Download Verbal memory in mesial temporal lobe epilepsy

doi:10.1093/brain/awp012
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BRAIN
A JOURNAL OF NEUROLOGY
REVIEW ARTICLE
Verbal memory in mesial temporal lobe epilepsy:
beyond material specificity
Michael M. Saling
School of Behavioural Science, The University of Melbourne, Victoria, Australia
Correspondence to: Michael M. Saling,
School of Behavioural Science,
Redmond Barry Building,
The University of Melbourne,
3010 Victoria, Australia
E-mail: [email protected]
The idea that verbal and non-verbal forms of memory are segregated in their entirety, and localized to the left and right hippocampi, is arguably the most influential concept in the neuropsychology of temporal lobe epilepsy, forming a cornerstone of
pre-surgical decision making, and a frame for interpreting postoperative outcome. This critical review begins by examining some
of the unexpressed but inescapable assumptions of the material-specificity model: (i) verbal and non-verbal memory are unitary
and internally homogenous constructs; and (ii) left and right memory systems are assumed to be independent, self-contained
modules. The next section traces the origins of an alternative view, emanating largely from three challenges to these assumptions: (i) verbal memory is systematically fractionated by left mesial temporal foci; (ii) the resulting components are differentially localized within the left temporal lobe; and (iii) verbal and non-verbal memory functions are not entirely lateralized. It is
argued here that the perirhinal cortex is a key node in a more extensive network mediating protosemantic associative memory.
Impairment of this fundamental memory system is a proximal neurocognitive marker of mesial temporal epileptogenesis.
Keywords: verbal memory; temporal lobe epilepsy; associative memory; perirhinal cortex; material specificity
Introduction
Fifty years have elapsed since the publication of the first seminal
papers on neuropsychological outcome after surgery for the alleviation of temporal lobe seizures (Scoville and Milner, 1957;
Penfield and Milner, 1958). Since then the phenomenon of temporal lobe epilepsy (TLE) has been a source of knowledge about
much, if not most, of what we know about the neurocognition of
human memory. Surgical programmes have provided the impetus
and rationale for the development of a major field of neuropsychological practice (Barr, 2007; Baxendale, 2008), charged with
the responsibility of averting the cognitive disaster that befell the
famous HM and others in a similar predicament (Baxendale,
2008).
Because neuropsychological practice in temporal lobe epileptology was born out of a series of postoperative disasters (Xia, 2006),
it has understandably adopted a conservative stance, and an
almost universal and persisting adherence to a single dominant
model. The purpose of this article is to show that research and
accumulated experience, particularly over the past 20 years, contains the seeds of a paradigmatic shift. This review will argue
that it is now possible to synthesize the outlines of a revised
Received November 5, 2008. Revised January 12, 2009. Accepted January 20, 2009
ß The Author (2009). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved.
For Permissions, please email: [email protected]
Verbal memory in epilepsy
neuropsychological model, with implications for pre-surgical decision making and our understanding of risks posed by surgery to
memory function.
Material-specificity
Memory difficulties have long been regarded as the chief neuropsychological issue in TLE. Some degree of memory impairment
can be documented in almost all cases (Fisher et al., 2000;
Hermann and Seidenberg, 2008). Ongoing seizure activity deepens and extends memory impairments in the long term (Hermann
et al., 2006), and despite the enormity of its success in the treatment of intractable TLE, surgical treatment also poses a risk to
memory, particularly if seizure outcome is poor (Helmstaedter
et al., 2003).
The most influential conceptualization of memory impairment
in temporal lobe epileptology is, unquestionably, the notion of
material-specificity. This parsimonious model owes much to the
pioneering work of Brenda Milner and her colleagues at the
Montreal Neurological Institute. At its most fundamental level it
holds that the left and right temporal lobes process different types
of material (Milner, 1970); i.e. ‘a complementary specialization of
the two temporal lobes of man with respect to memory . . . the
most significant variable is the verbal or non-verbal character of
the material to be retained’ (p. 29–30). Milner (1970) wondered
whether the prominence of the material specific effect, a predominantly postoperative phenomenon in her observations, was
caused by the extent of anterior temporal damage, which involved
mesial (amygdala, hippocampus, parahippocampal gyrus) as well
as lateral structures. Nevertheless, it fell to the well-known ‘big H,
little h’ correlational studies of Corsi to provide the empirical
impetus for the notion that lateralized hippocampal damage is
the cause of material-specific memory impairments. Corsi’s work
was plagued by the impossibility of disentangling the effects of
damage to the anterior temporal structures involved in en bloc
resection, and dissecting out in particular the extent of hippocampal resection from the extent of epileptogenic pathology.
From a clinical perspective, memory impairments objectively
restricted to one material type were mild and apparently devoid
of the devastating loss of autonoetic consciousness seen in HM
(Scoville, 1954; Scoville and Milner, 1957), who had undergone
bilateral mesial temporal resections, or in cases PB and FC
(Penfield and Milner, 1958), who had undergone left temporal
resections in the presence of a putatively diseased contralateral
temporal lobe (in the case of FC), or demonstrated right-sided
pathology (in the case of PB) (Penfield and Mathieson, 1974).
Objective study of these cases showed that new learning, irrespective of material type, was impaired, and the clinical syndrome
of severe amnesia later came to be equated with the notion
of a material non-specific (or general) learning deficit (Saykin
et al., 1992).
The parsimony of the material specificity hypothesis, and its
apparently straightforward mapping onto the factorially derived
verbal/non-verbal distinction embodied in the major standardized neuropsychological instruments of the day, must have been
appealing to an embryonic neuropsychological speciality. Once it
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had been accepted that material non-specific memory impairments
point to a condition of bitemporal vulnerability, and are therefore
the harbingers of a post-resection amnesia, the presence of a
non-congruent memory disorder (i.e. a memory impairment implicating the contralateral hippocampus in cases with an apparently
unilateral mesial temporal focus) was taken to contra-indicate
a surgical approach to treatment. This logic, and indeed the
material-specificity model, persists as a cornerstone of current
pre-surgical decision making, and the principal paradigm for interpreting neurocognitive outcome (Baxendale, 2008).
