Accepted Manuscript

Cognitive and functional correlates of accelerated long-term forgetting in temporal

lobe epilepsy

Samantha Audrain, Mary Pat McAndrews

PII: S0010-9452(18)30103-5
DOI: 10.1016/j.cortex.2018.03.022
Reference: CORTEX 2286

To appear in: Cortex

Received Date: 2 June 2017

Revised Date: 24 December 2017
Accepted Date: 19 March 2018

Please cite this article as: Audrain S, McAndrews MP, Cognitive and functional correlates of accelerated
long-term forgetting in temporal lobe epilepsy, CORTEX (2018), doi: 10.1016/j.cortex.2018.03.022.

This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to
our customers we are providing this early version of the manuscript. The manuscript will undergo
copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please
note that during the production process errors may be discovered which could affect the content, and all
legal disclaimers that apply to the journal pertain.
 ACCEPTED MANUSCRIPT

Cognitive and functional correlates of accelerated long-term forgetting in temporal lobe epilepsy

Samantha Audraina,b & Mary Pat McAndrewsa,b

a
Krembil Research Institute, University Health Network, Toronto, ON, M5T 2S8, Canada;
b
Department of Psychology, University of Toronto, Toronto, ON, M5S 3G3, Canada

Corresponding author: Samantha Audrain, samantha.audrain@mail.utoronto.ca

PT
Abstract: While we know that hippocampal dysfunction is responsible for the memory deficits

RI
that patients with temporal lobe epilepsy exhibit at relatively short study-test delays, the role of

SC
this region in accelerated long-term forgetting (ALF) is not yet clear. In the present study, we

probed the role of the hippocampus in ALF by directly comparing memory for associations to

U
memory that could be supported by item recognition during a forced choice recognition task over
AN
delays ranging from 15-minutes to 72-hours. We additionally examined resting-state functional

connectivity between the hippocampus and cortical regions known to be involved in processing
M

these types of stimuli, as well as the relationship between ALF and various clinical variables

including structural abnormality in the hippocampus, lateralization of epileptic focus, presence of

D

seizures across the retention period, and standardized composite memory scores. We found
TE

evidence of accelerated forgetting for item stimuli (but not associative stimuli) by 6 hours post-
EP

learning, which became statistically reliable by 72-hours. This finding suggests that unlike

controls, patients were unable to utilize novelty to reject the incorrect object-scene pair. While
C

none of the examined clinical variables were related to long-term forgetting, reduced resting-
AC

state functional connectivity between the affected anterior hippocampus and unaffected lateral

temporal cortex predicted forgetting of item stimuli over the 72-hour delay. Implications for the

role of the hippocampus in accelerated long-term forgetting, and existing theories of systems

consolidation in this context are discussed.

 ACCEPTED MANUSCRIPT

Keywords: accelerated long-term forgetting, temporal lobe epilepsy, hippocampus,

consolidation, resting state functional connectivity

Funding: This work was supported by the Natural Sciences and Engineering Research Council
[grant numbers RGPIN-2015-06471]

PT
RI
Highlights

• We found accelerated long-term forgetting for item stimuli by 72-hours

SC
• Patients appeared unable to use novelty to reject items they hadn’t seen before

• Connectivity between the hippocampus and temporal cortex predicted forgetting

U
AN
M
D
TE
C EP
AC
 ACCEPTED MANUSCRIPT

1 Introduction
While temporal lobe epilepsy (TLE) has long been associated with deficits in learning

and retrieval, research in the past decade has identified a specific problem with retention that has

PT
been termed accelerated long term forgetting (ALF) (Blake, Wroe, Breen, & Mccarthy, 2000; C

R Butler & Zeman, 2008). ALF is characterized by relatively normal learning and initial

RI
retention but rapid forgetting of long-term memories, which suggests a failure of consolidation.

SC
This phenomenon was first described in patients with epilepsy (De Renzi & Lucchelli, 1993;

Martin et al., 1991), and has since been further investigated in the context of transient epileptic

U
amnesia: a late-onset form of epilepsy characterized by discrete amnesic episodes (Asadi-Pooya,
AN
2014; Christopher R. Butler et al., 2007). ALF is of particular interest to memory researchers

given that the time-course of systems consolidation, and the time-delineated role of the
M

hippocampus in this process, has been the subject of considerable debate (Dudai, 2012; Dudai,

Karni, & Born, 2015; McGaugh, 2000; Squire & Alvarez, 1995; Winocur & Moscovitch, 2011;
D

Winocur, Moscovitch, & Bontempi, 2010). Since patients with TLE demonstrate variable
TE

structural and/or functional hippocampal abnormalities, ALF provides a unique context in which

to probe the question of hippocampal contribution to long-term memory and consolidation. Two
EP

pertinent questions have yet to be answered: at what point in time does long-term forgetting
C

become abnormal, and is hippocampal dysfunction the underlying cause of ALF?

AC

The time-course of ALF in epilepsy has thus far been detected at delays spanning 1 hour

(Wilkinson et al., 2012) to 8 weeks (Blake et al., 2000), though few studies of this population

have tested for ALF with intact memory within 30 minutes of encoding, and again within the

first 24 hours after learning (in epilepsy: Bell, Fine, Dow, Seidenberg, & Hermann, 2005; Cassel,

Morris, Koutroumanidis, & Kopelman, 2016; Fitzgerald, Thayer, Mohamed, & Miller, 2013; and

1
 ACCEPTED MANUSCRIPT

in transient epileptic amnesia: Muhlert, Milton, Butler, Kapur, & Zeman, 2010; Zeman et al.,

2013). Two studies have evaluated (and found) ALF within the first 12 hours of wakefulness,

suggesting that this is not necessarily a disorder of sleep-related consolidation (in TLE: Deak,

Stickgold, Pietras, Nelson, & Bubrick, 2011; in transient epileptic amnesia: Atherton, Nobre,

PT
Zeman, & Butler, 2014). Variability in estimating the onset of ALF stems from the fact that

RI
studies thus far have used different stimuli, paradigms, and delays, in what is already a

heterogeneous population. To determine the earliest time point at which ALF can be reliably

SC
detected may have important implications for the detection of ALF in the clinic given that there

is no standardized way to test for this phenomenon (though see Miller, Flanagan, Mothakunnel,

U
Mohamed, & Thayer, 2015 for normed standard clinical memory tests at longer delays). It may
AN
also speak to theories concerning the time course of consolidation, which propose relatively

“fast” molecular and synaptic changes that occur in the hippocampus and slower systems level
M

consolidation processes, whereby memory representations are thought to redistribute over

D

cortical brain networks (Dudai, 2012; Dudai et al., 2015; McGaugh, 2000; Winocur &
TE

Moscovitch, 2011; Winocur et al., 2010).

While we know that hippocampal dysfunction underlies memory difficulties that TLE
EP

patients may face at shorter delays, the role of this region in ALF is unclear. Structural brain

imaging studies have revealed mixed findings. Some studies have found an association between
C

ALF and hippocampal abnormality (Narayanan et al., 2012), and more specifically with medial
AC

temporal sclerosis (MTS; Muhlert et al., 2011), though ALF was also found in individuals

without abnormality. Wilkinson and colleagues (2012) found no association between ALF and

hippocampal integrity, while Cassel et al., (2016) found that MTS was associated with forgetting

of verbal material by 10 minutes and over a week, while those without MTS only showed

2
 ACCEPTED MANUSCRIPT

accelerated forgetting over longer delays. Furthermore, there is evidence that hippocampal

volume correlates with forgetting at shorter delays but not with ALF in patients with transient

epileptic amnesia (Butler et al., 2009, 2013). The functional neural correlates of ALF as

identified with neuroimaging techniques has thus far remained unexplored in both patient

PT
populations.

RI
Considering the different types of materials or testing protocols used to study ALF may

also yield insights into the engagement of medial temporal lobe and cortical regions. For

SC
instance, it has generally been found that ALF occurs for both recall and recognition (Blake et

al., 2000; Evans, Elliott, Reynders, & Isaac, 2014; Narayanan et al., 2012; Tramoni et al.,

U
2011). Recollection of specific episodic detail is known to involve the hippocampus, though
AN
over time as memories become more gist-like or schematic, recall relies to a greater extent on

neocortical areas (Moscovitch & Nadel, 1997; Winocur et al., 2010). In contrast, recognition can
M

involve recollection but also familiarity, which is the feeling of knowing you have encountered
D

something before without remembering the contextual details surrounding that event, and this
TE

has been attributed to extra-hippocampal cortices (Ranganath, 2010) . ALF has been shown for

lists of words (Deak et al., 2011; Fitzgerald et al., 2013; Narayanan et al., 2012) and visual
EP

designs (Fitzgerald et al., 2013; Narayanan et al., 2012; Wilkinson et al., 2012), and both of these

types of stimuli target item memory, which is considered to be supported by extra-hippocampal

C

regions such as the perirhinal cortex and lateral temporal areas (Chao, Haxby, & Martin, 1999;
AC

Kravitz, Saleem, Baker, Ungerleider, & Mishkin, 2013; Ranganath & Ritchey, 2012). Another

common type of stimulus used to probe for ALF are stories (Bell, 2006; Blake et al., 2000;

Cassel et al., 2016; Evans et al., 2014; Mameniskiene, Jatuzis, Kaubrys, & Budrys, 2006;

Tramoni et al., 2011; Wilkinson et al., 2012). This type of information involves schemas,

3
 ACCEPTED MANUSCRIPT

semantic knowledge, and what some investigators have considered to be context-bound

information (Tramoni et al., 2011), and depend on areas such as the anterior temporal neocortex

(Binney, Embleton, Jefferies, Parker, & Lambon Ralph, 2010; Martin & Chao, 2001). The few

studies that have used navigational tasks have found ALF (Cassel et al., 2016; Tramoni et al.,

PT
2011), while the two studies that have targeted autobiographical memory for staged events have

RI
had mixed results (Narayanan et al., 2012; Tramoni et al., 2011), and yet both navigation and

retrieval of specific details from autobiographical memory depend on hippocampal functioning

SC
(Addis, Moscovitch, Crawley, & McAndrews, 2004; O’Keefe, Burgess, Donnett, Jeffery, &

Maguire, 1998). One case study investigated memory for novel word pairs (which targets

U
hippocampal binding) and found impaired cued recall by 55 minutes in their TLE patient
AN
(McGibbon & Jansari, 2013). All of these studies suggest temporal lobe involvement, but do not

yet give a clear indication of relative hippocampal versus extrahippocampal contribution to long-
M

term forgetting.
D

What is lacking in the literature are direct comparisons of these different memory
TE

subsystems. Three studies have attempted to make these comparisons. Tramoni and colleagues

