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Neurobiology of self-awareness deficits in schizophrenia: A hypothetical model
Asian Journal of Psychiatry 4 (2011) 248–254
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Review
Neurobiology of self-awareness deficits in schizophrenia: A hypothetical model Mujeeb U. Shad a,*, Benjamin K. Brent b, Matcheri S. Keshavan b a b
The University of Texas Health Science Center, 1421 East Road BBSB # 3118, Houston, TX 77054, United States Beth Israel Deaconess Hospital, Harvard Medical School, Boston, MA, United States
A R T I C L E I N F O
A B S T R A C T
Article history: Received 11 August 2011 Accepted 28 September 2011
Self-awareness (SA) is a cognitive ability to differentiate between self and non-self cues and is pivotal to understand the behavior of other human beings. For this reason, there has been a significant interest to investigate the neurobiology of SA in human subjects. So far the majority of such research has been conducted in healthy subjects but a significant relationship between impaired SA and poor psychosocial outcome in schizophrenia has stimulated neuroimaging research in this patient population. The results from small number of neuroimaging studies in schizophrenia suggest that impaired SA may be mediated by a dysfunction of cortical midline structures. This paper is an attempt to review emerging functional magnetic resonance imaging (fMRI) data in schizophrenia and to propose a hypothetical model of deficits in SA in schizophrenia that can be tested in future research. The model is refined from the available literature and proposes that self-referential activity appears to reflect a shift from activation of anterior to posterior cortical midline structures in schizophrenia subjects, which may be related to lack of functional connectivity between different cortical midline regions. ß 2011 Elsevier B.V. All rights reserved.
Keywords: Neurobiology Self-awareness Deficits Schizophrenia Hypothetical Model
Contents 1. 2. 3. 4.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Functional neuroimaging studies of self-awareness in schizophrenia. . . . . . . . . . . Are SA deficits related to aberrant anterior-to-posterior shift in CMS activation? . Future steps . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. Introduction Self-awareness (SA) refers to a conscious cognitive ability to differentiate between self and non-self cues, in which a decision is made regarding oneself. Self-awareness requires an accurate representation of one’s own traits, abilities and attitudes and is pivotal in understanding the behavior of other human beings. For this reason, the study of SA has attracted significant research interest in healthy subjects as well as those with brain disorders commonly associated with deficits in SA. However, the majority of neuroimaging data with regards to SA are derived from fMRI studies in healthy adults. Although these studies have used different SA paradigms, a common feature is the presentation of self vs. non-self related trait adjectives or sentences. These studies
* Corresponding author. Tel.: +1 713 486 2759; fax: +1 713 486 2753. E-mail address: [email protected] (M.U. Shad). 1876-2018/$ – see front matter ß 2011 Elsevier B.V. All rights reserved. doi:10.1016/j.ajp.2011.09.002
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have uncovered a number of brain regions [such as medial prefrontal cortex (MPFC) and cingulate cortex], collectively labeled as Cortical Midline Structures (CMS) activated in response to selfreflective processing (Amodio and Frith, 2006; Northoff and Bermpohl, 2004; Northoff et al., 2006; van der Meer et al., 2010). The MPFC is a large brain region constituting ‘anterior CMS’ and includes medial orbitofrontal cortex (OFC), the anterior cingulate cortex (ACC) and the dorsomedial prefrontal cortex (DMPFC; also known as medial frontal gyrus) (Fig. 1). The medial OFC includes the gyrus rectus and the medial half of the orbital gyri. The ACC occupies the anterior part of the cingulate gyrus engulfing the genu and the anterior parts of body of the corpus callosum and is subdivided into a subgenual, pregenual and supracallosal region. The dorsal and ventral division of ACC is based on functional differences (see below). The ventral ACC includes subgenual and pregenual ACC and forms the ventral part of anterior CMS, also labeled as ventral medial prefrontal cortex (vMPFC), while the dorsal ACC along with the DMPFC constitutes the dorsal section of anterior CMS, also referred
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Fig. 1. Ventral anterior CMS (or ventral medial prefrontal cortex): med OFC = medial orbitofrontal cortex; ACC = anterior cingulate cortex; sgACC = subgenual ACC; pgACC = pregenual ACC, ventral scACC = ventral supracallosal ACC; dorsal anterior CMS (or dorsal medial prefrontal cortex): dorsal scACC; dorsal supracallosal ACC; DMPFC = dorsomedial prefrontal cortex. Posterior CMS: PC = precuneus; PCC = posterior cingulate cortex; RSC = retrosplenial cortex; arrows reflect bidirectional communication between anterior and posterior CMS.
to as dorsal medial prefrontal cortex (dMPFC). The DMPFC covers the dorsal parts of the prefrontal cortex, including the middle parts of the superior and medial frontal gyrus. The ‘posterior CMS’ includes posterior cingulate cortex (PCC), precuneus (PC) and retrosplenial cortex (RSC) or medial parietal cortex (Northoff et al., 2006) (Fig. 1). The PCC is the posterior part of cingulate gyrus, where it curves posteriorly around the body and splenium of the corpus callosum and borders with the precuneus and retrosplenial cortex. Functionally, the most anterior and ventral of the CMS, the vMPFC cluster (vMPFC) is associated with ‘‘emotional’’ self, sometimes labeled as ‘‘explicit’’ or ‘‘reflexive’’ self due to its involvement in a supra-modal representation of the mental object to be self-referred (Northoff and Bermpohl, 2004; Northoff et al., 2006). Dorsal MPFC (dMPFC) monitors ‘cognitive’ self’ (Northoff and Bermpohl, 2004; Northoff et al., 2006) primarily through its close connectivity with the DLPFC (Kerns et al., 2004; Brass et al., 2005). In this context, a network differentiation has also been noticed between a vMPFC–limbic ‘affective’ pathway and a dMPFC– cortical–hippocampal ‘cognitive’ pathway in a study that examined interactions during self-related decision-making (Schmitz and Johnson, 2006). Thus, damage to the vMPFC leads to an inability to develop a coherent model of one’s own self resulting in subsequent emotional lability (Damasio, 1999; Schore, 2003). In addition, patients with subgenual ACC lesions show deficits in selfmonitoring and show aberrant social behavior (Bush et al., 2000). While lesions in dorsal MPFC (such as DMPFC) have been associated with deficits in social functioning that may underlie inappropriate self-referential judgments and decision-making. Since posterior CMS process self- and other’s perspective for ultimate decisionmaking about contextual meaning of social interactions, functional deficits in posterior CMS may result in deficits in social cognition and theory of mind (D’Argembeau et al., 2007). However, despite having specific roles in the mediation of selfreferential processing, cortical midline regions represent a
cohesive neural network which maintain strong and reciprocal projections among each other and reflect a similar pattern of connectivity to non CMS brain regions (Devinsky et al., 1995; Ongur and Price, 2000), such as ventral and dorsolateral prefrontal cortex, and some of the paracingulate structures, such as insula, superior temporal sulcus, and temporal pole, which have also been involved during self-reflective processing in healthy subjects (Fossati et al., 2004; Kelley et al., 2002; Ochsner et al., 2005). This could be explained by the involvement of these paracingulate structures (especially anterior insula) in representing and processing internal affective bodily states (Mega et al., 1997). Other non-midline brain regions that have been frequently involved in self- vs. other-related activity include the temporoparietal junction (TPJ), which is in close proximity to inferior parietal lobule and supramarginal gyrus and is known to play a pivotal role in self vs. other distinction and theory of mind (TOM; Saxe and Kanwisher, 2003). However, unlike MPFC, TPJ appears to process temporary states such as goals, intentions, and desires of other people, which is an important component of mirror neuron system mediating sensory perception of temporary goals and intentions of others. Superior temporal sulcus (STS), a posterior extension of TPJ, is another brain region that has been consistently activated in studies of ToM abilities (STS; Frith and Frith, 2003). This sulcus separates superior and middle temporal gyri and appears to mediate a range of social cognitive abilities including application of self-perspective and others’ intentions towards causality (Gallagher and Frith, 2003; Materna et al., 2008). While inferior temporal gyri (ITG) have also been involved in ToM tasks involving inferences about the mental states of others (Vo¨llm et al., 2006). Disturbance in SA is a common feature of many neuropsychiatric disorders including schizophrenia (Frith, 1992; Sass and Parnas, 2003) and may reflect a variety of behavioral manifestations ranging from impaired insight into one’s own illness to a dysfunction of social cognition, which is generally referred to as an ability to empathize with other people (Dimaggio et al., 2008;
