Accepted Manuscript

Are there distinct forms of accelerated forgetting and, if so, why?

Andrew R. Mayes, Nicola M. Hunkin, Claire Isaac, Nils Muhlert

PII: S0010-9452(18)30130-8
DOI: 10.1016/j.cortex.2018.04.005
Reference: CORTEX 2301

To appear in: Cortex

Received Date: 10 April 2017

Revised Date: 27 March 2018
Accepted Date: 8 April 2018

Please cite this article as: Mayes AR, Hunkin NM, Isaac C, Muhlert N, Are there distinct forms of
accelerated forgetting and, if so, why?, CORTEX (2018), doi: 10.1016/j.cortex.2018.04.005.

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 ACCEPTED MANUSCRIPT
Title: Are there distinct forms of accelerated forgetting and, if so, why?

Short title: Patterns of accelerated forgetting

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Authors: Andrew R. Mayes1, , Nicola M. Hunkin2, Claire Isaac3 & Nils Muhlert1,4,5

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1: Division of Neuroscience & Experimental Psychology, University of

Manchester, UK

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2: School of Psychology, University of Sheffield, UK

3: Psychological Medicine, Oxford University Hospitals, UK

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4: School of Psychology, Cardiff University, UK

5: Neurodegeneration Imaging Group, King’s College London, UK

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Corresponding author:

Dr Nils Muhlert
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Division of Neuroscience & Experimental Psychology

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University of Manchester

Zochonis Building

Manchester

M13 9PT

Email: nils.muhlert@manchester.ac.uk

Tel: +44 (0) 161 275 2691

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Abstract

Whether accelerated long-term forgetting (ALF) and classic organic amnesia, particularly

hippocampal-amnesia, differ qualitatively or merely quantitatively is disputed. Qualitative

difference accounts postulate that ALF patients show normal recall memory for at least

minutes, during which hippocampal-amnesics already show accelerated forgetting and

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impaired recall but, thereafter, ALF patients show accelerated forgetting and impaired

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delayed recall. These delayed impairments may be more severe than those shown by

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hippocampal-amnesics. In contrast, quantitative difference accounts postulate that ALF

patients merely have mild hippocampal-amnesia, so their later forgetting rates and recall

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levels are sub-normal but always better than those of hippocampal-amnesics with worse
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initial recall levels (i.e., there is no cross-over in forgetting rates at longer delays). Many ALF

studies in people with epilepsy have demonstrated evidence of a single dissociation – with
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accelerated delayed forgetting relative to healthy controls. Even when initial recall seems
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genuinely normal, uncompromised by patients needing more learning trials or showing

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below-average performance on more demanding recall tests, without further evidence, a

quantitative interpretation remains possible. Resolution of the dispute requires evidence of

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a double dissociation between ALF patients and hippocampal-amnesics with more impaired
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initial recall in a comparison also involving matched controls. The only two studies that have
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made this comparison found that there was a cross-over interaction between initial and

delayed recall in the ALF and amnesic patients, inconsistent with quantitative difference

accounts. The functional and pathological conditions underlying this cross-over effect need

to be systematically explored, controlling for potential methodological confounds, in

temporal lobe epilepsy and transient epileptic amnesia as well as non-epileptic conditions.

Future research must also explore under what conditions, if any, milder hippocampal-

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amnesics show relatively normal delayed forgetting of recall, and for how long, if at all, ALF

patients show completely normal recall. Relatedly, the functional and pathological

heterogeneity of ALF needs systematic exploration.

Manuscript body

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Accelerated long-term forgetting (ALF) is often defined as normal learning and retention out

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to one hour but increased forgetting over longer delays (Elliott et al. 2014). Many studies

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have found evidence for a single dissociation in which patients show relatively normal early

recall with accelerated forgetting over longer delays relative to healthy controls (e.g.,

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Fitzgerald et al., 2013). This ALF-like pattern contrasts with the very rapid recall deficit that
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worsens over the first several minutes following learning (for a disputed period of time),

found in classic organic amnesia (e.g., Downes et al. 1998; Isaac & Mayes 1999a, 1999b).
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This has led to the common assumption that these patterns of forgetting represent
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functionally distinct deficits that are caused by separate pathophysiological mechanisms

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(e.g. Butler, Muhlert & Zeman, 2010).

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At a neurophysiological level, separate processes seem to support very short- vs longer-

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term memory (see Dudai 2004; Redondo & Morris 2011 for reviews). Learning rapidly
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triggers local changes in activated hippocampal synapses that can support memory for a

short time (rapid synaptic consolidation) and produces chemical signals that trigger de novo

protein synthesis in activated neurons’ nuclei. These synthesized proteins are then

transported to the activated and sensitized synapses, creating structural synaptic changes

that support longer lasting memories (slow synaptic consolidation). Even these memories

decay with time unless periodically boosted by physiological maintenance processes, often

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facilitated by rehearsal. Maintenance processes probably continue as long as memory lasts,

partially supported by protein kinase Mζ (Shema et al. 2011). Longer lasting memories may

also involve a systems consolidation process by which memories become independent of

the hippocampal system and reliant on neocortical structures outside the medial temporal

lobes (Alvarez & Squire 1994; Meeter & Murre 2004) (although whether episodic memory is

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ever completely independent of the hippocampus is disputed) (Nadel & Moscovitch 1997).

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The qualitative difference account of the relationship between ALF and classic organic

amnesia, therefore, usually postulates that classic hippocampal-amnesics suffer from

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impaired rapid and possibly also slow synaptic consolidation, depending on how long their
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recall deficit continues to worsen. In contrast, patients with ALF are postulated to suffer

from disruption of later consolidation/maintenance processes and/or systems

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consolidation, caused by several pathological mechanisms, including certain kinds of

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epileptiform activity (e.g. Ricci et al., 2015a). With appropriate pathology, patients may
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show both sets of consolidation/maintenance symptoms.

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The qualitative account has recently been challenged by Cassel et al. (2016). These
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researchers used a literature analysis and their studies of forgetting rates in people with
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temporal lobe epilepsy (TLE) to argue for a quantitative difference account of the organic

amnesia/ALF relationship. According to this account, ALF is merely mild amnesia, so

accelerated forgetting begins fairly immediately following post-learning distraction and

extends for at least a week. In other words, classic organic amnesia and ALF only differ with

respect to severity, so that different degrees of disruption of the neural resource underlying

a single functional mechanism can explain the forgetting patterns seen in both conditions.

