RUNNING HEAD: Impressionable social self of schizophrenia
The impressionable social self of schizophrenia:
Neural correlates of self-other confusion after social interaction
Daina Crafa1,2*, Caitlin M. Stoddart2, Carolina Makowski2,3, Martin Lepage2,4,
Mathieu B. Brodeur2,4
1 Interacting Minds Centre, School of Culture and Society, Aarhus University,
Aarhus, Denmark
2 McGill University, Montréal, Québec, Canada
3 University of California San Diego, San Diego, California, U.S.A.
4 Douglas Mental Health University Institute, Montréal, Québec, Canada
*Corresponding author:
Daina Crafa
Interacting Minds Centre
School of Culture and Society
Aarhus University
Jens Christian Skous Vej 4
8000 Aarhus, Denmark email: [email protected] phone: +45 87 15 00 00 Impressionable social self of schizophrenia Crafa et al. 2
Graphical Abstract
Special thanks to D.M. Higgins for graphical design.
Abstract
Background: Social interactions require rapid, real-time information integration and performative application of dynamic social information, and can be especially difficult for patients with schizophrenia. Their difficulty processing social information could lie in challenges extracting the information or in updating their actions to accommodate the new information, resulting in behaviors that may appear rigid or inappropriate.
Disruptions may emerge in the underlying, requisite behavioral or neural processes.
Methods: Seventeen matched healthy controls and seventeen patients with schizophrenia participated in an fMRI study, which included a social interaction priming procedure wherein they met a friendly stranger who held opposite social values from their own.
They answered self-judgement questions about their social values two days before the priming experiment and again during the fMRI scan. Impressionable social self of schizophrenia Crafa et al. 3
Results: Controls suppress social values when interacting with the stranger whereas patients with schizophrenia augment the opposite values, simultaneously holding two sets of social values. Compared to controls, patients display hyperactivity in dorsomedial prefrontal cortex and atypical activity in caudate, posterior cingulate and precuneus.
Discussion: Patients appear to correctly extract social information but apply the information atypically. They display evidence of atypical social flexibility on both performative and neural measures, resulting in confusion between self and other.
Key words: self-identity, social perception, prefrontal activity, Sasta paradigm
Highlights
• Patients with schizophrenia correctly extract but misapply social information
• Patients display self-other confusion and atypical flexibility patterns
• Patients process self and other in different brain regions than controls
• Patients display medial prefrontal hyperactivation
Impressionable social self of schizophrenia Crafa et al. 4
The impressionable social self of schizophrenia:
Neural correlates of self-other confusion after social interaction
1. INTRODUCTION
Schizophrenia is a disabling psychiatric disorder which is often characterized by both difficulties in daily life and clinical symptomatology of positive and negative symptoms.
Interpersonal pathology, such as difficulties with during social interactions, is also a key symptom of schizophrenia, (American Psychiatric Association, 2013), and numerous studies have identified deficits in many sociocognitive domains such as theory of mind, emotion recognition, attribution bias and social perception (Green & Horan, 2010). In addition to these domains, many patients appear to display difficulties with social flexibility. Social flexibility can be defined in terms of performative flexibility of thoughts and behaviors and neural flexibility of the underlying neurobiological mechanisms involved in integrating new or changing social information. Social interactions can be especially difficult for patients with schizophrenia because they require rapid, real-time information integration and performative application of dynamic social schemas. Greater social flexibility is linked to resilience and predicts better treatment outcomes for patients with schizophrenia and frequent social interactions promotes cognitive flexibility and functioning (Folke et al., 2010; Goldfarb-Rumyantzev et al., 2011; Roberts & Penn, 2009; Penn et al., 2007; Ybarra et al., 2008). Characterizing social flexibility during interactions may be particularly useful for improving social functioning in schizophrenia. Impressionable social self of schizophrenia Crafa et al. 5
Patient studies of social flexibility have mostly focused on performative measures of behavioral and cognitive tasks. Neural mechanisms corresponding with social flexibility deficits in patients with schizophrenia have yet to be identified. Additionally, many behavioral studies of social flexibility in schizophrenia use game theory to study how people compete or cooperate to gain an incentive (Billeke & Aboitiz, 2013). While these approaches are quite useful, they emphasize the flexibility of decision-making in patients rather than the flexibility of social schema information integration, which is arguably a central aspect of social interaction. The present study builds on our previous research of social schemas to evaluate neural and performative flexibility in patients with schizophrenia.
Social schema refers to the constellation of social values that a person has, which can act as context or subtext during a conversation and is often measured using self- judgement tasks (Chiao et al., 2010; Crafa et al., 2019a). When most people interact with someone who has a different social schema, they try to accommodate the person they are interacting with by downplaying their own social schema during the interaction (Crafa et al., 2019a). Doing so requires participants to understand that their interlocutor has a different social schema and then update their own beliefs and behaviors accordingly.
