Skip to main content
PMC home page
NIHPA Author Manuscripts logoLink to NIHPA Author Manuscripts
. Author manuscript; available in PMC: 2018 Jan 1.
Published in final edited form as: Schizophr Res. 2016 Sep 21;179:119–124. doi: 10.1016/j.schres.2016.09.025

Cortical Thickness of Neural Substrates Supporting Cognitive Empathy in Individuals with Schizophrenia

Suena H Massey a,b, Daniel Stern c, Eva C Alden a, Julie E Petersen a, Derin J Cobia a, Lei Wang a,d, John G Csernansky a, Matthew J Smith a,*
PMCID: PMC5222696  NIHMSID: NIHMS819490  PMID: 27665257

Abstract

Background

Cognitive empathy is supported by the inferior frontal gyrus (IFG), anterior mid-cingulate cortex (aMCC), insula (INS), supplementary motor area (SMA), medial prefrontal cortex (mPFC), right temporo-parietal junction (TPJ), and precuneus (PREC). In healthy controls, cortical thickness in these regions has been linked to cognitive empathy. As cognitive empathy is impaired in schizophrenia, we examined whether reduced cortical thickness in these regions was associated with poorer cognitive empathy in this population.

Methods

41 clinically-stable community-dwelling individuals with schizophrenia and 46 healthy controls group-matched on demographic variables completed self-report empathy questionnaires, a cognitive empathy task, and structural magnetic resonance imaging. We examined between-group differences in study variables using t-tests and analyses of variance. Next, we used Pearson correlations to evaluate the relationship between cognitive empathy and cortical thickness in the mPFC, IFG, aMCC, INS, SMA, TPJ, and PREC in both groups.

Results

Individuals with schizophrenia demonstrated cortical thinning in the IFG, INS, SMA, TPJ, and PREC (all p<0.05) and impaired cognitive empathy across all measures (all p<0.01) relative to controls. While cortical thickness in the mPFC, IFC, aMCC, and INS (all p<0.05) was related to cognitive empathy in controls, we did not observe these relationships in individuals with schizophrenia (all p>0.10).

Conclusions

Individuals with schizophrenia have reduced cortical thickness in empathy-related neural regions and significant impairments in cognitive empathy. Interestingly, cortical thickness was related to cognitive empathy in controls but not in the schizophrenia group. We discuss other mechanisms that may account for cognitive empathy impairment in schizophrenia.

Keywords: Cortical Thickness, Empathy, Social Cognition, Schizophrenia

1. Introduction

Empathy encompasses the ability to understand the emotional perspective of others through mentalizing (i.e., cognitive empathy), and the capacity to share the same emotional state as others (i.e., affective empathy) (Shamay-Tsoory, 2011; Zaki and Ochsner, 2011). Cognitive empathy is impaired among individuals with schizophrenia based on self-report (Achim et al., 2011; Smith et al., 2012; Sparks et al., 2010), behavioral task performance (Derntl et al., 2009; Smith et al., 2014), and functional neuroimaging (Benedetti et al., 2009; Derntl et al., 2012; Lee et al., 2010; Smith et al., 2015). Furthermore, cognitive empathy impairments have been associated with deficits in social functioning among individuals with schizophrenia (Smith et al., 2014; Smith et al., 2012; Smith et al., 2015). Meanwhile, the literature is mixed regarding whether affective empathy is impaired in schizophrenia. Thus, we may gain a deeper understanding of how to develop targeted treatments aimed at enhancing social functioning by evaluating deficits in cognitive empathy.

Most studies suggest that cognitive empathy is supported by the medial prefrontal cortex (mPFC) (Meyer et al., 2012; Rameson et al., 2012; Schnell et al., 2011), right temporo-parietal junction (TPJ) (Hooker et al., 2008; Schulte-Ruther et al., 2007; Vollm et al., 2006), precuneus (PREC) (Farrow et al., 2001; Meyer et al., 2012; Nummenmaa et al., 2008) and supplemental motor area (SMA) (Keysers and Gazzola, 2009; Lamm et al., 2007). Together, these regions are thought to support self-referential representations, transient mental inference of others, and mentalizing (Shamay-Tsoory, 2011). Additionally, research suggests that cognitive empathy is supported by regions of the brain that process emotion, such as the inferior frontal gyrus (IFG), anterior mid-cingulate cortex (aMCC), and anterior insula (INS) (Gonzalez-Liencres et al., 2013). Collectively, these are some of the specific neural substrates that support cognitive empathy.

There is also a link between morphologic differences in regions supporting mentalizing and social information processing. Studies in healthy individuals have shown that gray matter volume (Banissy et al., 2012; Sassa et al., 2012; Takeuchi et al., 2014) and density (Mutschler et al., 2013) in neural regions supporting empathy are associated with measures of cognitive empathy. Other studies suggest individuals with neurodevelopmental disorders (e.g., autism spectrum disorder) have cortical thinning in the mentalizing network that correlates with greater social impairment (Hadjikhani et al., 2006; Richter et al., 2015). Similarly, studies of individuals with schizophrenia have revealed cortical thinning in most, if not all, of the neural regions supporting empathy (Goldman et al., 2009; Kuperberg et al., 2003; Nesvag et al., 2008). However, the field has not yet evaluated whether cortical thinning in these regions is associated with impaired cognitive empathy.

In this study, we examined the relationship between cortical thickness in regions thought to subserve cognitive empathy and both self-reported and performance-based measures of cognitive empathy. We examined this relationship in individuals with schizophrenia and healthy controls. Based on our review of the literature, we had three primary hypotheses. First, we expected that individuals with schizophrenia would have cortical thinning in frontal, temporal, and parietal substrates of empathy relative to controls. Second, we hypothesized that individuals with schizophrenia would demonstrate deficits in performance-based and self-reported measures of cognitive empathy relative to controls. Third, we hypothesized that cortical thickness would correlate with both performance-based and self-reported measures of cognitive empathy in both individuals with schizophrenia and controls.