(2011) conducted a study with a small sample of 5 TLE patients who underwent various memory
EP

tasks designed to target context-bound and context-free memory, and found ALF for context-

bound tasks (story recall and recognition, recall and recognition of virtual and real routes, recall
C

and recognition of staged episode, and remote autobiographical memories) but not for context-
AC

free tasks (recognition of single items or recall of new facts). Evans and colleagues (2014) had

patients (n=7) recall and recognize stories and scenes, as well as freely recall items and their

locations in a subset of the scenes. They found ALF for story recall and recognition, as well as

for spatial and descriptive free recall in their visual task, with marginally significant ALF for

4
 ACCEPTED MANUSCRIPT

visual recognition, but did not find ALF for free recall of items. The fact that these two small

studies found ALF for context-specific information implicates the hippocampus in ALF, though

Narayanan et al. (2012, n=14) found ALF for a list of words and a list of visual designs but only

a trend towards greater forgetting for a staged autobiographical event. It is also peculiar that

PT
these studies did not find any ALF for items given that ALF has been documented several times

RI
for individual words (Deak et al., 2011; Fitzgerald et al., 2013; Narayanan et al., 2012) and

visual designs (Fitzgerald et al., 2013; Narayanan et al., 2012; Wilkinson et al., 2012). Of course,

SC
the nature of memory tasks for stories, routes, items, and autobiographical events are all quite

different in terms of difficulty, material specificity, and task demands, rendering them difficult to

compare directly.
U
AN
The purpose of our study was to probe the role of the hippocampus in ALF by directly

comparing long-term memory for associations to memory that could be supported by item
M

recognition in a task designed to target both types of memory with similar stimuli, and to
D

determine if resting state hippocampal connectivity to cortical areas known to be involved in

TE

processing such stimuli could predict accelerated forgetting. We also wanted to better gauge the

earliest time-point at which ALF could be reliably detected for associative and item memory, by
EP

testing memory multiple times over the first day of learning and beyond. Given the well-

established role of the hippocampus to contextual memory and consolidation, we hypothesized

C

that associative stimuli would be more sensitive to ALF than item stimuli, evidenced by faster
AC

proportion of forgetting by 6 hours after learning (given recent evidence that ALF can be

detected by 8 hours post-learning in TEA: Hoefeijzers, Dewar, Sala, Butler, & Zeman, 2015) and

that altered hippocampal connectivity to brain areas known to be involved in contextual memory

would reflect this accelerated forgetting.

5
 ACCEPTED MANUSCRIPT

2 Methods
2.1 Subjects
Twenty-three patients with temporal lobe epilepsy (Table 1) and 24 healthy controls were

PT
recruited for this study. Patients were recruited from the Epilepsy Monitoring Unit (EMU) at

RI
Toronto Western Hospital where they were being investigated for surgical candidacy. Patients

were classified as having TLE based on EEG recordings indicating exclusive temporal lobe

SC
onsets to seizures and interictal abnormalities. Given the difficulty of enlisting age-matched

controls who were able to be tested repeatedly at matched times to our inpatients, controls were

U
recruited through Amazon’s Mechanical Turk, an online crowdsourcing data collection platform,
AN
and had no self-reported history of psychiatric or neurological disorders. Overall, patients and

controls did not significantly differ on age (mean ±SD: controls: 35.25 ±9.28 years, TLE: 37.17
M

±12.35 years, F(1, 46)=0.35, p=0.65, r=0.09), years of post-secondary education (controls: 4.4
D

±2.33 years, TLE: 3.0 ±2.56 years, F(1, 46)=3.91, p=0.15, r=0.28), or gender (controls: 12 males,
TE

TLE: 15 males, X2(1)=0.21, p=0.65, φ=0.10). There was some degree of attrition during the

study for both patients and controls, the details of which can be located in Supplementary
EP

materials (Supplementary Table 1).

C
AC

Age of Composite Seizures

Age
ID Sex Onset Laterality MRI memory over 72h
(yrs)
(yrs) score delay

1 29 M 24 Left Normal 0.65 No

2 25 F 5 Left Normal -0.09 Yes
3 39 F 32 Bilateral Normal -0.77 Yes
(Right>Left)
4 42 F 32 Right Right MTS* 0.9 Yes
5 26 F 23 Left Bilateral MTS* -1.58 No

6
 ACCEPTED MANUSCRIPT

6 41 M 40 Left Left mesial 1.29 n/a test

temporal
ganglioma*
7 32 M 2 Right Right anterior 1.44 No
temporal
encephalocele
8 34 F 28 Right Normal 1.82 Yes

PT
9 50 F <1 Left Left MTS* -1.13 No
10 26 M 18 Left Left amygdala -2.18 Yes
harmatoma
11 61 M 30 Bilateral Left MTS* -1.58 No

RI
(Left>Right)
12 47 M 31 Left Normal -1.51 n/a test
13 24 M 18 Right Right MTS* 1.32 Yes

SC
14 27 M 7 Left Normal -2.44 No
15 55 M 35 Right Right MTS* 1.32 No
16 27 M 25 Right Right 1.32 n/a test
parahippocampal

U
DNET
17 36 M 16 Right Mild right MTL -1.29 No
AN
hypersignal
18 23 F 21 Left Left 1.47 Yes
amygdala/uncus
DNET
M

19 22 M 12 Left Left anterior -0.19 n/a test

temporal
encephalocele
20 37 F <1 year Left Left MTS* -0.13 Yes
D

21 54 M 39 Left Left MTS* -1.1 n/a test

22 61 M 18 Right Right MTL -1.49 n/a test
TE

glioma
23 37 F 32 Right Right MTL 0.96 n/a test
glioma*
Table 1. Clinical characteristics of patients with TLE. Composite memory scores represent
EP

standardized verbal memory for left TLE, and visual memory for right TLE. For patients with
C

bilateral TLE, scores for the hemisphere with the most epileptogenic activity was used. Laterality
AC

refers to seizure laterality. Patients with n/a test were not tested at the 72-hour delay. Asterisks

indicate subjects who had abnormal hippocampi. M=male, F=female, MTL= medial temporal

lobe, MTS= medial temporal sclerosis, DNET= Dysembryoplastic neuroepithelial tumour.

7
 ACCEPTED MANUSCRIPT

2.2 Task Design and Procedure

All patients were tested at bedside on the EMU, and were seated either in their bed or in a

chair adjacent to the bed, depending on where they were most comfortable. The curtain around

their bed was drawn to prevent visual distraction from the rest of the room. The testing laptop

PT
was placed on an adjustable table at a comfortable viewing angle, and they wore padded

RI
headphones to reduce auditory distraction from other patients and healthcare staff.

The task instructions and stimulus presentation were the same for patients and controls,

SC
except that patients were instructed to give their responses verbally and controls indicated their

responses via button press. Controls completed the study online through a combination of

U
Mechanical Turk and Inquisit 5 (2016), which is an experimental tool that allows the
AN
development and implementation of online experiments. Mechanical Turk was used to recruit

and to pay participants for their time, while Inquisit was used to display and record responses for
M

the actual experiment. Control participants were reminded to sit at their computer and ensure
D

they were in a quiet place with no distractions for every session.

TE

We developed a series of object-scene pairs for this experiment. Five different sets of

study stimuli, consisting of 78 trials each, and 5 corresponding sets of test stimuli, consisting of
EP

52 trials each, were used to create different stimulus lists for each of the 5 different delays. All

pictures of objects were useable tools or gadgets, foods, or animals, and were standardized on a
C

white background measuring 300 x 300 pixels. All scenes were photos of places and activities
AC

measuring 1024 x 768 pixels, which spanned the computer screen. None of the stimuli were

considered emotionally salient.

Both patients and controls provided informed consent and completed a brief practice test

before the first study session. Controls were then given access to the first set of stimuli (both the

encoding and test block for a given list) and instructions on how to comply with the delay

8
 ACCEPTED MANUSCRIPT

assigned for that set of stimuli. Organization of the timing of the encoding sessions, test sessions,

and delays were decided verbally between patients and the experimenter.

During the study sessions (Figure 1a), subjects viewed each object-scene pair one at a

time in the center of the screen. Each stimulus presentation began with a display of the scene for

PT
1 second, followed by a 3-second overlay of the object on the scene. Half of the objects were

RI
semantically related to the paired background, and the subject’s task was to indicate if each

object was related to the scene, the purpose of which was to promote deep encoding and

SC
consequently better recall at test (e.g. Henke, Weber, Kneifel, Wieser, & Buck, 1999). After each

response, a blank screen appeared for 4 seconds. During the last 3 seconds, a fixation cross

U
appeared in the center of the screen, promoting orientation of the subject’s gaze to a standardized
AN
center point before the next trial. Each object-scene pair was presented once and the order of

stimuli was randomized. A study block took approximately 10 minutes to complete.

M

Each study block was followed by a different delay: 15 minutes, 90 minutes, 6 hours, 16
D

hours, or 72 hours. The 15-minute delay was chosen as a baseline measure of “long-term”
TE

memory to assess equality of learning and initial retention of the different types of stimuli

between patients and controls. The 90-minute and 6-hour delays were chosen to probe forgetting
EP

over the same day of learning. The 16-hour delay provided a measure of forgetting after a night’s

sleep, and finally, the 72-hour delay provided longer-term assessment of retention over days. All
C

subjects were free to do as they pleased until subsequent testing. All study and test sessions were
AC

time-stamped, and we were able to verify that each control subject correctly complied with the

assigned delay period.

At each delay, memory was assessed with the corresponding forced-choice recognition

test for the studied list (Figure 1c). Stimuli consisted of a scene from the encoding block with

9
 ACCEPTED MANUSCRIPT

two objects superimposed, one on the left and one on the right. In half of the trials, one of the

objects had been seen at encoding (the target object) and one was new: these old-new (ON) trials

enabled the participant to choose the correct object by virtue of recollection or familiarity of old

items, or by identifying the new item as new, without necessarily remembering the association of

PT
the target item with the scene. We will refer to the memory processes targeted by these types of

RI
stimuli as item memory, though we acknowledge that accuracy during these trials could also be

due to recall or familiarity for the association between the object and scene. In the other half of

SC
the trials, both objects had been presented during the study phase, one having been paired with

the current background and the second paired with a different background. Familiarity of the

U
items was equated in these old-old (OO) trials, and memory for the object-scene association must
AN
be accessed to choose the correct match; hence we will refer to memory for these pairs as

associative in nature. Each stimulus appeared on the computer screen one at a time, wherein the
M

scene was presented for 1 second followed by a 3 second overlay of the objects. The
D

participants’ task was to indicate which object was originally paired with the scene. Whether the
TE

target object appeared on the right or left was randomized and equal across the trials. After each

response, a blank screen appeared for 4 seconds before onset of the next trial. During the last 3
EP

seconds, a fixation cross appeared in the center of the screen, promoting orientation of the

subject’s gaze to a standardized center point for the next trial. Each object from encoding was
C

only seen once during the testing phase, as either the target item or a familiar foil item. Each
AC

testing block took approximately 5 minutes to complete.

