Emotion recognition in temporal lobe epilepsy: A systematic review.

Neuroscience and Biobehavioral Reviews 55 (2015) 280–293

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Neuroscience and Biobehavioral Reviews journal homepage: www.elsevier.com/locate/neubiorev

Review

Emotion recognition in temporal lobe epilepsy: A systematic review Giulia Monti, Stefano Meletti ∗ Department of Biomedical, Metabolic, and Neural Science, NOCSAE Hospital, University of Modena e Reggio Emilia, Modena, Italy

a r t i c l e

i n f o

Article history: Received 17 February 2014 Received in revised form 30 April 2015 Accepted 8 May 2015 Available online 19 May 2015 Keywords: Emotion recognition Facial expression Emotional prosody Amygdala Temporal lobe epilepsy Temporal lobectomy

a b s t r a c t There is increasing interest in the understanding of emotion recognition deficits in temporal lobe epilepsy (TLE), the most common form of focal epilepsies. There are conflicting reports about impairments for different emotions in right and left temporal lobe epilepsy patients. A systematic review and a narrative synthesis was conducted for studies investigating emotion recognition (ER) in TLE. Embase, MEDLINE, PsychINFO and Pubmed were searched from 1990 to March 2015 and reference lists were reviewed. 996 citations were identified and 43 studies were finally included. ER deficits are consistently observed across studies. A fear recognition deficit is always reported, followed by deficits in sadness and disgust recognition. Deficits are observed across visual and auditory domains. Conflicting evidence is present concerning the severity of ER deficits in right and left TLE. Studies on anterior temporal lobectomy report data similar to that observed in pre-surgical patients. Current evidence supports the conclusion that recognition of negative emotions is commonly impaired in TLE, particularly for fear, and in the visual domain. Future work should focus on more ecologically valid test, on longitudinal studies to assess the role of anterior temporal lobectomy, and to correlate ER measures to social functioning in everyday life. © 2015 Elsevier Ltd. All rights reserved.

Contents 1. 2.

3.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 281 Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 282 2.1. Criteria for considering studies for this review. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .282 2.1.1. Types of studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 282 2.1.2. Types of participants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 282 2.1.3. Types of measures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 282 2.2. Search methods for identification of studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 282 2.2.1. Electronic searches . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 282 2.2.2. Other sources . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 282 2.3. Data collection and analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 282 2.3.1. Selection of studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 282 2.3.2. Data extraction and technical assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 282 2.3.3. Data synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 282 Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 283 3.1. Description of studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 283 3.1.1. Results of the search . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 283 3.1.2. Studies of facial emotion recognition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 283 3.1.3. Studies of auditory emotion recognition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 283 3.1.4. Stimulus presentation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 283

∗ Corresponding author at: Via Giardini, 1355 – Nuovo Ospedale Civile, Modena, Italy. Tel.: +39 059 3961676; fax: +39 051 3961336. E-mail addresses: [email protected] (G. Monti), [email protected] (S. Meletti). http://dx.doi.org/10.1016/j.neubiorev.2015.05.009 0149-7634/© 2015 Elsevier Ltd. All rights reserved.

G. Monti, S. Meletti / Neuroscience and Biobehavioral Reviews 55 (2015) 280–293

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3.1.5. Response option . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 283 3.1.6. Study populations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 283 3.1.7. Reporting of key demographic and electro-clinical data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 284 3.2. Statistical analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 285 3.2.1. Power analysis and sample size . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 285 3.2.2. Potential confounding variables . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 285 3.2.3. Normality of data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 285 3.2.4. Multiple statistical comparisons . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 285 3.2.5. Reporting of analysis and results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 285 3.3. Outcomes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 285 3.3.1. Facial emotion recognition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 285 3.3.2. Auditory emotion recognition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 286 3.3.3. Recognition of emotion from music . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 286 3.3.4. Cross-modal comparisons . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 287 3.3.5. Side of epilepsy/lobectomy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 287 3.3.6. Age of epilepsy onset and duration of epilepsy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 287 3.3.7. Emotion recognition before and after lobectomy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 287 3.3.8. Extent of anterior temporal lobectomy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 288 3.3.9. Emotion recognition and measures of intelligence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 288 3.3.10. Subjective measures of psychosocial well-being . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 289 3.3.11. Effect of anti-epileptic drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 289 Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 289 4.1. Right versus left temporal lobe damage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 289 4.2. Emotion recognition and age of temporal lobe damage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 289 4.3. Anterior temporal lobectomy effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 290 4.4. Other disease-related variables . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 290 4.5. Clinical relevance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 290 4.6. Study limitations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 290 4.7. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 290 Appendix A. Articles that did not meet inclusion criteria (chronological order) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 290 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 291

1. Introduction Temporal lobe epilepsy (TLE) is a group of disorders that predominately involves dysregulation of amygdalo-hippocampal function caused by neuronal hyper-excitability (Schwartzkroin, 1986; Graebenitz et al., 2011). Medial TLE in particular, is perhaps the best-characterized electroclinical syndrome of all the epilepsies. The inherent potential for the temporal lobe to be predisposed to focal seizures is based on the unique anatomic–functional networks that involve the amygdalo-hippocampal complex and entorhinal cortex. Beyond seizures, drug-resistant TLE is characterized by cognitive decline, especially involving memory functions, and by psychiatric co-morbidities (Hermann et al., 1997; Jokeit and Ebner, 1999; Helmstaedter and Kurthen, 2001; Helmstaedter et al., 2003). Behavioral deficits in TLE have a great impact on the burden of the disease, and often contribute much more than seizures per se to negatively impact on the patient’s quality of life (Hermann et al., 2008; Helmstaedter and Witt, 2012). The ability to recognize emotions in others is a key social skill, and much work has focused on studying the expression and recognition of basic emotions (happiness, fear, disgust, anger, sadness), which appear to be cross-cultural, and which are argued to have a biological basis (Ekman, 1992, 1993). The temporal lobe, and the amygdala in particular, have been demonstrated to play a crucial role in the processing of the appropriate cognitive, autonomic and behavioral responses to emotional relevant stimuli (Anderson and Phelps, 2001; Adolphs et al., 2002; Adolphs, 2010). The role and importance of the antero-medial temporal lobe region in decoding emotions has been demonstrated by a number of lesion and functional imaging studies (for reviews see Adolphs et al., 2003; Adolphs, 2008, 2013). In the field of epilepsy this knowledge has several clinical as well as speculative implications. Indeed, TLE is frequently characterized by lesions or gliosis/atrophy (hippocampal sclerosis) involving

the medial temporal lobe region. Moreover, antero-medial temporal lobectomy (ATL) is the “standard” treatment for drug-resistant medial TLE (Wiebe et al., 2001). Consequently, the investigation of emotional and social competence in TLE patients has been the focus of different studies (Meletti et al., 2003a,b, 2009; Broicher et al., 2012; Giovagnoli et al., 2011). After more than a decade of research in this field it has been reported that TLE patients show deficits in emotion recognition (ER) (either before and after ATL), especially for facial expressions, but also for different emotional stimuli such has prosody and music (Gosselin et al., 2005, 2011b; Bonora et al., 2011; Dellacherie et al., 2011). However, several questions are still open, concerning the “specificity” of fear recognition impairment and the role of the right and left temporal lobes. These two questions are relevant and contribute to our understanding of how the brain processes emotions. Other important questions to be elucidated concern the impact of several disease variables on emotion recognition, as well as the effect of anti-epileptic treatment, and temporal lobectomy procedures. These last issues are clearly relevant from a clinical perspective. The aim of this review is therefore to disambiguate the pattern of emotion recognition deficits in TLE through a systematic appraisal of previous reports. We believe that a systematic review of the current literature could help to obtain some relevant theoretical message; in particular, in order to assess the nature of the reported deficits, we aim to analyze whether differences (if any) in emotion recognition performance can be explained by disease-related factors, such as age of epilepsy onset, duration of disease, types and number of antiepileptic drugs, side of seizure focus, pathology, pre/post-surgery status. This review is warranted to better understand the conceptualization of the emotion recognition deficits in TLE patients, to improve our understanding of the social problems that occur in these patients, as well as to identify areas for future research.