Crafa et al. (2019b) reported evidence of neural flexibility corresponding with the suppression of self-values during social interaction in the dorsomedial and dorsolateral prefrontal cortex (dmPFC and dlPFC, respectively), caudate, and precuneus. The dmPFC facilitates top-down social processing, particularly in terms of the representations of self and others in experiments similar to the present study (Bzdok et al., 2013; Lieberman,
2007). The dlPFC and precuneus are brain regions that each relate to processing self- Impressionable social self of schizophrenia Crafa et al. 6
relevant information. The dlPFC is context-sensitive and some studies have tied it to self- control or to the identification of self-relevant information particularly in a social context while the precuneus has been associated specifically with strategic self-judgements, such as when an affiliation is in the subject’s best interest (Cabanis et al., 2013; Chiao et al.,
2010; Cavanna & Trimble, 2006; Hare et al., 2009). The caudate is a key region in theory of mind processing and is also active during implicit learning tasks (Grahn et al., 2008;
Sanfey, 2007; Shibata et al., 2010; Uchiyam et al., 2012). Together, these regions seem to play complementary yet independent roles in the construct of social flexibility (Crafa et al., 2019b).
In contrast with the results in control participants, when patients with schizophrenia interact with someone who has a different social schema, they tend to modify their own social schema to include the schema of the other person, essentially resulting in them holding two sets of social values simultaneously (Crafa et al., 2019a). This performative outcome suggests that patients process the other’s social schema but have difficulty updating their behaviors to appropriately accommodate the situation. In other words, the extraction of the social information appears roughly intact and patients’ social deficits instead seem to lie in the integration of the social information at hand into performative acts. They also demonstrate a performative convolution of self and other.
This convolution of self and other social schema echoes a larger body of literature from non-flexibility studies of self-other distinction in schizophrenia (Nelson et al., 2009; van der Weiden et al., 2015). Early studies described self-other confusion as a simultaneous difficulty with self-understanding paired with a rigidity of social interpretation; recent findings suggest that the problems include a conflation of the self Impressionable social self of schizophrenia Crafa et al. 7
with the other and with a difficulty with the integration of social information into action.
For example, a study by Liepelt et al. (2012) found that patients have difficulty with integrating self-other information when executing a joint task, resulting in a failure to distinguish between self-other responses. Ameller et al. (2014) reported that patients showed performative evidence of distinguishing between their own faces and the face of a familiar other, but were not displaying physiological signs of differentiation as observed in controls.
Numerous neuroimaging studies report disruptions in self-other processing. For example, Jardri et al. (2011) found that patients who listened to themselves or to another person read a text used a similar neural network compared to controls to process the social information. The key difference, however, resided in patients using a less segregated network; that is, patients recruited more overlapping brain regions compared to controls. Ebisch et al. (2013) reported that abnormal self-other processing during a video viewing task was mediated by abnormal interactions between the posterior cingulate cortex (PCC) and other brain areas. Abnormal processing in the default mode network of patients with schizophrenia was likewise identified in the PCC, as well as the precuneus (Whitfield-Gabrieli et al., 2009).
These studies each use passive measures of self-other processing, e.g., watching a video, which do not address social schema directly. Presumably, recent patient studies have avoided self-other judgement tasks because of poor insight that is characteristic of schizophrenia. However, some scientists argue that employing self-other judgement tasks confer access to disrupted social processes that indirect tasks do not (Crafa et al., 2019a; van der Meer et al., 2010). Even if a patient is not able to reliably and accurately report Impressionable social self of schizophrenia Crafa et al. 8
self-other information, findings still suggest that patients demonstrate performative disability on this type of task. The neurobiological processes associated with trying to report self-other information may also be particularly revealing in gaining a better understanding of self-other processing in schizophrenia.
Neuroimaging studies of self-other judgement tasks in healthy participants have identified key brain activity in the vlPFC, which is associated with self-relevant semantic memory, and dmPFC (Crafa et al., 2019b; Denny et al. 2012; van der Meer et al. 2010).
However, this has not been studied in patients. The present study investigates social adaptability in patients compared to controls by applying the social interaction priming paradigm used by our previous behavioral and neuroimaging studies (Crafa et al., 2019a) and examining emergent differences between patients and controls.
We defined evidence of performative flexibility in the patient cohort as a difference between baseline values and responses after the social interaction priming procedure.
Since the literature suggests that patients are able to derive self-other information, we hypothesized that activity in the dmPFC (top-down self-other social processing) would be roughly intact. We therefore defined neural flexibility in the patient cohort as dmPFC activity emerging for social conditions, indicating that patients are considering the new social information even if they are not correctly applying it. Since patients seem to have difficulty distinguishing between self and other and applying the derived social information, we hypothesized that we may see atypical activity in the dlPFC (context- sensitive self-relevant information), PCC and precuneus (abnormal self-other processing) and caudate (theory of mind and implicit learning).
Impressionable social self of schizophrenia Crafa et al. 9
2. METHODS
2.01 Participants
Twenty-five patients diagnosed with schizophrenia enrolled in this study and seventeen patients completed the study. Eight patients were excluded due to motion artifacts or scanner intolerance. Seventeen controls were matched with the final patient cohort by gender, age, IQ, education, ancestry and self-construal (Table 1). Estimated socioeconomic status (SES) was also recorded. All participants were adults living in
Montreal who had been born and raised in Canada, identified English as their first and primary language and were right-handed with normal or corrected vision. Participants provided informed written consent prior to data collection and were compensated for their participation at the end of the study. The Research Ethics Board at the Douglas
Mental Health University Institute approved study procedures.