After each test session, patients took a break for at least 10-minutes, during which time

they conversed with the experimenter or visiting friends or family in order to prevent

interference of recently recalled items with learning of the next set of stimuli. In contrast,

10
 ACCEPTED MANUSCRIPT

controls were given a code upon test completion, which they input back into Mechanical Turk

for payment. The experimenter then quality checked their work to ensure they had complied with

the delay, and then granted them access to the next set of stimuli, to be completed over a

different delay. This process took at least 10 minutes. This encoding-delay-test-break-encoding

PT
pattern was repeated until the subject’s memory for the visual stimuli had been tested at each of

RI
the 5 delays. The testing times, order of the delays, and stimulus lists at each delay were

counterbalanced across subjects to reduce the impact of effects of mental state due to different

SC
times of day, practice effects with repeated exposure to the task, and medication withdrawal of

the patients. However, controls had more command over the times that they were tested at, and

U
could schedule their sessions at night, while patient testing was generally restricted from 9am to
AN
7pm. The 16-hour delay lists were always studied in the evening and tested the next day after a

night of sleep. Each patient was tested over the period of a week in an effort to complete testing
M

before discharge from the hospital, and each control had two weeks to complete all of the delays.
D

Controls were allowed more time overall, because they had busier schedules that were more
TE

difficult to fit the delays into.

C EP
AC

11
 ACCEPTED MANUSCRIPT

PT
RI
U SC
AN
M

Figure 1. Stimuli and procedure. a) Each subject studied a series of object-scene pairs and
decided whether the object was related to the background scene. b) After each study session,
D

participants experienced a variable delay. c) Subjects were asked to choose which object was
originally paired with the scene. In half of the test-stimuli, the target object was presented
TE

alongside a new object to create old-new (ON) pairs. In the other half, the target object was
presented alongside a familiar object they had viewed during the study phase with a different
EP

background (OO pairs). Subjects studied new images and completed the corresponding
recognition task across all five delays, where possible. In this representation, the object:scene
C

ratio is not to scale, and there was an inter-trial fixation cross presented in the experiment.
AC

2.2.1 Statistical analysis of task data

Accuracy for OO and ON pairs at each delay was converted to proportion correct to

account for the odd missing response (total correct/total responses). These proportion correct

scores were used for statistical analysis of baseline memory (memory at 15 minutes). For all

other delays, we calculated proportion forgotten relative to baseline ((proportion correct at

12
 ACCEPTED MANUSCRIPT

15minutes - proportion correct at delay X)/proportion correct at 15 minutes) in order to

‘standardize’ forgetting rates given individual differences in baseline memory. Data wasn’t

included in the analysis for both patients and controls if the test was taken more than 15 minutes

late for the 15-minute delay, more than 30 minutes late for the 90-minute delay, more than 2

PT
hour late for the 6-hour delay, or more than 3 hours late for the 16-hour and 72-hour delays. Six

RI
controls had missing or inaccurate baseline data. For the two individuals who did not complete

the baseline test, we used their accuracy scores at 90 minutes as baseline to calculate proportion

SC
forgetting at the 6-hour, 16-hour, and 72-hour delays, given that there were no significant effects

of delay (F(1,44)=3.40, p=0.07, R2=0.15), or delay by trial interaction (F(1,44)=0.23, p=0.63,

U
R2=0.01) on accuracy scores at baseline and 90 minutes. The other four individuals were late in
AN
completing the baseline test, wherein they took it 40-50 minutes after study rather than 15-30

minutes. We used their scores at these times to calculate proportion forgetting at later delays, but
M

omitted these people from any analyses of baseline memory given that they had not completed
D

the test within 15-30 minutes after study, rendering them less comparable to the TLE group at
TE

this dely.

All statistical analysis was carried out using R studio version 1.0.136 (RStudio Team,
EP

2016). We used linear mixed effects models for the majority of analyses, which is a type of

multilevel model that is effective in managing unbalanced within-subject designs using

C

maximum likelihood estimation (Cnaan, Laird, & Slasor, 1997). All mixed effects models were
AC

computed using the lme function of the nlme package (Pinheiro, Bates, DebRoy, Sarkar, & R

Core Team, 2017) in R studio, with random intercepts for each subject as the random effect

structure, to account for inter-subject variability. Degrees of freedom were estimated with a

between-within method, and the model was estimated with an unstructured covariance matrix. A

13
 ACCEPTED MANUSCRIPT

weighted least squares estimation method using a constant variance structure function was used

to correct for heteroskedasticity where applicable (Pinheiro & Bates, 2000). Multiple

comparisons were corrected for each family of tests using False Discover Rate (FDR)

(Benjamini & Hochberg, 1995) analyzed with the p.adjust function in R Studio, and all reported

PT
p-values for planned comparisons are corrected. Effect sizes were calculated with Pearson

RI
correlations for all continuous predictors and 2-level categorical predictors, while semi-partial R2

was used for categorical predictors with more than 2 levels. Pearson correlations of 0.1 to 0.29

SC
were considered small effect sizes, 0.3 to 0.49 were considered medium effect sizes, and

correlations of 0.5 or greater were considered large effects (Cohen, 1992). An alpha level of

U
0.05 was used to determine statistical significance for all analyses.
AN
M

2.3 Clinical assessments

2.3.1 Neuropsychological assessment
D

Patients underwent a standard battery of neuropsychological testing as part of their

TE

surgical planning. Testing was either concurrent with the EMU stay or carried out up to several

weeks later. For the current study, we used composite scores reflecting verbal and visual
EP

memory, as described in previous work from our lab (St-Laurent et al., 2014). In brief, these
C

scores were obtained from principle components analyses of clinical measures of intellectual
AC

functioning (verbal and performance IQ scores), verbal memory (Rey Auditory Verbal Learning

Test total recall and percent retained over a 20-min delay, Warrington Recognition Memory

Test) and visual memory (total recall on Rey Visual Design Learning Test, Warrington Face

Recognition Memory Test, total trials on a conditional associative learning test). Composite

scores in Table 1 can be considered as pseudo-z scores, as they indicate how the individual

14
 ACCEPTED MANUSCRIPT

patient compares to the normative sample of TLE patients in terms of material-specific memory.

We have previously shown the resulting components for IQ, Verbal Memory and Visuospatial

Memory to provide high classification accuracy for left and right TLE patients as well as reliable

prediction of material-specific memory decline following anterior temporal lobe resection.

PT
RI
2.4 Neuroimaging Methods

SC
2.4.1 Data acquisition
Functional images were acquired for 16 out of the 23 subjects, 14 of whom had also

U
participated in the 72-hour delay (7 females, 35.86 ±12.18 years of age). Images were acquired
AN
on a 3T Sigma MR System (GE Medical Systems, Milwaukee). A whole brain high-resolution

anatomical scan was acquired for each subject using a 3D fast spoiled gradient echo sequence
M

with the following parameters: flip angle: 12º, TR=7.88 ms, 120 sagittal slices, FOV: 22 x

22cm2, 256 x 256 matrix, 0.9 x 0.9 x 1 mm voxels, 1-mm thick. Each subject also received a 6-
D

minute task-free resting state T2*-weighted functional MRI scan with an echo-planar pulse
TE

imaging sequence. The parameters were as follows: TR=2000 ms, TE=25 ms, FOV: 24 x 24

cm2, 64 x 64 matrix, 3.75 x 3.75 x 5 voxels, 5-mm thick, 28-32 slices depending on head size,
EP

for 180 volumes. During the scan, subjects were instructed to lie still and “not to think about
C

anything in particular”, and to keep their eyes closed.

AC

2.4.2 Preprocessing
Preprocessing and resting state connectivity analysis was conducted with CONN

(Whitfield-Gabrieli & Nieto-Castanon, 2012), a toolbox that runs through MATLAB v8 12.0

(Mathworks). The first three frames of each fMRI scan was dropped to allow for signal

15
 ACCEPTED MANUSCRIPT

equilibrium. Anatomical and functional images were reoriented to the anterior commissure, and

each functional scan was coregistered to each subject’s anatomical image, which was then

spatially realigned and unwarped. Each subject’s anatomical image was segmented and

normalized to the T1-weighted NBI152, and the normalization parameters were written to the

PT
functional data to align the anatomical and functional scans. fMRI data were then smoothed

RI
using a Gaussian kernel of 8-mm full-width half-maximum. A MNI152-T1-weighted image was

segmented into gray matter, white matter, and cerebrospinal fluid. The data were temporally

SC
preprocessed to restrict the analysis to frequencies of interest (<0.1 Hz). We used linear

regression to remove potential sources of noise such as estimated subject motion parameters (3

U
translation components and 3 rotation components) and removal of BOLD covariates in white
AN
matter and CSF areas with the anatomical component based noise correction method

(aCompCor; Behzadi, Restom, Liau, & Liu, 2007). Scans were flipped across the midline for
M

individuals with RTLE, in order to align the affected medial temporal lobes (MTLs) for the
D

functional connectivity analysis given that we did not have the statistical power to examine left
TE

TLE and right TLE separately.