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Carruthers, 2009). It has been proposed that impaired SA may be a core feature of impaired social cognition (Sprong et al., 2007). Impairment of insight into illness has been linked with psychosocial and clinical outcome in schizophrenia subjects. The clinical relevance of poor insight is underscored by its close link with clinical outcome measures such as treatment non-adherence (Dassa et al., 2010; Kamali et al., 2006). While deficits in social cognition have been reliable predictors of quality of life and other real-world outcomes in schizophrenia (Fisher et al., 2008; Irani et al., 2006; Kettle et al., 2008; Koren et al., 2004; Lysaker et al., 2005, 2009; Sergi et al., 2006; Vogeley, 2007). However, despite the clinical significance of these deficits in self-awareness, only a few studies, to our knowledge, have examined the neurobiological basis of deficits in SA in schizophrenia (Blackwood et al., 2004; Murphy et al., 2010; Holt et al., 2011). The aim of this paper is to provide an overview of the emerging, albeit limited fMRI data regarding the neural bases of selfreferential processing in schizophrenia and healthy subjects. Initially we will present the results from a small number of fMRI studies examining the functional correlates of SA in schizophrenia followed by a comparison of the brain activation in response to self-referential paradigms between schizophrenia and healthy subjects. Finally, we will present fMRI data supporting a hypothetical model of SA deficits in schizophrenia originally proposed by Holt et al. (2011). Of note, the MPFC in this review will include the medial frontal gyrus (medial part of medial frontal gyrus also known as DMPFC) (Lemogne et al., 2010) as well as the ACC (Amodio and Frith, 2006). In addition, the future steps to assess functional correlates of SA in schizophrenia will be discussed. However, a detailed discussion of neuroimaging studies investigating specific SA deficits (such as reduced insight and impaired social cognition) in schizophrenia is beyond the scope of this paper. 2. Functional neuroimaging studies of self-awareness in schizophrenia We conducted a literature search using the search terms ‘self AND (reflect* OR referen*) AND (fMRI OR ‘‘functional magnetic resonance imaging’’ OR ‘‘schizophrenia’’)’ in PubMed until December 2010. Furthermore, the references of the selected papers were searched for additional papers on self-reflection and neuroimaging that did not appear in the PubMed search. Three fMRI studies were found in schizophrenia that used a selfreflective or SA paradigm in which the subject had to decide whether or not a trait word or sentence was applicable to the self or to another (predefined) person. All these studies used auditory or visually presented trait words or sentences. Studies using facial stimuli or emotive pictures were excluded from this review. For reasons of brevity and clarity we only discussed group differences (i.e., schizophrenia and healthy subjects) in self-awarenessinduced activations and within group findings were not reviewed (although they are documented in Table 1). In the literature, several terms, such as SA and self-reflection have been used to define whether certain environmental cues apply to one’s self or not. In this paper, these terms will be used interchangeably to reflect conscious process of self. As can be seen from Table 1, the first reviewed study was conducted in a small sample of eight schizophrenia subjects with active persecutory delusions and eight matched normal controls (Blackwood et al., 2004). The target conditions consisted of ambiguous self-referent neutral (e.g., ‘he is eating’) or threatening (e.g., ‘he is bugged’) statements. The reference conditions consisted of unambiguous other-relevant neutral (e.g., ‘Graeme is eating’) or threatening (e.g., ‘Clive is bugged’) material. The result showed that the deluded subjects showed a marked absence of rostral–ventral
anterior cingulate activation together with increased posterior cingulate gyrus activation in response to self-relevance. However, contradictory to the prediction, the study did find a greater attribution of threatening statements in the target condition as self reflective in the deluded subjects than controls. In addition, only the self-relevance for threatening statements was associated with increased activity in left anterior paracingulate cortex within the control group, suggesting a subthreshold activation in the deluded patient group. In the second study, eleven SZ subjects and 10 healthy controls were presented a metacognitive evaluation task (Murphy et al., 2010). During the task, subjects were asked to make yes/no responses to presentations of adjectives in three conditions: selfevaluation (SE), other evaluation (OE), and a semantic positivityevaluation (SPE). In the SE condition, participants were asked whether adjectives correctly described their own personal attributes (e.g., ‘‘I am intelligent’’). In the OE condition, subjects were asked to apply the same criteria to a significant other (e.g., a family member or close friend) that had been identified by each participant prior to the experiment. Alternatively, for the SPE condition, participants decided whether or not adjectives had a positive emotional valence. The SPE condition was used to control for neural activation due to the emotional quality of the stimuli, language/motoric abilities, and the attentional/decision-making demands of the task. The results yielded a significant hypoactivation in the left superior temporal sulcus (STS) during metacognitive evaluations of others (OE) vs. semantic positivity evaluations (SPE). In addition, a significant hypoactivation was also seen in the right inferior temporal gyrus (ITG) in the OE vs. SE contrasts in the SZ group. However, no significant differences in activations were found in the SE vs. OE or SPE contrast. In a more recent fMRI study, 19 schizophrenia and 20 healthy volunteers performed on a self-reflection task judging the selfrelevance of trait adjectives (Holt et al., 2011) using cortical surface and region of interest-based analyses. The task had two active conditions (1) self-reflection (SR; does this word describe you?), (2) affect labeling (AL; is this a desirable or undesirable trait?) and two control conditions (1) other-reflection (OR; does this word describe your mother?), and (2) perceptual (P; is this word printed in uppercase or lowercase letters?). Similar to the findings from the study by Murphy et al. (2010), this study did not find any group difference in brain activation in response to self-reflective (SR) vs. other-referential (OR) stimuli. The study did observe a lower activation of the right vMPFC and greater activation of the mid/ posterior cingulate gyri in schizophrenia subjects than the controls in response to the SR vs. affect labeling (AL) contrast in a cortical surface-based analysis. In addition, functional connectivity between posterior cingulate gyrus and the dorsal anterior cingulate was lower in the schizophrenia patients compared with control subjects. A similar pattern was seen during overall social reflection. No between group differences in activation were discerned based on region-of interest (ROI) analysis. The reviewed studies in schizophrenia, despite significant differences in sample characteristics and imaging protocols and paradigms, share some common pattern of brain activation in response to self-related activity. For example, two out of the three studies that were reviewed (Blackwood et al., 2004; Holt et al., 2011) shared a lesser activation of vMPFC (i.e., ventral areas of anterior CMS) with a greater activation of posterior CMS [i.e., posterior cingulate cortex (PCC) or precuneus] in schizophrenia subjects than controls in response to self- vs. non self-referential stimuli. These changes in cortical activations represent an anterior-to-posterior shift in midline cortical activity in schizophrenia during self-reflection as proposed by Holt et al. (2011). However, Murphy et al. (2010) did not find any group differences in the activation of vMPFC and in contrast to results from other
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Table 1 Brain activation in response to self-reflective processing in healthy and schizophrenia subjects. Study
Subjects
Contrast
Brain regions activated
Blackwood et al. (2004)
8 SZ; 8 NC
Self-evaluative > other-evaluative
Within group NC: anterior paracingulate (actually ventral pregenual ACC), temporal poles, MFG, SFG, MTG and fusiform gyrus; SZ: PCC and temporal poles Between group NC > SZ: pregenual ACC (ventral MPFC) SZ > NC: PCC No within or between group differences
Murphy et al. (2010)
11 SZ; 10 NC
Threatening > neutral Self-evaluative > semantic positivity evaluative
Other evaluative > semantic positivity evaluative
Other evaluative > self-evaluative
Self-evaluative > other-evaluative
Holt et al. (2011)
18 SZ; 17 NC
Self-referential > affective labeling
Self- plus other-referential > affective labeling
Self-referential > other-referential
Within group NC: PCC, MPFC, MFG, STG; SZ: PCC, medial frontal gyrus, MFG, SFG Between groups NC > SZ: precuneus, angular gyrus, lingual gyrus; SZ > NC: none Within group NC: PCC, MTG, medial frontal gyrus, MFG, SFG; SZ: PCC Between groups NC > SZ: MFG, aposterior STG, lingual gyrus, IPL SZ > NC: none Within group NC: MTG, ITG SZ: none Between groups NC > SZ: STG pole, aITG, supramarginal gyrus SZ > NC: none Within group No activations Between groups No group differences Within group NC: medial frontal gyrus, ACC, MFG, PCC SZ: ACC, middle cingulate, retrosplenial cortex Between groups (cortical surface-based) NC > SZ: right medial OFC (MPFC) SZ > NC: middle & posterior (including PCC) Between Groups (Anatomic ROI analysis) No group differences Within group NC: MPFC, PCC SZ: MPFC, PCC Between groups NC > SZ: MPFC SZ > NC: middle & posterior cingulate (included PCC) Within group No activations Between groups No activations
NC = normal controls; SZ = schizophrenia; ACC = anterior cingulate; PCC = posterior cingulate; STG = superior temporal gyrus; MTG = middle temporal gyrus; ITG = inferior temporal gyrus; SFG = superior frontal gyrus; MFG = middle frontal gyrus; OFC = orbitofrontal; MPFC = medial prefrontal cortex; IPL = inferior parietal lobule. a FDR corrected (Murphy et al., 2010 study).