The material-specificity model is not as straightforward as it
might have appeared. It implicitly embodies a specific stance
towards the structure of verbal and non-verbal memory, and
their cerebral organization. In practice, its implementation depends
on the following assumptions:
(1) Verbal and non-verbal memory are unitary and internally
homogenous constructs. This assumption arises from the
common finding that a range of verbal memory tasks,
from single word paradigms to linguistically complex discourse, intercorrelate in normal populations and its operation
is reflected in the fact that widely different verbal memory
paradigms have been used interchangeably, or in summation, to characterize putatively verbal-specific impairments.
Correlations between any two verbal memory paradigms
(such as verbal paired associates and prose passages, to
cite a common example) are taken to mean that the correlated tasks are ‘really the same construct under two different
labels’ (Schmidt and Hunter, 1999), and that either task is a
valid measure of that construct. This approach to validity
assigns no particular importance to the nature of the task
(such as its cognitive architecture), or to the possibility that
task-specific factors might be subserved by different causal
mechanisms (Boorsboom et al., 2004). In particular, it does
not accommodate the possibility that scores on two tasks,
which correlate in a normal sample, might be differentially
affected by a strategic cerebral lesion.
(2) The left temporal-verbal memory system mediates all aspects
of verbal memory, but does not deal with non-verbal
memory, and vice versa for the right temporal memory
system. In other words, the left and right temporal regions
function as independent and self-contained material-specific
modules, characterized by Dobbins et al. (1998) as the
‘Laterality/Independence assumption’ (p. 116). Although
this assumption emanated from earlier interpretations of
post-resection studies of memory, trends in the accumulating
postoperative literature are poorly aligned with it. For example, postoperative decrements in verbal memory occur in a
significant minority of patients after a right temporal resection (Baxendale et al., 1998a, 2007; Bell and Davies, 1998;
Martin et al., 1998; Gleissner et al., 2002). In the non-verbal
domain, evidence for an exclusive nexus between the right
temporal lobe and spatial memory is considerably weaker,
since many aspects of the domain are also impaired by left
hippocampal sclerosis and anterior temporal resection
(Glikmann-Johnston et al., 2008; McConley et al., 2008).
Doubts about the foundations of the material-specificity
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model have also been raised by recent neuroimaging studies
(Kennepohl et al., 2007), which suggest a dynamic interaction between the left and right mesial temporal regions,
modulated by specific task demands (Nyberg et al., 2000;
Burgess et al., 2002; Law et al., 2005; Sommer et al., 2005;
Treyer et al., 2005; Kennepohl et al., 2007).
The emergence of
task-specificity
An early inkling that the first assumption is unsustainable came
in 1972 from a little known case with a left temporal focus on
surface EEG. She was seen by Dr Kevin Walsh at the Austin
Hospital, Melbourne, Australia, in response to the elegant referral
question: ‘does this lady have an amnesia to which she is not
entitled?’ The neuropsychological findings showed that verbal
memory was normal, apart from some difficulty with ‘novel’
word pairs (the ‘hard’ paired associates of the Wechsler Memory
Scale-Form I). Non-verbal memory was impaired. The patient
re-presented 8 months later. Depth electroencephalography
again implicated the left temporal lobe. In the interim the
patient died of a pulmonary embolus. At post-mortem, the right
temporal lobe, which had been electrically silent, was severely
atrophic. Cases of unexpected amnesia are particularly informative
(Kapur and Prevett, 2003), and a number of lessons can be drawn
from this one. While she was unlikely to have been regarded as
generally amnestic on the basis of conventional material-specificity
criteria, because most aspects of her verbal memory were normal,
a left temporal resection would have placed her at considerable
risk of an HM-like syndrome. Important to the argument presented here, the simple separation of ‘hard’ (unrelated) from
‘easy’ (semantically) word pairs, rather than relying on the standard scoring procedure of summating hard and easy pairs, disclosed a dissociation of significant neurocognitive interest.
More than a decade later, Rausch and her colleagues at UCLA
(Rausch, 1987–1988; Rausch and Babb, 1987, 1993) found that
left hippocampal neuronal loss specifically predicted the ability to
learn unrelated word pairs, but not immediate recall of prose. She
suggested that the neuropsychological detection of left hippocampal sclerosis depended on a ‘specific verbal memory task’ (1987–8,
p. 23), and characterized the cognitive demand as ‘simple, rote
association’ (p. 21). In 1993, we showed that story recall did not
differentiate between well characterized left and right mesial temporal foci, but was mildly impaired in both groups. Acquisition of
unrelated word pairs, however, was prominently impaired in the
left-sided group, but normal in the right-sided group, accounting
for 36% of the between group variance (Saling et al., 1993). This
finding was replicated in a second and larger group of well characterized patients with either left or right mesial temporal foci,
producing a similar effect size (Saling et al., 2002). It seemed
that the distinction between the groups of tasks could be drawn
along a semantico-syntactic continuum. In hard paired associate
learning tasks words are paired in a pseudo-random or arbitrary
manner, minimizing any semantic or syntactic relationship
between them. In neurocognitive terms, there is a very low
M. M. Saling
probability that the conjunction was previously represented in
semantic memory networks. At the opposite end of the continuum, prose such as that contained in the Logical Memory subtests is replete with semantic content and complex syntactical
structure. I return to the implications of this conceptualization
below.
A second line of work on epilepsy-induced dissociation of verbal
learning was pioneered by Hermann and his colleagues at the
University of Wisconsin. They showed in a number of studies
that patients with left MTS were worse at word list learning.
When language ability was partialled out, the side of focus
(i.e. left versus right TLE) did not account for significant variance
in list learning. Language adequacy has been found to be a powerful predictor of list learning (Hermann et al., 1988; Hermann
et al., 1992). In contrast, language adequacy was unrelated to
the magnitude of retroactive interference, leading Hermann
et al. (1988) to suggest that the drop-off in recall across an interference condition might serve as ‘the best pure indicator of
memory function in dominant temporal lobe patients’. We replicated Hermann’s finding (Saling et al., 2002), again showing
that language adequacy accounted for the poorer performance
of left TLE patients on list learning, but not on post-interference
recall.