Patients were diagnosed by a certified clinician using DSM-5 criteria (American
Psychiatric Association, 2013). The Wechsler abbreviated scale of intelligence second edition (WASI-II) was administered to all participants to obtain IQ scores (Wechsler &
Hsiao-pin, 2011). Control participants were screened for psychiatric disorders using the
Structured Clinical Interview for DSM-5 (SCID; First et al., 2007) and excluded participants were given the opportunity to participate in a different study. Patients were additionally administered the Scale for the Assessment of Positive/Negative Symptoms
(SAPS/SANS), Calgary Depression Scale for Schizophrenia (CDS), Hamilton Anxiety
Scale (HAS) and Liebowitz Social Anxiety Scale (LSAS; Fresco et al., 2001; Addington, Impressionable social self of schizophrenia Crafa et al. 10
Addington, Maticka-Tyndale, 1993; Andreasen, 1984a, 1984b; Hamilton, 1960).
Distributions of concomitant symptoms are depicted in Table 1.
Table 1
Demographics and symptoms.
N total Age IQ Education Estimated Construal total N (N female) SES (N female) Controls 17 (4) 33.2 107 13.5 29,444 11(2) IND; 6(2) COLL Patients 17 (4) 36.4 92 12.6 18,055 9(2) IND; 8(2) COLL
Average SAPS SANS CDS HAS Scores 8 9.5 5.3 9.4
Table 1: Patient demographics and symptoms. Participants were one-to-one matched as closely as possible by each demographic variable. Nine participants in each group had Canadian parents; the other eight participants in each group were matched by parents’ birth countries, which included the following: China, Greece, Italy, India, Morocco, Philippines, Ukraine and West Indies Lesser Antilles. Nine patients met LSAS criteria for concomitant social phobia.
2.02 General procedure
Participants completed a series of questionnaires assessing their self-construal and
social values schema prior to study procedures. After completing these questionnaires,
participants completed the social interaction priming procedure, in which they held semi-
scripted interactions with two researchers – the first researcher introduced the social
values of a new culture called Sasta to the participant and the second researcher, whom
they had not interacted with before, introduced themselves as someone from Sasta. The
interlocutor from Sasta held opposite self-construal and social values schema from the
participant. After the social interaction, participants complete the social values schema
questionnaire for a second time and were then trained on the MRI task. Immediately after Impressionable social self of schizophrenia Crafa et al. 11
participants underwent an fMRI scan, where participants completed an Eprime task specifically designed for this study (described below). The structural MRI scan was performed last to minimize decay of effects from the social interaction priming procedure. A complete description of the behavioral materials and methods can be found in Crafa et al. (2019a); all materials are available to download along with instructional videos and other resources at www.dainacrafa.com/sasta.
2.03 Questionnaires
2.03.01 Self-Construal Scale
The Self-Construal Scale (SCS; Singelis, 1994) contains 30 questions rated on a 7- point Likert scale (strongly agree to strongly disagree). The SCS is used to classify participants as either having primarily independent (INDE) or primarily interdependent
(INTER) values prior to testing, meaning that they are more oriented toward either individuality or community in social situations (cf. Chiao et al., 2010). Scores are calculated by subtracting INTER from INDE, and negative scores indicate INTER
(Kitayama et al., 2014). Participants with a positive score were classified as having primarily INDE self-construal and participants with a negative score were classified as having primarily INTER self-construal.
2.03.02 Sasta Social Values Schema Scale
The Sasta Social Values Schema Scale (Sasta SVS Scale; Crafa et al. 2019a) is a self- judgement questionnaire consisting of 12 general self-descriptions (“In general, I am”) followed by an INDE word and 12 contextual self-descriptions (“When I am with my mother, I am”) followed by an INTER word. This questionnaire is given at baseline and again after the social interaction. A modified version of this questionnaire is also given Impressionable social self of schizophrenia Crafa et al. 12
immediately after the social interaction, which includes the same 24 self-description words in the context of the social interaction (“When I am with a Sastan, I am”). Participants rate on a 10-point Likert scale how well a social value described them (from -5 extremely poorly to 5 extremely well, with no neutral “0” option). Scores are calculated by summing the Likert ratings for self-description words associated with INDE and separately for self- description words associated with INTER construal At Baseline (pre-interaction), Overall
(post-interaction), and During the Social Interaction (post-interaction). Effects of repeated administration of this questionnaire were previously assessed and deemed insignificant
(Crafa et al. 2019a).
2.03.03 Reading comprehension
To assess for potential effects of reduced reading skills within this sample due to IQ, education level or effects of symptoms or medication, the word list was reviewed prior to beginning the experiment. Participants indicated whether they understood each word and definitions were provided when they were uncertain. The experiment commenced only after a full understanding of the vocabulary was achieved.
2.04 Definition of Social Values Groups
Classification and priming procedures were performed per the same protocol used in a previous study (Crafa et al., 2019a, 2019b). Participants completed the SCS and SVS scale immediately after signing consent. Their score on the SCS was used to categorize them as having primarily INDE or INTER construal. Their score on the SVS scale provided a baseline for their social values schema and for their responses during the fMRI scan. To safeguard against differences emerging from the contents of participants’ values rather than the change in their values, participants’ agreement in social values were evaluated in a Impressionable social self of schizophrenia Crafa et al. 13
previous study using a data reduction method called Cultural Consensus Analysis;
Anglophone Canadians (patients and controls) included in the present study had high agreement in baseline social values (Crafa et al., 2019c).
2.05 Social Interaction Priming
Participants were primed with the opposite self-construal so that INDE on the SCS completed the INTER-PRIME versions of each task and vice versa. In a private testing room adjacent to the scanner, participants completed a 15-minute social interaction priming task that consisted of two modified procedures: Sasta Stories task (modified from the
Sumerian Warrior Story task) and the Similarities and Differences with Family and Friends task (see Trafimow et al., 1991; cf. Crafa et al., 2019a). Both tasks have been shown to reliably manipulate self-construal and have been used in other priming studies (Chiao et al., 2010).