2. Materials and Methods

2.1 Sample

Individuals with schizophrenia (n=41) and healthy controls (n=46) were group-matched for age (18–50 years), gender, ethnicity, parental socioeconomic status and handedness (Table 1). Individuals with schizophrenia were recruited using advertisements placed in outpatient clinics at an academic medical center, community mental health clinics in local and surrounding neighborhoods, and on local National Alliance for Mental Illness websites. Controls were recruited from the same geographic areas as the individuals with schizophrenia using paper and online advertisements. Participants were excluded if they: 1) met DSM-IV criteria for current substance abuse or dependence within the past six months; 2) had a severe medical condition; or 3) sustained a head injury with neurological sequelae. Controls were further excluded if they had a lifetime history of any DSM-IV Axis I disorder or a first-degree biological relative with a psychotic disorder. Written informed consent procedures were conducted with all participants. The Institutional Review Board at Northwestern University approved all study procedures.

Table 1.

Participant characteristics

Healthy Controls (n = 46) Individuals with Schizophrenia (n = 41) Test statistic
Mean (SD) or % t or χ2
Demographics
 Age 31.79 (8.56) 32.91 (6.59) 0.69
 Gender (% male) 52.20 65.90 1.67
 Non-Hispanic Caucasian (%) 45.70 39.00 1.44
 African American (%) 39.10 51.20
 Other ethnicity (%) 15.20 9.80
 Parental socioeconomic statusa 28.18 (9.78) 25.10 (9.40) −1.47
Alcohol and tobacco use
 Mean (SD) alcohol use in grams, past yearb 1248.93 (2147.34) 688.72 (1735.64) −1.30
 Mean (SD) cigarette consumption, past yearb 281.47 (873.00) 1794.54 (2808.63) 3.23***
Clinical Measures
 Duration of illness in years -- 12.87 (7.58)
 Years 1st generation antipsychotic treatment -- 0.38 (1.51)
 Years 2nd generation antipsychotic treatment -- 4.61 (3.70)
 Dosage of current antipsychotic medication (converted to milligrams of chlorpromazine) -- 510.79 (431.10)
 Hallucinations -- 2.90 (2.00)
 Delusion -- 3.10 (1.88)
 Bizarre behavior -- 1.56 (1.87)
 Positive formal thought disorder -- 2.24 (1.56)
 Affective flattening -- 3.29 (1.50)
 Alogia -- 2.49 (1.70)
 Avolition -- 3.43 (1.45)
 Anhedonia -- 3.21 (1.39)
 Attention -- 2.22 (1.85)
Open in a new tab
a

completed by N=44 CON and N=40 SCZ

b

completed by N=45 CON and N=39 SCZ

p<0.001***

2.2 Measures

2.2.1 Demographic and Clinical Measures

Demographic and clinical measures were collected using the Structured Clinical Interview for DSM-IV (SCID-IV) (First et al., 2002), which was administered by trained Masters- and PhD-level research staff. A diagnosis of schizophrenia was validated via consensus between a semi-structured psychiatrist interview and SCID ratings. Recent alcohol and cigarette consumption were assessed using a semi-structured interview adapted from the Lifetime Alcohol Consumption Assessment Procedure (Skinner, 1982). Antipsychotic medication dosages were converted into chlorpromazine equivalents using a standardized method (Andreasen et al., 2010). Psychopathology was assessed in schizophrenia subjects using the global ratings from the Scale for the Assessment of Positive Symptoms (Andreasen, 1983b) and the Scale for the Assessment of Negative Symptoms (Andreasen, 1983a). We measured parental socioeconomic status using the Barratt Simplified Measure of Social Status (Barratt, 2005).

2.2.2 Cognitive Empathy Task

Cognitive empathy was assessed using the Emotional Perspective-Taking Task (EPT) (Derntl et al., 2009; Smith et al., 2014). Participants viewed sixty 4-second scenes showing two Caucasian individuals involved in social interactions meant to portray five basic emotions, and neutral scenes (10 stimuli per condition). The face of one individual was masked. Participants were asked to infer the corresponding emotional expression of the masked face by selecting between two different emotional facial expressions or a neutral expression presented after each scene. One option was correct, while the incorrect option was selected at random from all other choices.

2.2.3 Cognitive Empathy Questionnaires

Participants also completed the perspective-taking subscale of the Interpersonal Reactivity Index (IRI) (Davis, 1983) and the cognitive empathy subscale of the Questionnaire of Cognitive and Affective Empathy (QCAE) (Reniers et al., 2011). The IRI is the most widely used self-report questionnaire that assesses empathy as a multidimensional construct. The 7-item perspective taking subscale includes first-person statements such as, “Before criticizing somebody, I try to imagine how I would feel if I were in their place.” Participants rate their response to the degree to which the statement describes them on a 5-point Likert scale (“Does not describe me well” to “Describes me very well”). The IRI perspective-taking subscale had an acceptable-to-low alpha reliability in controls (α=0.74) and individuals with schizophrenia (α=0.55), respectively.

The QCAE is a more recently developed scale of cognitive and affective components of empathy that integrates the strengths of several validated empathy questionnaires including the IRI. The cognitive empathy subscale contains 9 first-person statements (“I sometimes try to understand my friends better by imagining how things look from their perspective”). Participants rate the degree to which they agree with each statement on a 5-point Likert scale (“Strongly disagree” to “Strongly agree”). The QCAE cognitive empathy subscale had strong reliabilities in controls (α=0.87) and individuals with schizophrenia (α=0.84).

2.2.4 MRI Acquisition and Data Processing

Magnetic resonance imaging (MRI) scans were acquired on a 3T Tim Trio scanner (Siemens Medical Systems) and collected using an MPRAGE sequence (TR = 2400 mms, TE = 3.16 ms, flip angle = 8°, TI = 1000 ms, ACQ-2, Matrix = 256 × 256, FOV = 22 cm, scanning time = 17 min) with 1mm × 1 mm × 1 mm isotropic resolution. Scans were then analyzed and processed using FreeSurfer (FS, http://surfer.nmr.mgh.harvard.edu) release 5.1.0 (Dale et al., 1999). Inaccuracies were corrected using a combination of automatic and manual methods (Fischl et al., 1999). Manual editing was done according to established guidelines (Segonne et al., 2007). Reconstruction of white and pial surfaces was required for estimation of cortical measures.

