A meta-analysis of the associations between theory of mind and neurocognition in schizophrenia

SCHRES-08627; No of Pages 11 Schizophrenia Research xxx (xxxx) xxx

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A meta-analysis of the associations between theory of mind and neurocognition in schizophrenia Élisabeth Thibaudeau a,b,⁎, Amélie M. Achim a,c, Carolane Parent a,c, Mélissa Turcotte b, Caroline Cellard a,b a b c

CERVO Brain Research Center, Centre intégré universitaire de santé et de services sociaux de la Capitale-Nationale (CIUSSS-CN), 2601 Chemin de la Canardière, G1J 2G3 Québec, Québec, Canada École de psychologie, Université Laval, Pavillon Félix-Antoine-Savard, 2325 Allée des Bibliothèques, G1V 0A6 Québec, Québec, Canada Département de psychiatrie et neurosciences, Université Laval, Pavillon Ferdinand-Vandry, 1050 avenue de la Médecine, local 4873, G1V 0A6 Québec, Québec, Canada

a r t i c l e

i n f o

Article history: Received 16 May 2019 Received in revised form 17 December 2019 Accepted 19 December 2019 Available online xxxx Keywords: Theory of mind Mentalizing Schizophrenia Psychosis Social cognition Neurocognition

a b s t r a c t Theory of mind (ToM) refers to the ability to infer the mental states of others. ToM is impaired in schizophrenia and these deficits seem to hinder functional recovery. ToM is thus an important, but complex treatment target, supported by several processes. A large number of studies report significant associations between ToM and neurocognition (e.g. memory, attention), but the neurocognitive domains that are most closely linked to ToM remain to be identified. A meta-analysis was conducted to estimate the magnitude of the associations between ToM and neurocognition in people with schizophrenia. Correlations were extracted from the relevant literature, transformed into effect sizes Zr and pooled as weighted means. Focused-tests were employed to test for differences between neurocognitive domains and for differences linked to the characteristics of ToM tasks. Ninety-one studies (N = 5462) were included. Moderate associations emerged between ToM and each neurocognitive domain (Zrs 0.27–0.43), with no significant difference between domains (χ2(8) = 11.89, p = 0.156). Within the domain of executive functions, abstraction showed a stronger association with ToM (χ2(4) = 18.93, p = 0.001). Several ToM tasks characteristics (e.g. modality of stimuli, type of mental state), were significantly related to the magnitude of the associations between ToM and executive functions, visuospatial/problem solving, attention and episodic memory. These results suggest that ToM is linked to a wide range of neurocognitive abilities in schizophrenia, and that ToM tasks are a significant moderator of these associations. The assessment and treatment of ToM should consider the neurocognitive profile of each patient to understand his difficulties and to tailor interventions. © 2019 Elsevier B.V. All rights reserved.

1. Introduction Cognitive deficits are a core feature of schizophrenia (Schaefer et al., 2013) and are associated with major functional difficulties (Fett et al., 2011). Cognition can be divided into two main factors, namely neurocognition and social cognition (Sergi et al., 2007). Neurocognition refers to the mental processes that support several functions such as memory, attention and executive functions. Social cognition is defined as the mental processes underlying social interactions, including the abilities involved in perceiving and interpreting social information in order to guide social interactions (Green et al., 2015; Pinkham, 2014). Social cognition includes emotion processing, social perception, attributional style and theory of mind (Pinkham, 2014). People with schizophrenia present with moderate to large deficits in neurocognition (Schaefer et al., 2013) and social cognition (Savla et al.,

⁎ Corresponding author at: Pavillon Félix-Antoine-Savard, 2325 Allée des Bibliothèques, local 1528, Québec, QC G1V 0A6, Canada. E-mail addresses: [email protected] (É. Thibaudeau), [email protected] (A.M. Achim), [email protected] (C. Parent), [email protected] (M. Turcotte), [email protected] (C. Cellard).

2013) when compared with healthy controls and these deficits are relatively stable across all phases of the illness (Lien et al., 2010). Neurocognitive and social cognitive deficits have debilitating effects across different spheres of functioning (Fett et al., 2011), with 40 to 80% of the variance of functioning difficulties that can be explained by cognitive deficits. Neurocognition and social cognition together explain 79% of the variance of social functioning and the association between neurocognition and social functioning is fully mediated by social cognition (Addington, 2010). Social cognition hence appears to be a more direct predictor of social functioning than neurocognition (Brekke et al., 2005; Fett et al., 2011). However, among the social cognitive functions, theory of mind (ToM), the ability to infer the mental states of others (Pinkham, 2014), shows the strongest link with everyday functioning in schizophrenia (Achim et al., 2013b; Fett et al., 2011). ToM deficits are associated with difficulties in productive activities (Lo and Siu, 2015; Ventura et al., 2015) and social functioning (Kalin et al., 2015; Ventura et al., 2015) and ToM is a mediator between neurocognition and functioning (Achim et al., 2013b; Addington et al., 2006; Bell et al., 2009; Martinez-Dominguez et al., 2015). ToM is thus an important treatment target that is associated with several processes - such as neurocognition - to promote functional recovery in schizophrenia.

https://doi.org/10.1016/j.schres.2019.12.017 0920-9964/© 2019 Elsevier B.V. All rights reserved.

