NeuroImage: Clinical 25 (2020) 102134 Contents lists available at ScienceDirect NeuroImage: Clinical journal homepage: www.elsevier.com/locate/ynicl Brain imaging correlates of self- and other-reflection in schizophrenia T a,b,1 a,b,c,1 a,b Paola Fuentes-Claramonte , Marta Martin-Subero , Pilar Salgado-Pineda , Aniol Santo-Anglesa,b, Isabel Argila-Plazaa, Josep Salavertc,d, Antoni Arévaloe, Clara Bosquef, Carmen Sarrif, Amalia Guerrero-Pedrazaf, Antoni Capdevilag,h, Salvador Sarróa,b, ⁎ Peter J. McKennaa,b, Edith Pomarol-Cloteta,b, , Raymond Salvadora,b a FIDMAG Germanes Hospitalàries Research Foundation, Carrer Dr. Antoni Pujadas, 38, 08830 Sant Boi de Llobregat, Barcelona Spain b CIBERSAM (Centro de Investigación Biomédica en Red de Salud Mental), Spain c Department of Psychiatry and Forensic Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain d Psychiatry Department, Hospital Sant Rafael, Barcelona, Spain e Psychiatry Department, Hospital Sagrat Cor Martorell Barcelona, Spain f Benito Menni Centre Assistencial en Salut Mental, Sant Boi de Llobregat, Barcelona, Spain. g Radiology Unit, Hospital de la Santa Creu i Sant Pau (HSCSP), Barcelona, Spain h CIBER-BBN (Centro de Investigación Biomédica en Red en Bioingeniería, Biomateriales y Nanomedicina), Spain A R T I C LE I N FO A B S T R A C T Keywords: Background: An alteration in self/other differentiation has been proposed as a basis for several symptoms in Psychosis schizophrenia, including delusions of reference and social functioning deficits. Dysfunction of the right temporo- Schizophrenia parietal junction (TPJ), a region linked with social cognition, has been proposed as the basis of this alteration. Self-reflection However, imaging studies of self- and other-processing in schizophrenia have shown, so far, inconsistent results. Other-reflection Methods: Patients with schizophrenia and healthy controls underwent fMRI scanning while performing a task fMRI Temporo-parietal junction with three conditions: self-reflection, other-reflection and semantic processing. Results: Both groups activated similar brain regions for self- and other-reflection compared to semantic pro- cessing, including the medial prefrontal cortex, the precuneus and the TPJ. Compared to healthy subjects, pa- tients hyperactivated the left lateral frontal cortex during self- and other-reflection. In other-reflection, com- pared to self-reflection, patients failed to increase right TPJ activity. Conclusions: Altered activity in the right TPJ supports a disturbance in self/other differentiation in schizo- phrenia, which could be linked with psychotic symptoms and affect social functioning in patients. Hyperactivity of the lateral frontal cortex for self- and other-reflection suggests the presence of greater cognitive demand to perform the task in the patient group. 1. Introduction other processes (Eddy, 2016). As a result, it can also affect social in- teraction in terms of increasing social anhedonia and social withdrawal A disturbance in the process of distinguishing the self from others is (Eddy, 2016; van der Meer et al., 2010; van der Weiden et al., 2015). proposed as a relevant factor contributing to the symptom profile in Social functioning deficits are common in schizophrenia and can result schizophrenia: poor self/other distinction may lead to incorrect attri- in the misinterpretation of others’ intentions and difficulties in daily bution of one's own thoughts or intentions to others, resulting in social interactions (Green et al., 2015). These deficits are closely linked paranoia and ideas of reference, or to a disruption of the sense of to worse functional outcomes (Fett et al., 2011). Therefore, a better agency of behavior leading to delusions of control (Eddy, 2018). Self/ understanding of the alterations in processing self- and other-related other differentiation has been proposed to involve both motor processes information will be an important contribution to the improvement of underpinning imitation and cognitive processes linked to mentalizing therapeutic interventions and patients’ quality of life. and reasoning about the other's beliefs and emotions (Eddy, 2018), and Brain activity related to self-reflection is typically assessed with its failure (self/other blending) might impair perspective taking, among tasks that require the participant to decide whether a particular trait ⁎ Corresponding author at: FIDMAG Germanes Hospitalàries Research Foundation, Carrer Dr. Antoni Pujadas, 38, 08830 Sant Boi de Llobregat, Barcelona Spain. E-mail address: epomarol-clotet@fidmag.com (E. Pomarol-Clotet). 1 These authors contributed equally to this work. https://doi.org/10.1016/j.nicl.2019.102134 Received 6 August 2019; Received in revised form 29 November 2019; Accepted 13 December 2019 Available online 14 December 2019 2213-1582/ © 2019 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/BY-NC-ND/4.0/). P. Fuentes-Claramonte, et al. NeuroImage: Clinical 25 (2020) 102134 adjective or descriptive statement applies to themselves. For other-re- and controls (Holt et al., 2011; Tan et al., 2015; van der Meer et al., flection, the same kind of decision is applied to another personally or 2013; Zhang et al., 2015), or found differences outside the typical self/ publicly known person. Both conditions are associated with activation other-reflection areas (e.g., the precentral gyrus in Pauly et al., 2014). in a network of regions