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In this review, we consider the evidence for distinct functions and mechanisms underlying

organic amnesia and ALF. To do so, we will discuss in sequence: 1) Problems with

determining whether ALF is qualitatively distinct from classic hippocampal-amnesia. 2) The

form taken by forgetting rates in healthy controls and patients with hippocampal-amnesia.

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3) Functional deficits and their pathological causes that underlie early accelerated forgetting

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in classic hippocampal-amnesia . 4) Does the evidence for ALF better fit the qualitative or

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quantitative difference account? 5) The impaired functions and pathology that may

underlie ALF. 6) The areas of relative ignorance and how to reduce these in the future.

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1. Problems with determining whether ALF is qualitatively distinct from classic
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hippocampal-amnesia.
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Convincing qualitative accounts of ALF need to show that (1) these patients begin to show

recall deficits significantly later than classic hippocampal-amnesics and that (2) their recall
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deficits then get worse for a long time because of accelerated forgetting not only relative to
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controls but also classic hippocampal-amnesics. Both these things are very hard to show for
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several reasons.

Establishing when a pathological group begins to show impaired memory is hard. To

establish that a patient is unimpaired on a given kind of memory at a given delay

convincingly, s/he must perform very close to or above control levels on all equivalent tests

at this delay. Performance on equivalent tests must, by definition, depend on the same

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underlying memory function(s) or resource(s) (see Shallice, 1988). However, normal

performance on some equivalent tests may depend on high levels of the relevant

resource(s) whereas other tests are much less demanding of it/them, e.g., some recall tests

may demand more hippocampal resource(s) than are available whereas others do not.

Hence, a particular patient group may only have a small reduction in the key underlying

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resource so that performance is normal on less resource-demanding tests but not on more

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demanding ones. Indeed, the quantitative account of ALF (Cassel et al. 2016; Cassel &

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Kopelman, in press) is that ALF patients have very mild classic hippocampal or organic

amnesia, i.e., a small reduction of the resource underlying recall and/or recognition.

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Unfortunately, we rarely, if ever, know which tests are equivalent or how much of a specific

resource they need for normal performance. Equivalent memory tests must tap the same
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memory functions, which depend on the same neural mechanisms. However, declarative
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memory functions and mechanisms are currently still disputed. For example, patients’ recall
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and recognition test performance is sometimes differentially impaired but it is not clear if

this is because they differentially depend on different kinds of memory function supported
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by distinct brain regions or for other reasons. With respect to tests’ resource-demands, the
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danger is of using circular arguments, i.e., claiming that, when test performance is down, it
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must be more resource-demanding than another test on which performance is normal.

Most importantly, what factors predict how demanding a test is of a particular resource

remains largely informed guesswork. Given practical limitations, even if a patient has shown

intact memory at a specific delay on all apparently equivalent tests, there is a worry that

performance on a further more resource-demanding test would be impaired so the patient

might still have a very mild reduction of that resource.

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There is a similar risk of circularity when preserved memory is ascribed to poor

discrimination ability of a test, i.e. its having a relatively low hit rate and a relatively high

false alarm rate. This ability is very hard to determine because we need to know what

memory function the test taps, how accurately it does this, and whether one test does this

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better than another. Greater discrimination of memory impairment may require using tests

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with more studied items with minimal differences in difficulty between individual test items.

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Healthy individuals show very variable forgetting rates and an individual’s forgetting rate

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may differ markedly on different occasions (e.g., Huppert & Kopelman 1989). This is because
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known factors that influence forgetting rate, which include emotional arousal (e.g., LaBar &

Phelps 1998), arousal (e.g., Kleinsmith et al. 1963) and how new information relates to prior
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knowledge (e.g., Tse et al. 2007), may vary across occasions. They may also vary
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independently of memory-impairing pathologies. So, small group comparisons are often

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very noisy, increasing the risk of forgetting rate false negatives and positives between

pathological and normal groups. Better control will depend on much better knowledge of
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the major factors underlying forgetting rate. For example, it is not even known whether
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retrieval at long delays is more demanding of a specific memory-resource than retrieval at

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short delays.

Furthermore, great care must be taken to avoid ceiling effects at short delays and floor

effects at long delays (associated with false positives and false negatives, respectively). For

instance, in Cassel et al.’s (2016) study there was a risk of a ceiling effect in their controls,

which can affect how their results are interpreted (see supplementary material). To date,

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floor and ceiling effects have been common in studies of ALF (Elliott et al. 2014) and these

reduce the ability to correctly discriminate between groups.

Even if floor and ceiling effects are avoided, the behavioural measure of memory (e.g., free

or cued recall) is unlikely to be linearly related to the underlying neuropsychological

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variable(s) (e.g., memory strength or degree of consolidation) that it taps. Matching initial

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memory performance levels between groups is key to permitting confident claims about

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whether patients and controls differ in subsequent rates of decline. Such matching, always

necessary with classic hippocampal-amnesia even at delays of seconds and necessary with

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many putative ALF cases at delays between seconds and 30 minutes, requires that the
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learning experience (e.g., trial number/stimulus exposure) or delay factors (amount of

interference) differs between memory impaired and healthy participants. Even with
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matching at the shortest delay, if retrieval is only tapped at the shortest and longest delays,
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it remains unknown whether forgetting is accelerated throughout the interval or for only
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one part of it. This is important when considering what function is impaired. If the aim is to

determine confidently whether forgetting is accelerated between very long delays, such as
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between 1 and 3 months, matching on some memory measure at the shorter delay may be
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impossible to achieve.
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As already indicated, non-equivalent memory tests tap different kinds of memory that

depend on partially non-overlapping neural bases. Relevant to possible qualitative

differences between ALF and classic hippocampal-amnesia, recall, including the cued recall

of study context details associated with the target (recollection) that can help support

recognition depends on the hippocampus and functionally connected structures. In

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contrast, familiarity, which also supports recognition and involves no recall, does not

depend on the hippocampal system, but on the perirhinal and parahippocampal neocortices

of the medial temporal lobes (MTL) (Montaldi & Mayes 2010). Consistent with this, there is

some evidence that healthy people show faster forgetting on tests of recall than familiarity

(Sadeh et al. 2016; Yang et al. 2016). Although classic hippocampal-amnesics and ALF

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patients show abnormally fast forgetting on tests of recall (see next sections), results with

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item recognition in ALF patients are less clearcut, with faster forgetting sometimes being

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convincingly reported (e.g., Muhlert et al. 2011; Hoefejjzers et al., 2015 Weston et al. 2018).

