Psychiatry Research ∎ (∎∎∎∎) ∎∎∎–∎∎∎

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Cognitive mapping deficits in schizophrenia: Evidence from clinical correlates of visuospatial transformations Sri Mahavir Agarwal a,b, Vijay Danivas a,b, Anekal C. Amaresha a,b, Venkataram Shivakumar a,b, Sunil V. Kalmady a,b, Anushree Bose a,b, Janardhanan C. Narayanaswamy a,b, Ganesan Venkatasubramanian a,b,n a

The Schizophrenia Clinic, Department of Psychiatry, National Institute of Mental Health & Neurosciences (NIMHANS), Bangalore, India Translational Psychiatry Laboratory, Cognitive Neurobiology Division, Neurobiology Research Centre, National Institute of Mental Health & Neurosciences, Bangalore, India

b

art ic l e i nf o

a b s t r a c t

Article history: Received 15 August 2014 Received in revised form 21 May 2015 Accepted 24 May 2015

The ‘cognitive mapping’ component of spatial cognition, namely – the allocentric/egocentric function and its relation to symptoms in schizophrenia is relatively unexplored. In this study, we compared schizophrenia patients (N ¼44) to demographically-matched healthy controls (N ¼43) using computer-administered visuospatial transformation tasks with egocentric and allocentric components and analyzed their correlation with symptoms. Significant diagnosis X task-type interaction effect was seen on task accuracy. Patients performed significantly worse than controls in the allocentric letter rotation task (LRT) but not in the egocentric people rotation task (PRT). Accuracy in the LRT was significantly lesser than in PRT among patients but not among controls. Patients were significantly slower as compared to controls in both tasks. Both groups took longer to perform PRT as compared to LRT. LRT accuracy showed significant negative correlation with total positive symptoms as well as negative symptoms scores. Angle of rotation, perspective (front-facing/back-facing), orientation (mirrored/normal), and stimulus type (letter/ number) were found to significantly influence performance in both groups of subjects. The present data support the finding that there is a differential impairment of allocentric abilities in schizophrenia patients. Further systematic research in this area may facilitate better understanding of schizophrenia pathogenesis. & 2015 Elsevier Ireland Ltd. All rights reserved.

Keywords: Schizophrenia Allocentric Egocentric Perspective taking Mental rotation Cognitive mapping

1. Introduction Schizophrenia is a complex neuropsychiatric disorder characterized by delusions, hallucinations, disorganized behavior and progressive cognitive deficits (Keshavan et al., 2008; van Os and Kapur, 2009). Among several domains of cognitive functions that have been examined in this disorder, spatial cognition is an area of active inquiry (Bose et al., 2014); interestingly, visuospatial abilities have been found to have intriguing interactions with several measures that are related to schizophrenia pathogenesis like empathy (Decety and Lamm, 2007), schizotypy (Thakkar and Park, 2010), and theory of mind (Bosia et al., 2012; Iacoboni and Abbreviations: LRT, Letter rotation task; PRT, People rotation task; CPZ, Chlorpromazine; IMAP, Investigation of Mental Rotation, Allocentricity–Egocentricity and Perspective Taking n Correspondence to: Department of Psychiatry, National Institute of Mental Health & Neurosciences (NIMHANS), Bangalore. Fax: þ 91 80 26564830. E-mail address: [email protected] (G. Venkatasubramanian).

Dapretto, 2006). Models of visuospatial abilities posit two perspectives of visual space: allocentric (object- or environmentcentered) reference and egocentric (self-centered or body-centered) reference (O’Keefe and Nadel, 1978). While egocentrism refers to the ability to see the world from one's own perspective, allocentrism refers to the capacity to experience the world from an objective, more impersonal, point of view. Allocentric referencing is promoted by greater familiarity with the environment and distant body displacements while egocentric referencing is important in maintaining a stable moment-to-moment perception (Burgess, 2006). Studies exploring the neural basis of spatial navigation implicate the hippocampus and other medial temporal structures in allocentric representations while parietal and striatal areas are postulated to be important for egocentric processes (Burgess et al., 2001; Etchamendy and Bohbot, 2007). A more recent view suggests a greater overlap between the two systems of representations; involvement of posterior superior parietal cortex/precuneus

http://dx.doi.org/10.1016/j.psychres.2015.05.096 0165-1781/& 2015 Elsevier Ireland Ltd. All rights reserved.

