Moral processing deficit in behavioral variant frontotemporal dementia is associated with facial emotion recognition and brain changes in default mode and salience network areas

Abstract Introduction Behavioral variant frontotemporal dementia (bvFTD) is associated with abnormal emotion recognition and moral processing. Methods We assessed emotion detection, discrimination, matching, selection, and categorization as well as judgments of nonmoral, moral impersonal, moral personal low‐ and high‐conflict scenarios. Results bvFTD patients gave more utilitarian responses on low‐conflict personal moral dilemmas. There was a significant correlation between a facial emotion processing measure derived through principal component analysis and utilitarian responses on low‐conflict personal scenarios in the bvFTD group (controlling for MMSE‐score and syntactic abilities). Voxel‐based morphometric multiple regression analysis in the bvFTD group revealed a significant association between the proportion of utilitarian responses on personal low‐conflict dilemmas and gray matter volume in ventromedial prefrontal areas (p height < .0001). In addition, there was a correlation between utilitarian responses on low‐conflict personal scenarios in the bvFTD group and resting‐state fractional Amplitude of Low Frequency Fluctuations (fALFF) in the anterior insula (p height < .005). Conclusions The results underscore the importance of emotions in moral cognition and suggest a common basis for deficits in both abilities, possibly related to reduced experience of emotional sensations. At the neural level abnormal moral cognition in bvFTD is related to structural integrity of the medial prefrontal cortex and functional characteristics of the anterior insula. The present findings provide a common basis for emotion recognition and moral reasoning and link them with areas in the default mode and salience network.


