ORIGINAL INVESTIGATION

Neural bases of atypical emotional face processing in autism: A meta-analysis of fMRI studies

YUTA AOKI 1 , SAMUELE CORTESE 2,3,4 & MICHELE TANSELLA 5

1 Department of Neuropsychiatry, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan, 2 Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK, 3 Division of Psychiatry, Institute of Mental Health, University of Nottingham, Nottingham, UK, 4 Phyllis Green and Randolph Cowen Institute for Pediatric Neuroscience, Child Study Center of the NYU Langone Medical Center, New York, USA, 5 Department of Public Health and Community Medicine and WHO Collaborating Centre for Research and Training in Mental Health and Service Evaluation, University of Verona, Verona, Italy

Abstract Objectives. We aim to outline the neural correlates of atypical emotional face processing in individuals with ASD. Methods. A comprehensive literature search was conducted through electronic databases to identify functional magnetic resonance imaging (fMRI) studies of whole brain analysis with emotional-face processing tasks in individuals with ASD. The Signed Differential Mapping with random effects model was used to conduct meta-analyses. Identifi ed fMRI studies were further divided into sub-groups based on contrast ( “ emotional-face vs. non-emotional-face ” or “ emotional-face vs. non-face ” ) to confi rm the results of a meta-analysis of the whole studies. Results. Thirteen studies with 226 individuals with ASD and 251 typically developing people were identifi ed. We found ASD-related hyperactivation in subcortical struc-tures, including bilateral thalamus, bilateral caudate, and right precuneus, and ASD-related hypoactivation in the hypoth-alamus during emotional-face processing. Sub-analyses with more homogeneous contrasts preserved the fi ndings of the main analysis such as hyperactivation in sub-cortical structure. Jackknife analyses showed that hyperactivation of the left caudate was the most robust fi nding. Conclusions. Abnormalities in the subcortical structures, such as amygdala, hypotha-lamus and basal ganglia, are associated with atypical emotional-face processing in individuals with ASD.

Key words: Asperger ’ s syndrome , autistic disorder , functional magnetic resonance imaging , human , pervasive developmental disorders

Introduction

Autism spectrum disorder (ASD) is a neurodevelop-mental condition characterized by impairments in social communication and restricted interests/repeti-tive behaviours (Association 2013) without estab-lished curative treatment (Yamasue et al. 2012), affecting approximately one individual in 100 in the general population (Fombonne 2003; Kim et al. 2011).

It has been proposed that defi cits in the identifi ca-tion of the emotional status of others play a key role in disturbed social interaction and communication in individuals with ASD (Sigman et al. 1992; Yirmiya et al. 1992; Bellani et al. 2011). Indeed, a number of

behavioural studies reported that individuals with ASD have diffi culties in face identifi cation (Weigelt et al. 2012), particularly in facial emotion recogni-tion (Tantam et al. 1989; Celani et al. 1999; Pelphrey et al. 2002; Harms et al. 2010). Additionally, although it has been reported that individuals with ASD may in part compensate for these defi cits, even individu-als with high-functioning ASD experience diffi culties in recognizing facial expressions related to negative emotions, such as sadness or fear (Pelphrey et al. 2002; Harms et al. 2010).

A number of functional magnetic resonance imaging (fMRI) studies investigated the neural cor-relates of disturbed emotional-face processing in individuals with ASD. However, overall they have

Correspondence: Yuta Aoki, MD, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-8655, Japan. Tel: � 81-3-3815-5411. Fax: � 81-3-5734-8023. E-mail: yuaoki-tky@umin.ac.jp

(Received 22 April 2014 ; accepted 19 August 2014 )

The World Journal of Biological Psychiatry, 2014; Early Online: 1–10

ISSN 1562-2975 print/ISSN 1814-1412 online © 2014 Informa HealthcareDOI: 10.3109/15622975.2014.957719

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Methods

Data sources

A systematic literature search of fMRI studies in individuals with ASD with emotional-face process-ing tasks was conducted through the PubMed, Web of Knowledge and Ovid databases (Medline, PsychInfo, Embase � Embase classic) from their inception up to 1 July 2013. The search keywords, with adapted syntax for each database, were “ fMRI ” , and “ functional magnetic resonance ” combined with “ autism ” , “ ASD ” , “ Asperger ” , or “ pervasive devel-opmental disorder ” (see Supplementary Information for details about search terms and syntax in each database available online at http://informahealthcare.com/doi/abs/10.3109/15622975.2014.957719). Two authors (YA and SC) conducted the search and papers screening independently. Potential disagree-ment on selected studies was resolved by discussion with the senior author (MT).