This later accelerated item recognition forgetting in ALF patients probably only occurs when

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the relative contribution of recollection is high, which is hard to determine, depending on
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many factors, such as target/foil similarity and test format (e.g., Holdstock et al. 2002;

Bastin and Van der Linden 2003).

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2. Forgetting rates in patients with hippocampal-amnesia.

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Normal forgetting over time follows a power function rather than an exponential function

(e.g., Wixted 2004a). That is, the proportional rate of decline decreases across time and
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memory becomes more resistant to decline as the delay since acquisition increases. Wixted
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argued further that the processing of subsequent inputs had a major impact on forgetting
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over time following initial acquisition. He proposed three generalisations about how this

retroactive interference works: (1) it operates even when the interfering inputs are not

similar to the interfered with memories, (2) it reduces as time since learning increases, and

(3) it depends on the interfering inputs competing for storage processing with the original

memories in a limited capacity system, such as the hippocampus. This notion that

retroactive interference depends on reduced consolidation of recent memories is supported

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by evidence that sleep, alcohol and benzodiazepines reduce new learning that starts when

they are already present. In contrast, memories of events occurring just prior to sleeping or

taking any of those drugs are enhanced (Wixted 2004b).

In patients with classic organic amnesia, free recall is impaired as soon after learning as

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distraction occurs. Even after matching patients’ recall at 20 seconds to control levels by

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giving them more learning opportunity, by 10 minutes, their recall may be at floor levels

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whilst controls’ recall has hardly declined at all. Cued recall also declines at an accelerated

rate in hippocampal-amnesics, although the rate of acceleration is less than it is with free

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recall (e.g., Isaac and Mayes 1999b). The evidence, therefore, suggests that hippocampal-
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amnesics lose the ability for free and cued recall of information at an accelerated rate from

very few seconds after initial exposure to delays of around 10 minutes.

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The accelerated forgetting most evident over the first 10 minutes in hippocampal-amnesics
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with moderate damage probably requires competition for storage from retroactively acting

interfering inputs. Minimizing non-specific interference in the minutes immediately after

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learning broadly normalizes free recall at delays of around 10 minutes in some less severe
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hippocampal-amnesics (e.g., Dewar et al., 2010). In patients with head injury, stroke or mild
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cognitive impairment (MCI), free recall of related word lists, stories (Cowan et al. 2004; Della

Sala et al. 2005; Dewar et al. 2007; Dewar et al. 2012), complex associations and temporal

order (Craig et al. 2015) has been shown to decline at close to control levels when

interfering activities are replaced by resting quietly. Excitingly, if, after this short period of

quiet resting, MCI patients were tested a week later, these benefits persisted (Dewar et al.

2012). This occurred despite typical levels of interfering activity from 10 minutes onwards. If

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confirmed in patients with mild to moderate hippocampal-amnesia, this suggests that

patients have a very rapid recall deficit which gets worse for 10 minutes but then does not

worsen any more.

In contrast, after initial matching, item recognition declines at a normal rate in classic

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hippocampal-amnesics from 20 seconds out to delays of months (Kopelman 1985; Freed &

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Corkin 1988; Isaac & Mayes 1999a, 1999b). Extensive perirhinal and parahippocampal

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cortex damage rapidly impairs item familiarity and recognition. However, it remains

unknown whether this damage further accelerates familiarity and possibly even recognition,

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decline over the next 10 minutes or longer (see Montaldi & Mayes 2010). These issues are
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highly relevant to whether the functional deficits underlying ALF and classic organic amnesia

are distinct.
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3. Functional deficits and their pathological causes that underlie early accelerated
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forgetting in classic hippocampal-amnesia

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Direct hippocampal damage and/or damage to functionally connected structures that

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disturbs hippocampal activity (Snaphaan et al. 2009; Aggleton et al. 2016) varies markedly in
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extent so classic hippocampal-amnesics may have very different levels of residual

resource(s). Total destruction of such resource(s) probably leaves at least some recall

memory at very short, interference-filled delays, mediated by other brain systems that may

be damaged/destroyed with larger lesions. With such larger lesions, recall, familiarity and

recognition may already be at floor around the time of input because relevant high-level

associations may not even be represented (e.g., Lee et al. 2005) so cannot be later

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consolidated (e.g., Isaac & Mayes 1999a, b). These patients’ recall of high-level item-context

information should be effectively absent immediately. If so, they must clearly be

functionally distinct from putative ALF patients, who can initially encode top-level

associations and retrieve them relatively normally for some time (e.g., Ricci et al., 2015b).

Moderate selective hippocampal system disruption still leaves considerable hippocampal

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resource so recall memory may be only mildly impaired after a few seconds, easily matched

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to control recall, but then gets worse than control recall over a filled 10 minute delay. The

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moderately reduced resource may minimally disrupt input representation and, as already

indicated, moderately disrupt rapid synaptic consolidation of recall memory.

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However, slower consolidation/maintenance processes may be relatively normal in

hippocampal-amnesics because recall deficits after 10 minutes or so may not get any more
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impaired even if well off floor (e.g., see Dewar et al. 2012). Sparing of more slowly triggered,
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more enduring consolidation/maintenance processes is feasible in patients with moderately

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fewer remaining hippocampal neurons and correspondingly reduced resource. This is

because fewer hippocampal neurons are involved in storage reducing the resource available
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for synaptic change. As a result, rapid synaptic consolidation may be impaired but set a new,
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lower baseline so that slower consolidation/maintenance processes can work relatively

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normally on the smaller population of storage-related synapses enabling normal forgetting

after 10 minutes. This is feasible but unproved and it should be borne in mind that it

remains to be convincingly shown that moderate classic hippocampal-amnesics continue to

lose residual recall memory normally or abnormally fast after matching to control levels at

10 minutes delay.

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Although storage/consolidation deficit accounts of hippocampal-amnesia have long been

dominant, recent work has been used to support earlier retrieval deficit accounts (e.g.

