Neuroscience and Biobehavioral Reviews 34 (2010) 935–946

Review

Self-reflection and the brain: A theoretical review and meta-analysis ofneuroimaging studies with implications for schizophrenia

Lisette van der Meer a,b,*, Sergi Costafreda c,1, Andre Aleman a,b,2, Anthony S. David c,3

a Department of Neuroscience, University Medical Center Groningen, University of Groningen, Groningen, The Netherlandsb BCN Neuroimaging Center, University of Groningen, Groningen, The Netherlandsc Institute of Psychiatry, King’s College London, London, UK

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 936

1.1. Neural correlates of self-reflection and the Cortical Midline Structures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 936

2. Method. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 937

2.1. Statistical analysis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 937

3. Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 937

4. Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 941

4.1. Cortical midline structures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 941

4.2. Anterior paralimbic regions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 942

4.3. A model of self-reflection in the brain. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 942

4.4. Implications for defective self-processing in schizophrenia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 943

4.5. Schizophrenia, insight and self-reflection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 943

4.6. Limitations and directions for future research . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 944

Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 944

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 944

A R T I C L E I N F O

Article history:

Received in revised form 27 November 2009

Keywords:

Self-reflection

Self-appraisal

Other-reflection

Cortical Midline Structures

Dorsomedial PFC

Ventromedial PFC

Schizophrenia

Insight

A B S T R A C T

Several studies have investigated the neural correlates of self-reflection. In the paradigm most

commonly used to address this concept, a subject is presented with trait adjectives or sentences and

asked whether they describe him or her. Functional neuroimaging research has revealed a set of regions

known as Cortical Midline Structures (CMS) appearing to be critically involved in self-reflection

processes. Furthermore, it has been shown that patients suffering damage to the CMS, have difficulties in

properly evaluating the problems they encounter and often overestimate their capacities and

performance. Building on previous work, a meta-analysis of published fMRI and PET studies on self-

reflection was conducted. The results showed that two areas within the medial prefrontal cortex (MPFC)

are important in reflective processing, namely the ventral (v) and dorsal (d) MPFC. In this paper a model

is proposed in which the vMPFC is responsible for tagging information relevant for ‘self’, whereas the

dMPFC is responsible for evaluation and decision-making processes in self- and other-referential

processing. Finally, implications of the model for schizophrenia and lack of insight are noted.

� 2009 Elsevier Ltd. All rights reserved.

* Corresponding author at: University Medical Center Groningen, Department of Neurosciences, Cognitive Neuropsychiatry Group, P.O. Box 196, 9700 AD Groningen, The

Netherlands. Tel.: +31 0 50 3638999; fax: +31 0 50 3638875.

E-mail addresses: L.van.der.meer@med.umcg.nl (L. van der Meer), Sergi.Costafreda@iop.kcl.ac.uk (S. Costafreda), A.aleman@med.umcg.nl (A. Aleman),

anthony.david@kcl.ac.uk (A.S. David).1 Centre for Neuroimaging Sciences, Institute of Psychiatry, Box P089, De Crespigny Park, London SE5 8AF, United Kingdom. Tel.: +44 0 203 228 3052;

Contents lists available at ScienceDirect

Neuroscience and Biobehavioral Reviews

journa l homepage: www.e lsev ier .com/ locate /neubiorev

fax: +44 0 203 228 2116.2 University Medical Center Groningen, Department of Neurosciences, Cognitive Neuropsychiatry Group, P.O. Box 196, 9700 AD Groningen, The Netherlands.

Tel.: +31 0 50 363 5111; fax: +31 0 50 363 8875.3 Section of Cognitive Neuropsychiatry, P.O. Box 68, Institute of Psychiatry, King’s College, Denmark Hill, London SE5 8AF, United Kingdom. Tel.: +44 0 20 7 848 0138;

fax: +44 0 20 7 848 0572.

0149-7634/$ – see front matter � 2009 Elsevier Ltd. All rights reserved.

doi:10.1016/j.neubiorev.2009.12.004

4 The terms ventral and dorsal medial frontal cortex are not always well defined

in the literature. In this paper, a dividing line will be placed along Talairach z-

coordinate of 20. The area above will be referred to as dMPFC, whereas the area

underneath will be referred to as vMPFC (see Van Overwalle, 2009; Krueger et al.,

2009). This roughly corresponds to Brodmann’s areas 9 for dMPFC and 10 and 11 for

vMPFC (Northoff et al., 2006).

L. van der Meer et al. / Neuroscience and Biobehavioral Reviews 34 (2010) 935–946936

1. Introduction

The aim of this paper is to review the literature on self-reflection, and in particular its differentiation from other-reflectiveprocessing, by means of a meta-analysis of the fMRI and PETstudies published so far on the subject. We will present a model ofself-reflection and the brain based on the results of the meta-analysis. The discussion will be expanded to encompass theliterature on failure of self-reflection processes, in particular inschizophrenia patients who may be viewed as having importantproblems in this area (Carter et al., 2001; Baird et al., 2006;Addington et al., 2006; Sprong et al., 2007). Recent neuroimagingevidence (Taylor et al., 2007; Park et al., 2008) suggests thatprocesses relying upon these Cortical Midline Structures (CMS), aset of regions encompassing the posterior cingulate cortex (PCC),the medial prefrontal cortex (MPFC) and the anterior cingulatecortex (Northoff and Bermpohl, 2004), may be affected in thispatient group. Finally, the possible role for self-reflection abilitiesin illness awareness in schizophrenia patients will be discussed.

The study of self has become increasingly popular in cognitiveneuroscience over the past decade (Kircher and David, 2003).Several studies have investigated the neural correlates of self-reflection or self-referential processing. In the literature theseterms are used interchangably and refer to the evaluation processused to decide whether certain environmental cues apply to one’sself or not. Technically, self-referential processing is a broaderconcept in which all information that somehow refers to oneself isprocessed and encompasses subconscious as well as consciousprocessing. Self-reflective processing on the other hand implies aconscious process in which a decision is made regarding oneself.