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2. Methods

2.2. Search methods for identification of studies

2.1. Criteria for considering studies for this review

2.2.1. Electronic searches Searches were run in the following databases from 1990 to March 2015: Embase, MEDLINE, PsychINFO and PubMed. Searches were limited from 1990 to the present day, as studies carried out prior to this would necessarily have included participants without MRI to document medial temporal lobe damage. The search keywords were “TLE AND emotion recognition” or “Temporal lobe epilepsy AND emotion recognition” or “Amygdala AND emotion recognition” NOT (mouse OR rat OR mice)”. Using Ovid the search was run on Embase, MEDLINE and PsychINFO simultaneously and results were then deduplicated (a function within Ovid). Only peerreviewed published articles were accepted for inclusion in the review.

2.1.1. Types of studies In order to be eligible for inclusion in the review a study had to compare ER ability of patients with medial TLE or with previous antero-medial temporal lobectomy (to treat temporal lobe epilepsy) with respect to a control group/s. The following types of studies were included:

(a) cross-sectional studies comparing TLE versus healthy subjects or/and versus a clinical control group (i.e. patients with an epilepsy syndrome different from TLE); (b) cross-sectional studies comparing anterior temporal lobectomy (ATL) patients versus healthy subjects or/and versus a clinical control group; (c) longitudinal studies comparing patients’ performance before versus after ATL.

Emotion recognition was defined as any task in which stimuli conveying emotional information were presented, and for which participants were asked to state or choose the emotion represented by the stimuli. We included both labeling and rating tasks. We included only studies investigating emotions that are considered universal, independent by culture and innate by most of the researchers (fear, happiness, disgust, anger, sadness), and can be reliably recognized from facial expressions or other sensory modalities (Ekman, 1992, 1993). We therefore did not include in the review studies on complex or social emotions (i.e. trustworthiness, embarrassment, etc.). The stimuli could be of any modality (e.g. visual, vocal) and of any form (e.g. static faces, videos, sounds, music or sentences). Studies looking exclusively at “mood” or emotion production, or semantic knowledge (e.g. about situations that might be expected to induce emotions) were excluded. Studies investigating emotional memory were not considered in this review. Finally, fMRI studies that investigated facial emotion processing in TLE, but without overt, explicit, behavioral measures of emotion recognition during the fMRI task were excluded from analysis. Editorials, reviews, commentaries, letters or other articles that contained no original data were excluded.

2.1.2. Types of participants A syndromic diagnosis of temporal lobe epilepsy according to ILAE criteria was required to include the study in the review (Wieser, 2004; Blumke et al., 2012). Typically TLE was associated with structural brain MRI evidence of hippocampal sclerosis, or different injury involving the medial temporal lobe, such as gliomas, dysplasia, post-traumatic injury, encephalitis, etc. Single-case studies that included a clear TLE diagnosis were included in the review. We included both pediatric and adult patient populations. Studies of patients with unilateral or bilateral amygdala or hippocampal damage, but without seizures were excluded. Studies evaluating patients after temporal lobectomy to treat TLE were included in the analysis even if the “seizure status” at the time of the study was not reported (i.e. if it was not reported if the patient was cured/seizure free, or not, after surgery).

2.1.3. Types of measures Studies must have reported a quantitative measure of emotion recognition.

2.2.2. Other sources For each study included in the review, manual searches of reference lists were conducted and a citation search was also conducted to identify further potential studies. 2.3. Data collection and analysis 2.3.1. Selection of studies The initial searches identified 996 citations (after deduplication). The title and the abstract of each citation were examined (independently by GM and SM) according to the inclusion and exclusion criteria listed above. 64 citations could not be excluded on the basis of the title and abstract alone (all articles had abstract available). The full text of these citations was obtained (by GM) in order to assess whether they fully met inclusion criteria. Two additional citations were identified from the reference list and citation search. The total number of included studies is 66. 2.3.2. Data extraction and technical assessment Data were extracted to a standardized data collection form. Study structure and technical characteristics were assessed according to a number of criteria: sample size and power analysis; the nature of the control group; reporting of demographic data, the nature of stimuli, stimulus presentation and response options; ways in which potential confounding variables were measured and addressed; appropriate statistics; and reporting of quantitative outcome data. Demographic data considered necessary in order to be able to compare groups adequately between studies were: age, gender, some measure of estimated IQ or educational level, age at first seizures (febrile or not febrile), age at epilepsy onset, median duration of epilepsy (years of life). Moreover, when available we also analyzed also lateralization of the disease, psychiatric co-morbidity (such as depression), QOLIE-31 (quality of life), drug load (antiepileptic drugs). Note that these demographic and other supplementary data were considered desirable in order to assess studies fully, but these were not criteria for inclusion in the review overall. 2.3.3. Data synthesis Given that the data reviewed here were quantitative a metaanalytic approach was considered. Ultimately, however, a narrative synthesis was undertaken for three reasons. First, although attempts were made to contact representatives of all the studies included in the review, some authors could not be contacted and this meant that quantitative results were not available for all studies. Second, the ways in which the patients’ cohorts varied between studies were not uniform (e.g. etiology and extension of the temporal lobe injury, duration of epilepsy, psychiatric comorbidity). Third, the material and methods used to test emotion recognition were


extremely variable, including differences in: kind of the modalities used to test ER (visual or auditory tasks), kind of stimuli (faces, voices, videos, music, sentences), and modality of patients’ answers (labeling, rating, matching). This meant that it would not be possible to determine the extent to which differences in effect size were attributable to differences in these factors among the cohorts studied. 3. Results 3.1. Description of studies 3.1.1. Results of the search Out of the 66 revised studies, 43 reports met full inclusion criteria. 23 studies initially included on the basis of title and abstract were excluded after the full text was examined. The principal reasons for exclusion were: absence of diagnosis of seizures/epilepsy; inclusion of epilepsy patients with epileptogenic focus involving brain structures other than the medial temporal lobe (frontal lobe, non specific locations); inclusion of patients with idiopathic generalized epilepsies; electrophysiological studies with depth cerebral electrodes that evaluated neuronal activity in response to emotional stimuli but without an explicit emotion recognition task; poor explanation of the methods used to test emotion recognition; studies assessing emotional memory only (see Appendix A for a detailed description of the excluded studies). See Table 1 for characteristics of the included studies. 3.1.2. Studies of facial emotion recognition The majority (37/43) of studies included at least one test of facial emotion recognition. The most commonly used face stimulus series were static black and white images from Ekman and Friesen (1976). In some studies 60 pictures were used (Calder et al., 1996; Reynders et al., 2005; Walpole et al., 2008; Sedda et al., 2013; Wendling et al., 2015), with 10 stimuli for each basic emotion (happiness, fear, anger, sadness, disgust, surprise). In other studies 24–42 facial expressions were used (Adolphs et al., 1995, 2001; Young et al., 1996; Anderson et al., 2000; Meletti et al., 2003a,b, 2009; Benuzzi et al., 2004; Yamada et al., 2005; Shaw et al., 2007; Bonora et al., 2011), typically with four–five stimuli for each emotion. Some authors excluded surprise, to avoid mistaking fear for surprise and vice versa (Meletti et al., 2003a,b, 2009; Benuzzi et al., 2004; Bonora et al., 2011). In some studies the recognition of emotion posed with different intensity was tested creating “morphed” facial stimuli from prototypical facial expressions (Calder et al., 1996; Benuzzi et al., 2004; Brierley et al., 2004; Sedda et al., 2013). One study evaluated emotion recognition by means of the “Bubble test” (Gosselin et al., 2011a). This task is obtained by the presentation of computer generated stimuli to mask some part of the face. Other authors used tests composed by in-house made stimuli such as the TREFE (test de reconnaissance des emotions facials pour enfants), a battery of static pictures of children (Golouboff et al., 2008; Pinabiaux et al., 2013) to test emotion recognition in children. One study used the so-called FAB (Florida Affect Battery, 1991), a battery with different subtests for facial emotion recognition (Carvajal et al., 2009). Few studies (3/43) used dynamic stimuli in videos (Young et al., 1996; Ammerlaan et al., 2008; Tanaka et al., 2013). Finally, 31 out of 43 studies evaluated the ability to recognize face identity to control for patients visual perceptual abilities with face recognition (see Calder and Young, 2005 for a comprehensive review of this topic). The use of a control task was considered desirable to exclude that ER deficit could depend from impaired visuo-perceptual abilities, however we also included studies that did not clearly report face recognition tasks. The Benton Test of

