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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. etal. Nat. Rev. Neurol. 7, 154164 (2011); published online 8 February 2011; doi:10.1038/nrneurol.2011.3

Introduction
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 function 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 electroencephalographic abnormalities (such as the type, frequency and distribution of interictal epileptiform and slow wave activity).49 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 epilepsycognitive
Competing interests The authors declare no competing interests.

Department of Neurology, Matthews Neuropsychology Section, University of Wisconsin School of Medicine and Public Health, 600 North Highland Avenue, Madison, WI 53792, USA (B. Bell, B.Hermann). Department of Neurology, University of CaliforniaIrvine, 105Irvine Hall, Irvine, CA 926974275, USA (J.J. Lin). Department of Psychology Rosalind Franklin University of Medicine and Science, 3333 Green Bay Road, North Chicago, IL60064, USA (M.Seidenberg). Correspondence to: B. Hermann hermann@ neurology.wisc.edu

impairment. We focus specifically on temporal lobe epilepsy (TLE), the most common form of focal epilepsy. The cognitive complications of epilepsy can be heterogeneous, affecting diverse abilities such as language, attention, and higher-level problem solving skills, although episodic memory impairmenta signature cognitive deficit in TLEis 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 underlying neurobiology 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 relationship 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 cognition developed, interest in specific abilities such as memory ensued. Understanding of the neurobiological processes of disordered cognition and memory in epilepsy was accelerated 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 GuysMaudsley Hospital in London, UK.1216 These clinical investigators assessed patients before and following neurosurgical intervention, leading to the initial insights into the effects of surgery on cognition.

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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 behavioral 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 hippocampus 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 proposal, the serious memory consequences of bilateral temporal lobectomy were reported a few years later. Scoville and Milner 23 presented the memory outcome findings for their patient Henry Gustav Molaison (referred to as HM), along with seven other patients, following bilateral temporal lobe resection. Extensive anterograde memory loss ensued with concomitant preservation of overall intellectual 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 50years 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 hippocampal function was the less severe but common problem of memory decline following unilateral anterior temporal lobectomy (ATL).25,26 Milner 27 described materialspecific 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 socalled nonverbal memory was less affected before and after surgery. A corresponding, if less robust, selective vulnerability 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,
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Key points
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
15

Left ATL Right ATL

Number of patients

10

0 21 1620 1115 610 15 Decline 0 0 15 610 1115 1620 21 Improvement

Change in total words recalled from preoperative to postoperative assessments

Number of patients

10

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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.

influencing generations of investigators. Our refined understanding of memory change resulting from epilepsy and its surgical management is discussed in detail below.

Memory change following surgery


Approximately 3060% of patients who undergo left (speech dominant) ATL experience a substantial decline in verbal memory ability after surgery.21,2832 Despite this robust trend, a persistent finding has been variability in memory outcome following a standard surgical approach (Figure1).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 postoperative improvement. By contrast, right
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20 Left hippocampus with no or minimal sclerosis Left hippocampus with significant hippocampal sclerosis 10 CVLT postoperative change (%)

10

20

30

40 Trial 1 Trial 2 Trial 3 Trial 4 CVLT stage Trial 5 Short delay Long delay

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.

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 variability 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 heterogeneity 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 associated 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.3638 Biological factors Another possible cause of variable memory outcome was suggested by studies of the relationship between preoperative memory performance and the neuropathological status of the resected hippocampus. Rausch etal.39 found that a greater degree of neuron loss in the left hippocampus was associated with poorer preoperative performance on
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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 postoperative memory decline was associated with the structural integrity (or lack thereof) of the to-be-resected hippocampus.4245 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. Figure2 depicts the degree of change in rote verbal list learning performance that was apparent following resection of a left hippocampus in patients with minimal or no sclerosis (bottom curve) compared to patients with a left hippocampus with moderate to severe sclerosis (top curve). In a major theoretical paper, Chelune28 integrated findings 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 hippocampus. An intact contralateral hippocampus capable of subserving memory could offset the effect of resection of the ipsilateral (surgical) 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 hippocampus 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 (Box1, Figure 3). The data in Box 1 and Figure 3 do not all relate to Chelunes theoretical formulation.

Predicting memory outcome


The Wada test In response to the concern about producing severe global memory impairment following unilateral ATL, Milner etal.46 developed intracarotid amobarbitol testing as a means of assessing the memory ability of the contralateral 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 opportunity to assess the functional status of both the ipsilateral and contralateral hippocampus independently through transient hemispheric anesthesia.