studies (Blackwood et al., 2004; Holt et al., 2011) observed greater activation of precuneus (i.e., posterior CMS) in controls than schizophrenia subjects. But this finding was not corrected for false discovery rate. Also the study by Murphy et al. (2010) was the first to document greater activation of superior temporal sulcus and inferior temporal gyrus in response to self-related activity in controls than schizophrenia. Among several other methodological differences, one major difference between the reviewed studies that could explain differential brain activation is the fact that Murphy et al. (2010) was the only study that was conducted in early course schizophrenia. It is rather speculative at this time but it may be possible that there are progressive alterations in functional integrity of neural circuitry for SA during the course of schizophrenia. This explanation could only be confirmed in a large sample study followed up longitudinally. Interestingly, a similar
pattern of CMS activation was observed in a recent study in high risk population for psychosis (Modinos et al., 2011). An anterior-to-posterior shift in CMS activation has also been observed in response to social cognitive paradigms (Brune et al., 2008; Lee et al., 2006; Reske et al., 2009; Walter et al., 2009) suggesting shared neural substrates between different behavioral expressions of SA. Since vMPFC attributes emotional relevance to self-referential stimuli (Damasio, 1999; Schore, 2003) and PCC encodes and retrieves emotionally salient information (Gainotti et al., 1998; Gusnard and Raichle, 2001; Maddock, 1999; Vogt et al., 1992), a decreased activation of vMPFC along with an increased activation of PCC suggests that deluded schizophrenia subjects may have emotional instability and attribute a greater emotional salience to the self-relevant stimuli as compared to healthy subjects.
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It is worth mentioning that several cortical midline regions, including MPFC (anterior CMS) and PCC and PC (posterior CMS) are important components of the ‘Default Mode Network’ (DMN), which in healthy subjects represents a larger network of brain areas that consistently yield increased activation during resting states and self-relevant activity (Gusnard et al., 2001) and decreased activation (or task-induced deactivation) in response to externally directed cognitive or sensory tasks (Buckner et al., 2008; Gusnard and Raichle, 2001). It is interesting that this functional dissociation between anterior and posterior regions of DMN was not observed during an externally directed cognitive task (i.e., working memory task) in schizophrenia (Whitfield-Gabrieli et al., 2009). Instead of hypoactivation of MPFC during self-reflection, schizophrenia subjects yielded hyperactivity of the MPFC (with no changes in PCC or PC activation) and lacked task-induced deactivation that was observed in healthy subjects (Whitfield-Gabrieli et al., 2009). These findings suggest that DMN responds differently to the externally directed cognitive tasks and self-relevant information in schizophrenia. More specifically, a reduced activation of MPFC in schizophrenia would indicate that these patients could not disengage from the externally directed cognitive task(s) to process self-related stimuli or they had a diminished introspective activity (Lysaker et al., 2007). One of the most plausible explanations for the observed decoupling of activity between anterior and posterior CMS in schizophrenia is the deficit in functional connectivity between these midline brain regions. This view is supported by findings from one of the reviewed studies that reported lower functional connectivity between posterior CMS (mid/posterior cingulate) and dMPFC (dorsal anterior cingulate gyrus) in schizophrenia patients than controls (Holt et al., 2011). Although none of the reviewed studies observed significant group differences in dMPFC activation, the observed connectivity deficits between posterior CMS and dMPFC suggest that self-relevant stimuli may induce an altered response in dMPFC in schizophrenia. Further support for impaired connectivity is based on altered functional and anatomical link between CMS. For example, impaired connectivity was observed between ventral and dMPFC using fMRI paradigms and diffusion tensor imaging (DTI), respectively (Camchong et al., 2011). In addition, other studies have also documented structural deficits in MPFC in schizophrenia, such as thinner cortex and decreased volume (Baiano et al., 2007; Kreczmanski et al., 2005; Wang et al., 2007), decreased N-acetyl aspartate and glutamine levels (The´berge et al., 2002; Wood et al., 2007) and decreased anisotropy
in the vMPFC (Kumra et al., 2005; White et al., 2008) and cingulum bundle (Buchsbaum et al., 2007; Fujiwara et al., 2007; Kubicki et al., 2003; Sun et al., 2003; Wang et al., 2004). In another study, schizophrenia patients showed significant differences in connectivity between dMPFC and other brain regions (such as parietal cortex, the inferior temporal gyrus and the right dorsolateral prefrontal cortex) (Zhou et al., 2007). Emerging data have also revealed anisotropy in the posterior cingulate cortex (PCC) (Fujiwara et al., 2007) and decreased overall relative left and right gray matter volume in the anterior cingulate gyrus in persons with schizophrenia compared with healthy controls (Segal et al., 2010). 3. Are SA deficits related to aberrant anterior-to-posterior shift in CMS activation? With this background, we propose a hypothetical model of SA deficits in schizophrenia refined from an earlier study (Holt et al., 2011) that predicts that deficits in functional connectivity will induce an anterior-to-posterior shift from ventral anterior to posterior midline cortical activity in schizophrenia in response to self-referential stimuli. As can be seen in Fig. 2, we have divided anterior CMS into two regions (ventral and dorsal). The two anterior CMS along with the posterior CMS provide a network of three functionally distinct midline brain regions that mediate and synthesize various aspects of self-related information. Based on the fMRI data in schizophrenia, increased activation of posterior CMS and decreased activation of ventral anterior CMS (i.e., vMPFC) has been the most consistent findings in two of the three reviewed studies (Blackwood et al., 2004; Holt et al., 2011). However, despite deficits in functional connectivity between dorsal anterior CMS (i.e., dMPFC) and posterior CMS in one of the reviewed studies (Holt et al., 2011), no significant difference in activation has been reported in this brain region. Therefore, support for a potential role of dMPFC in mediating self-relevant activity in schizophrenia is primarily based on the emerging data in healthy subjects suggesting appraisals of self-relevance and introspection are facilitated by dMPFC (Schmitz and Johnson, 2007). Only fMRI studies with adequate sample size can confirm the hypothesis of altered selfreferential activity in dMPFC in schizophrenia. Nonetheless, a potential change in dMPFC response during selfreferential processing along with changes in vMPFC activation in schizophrenia (Blackwood et al., 2004; Holt et al., 2011) may represent a more emotionally biased than cognitively oriented
Corcal Midline Structures (CMS) (CMS
Posterior CMS
Anterior CMS
MPFC acvaon off vMPFC
Emoonal/Explicit /Reflexive SELF
acvaon of PCC or PC
Alt d ac Altered vaon off dMPFC dMPFC
Cognive/Implicit /Direct SELF
Increased SELF- & Decreased OTHER’S Perspecve
Self-Referenal Impaired SelfProcessing
Impaired Social Cognion/Empathy
Deficits in SelfSelf-Awareness Fig. 2. Hypothetical model of self-awareness deficits in schizophrenia. vMPFC = ventral medial prefrontal cortex; dMPFC = dorsal medial PFC; DLPFC = dorsolateral prefrontal cortex; PCC = posterior cingulate cortex; RSC = retroslenial cortex; PC = precuneus.