283

Facial Recognition (Benton et al., 1983) was used in 13 studies, while face recognition tasks created by means of the Ekman & Friesen series were used in 18 studies. 3.1.3. Studies of auditory emotion recognition Twelve out of 43 studies included tasks of emotion recognition in the auditory modality. Some authors tested the recognition of both short non-verbal vocal sounds (e.g. laughter, growls) as well as prosody from sentences of neutral meaning (Scott et al., 1997; Fowler et al., 2006). Other authors used only sentences with neutral meaning to evaluate emotional prosody (Adolphs and Tranel, 1999; Adolphs et al., 2001; Brierley et al., 2004; Bonora et al., 2011; Dellacherie et al., 2011; Meletti et al., 2014b; Laurent et al., 2014). The emotions tested in most of studies were happiness, sadness, fear, anger, disgust and surprise. Since disgust recognition from prosody is the most difficult emotion to be recognized even in healthy subjects, same authors excluded this emotion (Adolphs and Tranel, 1999; Adolphs et al., 2001). Only one study excluded fear (Laurent et al., 2014). In eight studies auditory perception was tested by audiometry to document normal hearing. Three innovative studies tested emotion recognition from music, using musical excerpts composed to induce fear, peacefulness, happiness and sadness (Gosselin et al., 2005; 2011b; Khalfa et al., 2008); patients’ musical education was considered and reported. 3.1.4. Stimulus presentation There were a number of subtle variations of presentation and response options, particularly pertinent to facial stimuli, as these are not naturally time-limited (as auditory stimuli are). In all the studies that tested facial expression recognition, the visual stimuli were presented until participants had made a choice. In the majority of the tests that used auditory stimuli, stimulus repetition was allowed until the subject had made a choice. 3.1.5. Response option Thirty studies out of 43 used a forced choice paradigm, in which patients were given a limited set of written verbal emotion terms and asked to pick the one that best described the stimulus. Most gave the same number of response options, as there were emotion categories (e.g. if six different emotions were presented, there would be six response options). In the remaining studies, 10 used rating scales: that is to rate the intensity of the expression in regard to an emotion term on a scale of 1 (not at all) to 6 or 10 (very much). Three studies used matching response option, that means to chose the same or different emotion expression in a list of pictures (McClelland et al., 2006; Hlobil et al., 2008; Laurent et al., 2014). 3.1.6. Study populations Study population were drawn from a range of countries, including United States (8), United Kingdom (7), Italy (9), France (5), Canada and Spain (3), Japan (2), Netherland, India, Australia, Germany, Czech Republic and Switzerland (1). Ethnicities of participants in each country were not explicitly reported in any study. All of the included studies compared patients’ ER abilities with healthy volunteers (HV). The HV-group was matched for principal demographic variables (age, education and sex) in the majority of studies. When the two populations differed, the relevant variables were included as covariates in statistical analysis. Twenty-three studies chose only healthy volunteers as control. Fifteen studies included also a clinical control group (frontal or extra temporal lobe epilepsy, generalized epilepsy) (see Table 1). The choice to compare medial TLE with other epilepsy patients is relevant to ascribe the specificity of the observed deficits (if any) to the medial temporal lobe region, and to exclude a generic effect of epilepsy per se. The rational for

284


Table 1 List of studies fulfilling the inclusion criteria of the review. Year

First author

No. of patients (%male)

Age (mean)

Age of epilepsy onset (mean)

Type of patients

Clinical control group

Facial expressions

1995 1996 1996 1997 1998 1999 2000 2001 2002 2003 2003 2004 2004 2005

Adolphs Young Calder Scott Anderson Adolphs Anderson Adolphs Adolphs Meletti Meletti Benuzzi Brierley Reynders

7 (43%) 1 (0%) 2 (50%) 1 (0%) 1 (0%) 9 (56%) 23 (30%) 26 (65%) 32 (47%) 63 (40%) 33 (39%) 13 (54%) 28 (43%) 37 (41%)

34 51 57 50 n.a. 30 34 34 36 35 36 33 30 39

n.a. 28 28 28 n.a. n.a. 6 11 n.a. n.a. 11 >10 10 12

ATL Bil. Amy. Bil. Amy. Bil. Amy. Bil. Amy. ATL ATL ATL ATL TLE TLE TLE ATL TLE with IF

• • •

2005 2005 2006 2006 2006 2007 2008 2008 2008 2008 2008 2009 2009 2009 2011 2011 2011 2011 2012 2013 2013 2013 2014 2014 2014 2014 2014

Yamada Gosselin N McClelland Fowler Sanz Martin Shaw Ammerlaan Khalfa Walpole Hlobil Golouboff Palermo Meletti Carvajal Gosselin N Bonora Gosselin F Dellacherie Broicher Tanaka Sedda Pinabiaux Amlerova Amlerova Meletti Benuzzi GomezIbanez Meletti Laurent Wendling

1 (0%) 16 (44%) 12 (n.a.) 28 (n.a.) 5 (n.a.) 19 (42%) 9 (22%) 26 (35%) 16 (56%) 76 (42%) 29 (45%) 15 (27%) 140 (45%) 43 (47%) 14 (50%) 41 (41%) 23 (39%) 18 (56%) 28 (43%) 88 (47%) 66 (48%) 25 (72%) 74 (61%) 30 (56%) 42 (60%) 6 (83%) 19 (42%)

25 40 30 37 n.a. 37 37 31 45 30 12 44 37 35 42 48 44 39 33 42 36 13 35 37 44 23 41

9 n.a. 3 10 n.a. n.a. 20 n.a. n.a. n.a. 5 13 13 n.a. n.a. 20 n.a. n.a. 20 27 n.a. 3 17 20 15 >10 20

TLE ATL ATL TLE/ATL TLE TLE AH ATL TLE TLE TLE/ATL ATL TLE ATL ATL TLE ATL ATL TLE TLE TLE ATL TLE/ATL TLE ATL TLE TLE

E-TLE None None None n.a. E-TLE None E-TLE E-TLE E-TLE E-TLE None None IGE; TLE without IF AH None ATL* None ATL ATL None None None ATL E-TLE None E-TLE None None None None None E-TLE ATL None None None ATL None ATL IGE

1 (0%) 39 (54%) 33 (51%)