Since arbitrary associative memory and retroactive interference
have played a crucial role in disclosing intratemporal specialization,
cognitive mechanisms that unite them are of particular interest.
When the interference condition has the same form as the material to-be-learned (Dewar et al., 2007), semantic structure in
memory tasks is protective, while arbitrariness increases susceptibility to the effects of retroactive interference (Bower et al., 1994;
Burns and Gold, 1999; Blank, 2002; Musca et al., 2004; Sahakyan
and Goodmon, 2007). Arbitrariness and semantic structure are not
absolutes, and the two coexist to varying extents in all meaningful
verbal material. While semantic clustering is a common list learning strategy, an arbitrary component arises because specific items
can be substituted (e.g. tambourine for drum) without affecting
potential semantic linkages. The magnitude of the retroactive
interference effect can be conceptualized, therefore, as a probe
of arbitrariness across a variety of verbal learning tasks.
A strong case exists for the view that verbal learning tasks are
differentially affected by left mesial temporal epileptogenic foci.
For tasks where performance is supported by pre-established
semantic associations, the effect of left mesial foci is minimal
or absent. Related-paired associates, list learning or prose recall
fall into this category. On the other hand, left mesial temporal
foci exert a consistent effect on tasks that do not load on preestablished language abilities to any significant extent. This category includes ‘hard’ or arbitrary paired associates and indices of
retention, such as post-interference recall. The material-specificity
model, in its theoretical stance and in its clinical implementation,
emphasizes the verbal versus non-verbal nature of material, to the
exclusion of any other attribute of the task, and therefore cannot
accommodate notions of dissociation (such as arbitrary versus
semantic forms of learning) and intratemporal specialization.
The arbitrary-semantic distinction is represented in the temporal
lobe as a medial versus lateral specialization, an idea that owes
much to comparative work on verbal memory outcomes after
Verbal memory in epilepsy
selective and en bloc temporal lobe resection. After standard
anterior temporal lobectomy in patients with left MTS, memory
tasks with a semantic component, such as related paired associate
learning, and recall of passages (Saling et al., 2002), or which elicit
the superimposition of semantic clustering, such as list learning
(Helmstaedter et al., 1997; Saling et al., 2002), decline from
preoperative levels. This change is not seen after selective
amygdalohippocampectomy (Helmstaedter et al., 1996, 1997),
providing converging evidence of mediolateral specialization
(Helmstaedter et al., 1997). Helmstaedter suggested that the lateral temporal cortex is involved in ‘short-term’ aspects of memory
(Helmstaedter et al., 1996, p. 5), or in ‘data acquisition and working memory’ (Helmstaedter et al., 1997, p. 113), while the medial
component is involved in consolidation processes. This conceptualization is based on putative paradigmatic differences between
the acquisition and post-interference trials of the Rey Auditory
Verbal Learning Test. The interpretation adopted here is that mediolateral specialization is more sharply drawn along semanticprotosemantic lines. The argument for this position is developed
in later sections. It is worth pointing out at this stage, however,
that tasks belonging to the same learning paradigm (paired associates), differing only in degree of semantic structure, are differentially associated with lateral and mesial structures (Weintrob
et al., 2002).
Intratemporal and lateral
specialization for verbal
memory
Hippocampal sclerosis is the commonest epileptogenic pathology
in refractory TLE. It is clearly detectable preoperatively by MRI,
and hippocampal sparing is a key consideration in surgical planning. The animal literature (Gaffan, 2001) ‘makes an overwhelming case against the strong version of the hippocampal memory
hypothesis’ (p. 9). In the present context three major lines of
evidence are particularly important: (i) the addition of perirhinal
lesions in monkeys with prior hippocampal damage exacerbates
the memory impairment (Baxter and Murray, 2001); (ii) neurotoxic
damage to the perirhinal cortex, with sparing of fibres of passage,
impairs some aspects of learning, while neurotoxic damage to the
hippocampus leaves the same aspects of learning intact (Malkova
et al., 2001); (iii) Perirhinal lesions produce a more severe impairment of learning than entorhinal lesions, suggesting a role for the
perirhinal cortex that transcends hippocampal deafferentation
(Leonard et al., 1995).
In addition, there is a substantial recent literature that characterizes the perirhinal cortex as a conjunctional or associative
processor (Bussey et al., 2005; Law et al., 2005; Jimenez-Diaz
et al., 2006; Tendolkar et al., 2007), as well as an experimental
lesion-based literature on primates implicating the entorhinal
(Buckmaster et al., 2004) and perirhinal cortex (Murray et al.,
1993; Higuchi and Miyashita, 1996; Buckley and Gaffan, 1998;
Parker and Gaffan, 1998) in basic forms of associative memory.
Given that impaired verbal paired associate learning is a hallmark
of left MTS, an obvious question arises: to what extent is
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perirhinal cortex recruited in the face of associative memory
demands in patients with mesial temporal lobe foci?
Alongside the issue of intramesial specialization, temporal lobe
specialization for verbal memory on a broader scale needs to be
considered: do arbitrary and verbal memory tasks map onto the
medial and lateral components on the epileptogenic temporal lobe
as definitively as the pre and postoperative lesion data suggest?
Unrelated paired associate scores, obtained from 27 patients with
left mesial TLE emanating from unilateral mesial temporal sclerosis
(MTS), were regressed on resting glucose uptake in a whole brain
18
F-fluorodeoxyglucose PET study (Weintrob et al., 2002). A peak
correlation was observed in the ipsilateral perirhinal cortex. This
contrasted with regressions involving related paired associate
scores, which produced a peak correlation in the anterior aspect
of the inferior temporal gyrus (Brodmann area 20).
