Introduction 1 2 3 4 5 6 7 7 8 9 11 10 12 9 11 11 13 14 16 17 18 19 20 21 15 22 23 24 25 26 27 30 31 6 7 32 33 34 35 36 However, empirically controlled investigations in which the cognitive profile of brain damaged patients was compared with schizophrenic subjects with an appropriate set of ToM and social intelligence tasks are lacking, thus leaving several crucial questions largely unresolved. In the current study, we examined the performance of stabilized schizophrenic outpatients, inpatients with focal damage of left and right ventromedial prefrontal lobes and healthy controls, in ToM abilities, in social competence and tactical strategy (Machiavellian Intelligence), to clarify whether schizophrenic patients demonstrate impairment similar to ventromedial prefrontal lesion patients and whether their performance in these tasks can be differentiated from their performance in tasks sensitive to neuropsychological dysfunction, including “executive” functions. Our prediction is that an overlapping dysfunctional cognitive profile should emerge between brain damaged and schizophrenic subjects, when compared to healthy subjects. We also addressed several methodological issues raised by earlier studies using social cognition tasks created for adults and not for children. Methods Participants The subjects for this study included 18 adult neurosurgical patients with unilateral frontal lobe lesions who had undergone surgery at the Department of Neurosurgery of “S. Salvatore” Hospital, L’Aquila, Italy. The patients were consecutively enrolled in the study from January 2003 to September 2005. Only patients with exclusive frontal lesions were identified and brain damage was confirmed through neuroimaging, with pre- and postoperative CT scanning and MRIs. 1A, B Fig. 1 A B  Thirteen subjects had intra- or extra-axial tumours (72%); 3 had spontaneous haemorrhage (17%) and 2 (11%) had intracerebral haemorrhage from ruptured aneurysms. In the RMPFC group seven patients had a tumour removed (four had a meningioma excised, 2 had a high grade glioma excised and 1 had an oligodendroglioma excised), one had a right anterior communicating artery (ACoA) aneurysm clipped, following rupture and one had spontaneous intracerebral haemorrhage with no evidence of arterial malformations. Of the LMPFC patients, six had a tumour removed (five had a meningioma excised and one had a high grade astrocytoma excised), two had spontaneous intracerebral haemorrhage with no evidence of arterial malformations and one had a left ACoA aneurysm clipped following rupture. 1 2 Table 1 Socio-demographic details of subjects with ventromedial frontal lobe lesions Subjects Site Age Education Aetiology M.D Right frontal lesion 56 13 Meningioma F.S. Right frontal lesion 50 8 Meningioma L.G Right frontal lesion 44 8 Meningioma P.G. Right frontal lesion 63 5 Oligodendroglioma T.R Right frontal lesion 62 5 Glioma grade III E.G Right frontal lesion 69 8 Spontaneous intracerebral haemorrhage S.M Right frontal lesion 64 13 Glioma grade IV A.U Right frontal lesion 35 18 Intra-cerebral haemorrhage from aneurismal sac rupture M.U Right frontal lesion 44 18 Meningioma L.F Left frontal lesion 41 8 Meningioma L.P Left frontal lesion 30 5 Meningioma M.N Left frontal lesion 68 13 Spontaneous intra-cerebral haemorrhage M.M. Left frontal lesion 55 13 Spontaneous intra-cerebral haemorrhage R.M Left frontal lesion 54 8 Meningioma D.S Left frontal lesion 62 8 Meningioma R.T Left frontal lesion 73 13 Astrocytoma grade III A.C Left frontal lesion 59 8 Meningioma R.G Left frontal lesion 38 8 Intra-cerebral haemorrhage from aneurismal sac rupture Table 2 Classification of the RMPFC and LMPFC experimental group according to the prefrontal sectors of functional significance into which the lesions encroached Patient Sex Age (years) Aetiology Lesion location Fronto-orbital Medial RF1 F 56 Meningioma +  RF2 F 50 Meningioma  + RF3 M 44 Meningioma  + RF4 F 63 Oligodendroglioma +  RF5 M 62 Glioma grade III +  RF6 M 69 SIH  + RF7 F 64 Glioma grade IV +  RF8 F 35 IhAsc  + RF9 M 44 Meningioma +  LF1 M 41 Meningioma  + LF2 M 30 Meningioma +  LF3 F 68 SIH  + LF4 M 55 SIH +  LF5 M 54 Meningioma  + LF6 M 62 Meningioma  + LF7 M 73 Astrocytoma grade III  + LF8 F 59 Meningioma  + LF9 M 38 IhAsc +  SIH = spontaneous intracerebral haemorrhage; IhAsc = intracerebral haemorrhage from aneurismal sac rupture Subjects were assessed with neuropsychological test batteries 20–40 days after surgery. A control group of schizophrenic subjects and a control group of psychiatrically and neurologically healthy subjects were studied as well. 37 38 Twenty neurologically and psychiatrically healthy control subjects (matched for age and education) were included. Exclusion criteria were: history of neurological disease including epilepsy, head trauma or mental retardation. All subjects provided informed consent to participate in the study. Materials and procedure Clinical assessment 39 40 39 40 41 42 The SAPS consists of 34 items and is divided into four subscales: hallucinations, delusions, bizarre behaviour and formal thought disorder. The SANS consists of 25 items and is designed to measure five domains: affective flattening or blunting, alogia, apathy, asociality and impaired attention. 