154 | MARCH 2011 | VOLUME 7
Section, University of
Wisconsin School of
Medicine and Public
Health, 600 North
Madison, WI 53792,
USA (B. Bell,
Neurology, University of
105 Irvine Hall, Irvine,
CA 92697–4275, USA
(J. J. Lin). Department
of Psychology Rosalind
Franklin University of
Medicine and Science,
3333 Green Bay Road,
IL 60064, USA
The neurobiology of cognitive disorders
in temporal lobe epilepsy
Brian Bell, Jack J. Lin, Michael Seidenberg and Bruce Hermann
Abstract | Cognitive impairment, particularly memory disruption, is a major complicating feature of epilepsy.
This Review will begin with a focus on the problem of memory impairment in temporal lobe epilepsy (TLE). We
present a brief overview of anatomical substrates of memory disorders in TLE, followed by a discussion of
how our understanding of these disorders has been improved by studying the outcomes of anterior temporal
lobectomy. The clinical efforts made to predict which patients are at greatest risk of experiencing adverse
cognitive outcomes following epilepsy surgery are also considered. Finally, we examine the vastly changing
view of TLE, including findings demonstrating that anatomical abnormalities extend far outside the temporal
lobe, and that cognitive impairments extend beyond memory function. Linkage between these distributed
cognitive and anatomical abnormalities point to a new understanding of the anatomical architecture of
cognitive impairment in epilepsy. Clarifying the origin of these cognitive and anatomical abnormalities, their
progression over time and, most importantly, methods for protecting cognitive and brain health in epilepsy,
present a challenge to neurologists.
Bell, B. et al. Nat. Rev. Neurol. 7, 154–164 (2011); published online 8 February 2011; doi:10.1038/nrneurol.2011.3
Epilepsy is a prevalent neurological disorder affecting an
estimated 50 million people worldwide.1 This condition is
defined by the presence of recurrent seizures, although it
can also adversely influence several aspects of daily func-
tion leading to comorbidities in cognition, emotional–
behavioral status, and social adaptive behaviors. At the
2007 conference sponsored by the National Institutes of
Neurological Diseases and Stroke (Curing Epilepsy 2007:
Translating Discoveries into Therapies), the prevention and
reversal of the comorbidities of epilepsy were identified as
major new benchmark areas for research.2
Cognitive impairment is a major concern for patients as
well as clinicians. A survey of 1,023 patients with epilepsy
in two community-based samples revealed that cognitive
problems (such as memory, concentration, ability to think
clearly) were viewed as the most important complications
associated with the disorder.3
Critical reviews over the decades have catalogued the
links between cognitive disorders and specific clinical
features of the epilepsies including their etiology, seizure
frequency and severity, complications of the disorder
(such as status epilepticus), antiseizure medications,
emotional complications (such as depression), and
electro encephalographic abnormalities (such as the type,
frequency and distribution of interictal epileptiform and
slow wave activity).4–9 We will critically review this topic
against this extensive background.
In this Review, we will focus on arguably the most
problematic of the comorbidities of epilepsy—cognitive
impairment. We focus specifically on temporal lobe epi-
lepsy (TLE), the most common form of focal epilepsy. The
cognitive complications of epilepsy can be hetero geneous,
affecting diverse abilities such as language, attention, and
higher-level problem solving skills, although episodic
memory impairment—a signature cognitive deficit in
TLE—is especially problematic. We will focus initially on
memory impairment in epilepsy, examining the effects of
surgical treatment of epilepsy on this cognitive system, and
conclude with a review of recent insights into the under-
lying neuro biology of TLE and the implications of these
findings for cognition and future research.
Epilepsy and memory: early insights
The first empirical studies of cognition in epilepsy were
published in the early 1900s, with a focus on the relation-
ship between intelligence and the clinical characteristics of
the epilepsy (such as age of onset and seizure frequency).10,11
As methods of assessment and knowledge of human cogni-
tion developed, interest in specific abilities such as memory
ensued. Understanding of the neurobiological processes of
disordered cognition and memory in epilepsy was accel-
erated by the development of epilepsy surgery programs.
An important aspect of the early surgical centers was the
inclusion and participation of research neuropsychologists,
including Donald Hebb and Brenda Milner at the Montreal
Neurological Institute, Canada, Ward Halstead at the
University of Illinois in Chicago, USA, and Victor Meyer
at the Guy’s–Maudsley Hospital in London, UK.12–16 These
clinical investigators assessed patients before and following
neurosurgical intervention, leading to the initial insights
into the effects of surgery on cognition.
The authors declare no competing interests.
© 2011 Macmillan Publishers Limited. All rights reserved
NATURE REVIEWS | NEUROLOGY
VOLUME 7 | MARCH 2011 | 155
The earliest surgeries for TLE, performed by Penfield
and Jasper in Montreal, and Bailey and Gibbs in Chicago,
largely avoided the hippocampal complex, in part because
of the results of animal experiments carried out by Kluver
and Bucy,14 which demonstrated the deleterious behav-
ioral consequences of bilateral temporal lobe resection.