36 10 40

8 5 12

Bil. Amy. TLE ATL

TLE None AH

2014 2014 2015

Prosody/ sounds

Music

R L L L R R R R L L L L L L

• • • • • • • • • • •

•

•

• • • • • • •

• •

• • • • • • • • • • • • • • • • • • • • • •

• • • •

• •

Response options

R R M L L R L L L M L R L L L L L R L L L L L L L L L L M L

TLE, temporal lobe epilepsy; ATL, antero-medial temporal lobectomy; AH, amigdalo-hippocampectomy; Bil. Amy., bilateral amygdala damage; E-TLE, extra medial temporal lobe epilepsy; IGE, idiopathic generalized epilepsy; IF, ictal fear; n.a., not available; R, rating; L, labeling; M, matching. * The study compared adult patients after ATL grouped by age of epilepsy onset (5 years cut-off).

using an Extra-TLE group is that these epileptic patients live in a similar social and emotional environment with respect to people with TLE; they experience epilepsy stigma and limitation in social and personal aspects due to epilepsy; they also are treated with anti-epileptic drugs. Only four longitudinal prospective studies were found including TLE patients that were evaluated before (1–3 months) and after (3–12 months) ATL (Sanz-Martin et al., 2006; Shaw et al., 2007; Benuzzi et al., 2014; Amlerova et al., 2014). One case report (Yamada et al., 2005) evaluated a patient’s performance 4 weeks before and 2 weeks after epilepsy surgery. 3.1.7. Reporting of key demographic and electro-clinical data TLE is a well-defined syndrome, but some demographic variables could be relevant to distinguish subtype of patients. Factors such as age, education, and intelligence, may affect performance on cognitive tasks in both TLE and control groups. The impact of these factors both within studies (between patient and control

groups) and between studies needs to be taken into account when assessing differences in outcome. Forty studies were considered to have reported adequate demographic data often summarized in tables: age, gender, education, and an index of intellectual ability (IQ), both for patients and controls subjects. More than half of studies reported age at seizures onset and the duration of epilepsy. Only eleven studies evaluated the presence and the age of occurrence of febrile seizures. Twenty-eight studies evaluated ER abilities in post-surgery temporal lobe epilepsy patients, as shown in Table 1. Only 17 out of 28 studies reported details about seizure outcome after surgery for intractable temporal epilepsy. In 11 out of 17 studies, drug-resistant epileptic patients were seizure free (Engel I class) at time of evaluation. In most of the studies (11) patients were evaluated between 1 and 8 years after surgery, in seven studies ER was tested after weeks or months post-surgery, and for the remaining 10 studies authors didn’t report the time of testing. Most of the patients were taking antiepileptic drugs at time of evaluation.


285

Fig. 1. Facial emotion recognition performance in patients relative (%) to healthy controls.

3.2. Statistical analysis 3.2.1. Power analysis and sample size No study reported considerations of power and sample size calculation. The sample size of most studies (29/43) ranged from 1 to 20–30 patients. Thirteen studies involved more than 30 patients, but only one analyzed more than 100 patients (Meletti et al., 2009). 3.2.2. Potential confounding variables Potential confounding variables were dealt with in a number of different ways. Almost all studies reported gender, age and some measure of estimated intelligence (IQ) or educational level. Some of these (24/43) reported that groups were “matched” for one or more of these variables, reporting a statistic to confirm that there were no significant differences between groups. Six studies reported demographic differences between healthy controls and patients, in particular in age and education level; healthy subjects were younger and had a higher level of education compared to patients (Adolphs et al., 2002; Benuzzi et al., 2004; Shaw et al., 2007; Hlobil et al., 2008; Bonora et al., 2011; Tanaka et al., 2013). In these studies the authors included these variables as covariates in the statistical analysis. Overall, potential confounding variables were dealt with satisfactorily in 30/43 studies. 3.2.3. Normality of data The majority of studies (21/43) used parametric tests (ANOVA) for between and within groups statistical comparisons. However, not all studies reported whether the data were normally distributed (Fowler et al., 2006; McClelland et al., 2006; Khalfa et al., 2008; Shaw et al., 2007). Most of the studies reported data that did not meet assumptions needed for parametric statistics, especially for single emotion recognition performance. In these cases the authors used non-parametric tests (e.g. such as Mann–Whitney tests, Kruskal Wallis test; Meletti et al., 2003a,b; Benuzzi et al., 2004; Bonora et al., 2011). Some authors used Z-score transformation to normalize data distributions (Adolphs et al., 2001; Fowler et al., 2006; Golouboff et al., 2008; Broicher et al., 2012; Gosselin et al., 2011b; Sedda et al., 2013). 3.2.4. Multiple statistical comparisons All studies reported multiple statistical comparisons. All used Bonferroni adjustments when multiple comparisons were made, to reduce the likelihood of type 1 errors. To check the correlations

between variables, Pearson’s and Spearman’s rank-order correlation coefficients were often calculated (17/43). Other studies used MANOVA for multivariate comparisons (Golouboff et al., 2008; Broicher et al., 2012). All studies set p < 0.05 as the cut-off for statistical significance. 3.2.5. Reporting of analysis and results The majority of studies reported their analyses and results clearly. Most studies reported two-tailed tests. No studies chose to use one-tailed tests for some of the comparisons based on a priori predictions. 3.3. Outcomes Outcomes are described as statistically significant if they were reported as such in the original study. We first analyzed emotion recognition of patients in the visual and auditory modalities (not considering the side of lesions/epilepsy) relative to HV, and when possible relative to a clinical control group. 3.3.1. Facial emotion recognition Thirty-seven out of 43 studies used facial recognition tasks. Of these, 12 reported the composite score performance of the patients group: in all studies TLE patients were impaired respect with HV (Fig. 1). Table 2 reports the results of ER performance in TLE/ATL versus HV for the single emotion category. The data were available for 32 out of 37 studies that evaluated facial ER. The most consistent result was the evidence of impairment in fear recognition (29/31). Fear recognition was documented as isolated in the 50% of the studies (14 out of 29). In the remaining studies fear recognition was frequently associated with deficits in the recognition of disgust (13 studies), and sadness (7 studies). Impairment in anger recognition was reported only in four out of 29 studies, whereas recognition of happiness was rarely observed (two out of 29 studies). A widespread emotion recognition deficit, involving all negative emotions, was observed in 4 studies (Meletti et al., 2009; Bonora et al., 2011; Sedda et al., 2013; Meletti et al., 2014a). Only one study (Fowler et al., 2006) found no evidence of impairment for any basic emotion in TLE patients. The emotion recognition impairment was found across different stimuli: static pictures, bubble methods, and videos.

286


Table 2 Recognition of basic facial emotions in TLE and ATL patients versus healthy controls. Year

First author

No. of patients

Type of patients

1995 1996 2000 2001 2003 2003 2004 2004 2005 2005 2006 2006 2006 2007 2008 2008 2008 2009 2009 2011 2011 2011 2012 2013 2013 2013 2014 2014 2014 2014 2014 2015

Adolphs Calder Anderson Adolphs Meletti Meletti Benuzzi Brierley Reynders Yamada McClelland Fowler Sanz Martin Shaw Ammerlaan Hlobil Golouboff Palermo Meletti Gosselin N Bonora Gosselin F Broicher Tanaka Sedda Pinabiaux Meletti Benuzzi Gomez Ibanez Meletti Laurent Wendling

7 2 23 26 63 33 13 28 37 1 12 28 5 19 9 76 29 15 140 14 41 23 28 88 66 25 42 6 19 1 39 33

Bil. amy. Bil. Amy. ATL ATL TLE TLE TLE ATL TLE TLE ATL TLE/ATL TLE TLE AH TLE TLE/ATL ATL TLE ATL TLE ATL TLE TLE TLE ATL ATL TLE TLE Bil. Amy. TLE ATL

Ha

Sa

Fe

An

Di

Su

Ne

32 out of 43 studies are reported. Five studies were not reported since they did not evaluate single basic emotion recognition; six studies did not analyze facial expressions. TLE, temporal lobe epilepsy; ATL, antero-medial temporal lobectomy; AH, amygdalo-hippocampectomy; Bil. amy., bilateral amygdala damage. Ha, happiness; Sa, sadness; Fe, fear; An, anger; Di, disgust; Su, surprise; Ne, neutral. Significant difference (p < 0.05); non significant difference; blank: not evaluated.