40 3 Table 3 Socio demographic, clinical details in the total sample  Schizophrenia (no. 20) Right medial prefrontal cortex lesion (no. 9) Left medial prefrontal cortex lesion (no. 9) Healthy controls (no. 20) Sex (M:F) 7:13 5:4 2:7 15:6 Age (years) 42.7 (1.8) 49.6 (10.3) 46.4 (18.6) 38.9 (2.8) Education (years) 8.8 (0.8) 9.2 (2.6) 12.2 (3.97) 13.4 (1.2) Day since surgery – 91.4 (11.6) 88.8 (13.7) – IQ level 88.8 (5.7) 93.1 (2.4) 98.7 (3.6) – NPI total score 6 (0) 10 (0) 9.8 (5.3) – Duration of illness (years) 12.30 (4.13) – – – BPRS total score 44 (11.1) 52.5 (4.9) 55.5 (17.5) – C.G.I. 4.5 (0.6) – – – SANS 50.42 (20.9) – – – SAPS 42.57 (19.1) – – – Social function (AD) 2.5 (1.1) – – – The values are means; standard deviation are in parenthesis Neuropsychological assessment 4 Table 4 Neuropsychological detailed of total sample  Schizophrenia (no. 20) Right medial prefrontal cortex lesion (no. 9) Left medial prefrontal cortex lesion (no. 9) Healthy controls (no. 20) Verbal fluency 33.1 (10.4) 21.2 (8.39) 11.3 (4.19) 38.7 (7.5) Tower of London 29.8 (4.4) 26.3 (6.5) 19.2 (4.3) 34.6 (1.9) WCST no. of category 3.46 (2.41) 2.66 (1.7) 1.87 (2.1) 5.7 (0.3) WCST % of perseverative errors 27.66 (15.12) 42.9 (22.6) 50.7 (21.3) 2.9 (2.6) Verbal memory 19.1 (8.7) 28.6 (8.01) 8.3 (2.25) 29.6 (3.01) The values are means; standard deviation are in parenthesis 43 44 45 46 47 Theory of mind tasks 9 9 48 49 9 False belief test question Fact question Memory question Social cognition tasks The following tasks addressed two aspects of social cognition. 21 Social situations task This task investigates the capacity to judge the appropriateness of behaviour that may induce anger in observers. Procedure. 21 Two scores were obtained for this task: one referring to the number of normative situations and the other to the number of violations correctly identified. The third refers to the extent to which the patient judged the violations to be socially inappropriate. For each situation, the participant obtained a score between 0 and 3, matching their response of “A” to “D” (i.e. “A” = 0, “D” = 3). Mach IV Scale 50 The Mach IV scale is a method for assessing awareness and social functioning in a social context characterised by interpersonal deception (“Machiavellianism”). From the 20 statements of the Mach IV Scale we extracted two groups of items: (1) 5 items describing duplicity tactics, e.g.: “It is wise to flatter important people” (“tactics+”) and (2) 4 items describing a disagreements with tactics duplicity, e.g.: “When you ask someone to do something for you, it is best to give the real reason” (“tactics−”). The items were labelled for coding as follows: Positive tactics (tactics+): subjects must agree with statements reporting the ability to manipulate other people’s intentions and actions, according to Niccolò Machiavelli’s beliefs. 32 51 Human nature components referring to “people’s knowledge”, in particular the degree of cynicism concerning other people’s intentions and decisions are strictly related to the ability to interpret other people’s mental states. Statistical analysis One-way ANOVA was used to compare demographic, clinical information and neuropsychological Assessment and social cognition tasks. The Kruskaal ± Wallis test was used to analyse the level of significance of patients’ scores on ToM tasks. Results F P F P F P 2 Clinical assessment F P F P F P F P F P Executive function F P F P F P F P 3 The LSD method was used for post hoc comparisons. This revealed that in Verbal Fluency both frontal groups (LMPFC and RMPFC) performed significantly worse than the schizophrenic group and control subjects. Bonferroni tests on the Tower of London task showed impaired performance for the LMPFC group only when compared to both the schizophrenic and healthy subjects control groups. The LMPFC group performed significantly worse than the RMPFC subjects. First-order