Selection of studies

Studies were included in the meta-analysis if they: (1) were full paper peer-reviewed fMRI studies whose abstract was written in English (Sonuga-Barke et al. 2014); (2) included individuals diagnosed with ASD according to established diagnostic tools; (3) used fMRI emotional-face processing task(s); (4) reported peak coordinates for the relevant contrasts; and (5) compared whole-brain contrasts of individuals with ASD and a control group of individuals with TD, i.e., they reported results of between-group analysis instead of within-group analysis. The Preferred Report-ing Items for Systematic Reviews and Meta-Analyses Statement was followed (Moher et al. 1999).

Data extraction

We extracted the number and mean age of partici-pants of both groups (i.e., ASD and TD), and the coordinates and effect sizes of peak coordinates, which were generally more available than other indi-ces of activation such as mean activations of clusters. Coordinates reported in Montreal Neurological Institute (MNI) space were converted to Talairach space using the Signed Differential Mapping (SDM) utility. When different types of statistical values were reported, such as Z or P values, they were converted to t -values, using the t -value calculator provided by the SDM projects, accounting for the number of participants in both groups, and the number of cova-riates (see Supplementary material available online at http://informahealthcare.com/doi/abs/10.3109/15622975.2014.957719) (Radua and Mataix-Cols 2009;

yielded inconsistent results (Kleinhans et al. 2011; Morita et al. 2011). The heterogeneity of ASD in terms of its aetiology (Happe et al. 2006) as well as to the heterogeneity of experimental paradigms across studies may contribute to explain the incon-sistency across studies. However, identifying consis-tent neural correlates of atypical emotional-face processing in individuals with ASD has the potential to outline brain regions that are involved in atypical behaviours associated with ASD (Hart et al. 2012, 2013). To the best of our knowledge, three meta-analyses of fMRI studies in individuals with ASD have been published so far, and all of them have tried to investigate neural correlates of atypical social cog-nition in individuals with ASD (Di Martino et al. 2009; Philip et al. 2012; Dickstein et al. 2013). How-ever, because of an insuffi cient number of studies reported before, they integrated studies with exten-sive heterogeneity in methodologies and psychologi-cal tasks, such as emotional-face processing tasks and executive function tasks. Thus, no meta-analysis has focused on specifi c component of social cogni-tion in individuals with ASD pooling results from fMRI studies with whole brain analysis. Hereby, we performed a systematic review and meta-analysis of fMRI studies of emotional-face processing in indi-viduals with ASD, without violating the assumption underlying the meta-analytic procedure that, under the null hypothesis, the likelihood of locating acti-vated foci is equal at every voxel, in order to deter-mine which brain regions are consistently hyper- or hypoactivated in individuals with ASD compared with controls (i.e., typically developing, TD, indi-viduals) across studies.

Previous fMRI studies of TD individuals reported that cortical structures are involved in conscious emo-tional-face processing, while subcortical structures, such as the basal ganglia, particularly the thalamus and striatum in addition to the amygdala, are related to unconscious emotional-face processing (Dalgleish 2004; Adolphs 2008; Tamietto and de Gelder 2010; Bornstein and Daw 2011; Peron et al. 2013). A previ-ous fMRI study with individuals with ASD has sug-gested that they may be trained in recognition of emotional face with improving atypical cortical activ-ity (Bolte et al. 2006). However, behavioural studies have demonstrated that individuals with ASD still have diffi culty in emotional-face processing (Pelphrey et al. 2002; Harms et al. 2010). Thus, we expected that disturbance in unconscious emotional-face pro-cessing would be diffi cult to be trained and a more basic and consistent defi cit than that in conscious processing. Therefore, we hypothesized that there are more abnormal activations in the subcortical struc-tures, such as the thalamus, striatum and amygdala than in cortical structures across studies.