The mesial temporal structures were, however, later found
to be critically involved in the epileptogenic network, and
in 1952 Penfield and Baldwin advised the removal of the
“the deepest, the most inferior and mesial portion” of
the temporal lobe,13,17 which became an accepted approach
from the 1950s.18 At the Annual Meeting of the American
Medical Association in 1950, Hugh W. Garol stated, during
discussion of a presentation by Bailey and Gibbs, that the
temporal lobe was involved with “many known functions”,
including hearing and sight, whereas the mesial aspect
involved “a host of unknowns.”19
As resection of the mesial temporal structures became
standard practice, the principal function of the hippo-
campus was elucidated16,20,21 owing to two factors. The
first was the unanticipated global amnesia experienced
by a small number of patients following surgery. Milner
and Penfield22 described two individuals who experienced
a severe recent-memory impairment following unilateral
temporal lobectomy. They hypothesized that these patients
had previously undetected, contralateral, nonsurgical
damage in the hippocampus, and the effect of resection of
the ipsilateral epileptogenic hippocampus was to produce
bilateral hippocampal damage. Consistent with this pro-
posal, the serious memory consequences of bilateral tem-
poral lobectomy were reported a few years later. Scoville
and Milner23 presented the memory outcome findings for
their patient Henry Gustav Molaison (referred to as HM),
along with seven other patients, following bilateral tem-
poral lobe resection. Extensive anterograde memory loss
ensued with concomitant preservation of overall intellec-
tual functioning and language ability. This profile came to
be regarded as the prototypical presentation of an amnesic
syndrome produced by bilateral temporal lobe damage.
Extensive study of HM over the next 50 years produced
important insights into the role of the hippocampus and
temporal lobe for memory, and provided a conceptual
framework for understanding the neural architecture of
diverse memory systems.24
The second factor underlying the elucidation of hippo-
campal function was the less severe but common problem
of memory decline following unilateral anterior tempo-
ral lobectomy (ATL).25,26 Milner27 described “material-
specific” memory difficulties, the clearest examples of
which were said to occur in patients with left TLE, in
whom verbal memory could be impaired before surgery
and became persistently worse afterwards, whereas so-
called non verbal memory was less affected before and after
surgery. A corresponding, if less robust, selective vulner-
ability to nonverbal memory impairment characterized
patients with right TLE and temporal lobectomy.
The influence of this early work was profound, and
early insights, including the material-specific model of
memory, served as a foundation for research and practice
far outside the narrow field of epilepsy and epilepsy surgery,
■ Episodic memory impairment is a key feature of temporal lobe epilepsy (TLE)
■ Examination of patients following epilepsy surgery has contributed substantially
to our understanding of the neuroanatomy of human memory
■ Wide variability is observed in the effects of anterior temporal lobectomy on
postoperative memory function
■ Understanding the cause of this variability has improved our ability to identify
patients at greatest risk of adverse cognitive outcomes
■ Cognitive morbidity in TLE can extend beyond memory function, and anatomical
abnormalities can extend far beyond the temporal lobe
■ Distributed cognitive abnormalities are being linked to anatomical
abnormalities outside the temporal lobe, providing a new neurobiological
understanding of the neuropsychology of TLE
influencing generations of investigators. Our refined under-
standing of memory change resulting from epilepsy and its
surgical management is discussed in detail below.
Memory change following surgery
Approximately 30–60% of patients who undergo left
(speech dominant) ATL experience a substantial decline
in verbal memory ability after surgery.21,28–32 Despite this
robust trend, a persistent finding has been variability in
memory outcome following a standard surgical approach
(Figure 1).33 On average, verbal memory outcome is
worse after left ATL than after right ATL, although many
patients who undergo left ATL show no change or might
even show post operative improvement. By contrast, right
16–20 11–15 6–10
Change in total words recalled from preoperative to postoperative assessments
Number of patients
Number of patients
1–5 ≥2116–20 11–15 6–101–50
Figure 1 | Variability in verbal memory change following left and right anterior
temporal lobectomy. Preoperative to postoperative changes in verbal learning
performance (total words recalled on California Verbal Learning Test) in 100
patients who underwent left or right anterior temporal lobectomy. The dependent
variable is the number of words recalled from a 16-item word list across five
learning trials. Abbreviation: ATL, anterior temporal lobectomy.
© 2011 Macmillan Publishers Limited. All rights reserved
156 | MARCH 2011 | VOLUME 7
ATL patients show postoperative improvement in verbal
memory on average, but some exhibit decline. Similar
variability for visual memory change following right ATL
has also been reported, although this effect is much less
robust.34 Determining the factors that underlie this vari-
ability has been a critical issue when determining the
suitability of ATL for treating patients with chronic TLE
and in developing presurgical protocols to assess the risk
of adverse memory outcome following surgery.