Having an accurate representation of one’s traits, abilities andattitudes is important in evaluating one’s own behavior andcomparing it with the behavior of other human beings. The mostcommonly used paradigm to address this concept in experimentaland neuroscientific research uses self-reflection in which subjectsare presented with trait adjectives or sentences and are askedwhether the trait or sentence applies to them. Results haveconsistently pointed to a role of the CMS in these self-reflectionprocesses, but this has not allayed misgivings regarding theconcept of self-reflective processing (Gillihan and Farah, 2005) andwhether the processing of self-reflective information is substan-tially different from the processing of information concerningother people. Finally, it has also been shown that patients whohave suffered damage to the CMS have difficulties in properlyevaluating their problems and often overestimate their capacitiesas well as their performance particularly on cognitively demandingoperations (Schmitz et al., 2006).

1.1. Neural correlates of self-reflection and the Cortical Midline

Structures

Most studies investigating self-reflection processes have foundevidence for medial prefrontal cortex (MPFC), posterior cingulatecortex (PCC) and anterior cingulate cortex (ACC) involvement indistinguishing self-related information from non-self-related infor-mation. Even though these studies report a similar functionalanatomy, the precise involvement of the component structures isdebated. One of the first studies looking at the neural correlates of the‘self-reference effect’, using PET was done by Craik et al. (1999). Theself-reference effect refers to the finding that people tend toremember words when processed in relation to themselves betterthan words processed more generally (see Symons and Johnson(1997) for a meta-analysis). Craik et al. (1999) found that theretrieval of self-referential information is mediated by rightprefrontal areas including the MPFC, whereas the encoding of suchinformation is similar to the encoding of information about others

and is mediated mainly by left prefrontal areas. This effect wasreplicated using fMRI by Kelley et al. (2002), by means of visualpresentation of trait adjectives and Johnson et al. (2002) who studiedself-reflection by means of a paradigm in which subjects werepresented auditorily with short questions, each entailing a trait,attitude or ability (e.g. ‘I am a good friend’). As a control condition,they used simple questions entailing general semantic knowledge(e.g. ‘You need water to live’). Both studies found anterior MPFC(aMPFC) and PCC activation in the self-reflection condition. Thestudies by Craik et al. (1999), Kelley et al. (2002) and Johnson et al.(2002) were followed up by a number of other studies using similarparadigms and reporting similar areas of activation. Macrae et al.(2004) demonstrated that activation in MPFC regions correspondedto self-reflective judgments and memory performance related toself-descriptive trait words. Fossati et al. (2003) were specificallyinterested in the processing of emotionally valenced words in self-reflection. They presented positive and negative trait words andfound dorsal MPFC (dMPFC) and PCC activation in a self versusbaseline contrast.4 Interestingly, this dMPFC activation was notspecific to either positive or negative stimuli but rather it was presentregardless of valence. Gusnard et al. (2001) and Johnson et al. (2005)found only MPFC activation in a similar contrast in which subjectswere asked to introspect either in response to pleasant/unpleasantvisual stimuli or color preference respectively. Johnson et al. (2006)similarly used an introspection paradigm in which subjectsruminated on hopes and duties in comparison with a conditionwithout self-reference and found MPFC and PCC activation.

Northoff and Bermpohl (2004) reviewed the literature on self-processing and neuroimaging and discussed the role of the CMS inself-processing. They discussed each area separately and came to theconclusion that different areas within the CMS represent differentfunctions, such as representation, monitoring, evaluation andintegration. However, their review focused on the processing ofself only. Many other recent studies have included an ‘other’condition in which the subject is asked to reflect upon anotherperson, either an unfamiliar person, a relative, close friend orsomeone famous, while presented with trait words (Kelley et al.,2002; Macrae et al., 2004; Schmitz et al., 2004; Ochsner et al., 2005;Heatherton et al., 2006; Schmitz and Johnson, 2006; D’Argembeauet al., 2007; Gutchess et al., 2007; Zhu et al., 2007), trait sentences(Pfeifer et al., 2007; Modinos et al., 2009), or when instructed tointrospect upon emotional pictures (Ochsner et al., 2004; Jenkins etal., 2008) or food preference (Seger et al., 2004). The involvement ofthe MPFC (Macrae et al., 2004; Ochsner et al., 2004; Schmitz et al.,2004; Johnson et al., 2005; Schmitz and Johnson, 2006; Zhu et al.,2007; Modinos et al., 2009) and PCC, precuneus (Ochsner et al.,2004; Seger et al., 2004; Heatherton et al., 2006; Johnson et al., 2006;Schmitz and Johnson, 2006; Modinos et al., 2009) in self-reflectiveprocessing is broadly confirmed. However, regarding ‘other’-reflective processing and the extent to which this differs fromself-reflective processing, the literature does not yield a consensus.

Even though most studies report differences in self-processingversus other-processing, the brain region that is mostly reported tobe functionally associated specifically with self-processing isreferred to as MPFC (Kelley et al., 2002; Ochsner et al., 2004;Heatherton et al., 2006; D’Argembeau et al., 2007; Gutchess et al.,2007; Pfeifer et al., 2007; Zhu et al., 2007; Jenkins et al., 2008;Modinos et al., 2009), while the same studies report this area to beinvolved in other-processing as well. Additional areas that are

L. van der Meer et al. / Neuroscience and Biobehavioral Reviews 34 (2010) 935–946 937

reported to be involved specifically in self-processing are theanterior cingulate cortex (Ochsner et al., 2005; Heatherton et al.,2006; D’Argembeau et al., 2007; Zhu et al., 2007; Modinos et al.,2009), dorsolateral PFC (DLPFC) (Schmitz et al., 2004), superiorparietal regions (Seger et al., 2004) and lateral temporal regions(Kjaer et al., 2002; Lou et al., 2004). The observation that theinvolvement of the MPFC is reported for self as well as other-processing indicates that there is a need to be more specificregarding the areas within the MPFC that are involved in eitherself- or other-processing or both.