Warrington & Weiskrantz, 1970; Gray & McNaughton, 2000). In this animal research,

treatment with protein synthesis blocker drugs caused a form of state- or context-

dependent forgetting that was reversed by restoring the encoding state at retrieval by

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applying the blocker drug again (Gisquet-Verrier & Riccio 2016). However, protein synthesis

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blockers may reduce but not abolish hippocampal consolidation resources so that memory

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is weaker and normal retrieval processes cannot reactivate it without additional support

from state or context cues (see Mayes 1988). This idea is supported by state-of-the-art

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animal research showing that, when the passage of time (Kitamura et al. 2017) or early
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Alzheimer’s disease (Roy et al. 2016) weakens memory storage, normal cues fail to

reactivate memories and hippocampal memory neurons. In contrast, direct optogenetic

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stimulation achieves both these things. This strongly suggests that storage weakens as time
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passes and moderate hippocampal-amnesia may increase the weakening but still allow for
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some storage, with retrieval functions remaining intact.

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The functional distinction between milder classic hippocampal-amnesics and putative ALF
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patients is not clearcut. The milder hippocampal-amnesics have relatively small recall
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deficits caused by smaller lesions to the hippocampus or functionally connected structures.

In these patients, sufficient hippocampal resource may be left to allow close to normal input

representation and the relatively normal passive fading of storage when interference from

rapidly following competing inputs is minimized (Hardt et al. 2013). However, residual

resource seems insufficient to allow normal rapid synaptic consolidation in the face of

competing inputs (see Dewar et al. 2010; Wixted 2004a, 2005). What happens beyond this

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point remains controversial. Claims that ALF is functionally distinct from classic amnesia

must, therefore, be based on showing that ALF patients’ early recall memory is at least close

to normal and better than in moderate classic hippocampal-amnesics. Even more important,

ALF patients’ early forgetting rate must be slower than hippocampal-amnesics whereas their

later forgetting rates should be faster to produce a double dissociation, as suggested by the

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qualitative difference account.

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4. Does the evidence for ALF better fit the qualitative or quantitative difference account?

Is ALF simply mild hippocampal-amnesia or does it dissociate from hippocampal-amnesia?

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In briefly reviewing the evidence about this question, it is important to consider three main
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possibilities. First, when ALF is selective and hippocampal-amnesia is sufficiently moderate,

the qualitative difference account predicts a complete double dissociation in forgetting rate,
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provided the classic hippocampal-amnesic forgetting rate normalizes after 10 minutes. A

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strong demonstration of this requires matching recall after 10 minutes to assess long-term
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forgetting rate (see Section 1), which might be done by allowing quiet rest in the short delay

(see Dewar et al., 2010), although a weaker demonstration could still be made without
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matching. A partial forgetting rate double dissociation might be demonstrable were

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moderate hippocampal-amnesics to continue to show accelerated forgetting after 10

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minutes provided there was a significant cross-over interaction (see Figure 1). At most, only

a partial double dissociation can be shown with recall because the hippocampal-amnesics

will be impaired at longer delays.

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90
Hypothetical items recalled (%)
80
70
60
50
40 Controls
30 Selective ALF
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Hippocampal amnesia
10
0

3 days
1 hour

1 week
1 day
15 seconds
Immediate

2 minutes
5 minutes
10 minutes
30 minutes

6 hours
12 hours

3 weeks+
1 minute

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Figure 1. Selective ALF consistent with the qualitative difference account – hypothetical
forgetting curves for recall memory, assuming that forgetting rate after a few minutes is
relatively normal in hippocampal patients. Timescales are hypothetical and could vary

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considerably.
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Second, according to the mild amnesia viewpoint, all putative cases of ALF have mild
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hippocampal-amnesia. Given the mildness of the deficit, it is difficult to show that patients

have impaired recall and accelerated forgetting in the first 10 minutes or so after learning.
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But tests on which normal recall needs sufficient hippocampal resource will show forgetting
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over both 10 minute and longer time periods at similar rates to an equivalently severe
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selective hippocampal-amnesia. This viewpoint is consistent with the quantitative difference

account of hippocampal-amnesia and ALF. Any kind of crossover effect is impossible on this
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account.
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90
Hypothetical items recalled (%)
80
70
60
50
40 Controls
30 ALF as mild amnesia
20

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Hippocampal amnesia
10
0

3 days
1 hour

1 week
1 day
15 seconds
Immediate

2 minutes
5 minutes
10 minutes
30 minutes

6 hours
12 hours

3 weeks+
1 minute

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SC
Figure 2. ALF as mild amnesia, consistent with the quantitative difference account –

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hypothetical forgetting curves for recall memory. Timescales are hypothetical and could
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vary considerably.
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Third, according to the combined mild amnesia and ALF viewpoint (Figure 3), many, if not
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most, ALF patients will have pathology that causes ALF combined with pathology typical for
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hippocampal-amnesia. These patients will show the functional deficits and causal pathology

that drives hippocampal-amnesia and also the functional deficit(s) and causal pathologies
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that drive selective cases of ALF. Some of these patients may need extra learning to match
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their initial recall to that of controls. A patient with combined hippocampal-amnesia and ALF
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should forget more over long delays of days or weeks than another patient with moderately

severe selective hippocampal-amnesia, even after matching initial recall. As we suspect that

many ‘ALF’ patients show the combined pathologies, it is critical to make these comparisons

between selective hippocampal-amnesic patients and patients who have both pathologies.

Only the qualitative difference account allows crossover effects with forgetting rate and

recall level to occur.

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90
Hypothetical items recalled (%)
80
70
60
50 Controls

40
ALF as combined mild
30
amnesia & ALF
20

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Hippocampal amnesia
10
0

3 days
1 hour

1 week
1 day
15 seconds

30 minutes

3 weeks+
Immediate

2 minutes
5 minutes
10 minutes

6 hours
12 hours
1 minute

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SC
Figure 3. ALF as combined mild amnesia & ALF, consistent with the qualitative difference

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account. Timescales are hypothetical and could vary considerably.
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Double dissociations supporting the qualitative difference account are most easily found if
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some ALF patients can be convincingly shown to be selective, i.e., have normal, or even
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above normal, recall memory for at least 10 minutes. One patient, who showed clear
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evidence of this pattern of impairment with normal learning and memory out to filled delays

of more than 10 minutes was patient JL (Holdstock, Mayes, Isaac, et al. 2002). Given the
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same learning opportunity as her matched controls, she showed recall of the Rey Osterrieth
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figure at a level slightly, but insignificantly, above that of her controls, after 20 second and
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30 minute filled delays. In contrast, her recall of the figure after a delay of 3 weeks was

markedly worse than that of her controls, indicating accelerated forgetting between these

delays (Mayes et al. 2003). JL’s performance on recalling a long story after 20 second and 30

minute filled-delays fell slightly, but not significantly, below her control group mean; there

was no sign of accelerated forgetting by 30 min but by 3 weeks she could not even recall

hearing a story. Interestingly, JL showed no evidence of hippocampal damage, although she

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did have temporal lobe seizures as well as extensive damage to the right perirhinal cortex,

temporal pole and parts of the orbitofrontal cortex.

