Introduction
Social cognition refers to the ability to perceive, interpret and provide an adequate response to affective and other interpersonal cues [
1]. Pioneering studies have found that schizophrenic subjects show social cognitive impairments, in particular in modifying their behaviour when interacting with other people and in recognizing social information cues [
2]. People with schizophrenia also show a great deal of social naivety in interpersonal situations [
3].
The ability to engage in competent social relations and to understand social information depends on the adequate functioning of a mental mechanism termed Theory of Mind (ToM), that allows people to understand and interpret their own and other people’s mental states and hence to predict and explain their behaviour [
4,
5]. Evidence from neuroimaging and neuropsychological studies has led researchers to conclude that ToM is subserved by dedicated brain systems, including the amygdala, the temporo-parietal junction, the orbital frontal cortex and, in particular, the medial frontal lobes [
6,
7]. The results of these studies have been used to argue that the medial frontal lobes play a critical role in a dedicated mentalizing system [
7,
8].
Neuropsychological literature specifically relevant to the medial frontal cortex is scarce. Actually, only three studies have included patients with relatively focal medial frontal lobe damage and have sought to investigate correlations between specific frontal brain areas and performance in ToM tasks [
9‐
11]. However, there are important limitations to these investigations. Stuss et al. [
10] reported that patients with right frontal and bilateral frontal lobe damage were impaired in their ability to infer visual experience in others. The authors conclude that acquired brain damage to the medial frontal lobes does impact on ToM ability, but aetiology of brain damage for each patient is not reported, the text implies that most of the bifrontal group had suffered head traumas. It is often very difficult to assess the extent of brain damage reliably after head trauma as widespread damage can often occur through axonal shearing and other effects (e.g. [
12]). The second neuropsychological study [
9] reports that patients with left and right-sided lesions were equally impaired, while lesion size was unrelated to performance and no effect of lesion location was found when comparing patients with focal dorsolateral, medial or orbital frontal lesions.
Also, a recent group study of empathy in patients [
11] included an assessment of performance on the Faux Pas Test, a probe of ToM ability. Patients with frontal lobe lesions were impaired in this task. Specifically, patients with ventromedial frontal lobe damage made significantly more errors than patients with posterior lesions or healthy controls in the Faux Pas Test.
However, a detailed analysis of lesion sites associated with ToM deficits in these previous studies revealed a particularly important role for the right ventromedial prefrontal frontal lobe [
11,
13]. Damage in these areas induces behavioural changes affecting personality (indifference), impaired social judgement, reduced affect and goal-directed behaviour, self-monitoring deficits [
14‐
16].
More recent studies have provided evidence that is in disagreement with a single area hypothesis involved in ToM processing. In fact, the neural network involving the right and left temporo-parietal-junction (TPJ R and L); the posterior cingulated (PC), and medial prefrontal cortex (MPFC) seems to be crucial in processing the complex reasoning involved in mentalizing [
17,
18]. Bird et al. [
19] studied a patient affected by extensive damage of the medial frontal lobes reporting, interestingly, a dysexecutive syndrome with confabulation with preserved performance on some ToM tasks.
Saxe and Wexler [
20] in an fMRI study in normal subjects, described an equally selective profile of activation of the above-mentioned areas in a multicomponent pattern of activation fMRI methodology. Frontal lobe damage in patients has long been linked to impairments in social behaviour [
21]; in fact, they have been described as presenting diminished social awareness and a lack of concern for social rules [
15,
22].
An interesting approach to social competence deficits in schizophrenic people may be represented by the Machiavellian Intelligence Hypothesis (MIH, [
23,
24]).
According to this hypothesis, in the development of intelligence, social, rather than technical, efficiency represents the main selective pressure of human evolution [
25]. Social efficiency is represented by the ability to understand the intentions and beliefs of others with the aim of deceiving and manipulating them to achieve relevant objectives, such as control of food sources or sexual partners [
26]. Recent literature fosters that these abilities are localised in the ventromedial prefrontal cortex: selective damage to these areas causes a relevant impairment of interpersonal relationships and in regulating behaviour according to social rules [
27‐
30].