| INTRODUCTION
Behavioral variant frontotemporal dementia (bvFTD) is a neurodegenerative disorder typically associated with changes in personality and behavior, accompanied by fronto-temporal and subcortical atrophy. Deficits in emotion recognition in bvFTD have been reported consistently and in multiple modalities like facial (Rosen et al., 2002), bodily (Van den Stock, De Winter, et al., 2015) and musical expressions (Omar et al., 2011). This has led to the hypothesis that there is a common basis for these multimodal socio-cognitive deficits. Clinically, one of the most striking symptoms of bvFTD patients is early loss of appropriate emotional reactions to salient events. For instance, bvFTD patients may react undisturbed to incidents which normally would trigger significant emotional reactions, e.g., losing their job (Miller, 2014). This example also illustrates that the deficit cannot be confined to "affective empathy" (Rankin, Kramer, & Miller, 2005), as it also pertains for events outside a social context. A deficit in emotional experience, i.e., feelings (Damasio & Carvalho, 2013) may indeed constitute the common underlying basis of multimodal emotion recognition deficits. Furthermore, should this indeed be the case, it can be hypothesized that it has a similar influence on other higher order socio-cognitive deficits like moral reasoning abnormalities (Baez, Kanske, et al., 2016;Baez, Morales, et al., 2016;Chiong et al., 2013;Mendez, 2006Mendez, , 2009Mendez, Anderson, & Shapira, 2005;Mendez & Shapira, 2009).
Assessment of moral reasoning typically consists of presenting subjects with moral dilemmas and one or more action alternatives.
A classical example is the trolley dilemma (Foot, 1967). It states that a runaway trolley is rapidly approaching five workers on the railway track. These five men can be saved, by pulling a lever, which will divert the trolley toward another track, where it will kill one other railway worker. The question for the subject is: "would you pull the lever so the trolley will kill one person instead of 5?". This type of dilemma has been used to assess, for instance, utilitarian moral reasoning and how it is influenced by the degree of conflict between the utilitarian benefit and the emotional aversion that is associated with the proposed action (high vs. low-conflict dilemmas).
Contemporary accounts of moral processing increasingly put emphasis on the emotional underpinnings of moral reasoning, in addition to the rational factors. A current dominant view on moral processing makes a distinction between "personal" (and putatively highly emotional) and "impersonal" (and putatively less emotional) moral thinking (Greene, Sommerville, Nystrom, Darley, & Cohen, 2001). A moral violation is personal if it causes serious bodily harm to a particular person, harm which does not result from the deflection of an existing threat onto a different party (Greene & Haidt, 2002), e.g., pushing a large person onto the tracks to stop a runaway trolley from killing five other people on the rail. A moral violation that does not fulfill these criteria is considered impersonal, e.g., hitting a switch that will divert the trolley to a different set of tracks where it will kill only one person instead of five. There is much debate on how emotional and cognitive processes interact during moral reasoning.
Impersonal moral dilemmas are thought to be driven by conscious cognitive processes (prefrontal regions) and require a utilitarian calculation of how to maximize welfare while "personal" moral dilemmas are likely driven by automatic emotional responses (limbic regions) (Greene, Nystrom, Engell, Darley, & Cohen, 2004;Moll, De Oliveira-Souza, & Zahn, 2008) and psychologically reflect socio-emotional processes. A study by Koenigs et al. (2007) provided support for the hypothesis that emotions play a crucial role in the generation of moral judgments. They observed that patients with damage to the ventromedial prefrontal cortex (vmPFC) showed an increased "utilitarian" pattern of judgments on personal but not impersonal moral dilemmas. Furthermore, the deficit was specific for so-called "high-conflict" personal dilemmas. High-conflict personal moral dilemmas oppose aggregate welfare to inflicting harm on others by means of a highly (emotionally) aversive action, e.g., smothering one's baby to save a group of people. In "low-conflict" personal dilemmas, the proposed utilitarian action is less emotional, e.g., ignoring the plea for help from a bleeding man at the side of the road for the sake of preserving the leather upholstery of one's car.
Interestingly, bvFTD is also associated with increased utilitarian judgments and autonomic reactivity on personal, but not on impersonal moral dilemmas (Chiong et al., 2013;Fong et al., 2016;Mendez & Shapira, 2009), although it is not known whether the deficit is related to high versus low-conflict personal dilemmas. Considering the significant emotional load in personal moral dilemmas, combined with the emotional recognition deficits in bvFTD (Kumfor & Piguet, 2012), this specific abnormality in judgments of personal moral dilemmas may link with a deficit in emotional recognition. However, no empirical association between emotion recognition and moral reasoning has been reported so far. In the present study, our aim was to fill these gaps in the literature and increase the knowledge of moral deficits in bvFTD.
For this purpose, we manipulated the level of conflict in personal moral dilemmas (high-vs. low-conflict). This allows a critical test of two conflicting hypotheses relating to the nature of emotional-moral deficits in bvFTD. The first one we term the "threshold"-hypothesis: if emotional deficits in bvFTD show a progression from subtle to manifest emotional cues and endorsement of a utilitarian action requires overcoming a critical level of emotional aversion against inflicting direct harm to another person, then a deficit on low-conflict personal dilemmas would precede a deficit on high-conflict personal dilemmas (which require a more severe blunting to emotional cues). Support for this hypothesis comes from studies showing that bvFTD impairs recognition of low-but not high-intense emotional expressions Kumfor et al., 2011) On the other hand, if bvFTD results in a reduced recognition of emotion cues regardless of intensity (i.e., from subtle to extreme), then a deficit on both low-and high-conflict moral dilemmas would be expected ("overall"-hypothesis). Support for the "overall"-hypothesis comes from a study documenting impaired recognition of caricature (i.e., exaggerated) facial expressions (Kumfor, Irish, Hodges, & Piguet, 2013). To further document the nature of moral deficits in bvFTD, particularly a possible involvement of emotional processes in moral judgments, the present study investigates for the first time associations between measures of emotion recognition and moral reasoning.
The second aim was to investigate the associated neuroanatomy of personal moral processing deficits in bvFTD, which has not been explored hitherto. There is evidence from other moral reasoning paradigms that moral processing abnormalities in bvFTD are primarily associated with regions in the salience and default mode network (anterior cingulate, ventromedial prefrontal and posterior cingulate cortex, temporo-parietal junction) (Baez, Kanske, et al., 2016;Baez, Morales, et al., 2016;Chiong et al., 2013). Analogous to findings in vmPFC patients, we hypothesize a critical involvement of the vmPFC (Koenigs et al., 2007). The novel aspect that the present study adds to the field is the functional brain characterization of moral processing deficits in bvFTD by means of fractional Amplitude of Low-Frequency Fluctuations (fALFF) (Zou et al., 2008). fALFF is a measure of regional brain activation over time and across the entire brain and has been proven a valuable biomarker in neurodegenerative disorders (Han et al., 2012;Mascali et al., 2015).