Please cite this article as: Agarwal, S.M., et al., Cognitive mapping deficits in schizophrenia: Evidence from clinical correlates of visuospatial transformations. Psychiatry Research (2015), http://dx.doi.org/10.1016/j.psychres.2015.05.096i

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and its interaction with the hippocampus is understood to be important for allocentric representation (Zhang and Ekstrom, 2013). Contextually, it is important to note that dysfunction in the activity of these brain regions have been associated with the pathogenesis of psychotic symptoms (Frith, 2005; Frith et al., 2000; Torrey, 2007); since these brain regions also have an intricate relationship with visuospatial transformation abilities, the study of perspective-taking offers an attractive avenue to explore for potential pathogenetic underpinnings of schizophrenia (Bose et al., 2014). Indeed, visuospatial abilities in patients with schizophrenia have been examined in previous studies (de Vignemont et al., 2006; Folley et al., 2010; Girard et al., 2010; Halari et al., 2006; Hanlon et al., 2006; Landgraf et al., 2010; Langdon et al., 2001; Siemerkus et al., 2012; Sorkin et al., 2006; Thakkar and Park, 2012; Villatte et al., 2010; Weniger and Irle, 2008). Many of these studies have shown deficits in allocentric referencing in patients with schizophrenia (Folley et al., 2010; Girard et al., 2010; Hanlon et al., 2006; Landgraf et al., 2010; Langdon et al., 2001; Weniger and Irle, 2008); intriguingly, schizophrenia patients were shown to have preserved egocentric referencing (Landgraf et al., 2010; Weniger and Irle, 2008). These observations are in tune with the Allocentric simulation hypothesis which postulates that the pathological referencing in schizophrenia is due to a problem in adopting a “world-centered” – inter-subjective – reference frame (Langdon et al., 2001). Previous studies have applied several types of spatial cognition tasks to evaluate visuospatial abilities [for example the letter and people rotation task (Thakkar and Park, 2010, 2012), the virtual Morris water task (Folley et al., 2010), the bin task (Girard et al., 2010) and the virtual park and the virtual maze task (Weniger and Irle, 2008)]; replicated observation of deficits through a variety of spatial cognition tasks offers compelling support for allocentric referencing deficits in patients with schizophrenia (i.e. seemingly different tasks have led to the same results in many of the above studies). However, the multitude of tests coupled with the small sample size in many of the studies is probably the reason why there is lack of consistency in findings with a few studies reporting no deficit in allocentric referencing abilities in patients (de Vignemont and Singer, 2006; Thakkar and Park, 2012). However, only a limited number of studies have examined for potential clinical correlates of allocentric referencing in schizophrenia; these studies have reported variable findings: significant positive correlation has been reported between allocentric referencing deficits and severity of psychotic symptoms (Folley et al., 2010), negative symptoms (Folley et al., 2010), positive symptoms (Siemerkus et al., 2012) and disorganization symptoms (Weniger and Irle, 2008). In this context, the current study attempted to understand the links between symptom severity in schizophrenia and deficits in visuospatial abilities in a larger group of patients and controls using the people and letter rotation task (Thakkar and Park, 2010, 2012). Based on the previous works (as reviewed above), it was hypothesized that the schizophrenia patients will have a selective deficit in allocentric referencing and this deficit will positively correlate with symptom severity.