Factors affecting memory outcome
Assessment issues and implications
One source of outcome variability relates to the hetero-
geneity of memory tests employed. As critically reviewed
by Saling,35 list learning, paragraph recall, and forming
of associations between related and unrelated word
pairs differ in their semantic demands and the associ-
ated underlying neural systems required for successful
task performance and should not be considered to be
equivalent measures of ‘verbal memory’. Even within
similar types of list-learning tasks, differences exist in
semantic relationships among the words that are used as
stimuli, thereby contributing to different sensitivities to
left temporal lobe dysfunction.36–38
Another possible cause of variable memory outcome
was suggested by studies of the relationship between pre-
operative memory performance and the neuropathological
status of the resected hippocampus. Rausch et al.39 found
that a greater degree of neuron loss in the left hippo campus
was associated with poorer pre operative performance on
an unrelated word paired-associate learning task, while
less neuron loss was associated with better verbal memory
performance. Similar findings were reported by others.40,41
Given this relationship, a reasonable expectation was that
the integrity of the to-be-resected hippocampus would
predict the risk of postoperative memory change, the risk
being greatest in those with less hippocampal cell loss and,
presumably, a more functionally intact hippocampus. This
assumption was upheld by findings from studies in the
early 1990s, which confirmed that the risk of post operative
memory decline was associated with the structural integrity
(or lack thereof) of the to-be-resected hippocampus.42–45
That is, verbal memory decline was less when the resected
left hippocampus was found to exhibit moderate to marked
sclerosis, while substantial verbal memory decline was
associated with resection of left hippocampus found to
contain minimal sclerosis. The memory decline in patients
found to have a minimally sclerotic left hippocampus can
be quite substantial. Figure 2 depicts the degree of change
in rote verbal list learning performance that was appar-
ent following resection of a left hippocampus in patients
with minimal or no sclerosis (bottom curve) compared to
patients with a left hippo campus with moderate to severe
sclerosis (top curve).
In a major theoretical paper, Chelune28 in tegrated find-
ings from studies examining memory outcome following
surgery and proposed a new model to understand the risk
of preoperative to postoperative memory decline. The
classic functional reserve model emphasized the status
of the contralateral nonsurgical hippo campus. An intact
contralateral hippocampus capable of subserving memory
could offset the effect of resection of the ipsilateral (surgi-
cal) hippocampus. This model was compared with a new
model of ipsilateral functional adequacy, which implied
that the functional status of the surgical hemisphere and
hippocampus before surgery was critical in predicting
memory outcome. Individuals with a more intact hippo-
campus were at greater risk of memory decline because
relatively functional tissue had been removed. A wide
range of findings have been found to be consistent with
the hippocampal adequacy model, and these findings will
be reviewed immediately below. In addition, theoretical
insights into human hippocampal function have resulted
from examination of patients following ATL (Box 1,
Figure 3). The data in Box 1 and Figure 3 do not all relate
to Chelune’s theoretical formulation.
Predicting memory outcome
The Wada test
In response to the concern about producing severe global
memory impairment following unilateral ATL, Milner
et al.46 developed intracarotid amobarbitol testing as a
means of assessing the memory ability of the contra-
lateral hemisphere. The test, developed by Juhn Wada,47
was already used to determine language dominance, and
this approach was extended to assessment of memory
ability before surgery. The Wada test provides an oppor-
tunity to assess the functional status of both the ipsilateral
and contralateral hippocampus independently through
transient hemispheric anesthesia.
Trial 2Trial 3
Left hippocampus with no or minimal sclerosis
Left hippocampus with significant hippocampal sclerosis
CVLT postoperative change (%)
Trial 4 Short
Figure 2 | Verbal memory change following left anterior temporal lobectomy in
relation to hippocampal pathology. Resection of left hippocampus with no or minimal
sclerosis results in significant preoperative to postoperative decline in trial-to-trial
learning. Long-delay recall is ≈35% lower compared with preoperative performance.
Resection of left hippocampus with significant hippocampal sclerosis has a minimal
effect on postoperative trial-to-trial learning compared to preoperative performance.
All patients were confirmed to be left hemisphere speech dominant by the Wada
test. Abbreviation: CVLT, California Verbal Learning Test.
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NATURE REVIEWS | NEUROLOGY
VOLUME 7 | MARCH 2011 | 157
The presence or absence of a marked memory asym-
metry score—defined as the accuracy of memory perfor-
mance in the ipsilateral or to-be-resected hippocampus
compared with accuracy of memory performance in the
contra lateral hippocampus—is a clear predictor of verbal
memory outcome following left ATL.48–51 Preoperative
Wada test memory asymmetry (impaired ipsilateral
and intact contralateral memory) has been found to be
positively associated with side of ictal EEG onset,52 hippo-
campal atrophy on MRI,53,54 and neuronal loss in the
resected hippocampus.41 This relationship is, however,
possibly affected by atypical language representation,55–57
the types of memory stimuli used,58 and the type of neuro-
psychological memory outcome measure employed; for
example, list-learning versus prose-recall change.59 The
Wada test has been less useful for predicting nonverbal
memory outcome following right ATL,60 partly owing to
difficulties associated with finding measures of memory
that are linked to a consistent right-hemisphere effect.61,62
Age of onset of recurrent seizures
Several studies have identified age at recurrent seizure onset
to be a predictor of ATL memory outcome. Earlier age at
seizure onset is associated with poorer memory before
ATL but less decline after ATL, while onset of epilepsy in
later life is associated with better pre operative memory and
a greater postoperative decline.63 These trends are probably
a result of the increased likelihood of hippo campal pathol-
ogy associated with earlier onset of epilepsy,64 which, in
turn, is related to functional adequacy.