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Atypical subcortical activity in autism 3

guessing the age or identifying the sex from the face, in order to control for non-emotionally-re-lated processes in face processing.

Sensitivity analysis

To challenge the robustness of the fi nding, we conducted a jackknife sensitivity analysis. Jackknife sensitivity analysis, otherwise phrased “ one study removed sensitivity analysis ” , is a kind of sensitivity analysis that repeats the same analysis excluding one study at one time. This is a way of assessing whether the result is infl uenced by only one study. It is usable when there is not suffi cient number of studies to conduct sensitivity analysis with more homogenous sub-group. In jackknife sensitivity analysis of meta-analysis of studies with whole brain analysis, it is assumed that the brain region where the more jackknife sensitivity analysis demonstrates signifi cant difference, the more the signifi cant dif-ference of the brain region is replicable and robust (Radua and Mataix-Cols 2009; Nakao et al. 2011).

Results

Study selection

Among 1197 potentially relevant studies, the com-prehensive literature search identifi ed at fi rst 26 studies as potential candidates for the meta-analysis. Of these studies, 11 fMRI studies were excluded because they did not adopt emotional-face process-ing tasks. Additionally, two fMRI studies were excluded because they did not report the results of between-group (ASD vs. TD) analyses. Conse-

Radua et al. 2012). Three studies showed different types of emotional-faces, such as happy, sad, and fearful faces, and reported results for each emotion-al-face (Deeley et al. 2007; Weng et al. 2011; Rahko et al. 2012). As the previous behavioural studies in individuals with ASD demonstrated that they have diffi culty in recognizing the emotional status of fearful and sad rather than happy faces (Harms et al. 2010), we retained data for fearful and sad faces. We obtained effect sizes and peak coordinates from fearful face condition in Deeley et al. (2007) and Rahko et al. (2012) and sad face condition in Weng et al. (2011). The contrasts from which we extracted the effect size of peak coordinates are shown in Supplementary Table 1 (available online at http://informahealthcare.com/doi/abs/10.3109/15622975.2014.957719).

Data analysis

Comparison of regional activation. We used the SDM software (www.sdmproject.com/software/) (Radua and Mataix-Cols 2009; Nakao et al. 2011; Hart et al. 2012; Aoki et al. 2013a) to analyse regional differences in activation during emotional-face pro-cessing tasks between individuals with ASD and TD controls. Unlike other approaches of voxel-based meta-analyses such as activation likelihood estima-tion (ALE), in SDM both positive and negative dif-ferences, such as hyper- and hypoactivation, are reconstructed in the same map, preventing a par-ticular voxel from appearing signifi cant in opposite directions. A random effects model was applied to integrate the effect sizes of the studies (Radua et al. 2012). The statistical signifi cance of each voxel was determined using randomization tests ( P � 0.001), as in previous studies (Bora et al. 2011; Aoki et al. 2013a). As there is potential aging effect in devel-opmental disorders (Aoki et al. 2012a, 2013b), we conducted a meta-regression analysis for the mean age of participants and effect size of each peak coor-dinate. Statistical theshold was set at P � 0.05 (see Supplementary material available online at http://informahealthcare.com/doi/abs/10.3109/15622975.2014.957719).

Paradigms of face processing. The comprehensive literature search identifi ed two types of fMRI stud-ies with emotional-face processing, in terms of comparison of psychological task conditions. The fi rst group compared neural activation during emotional-face processing conditions with that during non-face processing conditions. The sec-ond group contrasted neural activation during emotional-face processing conditions with non-emotional-face processing conditions, such as Figure 1. Process of study selection.

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Corbett et al. 2009; Deeley et al. 2007; Pelphrey et al. 2007; Ishitobi et al. 2011; Perlman et al. 2011; Weng et al. 2011; Rahko et al. 2012; Rudie et al. 2012) and “ emotional-face vs. non-emotional-face ” group (Critchley et al. 2000; Dalton et al. 2005; Wicker et al. 2008; Greimel et al. 2010), respec-tively.