Please cite this article as: É. Thibaudeau, A.M. Achim, C. Parent, et al., A meta-analysis of the associations between theory of mind and neurocognition in schizophrenia, Schizophrenia Research, https://doi.org/10.1016/j.schres.2019.12.017

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In their model, Achim et al. (2013a) suggested that to infer the mental state of others, it is necessary to integrate information that is perceived in the social situation, as well as information that is retrieved from memory regarding the person to whom a mental state is attributed as well as the context. According to this model, ToM deficits could arise from difficulties in different underlying abilities such as perception or memory. Several observations support the idea that neurocognition is necessary for ToM. First, in people with schizophrenia, many associations have been reported between ToM and neurocognitive functions such as verbal memory (Fanning et al., 2012; Koelkebeck et al., 2010), speed of processing (van Hooren et al., 2008), verbal fluency (Woodward et al., 2009), cognitive flexibility (Abdel-Hamid et al., 2009; FernandezGonzalo et al., 2014), inhibition (Fernandez-Gonzalo et al., 2014) and reasoning (Ziv et al., 2011). Second, Fanning et al. (2012) observed that neurocognition explained 19% of the variance of ToM in schizophrenia and that 77% of the patients who had ToM deficits also exhibited neurocognitive deficits. This suggests that a person who presents with neurocognitive deficits is more likely to also exhibit ToM deficits. Third, Bechi et al. (2018) demonstrated that in patients with a normal range ToM performance, 6% of the variance in ToM is explained by attention while in patients with ToM deficits, 19% of the variance in ToM is explained by executive functions. Finally, a recent multiple-case study showed that ToM deficits can be improved following a cognitive remediation therapy targeting neurocognition and metacognitive abilities (Thibaudeau et al., 2017). Taken together, these observations support the idea that neurocognition is involved in making adequate ToM judgments. Neurocognitive deficits in people with schizophrenia could thus interfere in the assessment and the treatment of ToM deficits. As an example, working memory deficits could interfere in the performance of a story-based ToM task that is presented verbally. Neurocognitive deficits could also interfere in the treatment of ToM deficits. In their study, Passerieux et al. (2014) showed that following a treatment that target ToM, patients with attention deficits did not improved as much as those with a better performance in attention. While it is well recognized that ToM and neurocognition are associated, the relationships between ToM and the specific neurocognitive domains are not yet fully understood. Despite the several studies that have looked at these associations, the large heterogeneity of the tasks makes it difficult to compare the results of these studies. Thus, we still need to identify if some neurocognitive abilities are more strongly linked to ToM, but also if the characteristics of the ToM tasks are significantly related to the magnitude of these associations (involved in the task, rather than in ToM per se). A better understanding of these associations could lead to more comprehensive assessment of ToM and to the development of personalized interventions. The general objective of this study was to estimate the magnitude of the association between ToM and neurocognition in schizophrenia by performing a meta-analysis. The first objective was to document and compare the magnitude of the associations between ToM and each neurocognitive domain and subdomain. We expected that executive functions and speed of processing would be more strongly related to ToM (Fanning et al., 2012; Pickup, 2008). The second objective was to assess if certain characteristics of the ToM tasks were significantly related to the magnitude of the association between ToM and neurocognition. We expected that some characteristics of ToM tasks would show different associations to specific neurocognitive domains (e.g. story-based tasks will be more strongly related to language, tasks using non-verbal stimuli will be more strongly linked to visuospatial/problem solving). 2. Materials and methods 2.1. Data sources and literature search Articles were identified through searches in Pubmed, PsycInfo, Embase, Proquest, SciVerse, ScienceDirect and Cochrane Library. The list of keywords is presented in Supplement 1.

As illustrated in Fig. 1, 7480 articles were identified through this search and 17 articles were identified through the references of the papers that were screened. After removing the duplicates, 4868 articles were considered for inclusion. 2.2. Inclusion and exclusion criteria The inclusion criteria were: 1) participants with a diagnosis of schizophrenia or schizoaffective disorder (criteria of the DSM-III to 5 (APA, 1983, 1989, 1996, 2003) or the ICD-9 to 10 (WHO, 1996, 2011)); 2) age between 18 and 65 years old; 3) publication written in English, French or Spanish; 4) made available between 1980 and December 19th 2018 (including Epub) and 5) provided a correlation between a ToM task and at least one neurocognition task (excluding a composite score of global neurocognition such as an intellectual quotient). However, composite scores for a specific domain (composite score of attention that includes several tasks) were included. To include the grey literature (e.g. dissertation), we did not include the status of publication as an inclusion criterion. 2.3. Procedure The procedure was based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (Moher et al., 2010). Following the initial search and the removal of the duplicates, the articles were screened based on the title and the abstract by two independent judges. In case of disagreement, which occurred for 5% of the articles, a third judge was consulted. The retained articles were screened based on the full-text by the same two judges and a third judge was consulted for 4% of the articles. The references of all eligible papers were screened to identify possible references that did not come up during the initial search. For these papers, the same screening for eligibility was done. The extraction was then conducted by the first author and independently by a second judge for 20% of the eligible articles (18/91). Since the percentage of error was very low (0.06% of discrepancies), the first author extracted the information for the remaining papers and the other judge (CP) double-checked the extraction. As recommended by the Revised Assessment of Multiple Systematic Reviews (Kung et al., 2010), we assessed the quality of the included studies using the Quality appraisal checklist-quantitative studies reporting correlations and associations. Two independent judges (ET, MT) scored the external and internal validity (range 1–3 for each scale) of each study. A third independent judge was consulted in case of disagreement (0.03% of discrepancies). An overall quality score was obtained by summing up the two validity scores. 2.4. Classification of neurocognition tasks into their respective domains The compendium of neuropsychological tests (Strauss et al., 2006) was consulted to link each test to the suggested construct. However, some tasks were experimental or too recent to be listed in the compendium. For these cases, the classification was based on neuropsychological models (e.g. Eustache and Desgranges, 2008; Shallice, 1982) and on a meta-analysis that listed different neuropsychological tasks used in schizophrenia (Schaefer et al., 2013). After the initial classification by the first author, the choices were discussed and endorsed by a doctoral student in neuropsychology and by a neuropsychologist (CC). The following domains were included: attention, working memory, episodic memory, speed of processing, language, visuospatial/problem solving, executive functions, early processing/perception and autobiographical memory. For episodic memory, the subdomains encoding and retrieval were included. For executive functions, the subdomains planning/organization, inhibition, flexibility, abstraction and fluency were included. The full list of neurocognition tasks included in each domain is presented in Supplement 2.