which include the medial prefrontal cortex The studies reviewed above reveal that, although self/other pro- (mPFC), the temporo-parietal junction (TPJ), and the posterior cingu- cessing and differentiation are proposed as a basis for several symptoms late cortex (PCC) (Denny et al., 2012), very similar to the regions as- in schizophrenia, consistent deficits in the neural correlates of these sociated with social cognition, theory of mind, autobiographical cognitive processes are yet to be characterized. This heterogeneity in memory or future planning, which are often referred to as the default- previous studies might be a result of the combination of different fac- mode network (DMN, Buckner et al., 2008). The involvement of DMN tors: first, most of the studies on self/other reflection in schizophrenia regions in such a broad range of cognitive functions has led to the have used tasks where trait adjectives or sentences are presented to the hypothesis that one of the core functions of the network is to process participants, who have to decide whether these traits apply to them- self-relevant or social information (Andrews-Hanna et al., 2014; selves or to another person. However, the control conditions against Molnar-Szakacs and Uddin, 2013). Patients with schizophrenia have which self- and other-reflection are contrasted vary from affect labeling shown altered brain activity in DMN regions during self-reflection, in- (i.e. judging whether the adjective is positive or negative) (Holt et al., cluding the PCC (Holt et al., 2011; van der Meer et al., 2013), the mPFC 2011; Murphy et al., 2010; Tan et al., 2015), semantic knowledge (i.e. (Tan et al., 2015), and the temporal cortex (Pauly et al., 2014). Other- answering Yes or No to sentences about general facts) (van der Meer reflection has been associated with altered activation of the PCC et al., 2013; Zhang et al., 2015) or perceptual tasks (Bedford et al., (van der Meer et al., 2013), the temporal cortex (Murphy et al., 2010), 2012; Pauly et al., 2014). Contrasting self- or other-reflection against and the mPFC and cuneus (Pauly et al., 2014), but also in regions not conditions that might impose different cognitive demands (e.g. se- traditionally linked to other-reflection like the insula (Pauly et al., mantic knowledge is likely to be more demanding than perceptual 2014) and the fusiform and lingual gyri (Tan et al., 2015). These tasks) may result in differences in the self and other activation maps. findings suggest that there is altered DMN function during self- and Secondly, the degree of familiarity with the individual chosen for other- other-reflection in schizophrenia, although the lack of consistency reflection also ranges from close relatives and friends (Holt et al., 2011; among the results makes it difficult to characterize the nature of the Murphy et al., 2010; Pauly et al., 2014; van der Meer et al., 2013) to alteration precisely. public figures (Bedford et al., 2012; Tan et al., 2015), which could also Although self- and other-reflection tend to activate a similar set of affect activation patterns (e.g. reflecting upon close relatives may rely brain regions, studies have also shown differences between the two more in autobiographical memory, while reflecting upon public figures conditions in the mPFC (with ventral mPFC more linked to self-reflec- may involve more semantic memory, and involve different brain re- tion and dorsal mPFC to other-reflection) and the TPJ, among other gions, see Murray et al., 2012). Finally, significant differences in patient areas (Denny et al., 2012). The TPJ (especially in the right hemisphere) status and small sample sizes might also explain the lack of consistency has been proposed as a key brain structure for self/other differentiation, among results. with its disruption generating deficits in self and other representations The present study aims to further examine self- and other-processing in several psychiatric disorders (Eddy, 2016). Literature on the function in schizophrenia, with an emphasis on self/other differentiation (i.e. the of the right TPJ has highlighted its involvement in tasks that require direct comparison between self- and other-reflection). We will use a processing information about others’ intentions and mental states, like self/other-reflection task based on previous studies (Modinos et al., theory of mind or moral judgments tasks (Saxe, 2010), which is con- 2009; van der Meer et al., 2013) that we have already used successfully sistent with such a role. Alteration of TPJ function by means of non- in healthy subjects (Fuentes-Claramonte et al., 2019), where we ob- invasive brain stimulation affects third-person perspective taking served significant differences between self- and other-reflection in DMN (Elk et al., 2016), which has signaled this region also as a potential regions with the specific involvement of the right posterior TPJ (an- target for intervention (Donaldson et al., 2015). It is important to note, gular gyrus) in other, but not self-reflection. Considering the variability though, that the TPJ is a functionally defined region that can be sub- in the tasks used in the previous literature, we have selected this task to divided in different portions (Mars et al., 2012): the most posterior and best isolate the components of interest for our study. We consider that dorsal parts of the TPJ (i.e. angular gyrus) seem to be more