Some studies suggest that a functional distinction should bemade between the ventral MPFC (vMPFC) and the dMPFC (Frithand Frith, 1999; Gusnard et al., 2001; Northoff and Bermpohl,2004; Northoff et al., 2006; Schmitz and Johnson, 2007) in whichthe dMPFC might process the non-emotional, and the vMPFC themore emotional content of the information. However, most studiesmentioned above do not make this explicit distinction. Hence westill do not have a definitive answer to the question formulated byGillihan and Farah (2005), namely, does the processing of self-referential information in the brain indeed differ as compared tothe processing of other-referential processing? And if so, whichbrain areas are functionally involved in these processes?

To this end, a meta-analysis was conducted to integrate andextend the published findings. The aim was to get a more objectiveand quantitative picture of which regions are involved in self-referential processing specifically and those which are implicatedin other-referential processing. The neuroimaging meta-analysissoftware algorithm that was applied allows visualization andprecise localization of foci of activation that are consistent acrossthe majority of studies.

2. Method

Articles included in the meta-analysis were identified through aliterature search using the search terms ‘self AND (reflect* ORreferen*) AND (fMRI OR ‘‘functional magnetic resonance imaging’’OR PET OR ‘‘positron emission tomography’’)’ in PubMed untilNovember 2008. Furthermore, the references of the selectedpapers were searched for additional papers on self-reflection andneuroimaging that did not appear in the PubMed search. A total of20 out of 29 PET or fMRI studies were selected based on theinclusion criteria below, resulting in a total of 16 and 17 studies forthe self > baseline and the self > other contrasts, respectively. Allstudies included in the meta-analysis are presented in Table 1(self > baseline) and Table 2 (self > other).

1. Only studies in which the whole brain was measured wereincluded in the meta-analysis.

2. Studies were only included when a paradigm was used in whichthe subject had to decide whether or not a trait word or sentencewas applicable to the self or to another (predefined) person.

3. Studies were only included when reporting a self versus baselinecontrast and/or a self versus other contrast.

4. All studies reporting a self > baseline contrast included a self-condition where the subject was asked to self-reflect and abaseline condition not involving self-processing.

5. All studies reporting a self > other contrast included a self-condition where the subject was asked to self-reflect and an‘other’ condition in which the subject was asked to reflect uponanother person.

6. Studies reporting a self versus non-self contrast, but notincluding a non-self semantic baseline were excluded fromthe meta-analysis.

7. Only studies using auditory or visually presented trait words orsentences were included in the meta-analysis. Studies using

facial stimuli or emotive pictures were excluded from the meta-analysis.

8. Only activation data and not deactivation data were included inthe meta-analysis.

Two contrasts will be explored in this meta-analysis, aself > baseline contrast and a self > other contrast. The self -> baseline contrast included peak activation data from 14 fMRIstudies and 2 PET studies (see Table 1). All studies reported a self-condition in which the subject is asked to self-reflect and a baselinecondition not involving self-processing. The self > other contrastincluded peak activation data from 15 fMRI studies and 2 PETstudies (see Table 2). The exclusion of 9 out of 29 studies wasmainly a result of criteria 2 and 3.

2.1. Statistical analysis

Parametric voxel-based meta-analysis (PVM; Costafreda et al.,2009) was employed to determine the brain areas where thestudies identified in the literature search reported activations witha degree of consistency that could not be explained by chancealone. Briefly, PVM compares the observed distribution of reportedactivations across studies with a spatial null distribution reflectingthe null hypothesis that the activations reported by each studyhave been generated at random locations across brain regions.

Based on this null model, a brain map representing theprobability of observing a given degree of concordance acrossstudies by chance alone is computed, and thresholded to reveal theareas of above chance concentration of activations across studiesusing the false discovery rate (q = 5%; Benjamini and Hochberg,1995). The purpose of the method is therefore to determine a cut-off point above which a certain foci overlap across studies isdeemed statistically significant, that is unlikely to have beengenerated by chance. The PVM method requires only the pre-specification of a smoothing parameter, which is here defined by aradius of 10 mm around each reported focus of activation. Eachindividual study map contribution to the final concordance map isweighted by the square root of its sample size. PVM implements arandom effects model, whereby each study is assigned its ownspecific signal and noise function, thus reflecting that studies maydiffer due not only to random error, but also because of differencesin equipment, analysis methods and subject population. Randomeffects modeling across studies results in better generalization ofpotential findings, and it is equivalent to the random effectsapproach for multisubject analysis in neuroimaging (Mumford andNichols, 2006). It also provides an easily interpretable summarystatistic, the percentage of studies reporting activation in thevicinity of a given voxel. Using simulated and real meta-analysisdata, this approach has been shown to be a valid and powerfultechnique for neuroimaging meta-analysis (Costafreda et al.,2009). The software has been implemented in R, and it is availablefrom the second author.

3. Results

The results of this meta-analysis are presented in Fig. 1(self > baseline) and 2 (self > other). Table 3 (self > baseline) and4 (self > other) summarize brain regions that were revealed bythis meta-analysis. The self > baseline contrast yielded fourclusters (see Table 3). The first large cluster with 58% and 55%of the studies reporting activation in this area included theposterior cingulate/precuneus (BA23/30) and the cuneus (BA 18),respectively. A second large cluster, with a similar 58% and 51% ofconcordance among studies showed frontal superior medial(BA10) and anterior cingulate (BA32) activation, respectively.Thirdly, a cluster including left frontal superior areas (BA9) and

Table 1Studies included in the meta-analysis. Contrast self>baseline.