Please cite this article as: É. Thibaudeau, A.M. Achim, C. Parent, et al., A meta-analysis of the associations between theory of mind and neurocognition in schizophrenia, Schizophrenia Research, https://doi.org/10.1016/j.schres.2019.12.017

É. Thibaudeau et al. / Schizophrenia Research xxx (xxxx) xxx

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Fig. 1. Flowchart of the meta-analysis.

2.5. Inclusion and classification of the ToM tasks

2.6. Statistical analysis

Definitions of ToM in the literature are heterogeneous and tasks assessing ToM can also be referred to as cognitive empathy, mentalizing or mental state attribution (Pinkham, 2014). The authors from the SCOPE initiative defined ToM as the “ability to represent the mental states of others including the inference of intentions, dispositions, and/or beliefs” (Pinkham, 2014). We certainly agree with this definition, but also identify the need for more operational boundaries in order to discriminate whether a task meets the definition of ToM, or rather of another social cognitive domain. As in previous meta-analyses from our team (Lavoie et al., 2013; Plana et al., 2014), tasks were here classified as evaluating ToM if “the participants had to attribute mental states (e.g. intentions, beliefs/knowledge, desires, and emotions) to specific characters that typically express something (facial, bodily or verbal expression) in a given situation (contextualized ToM), though for some tasks the expressions themselves were complex enough not to necessitate explicit contextual information (decontextualized ToM)” (Lavoie et al., 2013) (p. 130). The ToM tasks were classified based on different characteristics, including the specific ToM task that was used, the modality of the stimuli and of the answers (verbal, non-verbal, combination), the type of answers (open answers, multiple choices, picture arrangement, combination), the complexity of attribution (1st order i.e., attribution of a character's mental state about the physical world, 2nd order i.e. attribution of a character's mental state about the mental state of another character, combination), the type of context (contextualized, decontextualized, combination) and the type of mental states being inferred by the main character (belief/knowledge, intention, emotion, combination). Details regarding the tasks and their classification are presented in Supplement 2.

We used the meta-analytic procedure proposed by Rosenthal based on effect sizes Zr (Rosenthal and Rosnow, 1991). Each correlation between a ToM task and a neurocognition task was transformed into an effect size Zr through a Fisher Z transformation. To preserve the independence of the data, Zrs were combined when an article included more than one correlation of relevance for our targeted analyses (e.g. between ToM and a same neurocognitive domain). Weighted means were then calculated for the associations between ToM and each neurocognitive domain and subdomain, as well as for the overall mean association across all domains. Zrs can be interpreted as small (Zr ~ 0.10), moderate (Zr ~ 0.30) or strong (Zr ~ 0.50). One-sample ttests were used to determine if the effect sizes of each domain were significantly greater than zero. The strength of the associations was then compared between the different domains using focused-tests. Next, focused-tests were employed to compare the moderating effect of the specific ToM tasks as well as the task characteristics (see Section 2.5) on the magnitude of the associations between ToM and neurocognition. Finally, exploratory analyses were conducted to examine the moderating effect of the neurocognition tasks (specific task and tasks characteristics) as well as the moderating effect of clinical and demographic characteristics of the patients on the magnitude of the associations between ToM and neurocognition. 3. Results After the first screening based on the title and the abstract, 1192 of the 4868 articles were still considered for inclusion (see Fig. 1). Following the eligibility screening based on the entire article, 91 articles met all

Please cite this article as: É. Thibaudeau, A.M. Achim, C. Parent, et al., A meta-analysis of the associations between theory of mind and neurocognition in schizophrenia, Schizophrenia Research, https://doi.org/10.1016/j.schres.2019.12.017

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Table 1 Articles included in the meta-analysis. Sample

Study

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37a 37b 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73

Abdel-Hamid et al., 2009 Alfimova et al., 2009 Aydin et al., 2018 Bambini et al., 2016 Bechi et al., 2015 Bell et al., 2010 Bell et al., 2009 Bengochea-Seco et al., 2011 Binz and Brüne, 2010 Bliksted et al., 2014 Bora et al., 2006 Bora et al., 2007 Bosia et al., 2011 Bozikas et al., 2004 Bozikas et al., 2011 Brune et al., 2007 Brune et al., 2007 Brune, 2005 Brune and Bodenstein, 2005 Brune et al., 2009 Brune et al., 2011 Cavieres and Valdebenito, 2007 Champagne-Lavau and Stip, 2010 Champagne-Lavau et al., 2012 Chung et al., 2011 Corcoran et al., 1995 Corcoran and Frith, 2003 Corcoran, 2003 Croca et al., 2018 Davidson et al., 2017 de Achaval et al., 2010 Derntl et al., 2009 Docherty et al., 2013 Essizoglu et al., 2017 Fanning et al., 2012 Galderisi et al., 2018 Gavilán and García-Albea, 2011a Gavilán and Garcia-Albea, 2015 Giusti et al., 2013 Green et al., 2012 Green et al., 2008 Greig et al., 2004 Hajduk et al., 2018 Helle et al., 2017 Hirao et al., 2008 Ho et al., 2015 Hooker et al., 2011 Horton, 2010 Horton and Silverstein, 2011 Johannesen et al., 2018 Kee et al., 1998 Kelemen et al., 2005 Kim et al., 2013 Konstantakopoulos et al., 2014 Lam et al., 2014 Langdon et al., 2001 Langdon et al., 2002 Langdon et al., 2014 Li et al., 2017 Lincoln et al., 2011 Lo and Siu, 2018 Majorek et al., 2009 (forensic) Majorek et al., 2009 (non-forensic) Martinez-Dominguez et al., 2015 Marsh et al., 2013 Mazza et al., 2007 Mazza et al., 2012 (first-episode) Mazza et al., 2012 (chronic) Mehl et al., 2010 Mehta et al., 2014 Michelas et al., 2014 Mitchley et al., 1998 Okruszek et al., 2017 Pijnenborg et al., 2009