Both procedures were modified in the present study so that they were performed as social interactions (Figure 1a). Participants were first told that they would meet a person from Sasta after learning about Sasta’s cultural history. In the Sasta Stories task, participants read a story about a warrior who must select a general for an important mission.
The story text was modified so that the warrior was said to be from Sasta instead of Sumeria.
In the INDE-PRIME , the general is selected based on talent while in the INTER-PRIME the general is selected based on family ties. They also read a second story, which mimicked the structure of the first story, about an office manager. Participants then discussed the stories with a researcher who asked them a series of questions. The purpose of this approach was twofold: First, to give participants time to process the contents of the stories and, second, to mimic the effect of meeting someone from a real culture of which some previous Impressionable social self of schizophrenia Crafa et al. 14
knowledge usually exists. During this discussion, participants were encouraged to answer however they felt, with no right or wrong answers. In the Similarities and Differences task, participants met a second researcher who said they were from a country called Sasta and who had a scripted conversation with the participant. In the INDE-PRIME , the conversation was about how the participant is unique from family and friends, whereas in the INTER-PRIME , the conversation was about how the participant was similar to family and friends. Participants were debriefed after all study procedures were complete.
Additional details and procedural validation can be found in Crafa et al. (2019a).
2.06 Eprime Stimuli Presented in the MRI Scanner
Stimuli for the self-judgement task consisted of 144 images structured according to a
2x3 design. Each image displayed either an INDE or INTER word taken from the SVS
Scale presented either in italicized or plain text in one of three conditions: Overall, During
Interaction, and a Control Font condition (Figure 1b). Participants answered “yes” or “no” in response to each stimulus presented via button press and subsequently assigned Likert scale rating.
2.07 EPrime Presentation Procedure
After the social interaction priming procedure, participants completed the self- judgement task in the scanner. Stimuli were presented in a mixed block and event related design using Eprime version 2.0 (Psychology Software Tools, 2012) that was displayed using an LCD projector and mirror. Participants viewed 24 blocks consisting of 6 images each for 3800 ms. Both the block order and the image presentation within each block was randomized. Fixation crosses appeared between each word, jittered for 100-300 ms, for an average of 200 ms each per block, with an additional 100 ms pause between blocks. In Impressionable social self of schizophrenia Crafa et al. 15
two of the conditions (Self Overall, Self During Interaction), participants were asked to indicate via button press whether or not the word described them. In the third condition
(Control Font), participants were asked to indicate whether the word was in italics (see
Figure 1; cf. Chiao et al. 2009, 2010). Prior to the scan, participants were introduced to each type of stimulus and practiced the task until they were comfortable answering questions corresponding with each stimuli type.
2.08 Imaging parameters
The self-judgement task was performed in a 3-Tesla Siemens Tim Trio MRI scanner with a 32-channel coil at the Brain Imaging Center located at the Douglas Mental Health
University Institute (Montreal, QC, Canada). A T2*-weighted, gradient-echo, echo-planar imaging sequence (TR=2450ms, TE=30ms, FA=70°, FOV=256 mm, 86 x 86 matrix, 36 slices, voxel size=3.0mm3) covering the entire brain yielded 361 volumes. To minimize decay of the priming effect, a standard T1-weighted structural scan (TR = 2000 ms, TE =
2.63 ms, flip angle = 9°, FOV = 256 mm, 160 slices, voxel size = 1.0mm3) was collected after the functional scan.
2.09 Biophysiological noise reduction
Participants’ pulse and respiration waveforms were recorded via a pulse oximeter and a respiration belt using a laptop computer running Biopac data acquisition system (Biopac
MP 100 WS, Biopac System Inc., Goleta, CA, USA). To control for artifacts caused by physiological noise, the self-judgement stimuli and response times were synchronized with the MRI data acquisition and motion regressor estimations and physiological noise recordings were performed using the Tapas PhysIO toolbox in SPM12 (Kasper et al., 2017).
Output files were entered as multiple regressors during first level analyses. Impressionable social self of schizophrenia Crafa et al. 16
2.10 Behavioral statistical analysis
Group differences during social interaction were assessed by comparing scores between conditions on the Sasta SVS Scale. A 2x2x3 mixed design repeated measure
ANOVA was performed using IBM SPSS 24 for Mac (IBM Corp, 2016) with GROUP
(Patients vs. Controls) as a between-subject factor and SOCIAL VALUES (Self vs.
Primed) and SOCIAL INTERACTION (At Baseline, Overall, During Interaction) as within-subject variables. In line with Crafa et al. (2019a), the social interaction was considered effective if Self SOCIAL VALUES scores During Interaction fell below scores At Baseline and Overall. Reaction time likewise was assessed using a 2x2x3 repeated measure ANOVA using the same variable structure with GROUP (Patients vs.
Controls) as a between-subject factor and SOCIAL VALUES (Self vs. Primed) and
CONDITION (Overall, During Interaction, Font) as within-subject factors. In both cases, paired samples t-tests were applied post hoc to within-subject comparisons and independent samples t-tests were applied to between-subject comparisons.