Study Subjects (N) Method Contrast Brain region

vmPFC dmPFC IFC MFC Insula ACC PCC Precuneus RSC Cuneus SFG

Left Left Right Left Right Left Right Left

1 Schmitz and Johnson (2006) Healthy control

subjects (15)

fMRI Self-reference trait adjectives

>valence trait adjectives

� � �

2 Johnson et al. (2005) Healthy control

subjects (17)

fMRI Internal subject decision-making

>external subject decision-making

� � � � � � �

3 Johnson et al. (2002) Healthy control

subjects (11)

fMRI Self-evaluative statements

>general knowledge statements

� �

4 Johnson et al. (2006) Healthy control

subjects (19)

fMRI Self-reflection cues (preceded by

essay writing)>distraction cues

� � � � �

5 Johnson et al. (2006) Healthy control

subjects (19)

fMRI Self-reflection cues (NOT preceded

by essay writing)>distraction cues

� � � � � �

6 Lou et al. (2004) Healthy control

subjects (13)

PET Self-reference trait adjectives

>no. of syllables trait adjectives

� � �

7 Schmitz et al. (2004) Healthy control

subjects (19)

fMRI Self-reference trait adjectives

>valence trait adjectives

� �

8 Seger et al. (2004) Healthy control

subjects (12)

fMRI Self-food liking>no. of vowels

food name

� � � �

9 Fossati et al. (2003) Healthy control

subjects (10)

fMRI Self-reference trait adjectives

>generally desirable trait

� �

10 Heatherton et al. (2006) Healthy control

subjects (30)

fMRI Self-reference trait adjectives

> trait words upper/lower case

� � � �

11 Modinos et al. (2009) Healthy control

subjects (16)

fMRI Self-evaluative statements

>general knowledge statements

� � � � � �

12 Zhu et al. (2007) Healthy western

subjects (13)

fMRI Self-reference trait adjectives

> trait words upper/lower case

� � �

13 Zhu et al. (2007) Healthy chinese

subjects (13)

fMRI Self-reference trait adjectives

> trait words bold/light faced character

� � �

14 Craik et al. (1999) Healthy control

subjects (8)

PET Self-reference trait adjectives

>generally desirable trait

� �

15 Yoshimura et al. (2008) Healthy control

subjects (21)

fMRI Self-reference trait adjectives

>difficulty defining trait adjective

� � � �

16 Ochsner et al. (2005) Healthy control

subjects (17)

fMRI Self-reference trait adjectives

>no. of syllables trait adjectives

� �

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eta

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Table 2Studies included in the meta-analysis. Contrast self>other.

Study Subjects (N) Method Contrast Brain region

DLPFC Rostro

LPFC

vmPFC dmPFC IFC MFC Insula ACC PCC Precuneus Cuneus SFG IParietalC Para

hipp GLeft Right Left Right Left Right Left Left Right Left Right

1 D’Argembeau

et al. (2007)

Healthy control

subjects (17)

fMRI Self-reference trait adjectives

>other trait adjectives

� � � �

2 Ochsner

et al. (2005)

Healthy control

subjects (16)

fMRI Self-reference trait adjectives

>other trait adjectives

� � � � �

3 Lou et al.

(2004)

Healthy control

subjects (13)

PET Self-reference trait adjectives

>other trait adjectives

�

4 Schmitz et al.

(2004)

Healthy control

subjects (19)

fMRI Self-reference trait adjectives

>other trait adjectives

� � �

5 Kelley et al.

(2002)

Healthy control

subjects (24)

fMRI Self-reference trait adjectives

>other trait adjectives

� �

6 Seger et al.

(2004)

Healthy control

subjects (12)

fMRI Self-food liking> food

liking other

� �

7 Heatherton

et al. (2006)

Healthy control

subjects (30)

fMRI Self-reference trait adjectives

>other trait adjectives

� � � � � �

8 Kjaer

et al. (2002)

Healthy control

subjects (7)

PET Self-reference trait adjectives

>other trait adjectives

� � � � �

9 Jenkins et al.

(2008)

Healthy control

subjects (13)

fMRI Opinion question self

>opinion question other

�

10 Modinos et al.

(2009)

Healthy control

subjects (16)

fMRI Self-evaluative statements

>other evaluative statements

� � � � �

11 Zhu et al.

(2007)

Healthy Chinese

subjects (13)

fMRI Self-reference trait adjectives

>other trait adjectives

� �

12 Zhu

et al. (2007)

Healthy Western

subjects (13)

fMRI Self-reference trait adjectives

>other trait adjectives

� � �

13 Gutchess

et al. (2007)

Healthy aged

subjects (17)

fMRI Self-reference trait adjectives

>other trait adjectives

� � �

14 Gutchess

et al. (2007)

Healthy young

subjects (19)

fMRI Self-reference trait adjectives

>other trait adjectives

� � � �

15 Vanderwal

et al. (2008)

Healthy control

subjects (20)

fMRI Self-reference trait adjectives

wordpairs>other trait

adjectives wordpairs

� � � �

16 Pfeifer

et al. (2007)

Healthy control

subjects (12)

fMRI Self-evaluative statements

>other evaluative statements

�

17 Yoshimura

et al. (2008)

Healthy control

subjects (21)

fMRI Self-reference trait adjectives

>other trait adjectives

�

L.v

an

der

Meer

eta

l./Neu

roscien

cea

nd

Bio

beh

av

iora

lR

eview

s3

4(2

01

0)

93

5–

94

69

39

Fig. 1. Random-effects meta-analysis results for the contrast self-reflection > baseline. The score is the proportion of experiments reporting at least one activation peak

within a local neighborhood of size r = 10 mm, weighted by study size (FDR corrected, q = 0.05). Sagittal slices at X = {�40, �32, �24, �16, �8, 0, 8) in MNI space.

