Neural correlates of preserved facial affect perception in high functioning schizophrenia

Author’s Accepted Manuscript Neural Correlates of Preserved Facial Affect Performance in High Functioning Schizophrenia Tatiana M. Karpouzian, Matthew P. Schroeder, Samantha V. Abram, Harry Wanar, Eva C. Alden, Shaun M. Eack, John G. Csernansky, Matthew J. Smith www.elsevier.com

PII: DOI: Reference:

S0925-4927(17)30119-1 http://dx.doi.org/10.1016/j.pscychresns.2017.06.002 PSYN10699

To appear in: Psychiatry Research: Neuroimaging Received date: 17 April 2017 Revised date: 16 May 2017 Accepted date: 2 June 2017 Cite this article as: Tatiana M. Karpouzian, Matthew P. Schroeder, Samantha V. Abram, Harry Wanar, Eva C. Alden, Shaun M. Eack, John G. Csernansky and Matthew J. Smith, Neural Correlates of Preserved Facial Affect Performance in High Functioning Schizophrenia, Psychiatry Research: Neuroimaging, http://dx.doi.org/10.1016/j.pscychresns.2017.06.002 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 galley 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.

Neural Correlates of Preserved Facial Affect Performance in High Functioning Schizophrenia Tatiana M. Karpouziana, Matthew P. Schroedera, Samantha V. Abramb, Harry Wanara, Eva C. Aldena, Shaun M. Eackc, d, John G. Csernanskya, Matthew J. Smitha,e* a

Northwestern University Feinberg School of Medicine, Department of Psychiatry and Behavioral Sciences, 710 N Lake Shore Drive, Chicago, IL 60611, USA; b University of Minnesota, Twin Cities, Department of Psychology, 75 East River Parkway, Minneapolis, MN 55455, USA; c School of Social Work, University of Pittsburgh, 2117 Cathedral of Learning, Pittsburgh, PA 15260, USA; d Western Psychiatric Institute and Clinic, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; e School of Social Work, University of Michigan, 1080 South University Avenue Ann Arbor, MI, USA *Corresponding Author: Dr. Matthew J. Smith, School of Social Work, University of Michigan, 1080 South University Avenue Ann Arbor, MI, 48109 USA Phone: 1-(734) 764-9322, Fax: 1763-3372. [email protected].

Abstract Individuals with ‘high functioning’ schizophrenia (HF-SCZ) may have preserved facial affect perception (FAP) compared to individuals with ‘low functioning’ schizophrenia (LF-SCZ). The neural mechanisms supporting preserved FAP in HF-SCZ have yet to be evaluated. This study compared brain activation during FAP performance in HF-SCZ, LF-SCZ, and controls. Results demonstrated greater activation in the precuneus in CON compared to both SCZ groups, while HF-SCZ activated this region intermediate to controls and LF-SCZ. These preliminary findings suggest greater precuneus activation may be related to intact FAP in HFSCZ compared to LF-SCZ, though future research is needed to further evaluate differences between groups. Keywords: facial accept perception; schizophrenia; community functioning

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1. Introduction Facial affect perception (FAP) is the ability to observe and process nonverbal changes in affective states (LaBar et al., 2003). This ability is essential for informing higher-ordered social cognitive functions (e.g., empathy) (Hooker et al., 2008). Individuals with schizophrenia have deficits in FAP (Kohler et al, 2009), which contribute to poor community functioning (Abram et al., 2014; Kee et al., 2003; Brekke et al., 2005; Poole, et al., 2000). Recently, we observed that high functioning individuals with schizophrenia (HF-SCZ) had preserved FAP compared to low functioning individuals with schizophrenia (LF-SCZ) (Karpouzian et al., 2016). However, we have not yet evaluated the neural mechanisms that may underlie preserved FAP in HF-SCZ. Given the salience of the relationship between FAP and community functioning, it is critical to understand the neural mechanisms that may account for differences in FAP between HF-SCZ and LF-SCZ. Moreover, this approach is consistent with an increasing interest in understanding the neurobiological mechanisms that support community functioning in individuals with schizophrenia (Wojtalik et al., in press; Fox et al., 2017). Studies examining FAP utilizing the same stimuli employed in this study have shown that when compared to controls, individuals with schizophrenia demonstrated reduced activation in the inferior frontal gyrus, dorsomedial prefrontal cortex, anterior cingulate cortex, amygdala, fusiform gyrus, insula, and precuneus (Derntl et al., 2012; Habel et al., 2010). These studies concluded that fronto-temporo-parietal hypoactivation could contribute to FAP deficits among individuals with schizophrenia. For example, regions such as the fusiform gyrus are involved with facial perception, the anterior cingulate cortex, insula, and amygdala are associated with processing emotions, while the precuneus and medial prefrontal cortex are related to mentalizing (Green et al., 2015). HF-SCZ=high-functioning schizophrenia; LF-SCZ=low-functioning schizophrenia; FAP=facial affect perception