Preoperative memory performance
Patients displaying better preoperative memory per-
formance show greater decline in memory following
ATL,33,65 reflecting the association with the degree of
hippocampal sclerosis—less underlying sclerosis is
associated with better preoperative performance and,
thus, greater risk of postoperative decline. TLE patients
without hippocampal sclerosis are likely to have a func-
tional hippocampus that subserves stronger presurgical
memory performance. Resection will remove functional
tissue, leading to substantial memory decline.
The advent and refinement of neuroimaging techniques
including MRI, PET and functional MRI (fMRI) over the
past 20 years has provided a new opportunity to identify
alternative approaches for predicting memory outcome
following ATL.66 Absence of hippocampal atrophy on
MRI is associated with better pre-ATL verbal memory
performance and greater preoperative to postoperative
verbal memory decline.67,68 A few studies have examined
preoperative to postoperative memory change using
18F-fluorodeoxyglucose PET (FDG-PET). Griffith et al.69
found that an absence of preoperative left temporal lobe
hypometabolism was associated with poorer verbal
memory outcome following left ATL. A study published
in 2009, however, failed to find an appreciable relation-
ship between preoperative FDG-PET hippo campus
asymmetry and memory outcome.70
The rationale underlying the use of fMRI is that the
degree of presurgical hippocampal task activation reflects
the functional adequacy of the structure. Richardson
et al.71 showed that during a verbal encoding task, left TLE
patients with ipsilateral hippocampal sclerosis demon-
strated less activation in the region of the left hippocampus
than did nonsurgical control individuals. In 2010, Bonelli
et al.72 reported that increased left hippocampal activity in
individuals with left TLE was associated with better pre-
surgery memory performance and greater decline after
ATL, as measured by a word-list learning task. In patients
with right TLE, increased right hippocampal activity on
a face-encoding task before surgery was associated with
better presurgical memory performance when learning a
set of designs, and with increased memory decline follow-
ing ATL. Recent evidence raises the interesting possibil-
ity that hippo campal activation might not necessarily be
the best verbal memory outcome predictor, as language
laterali zation proved superior to scene encoding in a large
and carefully investigated series.73,74
With regard to fMRI, multiple methodological issues
remain to be resolved, including the optimal activation
tasks to use, which fMRI activation measure is the best
predictor, the influence of hippocampal pathology,
and the predictive incremental value of fMRI activity
in relation to other predictor variables.
Box 1 | Theoretical insights into hippocampal function
Careful preoperative to postoperative studies, particularly those relating cognitive
change to the neuropathological status of the resected hippocampus, provide
unique information about hippocampal function.
Serial position curve and human hippocampus
When presented with a supraspan list of words to learn and remember, people
tend to freely recall from the beginning (primacy) and end (recency) of the list, a
pattern termed the serial position curve. The primacy—and to some degree the
middle—portion of the list reflects secondary (or long-term) memory, while the
recency portion reflects primary or immediate memory. Resection of a minimally
sclerotic left hippocampus selectively affected the primacy and middle portions,
demonstrating reliance on the hippocampus, while the recency portion remained
unaffected, and was thus hippocampus independent (Figure 3).148
Retrieval or memory failure?
Inability to freely recall words following resection of nonsclerotic left hippocampus
could reflect difficulties in retrieving newly learned information, and recognition
testing via yes–no or multiple choice testing might normalize performance. In
addition, error patterns on presentation of both target words (words from the list)
and foils (non-list words) would be informative. If patients misidentified words
with certain attributes (semantic, phonological, prototypical), one would infer a
specific encoding contribution of the hippocampus. In reality, recognition testing
did not significantly facilitate performance, contradicting the retrieval hypothesis.
Moreover, resection of nonsclerotic left hippocampus selectively increased error
rates for semantically related words.149
Naming, hippocampus, and temporal neocortex
The hippocampus is traditionally viewed as having a time-limited role in memory
encoding, but recent findings indicate an ongoing role regarding visual object
naming. Resection of nonsclerotic left hippocampus leads to significant decline in
confrontation naming ability, with recall failures tending to affect words acquired
comparatively late in life,150,151 and different semantic categories showing
selective vulnerability. Studies highlight the importance of the temporal lobes
in recognition and naming of several object categories,10–13,152–155 while deficits
in recognition and familiarity judgment commonly occur following nondominant
anterior temporal lobectomy.156
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158 | MARCH 2011 | VOLUME 7
Many studies have examined the effect of a single predic-
tor in relation to memory outcome. More-informative
investigations involve a multivariate approach that makes
use of multiple, non-redundant sources of information.75
Stroup et al.76 reported that various factors, including
side of resection, baseline memory performance, extent
of hippocampal sclerosis and Wada test performance,
all provided independent information regarding predic-
tion of memory outcome. Lineweaver et al.77 found that
MRI volumes and baseline memory performance, but
not Wada test performance, were successful in predict-
ing memory outcome. Baxendale et al.78 also found that
preoperative memory level emerged as the most reliable
predictor of memory outcome when side of resection,
amount of cortical dysgenesis, chronological age, and IQ
were also entered into a prediction model.