How frequent this pattern of normal initial recall is in other reported ALF cases remains

unclear. Ironically, perhaps the strongest demonstration of initially normal recall with

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subsequent significant forgetting has been found recently in patients with presymptomatic

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autosomal dominant Alzheimer’s disease (Weston et al., 2018). After identical learning

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conditions were used, these patients showed very close to normal recall of word lists,

stories and figures at 30 minutes delay whereas, between this delay and 1 week, recall

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declined abnormally fast. Normal performance at short delays on several recall tests
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probably demands different levels of hippocampal system resource(s) so this is a powerful

demonstration of a single dissociation (see Section 1).

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Being a single dissociation, however, what Weston et al. observed remains consistent with
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both quantitative and qualitative difference accounts. Defenders of the quantitative

difference account might raise the proof demand to impossible levels by arguing that
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hippocampal system resource levels are reduced so little in ALF patients that recall on all
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tests may be preserved at short delays. Only as delay lengthens might more hippocampal
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resource be needed than is available so that recall deficits become apparent. This

quantitative interpretation is not implausible for Weston et al.’s patients; they probably

have very early and mild hippocampal deterioration and their delayed accelerated loss of

recall correlated with their estimated years to diagnosis. Impaired delayed recall may prove

extremely valuable as a behavioural marker of very early dementia but might do so because

selectively delayed recall deficits are the most sensitive signs of very early classic

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hippocampal-amnesia. This quantitative interpretation can only be refuted if patients’ recall

is initially better but later worse than that of mild hippocampal-amnesics. Weston et al. did

not make this comparison. A double dissociation of this kind would be more plausible if

these patients have a non-hippocampal pathology in, for example, a pre-frontal region that

research suggests leads to a systems consolidation deficit and undermines delayed recall

PT
(see Kitamura et al. 2007).

RI
SC
If the quantitative account is correct, any kind of double dissociation or crossover effect

between hippocampal-amnesia and selective ALF should be impossible. To test these

U
predictions it is necessary to compare selective moderate hippocampal-amnesics, selective
AN
ALF patients, and matched controls. However, we are only aware of two studies that

compared memory at both short and long delays in a classic hippocampal-amnesic, an ALF
M

patient, and matched controls. One of these studies compared a hippocampal patient, YR,
D

with a relatively selective ALF patient, JL (Holdstock, Mayes, Isaac, et al. 2002). In the course
TE

of several learning and forgetting studies YR’s, JL’s and their controls’ learning opportunities

were matched. Under these conditions, JL’s early recall memory (up to 1 day) was normal
EP

and better than YR’s which was impaired. Following delays of >3 weeks, JL’s recall memory
C

was grossly impaired. YR’s memory declined at what seemed to be a normal rate from 1 day
AC

(or less) onwards. This strongly suggests a complete double dissociation with forgetting rate

and a partial double dissociation with YR forgetting faster than JL for a short period after

learning and thereafter JL forgetting faster than YR. As indicated above, it is hard to see how

quantitative difference accounts can predict this pattern of forgetting results.

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The other study (Kapur 1994) compared an amnesic with mammillary body damage to a

patient who had been treated for a nasopharyngeal tumour with surgery and later

radiotherapy that caused epilepsy, anterior and inferior temporal lobe damage with perhaps

a slight involvement of the medial temporal lobe. The first patient, therefore, had slight

damage to the hippocampal recall memory system and showed a moderate impairment of

PT
recall at short delays. The second patient had very mild amnesia but was less impaired at

RI
recall at short delays than the mammillary body patient. Two experimental comparisons

SC
were made between the two patients and their controls. The first compared learning and

recall of information about people at a short delay and the second compared recall memory

U
for such information about people, like Norman Schwarzkopf, who were publicly known for
AN
up to several years. At the short delay, the mammillary body patient performed worse than

the tumour patient, although the mammillary body patient’s recall looked slightly below
M

that of his controls. At the long delay (up to several years), the tumour patient performed
D

much worse than the mammillary body patient, who looked effectively unimpaired. The
TE

crossover interaction pattern looked very similar to that shown by YR and JL, although the

longer delay was much greater, and the short and long delay tasks were slightly less closely
EP

matched in the Kapur study.

C
AC

Cassel and her colleagues (Cassel et al. 2016; Cassel & Kopelman, in press) have recently

argued that the difference between ALF and hippocampal-amnesia is quantitative, based on

their review of the literature and an experiment. They examined a group of 18 TLE patients

using an ‘amount of learning’ matching procedure where necessary and tested memory at

delays of 30 seconds, 10 minutes, 1 day and 1 week. Accelerated forgetting was reported

on a verbal cued recall task involving stories learned to a criterion but only for the longest

19
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delay period: 30 seconds to 1 week. With a visuospatial cued recall/recognition task,

accelerated forgetting of route memory, relative to a group of healthy controls, was only

reported between delays of 30 seconds and 10 minutes with normal forgetting rates

thereafter. The four patients with MRI evidence of medial temporal sclerosis (presumably

including the hippocampus) forgot the story significantly faster between the filled 30 second

PT
and 10 minute delays than the 12 patients without evidence of medial temporal sclerosis.

RI
There was also a trend for these 4 patients to forget the route faster over this time period

SC
(albeit non-significantly, perhaps reflecting a low sample size). Between 10 minutes and 1

week, inspection of both groups’ data shows no evidence of a faster forgetting relative to

U
their controls.
AN
Cassel et al.’s patients’ patterns of forgetting on both tasks were unlike the qualitative
M

difference accounts of ALF shown in Figures 1 and 3. Not only was cued recall in Cassel and
D

colleagues’ patients often impaired at 10 minutes delay, it was sometimes even impaired at
TE

delays of a few seconds as indicated by their need for more learning trials than their

controls. Interestingly, the patients with evidence of hippocampal damage (sclerosis) were
EP

the ones who forgot most in the first 10 minutes. Overall, this evidence suggests that the
C

TLE patients had varying degrees of slightly accelerated forgetting and impaired recall
AC

shortly after learning, which may still be compatible with what is shown in Figure 3,

although this was not tested by comparing the patients with moderate hippocampal-

amnesics. However, any weak tendency of these patients to forget faster than their controls

after delays of 10 minutes was far from significant and cannot be trusted so the patients’

longer term forgetting did not correspond to patterns suggested for ALF in either Figure 1 or

3.