| Participants
Thirteen patients diagnosed with probable bvFTD and 19 healthy controls took part in the study. Patients were recruited from the memory clinic and the Old Age Psychiatry Department of University Hospitals Leuven (Leuven, Belgium) (N = 8) as well as from the Neurology Department at the regional Onze-Lieve-Vrouw Ziekenhuis Aalst-Asse-Ninove (Aalst, Belgium) (N = 5). Diagnoses were made by experienced neurologists or old age psychiatrists after clinical assessment, collateral history, cognitive neuropsychological testing, and suggestive patterns of atrophy on structural MRI. In 11 patients, diagnosis was also based on a typical pattern of hypo-metabolism on a [18F] Fluorodeoxyglucose PET scan. All patients fulfilled the criteria for "Probable bvFTD" (Rascovsky et al., 2011). Patients initially presented with changes in behavior and personality displaying disinhibition, apathy and/or perseverative/ compulsive behavior. At inclusion, mean symptom duration assessed by hetero-anamnesis equaled 2.11 years (SD = 1.04). Patients were included after clinical judgment deemed them able to successfully undergo an experimental scanning session. Note that an additional six patients agreed to participate, but no experimental scanning data could be acquired due to a lack of cooperation and/or agitation. Genotyping for known mutations was performed in six patients (GRN & C9orf72 = 3; GRN = 2; GRN & MAPT = 1). All results of the genetic analyses were negative. All participants also took part in our previous studies on bvFTD (De Winter, Timmers, et al., 2016;Jastorff et al., 2016;Van den Stock, De Winter, et al., 2015).
Healthy control subjects were recruited through a database of elderly volunteers as well as through advertisements in a local newspaper. Exclusion criteria included present or past neurological or psychiatric disorders including substance abuse as well as significant systemic comorbidities or use of medication susceptible to affect the central nervous system.
The study was conducted according to the Declaration of Helsinki and approved by the ethical committee of University Hospitals Leuven, Belgium. All subjects gave written informed consent. All subjects had normal or corrected-to-normal visual acuity. All participants were right-handed as assessed through the Edinburgh Handedness Inventory. Demographic and clinical data are presented in Table 1.

| Judgment of moral dilemmas
Subjects were presented with 50 verbal descriptions of hypothetical scenarios (see: http://www.nature.com/nature/journal/v446/ n7138/extref/nature05631-s1.pdf). All the scenarios have a very similar grammatical structure and each scenario ends with the question whether the subject would perform a hypothetical action in the respective scenario, which subjects were instructed to answer. The scenarios were categorized into three groups: non-moral (involving practical dilemmas; n = 18), impersonal moral (involving impersonal weighting of harms and benefits; n = 11), and personal moral (involving utilitarian infringements of personal rights; n = 21) (Greene et al., 2001). The latter category was subdivided into two subcategories, based on a validation study in normal subjects (Koenigs et al., 2007).
The subdivision was related to the magnitude of the conflict between the utilitarian benefit and the emotional aversion that is associated with the proposed action: high (n = 13) versus low-conflict (n = 8) dilemmas. The scenarios were translated into Dutch by a registered translation company and the procedure was further similar to the one described in (Koenigs et al., 2007).
In The vast majority of people who take the vaccine develop an immunity to a certain deadly disease, but a very small number of people who take the vaccine will actually get the disease that the vaccine is designed to prevent. All the available evidence, which is very strong, suggests that the chances of getting the disease due to lack of vaccination are much higher than the chances of getting the disease by taking the vaccine. Would you direct your agency to encourage the use of this vaccine in order to promote national health?" • Personal low-conflict moral dilemma: "You are driving along a country road when you hear a plea for help coming from some roadside bushes. You pull over and encounter a man whose legs are covered with blood. The man explains that he has had an accident while hiking and asks you to take him to a nearby hospital. Your initial inclination is to help this man, who will probably lose his leg if he does not get to the hospital soon. However, if you give this man a lift, his blood will ruin the leather upholstery of your car. Would you leave this man by the side of the road in order to preserve your leather upholstery?" • Personal high-conflict moral dilemma: "Enemy soldiers have taken over your village. They have orders to kill all remaining civilians. You and some of your townspeople have sought refuge in the cellar of a large house. Outside you hear the voices of soldiers who have come to search the house for valuables. Your baby begins to cry loudly.
You cover his mouth to block the sound. If you remove your hand from his mouth his crying will summon the attention of the soldiers who will kill you, your child, and the others hiding out in the cellar. To save yourself and the others you must smother your child to death. Would you smother your child in order to save yourself and the other townspeople?" The stimuli were presented using presentation ® software.