These findings underline the relevance of the perirhinal cortex to
associative learning in patients with left MTS. They also reveal the
pattern of medial-lateral intratemporal specialization suggested by
the postoperative memory data. Semantically loaded associates are
clearly dependent on the anterior portion of the inferior temporal
gyrus. This region is recruited in tasks based on pre-established
semantic relations (Warburton et al., 1996; Dolan and Fletcher,
1997; Spitsyna et al., 2006), and has been implicated in earlystage semantic dementia (Hodges et al., 1992; Mummery et al.,
1999, 2000; Chan et al., 2001). Performance on semantically
loaded associates is also influenced, to a lesser extent, by perirhinal
activity (Weintrob et al., 2002). The perirhinal region receives
afferents from the primate area TE (van Hoesen and Pandya,
1975a), area 20/21 in humans (Gloor, 1997), forming a subsystem
involved in the processing of item-to-item conjunctions, and the
extraction of meaning from them. In our 1993 study related
paired associates differed significantly between the left and right
MTS groups, although the effect size was comparatively small.
This is not a robust finding and we were unable to replicate it
in a larger sample (Saling et al., 2002). Nevertheless, it raises that
possibility that the disruptive effects of mesial temporal foci extend
to semantically related material, albeit at a subtle level, possibly
by compromising inferotemporal neocortex and/or its underlying
white matter (Mitchell et al., 1999). Arbitrary paired associate learning also correlated with T2 signal in a left perirhinal
region of interest, but not with hippocampal T2 relaxation time
(Lillywhite et al., 2007), and so provides converging evidence
for the hypothesis that the perirhinal region is a key substrate
for arbitrary relational processing in temporal epilepsy. Postinterference recall on the Rey Auditory Verbal Learning Test, the
other variable sensitive to left MTS, showed the opposite pattern,
correlating better with hippocampal T2 relaxation time (Lillywhite
et al., 2007). Measures of delayed recall in general are related to
hippocampal integrity in previous work using T2 relaxometry in
a single region of interest (Incisa della Rocchetta et al., 1995;
Kalviainen et al., 1997; Baxendale et al., 1998b).
Taken together with the studies reviewed above, activation
evidence (Weintrob, 2004) suggests that the perirhinal cortex
represents a node in a more extensive network mediating arbitrary paired associate learning. Regional cerebral blood flow, using
PET and [15O]H2O, with a paradigm involving the acquisition of
arbitrary verbal paired associates, was pre-dominantly left sided,
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involving dorsolateral pre-frontal, fusiform, parahippocampal and
perirhinal cortices, and extensive posterior cingulate deactivation.
Patients with left MTS, in contrast, showed right-sided activation
involving dorsolateral pre-frontal cortex, and bilateral recruitment
of the anterior cingulate region. While a right dorsolateral prefrontal region of interest correlated with paired associate performance in the patient group, it does not represent an effective
compensatory shift since task performance was markedly worse
in patients than controls. A similar conclusion has been reached
on the basis of fMRI evidence (Powell et al., 2007). Contralateral
activation is more appropriately regarded as a marker of network
disruption in the presence of mesial temporal pathology
(Weintrob, 2004; Powell et al., 2007).
Déjà vu, familiarity and
recollection
The perirhinal cortex has long been thought to be the source of a
sense of familiarity, or knowing that an event has been encountered previously (Brown and Aggelton, 2001). Recollection, veridical memory of the detailed context surrounding a familiar event,
is thought to be a hippocampal function (Aggleton et al., 2005).
This putative dissociation is controversial, but a recent case study
(Bowles et al., 2007) offers strong support. The patient, NB, a
21-year-old female with intractable temporal lobe seizures,
underwent an anterior hippocampal-sparing resection for removal
of a ganglioglioma. The resection involved amygdala, entorhinal
cortex, and perirhinal cortex, but spared the hippocampus and
parahippocampal cortex. Four different experimental paradigms
provided converging evidence for the finding that familiarity was
impaired but recollection was entirely spared. Findings such as this
provide a neurocognitive framework for understanding transient
seizure-induced disorders of familiarity. Déjà vu and jamais vu
involve an inappropriate attachment of familiarity or unfamiliarity
to encountered events. Direct stimulation of perirhinal cortex
induces the phenomenology of déjà vu more frequently than stimulation of hippocampus or amygdala (Bartolomei et al., 2004).
The case of Dr Z, whose descriptions of his own episodes of
déjà vu (which he characterized as the ‘dreamy state’) contributed
to the Jacksonian concept of TLE. At post-mortem Dr Z had a
‘small cavity, collapsed and almost empty, with indefinite walls’
in the left uncinate gyrus. The rest of the brain was thought to
be normal. As Weintrob (2004) has pointed out, the coronal
section provided by Jackson (Hughlings-Jackson and Coleman,
1898, p. 588) shows that the lesion lies just lateral to the
fundus of the collateral sulcus, a zone of transition between the
ento and perirhinal cortices (Insausti et al., 1998). The case of
Dr Z is also well known for his amnestic episodes which fit well
with recent descriptions of transient epileptic amnesia (Butler
et al., 2007; Butler and Zeman, 2008). In the most extensive
account produced to date Butler et al. (2007) note that the anterograde amnesia was ‘incomplete’ in more than half of their
sample, and some patients felt that they could ‘remember not
being able to remember’. One might speculate that the incompleteness of the amnesic episode in the small majority of cases
M. M. Saling
reflects partial preservation of recollection of broad contextual
information, but a loss of familiarity with specific events.
Rhinal cortex, memory and
epileptogenesis: arbitrary
association as an
‘endophenotype’
Measures in epilepsy neuropsychology have tended to be global in
nature, essentially summating a variety of tasks to form a factorially derived scale, in line with the idea that comprehensiveness
is the goal of the ideal neuropsychological examination. The cost
of this approach is loss of neurocognitive specificity. Little attention has been devoted to the notion of neurocognitive markers,
i.e. components of the cognitive domain that might have a more
proximal relationship to the neurobiological aspects of the disease,
and therefore greater diagnostic sensitivity at a pre-surgical level.