Fig. 2. Random-effects meta-analysis results for the contrast self-reflection > other-reflection. The score is the proportion of experiments reporting at least one activation

peak within a local neighborhood of size r = 10 mm, weighted by study size (FDR corrected, q = 0.05). Sagittal slices at X = {�40, �32, �24, �16, �8, 0, 8) in MNI space.

L. van der Meer et al. / Neuroscience and Biobehavioral Reviews 34 (2010) 935–946940

frontal superior medial (BA9) showed 44% and 37% of concordanceamong studies, respectively. Finally, a cluster, with 38% of thestudies reporting activation in this area included the left inferiorfrontal, orbital part (BA47), the left temporal pole (BA38) and theleft insula (BA48).

Table 3Random-effects meta-analysis (FDR threshold, q = 5%), for self>baseline.

Cluster Anatomical label Coordinates

x

#1 Posterior cingulate/precuneus (BA23/30) �2

Cuneus (BA 18/23) �4

#2 Frontal superior medial (BA10) �2

Anterior cingulate (BA32) �2

#3 Left frontal superior (BA9) �10

Frontal superior medial (BA9) �12

#4 Left inferior frontal, orbital part (BA47) �38

Left temporal pole (BA38) �40

Left insula (BA48) �38

The score is the proportion of experiments reporting at least one activation peak within a

MNI space and refer to the voxel with maximum score.

The second contrast that was studied was the self > othercontrast (see Fig. 2 and Table 4) and yielded only one large clusterwith a concordance of 35–49% between studies showing anteriorcingulate (BA24/32), concordance 49%, frontal mid orbital (BA10),concordance 48%, frontal superior medial (BA10), concordance 43%

Max. score (%) Volume (cm3)

y z

�60 20 58 4.6

�64 24 55 1.2

56 8 58 2.3

42 12 51 2.1

44 32 44 1.0

45 34 37 0.1

22 �12 38 0.6

24 �20 38 0.2

16 �8 38 0.2

local neighborhood of size r = 10 mm, weighted by study size. The coordinates are in

Table 4Random-effects meta-analysis (FDR threshold, q = 5%), for self>other.

Cluster Anatomical label Coordinates Max. score (%) Volume (cm3)

x y z

#1 Anterior cingulate (BA24/32) 2 42 20 49 10.4

Frontal mid orbital (BA10) 0 50 �2 48 2.9

Frontal superior medial (BA10) �2 54 8 43 3.1

Left mid/superior frontal (BA 10/46) �18 50 16 35 1.2

The score is the proportion of experiments reporting at least one activation peak within a local neighborhood of size r= 10 mm, weighted by study size. The coordinates are in

MNI space and refer to the voxel with maximum score.

L. van der Meer et al. / Neuroscience and Biobehavioral Reviews 34 (2010) 935–946 941

and left mid/superior frontal (BA10/46), concordance 35%, activa-tion.

4. Discussion

4.1. Cortical midline structures

The areas that were most consistently activated across studiesin this meta-analysis largely converge with what one would expectfrom individual studies that investigated self-reflection. Regardingself-reflection > baseline the integration of the published evidenceleaves it beyond doubt that the Cortical Midline Structures (CMS)are associated with self-processing. However, this meta-analysisalso pointed to other areas that have not been particularlyhighlighted before in relation to self-processing, although theywere evidently activated in most individual studies: the insula,temporal pole and inferior frontal cortex (orbital part). Further-more, this meta-analysis demonstrates that a clear distinction canbe made in activation patterns for self-reflective and other-reflective processing.

As to the role of the CMS, the meta-analysis shows that areasconsistently activated included the vMPFC, dMPFC, PCC and ACC(see Fig. 1). We speculate that a functional distinction should bemade between these areas. Based on the meta-analysis and thereviewed literature, it is proposed that the dMPFC and PCC are notonly involved in the processing of self-relevant information, butrather are involved in the evaluation and decision-making processof whether a certain stimulus is applicable to the self or to anotherperson (dMPFC) and the consultation of autobiographical memory(PCC). In contrast, the vMPFC is specifically involved in theprocessing of self-referential stimuli and not in the processing ofother-referential stimuli. Other studies that have previouslysuggested a functional distinction between the vMPFC and dMPFChave focused on self-reflective processes only and have notdiscussed other-reflective processing. In a study by Gusnard et al.(2001) an increased activation in the dMPFC in the self-referentialcondition as compared to the non-self-referential condition wasdemonstrated. Importantly, the authors found a decrease inactivation in the vMPFC in both conditions. They suggest thatdMPFC activation is increased when processing self-referentialstimuli or when engaging in introspective activities. Regardingthe vMPFC, they suggest that this area is engaged in processes inwhich salience of stimuli is assessed. Furthermore, they suggestthat the function of the vMPFC should be distinguished fromthe function of the orbito-MPFC (oMPFC). Through the oMPFC, thevMPFC receives sensory information from inside and outside thehuman body (Barbas, 1993; Rolls and Baylis, 1994; Carmichaeland Price, 1995). Besides its connections with the oMPFC, thevMPFC is intimately connected to the limbic system (Ongur andPrice, 2000). These interconnections suggest that the vMPFC playsa key role in emotional processing (Drevets and Raichle, 1998;Bush et al., 2000; Simpson et al., 2000). Bechara et al. (1997) morespecifically proposed that the vMPFC is responsible for thecoupling of emotional and cognitive processes regarding decision-

making, which might involve constant monitoring of the internaland external world (Elliott et al., 2000).