We selected 12 a priori regions of interest (ROI), 6 per hemisphere, based on previous research implicating these specific regions in cognitive empathy ability (Farrow et al., 2001; Hooker et al., 2008; Keysers and Gazzola, 2009; Lamm et al., 2007; Meyer et al., 2012; Nummenmaa et al., 2008; Rameson et al., 2012; Schnell et al., 2011; Schulte-Ruther et al., 2007; Vollm et al., 2006). ROI definitions were based on modifications to the standard FS parcellation atlas (Desikan et al., 2006), and include the IFG, INS, aMCC, SMA, TPJ, and PREC. Estimated cortical thickness was calculated using embedded FS algorithms.

2.3 Data Analysis

Schizophrenia and control group demographics were compared using t- and χ2 tests for continuous and categorical variables, respectively. We used one-tailed t-tests to evaluate differences in cortical thickness, given prior evidence that individuals with schizophrenia have thinner cortical regions compared to controls (Goldman et al., 2009; Kuperberg et al., 2003). Finally, we examined whether cortical thickness in each ROI was associated with measures of cognitive empathy using partial correlations that covaried for any observed between-group differences and age, due to the association between age and cortical thickness (Lemaitre et al., 2012). We conducted one-tailed correlations between measures of cortical thickness and cognitive empathy, given that brain structure has been associated with empathic ability among healthy individuals (Banissy et al., 2012; Cheng et al., 2009; Mutschler et al., 2013; Sassa et al., 2012; Takeuchi et al., 2014) and individuals with clinical conditions characterized by empathic deficits (Hadjikhani et al., 2006; Meda et al., 2012). Corrections for multiple comparisons for the correlations were handled using the false discovery rate of 0.05 (Benjamini et al., 2001).

3. Results

Individuals with schizophrenia and controls did not differ with respect to age, parental socioeconomic status, handedness, or past year alcohol consumption (Table 1). Three individuals with schizophrenia reported past year alcohol consumption greater than 3 standard deviations above the mean and were excluded as outliers. Individuals with schizophrenia reported smoking more cigarettes per day in the past year compared to controls (p<0.01). Thus, we evaluated cigarette consumption as a covariate in our subsequent analyses. However, this variable was a non-significant covariate and was removed from the analyses to optimize statistical power.

When compared to the control group, schizophrenia subjects demonstrated significantly lower accuracy rates and higher response times during their performance on a cognitive empathy task (both p<0.001) and reported lower levels of cognitive empathy on both the QCAE and IRI (both p<0.01, Table 2).

Table 2.

Between-group differences in cognitive empathy

Healthy Controls (n = 43) Individuals with Schizophrenia (n = 39) Test statistic
Performance-based cognitive empathy
 EPT task accuracy 0.85 (0.08) 0.74 (0.10) t = −5.34***
 EPT response time (sec) 1.42 (0.27) 1.67 (0.39) t = 3.28**
Self-Reported cognitive empathy
 QCAE cognitive empathy total scorea 61.11 (8.49) 55.29 (9.21) t = 2.77**
 IRI perspective-taking 20.79 (4.74) 16.48 (4.76) t = 4.10***
Open in a new tab

Note. EPT, emotional perspective-taking; QCAE, questionnaire for cognitive and affective empathy; IRI, interpersonal reactivity index;

a

n=36 healthy controls and n=35 individuals with schizophrenia completed the QCAE.

**

p<0.01;

***

p<0.001.

We observed significant between-group differences in cortical thickness (Table 3), where schizophrenia subjects demonstrated greater thinning in the IFG (left: p=0.01; right: p=0.07 (trend)); aMCC (right: p=0.09); INS (both left and right: p<0.05); SMA (right: p<0.01; left: p=0.07 (trend)); TPJ (right: p<0.05; left: p=0.07 (trend)); and PREC (left: p=0.07 (trend)). Group differences in cortical thickness were not found in the mPFC, left aMCC, and right PREC.

Table 3.

Between-group differences in cortical thickness (mm) in neural regions associated with cognitive empathy

Cortical thickness (mm)
t df p
Healthy Controls (n = 46) Individuals with Schizophrenia (n = 41)
Frontal Regions
 mPFC, left, mean (SD) 2.44 (0.15) 2.43 (0.23) −0.46 85 0.32
 mPFC, right, mean (SD) 2.35 (0.14) 2.31 (0.22) −1.04 85 0.15
 IFG, left, mean (SD) 2.61 (0.12) 2.57 (0.15) −1.48 85 0.07
 IFG, right, mean (SD) 2.62 (0.14) 2.55 (0.14) −2.35** 85 0.01
 aMCC, left, mean (SD) 2.71 (0.22) 2.71 (0.25) −0.18 85 0.43
 aMCC, right, mean (SD) 2.50 (0.23) 2.57 (0.24) 1.34 85 0.09
 INS, left, mean (SD) 3.08 (0.16) 3.00 (0.15) −2.10* 85 0.02
 INS, right, mean (SD) 3.07 (0.21) 3.00 (0.12) −1.78* 85 0.03
 SMA, left, mean (SD) 2.63 (0.18) 2.58 (0.13) −1.50 85 0.07
 SMA, right, mean (SD) 2.62 (0.16) 2.55 (0.13) −2.46** 85 0.008
Temporo-Parietal Regions
 TPJ, left, mean (SD) 2.61 (0.17) 2.56 (0.12) −1.48 85 0.07
 TPJ, right, mean (SD) 2.66 (0.16) 2.60 (0.14) −1.91* 85 0.03
 PREC, left, mean (SD) 2.45 (0.14) 2.41 (0.12) −1.51 85 0.07
 PREC, right, mean (SD) 2.44 (0.15) 2.42 (0.11) −0.72 85 0.24
Open in a new tab

Note. mPFC, medial prefrontal cortex; IFG, inferior frontal gyrus; aMCC, anterio-mid cingulate cortex; INS, insula; SMA, supplementary motor area; TPJ, temporo-parietal junction; PREC, precuneus.