Regional difference of activation across all retained studies

A meta-analysis of the retained 13 studies demon-strated signifi cant hyperactivation in individuals with ASD vs. TD controls in the thalamus (left dominant) (Figure 2a), right caudate (Figure 2b), left cingulate gyrus (Figure 2c), right precuneus (Figure 2d), and left caudate (Figure 2b). We also found ASD-related hypoactivation in the hypothalamus (Figure 2e) (Table I). Meta-regression analysis did not demon-strate any signifi cant effect of mean age of partici-pants on effect size on each peak coordinate (Supplementary Table 2 available online at http://informahealthcare.com/doi/abs/10.3109/15622975.2014.957719).

Regional difference of activation considering emotional-face vs. non-face

We identifi ed similar results as the main meta-anal-ysis. We also found ASD-related hypoactivation in the hypothalamus. In addition, the sub-analysis showed hypoactivation in the parahippocampal gyrus

quently, we identifi ed 13 studies to be included in the meta-analysis (Figure 1) (Critchley et al. 2000; Dalton et al. 2005; Ashwin et al. 2007; Deeley et al. 2007; Pelphrey et al. 2007; Wicker et al. 2008; Corbett et al. 2009; Greimel et al. 2010; Ishitobi et al. 2011; Perlman et al. 2011; Weng et al. 2011; Rahko et al. 2012; Rudie et al. 2012). The initial study selection, independently and blindly per-formed by two authors (Y.A. and S.C.), had 86% agreement. After detailed analysis and discussion with the senior author (M.T.), complete agreement was achieved.

Characteristics of included studies

The 13 studies included in the meta-analysis (Supplementary Table 1 available online at http://informahealthcare.com/doi/abs/10.3109/15622975.2014.957719) examined a total of 226 individuals with ASD and 251 TD people. The mean age of individuals with ASD ranged from 9 to 37 years and that of comparisons from 9.2 to 28.6. All the stud-ies recruited age-matched group of TD subjects. The mean Intelligence Quotient (IQ) ranged from 81.8 to 114 in individuals with ASD. Eleven studies have recruited only high-functioning individuals with ASD, whereas two studies did not confi ne restrict participants to high-functioning individuals with ASD (Dalton et al. 2005; Wicker et al. 2008). Nine and four studies were categorized as the “ emotional-face vs. non-face ” (Ashwin et al. 2007;

Figure 2. Results of voxel-based meta-analysis of 13 functional magnetic resonance imaging studies on emotional-face processing tasks. Individuals with autism spectrum disorder (ASD) demonstrated hyperactivation in the bilateral thalamus (a), bilateral caudate (b), left cingulate gyrus (c), and right precuneus (d). Individuals with autism spectrum disorder (ASD) demonstrated hypoactivation in the hypothalamus (e).

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Atypical subcortical activity in autism 5

com/doi/abs/10.3109/15622975.2014.957719). Eleven jackknife sensitivity analyses demonstrated hyperactivation in the left cingulate and the right caudate, and 10 jackknife sensitivity analyses demonstrated hypoactivation in the mammillary body. Nine jackknife sensitivity analyses showed hyperactivation in the right precuneus in individu-als with ASD during face processing compared with TD.

Discussion

As we predicted, the meta-analysis of all retained studies showed atypical activation in subcortical structures. Specifi cally, individuals with ASD showed hyperactivation in the bilateral thalamus, bilateral caudate, left cingulate and right precuneus, and hypoactivation in the hypothalamus during emotion-al-face processing conditions, compared with TDs. This may suggest that disturbance of involuntary emotional-face processing is related to ASD, regard-less of voluntary efforts to compensate (at least partially) for defi cits in emotional-face processing. Jackknife sensitivity analyses demonstrated that hyperactivation in the left caudate is the most robust fi nding.

and amygdala (Supplementary Table 3 available online at http://informahealthcare.com/doi/abs/10.3109/15622975.2014.957719).