carefully ascertained by information obtained from at least one reliable adult relative. Clinical symptoms were assessed using the Scale for Assessment of Positive Symptoms (SAPS) (Andreasen, 1984), a 34-item tool which scores symptom severity under four domains – hallucinations, delusions, bizarre behavior and formal thought disorder on a 6-point Likert-type scale, and the Scale for Assessment of Negative Symptoms (SANS) (Andreasen, 1983), a 25-item tool which scores symptom severity under six domains – affective flattening or blunting, alogia, avolition–apathy, anhedonia–asociality and attention impairment on a 6-point Likert-type scale. These scales were administered with good inter-rater reliability. Healthy controls (N ¼ 43) who volunteered for study, were screened to rule out any psychiatric diagnosis using the MINI Plus as well as a comprehensive mental status examination. None of the controls had family history of psychiatric disorder in any of their first-degree relatives. The control group did not differ significantly from the patient group with regard to age, sex distribution and years of education (Table 1). There were no demographic differences between male and female subjects. Patients and controls did not have features suggestive of alcohol abuse/dependence. None used stimulant or opiate drug. None had history or clinical feature suggestive of neurological/medical disorder. None had abnormal movements as assessed by Abnormal Involuntary Movements Scale (Smith et al., 1979). All study subjects were right-handed (left-handedness or ambidexterity was an exclusion criteria) (Oldfield, 1971). After complete description of study to the subjects, written informed consent was obtained. The Institute’s ethics committee approved the study. 2.2. Spatial cognition task The computerized version of the spatial cognition task was designed as per previous description (Thakkar and Park, 2010). The task focused on the ability of the subjects to take perspective from an egocentric or allocentric point of view and to rotate mentally the stimulus or their point of view. Hence, it was named the Investigation of Mental Rotation, Allocentricity–Egocentricity & Perspective Taking [IMAP] task. The task had two sub-components: people rotation & letter rotation. A block design using alternating blocks of people rotation task and letter rotation task was used. The paradigm was designed using E-prime (PST Inc., PA, USA). 2.2.1. People rotation task (PRT) The stimuli consisted of photographs of two persons (one man and one woman, with faces blurred to hide their identity) dressed in white, with both their arms held straight a small angle away from their body presented in one of six possible angles ranging from 67.5° to 292.5° clockwise, from the upright position, in 45° steps i.e. 67.5°, 112.5°, 157.5°, 202.5°, 247.5° and 292.5° from the upright position (Fig. 1). Positions at angle of 12.5° and 337.5° were very similar to the upright position and hence, were not included in the task. In each stimulus, the person in the photograph faced either towards (front-facing perspective) or away (back-facing perspective) from the subject with one of the hands encircled red. Hence for each angle, four stimuli were possible per person [front and back-facing photographs with the right hand encircled and those with the left hand encircled]. Hence, for the six angles, 24 stimuli were generated per person (six possible angles, either facing towards or away and one of two hands encircled in each stimuli), and 48 stimuli overall for the two persons. Subjects were asked to imagine themselves in the position of the person in the stimulus and indicate whether the circled hand would be their left or right hand by pressing the left arrow key with their right index finger (indicating left hand) or right arrow key with their right middle finger (indicating right hand). Subjects were instructed to respond as quickly and accurately as possible. The stimuli subtended a visual angle of about 12° as described in a previous study (Thakkar and Park, 2010). 2.2.2. Letter rotation task (LRT) Four characters, two letters (R and F) and two numbers (5 and 4), were presented in either mirror or normal orientation at one of six possible angles, along the same lines as PRT. This arrangement gave a total of 12 possible stimuli per Table 1 Comparison of clinical and socio-demographic characteristics (Mean7 SD) of patients and controls. Parameter

Patients (N¼ 44) Controls (N¼ 43)

t/χ2 p

Age (years) Sex (male:female) Years of education Age at onset (years) Antipsychotic dose (mg/d, in chlorpromazine equivalents) SAPS total score SANS total score

30.4 7 7.1 31:13 15.2 7 1.7 24.07 5.7 408.0 7 259.6

28.0 75.2 22:21 14.9 7 2.0 – –

1.8 3.4 0.8 – –

0.074 0.081 0.452 – –

16.6 7 20.5 33.07 29.4

– –

– –

– –

2. Materials and methods 2.1. Subjects Patients attending the clinical services of the National Institute of Mental Health & Neurosciences (India), who fulfilled DSM-IV criteria for schizophrenia (N¼ 44) were examined in this study. The diagnosis of schizophrenia was established using Mini International Neuropsychiatric Interview (MINI) Plus (Sheehan et al., 1998), and was confirmed by another psychiatrist through an independent clinical interview. The information related to illness onset and treatment was

Please cite this article as: Agarwal, S.M., et al., Cognitive mapping deficits in schizophrenia: Evidence from clinical correlates of visuospatial transformations. Psychiatry Research (2015), http://dx.doi.org/10.1016/j.psychres.2015.05.096i

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as between-subjects factor and task type (PRT/LRT) as within-subjects factor to test our main hypothesis. Additionally, separate multivariate, multiway repeated measures ANOVAs were conducted on RT and accuracy in PRT and LRT, with diagnosis and sex entered as a between-subject factors. For PRT, perspective (front-facing or back-facing) and angle of rotation were entered as within-subject factors. For LRT, letter orientation (normal or mirrored), and angle of rotation were entered as within-subject factors. Greenhouse–Geisser correction was applied and corresponding values reported whenever sphericity assumptions were violated. Correlational analyses were performed to examine for potential relationship between the following variables: symptom severity (SAPS and SANS total scores), normalized antipsychotic dose in chlorpromazine (CPZ) equivalents and performance parameters for each task (like accuracy, mean RT, slope of change in accuracy/RT [with angle of rotation]) (Thakkar and Park, 2010). The slope of change in performance measures with angle of rotation is understood to isolate the mental rotation process from other processes involved in the task (Thakkar and Park, 2010). Correlations were also examined between performance parameters and symptom severity separately for the two perspectives (front-facing and back-facing) in PRT, the two orientations (mirrored and normal) in LRT and difference in accuracy and RT between perspectives/orientations for each of the tasks. Difference in performance parameters between perspectives and orientations indexes the relative increase in cognitive resources needed to perform an imagined perspective or orientation change (Thakkar et al., 2009; Thakkar and Park, 2010) and lets one explore if they are associated with and selectively affected by schizophrenia psychopathology. Correlations with psychopathology scores were performed using nonparametric tests (Spearman's s) since Shapiro–Wilk test revealed that their distribution was not normal.