linked with the present work will allow us to broaden the knowledge on the neural social information processing and tend to co-activate with other regions basis of self/other differentiation in schizophrenia. Although there is no involved in self-reflection and theory of mind, while anterior parts are consistent pattern of findings in the existing schizophrenia literature, associated with externally cued attention (Scholz et al., 2009). There we expect that alterations will arise in relevant DMN areas involved in also seems to be a hemispheric asymmetry in the TPJ, since social self/other differentiation, namely the mPFC, the PCC and the TPJ. cognition has been especially linked to the right TPJ while the left has been attributed a more general role in meta-representation (for a re- 2. Methods view, see Saxe, 2010). However, this remains an open issue since the left TPJ is sometimes also activated in social processing tasks 2.1. Subjects (Krall et al., 2015). Alterations in self/other differentiation in schizophrenia may be Thirty-two patients with a DSM-IV-TR diagnosis of schizophrenia observed in the comparison between self- and other-reflection. For recruited from three psychiatric hospitals (Benito Menni CASM, Sagrat example, Jardri et al. (2011), using a task where participants heard Cor de Martorell and Hospital Sant Rafael) in Barcelona participated in their own pre-recorded voice alternated with someone else's voice, the study. They all underwent diagnostic evaluation by trained raters found that the ‘self’ and ‘non-self’ cortical maps were more overlapped using the Spanish version of the Structured Clinical Interview for DSM in patients with schizophrenia than controls, affecting the medial Disorders (SCID). Psychotic symptoms were also scored using the frontal cortex and PCC/precuneus, the right middle temporal cortex Positive and Negative Syndrome Scale (PANSS, Kay et al., 1987) and and the right inferior parietal cortex (adjacent to the TPJ). This was the The Clinical Global Impressions Scale (CGI, Guy, 1976). Patients interpreted as impairment for self/other differentiation in the patient were excluded if they (a) were younger than 18 or older than 65 years, group. Bedford et al. (2012) found an alteration in the dorsomedial (b) had a history of brain trauma or neurological disease, and (c) had prefrontal cortex in patients, who showed similar levels of activity in shown alcohol/substance abuse within 12 months prior to participa- this region for self and other-processing, while the controls significantly tion. With respect to the last criterion, all participants were questioned increased its activity for self-reflection compared to other-reflection. about alcohol and drug use during the previous year by a psychiatrist. However, other studies have reported no differences between patients As well as excluding patients who showed evidence of substance abuse/ 2 P. Fuentes-Claramonte, et al. NeuroImage: Clinical 25 (2020) 102134 dependence, we also excluded those who reported habitual use of has very good ideas”, where OTHER was substituted by the chosen cannabis. All patients were right-handed and all were taking anti- person's name. In the Facts condition, sentences referred to general psychotic medication. knowledge, such as “A decade is a period of ten years” or “Insects only The control sample consisted of 33 right-handed healthy individuals have four legs”. As in the original version, half of the sentences in the recruited from non-medical staff working in the hospital, their relatives Self and Other conditions had a positive valence and the rest had a and acquaintances, plus independent sources in the community. They negative quality, while in the Facts condition half of the sentences were were selected to be similar to the patients in age, sex and IQ (premorbid true and the other half were false. Different from the original, the Self IQ in the patients). This last was estimated using the Word Accentuation and Other conditions only included statements referring to personality, Test (Test de acentuación de palabras (TAP) Del Ser et al., 1997; behavior and attitudes, but not physical appearance (these were a Gomar et al., 2011), which requires pronunciation of Spanish words minority in Modinos et al., 2009). All statements were written in whose accents have been removed. This test is conceptually similar to Spanish, and all participants were fluent Spanish speakers. the UK National Adult Reading Test (NART) (Nelson, 1982) and the US The task consisted of 54 trials (18 per condition) arranged in a block Wide Range of Achievement Test used in the USA (Jastak and design. Each block started with an instruction screen indicating the Wilkinson, 1984). Scores can be converted into full scale IQ estimates condition that corresponded to that block (“Sentences about Me”, (Gomar et al., 2011). The control sample met the same exclusion cri- “Sentences about Other”, “Sentences about Facts”), which lasted 3s. teria as the patients. They were also questioned and excluded if they After a 1s delay, three trials were presented, each lasting 9s, where the reported a history of mental illness and/or treatment with psychotropic sentence appeared in the center of the screen and the options “Yes” and medication and the SCID was also used to exclude current psychiatric “No” appeared at the bottom-right and bottom-left corners, respec- disorders. tively, to act as