The dMPFC area on the other hand, has been hypothesized to beinvolved specifically in self-referential processing (Frith and Frith,1999). In line with these suggestions, Northoff et al. (2006) andNorthoff and Bermpohl (2004) postulated that the dMPFC isimportant in the evaluation of self-referential stimuli, whereas thePCC is responsible for the integration of autobiographicalinformation and emotional information regarding the ‘self’. Finally,Schmitz et al. (2006), demonstrated evidence for a vMPFC-nucleusaccumbens-insula-amygdala network responsible for the affectivecomponent of decision-making regarding the self. Furthermore,they provided evidence for a dMPFC-dorsolateral PFC-hippocam-pus network which is involved in the cognitive control ormonitoring of decisions regarding the self. Recently, Schmitzand Johnson (2007) proposed that the vMPFC is particularlyimportant in detecting the self-relevance of the perceivedstimulus, while the role of the dMPFC is of a more introspectivenature.

This meta-analysis suggests that this vMPFC involvement maybe concerned with the affective processing of self-relevantinformation. However, in contrast to the suggestions of Schmitzand Johnson (2007), the results suggest that the involvement ofthe dMPFC is not unique to self-reflective processing but ratherthat this region is important for reflective processing on a broaderscale. Furthermore, Mitchell et al. (2006) compared activationswhen subjects reflected upon ‘similar others’ compared to‘dissimilar others’ and demonstrated activation in the vMPFCfor the former and dMPFC activation for the latter condition. Thusthe proposed dichotomy between the vMPFC and the dMPFC(Schmitz et al., 2006; Mitchell et al., 2006; Schmitz and Johnson,2007) is supported by this meta-analysis which enables it to betaken one step further. The results diverge from Schmitz et al.(2006, 2007) when the second contrast of this meta-analysis istaken into account. When comparing self > other-reflectionprocesses, no involvement of the dMPFC was found, but thevMPFC and vACC seem to be the core regions. This suggests thatthe dMPFC is important in reflection processes per se. We suggestthat the vMPFC and the vACC activation are related to a moreaffective process, namely the processing of self-relevant informa-tion. According to Northoff and Bermpohl (2004) and Northoff etal. (2006), an emotional component is inherent to self-processing.That is, they look upon emotional stimuli as being mentallysignificant and thus essential for decision-making regarding theself. They proposed a continuum of self-relevance and involve-ment for the vMPFC in coding the information for self-relevance:the more self-relevance, the more emotional, the greater theactivation of the vMPFC. Moran et al. (2006) demonstrated bymeans of an affective self-reflection paradigm that activation ofdMPFC is indeed independent of valence. This is in contrast tovACC activation, which was attenuated when the stimulus wasnegative and related to the self and heightened when the stimuluswas positive and related to the self. This perhaps explains whythese areas are less active in other-reflection processes since

L. van der Meer et al. / Neuroscience and Biobehavioral Reviews 34 (2010) 935–946942

when judging another person, it is less important to the self-imagewhether the stimulus is positive or negative. Similar results werefound by Yoshimura et al. (2008) and Fossati et al. (2003)confirming the affective role of the vMPFC and vACC in self-reflective processing. A number of studies do report ACCactivation in an other versus baseline contrast (Kelley et al.,2002; Seger et al., 2004; Ochsner et al., 2005; Heatherton et al.,2006; Pfeifer et al., 2007; Zhu et al., 2007). When these findingsare combined with the results of this meta-analysis, it seems thatthe ACC is involved in both self- and other-reflective processing.However, since ACC activation is present in the self > other contrast,this suggests that this area is more active in self- than in other-reflective processing and that the amount of activation in the ACCmay be an indicator for self-specificity. Unfortunately, due to thelimited number of studies reporting data on this contrast, this couldnot be included in the meta-analysis.

Interestingly, recent studies in patients with schizophreniasuggest that specifically the vMPFC shows abnormal activation inemotional tasks (Harrison et al., 2007; Taylor et al., 2007; Park et al.,2008). This may imply that these patients experience difficulties inself-reflection, resulting in an inaccurate representation of theirtraits, abilities and attitudes and thus hampering the evaluation oftheir own behavior and the comparison with the behavior of others.

4.2. Anterior paralimbic regions

Besides CMS activation, this meta-analysis showed insula,temporal pole and IFC orbital part activation in the self versusbaseline contrast (see Fig. 1). These structures are functionallyinterrelated and, together with the ACC, have been suggested toform a circuit involved in representing and processing internalaffective bodily states (Mega et al., 1997). A role that can be linkedto self-processing and has often been associated with the temporalpole is Theory of Mind (TOM) processing (Frith and Frith, 1999;Moriguchi et al., 2007). It has been shown that damage to thetemporal pole region can result in an impairment in the use ofknowledge a person has on the behavior of others and on situationsassociated with this behavior (Funnell, 2001). Damasio et al. (2004)suggested that the temporal pole unites information from differentmodalities and by this defines unique situations and individuals. It

Fig. 3. A model for self-reflection in the brain. In blue the pathway that is followed for bo

reflective processing only. Thus, if the stimulus is tagged for self, both the red and blu

is possible that this unification of information does not just occurwhen judging other individuals, but also when bits of informationabout one’s self are processed.

Regarding the insula, Damasio (1999) suggested that it plays arole in the representation of the current bodily state of theorganism, also called ‘protoself’. Anatomically, the insula is highlyconnected with the limbic system and with the prefrontal cortexand is believed to play a key role in the integration ofviscerosomatic information (Mayberg et al., 1999), that is,transient bodily states. Insula activation has been reported instudies on, amongst others, agency (Ruby and Decety, 2001), self-related episodic memory (Fink et al., 1996), self- and familiar faceprocessing (Kircher et al., 2001) and food preference processing(Seger et al., 2004). Furthermore, it has recently been demonstrat-ed that the insula is involved in decision-making processes onaffective stimuli (Grabenhorst et al., 2008; Craig, 2009).