N 50 103 34 43 75 62 151 43 49 36 50 58 118 35 36 38 26 23 31 50 25 42 20 32 41 55 59 39 18 48 20 24 63 47 119 740 22 22 20 191 24 128 43 87 20 41 21 34 31 32 28 52 21 58 58 32 25 43 42 75 62 33 38 21 14 20 49 178 55 170 10 18 48 46

% Age men

Education (years)

Illness duration Age at % Sz (years) onset

% Sz PANSS affective total

48 41 65 62 57 61 58 56 49 53 66 71 64 60 81 47 46 78 74 44 68 67 75 66 63 69 85 82 67 58 65 50 67 51 65 70 82 82 70 68 54 80 60 86 50 56 81 62 71 59 64 67 52 59 50 56 – 56 60 63 45 97 47 71 86 35 67 70 54 71 – 83 54 74

10.7 – 10.4 11.8 – 12.6 13.2 – 10.7 12.1 11.5 11.5 – 10.3 12.2 – – – – – – – 11.5 12.8 13.1 – – – 11.9 12.3 12.4 – 12 11 12.9 11.7 10.2 10.2 13.4 12.7 – 13.5 – – 13.5 12.9 13.1 – – 12.7 11.8 – 14.2 11.2 10.4 11.9 – 12.4 11.9 14.9 10.7 – – 16.1 10.9 8.8 12.6 11.5 15.1 10.1 12.1 – 13.4 –

9.0 7.0 10.6 15.5 – – – – 8.8 7.5 9.1 10.2 – 10.9 10.9 8.8 8 12.3 11.8 9.9 13.8 – 15.2 15.8 – – 13.9 13.2 28.4 – 9 11.5 – – – 16.4 19.9 19.9 11.6 24.2 19.8 – 11.3 27.3 10.6 20.0 24.5 – 25 – 19.9 – – 17.2 13.4 12.9 9.6 16.2 2.9 10 12.0 9.7 8.8 13.3 – 12.3 1.01 10.9 9.6 7.6 14.2 19.4 – 7

14 13 – – – 25 31 – 18 – – – – – – – – – – 18 – – – – – – – – – 13 – – 48 – 29 – – – – 9 – 32 28

37.1 29.0 30.1 39.7 – 42.7 42.8 42.3 37.8 22.7 30.6 32.6 – 36.5 36.7 35.9 37 38.8 38.6 39.2 42.7 24.3 42.7 41.6 36.9 31.8 40.5 40.9 53.2 51 30.9 8.7 40 39.3 44.9 40.0 42.8 42.8 36.2 46.6 41.5 – 38.2 12.9 36.7 27.7 44.3 45 47 48.8 37 37.3 39.1 42.3 40 37.3 – 41.5 26.4 33.9 37.9 31.8 35.4 39.2 29.9 42.7 26.4 34.6 32.1 32.7 36.3 45.3 35.8 27.4

28.4 – 19.5 24.5 – 23.5 22.6 25.6 – – 21.4 22.1 – – 25.8 27.4 29.5 26.5 26.4 29.3 28.6 – 42.7 – 21.8 – 26.7 27.9 24.7 21.2 23 28.9 – – – 24.1 23.1 23.1 – 11.3 – 21.9 – 100 – – 11.8 18 21 – – – – – 25.9 24.3 23.2 – 21.8 – 25.9 21.8 27.4 – 16.9 – – – – – – – – 24.2

86 87 100 100 100 74 69 100 82 100 100 100 100 100 100 100 100 100 100 76 100 100 100 100 100 100 100 100 100 77 100 100 52 100 71 100 100 100 100 91 100 68 72 – 100 100 57 76 77 100 100 100 100 100 100 94 92 74 100 88 100 100 100 100 64 100 100 100 78 92 100 100 100 100

– – 43 24 23 – – – – – – 6 8 26 – 12 – – – – 36 – – – 14 8 – – – –

– – – 77.4 – 64.9 – 55.1 72.9 – 54.3 – – 63.7 – 72.5 70.6 70.3 71.8 71.7 74.2 – – – – – – – 63.0 47.3 83.8 – 67.0 59.6 63.9 – 69.5 69.5 72.7 – – – – 76.3 – – – – – – – – – – – – – – – – – – – – – – – – – – 63.0 – – –

GAF

CPZ

– – – – – – – – – – – – – – – – – – – – – – – – – – – – – 40.4 – – 48.0 – – – – – 36.4 – – – – – – – – – – – – – – – – – – – – 44.3 – – – 65.7 – – – – – – – – – –

