**6. Social brain**

Leslie Brothers was one of the first scientists talking about the social brain, using proof from studies in nonhuman animals [89]. Later Prinz created the common coding theory, according to which perception and actions rely on common codes [90]. The discovery of the so‐called "mirror neurons" within the premotor and parietal cortices [91], activated while an action directed to the object is performed and while an action is perceived by the object [92, 93], became a basis for extensive research on the so‐called social brain [91].

The discovery of social cognitive impairments in patients with MS presupposes brain damage. The difficulty in facial expression identification is among the most sensitive indicators for social cognition impairments. It is supposed that a disconnection mechanism due to white matter lesions and cortical thinning of specific brain zones causes a cognitive decline. This worsens the processing of emotions and the decoding of mental states from facial expressions. Functional MRI study, conducted by Jehna et al., provides evidence of altered functional brain processing in the posterior cingulate cortex and precuneus during emotion recognition in subjects with MS (sample of 15 patients and 15 healthy individuals) [88]. Abnormalities in face encoding and recognition vary in different stages of MS. Patients with CIS experience increased recruitment of the posterior visual areas. In patients with RRMS, the thalamus, parahippo‐ campal gyrus and right anterior cingulum are more activated than in patients with CIS and SPMS. In SPMS, an increased recruitment in the frontal areas is also registered. Significant correlation has been described between the above‐mentioned abnormal activations, on the one hand, and clinical symptoms, conventional MRI findings and behavioral disorders, on the other [94].

results of most subjects with the greater impairment of ToM skills and partly with the higher

In 2010, Banati et al. found more prominent ToM deficits in patients with longer disease duration (*p* = 0.05) [56]. In some research, the duration of the disease did not correlate with the emotional and cognitive scores from nonverbal tests [80], while Kraemer reported positive correlation between impaired social cognitive skills and executive function deficits in the early

**5.3. Social cognition impairments in MS depending on the grade of physical disability**

Paradoxically, patients with more severe physical disorders relatively often show a higher level of empathy compared to controls and patients with mild neurological deficits. A positive correlation was found between the difficulty in emotional facial expression recognition and the degree of disability [44]. Patients with a higher grade of disability demonstrated greater difficulties in affective prosody recognition [75]. More interpretation errors and lower scores were reported for patients with MS when nonverbal tests were used [56]. With deterioration of the disability the results from ToM verbal tests also get worse [87]. In a study of Jehna, EDSS scores did not correlate significantly with scores from emotion recognition tests or with results from FST in MS subjects (sample of 20 patients: CIS *n* = 12, RRMS = 7, SPMS = 1) [80]. Results from other recent studies indicate that the severity of the disease (respectively the degree of physical disability) does not correlate with the degree of impaired emotion recognition or with the psychological and social aspects of the quality of life [71, 88]. Therefore, some researchers consider social cognition as a separate domain of cognition which could independently affect the quality of life of the individual, in particular, that of patients with MS. Based on the extensive review of the literature available, we can conclude that social cognition impairments

Leslie Brothers was one of the first scientists talking about the social brain, using proof from studies in nonhuman animals [89]. Later Prinz created the common coding theory, according to which perception and actions rely on common codes [90]. The discovery of the so‐called "mirror neurons" within the premotor and parietal cortices [91], activated while an action directed to the object is performed and while an action is perceived by the object [92, 93],

The discovery of social cognitive impairments in patients with MS presupposes brain damage. The difficulty in facial expression identification is among the most sensitive indicators for social cognition impairments. It is supposed that a disconnection mechanism due to white matter lesions and cortical thinning of specific brain zones causes a cognitive decline. This worsens the processing of emotions and the decoding of mental states from facial expressions. Functional MRI study, conducted by Jehna et al., provides evidence of altered functional brain processing in the posterior cingulate cortex and precuneus during emotion recognition in

became a basis for extensive research on the so‐called social brain [91].

emotional stress they were experiencing [22, 86].