3. Results 3.1. Differential task performance Multivariate repeated measures two way ANOVA for accuracy and RT revealed a significant diagnosis-by-task type interaction [F (2,84) ¼3.8, p ¼0.021, partial η2 ¼0.09] and main effects of diagnosis [F(2,84) ¼8.2, p o0.001, partial η2 ¼ 0.16] and task type [F (2,84) ¼29.6, p o0.001, partial η2 ¼0.44] Fig. 1. Illustration of Stimulus characteristics for mental rotation tasks (people & letter). character (six possible angles and one of two orientations in each stimuli), and 48 stimuli overall (Fig. 1). Subjects were asked to indicate whether the letter was presented in normal or mirror orientation by pressing the left arrow key with their right index finger (indicating normal/not mirrored) or right arrow key with their right middle finger (indicating mirrored). The stimuli subtended a visual angle of about 6° as described in a previous study (Thakkar and Park, 2010). Each session consisted of 12 alternating blocks of PRT and LRT, six blocks of each task. Each block consisted of 8 stimuli of a particular task in random order. All 96 possible stimuli across the two tasks were presented exactly once during the experiment. The stimulus stayed on screen for as long as the subject took to respond or a time period of 10 s elapsed. 2.2.3. Task administration We administered the test in a quiet environment with subjects being seated at 60 cm from the computer screen. The subjects were given a practice session of 16 trials to ensure familiarity with the task as well as to ascertain that they have understood the instructions correctly. Also, it was confirmed that all subjects were familiar with the English letters as well as numbers. The order of the task presentation was counterbalanced across subjects with half the subjects starting with the people rotation task and the other half with the letter rotation task. 2.3. Data analysis The demographic and clinical characteristics of this sample were examined using descriptive statistics. After ascertaining the normality of data distribution, statistical analyses were done using repeated measures analysis of variance (RMANOVA) and Spearman's correlation [SPSS-13.0 Chicago, IL, USA]. Trials in which the subject did not respond within the 10 s time-out period were excluded from further analysis. The number of such trials was low (about 1.5% of the trials) (mean number of trials rejected HC: 0.017 0.01, SZ: 0.03 7 0.4). Significantly more trials were excluded among patients compared to controls [t(85) ¼ 3.05, p ¼0.004]. From these trials, only correct trials were considered for calculating RT as per previous studies (Thakkar and Park, 2010, 2012). Multivariate RMANOVA on task accuracy and RT was conducted with diagnosis

3.1.1. Accuracy analyses Significant diagnosis-by-task type interaction effect was found on task accuracy [F(1,85) ¼ 5.7, p ¼0.02, partial η2 ¼0.06] along with the individual main effects [diagnosis: F(1,85) ¼8.3, p ¼0.005, partial η2 ¼0.09; task type: F(1,85) ¼10.3, p ¼0.002, partial η2 ¼ 0.11]. Patients performed significantly worse than controls in LRT (p o0.001) but not in PRT. Further, accuracy in the LRT was significantly lesser than in PRT in the patient group (p o0.001) but not in the control group (Fig. 2A and Table 2). 3.1.2. Reaction time analyses Significant main effects of diagnosis [F(1,85) ¼ 12.9, p ¼0.001, partial η2 ¼0.13] and task type [F(1,85) ¼34.5, po 0.001, partial η2 ¼ 0.29] were seen in the absence of any significant interaction. Patients were significantly slower compared to controls in both tasks (PRT: p ¼0.003; LRT: p ¼0.001). Further, both groups took longer to perform PRT compared to LRT (HC: p o0.001; SCZ: po 0.001) (Fig. 2B and Table 3). 3.2. PRT Multivariate multiway ANOVA for accuracy and RT revealed significant angle-by-perspective [F(10,62) ¼5.7, p o0.001, partial η2 ¼ 0.48], and diagnosis-by-sex interactions [F(2,70)¼ 6.3, p¼ 0.003, partial η2 ¼0.15] and significant main effects of angle [F (10,62) ¼6.0, p ¼ o0.001, partial η2 ¼0.49] and diagnosis [F (2,70) ¼7.5, p ¼ 0.001, partial η2 ¼ 0.18]. 3.2.1. PRT: accuracy analyses Significant angle-by-perspective interaction effect [F(3,231) ¼ 7.4, po 0.001, partial η2 ¼ 0.09] was found along with the main effect of angle [F(4,298) ¼6.2, p o0.001, partial η2 ¼ 0.08]. Accuracy