687.04 – 528.1 438.6 – – 684.7 – 671.2 – 493.8 – – – – – – – – 667.7 – – – 621.0 – – – – 410.0 – – – – – – – 833.5 833.5 – – 340.1 – – – – 418.8 – – – – – – 429.0 404.8 – – – – – 389.2 – – – 248.5 245.0 310.3 98.3 210.3 411.3 398.8 – – – –

Please cite this article as: É. Thibaudeau, A.M. Achim, C. Parent, et al., A meta-analysis of the associations between theory of mind and neurocognition in schizophrenia, Schizophrenia Research, https://doi.org/10.1016/j.schres.2019.12.017

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Table 1 (continued) Sample

Study

74 Pinkham and Penn, 2006 75 Piovan et al., 2016 76 Pousa et al., 2008 77 Pu et al., 2016 78 Riccardi et al., 2016 79 Rominger et al., 2016 80 Sarfati et al., 1997 81 Schenkel et al., 2005 82 Simons et al., 2016 83 Smith et al., 2014 84 Stouten et al., 2017 85 Stratta et al., 2007 86 Tomlinson et al., 2014 87 Tso et al., 2010 88 Tsoi et al., 2008 89 Uhlhaas et al., 2006 90 Varga et al., 2014 91 Whitton and Henry, 2013 92 Yamada et al., 2007 93 Ziv et al., 2011 Characteristics of the overall participants across all studies (means and standard deviations are presented)

N

% Age men

Education (years)

Illness duration Age at % Sz (years) onset

49 30 61 26 30 20 24 42 211 60 162 20 33 33 30 48 19 34 20 30 5462

57 63 79 31 70 80 79 60 73 63 72 85 67 67 70 85 53 41 50 70 65

14.3 9.6 – – 9.9 – 12.2 12.1 – – 11.9 11.7 – 13.8 12.8 11.7 13.6 13.6 13.5 11.4 12.1 (2.5)

10.4 16.0 10.7 10 13.9 12.5 – – 0.9 14.4 – 15.2 – 17.9 17.5 – 13 23.1 11.6 13.2 12.7 (7.8)

33.2 45.4 32.5 31.6 37.8 37.7 31.9 41.7 27.8 35.4 27.6 38.5 23.7 38.5 42.1 38.4 38.2 43.6 38.8 37.8 33.9 (8.4)

– 29.4 21.8 21.5 – – – – – – – 22.7 – – – 20.5 25.8 20.5 27.4 24.3 23.6 (7.4)

71 100 100 100 100 70 100 55 84 100 50 100 100 – 100 83 100 100 90 100 90.7

% Sz PANSS affective total – 82.4 63.9 63.4 95.1 – – – – – – 79.0 – – – – 68.1 – 64.5 58.1 61.3 (14.5)

25 – – – – 5 – 45 – – 6 – – – – 17 – – – – 6.9

GAF

CPZ

– – 62.7 – 55.6 – – – – – – – – 46.7 – – – – – – 49.7 (10.0)

352.7 415.5 – 30.3 – 440.0 – – – 360.9 – 536.2 – 505.1 445.2 – 605.0 – – – 451.6 (295.3)

Brune et al. (2007), Majorek et al. (2009) and Mazza et al. (2012) included two independent samples that were analysed separately. Sz = schizophrenia; Szaffective = schizoaffective; PANSS = Positive And Negative Syndrome Scale; GAF = Global Assessment of Functioning; CPZ = chlorpromazine equivalent. a Gavilán and García-Albea (2011, 2015) include the same participants, but different tasks. They were combined in all analyses to deal with overlapping sample.

our inclusion criteria. Some of the studies included two independent samples of patients for which relevant data was reported. We thus included 91 studies and 93 samples, listed in Table 1, along with clinical and demographic characteristics. 3.1. Publication bias and quality of the studies The Rosenthal failsafe-N (N = 19,699) and the symmetrical distribution of the funnel plot (Suurmond and van Rhee, 2017) (see Supplement 3) for the association between ToM and overall neurocognition revealed no indication of a publication bias. The mean quality of the studies was 5.17/6 and did not significantly influence the magnitude of the association between ToM and neurocognition (χ2(3) = 3.38, p = 0.337).

3.2. Correlations between ToM and neurocognitive domains and subdomains As reported in Table 2, when considered across all domains, the association between ToM and neurocognition was moderate, with no evidence for significant heterogeneity. The associations between ToM and the different neurocognitive domains were all in the moderate range (Zrs = 0.27–0.43), with no significant difference between the nine neurocognitive domains (χ2(8) = 11.89, p = 0.156). No significant difference was observed in the magnitude of the associations between ToM and the subdomains of episodic memory (encoding versus retrieval) (χ2(1) = 0.45, p = 0.502). However, a significant difference emerged between the subdomains of executive functions (χ2(4) = 18.93, p = 0.001), such that abstraction was more strongly associated

Table 2 Meta-analytic results for the associations between ToM and neurocognition. Neurocognitive domains

Overall neurocognition Neurocognitive domains

Total N

Effect size (weighted Zr)