The evidence reviewed thus far indicates that left mesial temporal foci exert a primary influence on a neurocognitive system
responsible for the rapid uptake of links or relations that have
yet to be established in personal episodic or semantic memory,
or which might conflict with pre-established knowledge (Saling,
2005). The role of this system is to acquire the myriads of
co-occurrences that signpost behavioural trajectories over time,
providing a temporary and consciously accessible record (Byrne
et al., 2007; Bird and Burgess, 2008; Moscovitch, 2008), irrespective of the meaningfulness or ultimate significance of its contents (Eichenbaum et al., 1994; McClelland and Goddard, 1996;
Moscovitch, 2008). The wider hippocampal system, including
rhinal cortices, has been characterized as domain-specific in that
it deals with ‘consciously apprehended information and none
other’ (Moscovitch, 2008). It behaves in a modular fashion in
that it picks up information obligatorily, and ‘delivers the stored
information as output in response to a cue’ (p. 66, emphasis
added), disclosing the fundamentally associative nature of the
system. Further, and of particular interest in the present context,
‘the output [is] shallow . . . the memory is not interpreted as to
its significance or veridicality’ (p. 66). The shallowness of hippocampal system processing allows for the retention of contiguities
that are initially devoid of previously represented meaning or
significance. This property is phylogenetically ancient, providing
a buffer (McClelland and Goddard, 1996) against the speed
and unpredictability of environmental events (McClelland and
Goddard, 1996; Moscovitch, 2008). The rhinal cortices are well
placed to mediate this aspect of the system’s function.
The nature of perirhinal involvement in cognition is controversial, but the themes of conjunction and association are consistently raised (Weintrob et al., 2002, 2007; de Curtis and Pare,
2004; Weintrob, 2004; Bussey et al., 2005; Fernandez and
Tendolkar, 2006; Jimenez-Diaz et al., 2006; Lillywhite et al.,
2007; Tendolkar et al., 2007). A model advanced by Fernandez
and Tendolkar (2006), e.g. imbues the ento and perirhinal cortices
with a ‘gatekeeper’ role in declarative memory, and postulates
that this gating function is modulated by the semantic-conceptual
Verbal memory in epilepsy
status of incoming information. Items with no prior representation
in semantic memory elicit widespread rhinal activity, increasing
the probability of transfer to the hippocampus for encoding. The
subjective counterpart is unfamiliarity. Rhinal activity is sparse in
the face of items with a pre-established semantic representation,
reducing the probability of transfer to the hippocampus and inducing a subjective sense of familiarity. This mechanism directs limited
encoding resources away from familiar towards novel information
(p. 358), thereby optimizing the operation of the declarative
memory system. On the other hand, electrophysiological evidence
derived from patients with TLE suggests the rhinal-hippocampal
coupling is potentiated by greater semantic content of verbal
material, increasing the probability of transfer between rhinal
cortex and hippocampus (Fell et al., 2006). While these differing
views are yet to be resolved, it is becoming clearer that activity at
this critical interface is modulated by a semantic dimension.
Entorhinal (Bernasconi et al., 2003) and perirhinal volumes
(Bonilha et al., 2003) are frequently reduced in TLE. These structures are considered to be highly significant in the initiation
of epileptiform activity (Schwarcz and Witter, 2002; Bartolomei
et al., 2005). Electrophysiological evidence suggests that the
rhinal cortices regulate the interaction between association
neocortex and the hippocampus (Schwarcz and Witter, 2002; de
Curtis and Pare, 2004; Fell et al., 2006; Fernandez and Tendolkar,
2006), and it could be argued that epileptogenesis and the
origins of declarative memory dysfunction are inextricably united
at the rhinal-hippocampal interface (de Curtis and Pare, 2004).
It follows, then, that fundamental forms of associative memory,
uncomplicated by semantic loadings, can be regarded as proximal
to the neurobiological mechanisms of mesial TLE, and therefore
potentially endophenotypic. On the other hand, the memory phenotype of mesial TLE as it manifests on semantically-loaded and
linguistically complex tasks (Giovagnoli et al., 2005), is likely to
be more distal. It is suggested here that the acquisition of arbitrarily contiguous items is usefully conceptualized as an internal
neurocognitive marker of dysfunction in rhinal cortex and rhinalhippocampal interface. The immediate impact of this conceptualization lies in pre-surgical diagnosis, leaving open the possibility
that it might turn out to be a candidate endophenotype in familial
temporal lobe epilepsies.
Arbitrary association in
non-verbal memory: is there
a neurocognitive marker for
right mesial temporal foci?
Defining cognition in terms of what is thought to be absent
(‘non-verbal’) opens up a large and heterogeneous category containing a multiplicity of memory functions relating to perceptual,
spatial, facial, musical or social and emotional domains. It is commonly observed that the nexus between right temporal foci or
resections and non-verbal memory is not as consistent as that
between left temporal damage and verbal memory (Bell and
Davies, 1998). This comment is usually made in relation to
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visuospatial forms of non-verbal memory, the domain most frequently studied in patients with TLE. The material-specificity perspective makes a series of implicit assumptions about spatial
memory which mirror those relating to verbal memory. The
most obvious of these is that the domain is unitary, leading to
the expectation that almost any test of spatial memory will be
sensitive to right temporal lobe damage. This, however, is clearly
not the case, and a number of standard tests of visuospatial
memory, commonly used in evaluation of TLE, do not reliably
distinguish between left or right TLE (Lee et al., 2002;
McConley et al., 2008).
Since the formulation of the material-specificity model, a substantial neuroscience of spatial memory has emerged, pointing to
a multiplicity of dissociable components (Schacter and Nadel,
1991; Hartley et al., 2003; Bird and Burgess, 2008; Burgess,
2008; Doeller et al., 2008). At a neuronal level, hippocampal
‘place’ cells respond to the subject’s location, while parahippocampal cells respond to the landmark being viewed. Of particular
importance, the hippocampus contains ‘place–goal conjunctive’
cells, which appear to play a role in ‘associating goal-related contextual inputs with place’ (Ekstrom et al., 2003). Place cells are
thought to drive spatial recall by re-activating a widespread network representing geometric and featural aspects of environments, the position of objects within them, and self-motion or
path integration signals (Byrne et al., 2007). At an interhemispheric level, regional activity during way-finding through virtual
environments is not restricted to the right mesial temporal region:
in all likelihood, there is a dynamic interaction between left and
right temporal lobes, depending on task demands (Burgess et al.,
2002; Sommer et al., 2005; Treyer et al., 2005), and individual
levels of navigational ability (Hartley et al., 2003). The uptake and
recall of object location, however, is one component of spatial
learning and memory most consistently lateralized to the right
mesial temporal region (Burgess et al., 2002; Sommer et al.,
2005; Treyer et al., 2005; Doeller et al., 2008).