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The presence or absence of a marked memory asymmetry scoredefined as the accuracy of memory performance in the ipsilateral or to-be-resected hippocampus compared with accuracy of memory performance in the contralateral hippocampusis a clear predictor of verbal memory outcome following left ATL.4851 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 hippocampal atrophy on MRI,53,54 and neuronal loss in the resected hippocampus.41 This relationship is, however, possibly affected by atypical language representation,5557 the types of memory stimuli used,58 and the type of neuropsychological 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 preoperative memory and a greater postoperative decline.63 These trends are probably a result of the increased likelihood of hippocampal pathology associated with earlier onset of epilepsy,64 which, in turn, is related to functional adequacy. Preoperative memory performance Patients displaying better preoperative memory performance show greater decline in memory following ATL,33,65 reflecting the association with the degree of hippocampal sclerosisless 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 functional hippocampus that subserves stronger presurgical memory performance. Resection will remove functional tissue, leading to substantial memory decline. Neuroimaging predictors The advent and refinement of neuroimaging techniques including MRI, PET and functional MRI (fMRI) over the past 20years 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 18 F-fluorodeoxyglucose PET (FDG-PET). Griffith etal.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 relationship between preoperative FDG-PET hippo campus asymmetry and memory outcome.70
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 primacyand to some degree the middleportion 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 (Figure3).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 yesno 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,1013,152155 while deficits in recognition and familiarity judgment commonly occur following nondominant anterior temporal lobectomy.156

The rationale underlying the use of fMRI is that the degree of presurgical hippocampal task activation reflects the functional adequacy of the structure. Richardson etal.71 showed that during a verbal encoding task, left TLE patients with ipsilateral hippocampal sclerosis demonstrated less activation in the region of the left hippocampus than did nonsurgical control individuals. In 2010, Bonelli etal.72 reported that increased left hippocampal activity in individuals with left TLE was associated with better presurgery 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 following ATL. Recent evidence raises the interesting possibility that hippocampal activation might not necessarily be the best verbal memory outcome predictor, as language lateralization 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.
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a
70 60 50 Recall (%) 40 30 20 Preoperative 10 0 Primacy Middle Recency Postoperative

index explained an additional 10% of the variance in predicting 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 cognitive 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, Helmstaedter 80 compared preoperative and postoperative verbal learning and memory performance in left TLE patients with hippocampal pathology who underwent ATL or selective amygdalohippocampectomy, 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.

Primacy Middle Recency

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 patients free recall of a supraspan word list.

Mutivariate prediction Many studies have examined the effect of a single predictor in relation to memory outcome. More-informative investigations involve a multivariate approach that makes use of multiple, non-redundant sources of information.75 Stroup etal.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 prediction of memory outcome. Lineweaver etal.77 found that MRI volumes and baseline memory performance, but not Wada test performance, were successful in predicting memory outcome. Baxendale etal.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 etal.79 examined 60 left ATL patients who underwent preoperative language mapping with fMRI, preoperative 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 performance, late age at onset of epilepsy, left dominance on fMRI, and left dominance on the Wada test were all predictive 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
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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 conceptualization facilitated increasingly careful characterization of the syndromes of localization-related TLE (MTLE, lesional TLE, and so called MRI-negative, paradoxical or cryptogenic TLE). The primary cognitive signature of MTLE was viewed to be material-specific memory impairment, demonstrated either through formal neuropsychological assessment or the Wada test. A stated contraindication to MTLE was the presence of generalized cognitive compromiseall reasonable characterizations at the time.81 Later studies examining the full range of cognitive abilities, however, found that patients with neuropathologically confirmed MTLE exhibited a pattern of generalized cognitive disruptionan unexpected finding.82 One possible 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 epileptogenic hippocampus. Using quantitative MRI tools that

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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 demonstrated that anatomical abnormalities in MTLE were not limited to the epileptogenic hippocampus. Early volumetric 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 structural 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 anatomical block from a patient with MTLE was compared with normal controls to assess for disproportional distribution 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 18VBM 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 curvature. These limitations provided the impetus to examine changes in other brain features such as indices of gyrification, cortical thickness, and surface area. Lin and colleagues examined cortical thickness in a group of MTLE patients with pathologically confirmed hippo campal sclerosis and found that these patients showed up to a 30% decrease in cortical thickness, with noticeable thinning of frontal poles, frontal operculum, and orbitofrontal, lateral temporal and occipital regions (Figure4a,b). 96 Interestingly, reductions in cortical thickness were evident in both cerebral hemispheres, despite unilateral seizure onset.96 Other investigators have reported bilateral cortical mantle thinning in select regions throughout the
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entire cerebral cortex, but most consistently in the frontal, central and temporal regions.97,98 Widespread abnormalities in gyrification patterns were found in multiple cortical regionsboth 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 abnormalities in the fornix and cingulum.102 Postulating on a diffuse epileptogenic network in TLE, other investigations extended this initial finding to frontaltemporal (uncinate fasciculus and arcuate fasciculus),103105 temporaloccipital (inferior longitudinal fasciculus),106 frontaloccipital (inferior frontal occipital fasciculus)106 and interhemispheric (corpus callosum) connections.107109 More recently, whole-brain voxelwise analysis techniques have mapped white matter profiles and delineated systemic differences between TLE patients and healthy individuals, without apriori 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 (Figure4c).111 Other studies have also demonstrated extensive bilateral white matter diffusion abnormalities, particularly in the temporal and frontal lobes ipsilateral to the side of seizure onset.112114 In summary, converging evidence indicates that while the primary epileptic zone might be contained within the confines of the hippocampus, considerable anatomical 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 contribute 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 cognitive impairments, affecting not only memory, but also a
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a b