Binder et al.79 examined 60 left ATL patients who under-
went preoperative language mapping with fMRI, preopera-
tive Wada testing for language and memory lateralization,
and preoperative and postoperative neuropsychological
testing. Demographic, historical, neuropsychological
and imaging variables were examined for their capacity
to predict preoperative to postoperative memory change.
The authors also used an interesting multivariate approach
in which the order of entry of the predictor variables to
predict verbal memory outcome following left ATL
was based on risk and cost. Verbal memory decline was
observed in >30% of patients. Good preoperative per-
formance, late age at onset of epilepsy, left dominance on
fMRI, and left dominance on the Wada test were all predic-
tive factors of memory decline. Preoperative performance
and age at onset, when taken together, accounted for ≈50%
of the variance in memory outcome. The fMRI language
index explained an additional 10% of the variance in pre-
dicting memory outcome,79 clearly suggesting its value in
predicting the risk of postoperative memory change.
Effects of surgical approach on memory outcome
Predictive models have not yet been standardized across
neurological centers, so currently each model applies
only to surgery as performed at the relevant reporting
center. Cross-center models are needed, but obtaining
suitable models is complicated by the fact that variations
in surgical approach might affect cognitive outcomes.
Growing clinical evidence documents the effects of
various surgical approaches to ATL and the variable cog-
nitive outcomes that might ensue,80 although one must
appreciate that the number of randomized clinical trials
comparing different surgical approaches is extremely small.
For example, Helmstaedter80 compared pre operative and
postoperative verbal learning and memory performance in
left TLE patients with hippocampal pathology who under-
went ATL or selective amygdalo hippo campectomy, as
well as patients with left lateral temporal lobe lesions who
underwent cortical lesionectomy. All three patient groups
exhibited similarly impaired preoperative verbal learning
and memory performance compared with control patients.
Postoperatively, long-term memory declines were similar
for the ATL and selective amygdalohippocampectomy
groups, but the ATL group also exhibited decline in new
verbal learning efficiency, presumably a result of resection
of the functional left lateral temporal neocortex. The left
cortical lesionectomy group showed minimal preoperative
to postoperative verbal learning and memory change.
Changing views of TLE
At the second Palm Desert International Conference on
the Surgical Treatment of the Epilepsies in 1993, focus was
placed on “surgically remediable syndromes”, among which
mesial TLE (MTLE) was prominent.81 This conceptualiza-
tion facilitated increasingly careful characterization of the
syndromes of localization-related TLE (MTLE, lesional
TLE, and so called MRI-negative, paradoxical or crypto-
genic TLE). The primary cognitive signature of MTLE
was viewed to be material-specific memory impairment,
demonstrated either through formal neuro psychological
assessment or the Wada test. A stated contraindication to
MTLE was the presence of generalized cognitive compro-
mise—all reasonable characterizations at the time.81 Later
studies examining the full range of cognitive abilities,
however, found that patients with neuro pathologically
confirmed MTLE exhibited a pattern of generalized cog-
nitive disruption—an unexpected finding.82 One pos-
sible explanation for the observed broad-based cognitive
impairment was that structural abnormality might also
extend beyond the confines of the mesial temporal lobe,
and that these extratemporal abnormalities could have
additional cognitive consequences.
Widespread anatomical abnormalities
In the 1990s, the examination of structural abnormalities
in people with MTLE was extended beyond the epilepto-
genic hippocampus. Using quantitative MRI tools that
Figure 3 | Change in the serial position curve following left anterior temporal
lobectomy as a function of left hippocampal pathology. a | Resection of left
hippocampus with no or minimal sclerosis results in significant preoperative to
postoperative alteration of the serial position curve with decreased recall of
primacy and middle portions of the list. b | Resection of left hippocampus with
notable hippocampal sclerosis has no effect on the serial position curve. The data
are derived from the patient’s free recall of a supraspan word list.
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NATURE REVIEWS | NEUROLOGY
VOLUME 7 | MARCH 2011 | 159
focused on manually delineated volumes to assess brain
size, investigators probed hippocampus-related structures
and found atrophy in the neocortical temporal lobes,67
entorhinal cortex,83,84 fornix,85 parahippocampal gyrus,84
and amygdala.84,86 Quantitative volumetric studies were
also applied to other subcortical structures, and showed
that abnormalities were present in the basal ganglia,87,88
thalamus,87,89,90 and cerebellum.91,92 These studies dem-
onstrated that anatomical abnormalities in MTLE were
not limited to the epileptogenic hippocampus. Early volu-
metric techniques, however, only permitted examinations
of one, or a limited number, of predetermined structures,
rather than simultaneously characterizing a broad range
of deficits throughout the entire brain.