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In this study, we compared the neural correlates of FAP using an emotion discrimination task between HF-SCZ, LF-SCZ, and healthy controls. We evaluated if: 1) HF-SCZ and LF-SCZ differed from each other and controls (CON) on in-scanner FAP performance; 2) brain activation differed between HF-SCZ and LF-SCZ during FAP performance; and 3) brain activation in HFSCZ and LF-SCZ differed from CON during the FAP performance. We hypothesized that no significant differences in brain activation would occur during FAP between HF-SCZ and CON. Based on our prior investigation (Karpouzian et al., 2016), we hypothesized that LF-SCZ would demonstrate reduced activation in regions underlying FAP compared to HF-SCZ and CON. 2. Methods 2.1. Participants Individuals with schizophrenia (n = 29) and healthy controls (n = 23), group-matched for age (18–50 years old), gender, race, parental socioeconomic status (Barratt 2005) and handedness (Supplementary Table 1), completed this study. Recruitment methods and inclusion/exclusion criteria have been previously reported (Smith et al., 2015). Northwestern University’s Institutional Review Board approved the study procedures, and all participants provided written informed consent. The individuals with schizophrenia from our prior study (Karpouzian et al., 2016) who completed fMRI scans were categorized into groups of HF-SCZ (n=15) and LF-SCZ (n=14) using a cluster analysis that evaluated three independent measures of functioning (Alden et al., 2015). The measures of functioning included social attainment (Schneider et al., 1983), social competence (Patterson et al., 2001), and functional capacity (Mausbach et al., 2007). Scores from these measures were z-transformed and then submitted to a series of cluster analytic techniques. For additional details regarding cluster analysis, refer to supplemental methods. These groups differed in verbal working memory performance, but did not differ on all other neurocognitive measures (see Alden et al., 2015).

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2.2. Measures Psychopathology was assessed in individuals with schizophrenia 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). Facial affect perception was assessed using an event-related emotion discrimination paradigm adapted from Derntl and colleagues (2012) and administered while participants underwent functional magnetic resonance imaging (fMRI). Participants were presented with color photographs (n=60) of individual Caucasian faces depicting five basic emotions (happiness, sadness, anger, fear, disgust) and neutral expressions (see Supplementary Figure 1). For additional task details and fMRI acquisition and processing procedures, refer to supplemental methods. 2.3. Group Analyses Using Functional Imaging Group analyses examining differences in BOLD signal were conducted using a one-way ANOVA between the three groups (i.e., controls, HF-SCZ, and LF-SCZ) to identify overall group differences in the blood-oxygen-level-dependent (BOLD) response during correctly answered trials. We utilized mixed-effects meta-analysis which uses group-level variation and a precision estimate of the effect of interest from individual participants (Chen et al., 2012) in order to compare the two schizophrenia subgroups. By analyzing only correct trials, we could detect differences between groups when engaged in the same behavior (i.e., accurate performance). Because there were not enough trials to independently model the activation during trials with an incorrect response, these trials were excluded from subsequent imaging analyses. Control trial data were not included in the imaging analyses due to the emotional nature of the control trial faces. This approach is consistent with prior work using this paradigm (Derntl et al., 2012). All analyses were corrected for multiple comparisons using an alpha probability simulation to compute the probability that a random field of noise would produce a cluster of a given size. The main effect of correct emotion discrimination across all three groups and the

5 significant differences between groups have a corrected p-value of ≤0.05 (individual voxel threshold p<0.001, minimum cluster size of 65 voxels). 3. Results 3.1. Participant Characteristics Study groups did not differ with respect to age, gender, parental SES or race (Supplementary Table 1). SAPS global ratings of positive thought disorder were lower in HFSCZ compared to LF-SCZ (t27=-2.13, p=0.04); no other symptom ratings differed. An ANOVA revealed a main effect of group on facial affect perception accuracy (F2,51=6.10, p=0.004). Bonferroni post-hoc comparisons showed that CON (M = 0.94, SD = 0.06) and HF-SCZ (M = 0.95, SD = 0.04) groups had higher accuracies than LF-SCZ (M = 0.82, SD = 0.20) during FAP performance (p=0.009, d=0.81 and p=0.01, d=0.90, respectively), while CON and HF-SCZ did not differ from each other (p>0.99, d=0.20). 3. 2. Brain Activation Differences during FAP Participants demonstrated widespread neural activation in the visual, parietal, and frontal cortices for correctly answered trials (Supplementary Figure 2). We observed deactivation in the anterior

