Uncovering the Neural Bases of Cognitive and Affective Empathy Deficits in Alzheimer’s Disease and the Behavioral-Variant of Frontotemporal Dementia

INTRODUCTION

Empathy represents a multifaceted and adaptive process that provides the foundation for successful social functioning and prosocial behavior. Despite its fundamental contributions to social cognitive function, there remains no firm consensus on how to define or accurately measure empathy [reviewed by 1]. Definitions of empathy have tended to emphasize cognitive and affective dimensions, wherein the individual must understand and appreciate the other person’s experience (cognitive) and share the emotional experience of the other person (affective) [2, 3]. These separable dimensions are typically proposed to map onto underlying mentalizing and experience sharing processing streams, respectively, which in turn engage largely dissociable neural systems [reviewed by 4]. While the capacity for empathy has been proposed to rely upon a number of transversal cognitive processes including affective arousal, emotion recognition, executive function, and emotion regulation [1], the modulating role of a set of domain-specific mechanisms to the experience of empathy remains a source of debate in the literature [reviewed by 4]. As such, the utility of current models of empathy has been questioned along with the tendency to deconstruct such complex cognitive phenomena into a discrete set of sub-processes [4]. The complexity of empathy is further reflected on the neuroanatomical level with functional neuroimaging studies implicating a distributed neural network including dorsolateral and medial prefrontal, frontoinsular, temporoparietal, and limbic structures during experimental tasks assessing empathy in healthy individuals [reviewed by 2, 5].

Impaired capacity for empathy represents one of the core clinical features of the behavioral-variant of frontotemporal dementia (bvFTD) with an early loss of empathy emphasized as a primary symptom in the recently revised diagnostic criteria [6]. BvFTD patients display emotional blunting, decreased social interest, loss of affection and warmth, and diminished responsiveness to the feelings of others [7, 8] in the context of marked emotion recognition difficulties [9, 10] and an inability to understand and infer the beliefs and perspectives of others [11, 12]. These striking deficits in socioemotional processing are typically interpreted as reflecting the selective vulnerability of frontoinsular and paralimbic structures in this syndrome [13, 14], and have a profound impact on the patient-caregiver relationship [8].

A large body of evidence points to pervasive deficits in the ability to mentalize, via theory of mind, to consider the thoughts, beliefs and perspectives of others in bvFTD [12]. These mentalizing impairments manifest across a range of experimental tasks assessing false belief [11], detection of social faux pas [15, 16], attribution of intentions in humorous cartoons [17–20] and social scenarios [21, 22], and understanding and adopting the viewpoint of others [23]. Cognitive empathy, defined here as the ability to understand and appreciate the emotions of others, is proposed to rely upon a core mentalizing component which enables the individual to draw inferences about the emotional experience of others [4]. The well-documented deficits in cognitive empathy in bvFTD potentially reflect the disruption of a core mentalizing mechanism, as well as broader processes including executive function and emotion recognition [24]. Importantly, these impairments occur irrespective of the emotional valence of the scenario, with reduced cognitive empathy manifesting across positive and negative stimuli on the Multifaceted Empathy Test in bvFTD [25]. Accordingly, a fundamental deficit in the ability to understanding the beliefs [23] and affective experiences [20] of others is present. These observations are further corroborated by caregiver reports of disrupted cognitive empathy in bvFTD relative to Controls [7, 26–28] and patients with Alzheimer’s disease (AD) [8, 29] using the Perspective Taking subscale of the Interpersonal Reactivity Index, as a surrogate for cognitive empathy.

A similar picture emerges with respect to affective empathy, defined here as the ability to share the emotions or the emotional experience of others [4]. These impairments are perhaps not surprising when considered in relation to the profound socioemotional disturbances characteristic of the bvFTD syndrome [6, 30]. Marked deficits have been observed in bvFTD regarding the sharing of emotional experiences of others on story-based empathy tasks [31]. These affective empathy deficits appear most pronounced where negative experiences are concerned with patients displaying significantly reduced levels of shared emotional experiences and significantly attenuated emotional reactions to negative stimuli on the Multifaceted Empathy Test [25]. Caregiver ratings again confirm reduced feelings of concern, warmth, and compassion for less fortunate others in comparison with healthy Controls [7, 26] and patients with AD [8, 29] using the Empathic Concern subscale of the Interpersonal Reactivity Index (IRI) [3] as a surrogate for affective empathy.