The first glimpse of the distributed nature of struc-
tural abnormalities in MTLE came from Sisodiya and
colleagues.93 Instead of manually tracing structures with
defined borders, they divided each hemisphere into
blocks and quantified the amount of cortical gray matter
and white matter throughout the entire brain. Each ana-
tomical block from a patient with MTLE was compared
with normal controls to assess for disproportional dis-
tribution of gray and white matter. Most patients with
hippocampal sclerosis exhibited diffuse abnormalities
throughout the cerebral cortex, but the exact location
could not be elucidated with this technique.
With the emergence of automated analysis tools such
as voxel-based morphometry (VBM), the whole brain can
be scrutinized voxel by voxel in the same patient group
to more precisely localize brain regions that are affected
in MTLE. Unbiased examination of the entire brain has
enabled an appreciation of the distribution and relative
degree of structural burden carried by many patients.
In this regard, a helpful summary of the presence and
distribution of structural abnormalities associated with
TLE was provided by Keller and Roberts.94 The authors
summarized 18 VBM studies and found 26 brain regions
that showed reduced volumes in TLE compared with
healthy controls. The distribution of abnormalities was
widespread, involving mesial, extramesial temporal lobe,
subcortical and extratemporal lobe cortical regions.
Although VBM studies provided an anatomical profile
of the extent of abnormalities, the pathological nature of
these changes was uncertain.95 The apparent reduced gray
matter volumes found in VBM studies might reflect both
losses in gray matter and increases in cerebrospinal fluid
volume, as well as differences in cortical surface curva-
ture. These limitations provided the impetus to examine
changes in other brain features such as indices of gyrifi-
cation, cortical thickness, and surface area. Lin and col-
leagues examined cortical thickness in a group of MTLE
patients with pathologically confirmed hippo campal
sclero sis and found that these patients showed up to a
30% decrease in cortical thickness, with noticeable thin-
ning of frontal poles, frontal operculum, and orbito frontal,
lateral temporal and occipital regions (Figure 4a,b).96
Interestingly, reductions in cortical thickness were evident
in both cerebral hemispheres, despite unilateral seizure
onset.96 Other investigators have reported bilateral cor-
tical mantle thinning in select regions throughout the
entire cerebral cortex, but most consistently in the frontal,
central and temporal regions.97,98 Widespread abnormali-
ties in gyrification patterns were found in multiple cortical
regions—both ipsilateral and contralateral.96,99,100
In addition to gray matter abnormalities, aberrant white
matter tracts and connections are present in chronic TLE.
Diffusion tensor imaging (DTI) techniques have allowed
investigators to measure white matter tract integrity by
assessing the magnetic resonance signal of water diffusion.
The primary measure of white matter integrity is fractional
anisotropy (FA), which is determined by the directional
magnitude of water diffusion in three-dimensional space.
Tightly packed white matter fascicles provide structural
coherence, which result in water diffusion in a preferred
direction (high FA). By contrast, white matter fascicles that
have poor structural organization will allow water to diffuse
more randomly (low FA).101 Like early quantitative gray
matter volumetric studies, initial DTI studies focused on
the limbic system and found bilateral diffusion abnormali-
ties in the fornix and cingulum.102 Postulating on a diffuse
epileptogenic network in TLE, other investigations
extended this initial finding to frontal–temporal (uncinate
fasciculus and arcuate fasciculus),103–105 temporal–occipital
(inferior longitudinal fasciculus),106 frontal–occipital
(in ferior frontal occipital fasciculus)106 and interhemi-
spheric (corpus callosum) connections.107–109 More recently,
whole-brain voxelwise analysis techniques have mapped
white matter profiles and delineated systemic differences
between TLE patients and healthy individuals, without
a priori bias for specific tracts or brain regions.110 Focke and
colleagues111 used this technique to evaluate diffusion
abnormalities in patients with MTLE, and found that white
matter integrity, as measured by FA, was reduced in the
mesial and lateral temporal lobe, limbic system (thalamus,
fornix and cingulum), and extratemporal regions (arcuate
fasciculus, external capsule and corpus collosum). The
white matter changes were most pronounced ipsilateral to
the side of seizure onset (Figure 4c).111 Other studies have
also demonstrated extensive bilateral white matter diffu-
sion abnormalities, particularly in the temporal and frontal
lobes ipsilateral to the side of seizure onset.112–114
In summary, converging evidence indicates that while
the primary epileptic zone might be contained within
the confines of the hippocampus, considerable anatomi-
cal abnormalities exist outside this region, affecting a
myriad of cortical, subcortical and cerebellar regions and
their direct and indirect connectivity. The extent and
locations of these structural abnormalities might con-
tribute to individual probability of seizure freedom after
epilepsy surgery and help predict surgical outcome. A
recent study showed that TLE patients who were seizure
free following surgery had a more restricted pattern of
gray matter atrophy on their preoperative MRI, while
those who continued to have refractory seizures had
more-widespread gray matter deficits.115
Distributed cognitive impairments
In concert with the extensive anatomical abnormalities,
patients with MTLE exhibit a pattern of distributed cog-
nitive impairments, affecting not only memory, but also a
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160 | MARCH 2011 | VOLUME 7
broad array of cognitive areas including IQ, executive func-
tions, language and sensorimotor skills.82,116,117 A cumula-
tive literature has now emerged, linking structural changes
with cognitive performance. In the cortical regions of the
brain, specific one-to-one structural–functional asso-
ciation in TLE is sparse, and is primarily limited to the
frontal and neocortical temporal lobes. Reduced volumes
in specific subregions of the prefrontal cortex, for example,
are related to poor executive functioning118 and impaired
memory,119 while left neocortical temporal lobe volume
predicts confrontation naming ability.120 Regarding ana-
tomical features of the entire cerebral cortex, only global
indices of structural integrity, such as overall gyrification,99
whole-brain volumes,121–123 and disproportionate distribu-
tion of white and gray matter volumes,124 are related to
cognitive performance. Indeed, a VBM study failed to
associate localized gray matter changes with material-
specific neuropsychological deficits.123 Thus, structural–
functional correlations in the cortical regions are more
evident at a global level than at a local level, implying that
the distributed nature of cognitive impairment in TLE
involves a widespread network of abnormalities.