Regional difference of activation considering emotional-face vs. non-emotional-face

The analysis of the fi ve studies that compared neural activation during emotional-face processing condition and non-emotional-face processing condition did not show any signifi cant hyperactivation in individu-als with ASD. On the other hand, individuals with ASD showed hypoactivation in the cuneus and cul-men (Supplementary Table 4 available online at http://informahealthcare.com/doi/abs/10.3109/15622975.2014.957719).

Sensitivity analysis

All of the jackknife sensitivity analyses demonstrated hyperactivation in the left caudate and 12 out of the 13 jackknife sensitivity analyses replicated hyperactivation in the thalamus during emotional-face processing in individuals with ASD, suggesting that these results are highly reliable (Supplementary Table 5 available online at http://informahealthcare.

Table I. Results of meta-analysis of fMRI studies with emotional face processing task, regional neural activation difference between individuals with ASD and TD at P � 0.001 and cluster size � 1 voxel.

Talairach Z value P value Voxels Description Cluster size

ASD � TD � 2, � 16,12 2.112 0.000107 34 Lt thalamus

Lt thalamus 11Rt thalamus 6Lt thalamus, midline nucleus 6Lt thalamus, medial dorsal nucleus 9Rt thalamus, medial dorsal nucleus 2

8,4,16 1.971 0.000243 8 Rt caudate, caudate body Rt caudate, caudate body 8

� 8, � 6,42 1.943 0.000289 32 Lt cingulate gyrus, BA 24 Lt limbic lobe, cingulate gyrus, BA 24 26Lt limbic lobe, cingulate gyrus, BA 31 5Lt frontal lobe, paracentral lobule, BA 31 1

6, � 58,62 1.819 0.000547 7 Rt precuneus, BA 7 Rt parietal lobe, precuneus, BA 7 7

� 16,8,16 1.809 0.000578 7 Lt caudate, caudate body Lt caudate, caudate body 7

TD � ASD � 2, � 8, � 10 � 1.074 0.000239 19 Lt mammillary body

Lt mammillary body 5Rt mammillary body 5Lt hypothalamus 3Rt hypothalamus 2Undefi ned hypothalamus 2Lt frontal lobe, subcallosal gyrus, BA 25 2

ASD, autism spectrum disorder; TD, typically developing; Lt, Left; Rt, Right; BA, Brodmann area.

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Result from sub-analyses

Sub-analyses with studies comparing emotional-face processing and non-face processing conditions showed hypoactivation in the amygdala and parahip-pocampal gyrus in individuals with ASD. As the amygdala is a brain region involved in the face recognition system that is disturbed in individuals with ASD (Cauda et al. 2011; Via et al. 2011), it is reasonable that comparison between face vs. non-face processing conditions showed differences. In addition, the amygdala is recognized as the centre of emotional processing, particularly fearful face pro-cessing (Adolphs 2008). Although there is debate as to whether the amygdala function is concordant with that of the thalamus (Lynch et al. 2013), it is reported that in the subcortical route of involuntary process-ing of fearful faces, the amygdala receives visual information from the retinal ganglion through the superior colliculus and thalamus in a subcortical route (Adolphs 2008). Thus, hypoactivation in the amygdala with hyperactivation in the thalamus may represent an unresponsive amygdala and an up-regulation of the thalamus in this subcortical pathway for fearful face processing.

Lack of atypical brain activity in social brain area

In the main meta-analysis, we have adopted rela-tively strict statistical threshold ( P � 0.001), although threshold for cluster extent is low (cluster size � 1) (Roland et al. 1993). Even when we adopted a more liberal statistical threshold for an exploratory analy-sis (such as P � 0.01), there were not substantial clusters where individuals with ASD showed atypical neural activation during emotional-face processing in cortical region (data available upon request). In addition, jackknife sensitivity analyses also demon-strated no atypical neural activation in individuals with ASD in cortical region. As emotional face pro-cessing is supposed to be a kind of social perception and cognition, it is reasonably expected that parts of social brain, such as fusiform gyrus, superior tempo-ral sulcus, medial prefrontal cortex, temporoparietal junction, and posterior cingulate, are involved in this process (Pelphrey and Carter 2008; Adolphs 2010). However the present analyses did not show any sig-nifi cant difference in brain activity in these brain regions between individuals with ASD and TD. One potential explanation of lack of atypical brain activity in these brain regions is that these brain regions are not involved in the pathophysiology of atypical emo-tional face processing in individuals with ASD. Instead, abnormality in thalamus and caudate that interface social brain may be more involved in pathophysiology of ASD (Langen et al. 2011a,b). Another possible explanation is a potential publica-