Table 3 reports the results of ER performance in TLE/ATL versus a clinical control group. TLE/ATL patients showed a deficit in fear recognition in seven out of 11 studies. No other ER deficit was observed.

3.3.2. Auditory emotion recognition Twelve studies addressed emotional prosody in TLE/ATL. In eight out of 12 studies, evidence of impairment in vocal fear recognition was found both for speech prosody and short non-verbal vocal sounds (Table 4). Three studies reported evidence that fear recognition was selectively impaired (Anderson and Phelps, 1998; Adolphs et al., 2001; Sanz-Martin et al., 2006), while the other studies observed more widespread ER deficits.

No studies demonstrated a deficit in recognition of happiness from voices or sounds.

3.3.3. Recognition of emotion from music Three studies evaluated emotion recognition (rating) in ATL patients using music, in the form of excerpts that express happiness, sadness, fear (scary music) and peacefulness. Gosselin et al. (2005, 2011b) reported a selective impairment in recognition of scary music. Khalfa et al. (2008) analyzed happiness and sad music recognition observing that both right and left ATL patients were impaired in sad music recognition, while only right ATL patients were defective in decoding happiness.

Table 3 Recognition of facial emotion in TLE/ATL patients versus extra-TLE. Year

First author

No. of patients

Type of patients

1995 2001 2002 2003 2003 2005 2008 2009 2012 2014 2015

Adolphs Adolphs Adolphs Meletti Meletti Reynders Golouboff Meletti Broicher Gomez-Ibanez Wendling

7 26 32 63 33 37 29 140 28 19 33

Bil. amy. ATL ATL TLE TLE TLE TLE/ATL* TLE TLE TLE ATL

Ha

Sa

TLE, medial temporal lobe epilepsy; ATL, anteromedial temporal lobectomy; Bil amy., bilateral amygdala damage. Ha, happiness; Sa, sadness; Fe, fear; An, anger; Di, disgust; Su, surprise; Ne, neutral. Significant difference (p < 0.05); Non significant difference; blank: not evaluated. * Only left TLE/ATL patients had significant deficit versus Extra-TLE.

Fe

An

Di

Su

Ne


287

Table 4 Recognition of emotional prosody in TLE/ATL patients versus healthy controls. Year

First author

No. of patients

Type of patients

1997 1998 1999 2001 2004 2006 2006 2011 2011 2012 2014 2014

Scott Anderson Adolphs Adolphs Brierley Sanz Martin Fowler Bonora Dellacherie Broicher Meletti Laurent

1 1 9 26 28 5 28 41 18 28 1 39

TLE TLE ATL ATL ATL TLE TLE/ATL TLE ATL TLE Bil. Amy. TLE

Ha

Sa

Fe

An

Di

Su

Ne

TLE, medial temporal lobe epilepsy; ATL, anteromedial temporal lobectomy; Bil. amy., bilateral amygdala damage. Ha, happiness; Sa, sadness; Fe, fear; An, anger; Di, disgust; Su, surprise; Ne, neutral. Significant difference (p < 0.05); non significant difference; blank: not evaluated.

3.3.4. Cross-modal comparisons Eight out of 43 studies tested ER for facial expressions and for emotional prosody (see Table 1). Four out of eight studies demonstrated that TLE/ATL patients were impaired in both visual and auditory ER tasks. A widespread emotion recognition deficit, involving all negative emotions independently on the sensory channel, was observed by Bonora et al. (2011). Broicher et al. (2012) reported fear and disgust recognition impairments both for facial and prosodic stimuli. Brierley et al. (2004) reported fear and anger recognition deficits from facial expressions in ATL patients, while a widespread ER impairment was observed for emotional prosody. One study compared facial and music ER (Gosselin et al., 2011b): a positive correlation was evident for fear recognition.

3.3.5. Side of epilepsy/lobectomy Overall 31 studies analyzed facial ER in right TLE/ATL and left TLE/ATL subgroups versus HV (Table 5). Ten studies observed that only right-side patients had impairment in facial ER tasks compared to HV. Of these, four studies reported that right TLE/ATL were impaired versus left TLE/ATL groups. In all these studies, right TLE/ATL groups showed fear recognition impairment: in half of the studies it was a selective impairment. Ten studies reported that both right and left-side groups were impaired relative to controls, but no statistical difference was present between right- and left-sided TLE/ATL patients. Six out of 31 studies reported fear and disgust ER deficits in leftside patients compared with HV (Yamada et al., 2005; Shaw et al., 2007; Ammerlaan et al., 2008; Carvajal et al., 2009; Gosselin et al., 2011a; Wendling et al., 2015). In summary, most of the studies reported the effect of side of brain damage on facial ER impairment. The majority demonstrated that right TLE/ATL patients had worse performance compared with HV; in few studies right TLE/ATL patients had ER deficit both respect to HV and to left TLE/ATL patients. However, other studies did not find a significant difference between right and left patients’ performance, and few studies found that only left-side patients were impaired in facial ER compared with HV. Few data are available concerning ER in the auditory domain according to the side of the epileptogenic temporal lobe. Three studies demonstrated ER deficits in both groups, with no significant difference between the two groups (Brierley et al., 2004; Bonora et al., 2011; Dellacherie et al., 2011). One study did not analyze sub-groups performance based on the side of TLE (Broicher et al., 2012).

3.3.6. Age of epilepsy onset and duration of epilepsy Eighteen studies analyzed possible influence of age of epilepsy onset on ER results. This issue was assessed in different ways:

(a) Authors divided the patients’ group setting the age of 5 years as cut-off (early onset epilepsy versus late onset epilepsy): four studies used this subdivision (Meletti et al., 2003a,b; McClelland et al., 2006; Bonora et al., 2011; Meletti et al., 2014a). Three of these found that early-onset TLE patients had impairment in ER, especially for fearful faces, with respect to late-onset groups. On the contrary, the opposite pattern was observed analyzing ER performance in a group of seizure-free ATL patients examined more than five years after lobectomy (Meletti et al., 2014a): this apparent discrepancy was interpreted as the result of a great decline, respect to pre-surgery performance, for the ‘late onset’ patients, compared with a less decline in ‘early onset’ patients. (b) Authors considered the correlations between facial ER performance and the age of epilepsy onset and/or duration of epilepsy (i.e. using Spearman rank-order correlations or Pearson’s rank order correlations): fourteen studies used this analysis (Anderson et al., 2000; Adolphs et al., 2001; Meletti et al., 2003a; Reynders et al., 2005; Golouboff et al., 2008; Meletti et al., 2009; Palermo et al., 2010; Pinabiaux et al., 2013; Tanaka et al., 2013; Sedda et al., 2013; Amlerova et al., 2014; Benuzzi et al., 2014; Laurent et al., 2014; Wendling et al., 2015). Eight of these found a positive correlation between the age at onset of epilepsy and ER performance, supporting the hypothesis that earlier onset of temporal lobe seizures led to worse performances for recognition of facial expressions. Nine studies also showed that long duration of the epileptic disease was associated with a severe impairment in recognition of emotion, in both the visual and auditory modalities.