*

p<0.05;

**

p<0.01;

One-tailed Pearson partial correlations (with age as covariate) revealed significant relationships between cortical thickness and performance-based cognitive empathy in the control group (Table 4). Specifically, cognitive empathy task performance was positively correlated with cortical thickness in the following bilateral ROIs: mPFC (left: r= 0.43, p=0.002 and right: r=0.41, p =0.003) and INS (left: r= 0.41, p=0.003 and right: r=0.35, p=0.012) as well as in the right IFG (r= 0.37, p=0.008) and left aMCC (r= 0.31, p=0.023). The IRI and QCAE measures of cognitive empathy did not correlate with any measures of cortical thickness among controls. No significant correlations between cortical thickness and measures of cognitive empathy were observed in the schizophrenia group; even when controlling for antipsychotic medication (all p>.10).

Table 4.

Partial correlations between cortical thickness and cognitive empathy (covaried with age)

Cognitive empathy task accuracy
Healthy Controls (n = 43) p-value Individuals with Schizophrenia (n = 39) p-value
mPFC, left .43 .002 .00 .493
mPFC, right .41 .003 −.09 .299
IFG, left .22 .085 .14 .194
IFG, right .37 .008 .11 .254
aMCC, left .31 .023 −.12 .235
aMCC, right .25 .055 −.19 .133
INS, left .41 .003 .20 .119
INS, right .35 .012 −.05 .374
SMA, left .04 .405 .13 .220
SMA, right .01 .481 .14 .196
TPJ, left .27 .043 .06 .353
TPJ, right .14 .188 .12 .234
PREC, left .12 .223 .04 .413
PREC, right .25 .056 .16 .165
Open in a new tab

Note: mPFC, medial prefrontal cortex; IFG, inferior frontal gyrus; aMCC, anterio-mid cingulate cortex; INS, insula; SMA, supplementary motor area; TPJ, temporo-parietal junction; PREC, precuneus.

4. Discussion

In this study, we detected reduced cortical thickness in individuals with schizophrenia relative to controls in regions supporting empathy, which is consistent with prior studies evaluating cortical thickness in schizophrenia (Ehrlich et al., 2012; Hartberg et al., 2011; Nesvag et al., 2012). Individuals with schizophrenia also demonstrated deficits in cognitive empathy as measured by self-report and behavioral performance, which was consistent with the findings of the larger sample from which they were drawn (Michaels et al., 2015; Smith et al., 2014). Although we observed correlations between regions supporting empathy and cognitive empathy performance in controls, we did not observe significant correlations among the individuals with schizophrenia.

Specifically, we found that individuals with schizophrenia were characterized by reduced cortical thickness of the right IFG, which is implicated in the functional support of emotion processing and triggers insular responses to facial expressions (Jabbi and Keysers, 2008; Liakakis et al., 2011). We also observed reduced cortical thickness bilaterally in the INS, which is thought to support a cognitive-evaluative form of empathy (Fan et al., 2011), and in the right SMA, which is involved in perceiving and processing action behaviors (Etkin et al., 2011; Keysers and Gazzola, 2009; Smith et al., 2015). Differences in cortical thickness were also noted in the TPJ, which is thought to be important for differentiating the mental state of others from oneself (Decety and Lamm, 2007; Saxe and Kanwisher, 2003).

In regard to the relationship between cortical thickness and cognitive empathy performance, we observed several correlations in controls. Consistent with prior studies of brain structure and empathy, these correlations predominantly involved the mPFC, IFG, INS, and aMCC (Banissy et al., 2012; Cheng et al., 2009; Mutschler et al., 2013; Sassa et al., 2012; Takeuchi et al., 2014). Specifically, we found that better cognitive empathy performance correlated with thicker left and right mPFC, which supports internal representation of others (i.e., mentalizing) (Rameson et al., 2012). In addition, we observed a correlation between cognitive empathy and left aMCC, which is thought to be involved in emotion discrimination, empathy for pain, and preparing behavioral responses to stressful situations (Bruneau et al., 2012; Torta and Cauda, 2011; Vogt, 2005). We also observed correlations between cognitive empathy performance and the right IFG and bilateral INS (functionally described above), which were regions that demonstrated reduced cortical thickness in the schizophrenia group.

Although we observed brain-behavior correlations among controls, we did not observe any significant correlations among the individuals with schizophrenia. We considered the possibility that changes in cognitive empathy or brain structure related to having schizophrenia may have reduced the variance in these measures, which could make it more difficult to detect correlations, but this was not the case given the observed standard deviations (Tables 2 and 3). There are several potential explanations for our negative findings. One possibility, is that schizophrenia is characterized by altered white matter pathways (Ellison-Wright and Bullmore, 2009; Karlsgodt, 2016), which may be accounting for the observed impairment in cognitive empathy in schizophrenia. Thus, Diffusion Tensor Imaging (DTI, e.g., fiber tractography) could be one possible tool to measure the complex integration of networks supporting cognitive empathy. Also, there is increasing evidence that schizophrenia is a disorder of functional disconnectivity (Anticevic et al., 2015), and network integrity involving the regions subserving empathy (and probably others), rather than reduced cortical thickness alone, contribute to empathic deficits in schizophrenia (Ioannides et al., 2004). In the context of observed social functioning deficits, the lack of a specific relationship between empathy-related regions and cognitive empathy in the schizophrenia group could reflect functional reorganization associated with abnormal neurodevelopment (Vertes and Bullmore, 2015).

In addition, it is possible that changes in cortical thickness may influence cognitive empathy, but only as evidenced by associated behavioral processes, such as social information processing deficits. Empathic processing is modulated by many other factors, including cognitive abilities, personality factors, context and motivation (Engen and Singer, 2013; Han et al., 2009). Moreover, empathy is a multifaceted construct, dependent on integration among various social information processing networks which are disrupted in schizophrenia (Green et al., 2015). For example, empathic responding requires intact self-other distinction, or the capacity to correctly distinguish between one’s own affective representations and those of another (Lamm et al., 2016), which are impaired in schizophrenia (Ebisch and Gallese, 2015; Liepelt et al., 2012). While these explanations are purely speculative, the absence of a correlation between cortical thickness and impaired cognitive empathy contributes incrementally to the understanding of the neurobiological mechanisms that underlie emotional processing deficits seen in schizophrenia. As such, future studies could evaluate these alternative hypotheses as explanations for the lack of relationship between cognitive empathy and cortical thickness.