a reminder of the required response (“Yes” with the All participants gave written informed consent prior to participa- right index finger, and “No” with the left index finger). Trials were tion. All the study procedures had been previously approved by the separated by a 1s blank screen. After the three trials, the next block Research Ethics Committee FIDMAG Sisters Hospitallers (Comité de started, for a total of 6 blocks per condition. Every 3 blocks there was a Ética de la Investigación de FIDMAG Hermanas Hospitalarias) and resting period of 16s in which only a crosshair was presented as fixation complied with its ethical standards on human experimentation and point. Block order was pseudorandomized, with each of the three with the Helsinki Declaration of 1975, as revised in 2008. Healthy conditions occurring once between resting periods. Total task duration controls received a gift-card as a compensation for their participation in was 12 min and 12 s. This design deviates from the task design used by the study. Modinos et al. (2009) in that the trials were longer, resulting in fewer trials overall, but with a similar amount of time spent in each condition. 2.2. Self-other task This change was made to ensure participants had time to read and re- flect on each statement before responding. As demonstrated in Fuentes- The task used in the present study was adapted from the one de- Claramonte et al. (2019), this version of the task is able to elicit acti- scribed in Modinos et al. (2009) and has already been used in healthy vation of relevant DMN brain regions in self and other-reflection. subjects by our group (Fuentes-Claramonte et al., 2019) to investigate the processing of information related to the self and another known 2.3. Image acquisition person, compared to general semantic knowledge. To best isolate the components of interest for our study, this task uses (1) a semantic Images were acquired with a 3T Philips Achieva scanner (Philips control condition (matched in perceptual and motor requirements and Medical Systems, Best, the Netherlands). Functional data were acquired in statement complexity with the conditions of interest) to separate self- using a T2*-weighted echo-planar imaging (EPI) sequence with 364 and other-reflection from processing of externally-oriented information, volumes and the following acquisition parameters: TR = 2000 ms, and (2) an ‘other’ condition aimed to compare reflection upon oneself to TE = 30 ms, Flip angle = 78O, in-plane resolution= 3 × 3 mm, reflection on other individuals within the participant's environment, for FOV = 240 mm, slice thickness = 3 mm, inter-slice gap = 1mm. Slices which we selected an ‘other’ personally known by the participant (so (32 per volume) were acquired with an interleaved order parallel to the responses might be based on previous interactions and not so much on AC-PC plane. Before the functional sequence, a high-resolution anato- semantic knowledge, and so exposure to this ‘other’ might be more mical 3D volume was acquired using a TFE (Turbo Field Echo) sequence uniform across participants than with public figures), but not a very for anatomical reference and inspection (TR = 8.15ms; TE = 3.73ms; close ‘other’ to avoid strong emotional investment. Flip angle = 8O; voxel size = 0.9375 × 0.9375 mm; slice thick- Before scanning, participants were given detailed task instructions ness = 1mm; slice number = 160; FOV = 240 mm). and were asked to choose an acquaintance to think about inside the scanner for the other-reflection condition. The chosen individual had to 2.4. Image preprocessing and analysis be familiar to the participant, but not too close in order to avoid eli- citing strong feelings towards them (valid examples were classmates or Preprocessing and analysis was carried out with the FEAT module co-workers), similar to the original implementation of the task included in the FSL (FMRIB Software Library) software, version 5.0 (Modinos et al., 2009). The final choice of acquaintance was made in (Smith et al., 2004). The first 20 s (10 volumes) of the sequence, cor- consultation with one of the researchers to ensure the degree of clo- responding to signal stabilization, were discarded. Preprocessing in- seness was similar for all participants. cluded motion correction (using the MCFLIRT algorithm) and co-re- During the task, participants viewed a series of statements which gistration and normalization to a common stereotactic space (Montreal were either about themselves (Self), about an acquaintance (Other) or Neurological Institute template). Before group analyses, normalized about general knowledge (Facts), which were similar in length and images were spatially filtered with a Gaussian filter (FWHM = 5 mm). complexity in the three conditions. Participants had to respond whether To minimize unwanted movement-related effects, individuals with an they considered the sentence to be true or false with a button press. In estimated maximum absolute movement >3.0 mm or an average ab- the Self condition, sentences referring to personal qualities, attributes solute movement >0.3 mm were excluded from the study. or attitudes were presented (e.g. “In general, I like order”, “I am a tense Statistical analysis was performed by means of a General Linear or very nervous person”). Similarly, in the Other condition sentences Model (GLM) approach. At the first level, three regressors of interest referred