Standard error

93

5462

0.32

17 28 25 21 10 25 31 24

919 2431 2339 2279 938 2515 1255 1440

65 23 9 34 7 17 6 2

4257 2052 349 1820 381 989 382 114

Difference from zero

Heterogeneity test

95% confidence interval

t-test

p-value

χ2

Dfs

p-value

0.15

0.30–0.35

20.64

b0.01

101.30

92

0.238

0.27 0.33 0.30 0.30 0.27 0.29 0.38 0.31

0.16 0.17 0.13 0.13 0.08 0.18 0.16 0.19

0.20–0.33 0.24–0.33 0.23–0.32 0.25–0.33 0.20–0.32 0.22–0.30 0.31–0.41 0.25–0.35

6.19 9.37 9.65 9.97 6.87 8.72 11.74 10.05

b0.01 b0.01 b0.01 b0.01 b0.01 b0.01 b0.01 b0.01

19.37 38.13 27.34 20.83 8.22 30.18 25.96 33.21

16 27 24 20 9 24 30 23

0.250 0.081 0.289 0.407 0.512 0.179 0.677 0.080

0.30 0.31 0.30 0.30 0.52 0.25 0.34 0.43

0.23 0.15 0.12 0.13 0.15 0.09 0.22 0.09

0.26–0.32 0.26–0.34 0.19–0.39 0.25–0.34 0.41–0.62 0.18–0.30 0.23–0.41 0.23–0.55

12.54 12.19 4.19 11.72 6.39 6.64 4.83 2.10

b0.01 b0.01 0.003 b0.01 0.001 b0.01 0.005 0.283

87.32 27.75 14.95 42.95 9.88 16.29 7.55 4.31

64 22 8 33 6 16 5 1

0.028 0.184 0.060 0.115 0.130 0.433 0.183 0.038

Neurocognitive subdomains

Attention Working memory Episodic memory Encoding Retrieval Speed of processing Language Visuospatial/problem solving Executive functions Plan/organize Inhibition Flexibility Abstraction Fluency Early processing/perception Autobiographical memory

Number of samples (k)

Total N = total participants in each analysis; χ2 = Chi-square; Dfs = degree of freedom. The results in bold are significant (pb0.05)

Please cite this article as: É. Thibaudeau, A.M. Achim, C. Parent, et al., A meta-analysis of the associations between theory of mind and neurocognition in schizophrenia, Schizophrenia Research, https://doi.org/10.1016/j.schres.2019.12.017

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heterogeneity for autobiographical memory may reflect the small amount of studies that fell into that category (N = 2).

*

0.5

3.3. Effects of ToM tasks characteristics on the associations between ToM and neurocognition

MEAN WEIGHTED ZR

0.4

The significant moderating effects of ToM tasks characteristics on the association between ToM and neurocognition are reported below, and the full set of results is presented in Supplement 4. For the relationship between ToM and attention (see Fig. 2 and Supplement 4), a stronger association was observed when the ToM tasks required the attribution of emotions compared to the attribution of intentions (χ2(1) = 7.3, p = 0.001), with an intermediate Zr for beliefs/knowledge. For episodic memory (see Fig. 3 and Supplement 4), a stronger association was observed when the ToM tasks required the attribution of intentions (χ2(1) = 8.19, p = 0.004) or of a combination of different mental states (χ2(1) = 8.18, p = 0.004) compared to the attribution of beliefs/knowledge. For visuospatial/problem solving and executive functions, the specific ToM task, the modality and the type of answers as well as the complexity of the attributions had a significant effect on the association with ToM, as illustrated and further detailed in Figs. 4 and 5 (see also Supplement 4).

0.3

0.2

0.1

0

k=3

Belief/Knowledge

k=11

k=6

Intention

Emotion

Fig. 2. Moderating effect of the type of mental state for attention.

with ToM (Zr = 0.52) compared to all the other executive functions (Zrs = 0.25–0.31; all ps ≤ 0.013). As presented in Table 2, the mean weighted Zrs observed for the associations between ToM and all neurocognitive domains and subdomains were different from zero, with the exception of autobiographical memory. The only domains to show significant heterogeneity between the Zrs of the studies were executive functions and autobiographical memory. While the heterogeneity observed for executive functions can be explained by the stronger association between abstraction and ToM, the

3.4. Exploratory analyses The moderating effects of the neurocognition tasks and of the characteristics of the patients are presented in Supplement 5. Regarding the characteristics of the patients, the results suggest that a higher dosage of medication (chlorpromazine equivalent), more severe psychiatric symptoms (PANSS total score) and a later age at onset of illness were significantly related to the magnitude of the associations between ToM and neurocognition.

0.5

* 0.4

MEAN WEIGHTED ZR

* 0.3

0.2

0.1

0

k=2

Belief/Knowledge

k=14

Intention

k=8

Emotion

k=7

Combination

Fig. 3. Moderating effect of the type of mental state for episodic memory.

Please cite this article as: É. Thibaudeau, A.M. Achim, C. Parent, et al., A meta-analysis of the associations between theory of mind and neurocognition in schizophrenia, Schizophrenia Research, https://doi.org/10.1016/j.schres.2019.12.017

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0.6

*

7

*

*

*

MEAN WEIGHTED ZR

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0.4

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Task

k=7

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k=18

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Combination

Type of answer

k=4

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k=19

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k=5

Picture arrangement

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Open

Hinting

k=3

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k=7

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k=2

RMET

k=6

PST-T

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Non-verbal

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Order of attribution

Fig. 4. Moderating effect of the characteristics of ToM tasks for visuospatial/problem solving. RMET = Reading the Mind in the Eyes Test; PST = Picture Sequencing task; T = Total; S = Sequencing; Q = Questionnaire.

specific ToM task, the type and modality of answers, the type of mental state and the complexity of the attributions. Finally, the results suggest no publication bias.