While this study provides insights into the relationship between the integrity of the neural circuitry supporting empathy and measures of cognitive empathy performance, the results must be interpreted in the context of some limitations. First, individuals with schizophrenia in this sample had lived with the illness for well over a decade. Thus, our results may not generalize to individuals in earlier or later stages of illness. Second, the cross-sectional study conducted does not allow for inference of a causal relationship between cortical thickness and cognitive empathy in either the control or schizophrenia group. Third, the self-reported measures of cognitive empathy were unrelated to cortical thickness in both of the control and schizophrenia groups. This finding raises an important question about whether self-report measures of cognitive empathy assess the same phenotypes as performance-based measures of cognitive empathy.

In conclusion, observed patterns of cortical thinning in empathy-related neural regions found in this study are consistent with the larger schizophrenia literature. Our correlation analyses suggest that there is an important, widespread relationship between cortical thickness and cognitive empathy performance in healthy individuals. However, this relationship was not found in individuals with schizophrenia. Thus, we conclude that cognitive empathy impairment in schizophrenia may not be related to alterations in cortical thickness in empathy-related brain regions. Abnormal neural synchrony, irregular connectivity between local and or distal brain regions, problems with integration, or other mechanisms may better account for performance on measures of cognitive empathy in schizophrenia. Future studies that combine functional imaging paradigms to probe cognitive empathy with the examination of structural connectivity using estimates of white matter integrity and fiber tractography are recommended to further elucidate this question.

Acknowledgments

Role of Funding Source

This study was supported by the Department of Psychiatry and Behavioral Sciences at the Northwestern University Feinberg School of Medicine and a grant from the National Institute of Mental Health (NIMH) to Dr. Csernansky (R01 MH056584). Manuscript preparation was supported by a grant from NIMH to Dr. Smith (R01 MH110524) and a grant from the National Institute on Drug Abuse (NIDA) to Dr. Massey (K23 DA037913). NIMH and NIDA had no role in the study design, collection, analysis or interpretation of data, writing the manuscript, or the decision to submit the paper for publication.

The authors would like to acknowledge the research staff at Northwestern University’s Schizophrenia Research Group for data collection and database management and the research participants for volunteering their time. They also acknowledge the Northwestern University Neuroimaging and Applied Computational Anatomy Laboratory (NIACAL) for assistance with image processing.

Footnotes

Authors Contributions

Dr. Massey was responsible for contributing to the literature search, interpreting the study results, and drafting the manuscript. Dr. Smith was responsible for study design, data collection, data analysis, interpreting the study results, and drafting the manuscript. Mr. Stern was responsible for contributing to literature searching, data analysis, and drafting the manuscript. Drs. Cobia, Csernansky, and Wang, Ms. Alden, and Ms. Petersen were responsible for study design and manuscript editing. All authors contributed to, and have approved the final manuscript.

Conflict of Interest

All authors declare that they have no conflicts of interest.

Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

References

  1. Achim AM, Ouellet R, Roy MA, Jackson PL. Assessment of empathy in first-episode psychosis and meta-analytic comparison with previous studies in schizophrenia. Psychiatry Research. 2011;190(1):3–8. doi: 10.1016/j.psychres.2010.10.030. [DOI] [PubMed] [Google Scholar]
  2. Andreasen NC. The Scale for the Assessment of Negative Symptoms. The University of Iowa; Iowa City, IA: 1983a. [Google Scholar]
  3. Andreasen NC. The Scale for the Assessment of Positive Symptoms. The University of Iowa; Iowa City, IA: 1983b. [Google Scholar]
  4. Andreasen NC, Pressler M, Nopoulos P, Miller D, Ho BC. Antipsychotic dose equivalents and dose-years: a standardized method for comparing exposure to different drugs. Biological Psychiatry. 2010;67(3):255–262. doi: 10.1016/j.biopsych.2009.08.040. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Anticevic A, Murray JD, Barch DM. Bridging Levels of Understanding in Schizophrenia Through Computational Modeling. Clin Psychol Sci. 2015;3(3):433–459. doi: 10.1177/2167702614562041. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Banissy MJ, Kanai R, Walsh V, Rees G. Inter-individual differences in empathy are reflected in human brain structure. Neuroimage. 2012;62(3):2034–2039. doi: 10.1016/j.neuroimage.2012.05.081. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Barratt W. The Barratt Simplified Measure of Social Status (BSMSS): Measuring SES. Indiana State University, Department of Educational Leadership, Administration, and Foundations; Terre Haute: 2005. [Google Scholar]
  8. Benedetti F, Bernasconi A, Bosia M, Cavallaro R, Dallaspezia S, Falini A, Poletti S, Radaelli D, Riccaboni R, Scotti G, Smeraldi E. Functional and structural brain correlates of theory of mind and empathy deficits in schizophrenia. Schizophr Res. 2009;114(1–3):154–160. doi: 10.1016/j.schres.2009.06.021. [DOI] [PubMed] [Google Scholar]
  9. Benjamini Y, Drai D, Elmer G, Kafkafi N, Golani I. Controlling the false discovery rate in behavior genetics research. Behav Brain Res. 2001;125(1–2):279–284. doi: 10.1016/s0166-4328(01)00297-2. [DOI] [PubMed] [Google Scholar]
  10. Bruneau EG, Pluta A, Saxe R. Distinct roles of the ‘shared pain’ and ‘theory of mind’ networks in processing others’ emotional suffering. Neuropsychologia. 2012;50(2):219–231. doi: 10.1016/j.neuropsychologia.2011.11.008. [DOI] [PubMed] [Google Scholar]
  11. Cheng Y, Chou KH, Decety J, Chen IY, Hung D, Tzeng OJ, Lin CP. Sex differences in the neuroanatomy of human mirror-neuron system: a voxel-based morphometric investigation. Neuroscience. 2009;158(2):713–720. doi: 10.1016/j.neuroscience.2008.10.026. [DOI] [PubMed] [Google Scholar]
  12. Dale AM, Fischl B, Sereno MI. Cortical surface-based analysis. I. Segmentation and surface reconstruction. Neuroimage. 1999;9(2):179–194. doi: 10.1006/nimg.1998.0395. [DOI] [PubMed] [Google Scholar]
  13. Davis MH. Measuring individual differences in empathy: Evidence for a multidimensional approach. Journal of Personality and Social Psychology. 1983;44(1):113–126. [Google Scholar]
  14. Decety J, Lamm C. The role of the right temporoparietal junction in social interaction: how low-level computational processes contribute to meta-cognition. Neuroscientist. 2007;13(6):580–593. doi: 10.1177/1073858407304654. [DOI] [PubMed] [Google Scholar]
  15. Derntl B, Finkelmeyer A, Toygar TK, Hulsmann A, Schneider F, Falkenberg DI, Habel U. Generalized deficit in all core components of empathy in schizophrenia. Schizophrenia Research. 2009;108(1–3):197–206. doi: 10.1016/j.schres.2008.11.009. [DOI] [PubMed] [Google Scholar]
  16. Derntl B, Finkelmeyer A, Voss B, Eickhoff SB, Kellermann T, Schneider F, Habel U. Neural correlates of the core facets of empathy in schizophrenia. Schizophrenia Research. 2012;136(1–3):70–81. doi: 10.1016/j.schres.2011.12.018. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Desikan RS, Segonne F, Fischl B, Quinn BT, Dickerson BC, Blacker D, Buckner RL, Dale AM, Maguire RP, Hyman BT, Albert MS, Killiany RJ. An automated labeling system for subdividing the human cerebral cortex on MRI scans into gyral based regions of interest. Neuroimage. 2006;31(3):968–980. doi: 10.1016/j.neuroimage.2006.01.021. [DOI] [PubMed] [Google Scholar]
  18. Ebisch SJ, Gallese V. A neuroscientific perspective on the nature of altered self-other relationships in schizophrenia. Journal of Consciousness Studies. 2015;22(1–2):220–240. [Google Scholar]
  19. Ehrlich S, Brauns S, Yendiki A, Ho BC, Calhoun V, Schulz SC, Gollub RL, Sponheim SR. Associations of cortical thickness and cognition in patients with schizophrenia and healthy controls. Schizophr Bull. 2012;38(5):1050–1062. doi: 10.1093/schbul/sbr018. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Ellison-Wright I, Bullmore E. Meta-analysis of diffusion tensor imaging studies in schizophrenia. Schizophr Res. 2009;108(1–3):3–10. doi: 10.1016/j.schres.2008.11.021. [DOI] [PubMed] [Google Scholar]
  21. Engen HG, Singer T. Empathy circuits. Curr Opin Neurobiol. 2013;23(2):275–282. doi: 10.1016/j.conb.2012.11.003. [DOI] [PubMed] [Google Scholar]
  22. Etkin A, Egner T, Kalisch R. Emotional processing in anterior cingulate and medial prefrontal cortex. Trends Cogn Sci. 2011;15(2):85–93. doi: 10.1016/j.tics.2010.11.004. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Fan Y, Duncan NW, de Greck M, Northoff G. Is there a core neural network in empathy? An fMRI based quantitative meta-analysis. Neuroscience and Biobehavioral Reviews. 2011;35(3):903–911. doi: 10.1016/j.neubiorev.2010.10.009. [DOI] [PubMed] [Google Scholar]
  24. Farrow TF, Zheng Y, Wilkinson ID, Spence SA, Deakin JF, Tarrier N, Griffiths PD, Woodruff PW. Investigating the functional anatomy of empathy and forgiveness. Neuroreport. 2001;12(11):2433–2438. doi: 10.1097/00001756-200108080-00029. [DOI] [PubMed] [Google Scholar]
  25. First MB, Spitzer RL, Miriam G, Williams JBW. Biometrics Research. New York State Psychiatric Institute; New York, NY: 2002. Structured clinical interview for DSM-IV-TR Axis I Disorders, Research Version, Non-patient Edition. [Google Scholar]