EP

2.4.3 Region of interest selection

C

In addition to examining the rate of forgetting for item and associative stimuli, we sought
AC

to determine if individual variability in resting state connectivity predicted forgetting of ON and

OO pairs. Given the episodic nature of our task, we hypothesized that the hippocampus would be

involved in both types of memory, but that resting-state connectivity associated with memory

would differ depending on the type of stimulus involved. In recent years, the literature has

started to emphasize that the hippocampus is not functionally homogeneous along its anterior-

16
 ACCEPTED MANUSCRIPT

posterior axis (Adnan et al., 2016; Poppenk, Evensmoen, Moscovitch, & Nadel, 2013; Strange,

Witter, Lein, & Moser, 2014). The anterior hippocampus demonstrates greater connectivity to

anterior regions in the brain, and of particular relevance here, it is connected to the perirhinal

cortex (which has been shown to be atrophic in a sample of patients with TEA; Butler et al.,

PT
2013; Kahn, Andrews-Hanna, Vincent, Snyder, & Buckner, 2008; Libby, Ekstrom, Ragland, &

RI
Ranganath, 2012) as well as anterior and lateral temporal cortex (Adnan et al., 2016; Kahn et al.,

2008; Poppenk & Moscovitch, 2011), which are regions involved in object processing and item

SC
memory (Poppenk et al., 2013; Ranganath & Ritchey, 2012). We therefore chose to target

connectivity between the anterior hippocampus and these lateral temporal regions, with the

U
hypothesis that connectivity here would covary with forgetting of stimuli that targets item
AN
memory (ON stimuli). In contrast to the anterior hippocampus, the posterior hippocampus is

more connected to posterior regions in the brain, including parahippocampal cortex (Kahn et al.,
M

2008; Libby et al., 2012) and posterior cingulate cortex (PCC, Adnan et al., 2016; Kahn et al.,
D

2008; Libby et al., 2012; Poppenk & Moscovitch, 2011). This posterior memory system is
TE

involved in recollection of perceptual and contextual details (Evensmoen et al., 2015;

McCormick, St-Laurent, Ty, Valiante, & McAndrews, 2015; Poppenk et al., 2013; Ranganath &
EP

Ritchey, 2012). Given this literature, as well as findings from our own lab that suggest

connectivity between the hippocampus and PCC is a good index of memory integrity in TLE
C

(McCormick et al., 2014; McCormick, Quraan, Cohn, Valiante, & McAndrews, 2013) and
AC

associative memory in particular (Adnan et al., 2016), we hypothesized that connectivity

between these regions would covary with forgetting of information where the object-scene

association must be evoked (OO pairs), given that this condition required remembering the

context that the items were viewed in. We used anterior and posterior hippocampal masks that

17
 ACCEPTED MANUSCRIPT

were created as part of another project in our lab. These masks were created by segmenting the

hippocampus of 19 healthy controls based on the divergent functional connectivity of the

anterior and posterior hippocampus, using a k-means clustering algorithm. This produced an

anterior and posterior ROI for each hippocampus in a data driven way. Detailed methods of this

PT
procedure are described in Supplementary material (Supplementary Figure 1). We arbitrarily

RI
used the left anterior and posterior hippocampal masks for analysis of the affected hippocampus,

but the left and right hippocampal masks derived from the aforementioned analysis were very

SC
similar.

Masks for the lateral temporal cortex (LTC) and PCC were created with 8-mm spheres at

U
the following MNI coordinates: left middle temporal gyrus [-60 -24 -18], right middle temporal
AN
gyrus [60 -24 -18], left PCC [-8 -56 26], and right PCC [8 -56 26]. These coordinates are based

on a comprehensive analysis of default mode network functional connectivity (Andrews-Hanna,

M

Reidler, Sepulcre, Poulin, & Buckner, 2010), which the authors showed were involved in self-
D

relevant, future-oriented, and memory-directed behaviour, and therefore relevant to episodic

TE

memory. Indeed, we have shown that connectivity using ROIs from this network is a useful

measure of memory integrity in TLE (McCormick et al., 2014, 2013).

C EP

2.4.4 Resting-state connectivity analysis

AC

The time series of voxels within each ROI was averaged, and those from the anterior and

posterior hippocampal ROIs were correlated with the time series of every other ROI for each

subject. These correlation values were then converted to z scores with a Fisher transformation.

Each subject’s score of proportion forgotten of OO and ON stimuli from baseline to 72-hours

was converted to a z-score relative to control subject’s group mean and standard deviation, to

18
 ACCEPTED MANUSCRIPT

quantify how abnormal long-term forgetting was for each subject. We chose to focus on the 72-

hour delay because we were the most confident that abnormal forgetting at this delay would be

reflective of ALF in the context of delays used in the existing literature. Each subject’s z-scores

of ON and OO forgetting at 72-hours relative to controls were added to the analysis as second-

PT
level covariates, to determine if hippocampal connectivity to the a priori defined regions

RI
covaried with long-term forgetting. Statistical maps of connectivity were thresholded at p<0.05,

one-tailed (we were only interested in instances of reduced connectivity), with FDR correction.

U SC
3 Results
AN
3.1 Task Results
We first wanted to determine if there were differences in baseline retention (memory at
M

15-minutes) within and between the two groups. There were significant differences in memory

for OO and ON stimuli at baseline within groups (controls: F(1, 20)=19.89, p<0.01, r=0.71, TLE:
D

F(1, 22)=11.34, p<0.01, r=0.58), with higher accuracy for ON pairs than for OO pairs in both
TE

controls (ON: 97.18 ±3.07%, OO: 89.15 ±6.61% ) and patients (ON: 95.39 ±5.71%, OO: 88.18
EP

±8.53%). There were no significant differences in accuracy scores between groups for either ON

(F(1, 42)<0.01, p=0.98, r<0.01) or OO pairs (F(1, 42)=0.06, p=0.98, r=0.04), suggesting that
C

both groups were able to initially learn and retain both types of stimuli to a comparable degree.
AC

Next, we investigated how group, delay, and stimulus-type affected forgetting over time.

We ran a linear mixed effects model with proportion forgotten as the dependent variable, and

group, delay, stimulus-type, and their interactions as fixed effects. We found significant main

effects of group (F(1, 42)=4.68, p=0.04, r=0.32), delay (F(3, 238)=9.27, p<0.01, R2=0.10), and

stimulus type (F(1, 238)=15.26, p<0.01, r=0.25), where subjects generally forgot more over time,

19
 ACCEPTED MANUSCRIPT

patients forgot more than controls, and more OO pairs were forgotten than ON pairs. There was

also a significant interaction between group and stimulus-type (F(1, 238)=4.29, p=0.04, r=0.13),

indicating that patients and controls forgot OO or ON pairs at different rates. Although delay did

not significantly interact with group (F(3, 238)=0.12, p=0.95, R2<0.01) or stimulus-type (F(3,

PT
238)=0.34, p=0.79, R2<0.01), we probed the group by stimulus-type interaction across the delays

RI
given that one of our research questions concerned identifying the point in time where

accelerated long-term forgetting becomes detectable in TLE for these different stimulus types.

SC
We next examined forgetting for OO and ON stimuli over time within each group by

running linear mixed effects models at each delay, with proportion forgotten as the dependent

U
variable and type of stimulus as the predictor. While controls forgot little on average over 90
AN
minutes for both types of stimuli (ON: 0 ±8.49%, OO: 3.14 ±14.38% , F(1, 15)=0.65, p=0.43,

r=0.20), they did forget a greater proportion of OO pairs than ON pairs by 6 hours (ON: 1.83
M

±6.66%, OO: 11.13 ±9.48%, F(1, 17)=11.60, p<0.01, r=0.64), and 16 hours (ON: 2.97 ±6.61%,
D

OO: 9.72 ±10.69%, F(1, 17)=6.42, p=0.04, r=0.52). This difference was not significant at 72-
TE

hours after FDR correction (ON: 7.00 ±9.34%, OO: 14.33 ±14.15%, F(1, 16)=3.34, p=0.12)

though the difference still produced a medium effect size (r=0.42) suggesting that OO pairs were
EP

indeed forgotten more than ON pairs but this difference was not quite reliable enough to denote

significance. In contrast, patients forgot ON and OO pairs at the same rate over time, with no
C

significant differences evident between forgetting of the two types of stimuli at 90 minutes (ON:
AC

4.49 ±11.36%, OO: 7.35 ±9.31%, F(1, 20)=1.06, p=0.68), 6 hours (ON: 8.11 ±10.95%, OO:

11.18 ±13.22%, F(1, 21)=0.97, p=0.68), 16 hours (ON: 9.57 ±12.34%, OO: 10.49 ±13.85%, F(1,

19)=0.06, p=0.89) or 72 hours (ON: 16.01 ±10.46%, OO: 16.52 ±13.79, F(1,15)=0.02, p=0.89).

20
 ACCEPTED MANUSCRIPT

While there were small effects of stimulus-type at 90 minutes (r=0.22) and 6 hours (r=0.21),

these effects become minuscule over time (16 hours: r=0.06, 72 hours: r=0.04).

Next, we compared proportion forgotten for OO and ON pairs between groups over time

(Figure 2), in order to determine if either type of stimulus was forgotten at an accelerated rate in

PT
patients compared to controls, and at what time point that occurred by. To do this, we ran linear

RI
mixed effects models at each delay with proportion forgotten as the dependent variable, and

group as the predictor for each stimulus type. We found no significant differences in forgetting

SC
for OO stimuli between patients and controls at any delay (90mins: controls: 3.14 ±14.38%,

TLE: 7.35 ±9.31%, F(1, 35)=1.04, p=0.99, r=0.17, 6 hours: controls: 11.13 ±9.48%, TLE: 11.18

U
±13.22%, F(1, 38)<0.01, p=0.99, r<0.01, 16 hours: controls: 9.72 ±10.69%, TLE: 10.49
AN
±13.85%, F(1, 36)=0.04, p=0.99, r=0.03, 72 hours: controls: 14.33 ±14.15%, TLE: 16.52 ±13.79,

F(1, 31)=0.20, p=0.99, r=0.08). In contrast, while patients and controls forgot ON stimuli at a
M

comparable rate by 90 minutes (controls: 0 ±8.49%, TLE: 4.49 ±11.36%, F (1, 35)=2.09, p=0.16
D

r=0.24), patients with TLE started to forget ON stimuli at a faster rate by 6 hours (controls: 1.83
TE

±6.66%, TLE: 8.11 ±10.95%, F(1, 38)=4.98, p=0.05, r=0.34) and 16 hours (controls: 2.97

±6.61%, TLE: 9.57 ±12.34%, F(1, 36)=4.33, p=0.05, r=0.33), and this difference survived FDR
EP

correction for statistical significance by 72 hours (controls: 7.00 ±9.34%, TLE: 16.01 ±10.46%,

F(1,31)=6.77, p=0.04, r=0.42). These results indicate that patients were forgetting OO and ON
C

pairs at the same rate due to an increase in forgetting of ON pairs beyond that which is normal,
AC

and this difference in retention became reliable by 72 hours post-learning.

21
 ACCEPTED MANUSCRIPT

PT
RI
SC
Figure 2. Group comparisons of forgetting over time (relative to baseline memory). Left panel shows forgetting
of OO pairs for patients and controls, while the right panel shows forgetting of ON pairs for the two groups.
Error bars represent standard error, tildes (~) represent marginal statistical significance (p=0.05 after FDR

U
correction) and asterisks (*) represent statistical significance (p<0.05 after FDR correction).
AN
M

3.2 Functional Connectivity Results

D

Another goal of this study was to examine whether resting state functional connectivity
TE

between the hippocampus and areas known to be involved in associative and item memory could

predict long-term forgetting of such stimuli at 72 hours. We first examined connectivity with the
EP

posterior hippocampus (Figure 3, left panel). We found that while functional connectivity

between the affected posterior hippocampus and the affected PCC correlated with forgetting of
C

OO stimuli, such that less connectivity between these regions predicted greater forgetting
AC

(r=0.45, t(12)=-1.75, p=0.05), this relationship did not survive correction for multiple

comparisons (p=0.21). There were no significant relationships between posterior hippocampus

connectivity with any of the other ROIs and forgetting of OO or ON pairs. Turning to the

anterior hippocampus (Figure 3, right panel), connectivity between the affected anterior

hippocampus and unaffected LTC predicted forgetting of ON pairs, where worse connectivity

22
 ACCEPTED MANUSCRIPT

between these regions predicted greater forgetting at 72 hours (r=0.62, t(12)=-2.77, p=0.03 FDR

corrected). Connectivity between the anterior hippocampus and the rest of the ROIs did not

predict forgetting of OO or ON pairs.