Please cite this article as: Agarwal, S.M., et al., Cognitive mapping deficits in schizophrenia: Evidence from clinical correlates of visuospatial transformations. Psychiatry Research (2015), http://dx.doi.org/10.1016/j.psychres.2015.05.096i

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decreased with increasing angle of rotation from the upright. This effect was more prominent when the stimuli were back-facing (accuracy decreased from 95.7% at 67.5° to 84.5% at 247.5°, all p o0.05; mean and SE in Supplementary Table 1) compared to when they were front facing (Fig. 3A). No main effect of perspective was seen. 3.2.2. PRT: reaction time analyses Significant angle-by-perspective interaction was found [F (3,231) ¼18.3, p o0.001, partial η2 ¼0.21] along with the main effect of angle [F(4,298) ¼17.0, po 0.001, partial η2 ¼ 0.19]. RT increased with increasing angle of rotation from the upright. This effect was only seen when the stimuli were back-facing (RT increased from 2254.6 ms at 67.5° to 3617.7 ms at 202.5°, all p o0.05; mean and SE in Supplementary Table 1). No effect of angle was apparent when stimuli were front facing (Fig. 3B). No main effect of perspective was seen. A significant diagnosis-by-sex interaction effect [F(1,71) ¼ 11.7, p ¼0.001, partial η2 ¼0.142] and main effect of diagnosis [F(1,71) ¼ 15.1, p o0.001, partial η2 ¼0.18] was also noted on RT in the PRT. Female patients performed PRT significantly slower than female HC (po 0.001) and also in comparison to male patients (p ¼0.020). Male patients did not differ significantly from male HC with respect to RT in PRT (Supplementary Fig. 1; mean and SE in Supplementary Table 2 ). No main effect of sex was seen. 3.3. LRT Multivariate multiway ANOVA for accuracy and RT revealed significant angle-by-orientation-by-diagnosis [F(10,64)¼ 2.2, p ¼0.032, partial η2 ¼0.25], and angle-by-orientation [F(10,64) ¼ 4.8, po 0.001, partial η2 ¼0.43], and main effects of angle [F (10,64) ¼9.3, p o0.001, partial η2 ¼0.59], orientation [F(2,72) ¼ 5.5, p ¼0.006, partial η2 ¼0.13] and diagnosis [F(2,72) ¼6.8, p¼ 0.002, partial η2 ¼ 0.16]. No effect of sex was noted on either performance measure (Supplementary Fig. 2). 3.3.1. LRT: accuracy analyses Significant angle-by-orientation-by-diagnosis interaction effect [F(4,279) ¼2.9, p ¼0.026, partial η2 ¼0.04] along with significant angle-by-orientation interaction [F(4,279) ¼4.2, p ¼0.003, partial η2 ¼ 0.05] and main effects of angle [F(4,285) ¼15.5, p o0.001, partial η2 ¼0.18] and diagnosis [F(1,73) ¼8.6, p ¼0.004, partial

Table 2 Comparison of percentage task accuracy (Mean7 SD) between the two groups and task types. Diagnosis Task type

Patients (N ¼44)

Controls (N¼ 43)

t

p

People rotation task Letter rotation task t p

88.4 7 11.4 80.4 7 11.8 4.0 o 0.001

90.3 7 10.1 89.1 710.2 0.6 0.6

0.8 3.6

0.4 o 0.001

Table 3 Comparison of reaction time (ms) (Mean 7 SD) between the two groups. and task types. Diagnosis Task type

Patients (N¼ 44)

Controls (N¼ 43)

t

p

People rotation task Letter rotation task t p

2935.87 1250.3 2320.6 7 917.2 4.6 o 0.001

2291.2 7647.1 1801.9 7 582.9 3.6 o 0.001

3.0 3.1

0.003 0.002

η2 ¼0.11] was found on task accuracy (Fig. 4A). Among healthy controls, accuracy decreased with increasing angle of rotation from the upright for letters and numbers with normal orientation while angle of rotation had no effect on accuracy when the letters and numbers were mirrored. Among patients, on the other hand, the effect of angle of rotation was present in both orientations, although it was more clearly apparent for normally oriented characters. Furthermore, at most angles of rotation, their accuracy was higher for mirrored letters and numbers (mean and SE in Supplementary Table 3). 3.3.2. LRT: reaction time analyses Significant angle-by-orientation-by-diagnosis [F(5,329) ¼3.3, p¼ 0.009, partial η2 ¼0.04] and angle-by-orientation interaction effect was found on RT [F(5,329) ¼10.3, p o0.001, partial η2 ¼0.12] along with the corresponding main effects Angle: F(4,318) ¼14.4, po 0.001, partial η2 ¼0.16; Orientation F(1,73) ¼11.1, p o0.001, partial η2 ¼0.13; Diagnosis [F(1,73) ¼ 9.0, p ¼0.004, partial η2 ¼0.11] (Fig. 4B). Overall, in both groups, RT increased with increasing angle of rotation from the upright for letters and numbers with normal orientation while angle of rotation had lesser effect