238 Trending Topics in Multiple Sclerosis

stages of the disease in fully ambulatory patients [6].

in these patients require further in‐depth research.

**6. Social brain**

It is considered that mentalization is carried out by a large network of functionally related neurons [26]. A correlation has been established among specific cortical areas involved in emotion identification from facial expression (right and left fusiform face area, frontal eye), emotion processing (right entorhinal cortex) and socially relevant information (left temporal pole) [95]. According to a model of Ross and Mesulam, affective prosody comprehension could be related to the right‐sided perisylvian region, whose structure is similar to the language areas in the left hemisphere [96]. Later studies have suggested an involvement of the basal ganglia and prefrontal cortex (PFC) [97, 98]. Alexithymia may be associated with deactivation and activation of the anterior cingulate cortex (ACC) in response to highly negative and respec‐ tively highly positive emotional stimuli [72].

The most active brain region involved in social cognitive processing is the medal frontal cortex (MFC) [99, 100], which is described as the brain's social cognitive center. This region is activated during tasks requiring self‐knowledge and reflection, person perception and attribution of intentions. It is supposed that von Economo neurons [101] serve as a relay tract from the frontoinsular and anterior cingulate cortices (responsible for fast intuitive processes) to parts of the frontal and temporal cortices (associated with making slower conscious decisions), thus playing an important role in ToM [102]. It was discovered that damage to the VM frontal lobe plays a crucial role in the existence of a higher level of social cognition: social reasoning [69].

Individuals with bilateral damage of the orbitofrontal cortex show a decline in their ability to attribute higher‐order mental states to other people from stories. In particular, they fail to detect faux pas during functional imaging study. Emotion recognition tasks establish priority activation of Brodman Area 47 (orbital area) compared to activation of the medial orbitofrontal region [103]. Tissue loss in BA47 correlates with the inability to recognize negative emotions [104].

It is reported that sections of the left medial prefrontal cortex also contribute significantly to understand the mental state of others [105] or to reasoning about the beliefs and intentions of others [106]. Functional MRI studies demonstrate activation of the amydgala during attribu‐ tion of mental states and intentions to other people by viewing pictures of their eyes [107].

The wide dissemination of demyelinating lesions and cortical thinning typical of patients with MS often lead to anatomic and functional disorders of the above‐mentioned specific brain structures. A subsequent disconnection mechanism leads to a cognitive decline [108]. Single‐ photon emission computed tomography (SPECT) studies in cognitively impaired patients with MS registered a deficiency of brain perfusion, mainly in the frontal and temporal lobe of the left hemisphere [109]. Positron emission tomography (PET) in these patients registered both global and regional reduction of cerebral glucose metabolism [110, 111]. An increase in the white matter lesion load, especially in the insula, precentral gyrus, prefrontal and temporal cortices, reduces the effectiveness of large‐scale brain structural networks in patients with MS, which leads to cognitive deficits [108]. Functional MRI studies point to a positive correlation between the degree of activation of certain cerebral zones during performance of specific cognitive tasks and lesion load. These findings support the notion that increased cortical activity in patients with MS occurs as a result of axonal damage related to MS activity and aims to limit the clinical impact of structural damage [112].