Despite some bilateral findings (Glikmann-Johnston et al.,
2008), performance on object-location tasks tend to be selectively
impaired in patients with right mesial temporal foci (Abrahams
et al., 1997, 1999; Bohbot et al., 1998), with circumscribed thermocoagulation lesions to the hippocampus or parahippocampal
cortex for the relief of mesial temporal seizures (Bohbot et al.,
1998; Stepankova et al., 2004), or after temporal lobe resection
(Smith and Milner, 1981, 1989; Pigott and Milner, 1993; Nunn
et al., 1998, 1999; Crane and Milner, 2005; Parslow et al., 2005;
Diaz-Asper et al., 2006). Interestingly, Diaz-Asper’s study showed
that right lateralization applied only to object location in 3D, but
not 2D displays, the latter task being impaired irrespective of side
of resection. Similarly, in a post-amygdalohippocampectomy study
object-location memory, assessed within a two-dimensional frame,
was found to be worse after left-, rather than right-sided surgery
(Kessels et al., 2004). This pattern of findings suggests the
existence of task-specificity within the object-location paradigm.
Further evidence of fractionation in object-location learning comes
from the finding that lateralization at a mesial temporal level might
depend or whether location or identity of the object is the more
salient component: detection of changes in location causes right
mesial temporal activation in normals, while detection of changes
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| Brain 2009: 132; 570–582
in the nature of the object activates the left mesial temporal region
(Treyer et al., 2005).
The question of specialization within the right mesial temporal
region is raised by the finding that performance on a human analogue of the Morris water maze is selectively impaired in patients
with right posterior parahippocampal lesions (Bohbot et al., 1998),
but is preserved in HM, whose resection did not include this
region (Bohbot and Corkin, 2007). It is possible that parahippocampal cortex represents the geometric properties of the environment (Epstein and Kanwisher, 1998; Burgess et al., 2002; Bird
and Burgess, 2008). Interestingly, thermocoagulatory damage
to right parahippocampal or right perirhinal cortex does not
increase object-place association deficits induced by ipsilateral
hippocampal damage (Stepankova et al., 2004). Object–object,
and face–face associative learning, however, was heavily influenced by the extent of anterior parahippocampal lesions in left
and right temporal lobe resections for the treatment of TLE
(Weniger et al., 2004).
The discovery of ‘grid cells’ in the entorhinal cortex (Hafting
et al., 2005) is a potentially important step in appreciating
mesial temporal specialization for spatial memory in patients
(Philbeck et al., 2004). These cells compute positional information
independent of external spatial context, and are responsive to
self-motion or ‘path integration’ cues (proprioceptive, vestibular,
movement generated re-afference). Philbeck et al. (2004) demonstrated path integration deficits in patients who had undergone
right anterior temporal lobectomies. The deficit was manifested
as a tendency to overshoot during locomotion towards a previously seen target with vision excluded. The overshoot errors
were not explained by a misperception of the target’s position.
In summary, the complexity of spatial memory and its cerebral
representation poses another difficulty for the material-specific
hypothesis in its strong form. While some components of the
domain are more sensitive to right than left temporal lobe
damage (Kessels et al., 2001), the underlying neurocognitive
architecture remains elusive, and the left temporal lobe also
appears to play a significant role in many spatial memory tasks.
With the aim of developing an associative marker of right mesial
temporal pathology, Wilson and Saling (2007) studied the ability
of patients with right or left mesial temporal epilepsy to learn
musical paired associates, constructed to mimic the arbitrary
(‘hard’) and semantically related (‘easy’) paradigm in verbal
paired associates. Each member of an easy pair consisted of a
three note tonal motif constructed around the tonic and dominant
chords of C major. Motifs comprising the hard pairs did not conform to a conventional scale, resulting in an unfamiliar novel and
non-tonal pattern. While the relationship between paired tonal
items is not directly analogous to the predicative, categorical or
antonymic relations in easy word pairs, they nevertheless occur
within a common tonal framework, which is available as a preexisting support for learning. The acquisition of the hard pairs, on
the other hand, is unsupported by a conventional musical framework. Learning was assessed by means of a recognition paradigm.
The right mesial TLE group was impaired on easy musical pairs,
while the left mesial TLE group did not differ from patient
controls. Both groups, however, were impaired on the hard
musical pairs, the left mesial TLE patients faring somewhat
M. M. Saling
worse. The right lateralized component is an inability to make
use of a tonal framework to support learning, and might constitute
a promising marker of right mesial temporal pathology. Like
the verbal and spatial domains, lateralization is task- rather than
material-specific (Wilson and Saling, 2007). Crucially from a diagnostic point of view, the co-occurrence of verbal and non-verbal
memory impairments in left TLE should not be surprising, and
should not in itself raise the question of amnesia.
The verbal memory syndrome
of left TLE
Figure 1 summarizes the model proposed here. For practical clinical purposes, a two component left temporal model of verbal
memory can be defined: a mesial protosemantic component, operationalized as arbitrary paired associate learning and a lateral
semantic component, operationalized as performance on tasks
that are meaningfully structured, or on which semantic structure
can readily be imposed (related paired associates, word lists, passages). These components are dissociable. The pattern of verbal
memory impairment in patients with left mesial temporal foci consists of impaired acquisition of semantically unrelated word pairs,
with relative preservation of semantically structured forms of
verbal learning.
Preserved verbal memory function on preoperative assessment
is a well-established risk factor for decline after left temporal
lobectomy. This principle has been built around a conventional
neuropsychological armamentarium, consisting of tasks with varying degrees of semantic loading, many of which are explicitly
related to measures of verbal intelligence. The postoperative
decline in patients with mesial temporal atrophy is, not surprisingly, a change in semantically based function imposed by resection of relatively normal neocortex in anterior temporal lobectomy.
