) < 0.1].
significant effect of condition [F (1,55) = 14.4, p < 0.001] reflected a There was no change in the results of any of the above analyses
more positive voltage for hits than correct rejections. Again, there except related to the central negativity in the 800–1200 ms inter-
was no interaction between condition and group, as the old/new val. With this subgroup, the old/new effect no longer reached a
trend level group interaction [CN: −0.59 μV; MCI: −0.14 μV;
F (1,47) = 1.9, p > 0.1].
Table 2 | Performance on ERP and behavioral memory task. RETRIEVAL ATTEMPT EFFECTS
To determine how effective the groups are in retrieval of
CN (n = 33) MCI (n = 24)
familiarity- and recollection-based memories, we compared all
studied and unstudied items regardless of the accuracy of their
Item memory (d ’) 1× 2.55 (0.55) 1.60 (0.58)**
associated memory judgments and not matched on perfor-
Item memory (d ’) 3× 3.50 (0.71) 2.24 (0.83)**
mance. The ERPs of studied and unstudied items and the
Item memory (d ’) Overall 2.88 (0.55) 1.88 (0.66)** scalp topographies of the difference waves are displayed in
Source memory 1× 0.60 (0.10) 0.52 (0.08)* Figures 4 and 5. As expected, the effect of condition was very
Source memory 3× 0.70 (0.12) 0.53 (0.07)** similar to the above described differences when using only
Source memory overall 0.66 (0.10) 0.53 (0.07)** veridical responses. However, the early and late effects visually
appeared somewhat diminished in the MCI group relative to CN
Recollection (proportion) 0.35 (0.23) 0.16 (0.17)*
participants.
Familiarity (d ’) 1.52 (0.53) 0.77 (0.48)**
Early (FN400) retrieval attempt effects
1×, test items with one prior study presentation; 3×, test items with three prior
study episodes; d’ = discrimination; source memory is proportion source hits
For comparison of the early old/new effect a study status (studied,
over total hits; estimates of recollection and familiarity from behavioral task in unstudied) × group (a-MCI, CN) ANOVA was again performed at
bottom two rows; *p < 0.01; **p < 0.001. CC during the 300–500 ms epoch. There was a significant effect of
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FIGURE 2 | Cognitively normal and amnestic mild cognitive impairment grand average ERP waveforms for hits (black) and correct rejections (red) in
the midline central (CC) and left parietal (LP) sites. Waves were generated from the 1× study condition in the CN group and the 3× study condition in the
amnestic mild cognitive impairment group.
study status [F (1,55) = 15.6, p < 0.001] and a study status × group Late posterior negativity and LFE retrieval attempt effects
interaction [F (1,55) = 6.0, p < 0.05]. These findings were driven As with the retrieval success analysis, we also examined the central
by studied items being more positive than unstudied items, but cluster of electrodes in the 800–1200 ms interval to assess differ-
the difference was larger in the CN group. To further evaluate ences in the observed central negativity (i.e., LPN). There was both
this interaction, paired sampled t-tests revealed a significant stud- a significant effect of study status [F (1,55) = 11.7, p < 0.01] and
ied/unstudied difference in the CN group [t (33) = 4.7, p < 0.0001], an interaction of study status with group [F (1,55) = 9.2, p < 0.01].
but not in those with MCI [t (23) = 1.0, p > 0.1]. This interaction was driven by a more negative response for stud-
ied than unstudied items in the CN group [t (33) = 4.6, p < 0.001],
Parietal (LPC) retrieval attempt effects which was not present in the a-MCI patients [t (23) < 1.0].
The analagous ANOVA at the left parietal cluster during the 600– Finally, we examined the LFE with a condition (studied,
800 ms interval revealed an effect of study status [F (1,55) = 24.4, unstudied) × group (a-MCI, CN) × electrode cluster (LFp, CFp,
p < 0.0001] and a trend toward an interaction of study status and RFp) ANOVA in the 1200–1500 ms epoch. While a main effect of
group [F (1,55) = 3.7, p = 0.06]. Again, the effect of study status condition was observed [F (1,55) = 6.2, p < 0.05] due to more posi-
was driven by a more positive voltage for studied than unstud- tive potentials associated with studied relative to unstudied items,
ied items while the interaction appeared due to this effect being there was no evidence of an interaction with group [F (1,55) < 0.1].