Finally, activation in the orbital part of the IFC was found. The IFCis commonly activated in the encoding of verbal information(Buckner et al., 1999). According to Kelley et al. (2002), this region isactivated in self-reflective processing due to semantic encodingprocesses. These processes are more thorough when processing self-relevant information than simple baseline processing, simplybecause it is likely to be more important to later recall informationabout oneself.

4.3. A model of self-reflection in the brain

To enhance the understanding of the mutual functional roles ofthe brain regions that emerge from this meta-analysis, we propose amodel of self-processing in the brain (see Fig. 3). When a person isconfronted with a situation in which decisions have to be maderegarding the self or another person, firstly self-directed attentionwill modulate the manner in which the stimulus is processed. Whenattention is directed to the self, self-relevant features of theinformation will be filtered out and will be tagged. This informationwill be coupled to information gathered from the internal world, thatis, from the affective bodily state. Furthermore, one needs to gatherpast information on the self in order to make an accurate decision,requiring autobiographical memory consultation. Lastly, an evalua-tion and decision regarding the applicability to the self or other has

th self- and other-reflective processes. In red the pathway that is followed for self-

e pathways are followed.

L. van der Meer et al. / Neuroscience and Biobehavioral Reviews 34 (2010) 935–946 943

to be made. Evaluations and decisions regarding another personmight still call upon autobiographical memory and emotionalprocesses since this person may be close to the self. However, asimplied by the results of this meta-analysis, the information will notreceive the self-relevance tags, which is so specific for self-processing. Thus, we distinguish two different pathways: (1) apathway that includes processes similar for self- and other-reflective processing and (2) an additional pathway that is specificfor self-reflective processing.

Regarding brain areas that are involved in the processes justdescribed, the results of our meta-analysis suggest that the ACCmay be important for directing attention to the self. Consequently,the vMPFC might be responsible for tagging the stimulus when it isrelevant for self (cf. Northoff and Bermpohl, 2004; Northoff et al.,2006). Anatomically, the vMPFC is connected to the limbic system(Young et al., 1994) as well as the DLPFC (Ghashghaei and Barbas,2002)—important for working memory performance and temporalorganization of behavior (Hermann and Wyler, 1988; Corcoran andUpton, 1993; Upton and Corcoran, 1995; Haut et al., 1996; Fuster,1997, 2000; Goldstein et al., 2004; Buchsbaum et al., 2005; Gilbertet al., 2006). DLPFC exerts executive control on the vMPFC, throughwhich in turn the limbic system is influenced (Phelps, 2006). Theinsula and PCC provide the individual with further informationregarding the internal bodily state and memory respectively, whilean evaluation and a decision concerning the applicability of thestimulus is likely to be finalized by the dMPFC (cf. Northoff andBermpohl, 2004; Northoff et al., 2006). It may be expected that ifany of these areas are damaged, this will hamper the gathering ofinformation in one or more areas, resulting in defective orimperfect evaluation and decision-making.

As can be seen in Fig. 3, the DLPFC is not included in the model.Our interpretation of the data is that the main function for theDLPFC is its role in executive control. This function is not specific tothe reflective network, whereas the proposed interplay betweenthe other regions suggested in the model is specific to reflectiveprocessing.

When self-processing is hampered this can lead to majorproblems in the social domain, particularly in the domain ofbehavior modification in a social situation as well as in therecognition of social cues (Atkinson and Robinson, 1961). Thistypically is one of the major problems encountered by schizophreniapatients.

4.4. Implications for defective self-processing in schizophrenia

In the recent literature there has been an interest in these socialcognitive deficits in schizophrenia patients, using paradigms suchas ‘Theory of Mind’ (TOM) or the capacity to put oneself in anotherperson’s shoes (see Sprong et al. (2007) for a meta-analysis), self-monitoring (Carter et al., 2001), or emotional face recognition(Baird et al., 2006; Addington et al., 2006). One area that hasreceived little attention is the relationship between schizophreniaand self-processing, in particular self-reflection.

Dimaggio et al. (2008) argued that to be able to recognizeemotions in others, one needs to be able to recognize one’s ownemotions. That is, to be able to put oneself in another person’s shoes,one uses one’s own perspective as a basis for the interpretation(Carruthers, 2009). Importantly, the areas found in this meta-analysis come close to an area which has been labeled the anteriorparacingulate cortex and which is thought to be of crucialimportance for the formation of shared expectations in the ownperson and another agent (McCabe et al., 2001; Gallagher et al.,2002; Gallagher and Frith, 2003). This implies that the deficits inTOM could be based on deficits in self-reflective capacities. This issupported by findings of Corcoran and Frith (2003, 2005) whodemonstrated a correlation between autobiographical memory

retrieval and TOM performance in schizophrenia patients. Corcoran(2001) argued that when people try to infer a person’s mental state,they consult autobiographical memory as a basis for this attempt.

If self-reflective processing in schizophrenia patients isimpaired, one would expect a deviant pattern of activation inself-reflective processing networks. FMRI data on an emotionalstroop paradigm indeed shows abnormal activation in the vMPFC(Taylor et al., 2007; Park et al., 2008) The present meta-analysisshows that the vMFPC seems to be of particular importance whenreflecting upon oneself as in the contrast self > other, implyingthat schizophrenia patients might experience particular difficultiesin self-reflection processes.

An interesting specification of impaired self-processing inschizophrenia patients may be the relationship between lack ofillness awareness and self-reflective processing. When one experi-ences problems in reflecting external information upon oneself, thismight lead to impaired insight in schizophrenia patients.

4.5. Schizophrenia, insight and self-reflection

Lack of insight is a widely recognized problem in clinicallypsychotic patients (Amador and David, 2004). Not only can thishamper the attempts of the clinician to help the patient, it alsocauses distress and feelings of frustration in family and friends. It isas yet unclear what causes unawareness of illness. Several studieshave related lack of insight to reduced cognitive function and inparticular cognitive set-shifting abilities (see Aleman et al. (2006)for a meta-analysis). However, this accounts for a relatively smallproportion of the variance in insight.