The link between subcortical atrophy and cognition in
TLE further highlights the importance of this integrated
network. Subcortical structures such as the thalamus, basal
ganglia and cerebellum are critical nodes in the cortico-
subcortical circuits that are involved in the transfer, con-
vergence and processing of cognitive information. To this
end, thalamic volumes correlate with IQ, memory125 and
executive function;126 basal ganglia changes relate to nega-
tive symptoms in patients with TLE;127 and cerebellar
abnormalities are associated with impaired procedural
memory128 as well as executive function.114 When the
degree of cortical thinning was combined with volume loss
in these subcortical regions, the collective structural
abnormality was found to be closely associated with pat-
terns of cognitive impairment (or cognitive phenotypes)
observed among patients with TLE.129
Another facet of the coordinated network in TLE is
derived from the link between white matter tract integ-
rity and cognitive ability. White matter fiber tracts that
connect cortical to cortical, cortical to subcortical, and
interhemispheric regions have been associated with
specific cognitive deficits in memory and language
(Table 1). Studies by Riley et al.,114 McDonald et al.,130
Diehl et al.131 and Hermann et al.132 have led to a uni-
fying hypothesis that disconnection between impor-
tant cortical and subcortical regions would impair
<10%P >0.05P = 0.02 P <0.00530% 20%
Figure 4 | Reduced gray matter thickness and white matter integrity in left MTLE. a | Mean percent reduction in cortical
thickness as a percentage of control average. Red areas in the bilateral in the frontal poles, frontal operculum,
orbitalfrontal, lateral temporal and occipital regions, and the right angular gyrus and primary sensorimotor cortex
surrounding the central sulcus denote ≤30% decrease in thickness, on average, compared with corresponding areas in
controls. b | Significance of these changes shown as a map of P values. c | Reductions in white matter integrity, measured
by decreased fractional anisotropy, were evident in mesial and lateral temporal lobe, limbic system and extratemporal
lobe regions, particularly ipsilateral to the side of seizure onset. Yellow and dark red regions indicate white matter tracts
with decreased fractional anisotropy. Green regions indicate areas not notably different from controls. Only left MTLE
patients are presented here, although similar gray and white matter abnormalities—albeit to a lesser degree—were
evident in right MTLE. Parts a and b are modified, with permission from Oxford University Press © Lin, J. J. et al. Cereb.
Cortex 17, 2007–2018 (2007). Part c is modified with permission from Elsevier Ltd © Focke, N. K. et al. Neuroimage 40,
728–737 (2008). Abbreviation: MTLE, mesial temporal lobe epilepsy.
© 2011 Macmillan Publishers Limited. All rights reserved
NATURE REVIEWS | NEUROLOGY
VOLUME 7 | MARCH 2011 | 161
information transfer and thus contribute to cognitive
impairments in TLE.
In summary, substantial evidence is now available
to show that cognitive impairment in TLE is a result
of network disruption rather than specific damage to
a certain brain structure. Importantly, the sum of these
distributed structural abnormalities could result in a
cumulative cognitive and behavioral burden that might
be substantial in patients with TLE.
Organization of higher cognitive functions
A defining characteristic of MTLE is childhood or early-
adolescent onset, often with an early initial precipitating
injury. This hallmark characteristic is important since
the timing and nature of the initial precipitating injury
and recurrent seizures could directly affect organization
of higher cognitive abilities, both within and between
Evidence of altered cerebral organization is now sub-
stantial. Increased rates of right hemisphere or bilateral
language dominance have been frequently observed
among patients with left TLE,133–135 and partial transfer
of language dominance often occurs in the presence of
early-onset epilepsy and left hippocampal sclerosis.136
Intrahemisphere reorganization of language has been
demonstrated by intraoperative and extraoperative
speech mapping, which has shown that early-onset epi-
lepsy is associated with relocation of visual and audi-
tory naming sites, especially more posteriorally in the
left cerebral hemisphere, compared with late-onset
Functional neuroimaging studies demonstrate abnor-
mal organization of memory in patients with TLE. Using
fMRI, Powell et al.140 showed that, compared with healthy
controls without epilepsy, both right and left TLE patients
showed less ipsilateral than contralateral hippocampal
activation while viewing word, picture and face stimuli.