Patients with lesions to the orbitofrontal cortex also have disinhibited/socially inappropriate behaviour. Grafman interpreted the patient’s impairment in terms of an inability to access “social schema knowledge” stored in the frontal lobes [
31]. Social schema knowledge is thought to inhibit aberrant behaviour. Patients with orbitofrontal cortex lesions who cannot access social schema knowledge fail to inhibit aberrant behaviour, such as physical threats and aggression.
The prediction of a similar cognitive profile in terms of ToM abilities and social competence between frontal lesion subjects and schizophrenic people has been investigated and confirmed [
6,
7]. An extensive and careful review recently published [
32], reported a general agreement about the nature and extension of ToM dysfunctions in people affected by schizophrenia. These dysfunctions are symptoms related [
33], disease specific and state independent.
The neural architecture of the social cognitive dysfunction of schizophrenia is of paradigmatic importance for the understanding of social cognitive dysfunction and, more importantly, for the understanding of the consequences at the behavioural level [
34]. A previous seminal study provided evidence that structural orbitofrontal cortex abnormalities are related to social dysfunction in schizophrenic people [
35]. Moreover this prefrontal area has been unequivocally involved in the social cognitive deficits associated with this disorder [
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.
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.
The main aim of the present paper is to establish whether patients affected by schizophrenia show an impairment in several social cognitive tasks as demonstrated in other researches [
5,
52‐
54] and if this cognitive profile is comparable to patients with a unilateral brain lesion involving orbito-ventromedial areas of the frontal lobes.
Our results are in line with other studies: in people with schizophrenia there was an impairment of social cognitive abilities and this deficit appears to be related to negative symptomatology [
55] and to be a key determinant of functional outcome, including social outcome [
56]. It has been suggested that theory of mind deficit make unable schizophrenic subjects to interact effectively with their social environment, but that a lack of certain aspects of social cognition will lead to social misperceptions.
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.
Among the several studies which investigated the effects of frontal lobe lesions (dorsolateral and ventromedial/orbital) on performance in ToM tasks [
9‐
11,
57‐
59], some of these including patients with bilateral frontal lobe damage, are limited because of a lack of detailed anatomical specification of lesion location [
10,
11,
57]. Moreover, most of patients with bilateral lesions had suffered head trauma, an aetiology associated with rather diffuse brain damage that is particularly likely to impinge on orbitofrontal brain areas.
Thus, the present study strictly tests the hypothesis that the unilateral (right or left) medial frontal cortex is implicated in the neural network sub serving ToM [
8] which is based on well established evidences suggesting the implication of the ventromedial frontal lobe areas in playing a critical role in a dedicated “mentalizing” or ToM network in human brains ([
7,
28,
60] for a review).
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.
This is clear evidence that the medial frontal cortex plays a critical role in a dedicated “mentalizing” brain network that underpins ToM ability [
7,
8].
Our findings are in agreement with previous “lesional” studies, showing the association between right medial area damage and more severe ToM deficits [
11,
13]. Siegal et al. [
13] reported that ToM impairments seem to be associated with right hemisphere damage.
In the present study we report a dissociation in RMPFC damage patients who displayed a defective ToM performance in contrast to LMPFC patients. LMPCF subjects show lower performances than RMPCF subjects in other cognitive competences but have normal performance in ToM competences and our results confirm the results obtained by Siegal and Surian [
61].
In addition, when a more sophisticated social ability is required in order to perform second order false belief tasks correctly, also LMPFC damaged subjects fail to perform at a normal level and show a statistically significant impairment, even though to a lesser degree, when compared to subjects with RMPFC and schizophrenic people. A possible explanation is that LMPFC is involved in more sophisticated mentalizing tasks and that an intact right hemisphere structure is nevertheless required [
58]. Normal subjects and neurosurgical subjects with unilateral LMPFC lesions perform fairly well on tasks related to tactical strategy, showing correspondingly low scores on the ingenuity aspect of thinking.