Regional neural activation

Existing studies have demonstrated that the thala-mus and caudate are not only anatomically close to each other but also functionally concordant (Tami-etto and de Gelder 2010; Liljeholm and O ’ Doherty 2012) and constitute functional circuit that involves both crotical and subcortical structures, such as cortico-striatal-thalamo-cortical circuit (Langen et al. 2011a,b; Aoki et al. 2012b; Andrzejewski et al. 2013). Likewise cortico-cortical network, lines of previous studies with individuals with TD and psy-chiatric disorder, including ASD, have shown that disturbance of the circuit is associated with abnor-mal social cognition and behaviour (Langen et al. 2011a,b; Aoki et al. 2013c). In particular, it is supposed that the thalamus and caudate constitute subcortical route with connections with cortical regions for emotional-face processing without any conscious awareness of the stimulus (Tamietto and de Gelder 2010). Based on these fi ndings, the pres-ent fi nding that individuals with ASD showed higher brain activity during emotional face processing than individuals with TD may refl ect neural bases of atypical emotional face processing without any con-scious awareness in individuals with ASD (Brambilla et al. 2004). On the other hand, a number of previ-ous studies have demonstrated abnormalities in development of the thalamus and caudate (Sears et al. 1999; Tsatsanis et al. 2003; Haznedar et al. 2006; Cauda et al. 2011; Aoki et al. 2012a; Horder et al. 2013; Lanegn et al. 2013; Nair et al. 2013), suggesting that these brain regions are potentially involved in pathophysiology of ASD. However, it should be noted that there are some previous meta-analyses of fMRI studies of emotional-face process-ing with other psychiatric condition. For example, a recent meta-analysis demonstrated hyperactivation in the thalamus and caudate during emotional-face processing in individuals with schizophrenia (Delvecchio et al. 2013). In contrast to the present meta-analysis, the meta-analysis of patients with schizophrenia has shown hyperactivation in cortex, such as right inferior occipital gyrus and right fusi-form gyrus (Delvecchio et al. 2013). Similarly, although a meta-analysis has demonstrated higher activity of the caudate during emotional face pro-cessing among patients with depression than healthy individuals (Norbury et al. 2010), the meta-analysis has also shown higher activity in cortex, such as middle frontal/superior frontal gyrus. Namely, although hyperactivation of the basal ganglia, such as thalamus and caudate, may not be specifi c to ASD, lack of hyperactivation of cortex with hyper-activation of basal ganglia may refl ect more specifi c component of neural correlates of atypical emotional-face processing of ASD.

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Atypical subcortical activity in autism 7