In addition, increased activation in the ipsilateral hippo-
campus correlated negatively with verbal memory in left
TLE and nonverbal memory in right TLE. By contrast,
greater contralateral hippocampus activity correlated with
poorer memory performance. The authors also suggested
that reorganization of memory ability to contralateral
hippo campus and mesial temporal lobe structures might
not lead to effective memory performance.
Abnormal organization of higher cognitive functions
could also be responsible in part for the distributed cogni-
tive compromise that might be observed in patients with
early-onset TLE. In individuals with early-onset epilepsy,
greater language shift to the right hemisphere correlated
with poorer performance in language, executive function
and memory.141 In addition, shifting of language to the
right hemisphere was associated with deficits in nonverbal
cognitive tasks, suggesting that reorganization of language
might adversely affect normal right hemisphere func-
tions.142 The shift of language to the right hemisphere alters
normal language networks, resulting in adverse cognitive
outcomes. Importantly, most of the above studies were
cross-sectional in nature and, as such, did not address the
important question of when and how the cognitive deficits
develop, or even whether they antedate the onset of TLE.
Conclusions and future directions
TLE is far more than a localization-related form of epilepsy
with a primary and limited influence on episodic memory.
Depending on the specific syndrome and its associated
underlying characteristics, the effect of TLE on brain
structure and function can be widespread, affecting brain
and cognitive development, evoking compensatory pro-
cesses including reorganization of function, and altering
the landscape of the usual brain–behavior relationships.
Despite the important progress that has been made in our
understanding of cognitive comorbidities in TLE, specific
biomarkers that predict development of cognitive deficits
have not been identified, and relatively few strategies exist
that identify individuals at risk of cognitive dysfunction.
Thus, the current state of knowledge highlights the need
for longitudinal studies across the lifespan to identify
brain-based predictors of cognitive comorbidities and
target candidates for effective cognitive intervention.
While cognitive reorganization has a fortuitous benefit
for those who undergo ATL by adventitiously preserv-
ing language and memory function postoperatively, the
broader implications of these diverse effects, including
brain and cognitive health in advanced age, remain uncer-
tain. While divergent views exist regarding the primary
Table 1 | Abnormal white matter tract connections and cognitive deficits in TLE
TractsConnections Cognitive deficits
Arcuate fasciculus Connects perisylvian frontal, parietal and temporal cortexConfrontational naming130
Connects temporal lobe to the occipital lobeDelayed memory114
Connects frontal lobe to occipital lobeDelayed memory130
Uncinate fasciculus Connects the mesial temporal structures (uncus and
amygdala) and mesial frontal region
Immediate memory, delayed memory and
Connects the uncus and parahippocampal gyrus to
subrostral areas of the frontal region
Fornix Connects hippocampus to other limbic regionsImmediate memory114
Corpus callosum Connects the two hemispheres Psychomotor speed and executive function132
Abbreviation: TLE, temporal lobe epilepsy.
© 2011 Macmillan Publishers Limited. All rights reserved
162 | MARCH 2011 | VOLUME 7
adverse influence on life course (early neurodevelopmen-
tal impact versus progressive decline versus mixed neuro-
developmental and degenerative decline),143–146 all views
are in agreement in terms of predicting worse cognitive
function in elder years compared with population-based
norms—an outcome that requires closer scrutiny.147
Clearly, much has been learned over the years about
memory and other cognitive processes in people with
TLE; however, many issues remain to be clarified. As can
be appreciated, the opportunity to carefully study persons
with TLE who are candidates for epilepsy surgery has
provided investigators with unparalleled opportunities
to learn more about the effects of epilepsy on cognition
and brain structure. However, these patients are among
the most intractable to medication treatment and are,
therefore, not representative of the larger population of
people with this form of epilepsy. Population-based inves-
tigations would provide a more representative picture of
the consequences of epilepsy for neurobehavioral status
and brain structure.
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and “MRI”. This search was supplemented with older
cognition, surgical and related historical literature known to
the authors from multiple sources, including peer-reviewed
publications, texts, and book chapters.
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We thank Dr David Loring and Dr John Langfitt for their
critical review of earlier versions of this manuscript.
Preparation of this paper was supported in part by the
National Institute of Neurological Disorders and
Stroke RO1–44351 (B. Hermann, M. Seidenberg) and
K–23 NS060993 (J. J. Lin).
All authors contributed equally to the researching the
data and writing the article, provided substantial
contributions to discussion of the content and
reviewing and editing of the manuscript.
© 2011 Macmillan Publishers Limited. All rights reserved