of greater magnitude in the CN group. Within group follow-up
comparisons revealed that the LPC was highly significant in the CORRELATIONS OF ERP COMPONENTS WITH RECOLLECTION AND
CN group [t (33) = 5.2, p < 0.0001], but of borderline significance FAMILIARITY
in the a-MCI patients [t (23) = 2.1, p = 0.05]. The FN400 and LPC effects have been argued to be associated with
Analysis of the left parietal cluster during the 800–1200 ms familiarity and recollection, respectively. Behavioral measures of
interval also produced a significant main effect of study status these processes essentially measure their integrity (e.g., the pro-
[F (1,55) = 18.8, p < 0.001] and an interaction of study status by portion of items recollected) in the given context of the memory
group [F (1,55) = 5.3, p < 0.05]. The interaction again appeared paradigm. Our retrieval attempt measures may provide the most
driven by a higher magnitude study status effect in the CN group analogous electrophysiologic correlate of this, as they index the
[t (33) = 5.5, p < 0.0001] than those with a-MCI [t (33) = 1.4, degree to which these ERP components are instantiated over all
p > 0.1]. test items, not just those with correct endorsements. Thus, we
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FIGURE 3 | Scalp topography maps for CN adults and patients with topographic maps are displayed on the right with electrode cluster used for
amnestic mild cognitive impairment for retrieval success effects (hits analysis indicated. Each head map represents 100 ms average and color
minus correct rejections) matched for performance. Highlighted voltage scale is presented.
correlated retrieval attempt effects (i.e., studied minus unstud- processes is further strengthened by the finding of an appar-
ied voltages) with behavioral estimates of these memory processes ent double dissociation in the relationship between behavioral
derived from a very similar memory paradigm. estimates of these processes obtained outside of the ERP record-
Behavioral recollection and familiarity estimates are displayed ing session and the ERP retrieval attempt effects. Importantly,
in Table 1 (bottom two rows). Consistent with our prior find- although a-MCI patients may be less effective in the retrieval of
ings, patients with a-MCI displayed significantly lower recollection recollection and familiarity-based memories, as exhibited by the
[t (55) = 3.4, p < 0.01] and familiarity [t (55) = 5.5, p < 0.001] retrieval attempt analysis, the neural signature of successful mem-
measures than the CN group. ory did not differ significantly from CN adults. We will discuss
We found a significant correlation between the FN400 retrieval each of these issues in turn.
attempt effect at the central cluster of electrodes and the familiarity
measure (ρ = 0.40, p < 0.01), but not with recollection (ρ = 0.20, IMPLICATIONS FOR INTEGRITY OF RECOLLECTION AND FAMILIARITY IN
p > 0.1). The opposite relationship was found for the LPC in a-MCI
the 600–800 ms epoch. No correlation was found with the famil- A number of recent studies have examined the relative impairment
iarity measure (ρ = 0.07, p > 0.1), but a significant correlation of recollection and familiarity in a-MCI given its potential theo-
was observed with recollection (ρ = 0.32, p < 0.05). This same retical and clinical implications. Indeed, two of the earliest regions
relationship was also observed with the left parietal cluster in the involved in the AD pathological process and associated with NFTs
800–1200 ms interval (recollection: ρ = 0.44, p < 0.01; familiarity: are the perirhinal and entorhinal cortices (Braak and Braak, 1991;
ρ = 0.12, p > 0.1). Delacourte et al., 1999). These are structures that have also been
argued to be essential for familiarity-based memory (Bowles et al.,
DISCUSSION 2007; Yonelinas et al., 2007; Ranganath, 2010; Wolk and Dickerson,
The current findings address several important issues related to 2011; Wolk et al., 2011) and, thus, prodromal AD (i.e., AD in the
the nature of memory impairment and its electrophysiologic a-MCI stage) may serve as a “lesion” model to test this hypothe-
underpinnings in a-MCI, and they also clarify some of the incon- sis. Further, if this anatomic relationship is correct, impairment
sistencies in the literature. Most importantly, the current work of familiarity could be an early feature of AD, qualitatively dis-
revealed evidence of less reliable generation, or attenuation, of parate from the relatively selective decline in recollection thought
both the early (FN400) and late (LPC) ERP memory compo- to be associated with “healthy” aging (Jacoby, 1999; Davidson and
nents in a-MCI patients. Prior work has suggested that these ERP Glisky, 2002; Howard et al., 2006; although see Duarte et al., 2006).
effects are associated with familiarity and recollection, respectively, As such, familiarity might then be a relatively sensitive and specific
and the present findings are consistent with behavioral studies marker for very early detection of AD-related pathology distinct
suggesting that both of these memory processes are impaired in from healthy age-associated memory loss (Wolk et al., 2013).