PT
RI
U SC
AN
M
D

Figure 3: Correlations between connectivity and forgetting over the 72-hour delay. The panel on the left
shows the relationship between forgetting of OO stimuli and resting state functional connectivity between
TE

the affected posterior hippocampus and PCC. The panel on the right represents the relationship between
forgetting of ON stimuli and connectivity between the affected anterior hippocampus and unaffected
EP

lateral temporal cortex. Blue circles represent patients who had seizures during the delay. Asterisks (*)
denote significance after FDR correction.
C
AC

3.3 Clinical characteristics associated with forgetting

We next wanted to determine if ALF for ON stimuli was related to any clinical variables.

We ran a linear mixed effects model where z-scores of forgetting of ON stimuli relative to

controls at 72 hours was the dependent variable, with laterality of seizure focus, clinical

composite memory score (representing verbal memory for patients with left TLE, and visual

23
 ACCEPTED MANUSCRIPT

memory for patients with right TLE), presence of hippocampal abnormality (including MTS, and

tumours or lesions directly affecting the hippocampus), and presence of seizures over 72 hours as

predictors. None of these variables predicted forgetting (laterality of focus: F(2, 6)=0.37, p=0.70,

r=0.24, composite memory score: F(1, 6)=0.83, p=0.40, r=0.35), presence of MTL abnormality:

PT
F(1, 6)=0.31, p=0.60, r=0.22), presence of seizures: F(1, 6)=0.03, p=0.86, r=0.07). Given that

RI
connectivity between the anterior hippocampus and LTC predicted accelerated forgetting of ON

pairs, we also wanted to determine if connectivity between these two regions was related to any

SC
clinical variables. We re-ran the same analysis with connectivity between the affected anterior

hippocampus and unaffected LTC as the dependent variable and found no reliable relationship

U
between connectivity and laterality of seizure focus (F(2, 5)=0.08, p=0.92, r=0.13), composite
AN
memory score (F(1, 5)=0.09, p=0.78, r=0.13), or presence of MTL abnormality (F(1, 5)=0.20,

p=0.67, r=0.20). Patients who had seizures over the 72-hour delay tended to have worse
M

connectivity, but this relationship was not reliable despite its medium effect size (F(1, 5)=1.31,
D

p=0.30, r=0.46).
TE
EP

4 Discussion
We found that accelerated long-term forgetting can be reliably identified at the group
C

level in patients with TLE by 72-hours after learning (r=0.42), though consideration of effect
AC

sizes indicate that greater forgetting is already present at 90-minutes (r=0.24, a small effect), and

is marginally significant by 6 hours (r=0.34, a medium effect, p=0.05 after FDR correction).

Contrary to expectation, we found that Old-New pairs of stimuli (which enabled the use of item

memory or familiarity/novelty detection to aid in the selection of the correct target) were

sensitive to ALF, while Old-Old pairs (which required associative memory) were not. While

24
 ACCEPTED MANUSCRIPT

both controls and patients with TLE had better item memory than associative memory at

baseline, controls forgot OO pairs faster than ON pairs while patients forgot both types of

information at the same rate, due to accelerated forgetting of the ON pairs. Forgetting of ON

stimuli over the 72-hour delay was related to reduced resting state functional connectivity

PT
between the affected anterior hippocampus and unaffected lateral temporal cortex in patients,

RI
compatible with a disruption of systems consolidation. With respect to clinical variables of

interest, there was some evidence that reduced connectivity between these regions was related to

SC
presence of seizures over the delay, but ALF itself, as defined by more rapid loss of accuracy

than seen in controls, was not related presence of seizures, side of epileptic focus, clinically-

U
relevant memory test performance, or presence of structural MTL abnormality.
AN
4.1 No evidence of ALF for old-old pairs
M

The fact that at baseline (15 minutes post-learning), patients retained more pairs in the

item memory than associative memory condition agrees with literature concerning the relative
D

integrity of item memory and familiarity in this population (e.g. Bowles et al., 2010) . Indeed,
TE

recognition accuracy was better when decisions could be based on item familiarity/novelty rather

than associative information at all delays in both controls and TLE (see Supplementary Figure
EP

2). Surprisingly, we found baseline (15-minute) recognition and forgetting rates for associative
C

stimuli were comparable for patients and controls, despite studies including from our own lab
AC

showing that TLE patients have more pronounced deficits for associative relative to item

memory, which are thought to relate to impairments in hippocampus-dependent associative

binding operations (Cohn, McAndrews, & Moscovitch, 2009; Saling, 2009). Furthermore, the

functional neuroimaging literature indicates that relational binding and associative retrieval

typically engages the hippocampus to a greater extent than encoding or retrieval of individual

25
 ACCEPTED MANUSCRIPT

items (Davachi, 2006; Ranganath, 2010), and imaging and lesion data indicate that such binding

operations can be evident even at very short study-test delays (Hannula, Tranel, & Cohen, 2006;

McAndrews, Girard, Wilkins, & McCormick, 2016; Olson, Page, Sledge Moore, Chatterjee, &

Verfaellie, 2006). The lack of a behavioral impairment associated with MTL damage or

PT
dysfunction in the current study may be a function of specific methodological choices, including

RI
the richness of encoding afforded by the use of visually complex scenes or the retrieval support

provided by forced-choice recognition test format. Nonetheless, we would have anticipated at

SC
least a main effect of group on associative memory and therefore the possibility that a different,

sub-optimal strategy was used by our online controls cannot be ruled out. Indeed, pilot data with

U
younger controls tested in person appeared to show overall better performance specifically in this
AN
condition (see Supplementary Figure 2).

In the context of ALF, no one to our knowledge has directly compared memory for items
M

and associations using the same type of stimuli. While most studies of ALF have used stimuli
D

amenable to item memory such as lists of words (Deak, Stickgold, Pietras, Nelson, & Bubrick,
TE

2011; Fitzgerald, Thayer, et al., 2013; Mameniskiene et al., 2006; Narayanan et al., 2012) or

visual designs (Fitzgerald et al., 2013; Giovagnoli, Casazza, & Avanzini, 1995; Mameniskiene et
EP

al., 2006; Narayanan et al., 2012; Wilkinson et al., 2012), only one TLE case study (McGibbon

& Jansari, 2013) has targeted associative memory and they did find ALF for pairs of words,
C

though they did not test item memory. Nevertheless, other types of stimuli that are known to be
AC

hippocampus-sensitive have failed to elicit ALF. Tramoni and colleagues (2011) found ALF for

a real world navigational task and for a staged autobiographical event, though their findings were

hindered by a small sample size (n=5). Cassel and colleagues (2016) found that while patients

with TLE and controls had comparable memory for a virtual navigation task at 30 seconds,

26
 ACCEPTED MANUSCRIPT

patients showed greater forgetting by 10-minutes after learning, which was maintained a week

later. However, 30 seconds may not be the best marker of healthy initial “long-term” memory,

which is a defining feature of ALF. Narayanan and colleagues (2012) used similar delays of

many weeks but failed to replicate Tramoni et al.’s (2011) finding of ALF for a staged

PT
autobiographical event, though they did note a medium to large effect size, suggesting that a

RI
difference might become significant with more statistical power. Needless to say, detecting ALF

with hippocampus-sensitive stimuli has been relatively inconclusive thus far.

SC
4.2 ALF for old-new pairs

U
In concert with much of the research on ALF that examines memory for single items, or
AN
stimuli that do not emphasize specific contextual details, we did find evidence of ALF for ON

pairs. In fact, TLE patients showed equivalent forgetting for OO and ON pairs, whereas controls
M

demonstrated a shallower forgetting curve for ON stimuli. Although formally the recognition

decision participants made was the same as in OO pairs (i.e., which object was studied in
D

conjunction with the background scene), ON stimuli afforded the use of item familiarity or,
TE

conversely, detection of item novelty to aid recognition. For those stimuli, one could simply

reject the less familiar/novel object as an appropriate response without needing to specifically
EP

evaluate the item-context relationship. There is considerable evidence for impaired novelty
C

detection in conjunction with MTL damage in both rodents who explore novel and familiar
AC

environments or objects equally (Burke, Wallace, Nematollahi, Uprety, & Barnes, 2010;

McTighe, Cowell, Winters, Bussey, & Saksida, 2010; Romberg et al., 2012) and patients with

mild cognitive impairment and Alzheimer’s disease who show abnormally high false alarm rates

to novel stimuli in recognition (Abe et al., 2011; Hildebrandt, Haldenwanger, & Eling, 2009).

We previously reported an exaggerated hippocampal fMRI response in a patient with transient

27
 ACCEPTED MANUSCRIPT

global amnesia during a recognition task to stimuli the patient thought were novel, even though

many of these stimuli had been seen a few minutes before (Westmacott, Silver, & McAndrews,

2008). Thus, a failure of this mechanism in TLE patients could explain why this condition is

even more susceptible to ALF than the associative memory condition.

PT
In the context of hippocampal damage, interference may play a significant role in failure

RI
to discriminate novel and familiar items (Sadeh, Ozubko, Winocur, & Moscovitch, 2014).

Yeung, Ryan, Cowell, and Barense (2013) found that individuals with mild cognitive impairment

SC
viewed novel objects as though they had been seen before under conditions of high visual

feature-level interference, which suggests that the novelty signal in question fails under

U
situations where pattern separation is required. The present experiment was not designed to
AN
target pattern separation, and it was very rare that the two objects at any given test trial would be

visually similar. We did however use some visually similar objects across the experiment (e.g.
M

there are about 5 different lightbulbs scattered throughout the 5 stimulus lists), and each
D

recognition trial was always in the context of a familiar background (all of the backgrounds at
TE

test were previously seen during the encoding period). It is possible that some of the objects look

visually similar enough to cause some interference, or otherwise the familiar background
EP

contributed to this feeling of familiarity/failure of novelty detection in patients.

C

4.3 Hippocampal connectivity to lateral temporal cortex

predicts ALF
AC

The patterns of connectivity between anterior and posterior hippocampal segments to

different cortical regions help illuminate the neurobiological basis of ALF in TLE. There was a

weak and non-significant correlation between resting-state functional connectivity in posterior

memory network nodes (posterior hippocampus and ispilateral PCC) and OO forgetting rate.