to the personality traits and behavior of the chosen acquain- were defined in the GLM corresponding to the three task conditions tance. Examples of sentences included in the Other condition are (Self, Other, Facts) in a block-design fashion. Instruction screens were “OTHER often makes decisions without thinking” or “OTHER usually modeled by an additional nuisance regressor. Fixation periods were not 3 P. Fuentes-Claramonte, et al. NeuroImage: Clinical 25 (2020) 102134 Table 1 Demographic and clinical sample characteristics. Patients Controls Significance (N = 23) (N = 27) Sex (M/F) 16/7 17/10 p = 0.623 Age 37.00 (8.06) 38.74 p = 0.512 (10.20) range 22-55 range 23-61 Estimated pre-morbid IQ (TAP) 100.64 104.07 p = 0.178 (10.23) (6.34) range 81-114 range 91-114 PANSS Total score 69 (18.19) range 39-115 PANSS Positive 16.04 (5.49) range 8-28 PANSS Negative 19.74 (5.79) range 11-33 PANSS General 33.22 (9.08) range 18-59 CGI 4.17 (0.89) range 3-6 Treatment (chlorpromazine 498.77 equivalent, daily dose in mg) (490.27) range 62.5- 2400 Measures are means (SD). Group differences were tested with a Chi-square test for sex and unpaired two sample t-tests for age and pre-morbid IQ. modeled and thus acted as an implicit baseline. GLMs were fitted to generate activation maps for each of the three conditions of interest compared to baseline and for the comparisons between conditions (Self Fig. 1. Mean activation in Self > Facts control group (A) and in the patient vs. Facts, Other vs. Facts, Other vs. Self). Second level analyses and group (B). Images are displayed in neurological convention (right is right). group comparisons between patients and controls were performed Color bar depicts z values. within the FEAT module, with mixed-effects GLMs (Beckmann et al., 2003). All statistical tests were carried out at the cluster level with a corrected p value of 0.05 using Gaussian random field methods. The default threshold of z = 2.3 was used to define the initial set of clusters. 3. Results Demographic and clinical characteristics of the final samples in- cluded in the analyses are detailed in Table 1. As can be seen, the pa- tients and the controls did not differ significantly in terms of age, sex and estimated premorbid IQ. Nine patients and 6 controls were ex- cluded from the analyses due to excessive head movement. All patients were on antipsychotic treatment (21 on atypical neuroleptics and 2 on both typical and atypical) and were admitted to inpatient (14 patients) or outpatient (9 patients) units. 3.1. Self vs. facts mean group results Brain activity associated to self-reflection was identified by the Self > Facts contrast, where both patients and controls showed similar re- gions of activation in the medial prefrontal cortex, the PCC and pre- cuneus, the left angular gyrus and TPJ area, the middle temporal cortex (bilateral), and parts of the visual cortex (calcarine cortex and lingual gyrus, see Fig. 1 and Supplementary Table S1 for details). Fig. 2. Group differences between healthy subjects and schizophrenic patients in the Self vs. Facts contrast. Plot shows the mean parameter estimates (average of all beta weights in the cluster) for the left DLFPC in the Self and Facts 3.2. Self vs. facts group comparison conditions (respective to baseline) for each group in the cluster of group dif- ferences. Error bars represent standard error of the mean. Images are displayed Group comparison in the Self vs. Facts contrast showed a cluster of in neurological convention (right is right). Color bar depicts z values. differences in the left DLFPC/middle frontal gyrus (MNI coordinates x = -52, y = 14, z = 36; Z = 3.94; cluster size = 527 voxels; 3.3. Other vs. facts mean group results p = 0.008). As seen in Fig. 2, the patients hyperactivated this region in self-reflection. Moreover, controls increased activity in the DLPFC in Other-reflection (Other > Facts contrast) yielded a very similar Facts with respect to Self, but this increase was not observed in the pattern of activation to that of Self-reflection, involving mostly the patients, who displayed similar (heightened) levels of activation in both same regions plus the right angular gyrus in the control group. In conditions. 4 P. Fuentes-Claramonte, et al. NeuroImage: Clinical 25 (2020) 102134 3.6. Self vs. other group comparison This group comparison showed a cluster of differences in the right angular gyrus (MNI coordinates x = 48, y = -64, z = 30; Z = 4.54; cluster size = 547 voxels; p = 0.007), which was activated for other- reflection in the control group, but not in the patients (Fig. 5). 4. Discussion This study aimed to examine the brain correlates of self/other dif- ferentiation in schizophrenia by comparing brain activation during self- and other-reflection. We report, for the first time, a significant altera- tion in right TPJ activity in patients with schizophrenia in other-re- flection. In healthy controls, self- and other-reflection activated a si- milar set of brain regions when compared with a semantic control condition, although direct comparison of self and other revealed that some of them were relatively more active in other-reflection. However, the right TPJ was not activated for self, but only for other-reflection, which is consistent with the role attributed to this area in self/other differentiation and social cognition (Eddy, 2016; Sowden and Shah, 2014). In contrast, patients with schizophrenia