**7. Discussion**

People are profoundly social creatures, and therefore, successful social communication is crucial to their satisfactory lifestyle. The quality of this communication depends on their ability to detect emotional and cognitive processes in others and to understand their own internal state. These two features of social cognition—affective and mental—are the basis for empathy and ToM (mentalization). During social interactions, these different levels of social cognitive response are highly intertwined and each is influenced by the other.

Between 40% and 70% of patients with MS are affected by cognitive impairments [5], which are linked to a significant decline in activities of daily living. Despite the rapidly growing amount of research establishing frequent social cognitive deficits in such patients, there is still no statistics on the frequency of this type of disturbances. We set ourselves the goal of providing an overview of studies in this scientific area and contributing, through summarizing the results, to a better understanding of the specifics of social cognitive disorders and the way they determine the functional outcome and quality of life of patients with MS. We also made attempts at discussing controversies, discovering outstanding issues and outlining a frame‐ work for future research.

A wide range of literary sources report that the pathology of white matter in MS has the potential not only to disrupt the basic parameters of cognitive functions but also to hinder important social perception skills. The accumulated data suggest that the neuronal processes of ToM and empathy are performed in different brain networks which partially overlap [56]. No significant controversies exist concerning the pathophysiological significance of altered brain activation patterns in MS [112]. Rather, various studies complement the knowledge on functional processing in specific brain areas responsible for the different aspects of social cognition. Common activation areas include the medial prefrontal cortex, the temporoparietal junction and the temporal poles. ToM stimuli lead to increased activation of the lateral orbitofrontal cortex, the middle frontal gyrus, the cuneus and the superior temporal gyrus, while empathy is associated with enhanced activations of the paracingulate, the anterior and posterior cingulate and the amygdale [135]. A more pronounced global and regional cortical atrophy in the left hemisphere, which is a frequent finding in MS [136], suggests more severe ToM deterioration. However, no studies have been conducted yet of the functional relation between empathy and ToM in MS.

Pathways composed of white matter, which have a key role in coordinating the information flow between different regions of gray matter of the brain, are particularly vulnerable in MS [108]. Patients with lesions located in the ventromedial prefrontal cortex demonstrate selective deficits in affective ToM. Lesions in the inferior frontal gyrus are associated with extremely impaired empathy and emotion recognition [137].

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

People are profoundly social creatures, and therefore, successful social communication is crucial to their satisfactory lifestyle. The quality of this communication depends on their ability to detect emotional and cognitive processes in others and to understand their own internal state. These two features of social cognition—affective and mental—are the basis for empathy and ToM (mentalization). During social interactions, these different levels of social cognitive

Between 40% and 70% of patients with MS are affected by cognitive impairments [5], which are linked to a significant decline in activities of daily living. Despite the rapidly growing amount of research establishing frequent social cognitive deficits in such patients, there is still no statistics on the frequency of this type of disturbances. We set ourselves the goal of providing an overview of studies in this scientific area and contributing, through summarizing the results, to a better understanding of the specifics of social cognitive disorders and the way they determine the functional outcome and quality of life of patients with MS. We also made attempts at discussing controversies, discovering outstanding issues and outlining a frame‐

A wide range of literary sources report that the pathology of white matter in MS has the potential not only to disrupt the basic parameters of cognitive functions but also to hinder important social perception skills. The accumulated data suggest that the neuronal processes of ToM and empathy are performed in different brain networks which partially overlap [56]. No significant controversies exist concerning the pathophysiological significance of altered brain activation patterns in MS [112]. Rather, various studies complement the knowledge on functional processing in specific brain areas responsible for the different aspects of social cognition. Common activation areas include the medial prefrontal cortex, the temporoparietal junction and the temporal poles. ToM stimuli lead to increased activation of the lateral orbitofrontal cortex, the middle frontal gyrus, the cuneus and the superior temporal gyrus, while empathy is associated with enhanced activations of the paracingulate, the anterior and posterior cingulate and the amygdale [135]. A more pronounced global and regional cortical atrophy in the left hemisphere, which is a frequent finding in MS [136], suggests more severe ToM deterioration. However, no studies have been conducted yet of the functional relation

Pathways composed of white matter, which have a key role in coordinating the information flow between different regions of gray matter of the brain, are particularly vulnerable in MS

response are highly intertwined and each is influenced by the other.

rehabilitation of each patient.

242 Trending Topics in Multiple Sclerosis

work for future research.

between empathy and ToM in MS.

**7. Discussion**

ToM tests based on verbal and nonverbal stimuli not only serve for clinical evaluation of social cognitive impairments, but are also at the core of studying the functional anatomy of ToM in fMRI research [47]. The MPFC, associated with mentalizing tasks, activates whenever the person is attending to certain states of the self or others. The MPFC is equally active when the person is engaged in true beliefs, knowledge of the world based on past experience applied to the current situation, and partially in personal observations and behavioural predictions (STS) [48] There is increasing evidence of functional cortical changes in the early stages of MS, even after a single clinical episode [138, 139], when expansion and recruitment of additional cortical fields as common compensation of brain damage are registered [112].

The ability to decode specific facial emotions and ToM skills, which largely determines social communication in the real world, was first studied in MS patients in 2009 by Henry et al. For the first time, researchers presented clear evidence of increased difficulties in both aspects of emotion understanding, as well as in mental state attribution. Although the authors realized that their research was limited due to the lack of study of structural brain changes, their data were the first to establish a correlation between cognitive capacities and important aspects of emotion perception [45].