28
 ACCEPTED MANUSCRIPT

This pattern of connectivity is known to be involved in associative retrieval (Adnan et al., 2016;

Poppenk et al., 2013), which was not selectively affected in our sample. In contrast, forgetting

for ON pairs was significantly correlated with decreased resting state connectivity between the

affected anterior hippocampus and unaffected lateral temporal cortex, regions that have been

PT
considered to be related to object processing and item memory (Poppenk et al., 2013; Ranganath

RI
& Ritchey, 2012). It is unclear as to why it is connectivity to the unaffected, rather than the

epileptogenic, anterolateral temporal cortex that predicts ALF. We know that there is decreased

SC
connectivity to the affected anterior temporal cortex in TLE patients (McCormick et al., 2013),

that seizure activity is more likely to arise from anterior than posterior hippocampus (King,

U
Bronen, Spencer, & Spencer, 1997) and that interictal discharges more frequently propagate in
AN
that direction (Emerson, Turner, Pedley, Walczak, & Forgione, 1995) through the uncinate

fasciculus. Here, we postulate that when reduced connectivity extends bilaterally it may
M

compromise functional reserve and impact memory more dramatically, but note that we do not
D

have resting state scans for our controls to be able to make this comparison.
TE

4.4 Relevance to mechanisms of consolidation

Consolidation is conceived as those biological processes that render memories resistant to
EP

interference or decay. The literature draws a distinction between synaptic consolidation, which
C

is thought to involve strengthening of local connections over minutes or hours, and systems
AC

consolidation, which engages a broader network of regions with a time-course of days to months.

As a function of systems consolidation, some memories, particularly those which represent gist

of an experience rather than perceptual detail, become reliant on neocortical structures and

resilient to hippocampal damage (Moscovitch & Nadel, 1997; Squire & Alvarez, 1995; Winocur

& Moscovitch, 2011). If we hypothesize ALF is in fact a systems consolidation deficit in the face

29
 ACCEPTED MANUSCRIPT

of adequate encoding and immediate retrieval, the faster loss of ON pairs in TLE could be due to

dysfunction in the neocortical environment where memory is eventually stored, or prevention of

memory establishment via disruption of hippocampal-neocortical interactions necessary to

establish those memory traces (Kapur et al., 1997; Squire & Alvarez, 2005). Thus, it is possible

PT
that the issue is not so much one of gross hippocampal dysfunction, which would prevent

RI
memories from being adequately encoded but rather a disruption of memory transfer or cortical

instantiation. The observed reduction in resting cross-talk between the hippocampus and lateral

SC
temporal cortex may reflect this, and the fact that we saw a medium effect of seizures as

predictive of worse connectivity between these regions suggests this transfer may be disrupted

U
by epileptic activity. Future studies with larger samples will be needed to evaluate this putative
AN
mechanism as well as to address the contributions of other neocortical regions in this process

over time. Given that existing clinical measures (such as structural damage to the medial
M

temporal lobe, laterality of seizure focus, performance on clinical memory tests) do not seem to
D

be good indicators of ALF, examining biological markers such as connectivity is an avenue

TE

worth exploring further.

EP

5 Limitations
C

There are several limitations to our findings that should be noted. There was considerable
AC

variability in the clinical characteristics of our sample of patients in terms of side of epileptic

focus, exact site of lesion, number of seizures across delays, etc., and these differences likely

contributed to the relatively large individual differences in patient forgetting rates. As with many

clinical studies, exploration of these multiple sources of variability systematically requires fairly

30
 ACCEPTED MANUSCRIPT

large cohorts but that also provides the opportunity to discover biological mechanisms that can

both advance basic science and ultimately inform clinical care.

Furthermore, for both patients and controls, baseline accuracy and forgetting on the item task

PT
over the 90 minute-delay was at ceiling for some of the participants as evidenced by the standard

deviation including the 100% accuracy and 0% forgetting respectively, which may indicate over-

RI
learning. Overlearning has been associated with reduced forgetting over the first 24-hours,

though this effect is less prevalent by two days post-learning (Driskell et al., 1992). It is therefore

SC
possible that early forgetting of ON stimuli was masked by overlearning in some individuals in

U
both groups. Given that our associative memory condition was more difficult than the item
AN
memory condition and ran the risk of falling to floor over 72-hours, and given that we wanted to

make direct comparisons between these two conditions, we did not want to increase the difficulty
M

of the current task. Nonetheless, future studies will be needed to probe recognition in the face of

novel lures over time, where ceiling effects are completely avoided.
D

Of additional importance, the patients in this study were recruited from the EMU, and were
TE

being evaluated for surgical candidacy. As part of this process, many of them were undergoing

medication withdrawal in order to increase the likelihood of epileptic activity to be captured for
EP

clinical considerations. Thus far, studies have generally shown no relationship between
C

medication and ALF (Christopher R. Butler et al., 2007; Cassel et al., 2016; Fitzgerald et al.,
AC

2013; Muhlert et al., 2011), though there is mixed evidence concerning if ALF is related to

epileptic activity (Cassel et al., 2016; Fitzgerald et al., 2013; Mameniskiene et al., 2006; Muhlert

et al., 2011). We ensured that testing for each patient began as soon as possible after admission,

and counterbalanced the order of the delays across participants to mitigate these effects as much

as possible. Patients were tested at bedside, and while we controlled the environment as much as

31
 ACCEPTED MANUSCRIPT

possible by drawing the curtain around their beds and giving them padded headphones, this

environment is not the quiet, standardized test room used in most cognitive studies. Likewise,

while we asked controls to complete the study and test sessions in a quiet environment with no

distractions, we cannot verify that they complied. In addition to this, controls completed study

PT
and test sessions around their own schedules, and while patients tended to be tested during

RI
working hours, many controls completed the tests early in the morning or later at night to prevent

interference with their own work schedules. Finally, since patients spent the duration of their stay

SC
in bed, they likely napped more than controls. Since sleep benefits associative memory (e.g.

Ellenbogen, Hulbert, Stickgold, Dinges, & Thompson-Schill, 2006) this may be a reason why we

U
did not see the expected difference between patients and controls for our associative stimuli.
AN
Likewise, we do not know how differences in sleep quality between the two groups may have

impacted the results, which may vary due to epileptic activity in the patient group, potential
M

noise at night due to other patients in the same room experiencing seizures, or simply being less
D

comfortable sleeping at the hospital than in their own beds.

TE

Despite the limitations of these testing environments, we feel that this was the most feasible

way to conduct an experiment of this nature. One of the challenges of probing forgetting over
EP

multiple delays concerns convincing participants to visit the lab for multiple sessions. While

piloting this task with undergraduate students (see Supplementary Figure 2), we found that
C
AC

subjects typically were only willing to participate in 2-3 test sessions. It is particularly difficult to

probe memory retention over inconvenient delays on the order of hours since subjects must stay

within proximity of the testing location. We felt that it was important to probe forgetting over

hours and days given that this time-frame has remained relatively unexplored not only in patients

with TLE, but also in healthy populations, and given that the brain is likely undergoing important

32
 ACCEPTED MANUSCRIPT

processes of reorganization over these periods of time (Dudai et al., 2015). We also felt that

testing the same participants over multiple delays as much as possible was important given the

degree of individual variability in forgetting we observed in our pilot study, and in order to

enhance statistical power. Finally, undergraduate students are much younger than many of our

PT
patients, and we felt that it was important to match the ages of our samples given that memory

RI
changes with age. Future studies will certainly be needed to replicate our findings with closer

matching of test environments for patients and controls. In fact, to the extent that we decide to

SC
forgo collecting EEG data during the study, our paradigm is clearly adaptable to being used by

both patients and controls over many different delays with online administration.

U
AN
6 Conclusions
M

To conclude, we found evidence of accelerated forgetting for item stimuli, wherein patients
D

with TLE appeared unable to utilize novelty as a cue to reject incorrect object-scene pairs. There
TE

was evidence of greater forgetting for these stimuli in patients by 6 hours after learning, which

became statistically reliable by 72-hours. While standardized composite memory scores,

EP

laterality of seizure focus, presence of MTL abnormality, and presence of seizures over the 72-
C

hour delay did not predict ALF, forgetting for item stimuli correlated with reduced resting state
AC

functional connectivity between the affected anterior hippocampus and unaffected lateral

temporal cortex. The observed decrease in resting communication between the hippocampus and

neocortical regions known to support object processing and item memory is in line with theories

concerning disrupted systems-level consolidation in TLE via impaired hippocampal-neocortical

interaction.

33
 ACCEPTED MANUSCRIPT

Acknowledgements: The authors would like to thank Doug McQuiggan for his help in setting

up the experiment, and Dr. David Gold for his role in patient recruitment. We would also like to

thank Alexander Barnett and Vincent Man for their creation of the anterior and posterior

PT
hippocampal masks used in the functional connectivity analysis.

RI
U SC
AN
M
D
TE
C EP
AC

34
 ACCEPTED MANUSCRIPT

References

Abe, N., Fujii, T., Nishio, Y., Iizuka, O., Kanno, S., Kikuchi, H., … Mori, E. (2011). False item

recognition in patients with Alzheimer’s disease. Neuropsychologia, 49(7), 1897–1902.

https://doi.org/10.1016/j.neuropsychologia.2011.03.015

PT
Addis, D. R., Moscovitch, M., Crawley, A. P., & McAndrews, M. P. (2004). Recollective

RI
qualities modulate hippocampal activation during autobiographical memory retrieval.

Hippocampus, 14(6), 752–762. https://doi.org/10.1002/hipo.10215

SC
Adnan, A., Barnett, A., Moayedi, M., McCormick, C., Cohn, M., & McAndrews, M. P. (2016).

Distinct hippocampal functional networks revealed by tractography-based parcellation.