Fig. 2. Mean task accuracy percentage (A) and mean reaction time (B) in the two tasks for schizophrenia patients and healthy controls. *p o 0.05. PRT: people rotation task; LRT: letter rotation task. Error bars represent 7 1 S.E. Note: The baseline is not to set to 0 to enable better appreciation of differences.

Please cite this article as: Agarwal, S.M., et al., Cognitive mapping deficits in schizophrenia: Evidence from clinical correlates of visuospatial transformations. Psychiatry Research (2015), http://dx.doi.org/10.1016/j.psychres.2015.05.096i

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Fig. 3. Mean task accuracy percentage (A) and mean reaction time (B) for healthy controls and schizophrenia patients in front-facing and back-facing perspective in the people rotation task. Error bars represent 7 1 S.E. Note: The baseline is not to set to 0 to enable better appreciation of differences.

Fig. 4. Mean task accuracy percentage (A) and mean reaction time (B) for healthy controls and schizophrenia patients in mirrored and normal orientation in the letter rotation task. Error bars represent 7 1 S.E. Note: The baseline is not to set to 0 to enable better appreciation of differences.

on RT when the letters and numbers were mirrored. Among controls, RT was significantly higher for mirrored characters compared to those with normal orientation only at angles closest to the upright (67.5° and 292.5°). Among patients, RT was significantly higher for mirrored characters in comparison to normal characters at 67.5°, 112.5°, 247.5° and 292.5°, and significantly lower for mirrored characters at 202.5° (mean and se in Supplementary Table 4).

3.4. Correlation between psychopathology and task performance LRT accuracy had significant negative correlation with both SAPS [s¼  0.34; p ¼0.023] (Fig. 5A) and SANS [s ¼  0.45; p ¼0.002] total scores (Fig. 5B). No other task performance parameter was found to correlate with psychopathology measures. Drug dosage did not correlate with any performance parameter.

4. Discussion In this study, we measured the egocentric and allocentric visuospatial abilities in the context of a mental rotation experiment in patients with schizophrenia and healthy controls. Consistent with our prediction, we observed a significant diagnosis-by-task type interaction effect on task accuracy; patients did selectively worse in the allocentric LRT and this correlated meaningfully with clinical severity scores. We also found that certain task related factors like angle of rotation, perspective (front-facing/back-facing), and orientation (mirrored/normal) significantly influenced performance. We discuss in brief the latter group of findings first and then move on to the main focus of this study. 4.1. Task related factors 4.1.1. PRT We found that accuracy decreased and reaction time increased

Please cite this article as: Agarwal, S.M., et al., Cognitive mapping deficits in schizophrenia: Evidence from clinical correlates of visuospatial transformations. Psychiatry Research (2015), http://dx.doi.org/10.1016/j.psychres.2015.05.096i

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Fig. 5. Correlation between mean task accuracy percentage in the letter rotation task and SAPS total score (A) and SANS total score (B).