2.11 Imaging processing and statistical analysis
Functional images were analyzed using SPM12 (Wellcome Trust Centre for
Neuroimaging, London, UK; http://www.fil.ion.ucl.ac.uk/spm) in Matlab R2016b
(Mathworks, 2016). The first 10 seconds of functional volumes were discarded. The T1 structural volume and all remaining functional volumes were visually inspected for movement across the full scan and manually reoriented to the anterior commissure of the first scan prior to realignment. Translations and degrees of rotation were assessed after realignment and all participants had translations smaller than 2mm (mean = .34mm) and rotations smaller than 2° (mean = .32°) during the scan. Functional scans were Impressionable social self of schizophrenia Crafa et al. 17
coregistered with the structural image and segmented by tissue types. Functional and structural images were normalized to MNI space and smoothed using a Gaussian kernel of full width half maximum 8 mm3 (Friston et al., 2002). A first-level general linear model (GLM) with a 2x3 design structure (Construal x Condition) was constructed using the canonical hemodynamic response function (HRF) and a standard 128s temporal high pass filter to remove slow drift. The 24 motion and biophysiological parameters estimated for each participant were entered as nuisance regressors. Individual subject maps were created using one-sample t-tests. The resulting contrasts (Table 2) were entered into second-level analysis and F-tests were generated for between-group comparison.
Table 2
Eight within-subject contrasts of interest were created using whole-brain clusterwise subtractions.
Contrast Condition number [1] (Self-Primed)(Overall-Font)* [2] (Primed-Self)(Overall-Font) [3] (Self-Primed)(Social Interaction-Font)* [4] (Primed-Self)(Social Interaction-Font) [5] Self(Overall-Social Interaction)* [6] Self(Social Interaction-Overall) [7] Primed(Overall-Social Interaction)* [8] Primed(Social Interaction-Overall) *Indicates hypothesis-defined contrasts of interest
Table 2: Eight within-subject contrasts of interest were created using whole-brain clusterwise subtractions. Final results were only generated for the contrasts that most effectively captured the relevant cognitive processes in order to maintain hypothesis- driven statistical stringency: [1] (Self-Primed)(Overall-Font), [3] (Self-Primed)(Social Interaction-Font), [5] Self(Overall-Social Interaction), and [7] Primed(Overall-Social Interaction).
Impressionable social self of schizophrenia Crafa et al. 18
Reported anatomical clusters are based on the nearest grey matter region defined by the AAL atlas (Tzourio-Mazoyer et al., 2002), although in cases where activation patterns were predominantly localized in white matter bundles, the appropriate white matter tract was labelled, given the emergent literature on fMRI activation in underlying white matter
(Cheng et al., 2015; Gawryluk et al., 2014; Buchsbaum et al., 2007).
2.12 Precautions against Type I errors associated with clusterwise analyses
This clusterwise approach allows for exploratory targeting of hypotheses and direct comparison with other publications using similar models as well as with our own previous study (i.e., Crafa et al., 2019b) and thus was determined to be the most suitable approach for the present study. However, considering recent concerns that clusterwise analyses may produce more Type I statistical errors compared to other analysis methods
(Eklund, Nichols, & Knutsson, 2016; Roiser et al., 2016; for response see Brown &
Behrmann, 2017), several precautions were taken: First, the experimental design mimicked other fMRI experiments that have yielded reproducible findings (precaution based on Lieberman & Cunningham, 2009; experiment based on Chiao et al., 2010; see also Ma et al., 2014; Rule, Freeman, & Ambady, 2013; Ma & Han, 2011; Wang et al.,
2011; Ng, Han, Mao, and Lai , 2010; Han et al., 2010; Wu et al., 2010; Han et al. 2008;
Zhu et al., 2007; Heatherton et al., 2006; D'Argembeau et al., 2005; Macrae et al., 2004;
Northoff & Bermpohl, 2004; Kelley et al., 2002; Hong et al., 2000). Second, contrasts of interest were defined using an a priori hypothesis-driven approach. Third, the Font condition acted as a language control and was excluded from the corresponding General and During Interaction conditions. Fourth, the maximum p-value of .005 was defined a priori based on the results presented by Chiao et al. (2010). Finally, a stringent Monte Impressionable social self of schizophrenia Crafa et al. 19
Carlo permutation correction was applied using 10,000 iterations with voxel-wise thresholding, which revealed that a minimum of 19 contiguous voxels were required to achieve a .005 p-value corrected to .01 (Flandin & Novak, 2013; Nichols, 2016, 2013).
3. RESULTS
3.1 Behavioral results
3.1.1 Group differences during social interaction
Significant interactions emerged between GROUP x SOCIAL INTERACTION,
F(2,64)=6.61, p=.002, and SOCIAL VALUES x SOCIAL INTERACTION,
F(2,64)=5.68, p=.005 (Figure 2). These data were spherical and similar to results from our previous behavioral study using this paradigm (Crafa et al., 2019a). When patients were compared with controls using an independent-samples t-test, Self During
Interaction was significantly lower in the control group, t(32)=-2.65, p=.013. Post-hoc paired samples t-tests revealed that Self During Interaction within the control group was significantly lower than all other conditions (Table 1). In the patient cohort, Prime At
Baseline was significantly lower than Self Overall, t(16)=-2.57, p=.021, and Self During
Interaction, t(16)=-2.27, p=.038. Prime At Baseline was marginally lower (p<.1) than the remaining three conditions; differences between these conditions were significant in our larger behavioral patient study (i.e., Crafa et al., 2019a). Impressionable social self of schizophrenia Crafa et al. 20
Figure 2. Responses on the Sasta SVS Scale by Cohort. Questionnaire responses in controls resemble outcomes from our previous behavioral study (Crafa et al. 2019a). Asterisks indicate value is significantly lower than other values within the cohort.