According to Krause et al., the orbitoinsular cluster, which includes the ventral lateral prefrontal cortex (VLPF) and parts of the anterior insula, is crucial to deficits in emotional perception in patients with MS [70], which is one of the most sensitive indications of impaired social cognition. Functional MRI studies have indicated that after initial activation of the early visual fields visual stimuli are selectively processed in a specific region of the fusiform gyrus, the fusiform face area (FFA) and the facial part of the superior temporal sulcus (fSTS) [113]. FFA is activated mostly with invariable traits, which is possibly related to person identification [70, 113], while fSTS activation is more often associated with variable aspects related to the eyes, spoken speech and expression of emotions and intentions [114–116]. The high‐level visual temporal cortex projects to a small proportion of amygdala neurons whose answers are relatively selectively modulated by viewing faces compared to other visual stimuli. Functional MRI research has proved that the amygdala is critical for emotion recognition from facial expression, especially with negative emotions, such as fear [117, 118]. The amygdala is involved in the automatic focusing of attention for detecting emotional stimuli and filtering emotionally relevant information through the signs perceived [119, 120]. Thus, it participates in making more complex social decisions in humans [121]. There is evidence that bilateral amygdala damage leads to severely impaired ability for the recognition of fear through facial expression [118, 122]. A study by Jehna et al. provided proof for functional differences between patients with MS and healthy controls concerning the perception of neutral and emotional facial expressions of anger and disgust. These differences were found relatively early in the course of the disease, even in the absence of behavioral differences between subjects and controls. Since the functional changes registered in the occipital areas of patients with MS during recognition of nonemotional faces are usually associated with face processing, the authors explain the excessive activation of the posterior cingulate and precuneus during emotion processing as an additional attentive requirement [88].

As regards the ability to simulate the emotional state of others, the anterior insula, functionally connected to the ventrolateral prefrontal cortex (VLPFC), shows reduced activation in subjects experiencing problems in facial emotion recognition [123]. More difficult cognitive tasks lead to higher activation of the more lateral regions of ventrolateral prefrontal cortex (VLPFC) [70, 124].

During performance of various sociocognitive tasks for mental state attribution, common areas of increased activation in the medial prefrontal gyrus and the temporoparietal junctions are registered bilaterally, while the area of the medial prefrontal cortex (the paracingulate cortex) is the only region uniquely activated by the performance of ToM tasks [47].

left hemisphere [109]. Positron emission tomography (PET) in these patients registered both global and regional reduction of cerebral glucose metabolism [110, 111]. An increase in the white matter lesion load, especially in the insula, precentral gyrus, prefrontal and temporal cortices, reduces the effectiveness of large‐scale brain structural networks in patients with MS, which leads to cognitive deficits [108]. Functional MRI studies point to a positive correlation between the degree of activation of certain cerebral zones during performance of specific cognitive tasks and lesion load. These findings support the notion that increased cortical activity in patients with MS occurs as a result of axonal damage related to MS activity and aims

According to Krause et al., the orbitoinsular cluster, which includes the ventral lateral prefrontal cortex (VLPF) and parts of the anterior insula, is crucial to deficits in emotional perception in patients with MS [70], which is one of the most sensitive indications of impaired social cognition. Functional MRI studies have indicated that after initial activation of the early visual fields visual stimuli are selectively processed in a specific region of the fusiform gyrus, the fusiform face area (FFA) and the facial part of the superior temporal sulcus (fSTS) [113]. FFA is activated mostly with invariable traits, which is possibly related to person identification [70, 113], while fSTS activation is more often associated with variable aspects related to the eyes, spoken speech and expression of emotions and intentions [114–116]. The high‐level visual temporal cortex projects to a small proportion of amygdala neurons whose answers are relatively selectively modulated by viewing faces compared to other visual stimuli. Functional MRI research has proved that the amygdala is critical for emotion recognition from facial expression, especially with negative emotions, such as fear [117, 118]. The amygdala is involved in the automatic focusing of attention for detecting emotional stimuli and filtering emotionally relevant information through the signs perceived [119, 120]. Thus, it participates in making more complex social decisions in humans [121]. There is evidence that bilateral amygdala damage leads to severely impaired ability for the recognition of fear through facial expression [118, 122]. A study by Jehna et al. provided proof for functional differences between patients with MS and healthy controls concerning the perception of neutral and emotional facial expressions of anger and disgust. These differences were found relatively early in the course of the disease, even in the absence of behavioral differences between subjects and controls. Since the functional changes registered in the occipital areas of patients with MS during recognition of nonemotional faces are usually associated with face processing, the authors explain the excessive activation of the posterior cingulate and precuneus during

to limit the clinical impact of structural damage [112].