with increase in angle of rotation from the upright, and this effect was modulated by the perspective (front-facing or back facing) of the stimulus (Fig. 3). The effect of angle was much more prominent for back-facing stimuli which is in line with the results of a previous study (Parsons, 1987) that reported a steeper slope (indicative of greater increase in reaction time with increase in angle from the upright) for back-facing stimuli. We also found that patients performed the task significantly slower than controls and this effect was most prominently seen in female patients. The task accuracy however did not show any similar effects of diagnosis-bysex interaction. Previous studies have found that males overall perform faster than females (Landgraf et al., 2010), and that diagnosis does not affect gender differences in visuo-spatial tasks (Halari et al., 2006). However, given some evidence for presence of disturbed sexual dimorphism in schizophrenia with respect to mental rotation abilities (Jimenez et al., 2010), this finding needs further exploration in future studies. 4.1.2. LRT In LRT, we found that task accuracy was significantly influenced, simultaneously, by the angle of rotation, the orientation of the stimulus and diagnosis (Fig. 4A). Presence of angle-by-orientation interaction effect is line with several studies that have looked at letter rotation tasks including the recent one by Thakkar and Park (2012) wherein the effect of angle is more prominent when the stimuli are normally oriented. The angle-by-orientationby-diagnosis interaction was driven by the observation that while controls showed no effect of angle when the stimuli were mirrored, patients showed the effect of angle in both orientations. This could be because angle and orientation have an additive effect on the computational resources in patients while among controls orientation is the predominant determinant of complexity. Once the stimuli are mirrored, the angle of rotation ceases to be an important factor. The angle-by-orientation effect seen on RT was along predictable lines. The angle-by-orientation-by-diagnosis interaction on RT was driven primarily by the unexpectedly low RT among schizophrenia patients for mirrored stimuli at 202.5° (Fig. 4B). This is also the angle at which the accuracy was least among patients (Fig. 4A). Hence, this finding has to interpreted with caution since the low number of trials may have contributed to the unexpectedly low RT. We were unable to replicate the diagnosis-by-angle of rotation effect reported in a previous study (Thakkar and Park, 2012) which could partly be because of the lower number of trials in our study. Future studies should include more trials per subjects so that these interesting interactions can be analyzed further. LRT accuracy and RT showed a significant main effect of diagnosis – patients performed the significantly slower and worse. This is discussed in detail below.

4.2. Schizophrenia and allocentric mental rotation The results of this study point towards differential deficit involving allocentric referencing (with relative sparing of egocentric referencing) in patients with schizophrenia. This is in line with previous studies (Landgraf et al., 2010; Weniger and Irle, 2008). Further, these deficits were found to correlate with psychopathology scores. The negative correlation between LRT accuracy and SAPS total score found in our study is in tune with a previous study wherein hallucinatory schizophrenia patients were found to perform less accurately than non-hallucinatory patients in the performance of an allocentric task (de Vignemont and Singer, 2006). This suggests a potential link between positive symptoms of schizophrenia and allocentric task performance. Interestingly, deficits in medial temporal lobe are shown to be associated with allocentric referencing as well as pathogenesis of positive symptoms. Moreover, medial temporal lobe does not influence egocentric referencing. Hence, one can speculate that the selective impairment in allocentric referencing (with relative sparing of egocentricity) as well as allocentric deficits correlating with positive symptom severity might reflect medial temporal deficits in schizophrenia [as reviewed by Bose et al. (2014)]. This plausibility needs further exploration with concurrent neuroimaging studies. Moreover, this dissociation is an encouraging finding because it rules out the possible confounding influences such as global cognitive impairment, familiarity with the computer interface or lack of involvement in task performance as potential cause behind the observed differences. Task accuracy variance was comparable between tasks in the two groups suggesting that the tasks were well matched for difficulty level and variance in performance. This further backs the argument against global cognitive impairment. The negative correlation between LRT accuracy and SANS score found in our study indicates that the deficit may be mediated in part by negative symptoms. This is in line with previous work which has also reported correlations between allocentric task performance and severity of negative symptoms (Folley et al., 2010). The same study (Folley et al., 2010) also reported negative correlation between total PANSS score and allocentric task performance, but the correlation was stronger with the negative symptoms subscale which perhaps was largely responsible for the significant correlation with overall psychopathology scores. Patients took significantly longer time than controls in both conditions. The number of trial excluded because of no response being provided in the allotted time of 10 s was also significantly greater in patients. In the absence of correlation of RT with psychopathology measures, this could probably be attributed to a generalized slowing of reaction time seen commonly in schizophrenia patients. However, this generalized slowing does not appear to have impacted the task accuracy probably because subjects found the time provided enough to complete the task on most

Please cite this article as: Agarwal, S.M., et al., Cognitive mapping deficits in schizophrenia: Evidence from clinical correlates of visuospatial transformations. Psychiatry Research (2015), http://dx.doi.org/10.1016/j.psychres.2015.05.096i