a-MCI (Wolk et al., 2008; Algarabel et al., 2009; Ally et al., 2009a). However, the literature has produced mixed results with regard
The mapping of these components to their respective memory to the integrity of familiarity in a-MCI patients using a variety
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FIGURE 4 | Cognitively normal and amnestic mild cognitive impairment grand average ERP waveforms for studied (black) and unstudied (red) words
in the midline central (CC) and left parietal (LP) sites. Studied waves were generated by averaging across the 1× and 3× study condition.
of different process estimation approaches. Almost all of these study influences these ERP components and an electrophysiologic
studies report a significant impairment in recollection, or asso- metric of the integrity of the memory process indexed. Thus, while
ciative memory (Westerberg et al., 2006; Wolk et al., 2008; Ally a-MCI patients may display a normal degree of familiarity when
et al., 2009a; Serra et al., 2010; Algarabel et al., 2012; Embree et al., they correctly recognize a previously studied item as suggested by
2012), consistent with the hippocampal involvement that is gener- an intact early retrieval success effect, on average fewer items may
ally present in patients with a-MCI (Guillozet et al., 2003; Petersen engender this degree of familiarity than in CN adults.
et al., 2006). Alternatively, while several studies have reported There have been only a few prior studies that have assessed
impairment in familiarity (Wolk et al., 2008; Algarabel et al., 2009; the integrity of this early component in a-MCI patients, and all
Ally et al., 2009a; Embree et al., 2012), other work has suggested a but one have just examined retrieval success effects. Consistent
relative sparing of this form of memory (Westerberg et al., 2006; with the current findings, Olichney et al. (2008) found a reduc-
Hudon et al., 2009; Serra et al., 2010). These conflicting data may tion in repetition effects within this epoch in a-MCI patients
be due to a number of factors, including patient characteristics, who later converted to clinical AD. In a study of retrieval suc-
task difficulty, and assumptions inherent in the various method- cess, a-MCI patients displayed an absent FN400 when words
ologies for estimating familiarity. The latter issue is of particular were used as stimuli, but not pictures (Ally et al., 2009b). The
relevance given controversies over the assumptions of each of these reduced early ERP effect for words is similar to the current find-
approaches. Thus, use of an “objective” electrophysiologic mea- ings and consonant with several behavioral studies that have
sure, not dependent on a defined stimulus or response class, is found words particularly sensitive to failures of familiarity in
appealing. a-MCI (Wolk et al., 2008; Ally et al., 2009a), but with rela-
An early (300–500 ms) frontocentral component, often referred tive sparing of familiarity for pictures (Westerberg et al., 2006;
to as the FN400, has been linked to familiarity-based memory. Our Embree et al., 2012), perhaps due to the enhanced perceptual
finding of a significantly reduced retrieval attempt effect (studied and semantic encoding engendered by visually rich stimuli.
versus unstudied items) for this component in patients with a-MCI Finally, a recent study reported absence of the FN400 in a-
supports the notion that familiarity is impaired in this popula- MCI and that this effect correlated with cortical MTL structures
tion. As noted above, the comparison of studied versus unstudied (Hoppstadter et al., 2013). In contrast, at least one prior study
items, as opposed to hits versus correct rejections (i.e., retrieval has suggested sparing of the FN400 effect even in mild AD, but,
success effect), is likely most analogous to a behavioral measure of notably, this was a relatively small sample (n = 10) and only
the relative integrity of a particular memory process. In essence, retrieval success effects were explored (Tendolkar et al., 1999). Fur-
this measure gives a metric of the average degree to which prior thermore, several studies of patients with clinical AD, as opposed
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FIGURE 5 | Scalp topography maps for CN adults and patients with topographic maps are displayed on the right with electrode cluster used for
amnestic mild cognitive impairment for retrieval attempt effects (studied analysis indicated. Each head map represents 100 ms average and color
minus unstudied words) matched for performance. Highlighted voltage scale is presented.
to a-MCI, have revealed absence of both the FN400 and LPC actually reduced the degree of FN400 difference with the a-
(Friedman et al., 1992; Olichney et al., 2002), which may sim- MCI group observed, underestimating the degree of familiarity
ply reflect the greater severity of underlying pathology in these impairment.