cingulate,

superior

frontal

gyrus

(extending

medially),

and

angular

gyrus

(Supplementary Table 3). A one-way ANOVA between the three groups revealed HF-SCZ and LF-SCZ demonstrated significant hypoactivation in the right precuneus relative to controls (F = 14.83, df = 2,49, p<0.001; d=1.17 and d=1.70, respectively; Figure 1). However, the right precuneus activation in HF-SCZ appeared to be intermediate between controls and LF-SCZ. Although the difference in right precuneus activation between HF-SCZ and LF-SCZ was characterized by a large effect size (d=0.77), the difference did not attain statistical significance (p=0.14). 4. Discussion We investigated differences in neural activity underlying accurate facial affect perception (FAP) between healthy controls and groups of high and low functioning individuals with

6 schizophrenia. We aimed to inform prior findings that demonstrated preserved FAP performance in HF-SCZ but not LF-SCZ. In this study, we observed HF-SCZ had preserved inscanner FAP performance compared to CON, while LF-SCZ was less accurate than both groups. Our main result revealed that both SCZ groups demonstrated reduced activation in the right precuneus compared to controls, while HF-SCZ demonstrated an intermediate level of activation between CON and LF-SCZ. Although the results did not support our hypothesis that HF-SCZ would have similar activation to CON, this observation may be due to inherent genetic and biological differences between SCZ and CON groups. Additionally, differences in neural activity underlying FAP between SCZ groups may be more subtle, and the neural mechanism for preserved task performance for HF-SCZ could be explained by structural or functional connectivity rather than the activation of a single region. The precuneus is involved in visuo-spatial processing, self-agency, (Cavanna and Trimble, 2006), making judgments about the emotions of others (Ochsner et al., 2004), and mentalizing (Green et al., 2015). Our observation that HF-SCZ and LF-SCZ demonstrated hypoactivation of the precuneus compared to CON is consistent with prior research, which found healthy controls had greater precuneus activation during emotion discrimination processes than individuals with schizophrenia (Derntl et al., 2012). However, precuneus activation in HF-SCZ was intermediate between CON and LF-SCZ. Given that the precuneus is involved in utilizing a first-person visuospatial perspective (Vogeley and Fink, 2004), HF-SCZ may be more self-reflective or have an enhanced ability to discriminate facial affect compared to LF-SCZ. Thus, these processes may contribute to the preserved FAP performance that we observed in HF-SCZ. Some limitations should be considered. Although we found a significant main effect across groups in the precuneus, our sample size limited the statistical power to observe significant differences between HF-SCZ and LF-SCZ. Thus, our results are preliminary, and need to be evaluated within a larger cohort. The computation of effect sizes attempted to assess

7 whether significant differences could be expected with more power. Also, the cross-sectional design limits our ability to draw causal inferences between FAP abilities and neural activity among the high and low functioning SCZ groups. Our results highlight a neural activation difference in response to accurate facial affect processing between high and low functioning individuals with schizophrenia and healthy controls. As expected, both schizophrenia groups had reduced activation in the precuneus compared to controls. However, HF-SCZ demonstrated an intermediate level of precuneus activation between CON and LF-SCZ. Thus, the observed elevated precuneus activation may be related to preserved FAP in HF-SCZ compared to LF-SCZ. However, these findings are preliminary and future research can further this work by investigating neural activation of high and low functioning individuals with schizophrenia in a larger sample.

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Role of Funding Source Funding: 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). NIMH 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.

Acknowledgements We would like to acknowledge the research staff at the Northwestern University Schizophrenia Research Group (NU-SRG) and Clinical Research Program for study coordination and data collection, and our participants for volunteering their time.

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Figure 1. One-way ANOVA comparing BOLD activation during correct emotion discrimination across the three groups

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BOLD % Activation

0.2

0.15 Controls

0.1

HF-SCZ LF-SCZ

0.05

0 R Precuneus

Highlights 

High-functioning schizophrenia participants show intact facial affect perception.

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Controls had greater precuneus activation compared to schizophrenia groups.

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High-functioning schizophrenia had an intermediate level of precuneus activation.

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Precuneus activation may be related to intact performance in this population.