4. Discussion The general objective of this meta-analysis was to estimate the magnitude of the association between ToM and neurocognition in schizophrenia. A total of 91 studies (K = 93, N = 5462) was included. A moderate association was observed for the relationships between ToM and each neurocognitive domain, with no significant difference between the magnitude of these associations. However, in the domain of executive functions, abstraction showed a stronger association with ToM than the other executive functions. Further, the results showed that some characteristics of the ToM tasks are significantly related to the magnitude of the associations with neurocognition, such as the

*

0.6

The hypothesis that neurocognition is necessary, but not sufficient for ToM has been proposed decades ago, but this hierarchical relationship was only supported later by Fanning et al. (2012). In their study, they showed that it is much more common to have ToM deficits along with neurocognitive deficits than to have ToM deficits along with a

* *

0.5

MEAN WEIGHTED ZR

4.1. Understanding the associations between ToM and neurocognition in schizophrenia

*

* *

*

*

*

*

0.4

0.3

0.2

Task

Verbal

k=16

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k=28

k=39

k=13

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Type of answer

k=15

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k=46

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k=16

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k=10

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k=21

Picture arrangement

k=38

Open

k=2

Strange stories

k=3

TASIT-III

k=4

Faux-pas

k=5

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k=14

PST-T

k=6

FB-PST

k=12

RMET

k=17

Hinting

0

Multiple choices

0.1

Order of attribution

Fig. 5. Moderating effect of the characteristics of ToM tasks for executive functions. RMET = Reading the Mind in the Eyes Test; FB = False Belief Task; PST = Picture Sequencing task; T = Total; S = Sequencing; Q = Questionnaire; TASIT = The Awareness of Social Inference Test.

Please cite this article as: É. Thibaudeau, A.M. Achim, C. Parent, et al., A meta-analysis of the associations between theory of mind and neurocognition in schizophrenia, Schizophrenia Research, https://doi.org/10.1016/j.schres.2019.12.017

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normal range performance in neurocognition. While the results of Fanning et al. (2012) support the idea that neurocognition is necessary but not sufficient for ToM in schizophrenia, the specific associations with the different domains of neurocognition remained to be better understood. Contrary to our initial hypothesis, the results of the current meta-analysis revealed no significant difference in the relationships between ToM and the different neurocognitive domains. These results are however in line with those of a recent multiple case study (Thibaudeau et al., 2017) in which we used a personalized computerized cognitive remediation therapy that targeted neurocognition and metacognition in four patients with schizophrenia who showed very different profiles of neurocognitive impairments at baseline. Following the treatment, all four patients improved significantly on ToM, along with improvement of their most impaired neurocognitive functions at baseline (Thibaudeau et al., 2017). This multiple case study led us to hypothesize that different neurocognitive difficulties can impact ToM performance. As suggested by Bora et al. (2009), a general cognitive deficit in schizophrenia could influence ToM, and this hypothesis could support the lack of difference between the cognitive domains in the current meta-analysis. In their meta-analysis, Bora et al. (2009) have demonstrated that general intelligence significantly contributed to ToM deficits, but only in remitted patients with schizophrenia. In the current meta-analysis, the relationship of ToM to IQ was not specifically explored since we were interested in the unique contribution of each cognitive domain to ToM. However, our results are in line with the idea of a broad neurocognitive deficit in schizophrenia that could explain the lack of difference in the associations between ToM and the different cognitive domains. Meta-analyses have consistently showed deficits in several neurocognitive domains in schizophrenia (Mesholam-Gately et al., 2009; Schaefer et al., 2013). As suggested by Gold and Dickinson (2013), “the more a task requires the integration of multiple cognitive operations, the more a tasks depends on the ‘general’ coordinated functions of the cortex, the more likely patients are to deviate from healthy performance levels” (p. 264). ToM is a higher-level social cognitive processes (Fiszdon et al., 2017) that involves the integration of multiple information and processes. In accordance with the results of the current study, it is possible to hypothesize that a broad neurocognitive deficit could contribute to ToM impairments in schizophrenia, and that deficits in any neurocognitive domain could negatively influence the treatment of ToM deficits. In the current meta-analysis, abstraction was the only subdomain that revealed a stronger association with ToM compared with the other executive functions. Abstraction can be defined as the process of formulating general concepts by abstracting common properties of instances (Goldstein, 1998; Packwood et al., 2011) and deficits in abstraction can lead to concrete thinking (Bambini et al., 2016). To make a ToM judgment, it is necessary to integrate concrete information such as facial expression and the context of the situation to deduct a mental state that is not concretely presented. It is thus possible that abstraction and ToM share similar processes that could explain this result, but future studies that specifically aim to understand these associations are necessary. 4.2. ToM tasks characteristics and implications for the assessment and the treatment of ToM deficits in schizophrenia