Neuroimaging studies point overwhelmingly to the degeneration of key frontoinsular, limbic, and lateral temporal regions in the social brain in driving these social cognitive deficits in bvFTD. Notably, grey matter atrophy in medial prefrontal regions has been shown to correlate with a reduction in empathic concern on experimental tasks indexing intentional harm [32], and ratings of empathic concern on the IRI [26]. In addition, limbic structures including the amygdala, and the temporoparietal junction have been found to correlate with empathy impairments on a non-verbal emotion attribution empathy task [33], while right-lateral temporal structures have been implicated across a range of social cognitive impairments in bvFTD including mental state attribution from cartoon scenarios [17], emotion attribution on a nonverbal task [33], and ratings of total empathy in a mixed FTLD sample on the IRI [7]. Interestingly, bvFTD patients have been shown to overestimate their capacity for empathic concern on the IRI, attributable to atrophy in predominantly right-sided structures including the right anterior inferior temporal gyrus, and right posterior insula [28]. In addition, a recent study revealed that alterations in resting-state activity in medial prefrontal and limbic networks underpin deficits in the attribution of emotions on a cartoon task in this syndrome [31]. As such, the evidence to date converges to suggest a specific vulnerability in a distributed network of regions in bvFTD that support the capacity for cognitive and affective aspects of empathy. It remains unclear, however, whether this susceptibility produces a global disruption in empathy, or impacts differentially on cognitive versus affective dimensions. In addition, it remains unclear how the neuroanatomical signature of empathy deficits potentially differs according to dementia subtype.

Delineating the precise neural substrates of cognitive versus affective empathy disruption is directly relevant for understanding disease-specific profiles of impairment in younger-onset dementia syndromes. With increasing evidence of prominent episodic memory impairments in bvFTD [34, 35], it has been suggested that social cognitive dysfunction represents a more effective means of differentiating between bvFTD and patients with AD [36]. While socioemotional processing is generally held to remain relatively intact in AD with advancing disease severity, a recent longitudinal study uncovered a significant decline across a range of socioemotional processes in AD including emotion recognition and sarcasm detection [37], albeit in the context of global cognitive dysfunction. Similarly, studies of social cognition in AD have revealed significant deficits in mental state attribution; however, these deficits appear largely modulated by general cognitive decline [17, 20]. As such, the evidence to date reveals a mixed picture where social cognitive deficits in AD are concerned, and the neural substrates of these processes remain unclear.

The objective of the present study was to contrast directly the capacity for cognitive versus affective empathy in bvFTD in comparison with disease-matched cases of AD and to elucidate the neural substrates of these deficits. We predicted that empathy would be globally disrupted across cognitive and affective domains in bvFTD, however, only cognitive empathy deficits would be evident in AD. Moreover, we hypothesized that cognitive empathy disruption in AD would stem largely from global cognitive dysfunction in this syndrome rather than a primary deficit in empathy per se. Using voxel-based morphometry of structural MRI scans, we sought to determine the neural correlates of these deficits as an important step to identify the mechanisms which drive social cognitive impairment in neurodegenerative disorders and to elucidate the key structures which must be functional to support complex social cognitive processes.

METHODS AND MATERIALS

RESULTS

DISCUSSION

The objective of this study was to investigate the capacity for empathy across cognitive and affective domains in bvFTD and AD, and to identify the neural substrates of empathy deficits in these syndromes. Our findings reveal important dissociations between bvFTD and AD patients in terms of their capacity to accurately understand and share the affective experience of others. Notably, a global disruption in the experience of empathy, irrespective of domain, was observed in bvFTD in keeping with their well-documented impairments in social cognition. In contrast, cognitive empathy was exclusively compromised in AD, in the context of a relative preservation of affective empathy. Controlling for overall cognitive functioning served to ameliorate cognitive empathy deficits in AD, yet impairments persisted in the bvFTD group across cognitive and affective subscales. This loss of empathy was found to relate to the vulnerability of a distributed network of regions, centered on the frontoinsular cortices, the integrity of which is crucial for successful social functioning.