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occasions. Hence, even though they took longer to complete the task, they were able to do it to the level of their abilities. A shorter allotted time would have probably resulted in hurrying subjects, in which case the generalized slowing would have perhaps impacted task accuracy as well. 4.3. Cognitive mapping and hippocampus The differential and circumscribed deficit in spatial abilities which bears pathogenetically relevant correlations with psychopathology scores draws one's attention to the conceptualization of schizophrenia as a disorder of cognitive mapping. By “Cognitive Mapping” we intend to refer to the concepts from the seminal works of O’Keefe and Nadel (1978) that led to the development of Cognitive Map Theory of Hippocampal Function. It posits that hippocampus is critical to the mediation of spatial memory and navigation by allowing flexible representations of the environment, its contents and their relationship to each other. Hippocampus has frequently been associated with allocentric spatial abilities. This has been confirmed by a recent study which points to the role of hippocampus and its connections with structures in the parietal cortex in utilization of the allocentric frame of reference in spatial navigation (Zhang and Ekstrom, 2013). In this context, it is important to note that hippocampus is critically implicated in the pathogenesis of schizophrenia. It figures prominently in metaanalyses of brain abnormalities associated with schizophrenia (Nelson et al., 1998; Vita et al., 2006; Wright et al., 2000) and pathophysiological theories of schizophrenia (Ashdown et al., 2006; Christensen and Bilder, 2000; Grace, 2000; Tamminga et al., 2010). Hence, evidence of presence of allocentric deficit which depends on hippocampus as well as its relationship with positive symptom severity lends further support to its importance and raises the likelihood of allocentric deficits being integral to the pathology on schizophrenia (Bose et al., 2014). Our study findings provide support to the existence of selective allocentric deficits in schizophrenia patients. This is the largest study till date to have explored both egocentric and allocentric processes in schizophrenia patients with demographically matched healthy controls and examined their correlation with disease severity scores. While a majority of the studies till date concur with the presence of allocentric mapping deficits in schizophrenia, two previous studies report differing results (de Vignemont et al., 2006; Thakkar and Park, 2012). In the study by de Vignemont et al., patients were found to be equally impaired on letter, hand and glove rotation tasks. The sample size in that study was also (13 subjects in each group) and the controls had received significantly more education than schizophrenia patients. Years of education was not used as a covariate during group comparisons and would have contributed to the study findings. Further, the task also differs from our study where the whole body instead of body parts were represented in the PRT. It is possible that schizophrenia patients perform better when a more complete context of the stimulus is provided which perhaps makes them understand the task better. In the Thakkar et al. study, the findings of the PRT task are in line with our findings – no significant group effect was noted on accuracy. However, the findings differed with respect to the LRT. While we also found a significant orientation-by-angle of rotation interaction effect on performance, we were unable to replicate the diagnosis-by-angle of rotation effect reported in that study. Instead, we found an orientation-by-angle-by-diagnosis interaction on performance measures. Perhaps a difference in the number of trials and sample size between the two studies is the cause for the divergence of findings, since we used exactly the same task with only minor modifications. The findings of this study must be interpreted in the context of its limitations. The study design was unable to test for the

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specificity of these deficits in schizophrenia with respect to other psychiatric disorders. All patients were stable on antipsychotic medication. Hence, the influence of medication on the results is difficult to isolate. The absence of any group differences in the PRT task rules out a general cognitive effect on antipsychotic medication on task performance. However, whether drugs specifically impair allocentric spatial abilities needs to be systematically tested.

Conclusion In summary, we observed schizophrenia patients to have deficits in allocentric task abilities with relatively preserved egocentric task accuracy. Allocentric referencing deficits had significant correlation with psychopathology scores. The results of this study point towards a pathogenetically relevant deficit in schizophrenia involving a well-demarcated cognitive domain that is critically dependent on the hippocampus; together, all the observations support the conceptualization of schizophrenia as a disorder of cognitive mapping (Bose et al., 2014). These findings need replication as well as further systematic evaluation in a larger sample of schizophrenia patients. Also, future work should aim at studying the neural correlates of these deficits in schizophrenia patients as well as assess the specificity of these findings by concurrent evaluation of other diagnostic categories.

Conflict of interest None.

Acknowledgment This study is supported by the Wellcome Trust/DBT India Alliance Senior Fellowship Research Grant to GV (500236/Z/11/Z) and CEIB Programme Support Grant to GV (BT/PR5322/COE/34/8/ 2012). SMA, VD, ACA, SVK, AB are supported by the Wellcome Trust/DBT India Alliance. VS is supported by the CEIB Programme Support Grant. We sincerely thank the anonymous reviewers for their valuable comments that were very helpful in revising the manuscript.

Appendix A. Supplementary information Supplementary data associated with this article can be found in the online version at http://dx.doi.org/10.1016/j.psychres.2015.05. 096.

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Please cite this article as: Agarwal, S.M., et al., Cognitive mapping deficits in schizophrenia: Evidence from clinical correlates of visuospatial transformations. Psychiatry Research (2015), http://dx.doi.org/10.1016/j.psychres.2015.05.096i

Cognitive mapping deficits in schizophrenia: Evidence from clinical correlates of visuospatial transformations.

The 'cognitive mapping' component of spatial cognition, namely - the allocentric/egocentric function and its relation to symptoms in schizophrenia is ...
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