them are not standardized and present psychometric limitations such as ceiling effects, limited internal consistency or reliability (Pinkham et al., 2018). Depending on the ToM task, the version of the task and the way the instructions are given, various neurocognitive processes could be recruited (Bechi et al., 2013; Bora et al., 2009). As an example, the Hinting task consists in short stories that are sometimes read to the participants and sometimes presented as written stories. A patient with working memory deficits could struggle performing a version of the task in which the items are read to him, but show less difficulty using a written version that can be consulted multiple times as needed. Thus the use of standardized tasks would help to identify which neurocognitive deficit could influence ToM performance. Using ToM tasks that take into account neurocognition could also help to understand the impact of neurocognitive deficits on ToM performance. As an example, the Combined Stories Test (Achim et al., 2012; Thibaudeau et al., 2018) aims to reduce the memory load by allowing patients to re-read and consult the stories as needed. It also includes non-social reasoning questions and control questions to identify and control for potential attention, memory or general reasoning deficits that could affect ToM performance. Other ToM tasks such as the Social Cognition and Screening Questionnaire (SCSQ) (Roberts et al., 2011) or the Social Attribution Task – Multiple Choice version (SAT-MC) (Bell et al., 2010) are also available to assess separately, or to reduce the impact of neurocognition. These types of ToM tasks can help clinicians to better understand the neuropsychological profile of the patient, to identify the need for additional neuropsychological assessment and to establish treatment targets in cognitive remediation therapy. Our results are indeed relevant for the personalization of the treatment of ToM deficits. As proposed by Medalia et al. (2016), cognitive remediation therapy in schizophrenia should be personalized to the cognitive profile of each patient to improve efficiency. Recent evidences support the role of neurocognition in the treatment of social cognitive deficits (Garety et al., 2015). Given the moderate association between ToM and each neurocognitive domain, it is possible to hypothesize that a deficit in any neurocognitive function could be associated with a negative impact on ToM. Inversely, improvement in any neurocognitive function could also have a positive impact on ToM. Thus, a personalized approach for treating ToM deficits should take into account not only the ToM performance at baseline but also the neurocognitive profile. As an example, for a patient with important attention deficits, the clinician could try to reduce the cognitive load of his intervention for ToM (Fanning et al., 2012), or might want to combine interventions that will target both ToM and attention. Further, the use of cognitive remediation techniques developed for neurocognition are proven effective to improve higher-order social cognitive processes such as ToM (Fiszdon et al., 2017; Kayser et al., 2006; Sarfati et al., 2000). To improve ToM, Kayser et al. (2006) and Sarfati et al. (2000) have used verbalisation to help patients with schizophrenia extracting information regarding the mental states of others. In their Understanding Social Situations (USS) training, Fiszdon et al. (2017) uses a large variety of neurocognitive remediation techniques (e.g. drill and practice, verbalisation, scaffolding, etc.) to improve higher-order social cognitive processes (i.e. ToM, attributional style). These types of techniques could help improving ToM in patients with schizophrenia, by supporting their neurocognitive deficits. Thus, interventions for ToM should consider neurocognitive deficits of patients with schizophrenia. 4.3. Limitations

The results of this meta-analysis suggest that several characteristics of the ToM tasks are significantly related to the magnitude of the associations between ToM and neurocognition, including the type of mental state, the type and the modality of answers, the specific ToM tasks as well as the complexity of the attributions. These results suggest that the choice of a ToM task could have a significant impact on the neurocognitive processes that are recruited, and ultimately on ToM performance. There is a large variety of ToM tasks available and several of

First, as with any meta-analysis, we were limited to the data from the available studies. Thus, some neurocognitive domains could not be included (e.g. source memory) or were under-represented (e.g. autobiographical memory). The conclusions that support a moderate and equivalent association between ToM and all targeted neurocognitive domains may not be generalizable to additional domains. The second limitation is that ToM tasks are rarely standardized and few of the

Please cite this article as: É. Thibaudeau, A.M. Achim, C. Parent, et al., A meta-analysis of the associations between theory of mind and neurocognition in schizophrenia, Schizophrenia Research, https://doi.org/10.1016/j.schres.2019.12.017

É. Thibaudeau et al. / Schizophrenia Research xxx (xxxx) xxx

included studies reported information about the administration. This could have influence the classification regarding the characteristics of the tasks, and in consequence, influence the results of the moderation analyses. This limitation stresses the importance of using standardized ToM tasks. 5. Conclusion As previously reported by Bora et al. (2009), while people with schizophrenia present with ToM deficits, important issues regarding the heterogeneity of ToM tasks and their cognitive demands, as well as the psychometric properties of ToM tasks were not sufficiently considered in previous studies. The current meta-analysis has explored not only the associations between ToM and neurocognition in schizophrenia, but has also taken into account the moderating effect of a large variety of ToM tasks characteristics on these associations. The results reveal a moderate association between ToM and neurocognition with a similar magnitude across a wide range of neurocognitive abilities, abstraction being the only exception as it was more strongly associated with ToM than other executive functions. The results also identified that several ToM tasks characteristics, as well as the ToM task itself, are significantly related to the magnitude of the associations between ToM and neurocognition. Overall, the results suggest that a deficit in any neurocognitive function could be associated with a negative impact on ToM performance, and that the choice of the ToM task is related to these associations. Thus the assessment and treatment of ToM in schizophrenia should consider the neurocognitive profile of each patient to better understand his difficulties and to provide intervention that will support the neurocognitive deficits. Supplementary data to this article can be found online at https://doi. org/10.1016/j.schres.2019.12.017. Funding body agreements and policies This work was supported by a studentship from Fonds de Recherche du Québec - Santé (FRQS) to ET, a salary grant from FRQS to AMA, and a studentship from the Social Sciences and Humanities Research Council of Canada to MT. Contributors ET, AMA and CC were involved in the design of the study, the analyses, the interpretation of the data, the decision to submit the paper and the writing of the manuscript. ET, CP and MT were involved in the search of the articles, the screenings, the extraction and the analysis of the quality of the articles. All authors contributed to and have approved the final manuscript. Declaration of competing interest All authors declare that they have no conflicts of interest. Acknowledgements We thank Alexandra R.-Mercier for her help with the classification of the neurocognition tasks.

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Please cite this article as: É. Thibaudeau, A.M. Achim, C. Parent, et al., A meta-analysis of the associations between theory of mind and neurocognition in schizophrenia, Schizophrenia Research, https://doi.org/10.1016/j.schres.2019.12.017