3.3.7. Emotion recognition before and after lobectomy Only five studies evaluated ER tasks in TLE patients, before and after ATL. One is a case report (Yamada et al., 2005) in which authors described an improvement in facial emotion recognition after left amygdalo-hippocampectomy. The patient had a high score of incorrect rating for several negative emotions before surgery. After surgery, the only deficit was found for disgust recognition. The second study compared a small group of TLE evaluated in facial and auditory emotion recognition (Sanz-Martin et al., 2006). The article was written in Spanish language and available information was incomplete. The authors described a lower number of

288


Table 5 Facial expression recognition in right and left TLE/ATL groups. Year

First author

1995 2000 2001 2002 2003 2003 2004 2004 2005 2005 2006 2006 2006 2007 2008 2008 2008 2008 2009 2009 2009 2011 2011 2011 2012 2013 2013 2013 2013 2014 2014 2014 2014 2014 2015

Adolphs Anderson Adolphs Adolphs Meletti Meletti Benuzzi Brierley Reynders Yamada McClelland Fowler Sanz Martin Shaw Ammerlaan Walpole Hlobil Golouboff Palermo Meletti Carvajal Gosselin N Bonora Gosselin F Broicher Tanaka Tanaka Sedda Pinabiaux Amlerova Meletti Gomez-Ibanez Benuzzi Laurent Wendling

No. of patients 7 23 9 26 33 63 13 28 37 1 12 28 5 19 9 16 76 29 15 140 43 14 41 23 28 63 25 66 25 74 42 19 6 39 33

Type of patients ATL ATL ATL ATL TLE TLE TLE ATL TLE with IF TLE ATL TLE/ATL TLE TLE AH TLE TLE TLE/ATL ATL TLE ATL ATL TLE ATL TLE TLE ATL TLE ATL TLE/ATL ATL TLE TLE TLE ATL

Right versus HC

Left versus HC

Right versus left*

Di, Ha; Sa Fe

Di; Fe; Ha; Sa

Di; Fe; Sa Di; Fe; Sa Fe An; Fe

Fe

An; Fe Di

Fe Fe Fe Di; Fe Fe Di Fe An; Fe; Sa Fe

Fe; Ne Fe n.r. Fe

Fe Fe An; Fe; Sa n.r.

Fe Di; Fe Fe; Sa An; Di; Fe; Sa Fe n.r.

Di; Fe Fe; Sa An; Sa Fe n.r.

Di; Fe

Fe; Di

Fe; Di

Fe

TLE, temporal lobe epilepsy; ATL, antero-medial temporal lobectomy; AH, amigdalo-hippocampectomy; Bil. Amy., bilateral amygdala damage. IF, ictal fear; HV, healthy vlunteers. Ha, happiness; Sa, sadness; Fe, fear; An, anger; Di, disgust; Su, surprise; Ne, neutral. n.r., not reported. Significant difference (p < 0.05); non significant difference; blank: not evaluated. * Right TLE/ATL lower scores respect with left TLE/ATL; the opposite pattern was not observed in any study.

correct responses both in facial and prosodic recognition in rightside ATL after surgery. The third study is a well-designed prospective study in a cohort of 19 patients before and after ATL (Shaw et al., 2007). The patients were tested between 1–3 months pre-operatively and 4–6 months post-operatively. Authors used a rating scale for facial ER tasks, in which patients were asked to rate the intensity of one of the six basic emotions. The results showed that pre-operatively right ATL and to a lesser extent left-ATL groups gave higher incongruent ratings for all negative emotions. Post-operatively, left-ATL group showed a significant improvement for incongruent fear rating. More recently, Benuzzi et al. (2014) compared six patients before and after ATL. They found an improvement in fear ER in two right-side patients, after ATL. A prospective study in a large population of 30 TLE patients (Amlerova et al., 2014) demonstrated that no significant changes in ER abilities before and after ATL were observed. The limitation of this study was due to the inclusion of patients not seizure-free after ATL. 3.3.8. Extent of anterior temporal lobectomy Eight studies out of 43 reported volumetric measures of brain damage in TLE patients due to surgery. These studies reported the details about the extent of temporal lobe lesions (confined to amygdala, extended to hippocampus, temporal pole or posterior temporal lobe). Four of these studies evaluated possible influence of the extent of brain damage after surgery in ER impairment (Adolphs et al., 2001; Gosselin et al., 2011b; Dellacherie et al., 2011; Wendling et al., 2015).

Adolphs et al. (2001) found a small, negative correlation between ER performance scores and extent of unilateral amygdala damage both for faces and prosody, neither of which, however, was statistically significant. Dellacherie et al. (2011) and Wendling et al. (2015) divided patients in two sub-groups based on extent of the resection (incomplete and complete removal of the amygdala in first study, selective amygdalo-hippocampectomy (SAH) versus standard temporal lobectomy in second). Dellacherie and colleagues demonstrated that resection of the basolateral complex of the amygdala was sufficient to impair the recognition of fearful and, to a lesser extent, surprised vocalizations. Wendling et al. demonstrated that ATL patients had deficit in fear recognition compared to SAH; instead SAH patients had worse performance in recognition of disgust compared with ATL group. Gosselin et al. (2011b) showed that patients’ score for fearful faces recognition negatively correlated with the resection size of ATL. 3.3.9. Emotion recognition and measures of intelligence Most of the studies reported measures of intelligence quotient (IQ), however only eight out of 43 studies formally analyzed possible influences of IQ on ER performance. Five studies obtained no significant correlation with all the different measures (overall IQ, verbal IQ, performance IQ) (Adolphs et al., 2001; Reynders et al., 2005; Walpole et al., 2008; Hlobil et al., 2008; Wendling et al., 2015). Bonora et al. (2011) found a positive correlation between emotional prosody recognition and overall IQ, as well as verbal IQ, in TLE patients. Also Broicher et al. (2012) reported that


lower performance in general emotion recognition tasks, in particular in auditory domain, were associated with reduced verbal IQ. Amlerova et al. (2014) demonstrated that the only significant predictor for impairment in ER abilities was the full-scale IQ. 3.3.10. Subjective measures of psychosocial well-being In four studies out of 43, the QOLIE-31 (Cramer et al., 1998) was administered to patients; only one study (single case) reported a significant positive correlation between correct fear attribution scores and overall quality of life (Reynders et al., 2005). Lack of correlation between facial and auditory recognition scores and QOLIE-31 was observed in the remaining three studies (Walpole et al., 2008; Bonora et al., 2011; Broicher et al., 2012). These studies also considered other scales to evaluate psychosocial well-being, such as Hospital Anxiety and Depression Scale (HADS) (Zigmond and Snaith, 1983), Toronto alexithymia scale (Kupfer et al., 2001), self report scales such as Symptom Check List-90-Revised (SCL-90R) (Derogatis, 1983), as well as the QOLIE-31 emotional well-being and social function sub-scale scores: no statistical correlations with ER impairment were found. Golouboff et al. (2008) evaluated a pediatric population using the Child Behavior Checklist (CBCL) (Achenbach, 1991). They found a positive correlation between ageadjusted emotion recognition scores and total CBCL scores in the group of children with right TLE. Eleven studies out of 43 evaluated depression by means of the Beck Depression Inventory (Beck et al., 1961). Of these, six analyzed a possible correlation between depressive symptoms and ER: only one study found an association between the emotion recognition and the score on depression scales (Walpole et al., 2008). 3.3.11. Effect of anti-epileptic drugs Only four studies out of 43 reported information about the number and types of anti-epileptic drugs (AED) used by patients in the period of evaluation. Three studies analyzed possible negative influence of number or type of AED on emotion recognition performance. Meletti et al. (2009) grouped TLE patients according to the number of AED taken (one, two, three and more-AED groups). No difference in ER scores was observed among the three groups. Then they analyzed ER in TLE patients using a given AED compared to TLE patients that were not taking that particular AED. They observed that only the use of Phenobarbital had a negative effect on emotion recognition abilities. Hlobil et al. (2008) described that fear recognition was significantly associated with the number of AEDs taken at time of testing. Laurent et al. (2014) compared ER performance in patients with monotherapy versus polytherapy founding no significant differences. 4. Discussion Certain general conclusions emerge from this review of studies of emotion recognition in TLE and ATL. Considering firstly the most widely used emotional stimulus (facial expressions), fear recognition appears to be most consistently impaired in TLE populations, closely followed by recognition of disgust and sadness, whereas recognition of anger and surprise are less consistently affected, and recognition of happiness only rarely affected. In both TLE and ATL patients, negative emotions, are affected more severely than the positive/ambiguous emotions of happiness and surprise. Notably, fear recognition deficits seem selective when comparing TLE/ATL patients respect with extra-temporal lobe epilepsies. In this sense fear recognition appears to be a good behavioral marker of chronic temporal lobe epilepsy. Information about recognition of emotions via other sensory channels in TLE remains too limited for firm conclusions to be drawn. However, at least for vocal emotion recognition, the emerging picture is broadly convergent with the data obtained for facial