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decision-making about relationship between the self and the object to be self-referred (Schmitz and Johnson, 2007). The changes in activation of vMPFC and dMPFC (i.e., anterior CMS) along with an increased activation of posterior CMS suggest that schizophrenia subjects may be so emotionally invested in ‘self’ to lose the ability to consider others’ perspective in their decision-making, which could explain frequently observed deficits in social cognition and empathy in this patient population (D’Argembeau et al., 2007). This affective labeling of self-reflectivity requires autobiographical memory consultation in order to make decisions regarding the self- vs. other-reflectivity of the stimuli (Cavanna and Trimble, 2006). The close connection between posterior CMS and hippocampus allows recruitment of autobiographical memory during self-referential processing in healthy subjects (Northoff et al., 2006). Schizophrenia subjects frequently lack the ability to assess self- and other’s perspectives, which may be mediated by an increased activation of PCC in chronic schizophrenia (Blackwood et al., 2004; Holt et al., 2011). Schizophrenia subjects also lack the ability to maintain differential representation of self and other’s attitudes and traits due to hippocampally mediated deficits in autobiographical memory, which could result in faulty processing of self- and other-related information over extended periods of time and across events. The model proposes that an increased activation of posterior CMS (i.e., PCC or PC) in response to selfreferential activity may be an effort to compensate for the reduced activation in the anterior CMS (i.e., vMPFC) (Blackwood et al., 2004; Holt et al., 2011) probably mediated by deficits in functional connectivity between these brain regions (Fig. 1). Although this hypothetical model tries to explain SA deficits based on regional deficits in CMS function, it is actually the balancing act between different CMS along with their communication with other brain regions to integrate complex details of selfvs. other-related information for optimal self-relevant decisionmaking. It is also worth mentioning that since schizophrenia is a heterogeneous illness with different etiobiological bases, a single model such as the one proposed in this study may fail to incorporate all neural networks processing self-related information in schizophrenia subjects. Furthermore the developmental brain changes may be responsible for potential age-related variations in neural circuitry for SA, such as those observed in Murphy et al. (2010) study, which was conducted in early course schizophrenia as opposed to those in chronic schizophrenia (Blackwood et al., 2004; Holt et al., 2011). Thus, the anterior– posterior shift in chronic schizophrenia may not be reflective of self-referential activity in first-episode schizophrenia (Murphy et al., 2010). More specifically, the findings from Murphy et al. (2010) study actually suggest a lateral-medial connectivity dysfunction rather than the anterior–posterior shift. 4. Future steps The proposed preliminary model, refined after originally proposed by Holt et al. (2011), is based on findings from a few studies with small samples. Thus, the model will need to be tested in a larger sample of schizophrenia subjects preferably in a longitudinal study starting during early psychosis so that not only the confounding effects of illness chronicity and long-term antipsychotic pharmacotherapy can be investigated but the developmental and functional brain changes can also be documented. Both structural and fMRI will be required to test the model. The structural connectivity can be studied using DTI, while functional connectivity will require a priori hypotheses based on the proposed model using an fMRI paradigm that is optimized based on lessons learned from prior studies. One of the major limitations of the imaging paradigms used in prior studies has been lack of
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significant findings in self- vs. other-referential contrasts (except Blackwood et al., 2004). We believe that his issue can be addressed by enhancing the limbic valence of the self-related statements by using patient’s name rather than a first- or third degree noun as employed in earlier studies (Murphy et al., 2010; Holt et al., 2011). In addition, the trait adjectives will need to actually incorporate the delusional themes of the study patients in an effort to investigate the neural substrates for unawareness of delusions. Furthermore, a detailed pre-scan task familiarization along with a pre- and post-scan questionnaire will be useful to confirm the study subjects’ behavioral responses. It will remain important to match patient and control groups for age, gender, premorbid IQ, education, and socioeconomic status. A detailed and careful description of eligibility criteria for antipsychotic treatment will also be extremely useful, especially with regards to the class, duration, dose, and antimuscarinic effects of antipsychotic medications. Of course, it may be preferable to recruit medication-free patients, but that can be extremely difficult besides being unethical (with regards to competency to provide consent) and scanning difficulties due to untreated psychosis. Finally, the future studies will need to test and refine neurobiological models for SA deficits in schizophrenia as the one proposed in this paper. Conflict of interest The primary author has received funding from Eli Lilly for other research. The other authors have no conflicts of interest. References Amodio, D.M., Frith, C.D., 2006. Meeting of minds: the medial frontal cortex and social cognition. Nat. Rev. Neurosci. 7 (4), 268–277. Baiano, M., David, A., Versace, A., Churchill, R., Balestrieri, M., Brambilla, P., 2007. Anterior cingulate volumes in schizophrenia: a systematic review and a metaanalysis of MRI studies. Schizophr. Res. 93, 1–12. Blackwood, N.J., Bentall, R.P., Ffytche, D.H., Simmons, A., Murray, R.M., Howard, R.J., 2004. Persecutory delusions and the determination of self-relevance: an fMRI investigation. Psychol. Med. 34 (4), 591–596. Brass, M., Derrfuss, J., Forstmann, B., von Cramon, D.Y., 2005. The role of the inferior frontal junction area in cognitive control. Trends Cogn. Sci. 9, 314–316. Brune, M., Lissek, S., Fuchs, N., Witthaus, H., Peters, S., Nicolas, V., Tegenthoff, M., Juckel, G., Lissek, S., 2008. An fMRI study of theory of mind in schizophrenic patients with passivity symptoms. Neuropsychologia 46, 1992–2001. Buchsbaum, M.S., Buchsbaum, B.R., Hazlett, E.A., Haznedar, M.M., Newmark, R., Tang, C.Y., Hof, P.R., 2007. Relative glucose metabolic rate higher in white matter in patients with schizophrenia. Am. J. Psychiatry 164, 1072–1081. Buckner, R.L., Andrews-Hanna, J.R., Schacter, D.L., 2008. The brain’s default network: anatomy, function, and relevance to disease. Ann. N. Y. Acad. Sci. 1124, 1– 38. Bush, G., Luu, P., Posner, M.I., 2000. Cognitive and emotional influences in anterior cingulate cortex. Trends Cogn. Sci. 4, 215–222. Camchong, J., MacDonald 3rd, A.W., Bell, C., Mueller, B.A., Lim, K.O., 2011. Altered functional and anatomical connectivity in schizophrenia. Schizophr. Bull. 37 (3), 640–650. Carruthers, P., 2009. How we know our own minds: the relationship between mindreading and metacognition. Behav. Brain Sci. 32, 121–138. Cavanna, A.E., Trimble, M.R., 2006. The precuneus: a review of its functional anatomy and behavioural correlates. Brain 129 (Pt 3), 564–583. D’Argembeau, A., Ruby, P., Collette, F., Degueldre, C., Balteau, E., Luxen, A., Maquet, P., Salmon, E., 2007. Distinct regions of the medial prefrontal cortex are associated with self-referential processing and perspective taking. J. Cogn. Neurosci. 19, 935–944. Damasio, A.R., 1999. The Feeling of What Happens: Body and Emotion in the Making of Consciousness. Harcourt Brace. Dassa, D., Boyer, L., Benoit, M., Bourcet, S., Raymondet, P., Bottai, T., 2010. Factors associated with medication non-adherence in patients suffering from schizophrenia: a cross-sectional study in a universal coverage health-care system. Aust. N. Z. J. Psychiatry 44 (10), 921–928. Devinsky, O., Morrell, M.J., Vogt, B.A., 1995. Contributions of anterior cingulate cortex to behaviour. Brain 118, 279–306. Dimaggio, G., Lysaker, P.H., Carcione, A., Nicolo, G., Semerari, A., 2008. Know yourself and you shall know the other to a certain extent: multiple paths of influence of self-reflection on mindreading. Conscious Cogn. 17, 778–789. Fisher, M., McCoy, K., Poole, J.H., Vinogradov, S., 2008. Self and other in schizophrenia: a cognitive neuroscience perspective. Am. J. Psychiatry 165, 1465–1472. Fossati, P., Hevenor, S.J., Lepage, M., Graham, S.J., Grady, C., Keightley, M.L., Craik, F., Mayberg, H., 2004. Distributed self in episodic memory: neural correlates of
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Asian Journal of Psychiatry journal homepage: www.elsevier.com/locate/ajp
Review
Neurobiology of self-awareness deficits in schizophrenia: A hypothetical model Mujeeb U. Shad a,*, Benjamin K. Brent b, Matcheri S. Keshavan b a b
The University of Texas Health Science Center, 1421 East Road BBSB # 3118, Houston, TX 77054, United States Beth Israel Deaconess Hospital, Harvard Medical School, Boston, MA, United States
A R T I C L E I N F O
A B S T R A C T
Article history: Received 11 August 2011 Accepted 28 September 2011
Self-awareness (SA) is a cognitive ability to differentiate between self and non-self cues and is pivotal to understand the behavior of other human beings. For this reason, there has been a significant interest to investigate the neurobiology of SA in human subjects. So far the majority of such research has been conducted in healthy subjects but a significant relationship between impaired SA and poor psychosocial outcome in schizophrenia has stimulated neuroimaging research in this patient population. The results from small number of neuroimaging studies in schizophrenia suggest that impaired SA may be mediated by a dysfunction of cortical midline structures. This paper is an attempt to review emerging functional magnetic resonance imaging (fMRI) data in schizophrenia and to propose a hypothetical model of deficits in SA in schizophrenia that can be tested in future research. The model is refined from the available literature and proposes that self-referential activity appears to reflect a shift from activation of anterior to posterior cortical midline structures in schizophrenia subjects, which may be related to lack of functional connectivity between different cortical midline regions. ß 2011 Elsevier B.V. All rights reserved.