Performative Flexibility in Controls Performative Flexibility in Patients 40 40
30 30 ** 20 ** 20
10 10
0 0 At Baseline Overall After Interaction At Baseline Overall After Interaction
Self Primed Self Primed
Reaction time
Significant effects emerged for SOCIAL VALUES x CONDITION, F(1.62,51.96)=3.48, p=.047, and GROUP x CONDITION, F(1.89,51.96)=3.78, p=.031. Post hoc t-tests revealed that controls answered fastest during the Font conditions compared to most other conditions (Table 3): Self Font compared with Self Overall, t(16)=-2.37, p=.030,
Self During Interaction, t(16)=-1.11, p<.001, Prime During Interaction, t(16)=-2.63, p=.018; and Prime Font compared with Self During Interaction, t(16)=-4.85, p<.001, and
Prime During Interaction, t(16)=-2.83, p=.012. Controls responded faster when answering questions about Self Overall compared with Self During Interaction, t(16)=-
2.90, p=.010, and Prime In General compared with Prime During Interaction, t(16)=-
3.86, p=.001. Patients answered Self Font questions faster than Prime Font questions, t(16)=-2.573, p=.020, and Prime During Interaction faster than Prime In General, t(16)=-
2.84, p=.012. The post-hoc independent samples t-test did not identify any differences between groups. Impressionable social self of schizophrenia Crafa et al. 21
Table 3
Self-Construal During Social Interaction of Controls
Construal Condition T-Test Results Self Baseline t(16)=3.81, p=.002 Self In general t(16)=3.77, p=.002 Primed Baseline t(16)=2.39, p=.030 Primed In general t(16)=2.52, p=.023 Primed During interaction t(16)=-2.641, p=.018
Table 3: Paired Samples T-Test Scores for Self-Construal During Social Interaction of Controls. Self-construal during social interaction was significantly lower compared to all other conditions in the control cohort.
3.2 Neuroimaging results
3.3 Main results
All regions reported were statistically significant after Monte Carlo correction with p- corrected to <0.01. Complete results are reported in Table 4. Controls showed significant activation only in two conditions: [1] (Self-Primed)(Overall-Font) and [7] Prime(Overall-
During Interaction), with greater caudate, PCC and anterior cingulate cortex (ACC) activity in the former (Figure 3) and greater superior temporal gyrus activity in the latter
(Figure 6).
Patients overall showed significantly more activation patterns than controls across multiple conditions and brain regions. Patients showed significant activation in the dmPFC (Figure 5), vlPFC and superior frontal gyrus which encompasses part of the dlPFC in the condition Self(Overall-During Interaction). Precuneus activation arose in the conditions [1] (Self-Primed)(During Interaction-Font) and [7] Prime(Overall-During
Interaction) and caudate activity was also observed for the condition [7] Prime(Overall- Impressionable social self of schizophrenia Crafa et al. 22
During Interaction) in patients (Figures 3 and 6). Other noteworthy activations included a
reliance on the parahippocampal gyrus in the condition [1] (Self-Primed)(Overall-Font),
and activation in the fusiform gyrus in conditions [3] (Self-Primed)(During Interaction-
Font) (see Figure 4) and [7] Prime(Overall-During Interaction). Substantial activation
within white matter also emerged in condition [7] Prime(Overall-During Interaction). In
patients, bilateral white matter activation emerged in the superior longitudinal fasciculus,
at the intersection of the frontal and parietal lobes.
Table 4
Main neuroimaging results depicting comparisons between the patient and control cohorts for each experimental condition. Any rows without voxel values belong to the same cluster as the row above with a value specified. Abbreviations: CT = control. PT = patient. BA = Brodmann Area. *Includes additional regions within 10 mm
Peak F Voxels x y z Hemisphere BA Region
Self vs. Primed Overall [1] (Self-Primed)(Overall-Font)
CT > PT Posterior Cingulate (PCC)*, Corpus 3.90 72 -15 -25 32 L 23 callosum 2.78 -18 -10 29 L - Caudate Anterior Cingulate (ACC)*, Corpus 3.31 62 12 -1 29 R 24 callosum 3.06 6 8 20 R - Caudate
PT > CT 4.22 54 18 -43 2 R 30 Parahippocampal Gyrus 3.36 25 66 -28 2 R 22 Superior Temporal Gyrus
Self vs. Primed During Interaction [3] (Self-Primed)(During Interaction-Font)
CT > PT None Impressionable social self of schizophrenia Crafa et al. 23
PT > CT 4.84 681 33 -58 -1 R 19 Fusiform Gyrus 4.38 24 -73 2 R 19 Lingual Gyrus 4.34 36 -46 14 R 19 Fusiform Gyrus* 3.72 110 -21 -70 35 L 7 Superior Occipital Gyrus 3.53 -18 -79 41 L 19 Precuneus 2.99 -12 -79 26 L 18 Cuneus
Self Overall vs. During Interaction [5] Self(Overall-During Interaction)
CT > PT None
PT > CT 4.83 296 12 56 32 R 9 Superior Medial Frontal Gyrus (dmPFC) 4.24 -9 59 32 L 9 Superior Medial Frontal Gyrus (dmPFC) 4.16 -18 53 35 L 9 Superior Frontal Gyrus (dlPFC) Inferior Frontal Gyrus, pars orbitalis 3.51 19 33 23 10 R 47 (vlPFC)
Peak F Voxels x y z Hemisphere BA Region
Primed Overall vs. During Interaction [7] Primed(Overall-During Interaction)
CT > PT 3.37 21 45 -7 16 R 22 Superior Temporal Gyrus
PT > CT White matter, superior longitudinal 5.17 241 27 -13 35 R - fasciculus 4.01 36 -46 17 R 13 Insula 3.53 36 -31 2 R - Hippocampus 4.60 208 27 -70 5 R 17 Calcarine Sulcus 4.52 39 -82 5 R 18 Middle Occipital Gyrus 3.87 33 -64 -1 R 19 Fusiform Gyrus White matter, superior longitudinal 4.13 38 24 -40 38 R - fasciculus Impressionable social self of schizophrenia Crafa et al. 24
3.54 21 -49 32 R 31 Precuneus 3.02 30 -52 35 R 7 Angular Gyrus White matter, superior longitudinal 3.81 21 -21 -49 35 L - fasciculus 3.37 51 -21 -7 32 L - Caudate White matter, superior longitudinal 3.31 -30 -43 20 L - fasciculus/arcuate fasciculus 3.13 -21 2 29 L - Caudate
Figure 3. Patients rely on different brain regions when thinking about self vs. primed values overall compared to controls. Controls (green) show significantly increased activation in the ACC and PCC for condition [1] (Self-Primed)(Overall-Font) while patients (red) show significantly increased activation in the parahippocampal gyrus (PHG) and the superior temporal gyrus (STG).