Same
<10% 20%

Thinner
30% P >0.05 P = 0.02 P <0.005

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 abnormalitiesalbeit to a lesser degreewere evident in right MTLE. Parts a and b are modified, with permission from Oxford University Press Lin, J.J. etal. Cereb. Cortex 17, 20072018 (2007). Part c is modified with permission from Elsevier Ltd Focke, N.K. etal. Neuroimage 40, 728737 (2008). Abbreviation: MTLE, mesial temporal lobe epilepsy.

broad array of cognitive areas including IQ, executive functions, language and sensorimotor skills.82,116,117 Acumulative literature has now emerged, linking structural changes with cognitive performance. In the cortical regions of the brain, specific one-to-one structuralfunctional association 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 functioning 118 and impaired memory,119 while left neocortical temporal lobe volume predicts confrontation naming ability.120 Regarding anatomical features of the entire cerebral cortex, only global indices of structural integrity, such as overall gyrification,99 whole-brain volumes,121123 and disproportionate distribution of white and gray matter volumes,124 are related to cognitive performance. Indeed, a VBM study failed to associate localized gray matter changes with materialspecific 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
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network. Subcortical structures such as the thalamus, basal ganglia and cerebellum are critical nodes in the corticosubcortical circuits that are involved in the transfer, convergence and processing of cognitive information. To this end, thalamic volumes correlate with IQ, memory 125 and executive function;126 basal ganglia changes relate to negative symptoms in patients with TLE;127 and cerebellar abnormalities are associated with impaired procedural memory 128 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 patterns 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 integrity 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 (Table1). Studies by Riley etal.,114 McDonald etal.,130 Diehl etal.131 and Hermann etal.132 have led to a unifying hypothesis that disconnection between important cortical and subcortical regions would impair

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Table 1 | Abnormal white matter tract connections and cognitive deficits in TLE Tracts
Arcuate fasciculus Inferior longitudinal fasciculus Inferior fronto-occipital fasciculus Uncinate fasciculus Parahippocampal cingulum Fornix Corpus callosum

Connections
Connects perisylvian frontal, parietal and temporal cortex Connects temporal lobe to the occipital lobe Connects frontal lobe to occipital lobe Connects the mesial temporal structures (uncus and amygdala) and mesial frontal region Connects the uncus and parahippocampal gyrus to subrostral areas of the frontal region Connects hippocampus to other limbic regions Connects the two hemispheres

Cognitive deficits
Confrontational naming130 Delayed memory114 Delayed memory130 Immediate memory, delayed memory and confrontational naming114,130,131 Delayed memory130 Immediate memory114 Psychomotor speed and executive function132

Abbreviation: TLE, temporal lobe epilepsy.

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 earlyadolescent 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 cerebral hemispheres. Evidence of altered cerebral organization is now substantial. Increased rates of right hemisphere or bilateral language dominance have been frequently observed among patients with left TLE,133135 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 epilepsy is associated with relocation of visual and auditory naming sites, especially more posteriorally in the left cerebral hemisphere, compared with late-onset epilepsy.136139 Functional neuroimaging studies demonstrate abnormal organization of memory in patients with TLE. Using fMRI, Powell etal.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 hippocampus 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
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hippocampus 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 cognitive 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 functions.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 processes including reorganization of function, and altering the landscape of the usual brainbehavior 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 preserving language and memory function postoperatively, the broader implications of these diverse effects, including brain and cognitive health in advanced age, remain uncertain. While divergent views exist regarding the primary
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adverse influence on life course (early neurodevelopmental impact versus progressive decline versus mixed neurodevelopmental and degenerative decline),143146 all views are in agreement in terms of predicting worse cognitive function in elder years compared with population-based normsan 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,
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therefore, not representative of the larger population of people with this form of epilepsy. Population-based investigations would provide a more representative picture of the consequences of epilepsy for neurobehavioral status and brain structure.
Review criteria
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