| Emotion processing
A series of psychophysical experiments was conducted to assess emotion processing across category (eyes, faces, bodies), motion (static, dynamic), and task (detection, discrimination, matching, selection, categorization). Only a brief description of every experiment is given here, as all procedures have been described in detail elsewhere.

Adapted Reading the mind in the eyes test (RMET)
We adapted the RMET to a simultaneous 2-alternative forced-choice match-to-sample task. Patients are presented with a rectangular pic-  Table S1.

Facial emotion discrimination
This task is a subtest from the Florida Affect Battery (FAB) (Bowers, Blonder, & Heilman, 1999) and consists of simultaneous presentation of two facial expressions. The subject has to indicate whether both pictures express the same emotion.

Static facial emotion matching
Subjects are asked which of two emotional faces displayed at the bottom express the same emotion as a third face displayed on top of the screen. The three faces on display always had a different identity (de Gelder, Huis in 't Veld, & Van den Stock, 2015).

Static bodily emotion matching
The procedure here is similar to the static facial emotion matching experiment, but with stimuli of bodies instead of faces (de Gelder & Van den Stock, 2011).

Dynamic facial emotion matching
The procedure here is similar to the static facial emotion matching experiment, but with dynamic instead of static stimuli (Zhu et al., 2013).

Dynamic bodily emotion matching
The procedure here is similar to the dynamic facial emotion matching experiment, but with stimuli of bodies instead of faces (Van den Stock, De Winter, et al., 2015).

Facial emotion selection
Subjects are instructed to indicate which of five facial expressions matches a verbal label. This is a subtest from the FAB (Bowers et al., 1999).

Facial emotion categorization
Subjects are instructed to indicate which of five verbal labels matches a picture of a facial expression. This is a subtest from the FAB (Bowers et al., 1999).
Stimuli of all these tasks except for the RMET and those from the FAB were presented using presentation ® software.

| Brain imaging
All subjects were scanned on a single 3 Tesla Philips Achieva scanner using a 32-channel head coil.

| Functional
Preprocessing of the functional scans included slice time scan correction by means of cubic spline interpolation, 3D motion correction by means of trilinear/sinc interpolation and linear trend temporal filtering. We used an adaptation of Amplitude of Low Frequency Fluctuation as a measure of variability in resting-state activation (Zang et al., 2007). In ALFF analyses, voxel time series are bandpass filtered

| bvFTD atrophy
GM images were entered in a general linear model and a two sample t-test was performed for a whole-brain group comparison (p height < .001, clustersize > 100 voxels). The results are displayed in Figure 1 and reveal reduced gray matter volume in the bvFTD group in anterior temporal, subcortical, and to a lesser extent frontal regions.
Visual inspection of the individual scans by an experienced clinician (MV) revealed that the sample was composed of patients with primarily temporal (N = 7), primarily frontal (N = 3) and fronto-temporal (N = 3) atrophy.

| Moral judgments
For the nonmoral judgments, we counted for every subject the number of "yes" responses. The moral judgment responses (i.e., yes or no) of every subject were coded as a function of utilitaristic or not. The results of the moral judgments as a function of group, personal affiliation (impersonal and personal) and conflict level are displayed in

| Emotion processing
For every experiment, we first computed the mean response time and standard deviation of the response times for every subject. There were no clear group differences on RMET (U = 140.5, p = .520) and face emotion selection (U = 85, p = .147).