did not activate right TPJ for either self- or other-reflection. TPJ hypoactivation in schizophrenia has been previously described with social cognition tasks (Benedetti et al., 2009; de Achával et al., 2012; Makowski et al., 2016; Thakkar et al., 2014; but see also Kronbichler et al. (2017), which shows meta-analytic evidence of both aberrant hypo and hyperactiva- Fig. 3. Mean activation in Other > Facts in the control group (A) and in the tion of the TPJ in mentalizing tasks). The present finding supports the patient group (B). Images are displayed in neurological convention (right is hypothesis that TPJ dysfunction may underlie a disturbance in self/ right). Color bar depicts z values. other differentiation processes in schizophrenia (Eddy, 2016). Self/other differentiation is believed to initially involve motor me- patients, other-reflection also activated the left insula and putamen (see chanisms underpinning imitation and recognition of action goals, as Fig. 3 and Supplementary Table S2 for details). well as interpretation of facial emotions and non-verbal communica- tion; followed by mentalizing processes that include inferring the mental state of the other or reasoning about their beliefs and emotions 3.4. Other vs. facts group comparison (Eddy, 2018). Successfully decoupling the self and other may aid higher level perspective taking. In contrast, when these processes are impaired, This group comparison showed three clusters of differences between self/other blending can occur and the person may have reduced ability patients and controls: one in the precuneus (MNI coordinates x = 22, in perspective taking, or may not be able to suppress imitation and this y = -46, z = 18; Z = 3.94; cluster size = 502 voxels; p = 0.02), one in could lead to confusion, personal distress and depersonalization the left DLPFC (MNI coordinates x = -42, y = 50, z = 14; Z = 4.06; (Eddy, 2016). The right TPJ is associated with decoupling mechanisms, cluster size = 594 voxels; p = 0.008), and one in the left precentral referring to the ability to dissociate an agent's mental state from one's gyrus (MNI coordinates x = -54, y = 8, z = 34; Z = 4.21; cluster own beliefs and to differentiate between belief and reality (van Veluw size = 552 voxels; p = 0.01). We observed that patients deactivated the and Chance, 2014). This could conceivably provide a basis for patients precuneus during the Other condition while controls did not (although with schizophrenia being impaired in identifying the origin of beliefs, both groups deactivated this region in the Facts condition, as shown in intentions, or actions, and so having difficulties testing them against Fig. 4). In the DLPFC and precentral gyrus, we observed increased ac- reality, resulting not only in difficulties in social interaction but also in tivation in the patient group in Other-processing (while activation in delusional explanations of others’ behavior (e.g. ideas/delusions of re- the Facts condition was similar in both groups). Interestingly, these last ference or persecution, grandiosity). two clusters were located very close to the area of differences found in It should be noted that the TPJ is not a unitary region, and at least the Self vs. Facts contrast and displayed a similar pattern of alteration in two subdivisions have been found using resting-state functional con- the patient group. nectivity: a more anterior part that shows connectivity with attentional regions (ventral PFC and anterior insula) and a more posterior sub- division connected with DMN regions (mPFC, PCC/precuneus) 3.5. Self vs. other mean group results (Mars et al., 2012). In the present study, group differences were found in the angular gyrus, which belongs to the posterior subdivision of the No region showed increased activity in Self trials when compared to TPJ, and is usually described as belonging to the DMN (Buckner et al., the Other condition (Self> Other contrast), neither in the patients nor 2008). Interestingly, though, there was a laterality effect: the left an- in the controls. On the other hand, several brain areas were more active gular gyrus was activated both by self- and other-reflection (although in the Other than in the Self condition: healthy subjects showed acti- BOLD signal was higher in the second), but the right was only active vation in the precuneus and PCC, mPFC extending into the right during other-reflection. This adds specificity to our results, since the hemisphere, angular gyrus, temporal pole and amygdalae, and right right TPJ has been more strongly linked to self/other differentiation superior frontal cortex (Supplementary Table S3, Fig. 5). Patients with and social cognition in the previous literature than the left schizophrenia, however, only showed activation in the PCC and the left (Eddy, 2016). Consistently, there were no group differences in the left temporal pole (Supplementary Table S3, Fig. 5). TPJ. The findings concerning the TPJ are also relevant because this re- gion has been proposed as a target for therapeutic intervention. Several 5 P. Fuentes-Claramonte, et al. NeuroImage: Clinical 25 (2020) 102134 Fig. 4. Group differences between healthy subjects and schizophrenic patients in the Other vs. Facts contrast. Plots show the mean parameter estimates (beta weights) for the precuneus (upper row), the DLPFC (middle row) and the precentral gyrus (lower row) in the Other and Facts conditions (respect to