U
Brain Structure and Function, 221(6), 2999–3012. https://doi.org/10.1007/s00429-015-
AN
1084-x

Andrews-Hanna, J. R., Reidler, J. S., Sepulcre, J., Poulin, R., & Buckner, R. L. (2010).
M

Functional-Anatomic Fractionation of the Brain’s Default Network. Neuron, 65(4), 550–

D

562. https://doi.org/10.1016/j.neuron.2010.02.005.Functional-Anatomic
TE

Asadi-Pooya, A. a. (2014). Transient epileptic amnesia: a concise review. Epilepsy & Behavior :

E&B, 31, 243–5. https://doi.org/10.1016/j.yebeh.2013.10.021

EP

Atherton, K. E., Nobre, A. C., Zeman, A. Z., & Butler, C. R. (2014). Sleep-dependent memory

consolidation and accelerated forgetting. Cortex; a Journal Devoted to the Study of the
C

Nervous System and Behavior, 54, 92–105. https://doi.org/10.1016/j.cortex.2014.02.009

AC

Bell. (2006). WMS-III Logical Memory Performance after a Two-Week Delay in Temporal

Lobe Epilepsy and Control Groups. Hearing Research, 10(6), 331–341.

https://doi.org/10.1016/j.jbiomech.2011.04.025.MOMENT

Bell, B., Fine, J., Dow, C., Seidenberg, M., & Hermann, B. (2005). Temporal Lobe Epilepsy and

35
 ACCEPTED MANUSCRIPT

the Selective Reminding Test: The Conventional 30-Minute Delay Suffices. Psychological

Assessment, 17(1), 103–109. https://doi.org/10.1038/jid.2014.371

Benjamini, Y., & Hochberg, Y. (1995). Controlling the false discovery rate: a practical and

powerful approach to multiple testing. Journal of the Royal Statistical Society B.

PT
https://doi.org/10.2307/2346101

RI
Binney, R. J., Embleton, K. V., Jefferies, E., Parker, G. J. M., & Lambon Ralph, M. A. (2010).

The ventral and inferolateral aspects of the anterior temporal lobe are crucial in semantic

SC
memory: Evidence from a novel direct comparison of distortion-corrected fMRI, rTMS, and

semantic dementia. Cerebral Cortex, 20(11), 2728–2738.

https://doi.org/10.1093/cercor/bhq019
U
AN
Blake, R. V, Wroe, S. J., Breen, E. K., & Mccarthy, R. A. (2000). Accelerated forgetting in

patients with epilepsy Evidence for an impairment in memory consolidation. Brain, 123,
M

472–483.
D

Bowles, B., Crupi, C., Pigott, S., Parrent, A., Wiebe, S., Janzen, L., & Köhler, S. (2010). Double
TE

dissociation of selective recollection and familiarity impairments following two different

surgical treatments for temporal-lobe epilepsy. Neuropsychologia, 48(9), 2640–2647.

EP

https://doi.org/10.1016/j.neuropsychologia.2010.05.010

Burke, S. N., Wallace, J. ., Nematollahi, S., Uprety, A. R., & Barnes, C. A. (2010). Pattern
C

Separation Deficits May Contribute to Age-Associated Recognition Impairments. Behav

AC

Neurosci, 124(5), 559–573. https://doi.org/10.1037/a0020893

Butler, C. R., Graham, K. S., Hodges, J. R., Kapur, N., Wardlaw, J. M., & Zeman, A. Z. J.

(2007). The syndrome of transient epileptic amnesia. Annals of Neurology, 61(6), 587–598.

https://doi.org/10.1002/ana.21111

36
 ACCEPTED MANUSCRIPT

Butler, C. R., & Zeman, A. Z. (2008). Recent insights into the impairment of memory in

epilepsy : transient epileptic amnesia , accelerated long-term forgetting and remote memory

impairment. https://doi.org/10.1093/brain/awn127

Butler, Bhaduri, A., Acosta-Cabronero, J., Nestor, P. J., Kapur, N., Graham, K. S., … Zeman, A.

PT
Z. (2009). Transient epileptic amnesia: regional brain atrophy and its relationship to

RI
memory deficits. Brain : A Journal of Neurology, 132(Pt 2), 357–68.

https://doi.org/10.1093/brain/awn336

SC
Butler, van Erp, W., Bhaduri, A., Hammers, A., Heckemann, R., & Zeman, A. (2013). Magnetic

resonance volumetry reveals focal brain atrophy in transient epileptic amnesia. Epilepsy &

U
Behavior : E&B, 28(3), 363–9. https://doi.org/10.1016/j.yebeh.2013.05.018
AN
Cassel, A., Morris, R., Koutroumanidis, M., & Kopelman, M. (2016). Forgetting in temporal
M

lobe epilepsy: When does it become accelerated? Cortex, 78, 70–84.

https://doi.org/10.1016/j.cortex.2016.02.005
D

Chao, L. L., Haxby, J. V, & Martin, A. (1999). Attribute-based neural substrates in temporal
TE

cortex for perceiving and knowing about objects. Nature Neuroscience, 2(10), 913–919.

https://doi.org/10.1038/13217
EP

Cnaan, A., Laird, N. M., & Slasor, P. (1997). Tutorial in Biostatistics: Using the General Linear

Mixed Model To Analyse Unbalanced Repeated Measures and Longitudinal Data.

C

STATISTICS IN MEDICINE Statist. Med, 16(16), 2349–2380. https://doi.org/3.0.CO;2-E

AC

Cohen. (1992). A power primer. Psychological Bulletin, 112(1), 155–159.

https://doi.org/10.1037/0033-2909.112.1.155

Cohn, M., McAndrews, M. P., & Moscovitch, M. (2009). Associative reinstatement: A novel

approach to assessing associative memory in patients with unilateral temporal lobe

37
 ACCEPTED MANUSCRIPT

excisions. Neuropsychologia, 47(13), 2989–2994.

https://doi.org/10.1016/j.neuropsychologia.2009.06.029

Davachi, L. (2006). Item, context and relational episodic encoding in humans. Current Opinion

in Neurobiology, 16(6), 693–700. https://doi.org/10.1016/j.conb.2006.10.012

PT
Deak, M. C., Stickgold, R., Pietras, A. C., Nelson, A. P., & Bubrick, E. J. (2011). The role of

RI
sleep in forgetting in temporal lobe epilepsy: a pilot study. Epilepsy & Behavior : E&B,

21(4), 462–6. https://doi.org/10.1016/j.yebeh.2011.04.061

SC
De Renzi, E., & Lucchelli, F. (1993). Dense retrograde amnesia, intact learning capability and

abnormal forgetting rate: a consolidation deficit?. Cortex, 29(3), 449-466.

U
https://doi.org/10.1016/S0010-9452(13)80253-5
AN
Driskell, J. E., Park, W., Willis, R. P., Copper, C., Corporation, F. M., & Ave, E. L. (1992).
M

Effect of Overlearning on Retention Correspondence concerning this article should be

addressed to. Journal of Applied Psychology, 77(5), 615–622.

D

Dudai, Y. (2012). The Restless Engram: Consolidations Never End. Annual Review of
TE

Neuroscience, 35(1), 227–247. https://doi.org/10.1146/annurev-neuro-062111-150500

Dudai, Y., Karni, A., & Born, J. (2015). The Consolidation and Transformation of Memory.
EP

Neuron, 88(1), 20–32. https://doi.org/10.1016/j.neuron.2015.09.004

Ellenbogen, J. M., Hulbert, J. C., Stickgold, R., Dinges, D. F., & Thompson-Schill, S. L. (2006).
C

Interfering with Theories of Sleep and Memory: Sleep, Declarative Memory, and
AC

Associative Interference. Current Biology, 16(13), 1290–1294.

https://doi.org/10.1016/j.cub.2006.05.024

Emerson, R. G., Turner, C. A., Pedley, T. A., Walczak, T. S., & Forgione, M. (1995).

Propagation patterns of temporal spikes. Electroencephalography and Clinical

38
 ACCEPTED MANUSCRIPT

Neurophysiology, 94(5), 338–348. https://doi.org/10.1016/0013-4694(94)00316-D

Evans, S. J., Elliott, G., Reynders, H., & Isaac, C. L. (2014). Can temporal lobe epilepsy surgery

ameliorate accelerated long-term forgetting? Neuropsychologia, 53, 64–74.

https://doi.org/10.1016/j.neuropsychologia.2013.11.007

PT
Evensmoen, H. R., Ladstein, J., Hansen, T. I., Møller, J. A., Witter, M. P., Nadel, L., & Håberg,

RI
A. K. (2015). From details to large scale: The representation of environmental positions

follows a granularity gradient along the human hippocampal and entorhinal anterior-

SC
posterior axis. Hippocampus, 25(1), 119–135. https://doi.org/10.1002/hipo.22357

Fitzgerald, Z., Thayer, Z., Mohamed, A., & Miller, L. a. (2013). Examining factors related to

U
accelerated long-term forgetting in epilepsy using ambulatory EEG monitoring. Epilepsia,
AN
54(5), 819–27. https://doi.org/10.1111/epi.12090

Giovagnoli, A. R., Casazza, M., & Avanzini, G. (1995). Visual Learning on a Selective
M

Reminding Procedure and Delayed Recall in Patients with Temporal Lobe Epilepsy.
D

Epilepsia, 36(7), 704–711. https://doi.org/10.1111/j.1528-1157.1995.tb01050.x

TE

Hannula, D. E., Tranel, D., & Cohen, N. J. (2006). The Long and the Short of It: Relational

Memory Impairments in Amnesia, Even at Short Lags. Journal of Neuroscience, 26(32),

EP

8352–8359. https://doi.org/10.1523/JNEUROSCI.5222-05.2006

Henke, K., Weber, B., Kneifel, S., Wieser, H. G., & Buck, A. (1999). Human hippocampus
C

associates information in memory. Proceedings of the National Academy of Sciences of the

AC

United States of America, 96(May), 5884–5889. https://doi.org/10.1073/pnas.96.10.5884

Hildebrandt, H., Haldenwanger, A., & Eling, P. (2009). False recognition helps to distinguish

patients with Alzheimer’s disease and amnestic MCI from patients with other kinds of

dementia. Dementia and Geriatric Cognitive Disorders, 28(2), 159–167.

39
 ACCEPTED MANUSCRIPT

https://doi.org/10.1159/000235643

Hoefeijzers, S., Dewar, M., Sala, S. Della, Butler, C., & Zeman, A. (2015). Accelerated Long-

Term Forgetting Can Become Apparent Within 3 – 8 Hours of Wakefulness in Patients

With Transient Epileptic Amnesia. Neuropsychology, 29(1), 117–125.

PT
Kahn, I., Andrews-Hanna, J. R., Vincent, J. L., Snyder, A. Z., & Buckner, R. L. (2008). Distinct

RI
Cortical Anatomy Linked to Subregions of the Medial Temporal Lobe Revealed by Intrinsic

Functional Connectivity. Journal of Neurophysiology, 100(1), 129–139.