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But even if none of these 18 TLE patients showed either selective ALF or ALF combined with

mild hippocampal-amnesia, this does not prove that there are no TLE, TEA or other patients

who show the selective or combined forms of ALF. In patients with focal epilepsy, selective

ALF may be less common than some believe because it depends on specific kinds of

PT
abnormal neural activity occurring in appropriate brain regions, which may be relatively

RI
uncommon in epilepsy. Cassel and colleagues allowed this possibility (see also Korczyn et al.

SC
2015) in their literature review (Cassel & Kopelman, In press). This is, however, inconsistent

with their quantitative difference account of ALF unless every exception results from using

U
tests that are poor at discriminating early memory deficits but good at discriminating later
AN
memory deficits or involve poor matching of conditions across different delays and groups.

These suggestions are very implausible and there is no evidence that they apply to studies
M

that seem to fit the qualitative difference accounts of ALF/organic amnesia.

D
TE

It remains unclear and hard to prove (because the bar can be raised indefinitely) what

proportion of putative ALF patients show completely preserved recall for 10 minutes or so.
EP

For example, Cassel et al. listed the Muhlert et al. (2010) study as consistent with the
C

quantitative account. In this group study of TLE patients, recall levels were matched at 80%
AC

correct, avoiding ceiling effects between patients and controls, who did not significantly

differ in learning trial number needed to reach the learning criterion after a 40 second filled

delay. Recall was still matched after a 30 minute delay. By implication, Cassel et al. must

have argued that the TLE patients forgot mildly, but non-significantly, faster between the

last learning trial and the 40 second filled delay, perhaps relying on eyeballing the forgetting

curves.

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But even if they were correct and the patients in Muhlert and colleagues (2010) showed

very mild early recall deficits and even if the same applies to all TLE/TEA patients this would

not disprove the qualitative account. Patients who forget slightly faster than normal in the

first 10 minutes could still differ qualitatively from moderately impaired hippocampal-

PT
amnesics. This would apply provided these patients initially forget significantly slower than

RI
moderate hippocampal-amnesics, but later forget significantly faster. Such a powerful

SC
crossover interaction cannot be explained if moderate hippocampal-amnesia and ALF only

differ quantitatively (see Figure 3). Indeed, a strong case can be made that even if a TLE

U
patient forgets as fast as a mild hippocampal-amnesic during the first 10 minutes but
AN
thereafter forgets faster, there must be a qualitative difference between the patients, in

which the TLE patient has an additional pathology that is accelerating later forgetting.
M
D

Identifying putative ALF patients with the mildest early recall deficits can be achieved by
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detecting those with the least structural damage to recall memory mediating structures,

such as the hippocampus, fornix, mammillary bodies and anterior thalamus. Importantly,
EP

Butler et al. (2009) found that extent of hippocampal damage, measured as extent of
C

reduction of hippocampal volumes, correlated significantly with forgetting over the first 30
AC

minutes but not with forgetting over a week. The neural markers of early and late forgetting

clearly differ. Identifying the key factors in driving delayed accelerated forgetting is still in its

infancy: the degree to which later recall forgetting is accelerated is the key feature of ALF

and occurs whether initial forgetting is normal or otherwise. Epilepsy is clearly not enough

to enhance later forgetting because adults with TLE have been found to show a higher

incidence of accelerated forgetting over 3 week delays than adults with idiopathic

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generalized epilepsies and no medial temporal lobe pathology, who showed a similar

incidence rate of accelerated forgetting to healthy controls (Muhlert et al. 2011). However,

this may not be the case in children, where ALF in children with idiopathic generalized

epilepsies has been reported (Davidson et al. 2007; Gascoigne et al. 2012). Even so, single

dissociations between adult epilepsy groups in rates of forgetting over 3 week delays when

PT
30 minute recall is similar suggest that long-term forgetting is accelerated by some epilepsy-

RI
related features but not others.

SC
TLE shows substantial heterogeneity and is often insufficient to produce accelerated long-

U
term forgetting of recall memory. Analysis suggests that somewhere between one third and
AN
one half of TLE patients show accelerated forgetting over 3 weeks, relative to healthy

controls, depending on the test used (Muhlert et al. 2011). A recent study in patients with
M

focal seizures, including both TLE and frontal lobe epilepsy, estimates that roughly 18%
D

show ALF (Miller et al., 2017). People with TEA, a subtype of TLE characterized by transient
TE

periods of global amnesia and evidence of epilepsy, appear to also show a relatively high

frequency of ALF (Butler et al. 2007; Muhlert et al. 2010), although prevalence rates have
EP

not yet been established.

C
AC

5. The impaired functions and pathology that underlie ALF

ALF may well involve a functional deficit and underlying pathology that is distinct from the

one underlying hippocampal-amnesia. If those with hippocampal-amnesia show a specific

increase in early forgetting rates, their functional deficit may involve just rapid

consolidation. Only if the recall impairment continues to worsen over long time periods, will

additional impairments in maintenance and/or slower consolidation be implicated. In

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contrast, in ALF, different functional deficit(s) that impair maintenance or long-term

consolidation processes, leaving rapid consolidation processes intact, are probably involved.

Given that ALF and hippocampal-amnesia almost certainly have different pathologies, we

expect little overlap in the way memory is disrupted in the two conditions.

PT
We need to know whether ALF, as is almost certainly the case with hippocampal-amnesia, is

RI
a functionally and pathologically heterogeneous collection of disorders. The degree to which

SC
the long-term forgetting rate is accelerated should vary as a function of ALF severity, but the

time period over which it is accelerated may also vary between patients, suggesting

U
different forms of ALF. Accordingly, the way ALF differs from hippocampal-amnesia will vary
AN
depending on the kind of ALF.
M

Selective ALF is probably triggered by disruption of memory storage that does not occur for
D

some time and continues intermittently or uninterruptedly for as long as accelerated

TE

forgetting continues. Whether the deficit affects the slower forms of cellular or systems

consolidation or storage maintenance processes is unclear. Functionally, there is likely to be

EP

an active disruption of one or more processes that support long-term storage. Even if
C

hippocampal-amnesics and ALF patients both show abnormally faster forgetting over long
AC

delays, evidence that selective ALF patients forget at an even faster rate over these longer

time periods (producing a crossover interaction, Figures 1 & 3) cannot be reconciled with

their having exactly the same storage problem as amnesics. Reports of some ALF patients

make it clear that after good initial recall, forgetting over a week or longer can be dramatic

(e.g. Butler & Zeman, 2008).