Keywords: Neurobiology Self-awareness Deficits Schizophrenia Hypothetical Model
Contents 1. 2. 3. 4.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Functional neuroimaging studies of self-awareness in schizophrenia. . . . . . . . . . . Are SA deficits related to aberrant anterior-to-posterior shift in CMS activation? . Future steps . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. Introduction Self-awareness (SA) refers to a conscious cognitive ability to differentiate between self and non-self cues, in which a decision is made regarding oneself. Self-awareness requires an accurate representation of one’s own traits, abilities and attitudes and is pivotal in understanding the behavior of other human beings. For this reason, the study of SA has attracted significant research interest in healthy subjects as well as those with brain disorders commonly associated with deficits in SA. However, the majority of neuroimaging data with regards to SA are derived from fMRI studies in healthy adults. Although these studies have used different SA paradigms, a common feature is the presentation of self vs. non-self related trait adjectives or sentences. These studies
* Corresponding author. Tel.: +1 713 486 2759; fax: +1 713 486 2753. E-mail address: [email protected] (M.U. Shad). 1876-2018/$ – see front matter ß 2011 Elsevier B.V. All rights reserved. doi:10.1016/j.ajp.2011.09.002
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have uncovered a number of brain regions [such as medial prefrontal cortex (MPFC) and cingulate cortex], collectively labeled as Cortical Midline Structures (CMS) activated in response to selfreflective processing (Amodio and Frith, 2006; Northoff and Bermpohl, 2004; Northoff et al., 2006; van der Meer et al., 2010). The MPFC is a large brain region constituting ‘anterior CMS’ and includes medial orbitofrontal cortex (OFC), the anterior cingulate cortex (ACC) and the dorsomedial prefrontal cortex (DMPFC; also known as medial frontal gyrus) (Fig. 1). The medial OFC includes the gyrus rectus and the medial half of the orbital gyri. The ACC occupies the anterior part of the cingulate gyrus engulfing the genu and the anterior parts of body of the corpus callosum and is subdivided into a subgenual, pregenual and supracallosal region. The dorsal and ventral division of ACC is based on functional differences (see below). The ventral ACC includes subgenual and pregenual ACC and forms the ventral part of anterior CMS, also labeled as ventral medial prefrontal cortex (vMPFC), while the dorsal ACC along with the DMPFC constitutes the dorsal section of anterior CMS, also referred
M.U. Shad et al. / Asian Journal of Psychiatry 4 (2011) 248–254
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Fig. 1. Ventral anterior CMS (or ventral medial prefrontal cortex): med OFC = medial orbitofrontal cortex; ACC = anterior cingulate cortex; sgACC = subgenual ACC; pgACC = pregenual ACC, ventral scACC = ventral supracallosal ACC; dorsal anterior CMS (or dorsal medial prefrontal cortex): dorsal scACC; dorsal supracallosal ACC; DMPFC = dorsomedial prefrontal cortex. Posterior CMS: PC = precuneus; PCC = posterior cingulate cortex; RSC = retrosplenial cortex; arrows reflect bidirectional communication between anterior and posterior CMS.
to as dorsal medial prefrontal cortex (dMPFC). The DMPFC covers the dorsal parts of the prefrontal cortex, including the middle parts of the superior and medial frontal gyrus. The ‘posterior CMS’ includes posterior cingulate cortex (PCC), precuneus (PC) and retrosplenial cortex (RSC) or medial parietal cortex (Northoff et al., 2006) (Fig. 1). The PCC is the posterior part of cingulate gyrus, where it curves posteriorly around the body and splenium of the corpus callosum and borders with the precuneus and retrosplenial cortex. Functionally, the most anterior and ventral of the CMS, the vMPFC cluster (vMPFC) is associated with ‘‘emotional’’ self, sometimes labeled as ‘‘explicit’’ or ‘‘reflexive’’ self due to its involvement in a supra-modal representation of the mental object to be self-referred (Northoff and Bermpohl, 2004; Northoff et al., 2006). Dorsal MPFC (dMPFC) monitors ‘cognitive’ self’ (Northoff and Bermpohl, 2004; Northoff et al., 2006) primarily through its close connectivity with the DLPFC (Kerns et al., 2004; Brass et al., 2005). In this context, a network differentiation has also been noticed between a vMPFC–limbic ‘affective’ pathway and a dMPFC– cortical–hippocampal ‘cognitive’ pathway in a study that examined interactions during self-related decision-making (Schmitz and Johnson, 2006). Thus, damage to the vMPFC leads to an inability to develop a coherent model of one’s own self resulting in subsequent emotional lability (Damasio, 1999; Schore, 2003). In addition, patients with subgenual ACC lesions show deficits in selfmonitoring and show aberrant social behavior (Bush et al., 2000). While lesions in dorsal MPFC (such as DMPFC) have been associated with deficits in social functioning that may underlie inappropriate self-referential judgments and decision-making. Since posterior CMS process self- and other’s perspective for ultimate decisionmaking about contextual meaning of social interactions, functional deficits in posterior CMS may result in deficits in social cognition and theory of mind (D’Argembeau et al., 2007). However, despite having specific roles in the mediation of selfreferential processing, cortical midline regions represent a
cohesive neural network which maintain strong and reciprocal projections among each other and reflect a similar pattern of connectivity to non CMS brain regions (Devinsky et al., 1995; Ongur and Price, 2000), such as ventral and dorsolateral prefrontal cortex, and some of the paracingulate structures, such as insula, superior temporal sulcus, and temporal pole, which have also been involved during self-reflective processing in healthy subjects (Fossati et al., 2004; Kelley et al., 2002; Ochsner et al., 2005). This could be explained by the involvement of these paracingulate structures (especially anterior insula) in representing and processing internal affective bodily states (Mega et al., 1997). Other non-midline brain regions that have been frequently involved in self- vs. other-related activity include the temporoparietal junction (TPJ), which is in close proximity to inferior parietal lobule and supramarginal gyrus and is known to play a pivotal role in self vs. other distinction and theory of mind (TOM; Saxe and Kanwisher, 2003). However, unlike MPFC, TPJ appears to process temporary states such as goals, intentions, and desires of other people, which is an important component of mirror neuron system mediating sensory perception of temporary goals and intentions of others. Superior temporal sulcus (STS), a posterior extension of TPJ, is another brain region that has been consistently activated in studies of ToM abilities (STS; Frith and Frith, 2003). This sulcus separates superior and middle temporal gyri and appears to mediate a range of social cognitive abilities including application of self-perspective and others’ intentions towards causality (Gallagher and Frith, 2003; Materna et al., 2008). While inferior temporal gyri (ITG) have also been involved in ToM tasks involving inferences about the mental states of others (Vo¨llm et al., 2006). Disturbance in SA is a common feature of many neuropsychiatric disorders including schizophrenia (Frith, 1992; Sass and Parnas, 2003) and may reflect a variety of behavioral manifestations ranging from impaired insight into one’s own illness to a dysfunction of social cognition, which is generally referred to as an ability to empathize with other people (Dimaggio et al., 2008;