| Moral-emotion processing correlation
As a first step in investigating an association between abnormal moral processing and emotion processing capacities in bvFTD, we performed a variable reduction of the emotion processing experiments.
We conducted a principal component analysis ( In addition to controlling for general global cognitive capacity as measured the MMSE-score, we also performed a partial correlation analysis in which we controlled for semantic capacity, i.e., language comprehension, as measured in the subtest "comprehension" of the Aachen Aphasia Test (AAT_comprehension). This also revealed a signif-

| Structural
The GM maps were submitted to a multiple regression analysis in which the score on low-conflict moral dilemmas (i.e., the proportion utilitarian responses) was entered as covariate in order to investigate correlations between performance and voxel-wise GM volume (p height < .0001, minimal cluster size = 50 voxels). Age, gender and total intracranial volume (TIV) were entered as covariates of non-interest.
Significant results were primarily located in bilateral ventromedial prefrontal cortex and frontal operculum/anterior insula (see Figure 3 and Table S2).

| Functional
The fALFF maps were submitted to a multiple regression analysis in which the score on low-conflict moral dilemmas was entered as covariate in order to investigate correlations between performance and voxel-wise fALFF (p height < .005, minimal cluster size = 10 voxels). Age and gender were entered as covariates of noninterest. Significant results were primarily located in the right frontal operculum/anterior insula (see Figure 3 and Table S2).