240 Trending Topics in Multiple Sclerosis

emotion processing as an additional attentive requirement [88].

prefrontal cortex (VLPFC) [70, 124].

As regards the ability to simulate the emotional state of others, the anterior insula, functionally connected to the ventrolateral prefrontal cortex (VLPFC), shows reduced activation in subjects experiencing problems in facial emotion recognition [123]. More difficult cognitive tasks lead to higher activation of the more lateral regions of ventrolateral

During performance of various sociocognitive tasks for mental state attribution, common areas of increased activation in the medial prefrontal gyrus and the temporoparietal junctions are A hypothesis has been developed for explaining social cognition via three related but distinct dimensions of anatomical and functional brain organization [124]. It states that the medial‐ lateral dimension connects the medial prefrontal cortex (MPFC) (emotional aspects of mental state attribution and emotions) to the lateral prefrontal cortex (LPFC), associated with visuospatial centers supporting externally generated representations (cognitive aspects of mental state attribution and emotions) [125, 126]. The midline posterior‐anterior dimension links the "first‐order" perceptual substratum for the flow of socioemotional processing (superior temporal sulcus), the posterior insula and the middle ACC to the anterior insula and MPFC, where it is presented again with increased complexity [99, 127] and results in awareness and explicit judgments of affective mental states. The third dimension is the projection from ventral regions of the frontal midline involved mainly in stimulus‐driven processes (amygdala, striatum and OFC) to dorsal regions supporting monitoring and reflective processes (dorso‐ medial and lateral prefrontal cortex) [124, 126]. This means that mental state attributions are supported by various neural structures depending on the type of sociocognitive task and processing demands.

Most MRI studies of patients with MS found a correlation between the cognitive and/or affective disorders, on the one hand, and lesion localization [128], total lesion load [129] or cerebral atrophy, on the other [129, 130]. A significant correlation was also reported between abnormal activities in specific cortical zones on fMRI, on the one hand, and clinical manifes‐ tation, conventional MRI findings and behavioral changes, on the other [94]. However, a study of voxel‐based lesion symptom mapping did not reveal a significant connection of the total lesion volume to the degree of emotional recognition or to the activation of specific cortical areas during task performance. A statistically significant relationship was discovered between lesions in the left temporal periventricular white matter and decreased accuracy in dealing with cognitive tests, which points to a disturbance in information transmission from the temporal visual processing areas to the frontal regulation areas [70, 131].

Altered patterns of brain activity were found in all clinical phenotypes of MS, including when cognitive abilities were intact and/or restored [112, 132, 133]. However, such research is still insufficient. A recent fMRI study of different forms and stages of MS reported results from performance of face encoding and recognition [94]. In patients with CIS an increased recruit‐ ment of the posterior visual area, where face perception and encoding is processed, was revealed. The result was interpreted as an adaptive response of cerebral reorganization for compensating sociocognitive functioning in the early stages of the demyelinating disease. In patients with RRMS, an increased activation of the thalamus, parahippocampal gyrus and right anterior cingulum was reported. In patients with SPMS, an increased recruitment of the frontal fields, associated with higher cognitive functions, was registered. The findings suggest disadaptation and inadequate coping with cognitive tasks in a social context as the disease progresses. MRI findings show that in different clinical subtypes of MS the decreased cortical recruitment often correlates with increased T2 lesion load [112, 134].

Functional MRI studies in patients with MS prove that cortical plastic changes are a dynamic phenomenon that can be modulated by external factors. Unfortunately, fMRI studies of social cognitive abilities are still scarce, especially in patients with MS. Accumulation of data from future studies will allow early registering of the specifics of morphological and functional brain changes. This would facilitate the mapping of individual strategies for adequate treatment and rehabilitation of each patient.