Figure 4. Only patients displayed increased activation for contrast [3] (Self- Primed)(During Interaction-Font). This contrast examines activation when thinking Impressionable social self of schizophrenia Crafa et al. 25
about the social interaction. Fusiform gyrus and precuneal activity emerge in the patient cohort. Impressionable social self of schizophrenia Crafa et al. 26
Figure 5. Patients have increased activity in the dmPFC when comparing self overall vs. during interaction. For contrast [5] Self(Overall-During Interaction), patients exhibit activity in the dmPFC that does not emerge in controls. Impressionable social self of schizophrenia Crafa et al. 27
Figure 6. Patients are differently influenced by the priming. When thinking about primed values during condition [7] Primed(Overall-During Interaction), patients (red) displayed different activation patterns compared to controls (green). 4. DISCUSSION
4.1 Performative and neural flexibility in patients
Patients displayed evidence of performative and neural flexibility, but both were atypical relative to controls. Hyperactivity in the dmPFC corresponded with the simultaneous endorsement of multiple social schemas, demonstrating that patients convolve self and other on both performative and neuroimaging measures. Evidence of compensatory frontoparietal activity and evidence of disruptions in long-range connections of the frontopartietal network also emerge when processing the social schema of another person during a dynamic social interaction.
Social flexibility in this study was defined in terms of performative flexibility, represented by a change in SVS scale scores before and after Baseline, and neural flexibility scores, which were defined by activity in the dmPFC during social interaction.
As in our previous study, patients exhibit different performative flexibility compared to controls. Instead of suppressing their social schemas during an interaction with a stranger who holds an opposite view, patients augment values associated with the opposite schema. Essentially this amounts to changing their self-identity and maintaining two sets of social values simultaneously (Crafa et al., 2019a).
Atypical activity in the dmPFC, which is associated with top-down representation of self and other, corresponds with these behavioral results. In our previous study of healthy participants using the same subjects (Crafa et al., 2019b), we observed dmPFC activity for [5] Self(Overall-During Interaction). In the present study, the dmPFC activity that emerged in patients represents hyperactivity in the same condition. This finding Impressionable social self of schizophrenia Crafa et al. 29
corresponds with the performative condition in which healthy controls suppress their social schema while patients do not.
The employment of other brain areas supports the supposition that patients are exhibiting hyperactive neural flexibility in comparison with controls. For example, activity in the dlPFC, which is associated with self-awareness, and vlPFC, which is associated with self-relevant semantic memory, emerges for patients in the Self(Overall-
During Interaction) condition, while no such activity is observed for controls (Goldberg et al., 2006).
Hyperactivity of brain responses in schizophrenia has been observed in other studies, and some studies have suggested that positive and/or negative symptoms could be at play.
It is worth pointing out that patients in this study had roughly equal scores on the SAPS and SANS for positive and negative symptoms, respectively. We suggest instead that level of patient functioning may be a significant factor. All of the patients in this study were relatively high functioning, and therefore may have already developed some adaptive social strategies. Greater performative and neural rigidity may be seen in a more severe population.
4.2 Neural correlates of self-other confusion in patients
Patients displayed a distinct neural signature of self-other confusion, which was defined a priori as atypical activity in the dlPFC, PCC and precuneus. Controls displayed greater PCC activity, which is associated with self-identity and self-referential stimuli, during the condition [1] (Self-Primed)(Overall-Font). Patients displayed relatively greater precuneus activity, which is associated with self-other judgements, than controls during conditions [3] (Self-Primed)(During Interaction-Font) and [7] Primed(Overall-During Impressionable social self of schizophrenia Crafa et al. 30
Interaction). Patients show a reduced recruitment of self-processes when Self is compared with Prime Overall. Increased activity in the precuneus may play a role in promoting the values of the interlocutor, while reduced PCC activity may reflect the entanglement of the self.