  26. Fischl B, Sereno MI, Dale AM. Cortical surface-based analysis. II: Inflation, flattening, and a surface-based coordinate system. Neuroimage. 1999;9(2):195–207. doi: 10.1006/nimg.1998.0396. [DOI] [PubMed] [Google Scholar]
  27. Goldman AL, Pezawas L, Mattay VS, Fischl B, Verchinski BA, Chen Q, Weinberger DR, Meyer-Lindenberg A. Widespread reductions of cortical thickness in schizophrenia and spectrum disorders and evidence of heritability. Arch Gen Psychiatry. 2009;66(5):467–477. doi: 10.1001/archgenpsychiatry.2009.24. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Gonzalez-Liencres C, Shamay-Tsoory SG, Brune M. Towards a neuroscience of empathy: ontogeny, phylogeny, brain mechanisms, context and psychopathology. Neuroscience and Biobehavioral Reviews. 2013;37(8):1537–1548. doi: 10.1016/j.neubiorev.2013.05.001. [DOI] [PubMed] [Google Scholar]
  29. Green MF, Horan WP, Lee J. Social cognition in schizophrenia. Nat Rev Neurosci. 2015;16(10):620–631. doi: 10.1038/nrn4005. [DOI] [PubMed] [Google Scholar]
  30. Hadjikhani N, Joseph RM, Snyder J, Tager-Flusberg H. Anatomical differences in the mirror neuron system and social cognition network in autism. Cereb Cortex. 2006;16(9):1276–1282. doi: 10.1093/cercor/bhj069. [DOI] [PubMed] [Google Scholar]
  31. Han S, Fan Y, Xu X, Qin J, Wu B, Wang X, Aglioti SM, Mao L. Empathic neural responses to others’ pain are modulated by emotional contexts. Hum Brain Mapp. 2009;30(10):3227–3237. doi: 10.1002/hbm.20742. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Hartberg CB, Sundet K, Rimol LM, Haukvik UK, Lange EH, Nesvag R, Dale AM, Melle I, Andreassen OA, Agartz I. Brain cortical thickness and surface area correlates of neurocognitive performance in patients with schizophrenia, bipolar disorder, and healthy adults. J Int Neuropsychol Soc. 2011;17(6):1080–1093. doi: 10.1017/S1355617711001081. [DOI] [PubMed] [Google Scholar]
  33. Hooker CI, Verosky SC, Germine LT, Knight RT, D’Esposito M. Mentalizing about emotion and its relationship to empathy. Soc Cogn Affect Neurosci. 2008;3(3):204–217. doi: 10.1093/scan/nsn019. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Ioannides AA, Poghosyan V, Dammers J, Streit M. Real-time neural activity and connectivity in healthy individuals and schizophrenia patients. Neuroimage. 2004;23(2):473–482. doi: 10.1016/j.neuroimage.2004.06.023. [DOI] [PubMed] [Google Scholar]
  35. Jabbi M, Keysers C. Inferior frontal gyrus activity triggers anterior insula response to emotional facial expressions. Emotion. 2008;8(6):775–780. doi: 10.1037/a0014194. [DOI] [PubMed] [Google Scholar]
  36. Karlsgodt KH. Diffusion Imaging of White Matter In Schizophrenia: Progress and Future Directions. Biol Psychiatry Cogn Neurosci Neuroimaging. 2016;1(3):209–217. doi: 10.1016/j.bpsc.2015.12.001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Keysers C, Gazzola V. Expanding the mirror: vicarious activity for actions, emotions, and sensations. Curr Opin Neurobiol. 2009;19(6):666–671. doi: 10.1016/j.conb.2009.10.006. [DOI] [PubMed] [Google Scholar]
  38. Kuperberg GR, Broome MR, McGuire PK, David AS, Eddy M, Ozawa F, Goff D, West WC, Williams SC, van der Kouwe AJ, Salat DH, Dale AM, Fischl B. Regionally localized thinning of the cerebral cortex in schizophrenia. Arch Gen Psychiatry. 2003;60(9):878–888. doi: 10.1001/archpsyc.60.9.878. [DOI] [PubMed] [Google Scholar]
  39. Lamm C, Batson CD, Decety J. The neural substrate of human empathy: effects of perspective-taking and cognitive appraisal. J Cogn Neurosci. 2007;19(1):42–58. doi: 10.1162/jocn.2007.19.1.42. [DOI] [PubMed] [Google Scholar]
  40. Lamm C, Bukowski H, Silani G. From shared to distinct self-other representations in empathy: evidence from neurotypical function and socio-cognitive disorders. Philos Trans R Soc Lond B Biol Sci. 2016;371(1686):20150083. doi: 10.1098/rstb.2015.0083. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Lee SJ, Kang do H, Kim CW, Gu BM, Park JY, Choi CH, Shin NY, Lee JM, Kwon JS. Multi-level comparison of empathy in schizophrenia: an fMRI study of a cartoon task. Psychiatry Research. 2010;181(2):121–129. doi: 10.1016/j.pscychresns.2009.08.003. [DOI] [PubMed] [Google Scholar]
  42. Lemaitre H, Goldman AL, Sambataro F, Verchinski BA, Meyer-Lindenberg A, Weinberger DR, Mattay VS. Normal age-related brain morphometric changes: nonuniformity across cortical thickness, surface area and gray matter volume? Neurobiol Aging. 2012;33(3):617, e611–619. doi: 10.1016/j.neurobiolaging.2010.07.013. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Liakakis G, Nickel J, Seitz RJ. Diversity of the inferior frontal gyrus--a meta-analysis of neuroimaging studies. Behav Brain Res. 2011;225(1):341–347. doi: 10.1016/j.bbr.2011.06.022. [DOI] [PubMed] [Google Scholar]
  44. Liepelt R, Schneider JC, Aichert DS, Wostmann N, Dehning S, Moller HJ, Riedel M, Dolk T, Ettinger U. Action blind: disturbed self-other integration in schizophrenia. Neuropsychologia. 2012;50(14):3775–3780. doi: 10.1016/j.neuropsychologia.2012.10.027. [DOI] [PubMed] [Google Scholar]
  45. Meda SA, Pryweller JR, Thornton-Wells TA. Regional brain differences in cortical thickness, surface area and subcortical volume in individuals with Williams syndrome. PLoS One. 2012;7(2):e31913. doi: 10.1371/journal.pone.0031913. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Meyer ML, Masten CL, Ma Y, Wang C, Shi Z, Eisenberger NI, Han S. Empathy for the social suffering of friends and strangers recruits distinct patterns of brain activation. Soc Cogn Affect Neurosci. 2012 doi: 10.1093/scan/nss019. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Michaels TM, Horan WP, Ginger EJ, Martinovich Z, Pinkham AE, Smith MJ. Cognitive empathy contributes to poor social functioning in schizophrenia: Evidence from a new self-report measure of cognitive and affective empathy. Psychiatry Res. 2015;220:803–810. [PubMed] [Google Scholar]