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Carruthers, 2009). It has been proposed that impaired SA may be a core feature of impaired social cognition (Sprong et al., 2007). Impairment of insight into illness has been linked with psychosocial and clinical outcome in schizophrenia subjects. The clinical relevance of poor insight is underscored by its close link with clinical outcome measures such as treatment non-adherence (Dassa et al., 2010; Kamali et al., 2006). While deficits in social cognition have been reliable predictors of quality of life and other real-world outcomes in schizophrenia (Fisher et al., 2008; Irani et al., 2006; Kettle et al., 2008; Koren et al., 2004; Lysaker et al., 2005, 2009; Sergi et al., 2006; Vogeley, 2007). However, despite the clinical significance of these deficits in self-awareness, only a few studies, to our knowledge, have examined the neurobiological basis of deficits in SA in schizophrenia (Blackwood et al., 2004; Murphy et al., 2010; Holt et al., 2011). The aim of this paper is to provide an overview of the emerging, albeit limited fMRI data regarding the neural bases of selfreferential processing in schizophrenia and healthy subjects. Initially we will present the results from a small number of fMRI studies examining the functional correlates of SA in schizophrenia followed by a comparison of the brain activation in response to self-referential paradigms between schizophrenia and healthy subjects. Finally, we will present fMRI data supporting a hypothetical model of SA deficits in schizophrenia originally proposed by Holt et al. (2011). Of note, the MPFC in this review will include the medial frontal gyrus (medial part of medial frontal gyrus also known as DMPFC) (Lemogne et al., 2010) as well as the ACC (Amodio and Frith, 2006). In addition, the future steps to assess functional correlates of SA in schizophrenia will be discussed. However, a detailed discussion of neuroimaging studies investigating specific SA deficits (such as reduced insight and impaired social cognition) in schizophrenia is beyond the scope of this paper. 2. Functional neuroimaging studies of self-awareness in schizophrenia We conducted a literature search using the search terms ‘self AND (reflect* OR referen*) AND (fMRI OR ‘‘functional magnetic resonance imaging’’ OR ‘‘schizophrenia’’)’ in PubMed until December 2010. Furthermore, the references of the selected papers were searched for additional papers on self-reflection and neuroimaging that did not appear in the PubMed search. Three fMRI studies were found in schizophrenia that used a selfreflective or SA paradigm in which the subject had to decide whether or not a trait word or sentence was applicable to the self or to another (predefined) person. All these studies used auditory or visually presented trait words or sentences. Studies using facial stimuli or emotive pictures were excluded from this review. For reasons of brevity and clarity we only discussed group differences (i.e., schizophrenia and healthy subjects) in self-awarenessinduced activations and within group findings were not reviewed (although they are documented in Table 1). In the literature, several terms, such as SA and self-reflection have been used to define whether certain environmental cues apply to one’s self or not. In this paper, these terms will be used interchangeably to reflect conscious process of self. As can be seen from Table 1, the first reviewed study was conducted in a small sample of eight schizophrenia subjects with active persecutory delusions and eight matched normal controls (Blackwood et al., 2004). The target conditions consisted of ambiguous self-referent neutral (e.g., ‘he is eating’) or threatening (e.g., ‘he is bugged’) statements. The reference conditions consisted of unambiguous other-relevant neutral (e.g., ‘Graeme is eating’) or threatening (e.g., ‘Clive is bugged’) material. The result showed that the deluded subjects showed a marked absence of rostral–ventral
anterior cingulate activation together with increased posterior cingulate gyrus activation in response to self-relevance. However, contradictory to the prediction, the study did find a greater attribution of threatening statements in the target condition as self reflective in the deluded subjects than controls. In addition, only the self-relevance for threatening statements was associated with increased activity in left anterior paracingulate cortex within the control group, suggesting a subthreshold activation in the deluded patient group. In the second study, eleven SZ subjects and 10 healthy controls were presented a metacognitive evaluation task (Murphy et al., 2010). During the task, subjects were asked to make yes/no responses to presentations of adjectives in three conditions: selfevaluation (SE), other evaluation (OE), and a semantic positivityevaluation (SPE). In the SE condition, participants were asked whether adjectives correctly described their own personal attributes (e.g., ‘‘I am intelligent’’). In the OE condition, subjects were asked to apply the same criteria to a significant other (e.g., a family member or close friend) that had been identified by each participant prior to the experiment. Alternatively, for the SPE condition, participants decided whether or not adjectives had a positive emotional valence. The SPE condition was used to control for neural activation due to the emotional quality of the stimuli, language/motoric abilities, and the attentional/decision-making demands of the task. The results yielded a significant hypoactivation in the left superior temporal sulcus (STS) during metacognitive evaluations of others (OE) vs. semantic positivity evaluations (SPE). In addition, a significant hypoactivation was also seen in the right inferior temporal gyrus (ITG) in the OE vs. SE contrasts in the SZ group. However, no significant differences in activations were found in the SE vs. OE or SPE contrast. In a more recent fMRI study, 19 schizophrenia and 20 healthy volunteers performed on a self-reflection task judging the selfrelevance of trait adjectives (Holt et al., 2011) using cortical surface and region of interest-based analyses. The task had two active conditions (1) self-reflection (SR; does this word describe you?), (2) affect labeling (AL; is this a desirable or undesirable trait?) and two control conditions (1) other-reflection (OR; does this word describe your mother?), and (2) perceptual (P; is this word printed in uppercase or lowercase letters?). Similar to the findings from the study by Murphy et al. (2010), this study did not find any group difference in brain activation in response to self-reflective (SR) vs. other-referential (OR) stimuli. The study did observe a lower activation of the right vMPFC and greater activation of the mid/ posterior cingulate gyri in schizophrenia subjects than the controls in response to the SR vs. affect labeling (AL) contrast in a cortical surface-based analysis. In addition, functional connectivity between posterior cingulate gyrus and the dorsal anterior cingulate was lower in the schizophrenia patients compared with control subjects. A similar pattern was seen during overall social reflection. No between group differences in activation were discerned based on region-of interest (ROI) analysis. The reviewed studies in schizophrenia, despite significant differences in sample characteristics and imaging protocols and paradigms, share some common pattern of brain activation in response to self-related activity. For example, two out of the three studies that were reviewed (Blackwood et al., 2004; Holt et al., 2011) shared a lesser activation of vMPFC (i.e., ventral areas of anterior CMS) with a greater activation of posterior CMS [i.e., posterior cingulate cortex (PCC) or precuneus] in schizophrenia subjects than controls in response to self- vs. non self-referential stimuli. These changes in cortical activations represent an anterior-to-posterior shift in midline cortical activity in schizophrenia during self-reflection as proposed by Holt et al. (2011). However, Murphy et al. (2010) did not find any group differences in the activation of vMPFC and in contrast to results from other
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Table 1 Brain activation in response to self-reflective processing in healthy and schizophrenia subjects. Study
Subjects
Contrast
Brain regions activated
Blackwood et al. (2004)
8 SZ; 8 NC
Self-evaluative > other-evaluative
Within group NC: anterior paracingulate (actually ventral pregenual ACC), temporal poles, MFG, SFG, MTG and fusiform gyrus; SZ: PCC and temporal poles Between group NC > SZ: pregenual ACC (ventral MPFC) SZ > NC: PCC No within or between group differences
Murphy et al. (2010)
11 SZ; 10 NC
Threatening > neutral Self-evaluative > semantic positivity evaluative
Other evaluative > semantic positivity evaluative
Other evaluative > self-evaluative
Self-evaluative > other-evaluative
Holt et al. (2011)
18 SZ; 17 NC
Self-referential > affective labeling
Self- plus other-referential > affective labeling
Self-referential > other-referential
Within group NC: PCC, MPFC, MFG, STG; SZ: PCC, medial frontal gyrus, MFG, SFG Between groups NC > SZ: precuneus, angular gyrus, lingual gyrus; SZ > NC: none Within group NC: PCC, MTG, medial frontal gyrus, MFG, SFG; SZ: PCC Between groups NC > SZ: MFG, aposterior STG, lingual gyrus, IPL SZ > NC: none Within group NC: MTG, ITG SZ: none Between groups NC > SZ: STG pole, aITG, supramarginal gyrus SZ > NC: none Within group No activations Between groups No group differences Within group NC: medial frontal gyrus, ACC, MFG, PCC SZ: ACC, middle cingulate, retrosplenial cortex Between groups (cortical surface-based) NC > SZ: right medial OFC (MPFC) SZ > NC: middle & posterior (including PCC) Between Groups (Anatomic ROI analysis) No group differences Within group NC: MPFC, PCC SZ: MPFC, PCC Between groups NC > SZ: MPFC SZ > NC: middle & posterior cingulate (included PCC) Within group No activations Between groups No activations
NC = normal controls; SZ = schizophrenia; ACC = anterior cingulate; PCC = posterior cingulate; STG = superior temporal gyrus; MTG = middle temporal gyrus; ITG = inferior temporal gyrus; SFG = superior frontal gyrus; MFG = middle frontal gyrus; OFC = orbitofrontal; MPFC = medial prefrontal cortex; IPL = inferior parietal lobule. a FDR corrected (Murphy et al., 2010 study).