The diffuse demyelination and atrophy of both gray and white matter typical of MS lead to pronounced deficits in empathy and ToM. While white matter lesion load accounts only for some cognitive deficits in MS, this type of disorders can be better explained through patho‐ logical processes affecting gray matter, which are revealed in very early stages of the disease [140–142]. A significant positive correlation was established between neocortical volume and cognitive damage in patients with RRMS [143], as the gray matter atrophy occurring faster than white matter atrophy and, as recent research indicates, probably playing a central role in the emerging and deepening of cognitive deficits [144].

New technologies can help maximize our ability to assess cerebral integrity in MS. Regardless of the rapid development of imaging technology for detecting the earliest possible morpho‐ logical abnormalities in MS, the focus of research has primarily been on the physical disability and/or general cognition. Unfortunately, the study of social cognition still remains outside the scope of such type of research. We strive to contribute to a better understanding of the neurobiological correlates of social cognitive deficits, hoping in this way to provide opportu‐ nities for future research to develop medicinal and therapeutic strategies for modifying the pathological brain processes involved in these deficits. This would increase the level of empathy and ToM skills in patients with MS and could also facilitate their successful social adaptation.

On the other hand, morphological damage in MS is highly variable both with regard to the load, location and size of demyelinating lesions and in relation to individual global and regional cortical thinning. The particular phenotype of MS introduces additional specific features of brain damage. This explains the heterogeneity of social cognition impairments in terms of their severity and regarding the predominant disturbance of certain social cognitive domains. According to Henry, while testing empathy and ToM skills, it is also recommended to perform in parallel direct mapping of underlying MS‐related neuropathology for detecting a link between structural brain pathology and social cognitive impairments. Pöttgen estab‐ lished a deficient ability to reason about the mental state of others (ToM) and to have insight into the emotional stages and feelings of others (empathy) in the early stages of RRMS [21, 22], even in patients who have no substantial neuropsychological deficits. Emotional prosody comprehension may also be disrupted in the early stages of RRMS [6]. It is argued that this is the earliest social cognitive impairment in patients with MS. Deteriorated emotional percep‐ tion at this early stage can create a difficulty in perceiving nuances, such as sarcasm, irony and sincerity, which may lead to interpersonal problems. To confirm these observations, interna‐ tional research with larger groups of patients is required. Data from this study indicate that one year after diagnosing a patient with CIS and RRMS, they experience diminished power of attention and memory speed, which is related to a capacity for fewer working hours, fatigue, depression and may have a negative impact, as opposed to self‐efficacy, which affects working hours positively. The level of ToM abilities and their relation to the above‐mentioned conse‐ quences have not been followed up.

Information on social cognition impairments and different forms of MS is still scarce. The main controversies that we encountered in the course of reviewing the material on the topic are about how the grade of disturbance of social cognition skills relates to the state of general cognition, on the one hand, and to the grade of physical disability and/or the duration of the disease, on the other. These issues remain disputable due to the small size of patient cohorts and the lack of homogeneity within the groups of conducted studies. Moreover, the majority of studies on social cognition skills in MS assess the patients' social cognitive skills at a given point without following up on their development over time. This prevents us from making conclusions about their dynamics during the course of the disease or taking into account the effect of a therapeutic and/or rehabilitation approach. Extensive long‐term follow‐up studies with well‐defined inclusion criteria, consistent sample characteristics and a wide range of clinical and imaging measurements could establish which domains of ToM change in the course of the disease, in what way and at to what extent.

We devoted a lot of time to reviewing studies on social cognition also in other neurodegener‐ ative and mental diseases. We were impressed with the extensive research in skills for interpersonal problem solving, for recognizing social cues, for detecting situational character‐ istics and for solving situation connection tasks. Our opinion is that a similar approach towards social cognitive impairments in MS would throw additional light on the objective evaluation of the patient's dealing with real situations in a social context. Even studies on the relation between social cognition disturbances and functional outcome define this relation in general terms, without specifying which domains of social cognition should refer to which functional outcome domains. Resolving these issues in the MS field is a challenge for scientists requiring uniform strategies, long‐term follow‐up, creativity and interdisciplinary cooperation among researchers.

Two longitudinal studies in schizophrenia provide evidence for the predictive role of emo‐ tional perception in the functional outcome at a later point in time [145, 146]. Their findings support the causal relationship between social cognition and functional outcome, which gives us good grounds for drawing attention to the opportunity for similar long‐term studies in patients with MS. Surprisingly, despite the chronic nature of MS, which affects young people and inevitably disables them both physically and neuropsychologically, psychotherapeutic or psychoeducational programs are still widely lacking for MS, while being successfully imple‐ mented for other neuropsychiatric diseases associated with social cognition deficiency, such as alcoholism, schizophrenia, autism, Parkinson's disease and depression [22].

Irrespective of the limitations of most studies, they share the unanimous opinion that social cognition impairments in MS are a common finding in the early stages of the disease and are characterized by clinical significance. Functional MRI often objectifies deteriorations within the mentalizing network before structural brain disorders are detected. The cortical reorgan‐ ization reported in these studies may serve as an objective marker for follow‐up over time. Unfortunately, fMRI is not yet a routine method of examination due to the high cost, study complexity and lack of unified standards of interpretation.