Alternatively, the precuneus has been associated with strategic self-affiliation, such as expressing identity to gain social clout and significant activity could potentially emerge if participants in the patient cohort either consciously or unconsciously catered to their interlocutor’s expectations. Debriefing interviews suggest that this was not conscious; no patients reported answering the way they thought their interlocutor would want them to and all patients felt their responses were generally accurate. The possible unconscious nature of these results agrees with a body of other studies reporting higher susceptibility in patients with schizophrenia, and support the likelihood that unconscious processes contribute to the conflation of self and other in this population (Renard et al., 2016;
Iosebadze & Dzagania, 2013).
4.3 Other findings: caudate, superior temporal and fusiform gyri
Atypical activation of other regions in patients potentially reflects greater recruitment of high cognitive processes and may represent a more effortful process of integrating the new social information. For example, in patients, activation of the caudate, which is associated with theory of mind and implicit learning, emerged during the condition [7]
Primed(Overall-During Interaction). By contrast, controls showed activation in the superior temporal gyrus, which is associated with auditory processing as well as semantic and emotional meaning, in the same condition (Alba-Ferrara et al., 2012) and a known area of disruption in psychosis (Brüne et al., 2011; Habel et al., 2010). In contrast with Impressionable social self of schizophrenia Crafa et al. 31
patients, controls displayed caudate activation during the condition [1] (Self-
Primed)(Overall-Font) as well as activity in the ACC, which is associated with processing the emotions of others and with selective response preferences for personally relevant information (Adolfi et al., 2017; Moran et al., 2006). Patients, in this condition, displayed activation in the parahippocampal gyrus, which is associated with social context interpretation and is a known region of disruption in patients (Yamawaki et al.,
2017). While controls did not show any significant activation for the condition [3] (Self-
Primed)(During Interaction-Font), patients showed activation in the fusiform gyrus. The fusiform gyrus is known for facial processing, and previous studies suggest that it also facilitates top-down processing of sociocontextual information (Gutchess et al., 2006).
4.4 Interpretation of white matter activity
White matter activity is rare in fMRI studies due to grey matter being both more vascular and having higher blood flow; however, it should be noted that fMRI-captured white matter activity is also less likely to be caused by an artifact than grey matter
(Cheng et al., 2015; Gawryluk et al., 2014). Recent studies of fMRI-captured white matter activity in schizophrenia have reported significant agreement in regional information derived from DTI, PET and fMRI measures and that understanding white matter activity may be key to understanding certain deficits in schizophrenia (Cheng et al., 2015).
Patients in the present study display evidence of disruptions in long-range connections of the frontopartietal network when processing the social schema of another person (Nielsen et al., 2017; Chang et al., 2014; Lawson et al., 2013). Patients displayed a Impressionable social self of schizophrenia Crafa et al. 32
great deal of bilateral white matter activation patterns in the superior longitudinal fasciculus, near the junction of the frontal and parietal lobes, for the condition [7]
Primed(Overall-During Interaction). Patients with schizophrenia are specifically known to have higher metabolic rates in the superior longitudinal fasciculus and disruptions in the frontopartietal network, which may be exasperated when maintaining two social schemas simultaneously (Buchsbaum et al., 2007).
4.5 Potential clinical relevance
These findings characterize social flexibility and deviance in patients with chronic schizophrenia who report experiencing social difficulties. They may be useful for clinical interventions designed to train patients in social and daily life skills, such as Cognitive
Enhancement Therapy, Social Cognition and Interaction Training (SCIT), and Integrated
Psychological Therapy, which teach social skills to patients and have shown promising results (Eack et al., 2007; Roder et al., 2006). Such therapies are based on the current state of research, which has identified areas of deficits, including interpretation of social schemas (Matsui et al., 2009; Roberts et al., 2015). According to the findings from this study, patients participating in such therapies may benefit from tasks that practice distinguishing self from other or applying socially-relevant information. Future studies should examine whether the atypical performative and neural responses directly correspond with social discomfort or distress and whether they are alterable through social skills training.
4.6 Closing remarks Impressionable social self of schizophrenia Crafa et al. 33
Patients display evidence of atypical performative and neural flexibility, as well as a conflation between self and other. This study suggests that dmPFC hyperactivity in patients combined with atypical recruitment of the PCC, precuneus, caudate, superior temporal and fusiform gyri echo behavioral confusion of self and other observed during social interactions. Findings have implications for therapies that target social skills.
5. CONTRIBUTIONS & ACKNOWLEDGEMENTS
DC Conceptualization; Data curation; Formal analysis; Funding acquisition;
Investigation; Methodology; Project administration; Visualization; Roles/Writing - original draft
CMS Project administration; Software; Writing - review & editing
CM Validation; Writing - review & editing
ML Resources; Validation; Writing - review & editing
MBB Funding acquisition; Resources; Supervision; Validation; Writing - review & editing
Special thanks to Karyne Anselmo and Danielle Penney for recruiting eligible patients, to
Willa Voorhies, Kristina Goerlitz, and Angela Shen for assisting with data collection in a pinch and to D.M. Higgins and Orla Mallon for proof-reading.
This work is funded by the RBIQ-QBIN Quebec Bioimaging Network (grant number
11.19) and the Douglas Hospital Brain Imaging Center (in-kind award). Thanks to the
Interacting Minds Centre for funding publication fees. There are no conflicts of interest.
Impressionable social self of schizophrenia Crafa et al. 34
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