A profound disruption in the capacity for empathy was found in bvFTD, in keeping with previous findings in the literature [7, 33] and reflecting the hallmark clinical features of behavioral egocentrism and interpersonal difficulties in this group [6]. These deficits emerged irrespective of empathy subdomain and persisted despite controlling for overall level of cognitive dysfunction. Voxel-based morphometry analyses permitted us to dissociate between current cognitive versus affective empathy disruption on the neuroanatomical level, revealing separable neural substrates of empathy loss in bvFTD. Impaired capacity for cognitive empathy in bvFTD was strongly associated with grey matter intensity decrease in a distributed set of regions including the lateral temporal cortices and temporal pole, OFC, medial PFC, and insular cortices bilaterally - key nodes of the “social brain” [66]. While this pattern of results was bilateral, right-sided involvement was particularly prominent, in keeping with previous reports of empathy disruption in neurodegenerative disorders using the IRI [7]. The right temporal pole has been suggested to play an integral role in the linking of sensory representations with emotional responses and social memory [67], facilitating the preferential processing of socially relevant concepts [68]. As such, damage to this region may disrupt knowledge of social concepts which are essential to accurately infer the perspective of another [69]. Our findings underscore the prominence of medial prefrontal regions in facilitating complex mental attribution processes [70] and highlight a specific vulnerability of medial prefrontal, frontoinsular, and anterior cingulate regions in the origin of cognitive empathy disruption in bvFTD [71]. Notably, these anterior brain regions largely recapitulate the Salience Network, which is proposed to play a unique role in processing emotionally salient internal and external stimuli, permitting the differentiation between self- and other [71, 72]. Importantly, our results add to a growing body of evidence emphasizing the importance of right-sided brain structures in mediating the characteristic interpersonal and socioemotional disturbances seen in this syndrome [17, 73–75].

Turning our attention to affective empathy disruption in bvFTD, our analyses revealed that grey matter intensity decrease in predominantly left-sided regions including the left OFC, left inferior frontal gyrus, left insular cortex, left thalamus, left putamen, and the bilateral mid-cingulate gyrus related to empathic concern deficits in this group. Our findings resonate with previous reports of significant left orbitofrontal, lateral temporal [30], and insula [33] involvement in socioemotional deficits in this syndrome, yet depart from a recent study demonstrating an association between right-sided anterior temporal and insular atrophy and the inaccurate estimation of affective empathy capacity in bvFTD [28]. As such, the neural substrates of the capacity for affective empathy diverge somewhat from those underpinning the accurate self-evaluation of this process. Interestingly, a recent study demonstrates that damage to left frontoinsular circuits in bvFTD disrupts prosocial reasoning with the suggestion that deviations from normative social behavior may, in part, reflect alterations in empathic concern [76]. Our finding of a prominent role for the mid-cingulate gyrus in empathic concern in bvFTD is in line with the view that this region occupies a central position in the neural circuits specialized for affective empathy [77]. Moreover, functional neuroimaging studies reveal robust activation of this region when healthy individuals immerse themselves in the affective context of another person, most prominently when that context requires empathy for personal distress or pain [5, 79]. As such, the mid-cingulate cortex is well placed to integrate affective with contextual information, and in coordination with the anterior insular, forms part of an affective-motivational network that is engaged in interoceptive awareness and the representation of emotional experiences [80]. Finally, our overlap analysis localized the left OFC and insular cortices as the common regions implicated in empathy disruption, irrespective of IRI subscale, in bvFTD in line with influential theories espousing a critical role for frontoinsular circuits in the origin of the hallmark socioemotional disturbances in this syndrome [71]. Damage to this frontoinsular network likely underlies much of the affective disturbance displayed by patients in their everyday lives, and potentially accounts for the consistent findings of grossly attenuated responses to the suffering of others in bvFTD [32].