false belief tasks False-belief test question: 2 P Bonferroni methods P Fact questions: Memory questions: 2 Fig. 2 Performance of study groups (schizophrenics, Right Medial Prefrontal Cortex—RMPFC Lesion Subjects, Left Medial Prefrontal Cortex—LMPFC Lesion Subjects and healthy controls) on First-order False Belief tasks  Second order theory of mind False-belief test question 2 P Bonferroni methods P P Fact questions: Memory questions: 3 Fig. 3 Performance of study groups (schizophrenics, Right Medial Prefrontal Cortex—RMPFC Lesion Subjects, Left Medial Prefrontal Cortex—LMPFC Lesion Subjects and healthy controls) on second-order False Belief tasks  Social situation task F P Bonferroni methods P P 4 Fig. 4 Performances on social situation task in all groups (schizophrenics, Right Medial Prefrontal Cortex—RMPFC Lesion Subjects and Left Medial Prefrontal Cortex—LMPFC Lesion Subjects). The figure reports the scores in correct identification of normative situation and the mean scores of norm violations  Mach IV scale F P F P F P F P Bonferroni methods 5 Fig. 5 Performance on items of Mach IV Scale in the four groups for strategic thinking  Correlation analyses No significant correlations were found between ToM first order and ToM second order questions and executive functions (verbal fluency, WCST number of categories and perseverative errors, Tower of London) in normal controls, and in subjects with left and right frontal lesions. No significant correlations were found between the Mach IV scales (good tactical strategy and negative tactical strategy) and executive functions (verbal fluency, WCST no. of categories and perseverative errors, Tower of London) in normal controls, and in subjects with left and right MPFC. r P r P P r P r P No significant correlations were found between the Mach IV scale and social cognition task and psychopathological and clinical variable (SANS, SAPS and CGI). Discussion One of the distinctive attributes of human social cognition is our propensity to build models of other people’s minds: to make inferences about the mental states of others. Several neuroimaging studies have attempted to elucidate the neural substrates that support this distinctively human ability that is impaired in people with schizophrenia. 5 52 54 55 56 In addition to these clinical and outcome goals, there is increasing interest in identifying the neural substrates that underlie social cognitive deficits in schizophrenia. For all of these reasons we compared the performances on social cognition tasks of schizophrenic subjects with the performances of MPFC subjects. 9 11 57 59 10 11 57 8 7 28 60 We found out that subjects with RMPFC lesion are impaired in ToM tasks of “false beliefs”, showing thus a very similar cognitive dysfunctional profile to people affected by schizophrenia in all Theory of Mind tasks and in all social cognition tasks. A normal performance on control questions indicates an unimpaired comprehension of stories and suggest that the task was sensitive in detecting TOM impairments. In addition, schizophrenics and subjects with RMPFC lesion also showed impairment in the social cognition tasks, in fact they both failed to discriminate in judging inappropriate behaviour likely to induce anger in observers. This was unlike patients with LMPFC who showed no impairment on any of these tasks. 7 8 11 13 13 61 58 21 26 27 28 62 31 21 63 64 9 8 65 7 66 67 Despite this limitation, this study provides further evidence that social competence is compromised in RMPFC subjects very closely to schizophrenics and these data seem to elucidate the possible neuroanatomic structure alteration present in schizophrenia. However, we are confident that there is a wide range of behavioural manifestations of frontal lobe dysfunction, and ToM impairments clearly cannot account for all of these, nor is it likely to be responsible for all reported difficulties in social cognition. In contrast, ToM tests are designed with the aim of isolating those aspects of social cognition associated with two-way reciprocal interactions that rely crucially on ToM ability and false belief tasks have facilitated the demonstration of a mentalizing impairment in subjects with lesions of the prefrontal cortex, which is independent of non-mental state inference. 13 68 61 13 61 69 70 We support two positions: first, that a specialized, discrete ToM module, or set of modules, is located in the frontal lobes, but is functionally independent and second that these deficits can co-occur, on the basis of the proximity of the respective underlying neural areas.