studies (Blackwood et al., 2004; Holt et al., 2011) observed greater activation of precuneus (i.e., posterior CMS) in controls than schizophrenia subjects. But this finding was not corrected for false discovery rate. Also the study by Murphy et al. (2010) was the first to document greater activation of superior temporal sulcus and inferior temporal gyrus in response to self-related activity in controls than schizophrenia. Among several other methodological differences, one major difference between the reviewed studies that could explain differential brain activation is the fact that Murphy et al. (2010) was the only study that was conducted in early course schizophrenia. It is rather speculative at this time but it may be possible that there are progressive alterations in functional integrity of neural circuitry for SA during the course of schizophrenia. This explanation could only be confirmed in a large sample study followed up longitudinally. Interestingly, a similar
pattern of CMS activation was observed in a recent study in high risk population for psychosis (Modinos et al., 2011). An anterior-to-posterior shift in CMS activation has also been observed in response to social cognitive paradigms (Brune et al., 2008; Lee et al., 2006; Reske et al., 2009; Walter et al., 2009) suggesting shared neural substrates between different behavioral expressions of SA. Since vMPFC attributes emotional relevance to self-referential stimuli (Damasio, 1999; Schore, 2003) and PCC encodes and retrieves emotionally salient information (Gainotti et al., 1998; Gusnard and Raichle, 2001; Maddock, 1999; Vogt et al., 1992), a decreased activation of vMPFC along with an increased activation of PCC suggests that deluded schizophrenia subjects may have emotional instability and attribute a greater emotional salience to the self-relevant stimuli as compared to healthy subjects.
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It is worth mentioning that several cortical midline regions, including MPFC (anterior CMS) and PCC and PC (posterior CMS) are important components of the ‘Default Mode Network’ (DMN), which in healthy subjects represents a larger network of brain areas that consistently yield increased activation during resting states and self-relevant activity (Gusnard et al., 2001) and decreased activation (or task-induced deactivation) in response to externally directed cognitive or sensory tasks (Buckner et al., 2008; Gusnard and Raichle, 2001). It is interesting that this functional dissociation between anterior and posterior regions of DMN was not observed during an externally directed cognitive task (i.e., working memory task) in schizophrenia (Whitfield-Gabrieli et al., 2009). Instead of hypoactivation of MPFC during self-reflection, schizophrenia subjects yielded hyperactivity of the MPFC (with no changes in PCC or PC activation) and lacked task-induced deactivation that was observed in healthy subjects (Whitfield-Gabrieli et al., 2009). These findings suggest that DMN responds differently to the externally directed cognitive tasks and self-relevant information in schizophrenia. More specifically, a reduced activation of MPFC in schizophrenia would indicate that these patients could not disengage from the externally directed cognitive task(s) to process self-related stimuli or they had a diminished introspective activity (Lysaker et al., 2007). One of the most plausible explanations for the observed decoupling of activity between anterior and posterior CMS in schizophrenia is the deficit in functional connectivity between these midline brain regions. This view is supported by findings from one of the reviewed studies that reported lower functional connectivity between posterior CMS (mid/posterior cingulate) and dMPFC (dorsal anterior cingulate gyrus) in schizophrenia patients than controls (Holt et al., 2011). Although none of the reviewed studies observed significant group differences in dMPFC activation, the observed connectivity deficits between posterior CMS and dMPFC suggest that self-relevant stimuli may induce an altered response in dMPFC in schizophrenia. Further support for impaired connectivity is based on altered functional and anatomical link between CMS. For example, impaired connectivity was observed between ventral and dMPFC using fMRI paradigms and diffusion tensor imaging (DTI), respectively (Camchong et al., 2011). In addition, other studies have also documented structural deficits in MPFC in schizophrenia, such as thinner cortex and decreased volume (Baiano et al., 2007; Kreczmanski et al., 2005; Wang et al., 2007), decreased N-acetyl aspartate and glutamine levels (The´berge et al., 2002; Wood et al., 2007) and decreased anisotropy
in the vMPFC (Kumra et al., 2005; White et al., 2008) and cingulum bundle (Buchsbaum et al., 2007; Fujiwara et al., 2007; Kubicki et al., 2003; Sun et al., 2003; Wang et al., 2004). In another study, schizophrenia patients showed significant differences in connectivity between dMPFC and other brain regions (such as parietal cortex, the inferior temporal gyrus and the right dorsolateral prefrontal cortex) (Zhou et al., 2007). Emerging data have also revealed anisotropy in the posterior cingulate cortex (PCC) (Fujiwara et al., 2007) and decreased overall relative left and right gray matter volume in the anterior cingulate gyrus in persons with schizophrenia compared with healthy controls (Segal et al., 2010). 3. Are SA deficits related to aberrant anterior-to-posterior shift in CMS activation? With this background, we propose a hypothetical model of SA deficits in schizophrenia refined from an earlier study (Holt et al., 2011) that predicts that deficits in functional connectivity will induce an anterior-to-posterior shift from ventral anterior to posterior midline cortical activity in schizophrenia in response to self-referential stimuli. As can be seen in Fig. 2, we have divided anterior CMS into two regions (ventral and dorsal). The two anterior CMS along with the posterior CMS provide a network of three functionally distinct midline brain regions that mediate and synthesize various aspects of self-related information. Based on the fMRI data in schizophrenia, increased activation of posterior CMS and decreased activation of ventral anterior CMS (i.e., vMPFC) has been the most consistent findings in two of the three reviewed studies (Blackwood et al., 2004; Holt et al., 2011). However, despite deficits in functional connectivity between dorsal anterior CMS (i.e., dMPFC) and posterior CMS in one of the reviewed studies (Holt et al., 2011), no significant difference in activation has been reported in this brain region. Therefore, support for a potential role of dMPFC in mediating self-relevant activity in schizophrenia is primarily based on the emerging data in healthy subjects suggesting appraisals of self-relevance and introspection are facilitated by dMPFC (Schmitz and Johnson, 2007). Only fMRI studies with adequate sample size can confirm the hypothesis of altered selfreferential activity in dMPFC in schizophrenia. Nonetheless, a potential change in dMPFC response during selfreferential processing along with changes in vMPFC activation in schizophrenia (Blackwood et al., 2004; Holt et al., 2011) may represent a more emotionally biased than cognitively oriented
Corcal Midline Structures (CMS) (CMS
Posterior CMS
Anterior CMS
MPFC acvaon off vMPFC
Emoonal/Explicit /Reflexive SELF
acvaon of PCC or PC
Alt d ac Altered vaon off dMPFC dMPFC
Cognive/Implicit /Direct SELF
Increased SELF- & Decreased OTHER’S Perspecve
Self-Referenal Impaired SelfProcessing
Impaired Social Cognion/Empathy
Deficits in SelfSelf-Awareness Fig. 2. Hypothetical model of self-awareness deficits in schizophrenia. vMPFC = ventral medial prefrontal cortex; dMPFC = dorsal medial PFC; DLPFC = dorsolateral prefrontal cortex; PCC = posterior cingulate cortex; RSC = retroslenial cortex; PC = precuneus.