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expressions. The recognition of vocal fear is consistently impaired, although recognition of vocal disgust and sadness are often also impaired. The few studies that investigated emotion recognition from musical excerpts suggest that TLE/ATL impairs also the emotional attributions to complex, and strongly emotional stimuli, as the music ones are. In particular scary music recognition was consistently impaired. In accordance with these findings cross-modal recognition deficits were observed in the few studies where this issue has been specifically investigated (Bonora et al., 2011; Broicher et al., 2012; Gosselin et al., 2011b). 4.1. Right versus left temporal lobe damage The majority of studies have addressed the question of whether or not the ER deficit is lateralized to the right or left temporal lobe. The answer to this question obviously has a dual significance. On one hand, it can contribute to our understanding of the role of the two temporal lobes in the perception of stimuli with emotional valence. On the other hand it may indicate which patients are most at risk of developing deficits in emotion recognition. The results of this review do not provide a framework for unambiguous interpretation. In fact, in one third of the analyzed studies a deficit was evident only in patients with lesions confined to the right temporal lobe; however in a third of the studies a deficit in both right and left TLE/ATL groups was observed, and finally, six studies document a deficit only in patients with left TLE/ATL. Therefore it is not possible to give a precise answer. There are several possible explanations for these discordant results. Apart from methodological differences regarding the type of stimuli and presentation, it must be considered that TLE is a complex disease. Moreover in some case the presumed lateralization of epilepsy may be incorrect, or even if correct it can be misleading. For example, even in cases with unilateral hippocampal sclerosis, the epileptogenic network dysfunction might involve bi-temporal and extra-temporal regions (Bernasconi et al., 2003; Chassoux et al., 2004; Lee et al., 2005). Also, in cases of early onset seizures, plasticity phenomena may have resulted in a remodeling of memory function, language, and emotions in the two temporal lobes (Saykin et al., 1989; Davies et al., 1996). Finally, many studies are small series and are probably underpowered to show statistically significant differences. Clearly the natural clinical variability may underlie many of the inter-study differences reported here, meaning that where differences do exist, they are not necessarily contradictory. 4.2. Emotion recognition and age of temporal lobe damage Several studies tried to understand if there is a particular age of life that exposes one to risk of developing deficits in the recognition of emotions. In this sense, the review provides a clear answer, despite the different methodologies used across studies. That is, exposure to seizures in early childhood (febrile or afebrile) correlates with a more severe deficit of recognition. It is important to emphasize, however, that in the case of TLE the term “exposure” does not mean a contact with a discrete event (that start and stop), but it means the exposure to a damage that begins at a specific timepoint and then continues chronically in subsequent years. Evidence suggested that impaired recognition of facial expressions of fear occurs early in TLE (Golouboff et al., 2008). Interestingly, a recent study investigated ER in a group of school-aged children that were exposed to febrile seizures in early infancy: a proportion of patients had ER deficits even if they had not (yet) developed overt epilepsy (Cantalupo et al., 2013). Taken together, the evidence emerging from the review suggests that recognition of various negative emotions may be affected from an early stage in TLE, and that impairments become more

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likely, more severe and more widespread across emotions as disease evolves. Indeed, also the duration of epilepsy was observed as a negative factor, able to influence ER performance: longer duration of epilepsy was related to worst performance in ER tasks, especially for fear recognition. However, the lack of uniformity in measures of disease stage and severity across studies precludes a precise statement about the time course or profile of these deficits; this is one of the weaknesses in the literature.

of global and emotional wellbeing. This is one important question that needs to be elucidated in future studies. Indeed, the possibility exists that the studies carried out so far have not documented a correlation because patients with TLE have little awareness of their own social difficulties. Therefore, future studies should also use different measures, and not only subjective ones, to quantify the difficulty that patients have in everyday life and possible changes overtime (Quintas et al., 2012). 4.6. Study limitations

4.3. Anterior temporal lobectomy effects The review showed that in patients with ATL there is a lack of emotion recognition skills, with qualitative and quantitative characteristics apparently similar to that observed in patients with pre-surgical TLE. Unfortunately, there are currently only five studies that have investigated the longitudinal changes before and after temporal lobectomy, moreover these studies are with small groups or case reports. It is therefore not possible to determine the real effect of temporal lobectomy in TLE patients. Finally, a major weakness, observed in some of the studies, is the lack of clinical information pertaining to the surgical outcomes, with respect to seizure control. This is a highly relevant issue in the analysis of neuropsychological outcomes. The literature suggests that temporal lobectomy in this clinical context does not cause additional deficits in emotion recognition. Indeed, some evidence exists that after lobectomy, and seizure-freedom, patients can improve in ER (Yamada et al., 2005; Shaw et al., 2007; Benuzzi et al., 2014; Amlerova et al., 2014). 4.4. Other disease-related variables To date few studies have evaluated formally the relationship between global intelligence measures and emotion recognition in TLE. Two studies documented a negative effect of low overall and verbal IQ scores on auditory emotion recognition. Almerova et al. (2014) demonstrated that full-scale IQ was significant predictor for impairment in FER abilities. However, data are not sufficient to make a final judgment. Finally, only three studies have evaluated the effect of antiepileptic drugs. The largest study (Meletti et al., 2009) did not report statistically significant differences in the recognition of facial emotions as a function of the number of drugs taken. It was impossible to determine the effects of specific antiepileptic drugs with the exception of Phenobarbital whose administration was associated with poor performance. 4.5. Clinical relevance Overall, the findings of this review have clinical implications. One key implication is that emotion recognition could potentially serve as a behavioral marker of disease onset and progression in TLE. Emotion scores (both composites and individual emotions) are indeed a part of the neuropsychological deficits of patients with chronic TLE and further work should demonstrate how sensitive emotion recognition is at tracking decline over time, relative to other potential markers. From the perspective of the individual patient with TLE, these results clearly show that TLE is associated with impaired recognition of negative emotions, and especially fear. There is however, little formal evidence concerning the impact of emotional deficits on the social functioning of people with TLE. The studies that investigated measures of wellbeing such as QOLIE-31 failed to demonstrate a correlation between measures of ER and measures

There are important limitations on an analysis of this kind. The review was limited to peer-reviewed publications and this represents an important potential source of bias in attempting to estimate the overall significance of emotion recognition deficits in TLE. In addition, the size and comprehensiveness of the studies included in the review varied widely. Small studies are potentially under-powered to detect small effects or to adjust for confounding factors (particularly for non-standard data distributions), whilst in large studies it may be more difficult to tailor assessments to particular kinds of deficits or to assess deficits comprehensively. A further source of variation between studies is linked to the different paradigms used to assess emotion recognition, even within a modality (e.g., facial expressions). Finally, some potential relevant issue has not been addressed in the published studies. Indeed, it has been observed that the processing of emotions is somewhat different in males and females, particularly concerning the involvement of the amygdala (Derntl et al., 2009; Stevens and Hamann, 2012). No study has investigated the effect of TLE and ATL comparing groups in reference to gender and this point need to be assessed in future studies. 4.7. Conclusions This review suggests certain clear directions for further work. There is a need for large, longitudinal studies of emotion comprehension in TLE (and especially before and after ATL) that are informed by emerging neurobiological data and which use consistent measures of disease stage and overall severity as well as uniform assessment instruments. In future studies it will be important to compare emotion processing in different sensory modalities, and at different levels of response (autonomic as well as cognitive), and to extend the assessment to include more ecological kinds of emotion processing beyond the relatively artificial scenario of the forced-choice recognition protocol. There is also a need to understand how these deficits, and the other cognitive difficulties noted in this disease, impact on patients’ everyday lives. Like other diseases, TLE will almost certainly benefit from the progress currently being made in the basic neuroscience of human emotion. The structural and functional anatomical bases for altered emotion processing in TLE should be addressed in hypothesis-driven studies motivated by the neuropsychological data.