In contrast, our findings suggest that perspective taking deficits in AD arise primarily as a consequence of cognitive dysfunction, rather than a primary impairment in empathy per se [15, 81]. Caregivers rated the capacity for cognitive empathy as being disrupted in AD, however, these impairments were ameliorated when overall cognitive functioning was controlled for in the analyses. The neural substrates of these deficits reflected atrophy primarily in left temporoparietal regions of the brain including the left temporal fusiform cortex, left inferior temporal gyrus, left angular gyrus, and bilateral middle and superior posterior temporal gyrus. These regions are consistently affected from early in the AD disease course with well documented alterations in volume [82] and glucose metabolism [83]. The temporoparietal junction is posited to serve a central role in representing the mental states of others [84] with the observation that damage to left temporoparietal structures impairs higher-level social reasoning [85]. Our findings resonate with a recent study which reported an impaired capacity to infer the beliefs of others in AD attributable to reduced metabolism in the left temporoparietal junction [23]. The authors proposed that with advancing disease severity, and increasing pathology in temporoparietal regions, social cognitive deficits likely become more pronounced in AD. This position is supported by longitudinal studies demonstrating significant decline in social cognitive functioning in AD with disease progression [37]. Our findings suggest, however, that the origin of these deficits are predominantly cognitively driven, in that controlling for global cognitive function ameliorated perspective-taking deficits in this group. This finding stands in contrast with the bvFTD group, in which the persistence of perspective-taking deficits likely reflects the disruption of core socioemotional processes, beyond that attributable to global cognitive dysfunction. Importantly, our findings underscore clinical and anecdotal reports of relatively spared capacity for affective empathy [8], with AD patients retaining a sense of warmth and compassion for others and a preserved sensitivity to detect salient socioemotional cues [71]. We suggest that it will be important for future studies to clarify the evolution of cognitive versus affective dimensions of empathy with disease progression in AD and to determine the neural substrates which support this spared capacity for empathic concern.

A number of methodological limitations warrant consideration in the current context. While our results converge well with previous studies using the IRI in bvFTD, the reliability and validity of this measure in neurodegenerative populations remains unknown. As we relied upon caregiver ratings of empathy in our patient groups, future studies using experimental tasks to investigate the expression of empathy in naturalistic settings are required to clarify how the deficits we report here manifest in the everyday environment of the individual. This is particularly relevant to determine the relationship between loss of empathy and the hallmark affective disturbances typically seen in FTD. Further, we compared caregiver ratings for patients with that of self-report in Controls. While we would not expect cognitively intact healthy older Controls to show a loss of empathy, it will be important to replicate our findings using informant ratings in the Control group. Notably, we did not find evidence of a significant relationship between facial emotion processing and affective empathy in FTD, a finding which may reflect some degree of separation between empathy and basic emotion processing. This proposal clearly warrants further exploration. Our voxel-based neuroimaging results did not survive conservative corrections for multiple comparisons (i.e., Family-Wise Error) and were therefore reported uncorrected at p < 0.001. We reduced the potential for false positive results, however, by employing a strict cluster extent threshold of 100 contiguous voxels [86]. Given our sample size and this application of strict thresholds, we are confident that our results do not represent false positives. In addition, co-atrophy effects represent a potential confound when dealing with neurodegenerative conditions displaying progressive brain atrophy across distributed regions, although our findings here dovetail well with previous reports in the literature. We suggest, however, that it will be important to replicate these findings in a larger patient cohort using corrected neuroimaging results and controlling for possible co-atrophy effects. Finally, given the recent shift in perspective from studying brain structures in isolation to considering the integrity of large-scale functional brain networks [71, 87], we suggest it will be important for future work to delineate how alterations in structural and functional connectivity particularly of frontoinsular regions of the Salience Network impinge upon the capacity for cognitive and affective empathy across dementia syndromes.

CONCLUSIONS

In summary, our findings corroborate the well-established observation of marked social cognitive deficits in bvFTD, manifesting across cognitive and affective forms of empathy. These socioemotional deficits reflect the degeneration of medial prefrontal, frontoinsular, and lateral temporal regions, which appear crucial for successful social cognitive functioning. Our results offer important insights into the neurocognitive mechanisms underpinning socioemotional changes in bvFTD and underscore the importance of frontoinsular regions in supporting successful social functioning.