baseline) for each group. Error bars represent standard error of the mean. Images are displayed in neurological convention (right is right). Color bars depict z values. drugs may affect its function, for instance, drugs that alter nor- Deactivation of the precuneus is characteristic of tasks that place cog- epinephrine (Strange and Dolan, 2007), selective serotonin reuptake nitive demands on the subject, such as classical attention or working inhibitors (Cremers et al., 2016) and intranasal oxytocin (Hu et al., memory tasks (Cavanna and Trimble, 2006), even in schizophrenic 2016). In addition, the TPJ is a promising target for neuromodulation patients (Pomarol-Clotet et al., 2008). In the patients in our study, self- techniques such as repetitive transcranial magnetic stimulation (rTMS) and other-reflection seem to have imposed greater cognitive demands and transcranial direct current stimulation (tDCS) (Donaldson et al., than in controls, leading to hyperactivity of the lateral prefrontal cortex 2015). and deactivation of the precuneus in conditions that should not require In the present study, we also observed hyperactivation of the left these changes (more akin to cognitive, attention-demanding tasks). An lateral frontal cortex (including the DLPFC and the precentral gyrus) alternative, or perhaps complementary interpretation of this finding, during self- and other-reflection. Detailed examination of the activation would be that healthy participants treat self- and other-related in- pattern in this area revealed that hyperactivation was specific to self/ formation differently from semantic knowledge, as evidenced by the other processing, while activation levels were similar between groups in obvious differences in patterns of brain activity between these condi- the semantic condition. Given the attentional role that the lateral tions. In schizophrenia, however, the ability to distinguish between frontal cortex has been assigned (Badre, 2008), and its involvement in these two kinds of information may be disturbed, leading to difficulties semantic memory (Raposo et al., 2012), activation of this region would in the management of social information. arguably be expected during semantic processing (i.e. Facts condition), This activation pattern is also interesting because DMN regions in- but not in self- and other-reflection. Moreover, we observed that the volved in self/other-reflection tend to decrease their activation when patients deactivated a cluster in the precuneus for both semantic and attention is externally focused, which in turn involves an increase in other processing, while controls only did so for semantic processing. activity of attentional or executive networks, where the lateral 6 P. Fuentes-Claramonte, et al. NeuroImage: Clinical 25 (2020) 102134 Fig. 5. Mean activation in Other > Self in the control group (A) and in the patient group (B). (C) Group differences between healthy subjects and schizophrenic patients in the Other vs. Self contrast. Plot shows the mean parameter estimates (beta weights) for the cluster in the right angular gyrus in the Self and Other conditions (respect to baseline) for each group. Patients fail to activate the right angular gyrus in the Other condition. Error bars represent standard error of the mean. Images are displayed in neurological convention (right is right). Color bars depict z values. prefrontal cortex is a relevant node (Fox et al., 2005). Thus, adequate required to be a close friend or family member. Other studies have used balance between these intrinsic networks seems necessary for adaptive a public ‘other’; however, this may impose significant variation in the cognitive functioning, and a failure in its regulation might be linked to amount of exposure to such individuals. Although we tried to control psychiatric symptoms. Alterations in the DMN are well-established in the level of closeness between the participant and the ‘other’, it is im- schizophrenia (Dreher et al., 2012; Haatveit et al., 2016; Pomarol- portant to keep in mind that there is some degree of variability that Clotet et al., 2008; Salgado-Pineda et al., 2011; Schneider et al., 2011). could not be controlled. It might also be important to bear in mind that Some authors have proposed that there is a stable difference in the relationships and attachments might be different in schizophrenia pa- DMN structure and its connections with the salience network and the tients than in controls. It is also of course possible that discrepancies central executive network (Menon, 2011; Woodward et al., 2011). between studies could be explained in terms of prevalence of positive Given that healthy subjects showed activation differences between task and negative symptoms in the schizophrenia samples, stage of the conditions in the lateral prefrontal cortex, the precuneus and the right disorder, or medication use. angular gyrus, and these changes were not found in patients, our results could also be linked to a failure in network balance between the DMN and the executive network in schizophrenia. These results may suggest 4.1. Conclusions that the process of functional specialization of the DMN may be altered in schizophrenia. The present study is the first to reveal diminished activation of the The present results add evidence to the range of alterations in self/ right TPJ, a brain region with a relevant proposed role for self/other other-reflection