  48. Mutschler I, Reinbold C, Wankerl J, Seifritz E, Ball T. Structural basis of empathy and the domain general region in the anterior insular cortex. Front Hum Neurosci. 2013;7:177. doi: 10.3389/fnhum.2013.00177. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Nesvag R, Bergmann O, Rimol LM, Lange EH, Haukvik UK, Hartberg CB, Fagerberg T, Soderman E, Jonsson EG, Agartz I. A 5-year follow-up study of brain cortical and subcortical abnormalities in a schizophrenia cohort. Schizophr Res. 2012;142(1–3):209–216. doi: 10.1016/j.schres.2012.10.004. [DOI] [PubMed] [Google Scholar]
  50. Nesvag R, Lawyer G, Varnas K, Fjell AM, Walhovd KB, Frigessi A, Jonsson EG, Agartz I. Regional thinning of the cerebral cortex in schizophrenia: effects of diagnosis, age and antipsychotic medication. Schizophr Res. 2008;98(1–3):16–28. doi: 10.1016/j.schres.2007.09.015. [DOI] [PubMed] [Google Scholar]
  51. Nummenmaa L, Hirvonen J, Parkkola R, Hietanen JK. Is emotional contagion special? An fMRI study on neural systems for affective and cognitive empathy. Neuroimage. 2008;43(3):571–580. doi: 10.1016/j.neuroimage.2008.08.014. [DOI] [PubMed] [Google Scholar]
  52. Rameson LT, Morelli SA, Lieberman MD. The neural correlates of empathy: experience, automaticity, and prosocial behavior. J Cogn Neurosci. 2012;24(1):235–245. doi: 10.1162/jocn_a_00130. [DOI] [PubMed] [Google Scholar]
  53. Reniers RL, Corcoran R, Drake R, Shryane NM, Vollm BA. The QCAE: a Questionnaire of Cognitive and Affective Empathy. Journal of Personality Assessments. 2011;93(1):84–95. doi: 10.1080/00223891.2010.528484. [DOI] [PubMed] [Google Scholar]
  54. Richter J, Henze R, Vomstein K, Stieltjes B, Parzer P, Haffner J, Brandeis D, Poustka L. Reduced cortical thickness and its association with social reactivity in children with autism spectrum disorder. Psychiatry Res. 2015;234(1):15–24. doi: 10.1016/j.pscychresns.2015.06.011. [DOI] [PubMed] [Google Scholar]
  55. Sassa Y, Taki Y, Takeuchi H, Hashizume H, Asano M, Asano K, Wakabayashi A, Kawashima R. The correlation between brain gray matter volume and empathizing and systemizing quotients in healthy children. Neuroimage. 2012;60(4):2035–2041. doi: 10.1016/j.neuroimage.2012.02.021. [DOI] [PubMed] [Google Scholar]
  56. Saxe R, Kanwisher N. People thinking about thinking people. The role of the temporo-parietal junction in “theory of mind”. Neuroimage. 2003;19(4):1835–1842. doi: 10.1016/s1053-8119(03)00230-1. [DOI] [PubMed] [Google Scholar]
  57. Schnell K, Bluschke S, Konradt B, Walter H. Functional relations of empathy and mentalizing: an fMRI study on the neural basis of cognitive empathy. Neuroimage. 2011;54(2):1743–1754. doi: 10.1016/j.neuroimage.2010.08.024. [DOI] [PubMed] [Google Scholar]
  58. Schulte-Ruther M, Markowitsch HJ, Fink GR, Piefke M. Mirror neuron and theory of mind mechanisms involved in face-to-face interactions: a functional magnetic resonance imaging approach to empathy. J Cogn Neurosci. 2007;19(8):1354–1372. doi: 10.1162/jocn.2007.19.8.1354. [DOI] [PubMed] [Google Scholar]
  59. Segonne F, Pacheco J, Fischl B. Geometrically accurate topology-correction of cortical surfaces using nonseparating loops. IEEE Trans Med Imaging. 2007;26(4):518–529. doi: 10.1109/TMI.2006.887364. [DOI] [PubMed] [Google Scholar]
  60. Shamay-Tsoory SG. The neural bases for empathy. Neuroscientist. 2011;17(1):18–24. doi: 10.1177/1073858410379268. [DOI] [PubMed] [Google Scholar]
  61. Skinner HA. Development and Validation of a Lifetime Alcohol Consumption Assessment Procedure. Addiction Research Foundation; Toronto, Canada: 1982. [Google Scholar]
  62. Smith MJ, Horan WP, Cobia DJ, Karpouzian TM, Fox JM, Reilly JL, Breiter HC. Performance-based empathy mediates the influence of working memory on social competence in schizophrenia. Schizophrenia Bulletin. 2014;40(4):824–834. doi: 10.1093/schbul/sbt084. [DOI] [PMC free article] [PubMed] [Google Scholar]
  63. Smith MJ, Horan WP, Karpouzian TM, Abram SV, Cobia DJ, Csernansky JG. Self-reported empathy deficits are uniquely associated with poor functioning in schizophrenia. Schizophrenia Research. 2012;137(1–3):196–202. doi: 10.1016/j.schres.2012.01.012. [DOI] [PubMed] [Google Scholar]
  64. Smith MJ, Schroeder MP, Abram SV, Goldman MB, Parrish TB, Wang X, Derntl B, Habel U, Decety J, Reilly JL, Csernansky JG, Breiter HC. Alterations in brain activation during cognitive empathy are related to social functioning in schizophrenia. Schizophr Bull. 2015;41(1):211–222. doi: 10.1093/schbul/sbu023. [DOI] [PMC free article] [PubMed] [Google Scholar]
  65. Sparks A, McDonald S, Lino B, O’Donnell M, Green MJ. Social cognition, empathy and functional outcome in schizophrenia. Schizophrenia Research. 2010;122(1–3):172–178. doi: 10.1016/j.schres.2010.06.011. [DOI] [PubMed] [Google Scholar]
  66. Takeuchi H, Taki Y, Sassa Y, Hashizume H, Sekiguchi A, Fukushima A, Kawashima R. Regional gray matter volume is associated with empathizing and systemizing in young adults. PLoS One. 2014;9(1):e84782. doi: 10.1371/journal.pone.0084782. [DOI] [PMC free article] [PubMed] [Google Scholar]
  67. Torta DM, Cauda F. Different functions in the cingulate cortex, a meta-analytic connectivity modeling study. Neuroimage. 2011;56(4):2157–2172. doi: 10.1016/j.neuroimage.2011.03.066. [DOI] [PubMed] [Google Scholar]
  68. Vertes PE, Bullmore ET. Annual research review: Growth connectomics--the organization and reorganization of brain networks during normal and abnormal development. J Child Psychol Psychiatry. 2015;56(3):299–320. doi: 10.1111/jcpp.12365. [DOI] [PMC free article] [PubMed] [Google Scholar]
  69. Vogt BA. Pain and emotion interactions in subregions of the cingulate gyrus. Nat Rev Neurosci. 2005;6(7):533–544. doi: 10.1038/nrn1704. [DOI] [PMC free article] [PubMed] [Google Scholar]
  70. Vollm BA, Taylor AN, Richardson P, Corcoran R, Stirling J, McKie S, Deakin JF, Elliott R. Neuronal correlates of theory of mind and empathy: a functional magnetic resonance imaging study in a nonverbal task. Neuroimage. 2006;29(1):90–98. doi: 10.1016/j.neuroimage.2005.07.022. [DOI] [PubMed] [Google Scholar]
  71. Zaki J, Ochsner K. Reintegrating the study of accuracy into social cognition research. Psychological Inquiry. 2011;22(3):159–182. [Google Scholar]

RESOURCES