A possible new approach to the insight problem is to look atself-processing. So far, no studies have looked directly at therelationship between insight in psychosis and self-reflectiveprocessing, despite the apparent link. Patients, who experiencedifficulties in reflecting upon themselves, will most likely also havedifficulty reflecting upon themselves in the light of their illness,symptoms and use of medication. In a paper by Ries et al. (2007)this train of thought was confirmed in individuals with MildCognitive Impairment. Individuals who had impaired insight,showed significantly attenuated activation of the CMS during self-appraisal. Importantly, the authors demonstrated that thisrelationship was not influenced by the cognitive impairmentitself. In line with these findings Lysaker et al. (2005)demonstrated that better meta-cognitive skills, such as the abilityto think about one’s own thoughts, were related to better insight inpatients with schizophrenia. This concept is closely linked to theconcept of TOM, namely to think about the thoughts and actions ofanother agent. Interestingly, some studies suggest that thecapability to think about another agent’s thoughts does not implyfull meta-cognitive capacities (Rockeach, 1964; McEvoy et al.,1993; Startup, 1997). These studies demonstrate that patientslacking insight into their own illness, were fully capable ofrecognizing the illness and symptoms in fellow patients. Thus asWiffen and David (2009) proposed, self-reflective processing maymake use of similar cognitive mechanisms as TOM processing, butthis does not imply that these processes cannot be affectedautonomously.

Several structural MRI studies have related lack of insight inschizophrenia to the structure of prefrontal sub-regions (Flashmanet al., 2001; Shad et al., 2004, 2006), such as the DLPFC (Flashmanet al., 2001; Shad et al., 2006), OFC (Flashman et al., 2001; Shad etal., 2006), MFG (Flashman et al., 2001), IFG (Sapara et al., 2007)and SFG (Sapara et al., 2007). Due to cognitive control on themedial PFC and then the limbic system (Phelps, 2006) one mightassume that the DLPFC does not only exert control in executivefunctioning or set-shifting, but also in more emotionally relatedcognition including self-reflective processing. This reasoning is

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confirmed by a study by Schmitz et al. (2004) who found arelationship between bilateral DLPFC activation, MPFC activationand self-evaluative metacognition. Furthermore, a functionalrelationship between the DLPFC and the PCC, which has beenassociated with the storage of autobiographical memory (Andreasenet al., 1995; Maguire and Mummery, 1999; Maddock et al., 2001), isreflected in the dense connections between the DLPFC and the PCC(Petrides and Pandya, 1999; Petrides, 2005). As mentioned before, inthe process of self-reflection, one needs to gather past informationon the self in order to make an accurate decision, requiringautobiographical memory consultation.

Due to a deficit in cognitive control caused by DLPFCdysfunction, patients who lack insight may not only be impairedon more cognitive tasks, but also experience problems in self-reflective processing. In terms of the proposed model, due to animpaired controlling function of the DLPFC, the other areasimportant for self-evaluative and meta-cognitive problems, thevMPFC, dMPFC and PCC, will show sub-optimal functioning eachleading to impaired self-evaluative processing and an unwilling-ness to accept that one is ill and needs treatment.

To test the validity of the proposed model, more researchshould be conducted looking at self-reflective processing and itsneural correlates in patients lacking insight. This might guide us tothe processes that are impaired in this patient group and give us adirection in which treatment should be directed in order to helpthese patients. The current proposal and meta-analysis of datafrom healthy subjects prepares the ground for such a project.

4.6. Limitations and directions for future research

One important drawback of meta-analysis is that it relies onlyon published data which is biased against negative results; oftencalled the ‘‘file-drawer’’ problem. The central aim of fMRI meta-analysis, however, lies not on the aggregation of power acrossstudies, but rather on its capacity to assess the reliability offindings across studies, thereby determining the location of anaggregate effect, and simultaneously reducing the likelihood offalse positive reporting. It is arguable that this function–locationaim is less affected by a file-drawer problem (Fox et al., 1998).However, no guarantee can be given that in addition to thesignificant regional effects reported here, other effects exist inother areas that have not been picked up by the meta-analysisbecause of low reproducibility across studies. On the other hand,the statistically significant meta-analysis results are very likely torepresent true effects, even in the presence of a file-drawerproblem (for a more detailed discussion of power, reliability andthe limitations of fMRI meta-analysis; Costafreda, 2009).

In the current meta-analysis only two contrasts were included,self > baseline and self > other. Unfortunately, most studiessuitable for inclusion in the meta-analysis did not reportcoordinates for a third contrast: other > baseline. Therefore, thisprocess could not be discussed. Furthermore, readers should notethat only self-reflection studies using trait words and sentenceswere included in the meta-analysis, which limits the conclusionsregarding self-processing in general. Finally, besides making adistinction between self- and other-reflective processing, a finerdistinction may be that of distant and close others. Reflecting upona close other may come closer to self-reflection and recruit thevMPFC, whereas reflecting upon a distant other should not. Thepresented model provides a theoretical framework by which theseand similar hypotheses can be explicitly tested.

Acknowledgements

This work was supported by the European Science FoundationEURYI grant (NWO no. 044035001) to Professor A. Aleman. The

authors would like to thank Marieke Pijnenborg for her usefulcomments on the manuscript. Sergi Costafreda would like togratefully acknowledge support from the National Institute forHealth Research (NIHR) Specialist Biomedical Research Centre forMental Health award to the South London and Maudsley NHSFoundation Trust and the Institute of Psychiatry, King’s CollegeLondon. Finally, we would like to thank the reviewers for theircomments and suggestions.

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