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decision-making about relationship between the self and the object to be self-referred (Schmitz and Johnson, 2007). The changes in activation of vMPFC and dMPFC (i.e., anterior CMS) along with an increased activation of posterior CMS suggest that schizophrenia subjects may be so emotionally invested in ‘self’ to lose the ability to consider others’ perspective in their decision-making, which could explain frequently observed deficits in social cognition and empathy in this patient population (D’Argembeau et al., 2007). This affective labeling of self-reflectivity requires autobiographical memory consultation in order to make decisions regarding the self- vs. other-reflectivity of the stimuli (Cavanna and Trimble, 2006). The close connection between posterior CMS and hippocampus allows recruitment of autobiographical memory during self-referential processing in healthy subjects (Northoff et al., 2006). Schizophrenia subjects frequently lack the ability to assess self- and other’s perspectives, which may be mediated by an increased activation of PCC in chronic schizophrenia (Blackwood et al., 2004; Holt et al., 2011). Schizophrenia subjects also lack the ability to maintain differential representation of self and other’s attitudes and traits due to hippocampally mediated deficits in autobiographical memory, which could result in faulty processing of self- and other-related information over extended periods of time and across events. The model proposes that an increased activation of posterior CMS (i.e., PCC or PC) in response to selfreferential activity may be an effort to compensate for the reduced activation in the anterior CMS (i.e., vMPFC) (Blackwood et al., 2004; Holt et al., 2011) probably mediated by deficits in functional connectivity between these brain regions (Fig. 1). Although this hypothetical model tries to explain SA deficits based on regional deficits in CMS function, it is actually the balancing act between different CMS along with their communication with other brain regions to integrate complex details of selfvs. other-related information for optimal self-relevant decisionmaking. It is also worth mentioning that since schizophrenia is a heterogeneous illness with different etiobiological bases, a single model such as the one proposed in this study may fail to incorporate all neural networks processing self-related information in schizophrenia subjects. Furthermore the developmental brain changes may be responsible for potential age-related variations in neural circuitry for SA, such as those observed in Murphy et al. (2010) study, which was conducted in early course schizophrenia as opposed to those in chronic schizophrenia (Blackwood et al., 2004; Holt et al., 2011). Thus, the anterior– posterior shift in chronic schizophrenia may not be reflective of self-referential activity in first-episode schizophrenia (Murphy et al., 2010). More specifically, the findings from Murphy et al. (2010) study actually suggest a lateral-medial connectivity dysfunction rather than the anterior–posterior shift. 4. Future steps The proposed preliminary model, refined after originally proposed by Holt et al. (2011), is based on findings from a few studies with small samples. Thus, the model will need to be tested in a larger sample of schizophrenia subjects preferably in a longitudinal study starting during early psychosis so that not only the confounding effects of illness chronicity and long-term antipsychotic pharmacotherapy can be investigated but the developmental and functional brain changes can also be documented. Both structural and fMRI will be required to test the model. The structural connectivity can be studied using DTI, while functional connectivity will require a priori hypotheses based on the proposed model using an fMRI paradigm that is optimized based on lessons learned from prior studies. One of the major limitations of the imaging paradigms used in prior studies has been lack of
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significant findings in self- vs. other-referential contrasts (except Blackwood et al., 2004). We believe that his issue can be addressed by enhancing the limbic valence of the self-related statements by using patient’s name rather than a first- or third degree noun as employed in earlier studies (Murphy et al., 2010; Holt et al., 2011). In addition, the trait adjectives will need to actually incorporate the delusional themes of the study patients in an effort to investigate the neural substrates for unawareness of delusions. Furthermore, a detailed pre-scan task familiarization along with a pre- and post-scan questionnaire will be useful to confirm the study subjects’ behavioral responses. It will remain important to match patient and control groups for age, gender, premorbid IQ, education, and socioeconomic status. A detailed and careful description of eligibility criteria for antipsychotic treatment will also be extremely useful, especially with regards to the class, duration, dose, and antimuscarinic effects of antipsychotic medications. Of course, it may be preferable to recruit medication-free patients, but that can be extremely difficult besides being unethical (with regards to competency to provide consent) and scanning difficulties due to untreated psychosis. Finally, the future studies will need to test and refine neurobiological models for SA deficits in schizophrenia as the one proposed in this paper. Conflict of interest The primary author has received funding from Eli Lilly for other research. The other authors have no conflicts of interest. References Amodio, D.M., Frith, C.D., 2006. Meeting of minds: the medial frontal cortex and social cognition. Nat. Rev. Neurosci. 7 (4), 268–277. Baiano, M., David, A., Versace, A., Churchill, R., Balestrieri, M., Brambilla, P., 2007. Anterior cingulate volumes in schizophrenia: a systematic review and a metaanalysis of MRI studies. Schizophr. Res. 93, 1–12. Blackwood, N.J., Bentall, R.P., Ffytche, D.H., Simmons, A., Murray, R.M., Howard, R.J., 2004. Persecutory delusions and the determination of self-relevance: an fMRI investigation. Psychol. Med. 34 (4), 591–596. Brass, M., Derrfuss, J., Forstmann, B., von Cramon, D.Y., 2005. The role of the inferior frontal junction area in cognitive control. Trends Cogn. Sci. 9, 314–316. Brune, M., Lissek, S., Fuchs, N., Witthaus, H., Peters, S., Nicolas, V., Tegenthoff, M., Juckel, G., Lissek, S., 2008. An fMRI study of theory of mind in schizophrenic patients with passivity symptoms. Neuropsychologia 46, 1992–2001. Buchsbaum, M.S., Buchsbaum, B.R., Hazlett, E.A., Haznedar, M.M., Newmark, R., Tang, C.Y., Hof, P.R., 2007. Relative glucose metabolic rate higher in white matter in patients with schizophrenia. Am. J. Psychiatry 164, 1072–1081. Buckner, R.L., Andrews-Hanna, J.R., Schacter, D.L., 2008. The brain’s default network: anatomy, function, and relevance to disease. Ann. N. Y. Acad. Sci. 1124, 1– 38. Bush, G., Luu, P., Posner, M.I., 2000. Cognitive and emotional influences in anterior cingulate cortex. Trends Cogn. Sci. 4, 215–222. Camchong, J., MacDonald 3rd, A.W., Bell, C., Mueller, B.A., Lim, K.O., 2011. Altered functional and anatomical connectivity in schizophrenia. Schizophr. Bull. 37 (3), 640–650. Carruthers, P., 2009. How we know our own minds: the relationship between mindreading and metacognition. Behav. Brain Sci. 32, 121–138. Cavanna, A.E., Trimble, M.R., 2006. The precuneus: a review of its functional anatomy and behavioural correlates. Brain 129 (Pt 3), 564–583. D’Argembeau, A., Ruby, P., Collette, F., Degueldre, C., Balteau, E., Luxen, A., Maquet, P., Salmon, E., 2007. Distinct regions of the medial prefrontal cortex are associated with self-referential processing and perspective taking. J. Cogn. Neurosci. 19, 935–944. Damasio, A.R., 1999. The Feeling of What Happens: Body and Emotion in the Making of Consciousness. Harcourt Brace. Dassa, D., Boyer, L., Benoit, M., Bourcet, S., Raymondet, P., Bottai, T., 2010. Factors associated with medication non-adherence in patients suffering from schizophrenia: a cross-sectional study in a universal coverage health-care system. Aust. N. Z. J. Psychiatry 44 (10), 921–928. Devinsky, O., Morrell, M.J., Vogt, B.A., 1995. Contributions of anterior cingulate cortex to behaviour. Brain 118, 279–306. Dimaggio, G., Lysaker, P.H., Carcione, A., Nicolo, G., Semerari, A., 2008. Know yourself and you shall know the other to a certain extent: multiple paths of influence of self-reflection on mindreading. Conscious Cogn. 17, 778–789. Fisher, M., McCoy, K., Poole, J.H., Vinogradov, S., 2008. Self and other in schizophrenia: a cognitive neuroscience perspective. Am. J. Psychiatry 165, 1465–1472. Fossati, P., Hevenor, S.J., Lepage, M., Graham, S.J., Grady, C., Keightley, M.L., Craik, F., Mayberg, H., 2004. Distributed self in episodic memory: neural correlates of
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