To the extent that mesial temporal epileptogenic pathology is
present, however, arbitrary relational learning is highly likely to
be impaired. Cases with the best psychometrically defined
memory outcome are those with impaired preoperative memory
across both components. Neurologically, these are most likely to
have mesial temporal pathology, and secondary damage to neocortical tissue or subjacent white matter. It is, therefore, not so
much a matter of reduced hippocampal adequacy, as reduced
temporal lobe adequacy. Conversely, cases at greatest risk for
memory change are those with late onset seizures, no evidence
of structural pathology, and who are normal across arbitrary and
semantic components of memory function.
Memory after temporal lobe
resection
Amnesia is a rare postoperative memory complication. The
number of patients known to have become amnesic after a unilateral temporal lobectomy is small (Baxendale, 1998; Kapur and
Prevett, 2003), and all are likely to have had undetected bilateral
mesial temporal damage prior to surgery. A recent survey showed
Verbal memory in epilepsy
Figure 1 Diagrammatic representation of the left inferior
temporal region extending from inferior temporal cortex
(ITC) laterally to the hippocampal complex (HC) medially.
(A) Summary of mediolateral specialization underlying verbal
memory. Rhinal-hippocampal cortices are involved in the
uptake, temporary retention and processing of protosemantic
conjunctions (blue shading). Incoming associations are
represented in perirhinal cortex, and compared with
pre-established semantic representations in ITC (red lines).
Unfamiliarity, mediated by rhinal gating mechanisms,
determines the likelihood of hippocampal involvement
(broken blue line). (B) Mesial temporal sclerosis (dark green
speckled shading) and epileptogenesis impairs rhinal memory
mechanisms, resulting in degraded representation of arbitrary
linkages, inefficient attribution of familiarity (broken green line)
and impaired rhinal-hippocampal transaction (black broken
line). Learning and memory are heavily dependent on
top-down semantic input from ITC and other neocortical
systems (thick green line). CS = collateral sulcus;
ERC = entorhinal cortex; HC = hippocampus; ITC = inferior
temporal cortex; AM = association module.
Brain 2009: 132; 570–582
| 577
that there are no reports of cases of postoperative amnesia with
presurgical neuroimaging evidence of a normal contralateral temporal lobe (Baxendale et al., 2008b). The bi-temporal model of
amnesia therefore remains an important concept in pre-surgical
decision-making, and patients with pre-surgical neuroimaging evidence of bilateral damage should always be considered to be at
an elevated risk of an amnestic syndrome (Baxendale et al.,
2008b). Recent findings (Bohbot and Corkin, 2007) suggest that
conceptualizing amnesia within the framework of materialspecificity theory, by defining it as a material non-specific phenomenon, could lead to the counter-clinical conclusion that not
even HM is amnestic. Bohbot and Corkin found that HM is capable of rapid place learning on a human analogue of the Morris
water maze despite his well-documented bilateral mesial temporal resection. The neuroanatomical basis of HM’s preserved place
learning lies in the preservation of his right posterior parahippocampal cortex, on which this task depends (Bohbot et al., 1998).
This example makes it clear that while a ‘general’ or ‘material
non-specific’ memory impairment might be seen in patients with
severe amnesia, this is not invariable. More importantly, material
non-specific impairments do not constitute a sufficient condition
for the diagnosis of amnesia.
Cases with left mesial temporal seizures, congruent MTS, but
apparently normal verbal memory (Loring et al., 2004), reveal a
pivotal distinction between the material-specificity approach and
the view presented here. In conventional approaches to neuropsychological assessment semantic aspects of verbal memory are
over-represented, or conflated with arbitrary forms. The net result
is reduced sensitivity to mesial damage. When arbitrary and
semantic forms are considered separately, however, patients with
well circumscribed left MTS exhibit a differential pattern, characterized above as the verbal memory syndrome of left mesial TLE.
The clinical relevance of this formulation is illustrated by a less
frequent, but no less important presentation characterized by
well defined left hippocampal sclerosis, but normal arbitrary and
semantic forms of verbal memory. Contrary to the principle that
high (putatively left) hippocampal adequacy leads to postoperative verbal memory decline, these patients are more likely to
retain their memory function at preoperative levels. We have
recently assembled a cohort representing 3% of patients seen
in the Comprehensive Epilepsy Program at Austin Health,
Melbourne. Since the arbitrary associative marker is normal,
early re-organization of verbal memory at a fundamental level
is implied.
The verbal memory syndrome of left mesial TLE also provides a
clearer understanding of the memory effects of anterior temporal
lobe resections intended to spare hippocampus. We studied two
cases who underwent anterior temporal resections, one for an
anteromesial dysembryoplastic neuroepithelial tumour involving
the left amygdala (Case #1), and the other for a ganglioglioma
in a similar location (Weintrob et al., 2007). Verbal memory
was entirely normal preoperatively. Both resections involved the
ento and perirhinal cortices, impinging as well on the anterior
2–3 cm of the temporal neocortex, but sparing the hippocampus.
At a 1 month postoperative review acquisition of unrelated
paired associates was severely impaired, with an accompanying
impairment of list learning. Related verbal paired associates
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| Brain 2009: 132; 570–582
were unaffected. At the 12-month review, performance on unrelated pairs showed no recovery, despite a return of list learning to
normal levels. Two control cases whose resections did not involve
ento or perirhinal cortex retained their ability to learn unrelated
paired associates. Since publication of these findings, Case #1 has
been re-assessed, 7-years post-resection and continues to show a
selective impairment of arbitrary word pairs, able to learn only
17% of unrelated paired associates, compared with a control
value of 61%. This finding provides converging evidence for the
model proposed here by showing that the mesial temporal
memory syndrome can be replicated by anterior temporal resections that do not involve hippocampus.
M. M. Saling
long-term study of the functional significance of postoperative
psychometrically defined memory status has yet to be done.
There is also a growing awareness that treatment resistant TLE
is associated with progressive memory change (Helmstaedter and
Elger, 1999; Jokeit and Ebner, 1999; Pitkanen and Sutula, 2002;
Helmstaedter et al., 2003; Dodrill, 2004; Hendriks et al., 2004;
Hoppe et al., 2006; Seidenberg et al., 2007; Hermann et al.,
2008). Seizure load appears to be the major risk factor
(Thompson and Duncan, 2005). Poor seizure outcome after unilateral temporal lobe resection might therefore set up a double
jeopardy (Helmstaedter et al., 2003), and Baxendale has suggested that poor seizure control in cases with bitemporal pathology poses a lifetime risk of amnesia (Baxendale, 2007; Baxendale
et al., 2008b).