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Sleep has been associated with longer-term consolidation processes (e.g., Feld et al., 2013)

so comparisons of forgetting during periods of sleep and wakefulness in TLE patients may be

enlightening. Following this approach, Atherton and colleagues (2014) found that, whereas

12 hours of wakefulness following learning led to accelerated forgetting in ALF patients, if

the 12 hours were spent asleep, forgetting was not only minimal but equivalent to that of

PT
controls, i.e., ALF did not appear. The study controlled for circadian rhythm effects on

RI
alertness so minimizes differences between the effects of sleep and wakefulness on

SC
memory. This recent evidence suggests that interference caused by the kinds of non-specific

input that occur during wakefulness is necessary for longer term accelerated forgetting to

U
appear (Atherton et al. 2014; Hoefeijzers et al. 2015). It remains to be explored whether this
AN
applies to all selective ALF patients over all longer delays or only to TEA patients and for

delays between 10 minutes and 12 hours of learning.

M
D

As the evidence currently stands, wakefulness seems necessary for ALF. The issue is not
TE

straightforward, so several interrelated factors need to be considered. First, partial

hippocampal lesions may therefore only disrupt initial consolidation and accelerate patient
EP

forgetting during wakefulness (i.e. when there is competition for storage from new inputs).
C
AC

Second, sleep has been argued to play a key role in various forms of longer-term (hours or

more) declarative memory consolidation/maintenance that wakefulness contributes to less

or not at all (e.g., Feld et al. 2013). Currently, there is mixed evidence regarding associations

between durations of slow wave sleep and forgetting in TLE. In TEA patients, more slow

wave sleep was associated with worse retention over 12 hours (Atherton et al. 2016). In

contrast, TLE patients show a positive (albeit non-significant) relationship, with more slow

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wave sleep associated with better retention (Deak et al. 2011). These findings make it

unclear what is happening in ALF cases, and direct comparisons between TEA and more

typical TLE patients is clearly needed, but at least some of the kinds of longer-term

consolidation/maintenance that occur best or only in sleep seem to be occurring normally

or nearly so in ALF.

PT
RI
Third, the functional deficit that operates particularly during wakefulness may be caused by

SC
a pathology that involves seizures or sub-threshold seizure-like activity occurring in storage

sites. However, seizure activity occurs both throughout sleep and wakefulness. If ALF only

U
involves disruption of longer-term memory consolidation/storage during wakefulness, the
AN
abnormal electrical activity must interact very differently with background physiology in

wakefulness so as to only disrupt long-term memory storage processes during the day.
M
D

ALF, therefore, may only develop during wakefulness when the storage of new inputs occurs
TE

in conjunction with intermittent abnormal electrical activity in storage sites. It is possible

that the abnormal activity causes the storage trace of the older memories to become
EP

overwritten and erased by the newer developing memories.

C
AC

The possible involvement of abnormal electrical activity in the causation of ALF leads

naturally to a consideration of the underlying pathology (see Elliot et al. 2014). How

epilepsy-related factors may contribute to memory loss must be considered. Various

theories have been put forward regarding the pathophysiological factors contributing to ALF

in TLE. These factors centre on epileptiform activity, medication effects, structural and

metabolic abnormalities and functional brain changes (Baker & Zeman 2017). Subclinical

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epileptiform activity, which may have a cumulative effect over time, has been suggested to

play a role, and has been linked to memory decline over long delays (Fitzgerald et al. 2013).

Overt seizures are unlikely to be the primary cause, as ALF is reported in people with TEA, in

whom overt seizures are rare following treatment with anti-epileptic medication (Butler et

al. 2007). Furthermore, ALF was not found to correlate with overt seizures recorded during

PT
intervening delay periods (e.g., Muhlert et al. 2011), although one case study reported

RI
dramatic increases in forgetting when a seizure occurred soon after new learning (O'Connor

SC
et al. 1997). It is plausible to argue that seizures have maximal detrimental effect on

memories when they occur shortly after learning; at longer delays those memories may be

U
more stable and robust to the effects of seizures.
AN
It is, therefore, perhaps unsurprising that metabolic changes without seizures may be
M

sufficient to trigger ALF, with accruing evidence implicating GABAergic changes in its
D

appearance. Most strikingly, direct evidence for a role of GABAergic changes in ALF was
TE

seen in the case of a 52 year old female who developed ALF following administration of the

GABA B receptor agonist Baclofen, with remittance following Baclofen withdrawal (Zeman
EP

et al. 2016). Of particular importance with this patient, there was no evidence that she
C

suffered from seizures, although, because of its rather open-ended nature, subclinical
AC

seizure activity cannot be completely excluded. Similarly, increased rates of ALF-like long-

term forgetting that were not associated with overt seizures have been reported following

glutamic acid decarboxylase antibody-related limbic encephalitis (Witt et al., 2015). This

antibody may be present in some patients with refractory TLE (Peltola et al. 2000) and is

linked to lower cortical GABA levels (Stagg et al. 2010). It could be that abnormal GABA

levels in appropriate brain regions (perhaps including neocortex) causes ALF. This pathology

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may have non-epileptic or epileptic causes (see Witt et al. 2015). This raises the possibility

that seizures may not cause ALF unless they produce appropriate GABA changes in certain

brain regions; this possibility should be systematically investigated. Associations between

ALF and in vivo GABA levels could, in future, be explored using neuroimaging techniques,

such as GABA PET (e.g. [11c]flumazenil) or MR spectroscopy in people with TLE.

PT
RI
A role for the hippocampus in ALF has also been suggested. TEA patients with ALF show

SC
subtly (but significantly) reduced hippocampal volume at a group level compared to healthy

controls (Butler et al. 2009; Wilkinson et al. 2012). However, the pattern of statistical

U
correlations between hippocampal volumes and early but not late recall (Butler et al., 2009)
AN
suggest that the hippocampal changes are unlikely to underpin the delayed accelerated

forgetting that defines ALF. Overall, whilst many TLE and TEA cases show hippocampal
M

structural as well as metabolic changes, there is no convincing evidence that these changes
D

predict rates of ALF (Butler et al., 2009; Wilkinson et al., 2012; Tramoni et al, 2011).
TE

Furthermore, hippocampal reduction in N-Acetyl Aspartate (a marker of neuronal integrity)

in TLE, alongside reductions in glucose metabolism within the medial temporal lobes were
EP

not found to be correlated with ALF (Tramoni et al. 2011).