patients. These findings can also be placed within the context of
Less controversial is the current finding of a diminished recent work which has suggested that the anterior and pos-
LPC effect in the a-MCI patients. This finding is consonant terior MTL appear to represent nodes of dissociable net-
with the near universal finding of recollection impairment works (Kahn et al., 2008; Didic et al., 2011; Libby et al., 2012;
reported in behavioral studies of a-MCI (Westerberg et al., 2006; Ranganath and Ritchey, 2012). It has been argued that the ante-
Anderson et al., 2008; Wolk et al., 2008; Ally et al., 2009a; Serra rior network, which includes the PRC, head of the hippocampus,
et al., 2010; Algarabel et al., 2012). Similarly, almost all ERP stud- ventral temporopolar cortex, and orbitofrontal cortex, may be
ies of this population have reported reduction in the LPC, thought linked to familiarity-based memory. Alternatively, the poste-
to index this memory process (Olichney et al., 2008; Ally et al., rior network, which includes the body/tail of the hippocampus,
2009b; Hoppstadter et al., 2013; although see Schefter et al., 2012, parahippocampus, retrosplenial cortex, posterior cingulate, pre-
for exception). cuneus, and angular gyrus, is more tightly linked with the
It is worth contrasting the finding of a diminished FN400 and contextual and self-referential aspects of recollection (Ranganath
LPC in a-MCI patients with reports of non-neurodegenerative and Ritchey, 2012). Scalp EEG recordings are unlikely to directly
amnesics who have isolated hippocampal lesions (Duzel et al., reflect activity from MTL structures and are more likely to be
2001; Addante et al., 2012). These studies have revealed spar- associated with cortical activity that is perhaps downstream of
ing of the early component, but significant diminution of the MTL processing. While the cortical localization based on scalp
LPC relative to controls. This set of findings can be argued topography is dubious, it is tempting to note that that the ante-
to support the notion that the hippocampus is critical for rec- rior to posterior location of the FN400 and LPC is in keeping
ollection (indexed by LPC), but not familiarity (indexed by with the main cortical nodes of the anterior and posterior MTL
FN400), which has been posited to depend on perirhinal and networks and their mappings to familiarity and recollection,
entorhinal cortices. As the NFT pathology of early AD includes respectively.
extrahippocampal MTL regions even prior to involvement of As the anterior MTL is affected earliest with NFT pathology,
the hippocampus proper, the current finding is consistent with derangements of the anterior network and its functions may rep-
these mappings. Indeed, as noted above, a recent report has resent the earliest features of AD and potentially an important
more directly related the FN400 to cortical MTL atrophy in biomarker at the preclinical and prodromal stages (Didic et al.,
an a-MCI cohort (Hoppstadter et al., 2013). It should also be 2011; Gour et al., 2011). Indeed, a number of studies have sug-
pointed out that the CN group had a greater proportion of gested that cognitive measures dependent on the integrity of the
ApoE ε4 carriers than typical in the population and, thus, PRC and this anterior MTL network, including a series of stud-
may be over-represented in individuals who could harbor pre- ies assessing visual object recognition memory, may be sensitive
clinical AD. Given the early PRC involvement, this may have to these early disease stages (Barbeau et al., 2004, 2008; Guedj
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et al., 2006; Didic et al., 2013; Wolk et al., 2013). Also a poten- et al., 2007). It is possible that in visual source memory tasks,
tial surrogate for this system, the FN400 may serve as a useful this additional processing is necessary for accurate memory deci-
electrophysiologic biomarker. sions. Finally, it is notable that from a quantitative perspective, the
LPC effect was somewhat smaller than in the CN group, which
RETRIEVAL SUCCESS EFFECTS may suggest that, in general, fewer associative details were actually
Measurement of retrieval success effects (hits versus correct rejec- retrieved. In light of the relatively low source accuracy of the CN
tions) allows for assessment of the neural signature of veridical group for this comparison (60%), a small difference in the LPC
memory and is the approach most frequently examined in ERP could result in the a-MCI group to approach chance performance.
studies of memory. By comparing a-MCI (enriched in patients Further, as noted above, the somewhat higher than typical ApoE
with AD pathology) and CN adults, one can determine whether ε4 allele carrier rate in the CN group may have attenuated group
prodromal AD is associated with engagement of the same neural differences.
processes in support of accurate memory; however, as delin- Importantly, there was also no evidence of possible “compen-
eated above, this type of comparison does not necessarily reflect satory” recruitment of alternative networks, including the LFE,
the effectiveness by which these processes or representations are which has been observed in CN older adults relative to young
instantiated across all test items. Nonetheless, one can assess adults (Swick et al., 2006; Wolk et al., 2009). This result echoes that
whether alternative networks are recruited in support of successful of Ally et al. (2009b) who also did not observe evidence of a com-
memory with this type of analysis. pensatory effect when word stimuli were used, but did see such an
We found that for correct responses, patients with a-MCI effect with pictures.
displayed both an FN400 and LPC, which did not statisti-
cally differ from that of CN adults. This result suggests that BEHAVIORAL–ERP CORRELATIONS
similar neural generators support veridical memory in a-MCI The current study used ERP indices of recollection and familiar-
patients as in CN adults despite the overall poorer memory ity to estimate the integrity of these memory processes in a-MCI.