Appendix A. Articles that did not meet inclusion criteria (chronological order) Reference

Reasons of exclusion

LaBar, K.S., LeDoux, J.E., Spencer, D.D., Phelps, E.A.J., 1995. Impaired fear conditioning following unilateral temporal lobectomy in humans. Neuroscience 15 (10), 6846–6855.

The study evaluated skin conductance responses to auditory stimuli. No measures of explicit ER.


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Reference


Reference


Adolphs, R., Tranel, D., Hamann, S., Young, A.W., Calder, A.J., Phelps, E.A., Anderson, A., Lee, G.P., Damasio, A.R. 1999. Recognition of facial emotion in nine individuals with bilateral amygdala damage. Neuropsychologia 37 (10), 1111–1117. Anderson, A.K., Phelps, E.A. 2001. Lesions of the human amygdala impair enhanced perception of emotionally salient events. Nature 17, 411 (6835), 305–309. Glascher, J., Adolphs, R.J., 2003. Processing of the arousal of subliminal and supraliminal emotional stimuli by the human amygdala. Neuroscience 23 (32), 10274–10282.

No history of epilepsy in any patients.

Machado, Lde V., Frank, J.E., Tomaz, C., 2010. Emotional declarative memory assessment of patients with mesial temporal lobe epilepsy and patients submitted to mesial temporal lobectomy. Arq. Neuropsiquiatr. 68 (5), 737–743. Ahs, F., Kumlien, E., Fredrikson, M., 2010. Arousal enhanced memory retention is eliminated following temporal lobe resection. Brain Cogn. 73 (3), 176–179. Rutishauser, U., Tudusciuc, O., Neumann, D., Mamelak, A.N., Heller, A.C., Ross, I.B., Philpott, L., Sutherling, W.W., Adolphs, R., 2011. Single-unit responses selective for whole faces in the human amygdala. Curr. Biol. 21 (19), 1654–1660. Meletti, S., Cantalupo, G., Benuzzi, F., Mai, R., Tassi, L., Gasparini, E., Tassinari, C.A., Nichelli, P., 2012. Fear and happiness in the eyes: an intra-cerebral event-related potential study from the human amygdala. Neuropsychologia 50 (1), 44–54. Cantalupo, G., Meletti, S., Miduri, A., Mazzotta, S., Rios-Pohl, L., Benuzzi, F., Pisani, F., Tassinari, C.A., Cossu, G., 2013. Facial emotion recognition in childhood: the effects of febrile seizures in the developing brain. Epilepsy Behav. 29 (1), 211–216. Bach, D.R., Hurlemann, R., Dolan, R.J., 2013. Unimpaired discrimination of fearful prosody after amygdala lesion. Neuropsychologia 51 (11), 2070–2074.

Emotional memory tasks were used. No measures of explicit ER.

Krolak-Salmon, P., Hénaff M.A., Isnard, J., Tallon-Baudry, C., Guénot, M., Vighetto, A., Bertrand, O., Mauguière, F., 2003. An attention modulated response to disgust in human ventral anterior insula. Ann. Neurol. 53 (4), 446–453. Stone, V.E., Baron-Cohen, S., Calder, A., Keane, J., Young, A., 2003. Acquired theory of mind impairments in individuals with bilateral amygdala lesions. Neuropsychologia. 41 (2), 209–220. Vuilleumier, P., Richardson, M.P., Armony, J.L., Driver, J., Dolan, R.J., 2004. Distant influences of amygdala lesion on visual cortical activation during emotional face processing. Nat. Neurosci. 7 (11), 1271–1278. Glogau, S., Ellgring, H., Elger, C.E., Helmstaedter, C., 2004. Face and facial expression memory in temporal lobe epilepsy patients: preliminary results. Epilepsy Behav. 5 (1), 106–112. Krolak-Salmon, P., Hénaff, M.A., Vighetto, A., Bertrand, O., Mauguière, F., 2004. Early amygdala reaction to fear spreading in occipital, temporal, and frontal cortex: a depth electrode ERP study in human. Neuron 42 (4), 665–676. Shaw, P., Lawrence, E.J., Radbourne, C., Bramham, J., Polkey, C.E., David, A.S., 2004. The impact of early and late damage to the human amygdala on ‘theory of mind’ reasoning. Brain 127 (Pt 7), 1535–1548. Shaw, P., Brierley, B., David, A.S., 2005. A critical period for the impact of amygdala damage on the emotional enhancement of memory? Neurology 65 (2), 326–328. Graham, R., Devinsky, O., LaBar, K.S., 2006. Sequential ordering of morphed faces and facial expressions following temporal lobe damage. Neuropsychologia 44 (8), 1398–13405. Müller, N.G., Wohlrath, B., Kopp, U.A., Lengler, U., 2009. Emotional content does not interfere with verbal memory in patients with temporal lobe epilepsy. Epilepsy Behav. 15 (3), 367–371. Brand, J.G., Burton, L.A., Schaffer, S.G., Alper, K.R., Devinsky, O., Barr, W.B., 2009. Emotional recognition in depressed epilepsy patients. Epilepsy Behav. 15 (3), 333–338. Bonelli, S.B., Powell, R., Yogarajah, M., Thompson, P.J., Symms, M.R., Koepp, M.J., Duncan, J.S., 2009. Preoperative amygdala fMRI in temporal lobe epilepsy. Epilepsia 50 (2), 217–227. Pourtois, G., Spinelli, L., Seeck, M., Vuilleumier, P., 2010. Temporal precedence of emotion over attention modulations in the lateral amygdala: intracranial ERP evidence from a patient with temporal lobe epilepsy. Cogn. Affect Behav. Neurosci. 10 (1), 83–93. Hayakawa, Y., Mimura, M., Murakami, H., Kawamura, M., 2010. Emotion recognition from stimuli in different sensory modalities in post-encephalitic patients. Neuropsychiatr. Dis. Treat. 6, 99–105.

No measures of explicit ER.

The study evaluated skin conductance responses to emotional stimuli. No measures of explicit ER. Intracranial event-related potentials in response to emotional faces. No measures of explicit ER. Study based on ToM. No measures of basic emotion recognition tasks. fMRI study. No measures of explicit ER.

No measures of explicit ER.

Intracranial event-related potentials in response to emotional faces. No measures of explicit ER. No measures of explicit basic ER.

The study evaluated emotional memory task. No measures of explicit ER. No measures of explicit ER.

The study evaluated emotional memory tasks. No measures of explicit ER. The patients’ group is a mixed cohort of different epilepsy syndromes (IGE, TLE, FLE). fMRI study. No measures of explicit ER.

Intracranial event-related potentials in response to emotional faces. No measures of explicit ER. No history of epilepsy in any patients.

Emotional memory tasks. No measures of explicit ER. Intracranial recording with single unit response to face part and whole faces. No measures of explicit ER. Intracranial event-related potentials in response to emotional faces. No measures of explicit ER. No history of MTLE in any patients.

No history of epilepsy in any patients.

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