C
AC

6. The areas of relative ignorance and how to reduce these in the future.

We have argued that at least some putative ALF patients have a recall memory deficit that is

qualitatively different from that of mild hippocampal-amnesia without epilepsy. The key ALF

deficit is disproportionately fast delayed forgetting on tests of recall relative to

hippocampal-amnesics who show slightly worse or even equivalently impaired early recall

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memory. Although this pattern of deficit can be shown by comparisons between putative

ALF patients and mild hippocampal-amnesics as well as matched controls, to our knowledge

only two such comparisons have been made (Holdstock et al., 2002; Kapur, 1994). Not

surprisingly, therefore, there is still great ignorance about the patterns of memory shown in

ALF and relatedly the functional deficit(s) and pathologies that underlie it.

PT
RI
First, we know little about whether TLE/TEA ALF only affects recall memory or whether

SC
there are other forms of ALF that affect other kinds of delayed memory. TLE and TEA

patients most clearly show delayed accelerated forgetting of recall/recollection. Indeed,

U
their deficit may only affect recall/recollection, although this needs to be confirmed in
AN
future research. So far, Carlesimo et al. (2017) have reported that a TLE patient showed ALF

for recollection but that item familiarity was unaffected in this patient. In a similar way, no
M

ALF was found on a motor sequence task over 24 hours in TEA patients (Muhlert et al. 2010)
D

or TLE patients (Deak et al. 2011). It is unknown but it could be that ALF of procedural
TE

memories will be produced by epilepsies or certain kinds of metabolic disorders that are

focused on basal ganglia circuits. Similarly, ALF of item familiarity might be caused by
EP

epileptic/metabolic disorders focused on perirhinal cortex.

C
AC

Second, when recall begins to become impaired in ALF and whether the accelerated

forgetting stops is unclear. Consequently, it is unknown whether there are different kinds of

ALF that affect recall for different time periods. Determining when impairment starts is

complicated: many ALF patients will show fairly immediate recall deficits because they also

have mild hippocampal-amnesia so it is necessary to find patients who have completely

normal performance on good recall tests at delays of at least 10 minutes. Also, measuring

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how long ALF is accelerated for will depend on severity as well as possible heterogeneity. A

severe ALF patient may typically forget everything about an event very quickly whereas a

milder case will forget more slowly. This does not mean that the underlying functional

impairment lasts longer in the milder case.

PT
Third, it remains unclear as to what pathology underlies the delayed accelerated forgetting

RI
of recall memories of ALF. Hippocampal damage is probably neither necessary (e.g., Butler

SC
et al. 2009) nor sufficient to cause the kind of forgetting found in ALF (e.g., Holdstock et al.,

2002). However, TLE/TEA is not sufficient either (e.g., Muhlert et al., 2011) and seizures may

U
not even be necessary in all cases (e.g., Zeman et al., 2016; Weston et al., 2018). An
AN
unknown but certainly small proportion of TLE and TEA patients show both completely

intact early recall and accelerated delayed forgetting relative to non-epileptic hippocampal-
M

amnesics with mildly worse or equivalent early recall. We are still unsure but some degree
D

of hippocampal destruction in many TLE/TEA putative ALF cases probably causes their
TE

slightly impaired early recall with some tests. Most likely, delayed accelerated forgetting is

either caused directly by certain kinds of abnormal activity focused on key recall storage
EP

sites or by similarly located metabolic abnormalities (e.g., GABA changes) that may be
C

caused indirectly by epileptic activity linked to TLE/TEA, by drugs (Zeman et al., 2016), or by
AC

non-epileptic pathologies, such as mild cognitive impairment (e.g., Manes et al.,2008) and

presymptomatic autosomal dominant Alzheimer’s disease (e.g., Weston et al., 2018).

The problem with assuming that seizure-related abnormal activity directly causes ALF is that

hippocampal seizures at or shortly after learning disrupt recall memory at very short delays

(e.g. O’Connor et al., 1997) but even more tonic-clonic-like electroconvulsive shock

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treatment does not normally disrupt memory at longer delays (but see Squire, 1981). This is

the opposite of what is reported to occur in ALF. Only metabolic abnormalities have been

shown to disrupt memory at longer delays that probably involve maintenance as well as

systems consolidation (e.g., Shema et al. 2011). There needs to be systematic investigation

of what kind of metabolic abnormality causes ALF and where it needs to act. Given animal

PT
evidence that storage changes driving recall memory may weaken in the hippocampus over

RI
the medium term but strengthen in prefrontal regions (e.g., Kitamura et al. 2017), the

SC
disruptive process may initially focus on the hippocampus and only later on prefrontal

regions. Lesions to regions, such as the prefrontal ones, may even disturb recall not

U
immediately but after a longer delay.
AN
Future theoretical ALF research needs to more clearly set out its aims. Many studies are
M

clinical and have mainly focused on identifying the patterns of forgetting seen in people
D

with specific forms of epilepsy. This is useful in helping to explain, for example, why many
TE

people with TLE report poor memory but perform relatively normally on clinical memory

tests given at short delays. Theoretical ALF research, however, must systematically explore
EP

the detailed ALF-related forgetting patterns together with the likely functional deficit(s) and
C

pathologies in a variety of patients. For this, a screening process involving a large mixed
AC

patient cohort and a range of appropriate tests is probably essential. From this cohort,

patients with normal, but also close to normal, learning and recall for at least 10 minutes

followed by accelerated forgetting will be selected. These patients will then be compared

with non-epileptic hippocampal-amnesics with relatively mild learning and early recall

deficits as well as with matched controls to further explore patterns of memory breakdown,

functional deficit(s) and pathologies.

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Hopefully, by systematically exploring any identified ALF cases, studies will throw more light

on the brain’s later consolidation and maintenance processes that subserve memory as it

ages from a few minutes to perhaps as long as it lasts. In parallel, other work needs to

explore whether ALF-related effects can be found in different kinds of patients and with

PT
other kinds of memory, such as item familiarity, priming and kinds of procedural memory.

RI
Careful controls will be essential for this. These controls will include tests and procedures

SC
that are good at discriminating impaired from intact memory, free from obvious confounds

like tapping inappropriate and non-equivalent memory and other functions, differences in

U
initial memory levels, and ceiling and floor effects.
AN
M
D
TE
C EP
AC

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