of the former group. In other words, while a-MCI patients While there is largely consensus in the literature that the LPC is
may be less effective in encoding and retrieving memories, related to recollection-based retrieval and even that its amplitude
when they do, similar neural representations are instanti- may be directly related to the amount of information recollected
ated. In this case, additional study is required (3× condition) (Curran, 2000; Vilberg et al., 2006; Woodruff et al., 2006; Rugg
for the a-MCI patients to achieve similar performance and and Curran, 2007; Wolk et al., 2007; Vilberg and Rugg, 2009),
the concomitant neural signature of success as CN adults there is greater controversy surrounding the meaning of the FN400
(1× condition). (see Mecklinger et al., 2012; Paller et al., 2012 for opposing view-
As described above, most of the prior studies examining points). Indeed, Voss and colleagues have thoughtfully argued,
these effects in a-MCI have focused on retrieval success results based on several experiments, that this ERP index is more closely
with variable findings (Ally et al., 2009b; Schefter et al., 2012; tied to conceptual priming and that the association with familiar-
Hoppstadter et al., 2013). One important difference between these ity is driven, in large part, by the fact that these processes often
prior studies and the current one is that we attempted to better co-occur (Voss and Paller, 2007, 2009; Voss et al., 2008, 2010b). In
match task performance. Retrieval success effects can be con- fact, the FN400 was named based on its very similar appearance
founded by differences in performance due to “lucky guesses” to the N400, which has frequently been implicated in concep-
contributing to both hits and correct rejections in the poorer tual priming (Wolk et al., 2004). Adding to the complexity of
performing group (Wilding and Rugg, 1996; Cansino et al., 2012; this relationship is the notion that conceptual fluency may con-
Wang et al., 2012). The attempt to more closely match perfor- tribute to familiarity-based memory (Whittlesea and Leboe, 2000;
mance in the current study, as well as the relatively high item Wolk et al., 2004) and that both conceptual priming and famil-
discrimination, significantly mitigates against this concern. iarity may be dependent on overlapping neural substrates (i.e.,
The presence of an intact LPC effect may be considered some- perirhinal cortex; Voss et al., 2009; Wang et al., 2010). Indeed,
what surprising in the a-MCI patients given that their source some may consider familiarity to be “non-episodic” in nature
memory was essentially at chance for items correctly identified and to more closely align with semantic memory (Didic et al.,
as old. In light of the fact that the LPC is thought to index rec- 2011).
ollective, associative memory, one would expect that it would be Further, it is also worth pointing out that our“retrieval attempt”
related to accurate source memory decisions. One potential expla- analysis is essentially a repetition effect (studied versus unstud-
nation for this apparent contradiction is that while a-MCI patients ied items), as we did not conditionalize on the basis of response.
retrieved some associative details of the prior study episode, they As such, examination of these effects alone does not adjudicate
did not tend to recollect the study color. In other words, they between explicit or implicit correlates. However, the relationship
had non-criterial recollection relevant to the source memory task. between these ERP indices and behavioral estimates of recollec-
Another possibility may be revealed by the lack of LPN in this tion and familiarity, using a highly similar task performed outside
group. While still of uncertain significance, this negative wave has of the electrophysiologic recording session, does provide sup-
been associated with visual source memory tasks and has been port for their role in explicit memory. Namely, we found that
postulated to be related to recapitulation of study details at test, the FN400 significantly correlated with a behavioral estimate of
representing bound features of prior study (Cycowicz and Fried- familiarity, but not recollection. Alternatively, the LPC correlated
man, 2003; Johansson and Mecklinger, 2003; Li et al., 2004; Wolk only with the behavioral estimate of recollection. This relative
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Received: 16 October 2013; paper pending published: 07 November 2013; accepted: 20 Copyright © 2013 Wolk, Manning, Kliot and Arnold. This is an open-access article
November 2013; published online: 11 December 2013. distributed under the terms of the Creative Commons Attribution License (CC BY).
Citation: Wolk DA, Manning K, Kliot D and Arnold SE (2013) Recognition memory The use, distribution or reproduction in other forums is permitted, provided the original
in amnestic-mild cognitive impairment: insights from event-related potentials. Front. author(s) or licensor are credited and that the original publication in this journal is cited,
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ORIGINAL RESEARCH ARTICLE

published: 11 December 2013

Recognition memory in amnestic-mild cognitive

INTRODUCTION retrieval of contextual aspects of a prior event (e.g., when or

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array placing each electrode in equidistant concentric circles from RESULTS

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double dissociation supports the proposed mappings of these ERP REFERENCES

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