Predicting post-surgical
memory outcome
Conclusion
Until recently, the Wada technique was regarded as the ‘gold
standard’ for estimating the risk of postoperative amnesia. Since
1993, when the first international survey was conducted, routine
use of the Wada has declined dramatically (Baxendale et al.,
2008a). The Wada also gained ‘gold standard’ status for evaluating lateralized material-specific memory outcomes. Recent
predictive studies, however, show that baseline neuropsychological evaluation, structural imaging and neuropathology are
effective predictors of quantitative postoperative memory status
(Baxendale et al., 2006), with the Wada making little or no independent contribution (Chelune and Najm, 2000; Stroup et al.,
2003; Lineweaver et al., 2006).
Predictive models such as these have come to play a role in
pre-surgical counselling providing an empirical base for informed
consent. While actuarial models might be helpful in meeting an
immediate management issue, they yield a short term quantitative end-point with an unknown relationship to subjective and
adaptive aspects of postoperative memory function (Ferguson
et al., 2006), or to neurocognitive changes that evolve over the
long term.
Even in cases with good seizure outcomes, adjustment difficulties have the potential to bring increased salience to stable postoperative memory dysfunctions. Contrary to the expectation that
postoperative seizure freedom should result in optimal quality of
life, it can provoke a burden of normality, manifesting as a complex trajectory of now well documented adjustment difficulties
(Wilson et al., 2001, 2004). Psychometric memory findings
account for little of the inter-individual variation in subjectively
perceived or ecologically significant memory outcomes (Sawrie
et al., 1999; Lineweaver et al., 2004; Baxendale and Thompson,
2005). Minor psychometrically defined memory dysfunction might
be amplified over time by adverse seizure outcome or ageing,
pre-existing psychological vulnerabilities, distorted metamemory
perspectives, newly emerging anxiety and depression, memory
demands of individual ecological niches, adjustment difficulties or
the absence of neuropsychological support. Conversely, a more
significant psychometric impairment might not manifest as a
significant disability if these settings are optimized. A definitive
Despite its simplicity, the idea of material-specificity came to dominate neuropsychological practice in temporal lobe epileptology,
offering a monolithic diagnostic strategy, an operational definition
of amnesia, a framework for assessing the cognitive risks associated with epilepsy surgery and understanding postoperative outcomes, and a rationale for deploying the dominant psychometric
paradigm of the day. With advances in the cognitive neuroscience
of memory, the application of theoretically driven paradigms to
the problem of memory function in focal epilepsies, and a broader
understanding of the course of postoperative recovery, the notion
of material-specificity has become too restrictive on a number of
levels.
Material-specificity achieves parsimony by assuming two
‘mirror-image’ categories of memory distinguished on the basis
of (i) presence or absence of words; (ii) fully lateralized to the
left or to the right; and (iii) associated more closely with audition in the case of verbal memory and vision in the case of nonverbal memory. Reviews within the field have drawn attention to
the tighter verbal-left temporal nexus, encouraging a continued
search for a form of non-verbal memory that exhibits equal but
opposite properties of lateral representation. Studies reviewed here
strongly suggest that verbal and non-verbal memory are not
opposites in terms of their respective patterns of cerebral organization, and at complex levels of expression neither are fully
lateralized. This has obvious implications for neuropsychological
approaches to a mesial temporal disorder that commonly manifests as a lateralized phenomenon. For instance, the definition of
amnesia as a material non-specific impairment loses meaning,
because a left mesial temporal focus is capable of affecting
aspects of non-verbal, as well verbal memory. Similarly, with the
use of discourse-based tasks, a right mesial temporal focus might
also exert a material non-specific, or even a purely verbal effect
on the assessment instrument.
I argue that neuropsychological practice in epileptology needs to
incorporate an approach that recognizes the relationship between
lateral and intratemporal specialization, on one hand, and the
neurocognitive structure of its assessment techniques. This is particularly important at a preoperative level, where questions of
congruity, anomalous organization or re-organization of memory
Verbal memory in epilepsy
functions arise. Butler and Zeman (2008) point out that the insensitivity of standard memory tests poses a challenge to current
theoretical models. In terms of the view presented here, insensitivity of standard memory tasks to mesial temporal foci arises
from the conflation of differentially represented components.
Effective neuropsychological markers of lateralized mesial temporal dysfunction are likely to be elemental and fundamental
aspects of the function, ideally stripped of associations with
general intellectual function, or complex expressions that are
now known to be bilaterally represented. The rapid uptake of
co-occurrences, devoid of a previously represented connection,
are fundamental to the construction of episodic and semantic
memories, and associative paradigms based on this principle are
promising candidate markers of lateralized mesial temporal dysfunction, as are paradigms based on retro-active interference,
path integration or music tonality. With the advent of sophisticated neuroimaging, the anatomical distribution of epileptogenic
pathology can be characterized in vivo, as can the boundaries
of surgical resection. Correspondingly, concepts of intratemporal
specialization should assume a prominent position in neuropsychological practice.
While the principle of material-specificity receives its strongest
support at a postoperative level, the broader issues of distress
associated with subjective memory symptomatology and the functional impact of memory disability assume greater prominence.
The medium and long-term implications of psychometrically
defined changes in memory for real world functional capacities
are not known. Current evidence does suggest that optimal
memory outcomes are intimately dependent on seizure relief,
and in all likelihood, successful management of the psychosocial
vicissitudes that often follow surgical treatment.
Acknowledgements
I am indebted to the following members of the Comprehensive
Epilepsy Program at Austin Health, Victoria, Australia for their
constructive comments and criticisms of the ideas contained in
this article: Professor Samuel Berkovic, FRS; Dr Peter Bladin, AO;
Professor Graeme Jackson; Associate Professor Sarah Wilson;
Dr David Weintrob; Dr Marie O’Shea; Dr Leasha Lillywhite;
and Professor David Reutens, Queensland Brain Institute, The
University of Queensland, Australia.
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