reported in schizophrenia. However, our findings con- differentiation and social cognition, in patients with schizophrenia verge only partially with previous results. In the Other vs. Facts con- during other-reflection. Additionally, it found evidence that schizo- trast, we found altered activation of a region close to the PCC as also phrenic patients rely more on cognitive control areas (i.e. left lateral found by Tan et al. (2015) and van der Meer et al. (2013), but other prefrontal cortex) for self- and other-reflection, suggesting that this type findings have not been replicated. Our task was based on the design of cognitive process might place greater cognitive demands in patients used by van der Meer et al. (2013); however, we did not include sen- with this disorder. Taken together, the results support a failure in self- tences about physical attributes in the Self or the Other conditions. A and other-related information processing in schizophrenia and provide second reason for differences might be the degree of familiarity with the evidence for disturbances in self/other differentiation, which might individual chosen as ‘other’ in the Other condition (Murray et al., lead to altered judgments of others’ behavior and personality. An al- 2012). In our study, participants were instructed to choose a known teration in the right TPJ activity is a potential neural mechanism for person but not someone with a close relationship with them, so that the this disturbance. This latter finding may be relevant for future studies, ‘other’ was personally known and had a history of past interactions with particularly those aiming to examine psychosocial treatments and the participant, but not as close as in other studies where the ‘other’ was neuromodulation techniques in schizophrenia. 7 P. Fuentes-Claramonte, et al. NeuroImage: Clinical 25 (2020) 102134 Financial support schizophrenia. Schizophr. Res. 134, 171–179. https://doi.org/10.1016/j.schres. 2011.11.010. Del Ser, T., Gonzalez-Montalvo, J., Martinez-Espinosa, S., Delgado-Villapalos, C., This work was supported by Generalitat de Catalunya (2017 SGR Bermejo, F., 1997. Estimation of premorbid intelligence in spanish people with the 01271 to EP-C and 2017 SGR 1265 to PF-C from AGAUR). Also by word accentuation test and its application to the diagnosis of dementia. Brain Cogn grants from Ministerio de Ciencia, Innovación y Universidades: Juan de 33, 343–356. https://doi.org/10.1086/518948. Denny, B.T., Kober, H., Wager, T.D., Ochsner, K.N., 2012. A meta-analysis of functional la Cierva-formación contract (FJCI-2015-25278 to PF-C) and from neuroimaging studies of self and other judgments reveals a spatial gradient for Ministerio de Economía y Competitividad (FFI2016-77647-C2-2-P mentalizing in medial prefrontal cortex. J. Cogn. Neurosci. 24, 1742–1752. https:// to PS-P). And by the Instituto de Salud Carlos III, co-funded by doi.org/10.1162/jocn. Donaldson, P.H., Rinehart, N.J., Enticott, P.G., 2015. Noninvasive stimulation of the European Regional Development Fund/European Social Fund temporoparietal junction: a systematic review. Neurosci. Biobehav. Rev. 55, “Investing in your future”: Miguel Servet Research contract (CPII16/ 547–572. https://doi.org/10.1016/j.neubiorev.2015.05.017. 00018 to EP-C), Rio Hortega contract (CM15/00024 to MM-S), and Dreher, J.C., Koch, P., Kohn, P., Apud, J., Weinberger, D.R., Berman, K.F., 2012. Common and differential pathophysiological features accompany comparable cognitive im- Research Project Grants (PI14/01151 to RS, PI14/01148 to EP-C, PI18/ pairments in medication-free patients with schizophrenia and in healthy aging sub- 00810 to EP-C, PI18/00877 to RS and PI18/00880 to PM). jects. Biol. Psychiatry 71, 890–897. https://doi.org/10.1016/j.biopsych.2012.01. 002. CRediT authorship contribution statement Eddy, C.M., 2018. Social cognition and self-other distinctions in neuropsychiatry: insights from schizophrenia and Tourette syndrome. Prog. Neuro-Psychopharmacol. Biol. Psychiatry 82, 69–85. https://doi.org/10.1016/j.pnpbp.2017.11.026. Paola Fuentes-Claramonte: Investigation, Data curation, Formal Eddy, C.M., 2016. The junction between self and other? Temporo-parietal dysfunction in analysis, Writing - original draft, Writing - review & editing, neuropsychiatry. Neuropsychologia 89, 465–477. https://doi.org/10.1016/j. neuropsychologia.2016.07.030. Visualization. Marta Martin-Subero: Investigation, Data curation, Elk, M.Van, Duizer, M., Sligte, I., Schie, H.Van, 2016. Transcranial direct current sti- Formal analysis, Writing - original draft, Writing - review & editing, mulation of the right temporoparietal junction impairs third-person perspective Visualization. Pilar Salgado-Pineda: Conceptualization, Methodology, taking. Cogn. Affect. Behav. Neurosci. 9–23. https://doi.org/10.3758/s13415-016- 0462-z. Investigation, Data curation. Aniol Santo-Angles: Investigation. Isabel Fett, A.K.J., Viechtbauer, W., Dominguez, M., de, G., Penn, D.L., van Os, J., Krabbendam, Argila-Plaza: Investigation. Josep Salavert: Investigation. Antoni L., 2011. The relationship between neurocognition and social cognition with func- Arévalo: Investigation. Clara Bosque: Investigation. Carmen Sarri: tional outcomes in schizophrenia: a meta-analysis. Neurosci. Biobehav. Rev. 35, 573–588. https://doi.org/10.1016/j.neubiorev.2010.07.001. Investigation. 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