The present study also provides further data on the neural prefrontal areas involved in social cognition tasks and in strategic thinking [
21]. Social efficiency is represented by the ability to understand the intentions and beliefs of others with the aim of deceiving and manipulating them to achieve relevant objectives, such as control of food sources or sexual partners [
26]. Recent literature fosters that these abilities are localised in the frontal cortex [
27,
28]; the ability to recognise and manipulate hierarchical states to achieve some advantage would be localised in the amygdala and right hemisphere [
62].
Schizophrenic people and subjects with RMPFC lesion showed impaired performance on tactical strategy associated with relatively “high levels” of social ingenuity and have an impaired ability to access “social schema knowledge” which is stored in the frontal lobes [
31]. Such patients cannot access social schema knowledge and fail to inhibit aberrant behaviour, such as physical threats and aggression [
21,
63]. Interestingly a completely reversed pattern characterizes the performance of LMPFC lesion subjects and healthy controls, in fact we found out a complete disassociation of the neural prefrontal areas located in the medial part of the hemisphere in sub serving human ability to think strategically, indicating that the cortical organization related to tactical aspects of Machiavellian Intelligence is lateralized to the right hemisphere [
64]. Our results are at slight variance with the pioneering study of Rowe et al. [
9] who found a significantly impaired performance of both the RMPFC and LMPFC subjects in first and second order ToM tasks. In this study cortical lesions were non-exclusive medial hemisphere but includes subjects with dorsolateral prefrontal cortex (DLPC) damage.
Studies of normal subjects have used a variety of imaging techniques, designs, and test materials, but especially PET and fMRI to define brain regions specifically activated during a ToM task [
8,
65]. Such studies have consistently shown activation of the medial prefrontal gyrus (MPFG) and the Temporo Parietal Junction.
Frith and Frith [
7], reporting data on studies carried out in adults, have revealed an MPFC system of three components that are consistently activated during both implicit and explicit mentalizing tasks. This brain region is probably the basis of the decoupling mechanism that distinguishes mental state representations from physical state representations. We can speculate, according to the Edelman model [
66,
67], that a hierarchical organization of mental operation, when disrupted at a specified level, impairs the integrity of final output via an interruption of the chain of events required to perform a task. This study is limited by the small number of patients with unilateral frontal lobe lesions due to the rarity of such lesion.
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.
In conclusion, our findings provide evidence that lesions to the right MPCF determine an incapacity to understand ToM “false belief” stories and to use tactical strategy and understanding of social schema. Other authors have reported the same results: subjects with right hemisphere damage, but not subjects with left hemisphere damage, had difficulties in performing simple theory of mind tasks [
13,
68].
The difficulties shared by subjects with right hemisphere damage and young children on ToM tasks may have a similar origin [
61]. These may both derive from a pragmatic deficit that prevents subjects from interpreting the implicit questions correctly, rather than from a conceptual deficit concerning the ability to represent mental states.
The response pattern of subjects with ventromedial prefrontal damage on ToM tasks adds new evidence to the growing literature on the effects of the right hemisphere on various pragmatic aspects of language production and comprehension [
13].
The good performance of subjects with RMPCF lesions in executive function and verbal memory tasks suggests that their difficulties are due to a reduced sensitivity to the constraints that guide the interpretation and production of contextually appropriate utterances [
61].
It may be concluded that the ToM disorder in RMPCF subjects does not stem from executive function or memory deficits and that deficits in ToM and executive functioning in subjects with frontal lobe lesions are not causally related, even though our findings are in disagreement with Channon and Crawford [
69] who found a relationship between executive functioning and ToM ability in adults with damage to the frontal lobes [
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.