comparisons under different conditions. Thus, the current analysis demonstrated relatively small clus-ters. Despite these limitations, we note that jackknife sensitivity analyses demonstrated that the signifi -cance of each cluster was highly replicable. Fifth, potentially because of the lack of a suffi cient number of included studies, the sub-analysis “ emotional-face vs. non-emotional-face ” did not yield consistent results with those of the whole analysis with all 13 studies or the sub-analysis “ emotional-face vs. non-face ” . But as the comparison “ emotional-face vs. non-emotional-face ” does not refl ect the neural correlate of face processing as much, it is expected that the comparison of “ emotional-face processing vs. non-face processing ” would yield greater differ-ences. In addition, as we have pooled studies with explicit and implicit emotional-face processing tasks, our results should be considered with caution. Fur-ther, the notion that abnormal activation in cortical regions and in subcortical regions is indicative of conscious emotional-face processing and of uncon-scious emotional-face processing, respectively, is an oversimplifi ed view. As we have mentioned above, subcortical routes that bypass cortical regions have been identifi ed as playing a role in rapid and auto-matic face processing, subcortical regions also have reciprocal connections with cortical regions (Tamietto and de Gelder 2010). Indeed, subcortical regions are often activated via projections from cor-tical regions (Dalgleish 2004; Tamietto and de Gelder 2010; Bornstein and Daw 2011; Peron et al. 2013). As this is a meta-analysis of event-related fMRI studies, it is not possible to address potential cause or relation of these atypical activities. Thus, it is not possible to tell why these brain regions were atypi-cally activated or what kind of brain network or circuit are involved in emotional face processing. However, the present result may outline brain regions that are involved in atypical emotional face process-ing, although link between these brain regions are yet to be elucidated. The present results set the ground for further research assessing therapeutic approaches addressing the currently untreatable social defi cit of individuals with ASD (Lemonnier et al. 2012; Gordon et al. 2013; Lin et al. 2014). Although the nature of this study does not prove causative mechanisms, our results suggest that subcortical regions could be the target of such ther-apeutic approaches or, at least, they may represent objective markers of treatment response.

Conclusion

The current voxel-based meta-analysis suggested that atypical activation in the subcortical and paral-

tion bias. Indeed, in order not to violate the assump-tion that the likelihood of locating activated foci is equal at every voxel, under the null hypothesis, we have integrated only studies with whole brain analy-sis (Cortese et al. 2012). However, during the screen-ing process, a number of studies with ROI analysis that reported atypical brain activity in social brain area were discarded (Hubl et al. 2003; Bolte et al. 2006; Kleinhans et al. 2011). With regard to amygdala, although the main meta-analysis did not demonstrate any signifi cant atypical brain activity in this structure, sub-analysis did. Although it is not common that whole brain analysis show signifi cant difference in the amygdala but sub-analysis has shown atypical brain activity in the amygdala, lack of signifi cant difference in amygdala activity between individuals with ASD and TD in main meta-analysis may also derive from heterogeneity of contrast.

Limitations

There are a number of limitations in the current meta-analysis. First, although we integrated the results from the studies that adopted the same threshold at a whole brain level, in the case where studies did not report the exact effect size of the peak coordinate (Dalton et al. 2005; Pelphrey et al. 2007; Corbett et al. 2009; Perlman et al. 2011), we deter-mined the threshold value as the effect size of the coordinates. Thus, as it is expected that effect size in each peak coordinate is different, the current result should be treated with caution. Second, because of an insuffi cient number of included studies, it was not possible to conduct adequate sensitivity analyses or meta-regression analyses to investigate potential fac-tors infl uencing on regional neural activation, such as methodological heterogeneity, including differ-ences in full-width at half-maximum, and partici-pants ’ factors, including severity of symptoms, pharmacological status, and psychiatric comorbidity. Third, although the current meta-analysis integrated studies using a random effects model, there is considerable between-study heterogeneity among studies included in the current analysis. For exam-ple, while some studies did not correct for multiple comparisons, others did. Further, the methods used to correct for multiple comparisons differ among studies. In addition, the different studies included in this meta-analysis used different statistical thresh-olds. Fourth, we adopted relatively severe thresholds for signifi cance to identify core and common neural correlates of disturbed emotional-face processing: P � 0.001, uncorrected, which has been reported to be empirically equivalent to P � 0.05, corrected (Radua et al. 2010; Fusar-Poli 2012), for multiple

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imbic/limbic brain regions underpins abnormal emotional-face processing in individuals with ASD.

Acknowledgments

We are grateful to Drs Paolo Brambilla (University of Texas Medical School at Houston), Department of Experimental & Clinical Medicine, Inter-University Center for Behavioural Neurosciences (ICBN), University of Udine, and IRCCS “ E. Medea ” Scien-tifi c Institute, UDGEE, Udine, Italy and Marcella Bellani (University of Verona) for giving us construc-tive comments for the manuscript.

Statement of Interest

In the past year, Dr. Samule Cortese has received royalties from Aargon Healthcare Italy.

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Supplementary material available online

Supplementary Information

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