SC
https://doi.org/10.1152/jn.00077.2008

King, D., Bronen, R. A., Spencer, D. D., & Spencer, S. S. (1997). Topographic distribution of

U
seizure onset and hippocampal atrophy: Relationship between MRI and depth EEG.
AN
Electroencephalography and Clinical Neurophysiology, 103(6), 692–697.

https://doi.org/10.1016/S0013-4694(97)00090-4
M

Kravitz, D. J., Saleem, K. S., Baker, C. I., Ungerleider, L. G., & Mishkin, M. (2013). The ventral
D

visual pathway: An expanded neural framework for the processing of object quality. Trends
TE

Cogn Sci, 17(1), 26–49. https://doi.org/10.1016/j.tics.2012.10.011.The

Libby, L. A., Ekstrom, A. D., Ragland, J. D., & Ranganath, C. (2012). Differential Connectivity
EP

of Perirhinal and Parahippocampal Cortices within Human Hippocampal Subregions

Revealed by High-Resolution Functional Imaging. Journal of Neuroscience, 32(19), 6550–

C

6560. https://doi.org/10.1523/JNEUROSCI.3711-11.2012
AC

Mameniskiene, R., Jatuzis, D., Kaubrys, G., & Budrys, V. (2006). The decay of memory

between delayed and long-term recall in patients with temporal lobe epilepsy. Epilepsy and

Behavior, 8(1), 278–288. https://doi.org/10.1016/j.yebeh.2005.11.003

Martin, A., & Chao, L. L. (2001). Semantic memory and the brain: Structure and processes.

40
 ACCEPTED MANUSCRIPT

Current Opinion in Neurobiology, 11(2), 194–201. https://doi.org/10.1016/S0959-

4388(00)00196-3

Martin, R. C., Loring, D. W., Meador, K. J., Lee, G. P., Thrash, N., & Arena, J. G. (1991).

Impaired long-term retention despite normal verbal learning in patients with temporal

PT
lobe dysfunction. Neuropsychology, 5(1), 3-12. http://dx.doi.org/10.1037/0894-

RI
4105.5.1.3

McAndrews, M. P., Girard, T. A., Wilkins, L. K., & McCormick, C. (2016). Semantic

SC
congruence affects hippocampal response to repetition of visual associations.

Neuropsychologia, 90, 235–242. https://doi.org/10.1016/j.neuropsychologia.2016.07.026

U
McCormick, C., Protzner, A. B., Barnett, A. J., Cohn, M., Valiante, T. A., & McAndrews, M. P.
AN
(2014). Linking DMN connectivity to episodic memory capacity: What can we learn from

patients with medial temporal lobe damage? NeuroImage: Clinical, 5, 188–196.

M

https://doi.org/10.1016/j.nicl.2014.05.008
D

McCormick, C., Quraan, M., Cohn, M., Valiante, T. A., & McAndrews, M. P. (2013). Default
TE

mode network connectivity indicates episodic memory capacity in mesial temporal lobe

epilepsy. Epilepsia, 54(5), 809–818. https://doi.org/10.1111/epi.12098

EP

McCormick, C., St-Laurent, M., Ty, A., Valiante, T. A., & McAndrews, M. P. (2015).

Functional and effective hippocampal-neocortical connectivity during construction and

C

elaboration of autobiographical memory retrieval. Cerebral Cortex, 25(5), 1297–1305.

AC

https://doi.org/10.1093/cercor/bht324

McGaugh, J. L. (2000). Memory--a Century of Consolidation. Science, 287(5451), 248–251.

https://doi.org/10.1126/science.287.5451.248

McGibbon, T., & Jansari, A. S. (2013). Detecting the onset of accelerated long-term forgetting:

41
 ACCEPTED MANUSCRIPT

evidence from temporal lobe epilepsy. Neuropsychologia, 51(1), 114–22.

https://doi.org/10.1016/j.neuropsychologia.2012.11.004

McTighe, S. M., Cowell, R. A., Winters, B. D., Bussey, T. J., & Saksida, L. M. (2010).

Paradoxical False Memory for Objects After Brain Damage. Science, 330(6009), 1408–

PT
1410. https://doi.org/10.1126/science.1194780

RI
Miller, L. a., Flanagan, E., Mothakunnel, A., Mohamed, A., & Thayer, Z. (2015). Old dogs with

new tricks: Detecting accelerated long-term forgetting by extending traditional measures.

SC
Epilepsy & Behavior, 45, 205–211. https://doi.org/10.1016/j.yebeh.2015.01.024

Moscovitch, & Nadel. (1997). Memory Consolidation , Retrograde Amnesia , and the Temporal

U
Lobe Memory consolidation , retrograde amnesia and the hippocampal complex. Current
AN
Opinion in Neurobiology, (October 2012), 217–227.

Muhlert, N., Grünewald, R. a, Hunkin, N. M., Reuber, M., Howell, S., Reynders, H., & Isaac, C.
M

L. (2011). Accelerated long-term forgetting in temporal lobe but not idiopathic generalised
D

epilepsy. Neuropsychologia, 49(9), 2417–26.

TE

https://doi.org/10.1016/j.neuropsychologia.2011.04.018

Muhlert, N., Milton, F., Butler, C. R., Kapur, N., & Zeman, a Z. (2010). Accelerated forgetting
EP

of real-life events in Transient Epileptic Amnesia. Neuropsychologia, 48(11), 3235–44.

https://doi.org/10.1016/j.neuropsychologia.2010.07.001
C

Narayanan, J., Duncan, R., Greene, J., Leach, J.-P., Razvi, S., McLean, J., & Evans, J. J. (2012).
AC

Accelerated long-term forgetting in temporal lobe epilepsy: verbal, nonverbal and

autobiographical memory. Epilepsy & Behavior : E&B, 25(4), 622–30.

https://doi.org/10.1016/j.yebeh.2012.06.038

O’Keefe, J., Burgess, N., Donnett, J. G., Jeffery, K. J., & Maguire, E. A. (1998). Place cells,

42
 ACCEPTED MANUSCRIPT

navigational accuracy, and the human hippocampus. Philosophical Transactions of the

Royal Society B: Biological Sciences, 353(1373), 1333–1340.

https://doi.org/10.1098/rstb.1998.0287

Olson, I. R., Page, K., Sledge Moore, K., Chatterjee, A., & Verfaellie, M. (2006). Working

PT
Memory for Conjunctions Relies on the Medial Temporal Lobe. J Neurosci, 26(17), 4596–

RI
4601. https://doi.org/10.1523/JNEUROSCI.1923-05.2006

Poppenk, J., Evensmoen, H. R., Moscovitch, M., & Nadel, L. (2013). Long-axis specialization of

SC
the human hippocampus. Trends in Cognitive Sciences, 17(5), 230–240.

https://doi.org/10.1016/j.tics.2013.03.005

U
Poppenk, J., & Moscovitch, M. (2011). A hippocampal marker of recollection memory ability
AN
among healthy young adults: Contributions of posterior and anterior segments. Neuron,

72(6), 931–937. https://doi.org/10.1016/j.neuron.2011.10.014

M

Ranganath, C. (2010). A unified framework for the functional organization of the medial
D

temporal lobes and the phenomenology of episodic memory. Hippocampus, 20(11), 1263–
TE

1290. https://doi.org/10.1002/hipo.20852

Ranganath, C., & Ritchey, M. (2012). Two cortical systems for memory-guided behaviour.
EP

Nature Reviews Neuroscience, 13(10), 713–726. https://doi.org/10.1038/nrn3338

Romberg, C., McTighe, S. M., Heath, C. J., Whitcomb, D. J., Cho, K., Bussey, T. J., & Saksida,
C

L. M. (2012). False recognition in a mouse model of Alzheimer’s disease: Rescue with

AC

sensory restriction and memantine. Brain, 135(7), 2103–2114.

https://doi.org/10.1093/brain/aws074

Sadeh, T., Ozubko, J. D., Winocur, G., & Moscovitch, M. (2014). How we forget may depend on

how we remember. Trends in Cognitive Sciences, 18(1), 26–36.

43
 ACCEPTED MANUSCRIPT

https://doi.org/10.1016/j.tics.2013.10.008

Saling, M. M. (2009). Verbal memory in mesial temporal lobe epilepsy: Beyond material

specificity. Brain, 132(3), 570–582. https://doi.org/10.1093/brain/awp012

Squire, R. L., & Alvarez, P. (1995). Reterograde amnesia and memory consolidation: a

PT
neurobiological persepctive. Current Opinion in Neurobiology, (5), 169–177.

RI
St-Laurent, M., McCormick, C., Cohn, M., Mišić, B., Giannoylis, I., & McAndrews, M. P.

(2014). Using multivariate data reduction to predict postsurgery memory decline in patients

SC
with mesial temporal lobe epilepsy. Epilepsy & Behavior, 31, 220–227.

https://doi.org/10.1016/j.yebeh.2013.09.043

U
Strange, B. A., Witter, M. P., Lein, E. S., & Moser, E. I. (2014). Functional organization of the
AN
hippocampal longitudinal axis. Nature Reviews Neuroscience, 15(10), 655–669.

https://doi.org/10.1038/nrn3785
M

Tramoni, E., Felician, O., Barbeau, E. J., Guedj, E., Guye, M., Bartolomei, F., & Ceccaldi, M.
D

(2011). Long-term consolidation of declarative memory: insight from temporal lobe

TE

epilepsy. Brain : A Journal of Neurology, 134(Pt 3), 816–31.

https://doi.org/10.1093/brain/awr002
EP

Westmacott, R., Silver, F. L., & McAndrews, M. P. (2008). Understanding medial temporal

activation in memory tasks: Evidence from fMRI of encoding and recognition in a case of
C

transient global amnesia. Hippocampus, 18(3), 317–325. https://doi.org/10.1002/hipo.20397

AC

Wilkinson, H., Holdstock, J. S., Baker, G., Herbert, A., Clague, F., & Downes, J. J. (2012).

Long-term accelerated forgetting of verbal and non-verbal information in temporal lobe

epilepsy. Cortex; a Journal Devoted to the Study of the Nervous System and Behavior,

48(3), 317–32. https://doi.org/10.1016/j.cortex.2011.01.002

44
 ACCEPTED MANUSCRIPT

Winocur, G., & Moscovitch, M. (2011). Memory Transformation and Systems Consolidation.

Journal of the International Neuropsychological Society, 17(5), 766–780.

https://doi.org/10.1017/S1355617711000683

Winocur, G., Moscovitch, M., & Bontempi, B. (2010). Memory formation and long-term

PT
retention in humans and animals: Convergence towards a transformation account of

RI
hippocampal-neocortical interactions. Neuropsychologia, 48(8), 2339–2356.

https://doi.org/10.1016/j.neuropsychologia.2010.04.016

SC
Zeman, A. Z. J., Butler, C. R., Muhlert, N., Milton, F., Wilkinson, H., Holdstock, J. S., … Asadi-

Pooya, A. a. (2013). Can temporal lobe epilepsy surgery ameliorate accelerated long-term

U
forgetting? Epilepsy & Behavior : E&B, 54(3), 622–30.
AN
https://doi.org/10.1016/j.neuropsychologia.2013.11.007
M
D
TE
C EP
AC

45