| DISCUSSION
The present results reveal that increased utilitaristic moral behavior is associated with decreased face emotion recognition in bvFTD.
The control analyses we performed did not provide any evidence that global cognitive decline or semantic abilities could explain this link, as we statistically controlled for these confounds. The correlation between moral deficits and face emotion recognition is in line with current views on moral cognition, which emphasize the importance of emotional underpinnings in moral behavior (Damasio, 1994;Haidt, 2001). Here, we report that deterioration of moral reasoning is associated with abilities in facial emotion recognition. We hypothesize that a diminished subjective experience of emotional sensations links emotion recognition and moral cognition impairment. Notably, reduced experience of physical sensations like pain and temperature have also been reported in bvFTD (Fletcher et al., 2015). Reduced experience of emotional sensations is a key clinical manifestation of bvFTD, which extends empathic deficits (Rascovsky et al., 2011). Both emotion recognition and moral cognition have been associated with empathic abilities in the normal population (Bzdok et al., 2012 T A B L E 2 Component loadings and communalities based on a principal components analysis with oblimin rotation for nine emotion processing variables in bvFTD in bvFTD (Baez et al., 2014;Rankin et al., 2005). As the present main finding is correlational in nature, no claims can be made regarding the causal and consequential socio-cognitive deficits in bvFTD and -by extension -in other syndromes associated with deficits in emotion recognition, moral cognition, and feelings.
The moral deficit in bvFTD was specific for low-conflict and not high-conflict personal dilemmas. It is unlikely that this pattern is explained by cognitive deficits, such as impaired language or executive functions, as these have a similar influence in all conditions. A similar argument can be made regarding the confounding influence of mentalizing deficits, as these also equally apply to the high-conflict condition. It has been proposed that an emotional response (preventing direct harm to others) has to be overcome in order to enable utilitaristic behavior (Greene et al., 2001(Greene et al., , 2004, and that this threshold is increased for high-conflict compared to low-conflict personal dilemmas. It is possible, then, that the emotional response triggered by the high-conflict dilemmas was too strong to be overcome in our bvFTD sample. At the same time, subjects were more easily inclined towards utilitaristic behavior in low-conflict dilemmas, where the emotional response was less salient. The present results thus support the "threshold"-hypothesis for moral-emotion deficits in bvFTD stating that recognition deficits of subtle emotion cues precede those of more intense emotion signals Kumfor et al., 2011).
The present results profile of the moral dilemma's contrasts to some extent with results from vmPFC patients (Koenigs et al., 2007), where a specific deficit for high-conflict dilemmas was observed.
vmPFC patients only show increased utilitarian responses in moral dilemmas where a strong emotional reaction has to be overcome, and not on dilemmas where a more subtle emotional reactions has to be overcome. The authors hypothesize that vmPFC patients use compensatory strategies when judging low-conflict moral dilemmas and do not rely on processing of social emotion cues, but rather on preserved knowledge of explicit social conventions and norms. Interestingly, these latter aspects are typically impaired in bvFTD (Bora, Walterfang, & Velakoulis, 2015;Kumfor et al., 2017).
Several anatomical subtypes of bvFTD with differential degrees of atrophy in frontal, temporal and subcortical areas have been described (Ranasinghe et al., 2016;Whitwell et al., 2009). Our sample was constituted by patients with (i) primarily frontal, (ii) primarily temporal, F I G U R E 3 Brain-behavior results. Statistical maps displaying association between proportion utilitaristic responses on the one hand and gray matter volume (red to white color coding) and restingstate activity fluctuations (blue to green color coding) on the other hand, overlaid on a normal template. Coordinates refer to MNI-space as well as (iii) fronto-temporal atrophy. However, at the group level, the atrophy was concentrated around the temporal poles, but also included orbitofrontal and anterior insular regions. The samples of other studies using the same moral paradigm (Chiong et al., 2013;Koenigs et al., 2007) showed more extensive vmPFC pathology. In that sense, the present findings complement those. On the other hand, as our sample as a group mainly displayed anterior temporal atrophy, the results may not be equally applicable to the bvFTD population with more fronto-temporal atrophy.
The imaging results are in line with recent findings in studies using a similar moral cognition paradigm. These revealed that normal subjects recruit default mode network regions during processing of personal moral dilemmas (Chiong et al., 2013;Greene et al., 2004) and that this recruitment is influenced by the salience network, in particular the anterior insula (Chiong et al., 2013). The contribution of the anterior insula has been specifically related to the processing of the emotional appraisal of moral dilemmas (Hutcherson, Montaser-Kouhsari, Woodward, & Rangel, 2015). Furthermore, increased utilitaristic responses to personal moral dilemmas in bvFTD involves diminished recruitment of the default mode network as well as a diminished influence of the salience network on this recruitment (Chiong et al., 2013). In our study, we observed that increased utilitaristic responses in bvFTD are associated with decreased gray matter volume of areas associated with the default mode network (vmPFC). This is in line with increased utilitaristic responses to personal dilemmas in patients with ventromedial prefrontal cortex lesions (Koenigs et al., 2007). Our findings extend those results by revealing that in a neurologic sample with primarily anterior temporal structural brain pathology, it is not the locus of highest atrophy, but the integrity of the vmPFC that predicts utilitaristic behavior. Hence, our findings and those from Koenigs et al. (2007) support the notion that the vmPFC constitutes an important region in the processing of emotional characteristics of moral judgments. Furthermore, we observed that baseline activation fluctuation in the anterior insula correlates with moral deficits in bvFTD.
The involvement of this region underscores the importance of emotions in moral cognition. Indeed the anterior insula has primarily been associated with awareness of feelings and internal sensations (Craig, 2009), and this area is typically atrophic in FTD (Seeley, 2010) and related to symptom severity (Van den Stock & Zhou & Seeley, 2014). In combination, these findings provide a structural and functional neuro-anatomical framework for the behavioral findings that are in line with previous studies. We hypothesize that the vmPFC is structurally associated with processing personal (high-and low-conflict) moral dilemmas. Preserved knowledge of explicit social and moral norms may partly compensate for damage to the vmPFC, but only when the emotional response that is triggered by the dilemma is below a critical threshold.
We hypothesize that the normal response profile in the bvFTD sample on the high-conflict condition may reflect the level of conflict needed to activate the anterior insula sufficiently to compensate for the lower baseline activation.
On the psychological level, high-conflict dilemmas may have the intensity to evoke emotional subjective sensations in the bvFTD group, while the intensity of the low-conflict dilemmas was insufficient to trigger a supra-threshold emotional experience.
In conclusion, the present study supports the threshold hypothesis of emotional deficits in bvFTD, stating that processing of subtle emotion cues is affected first. Secondly, the results provide evidence for an association between impaired face emotion recognition and increased utilitarian moral cognition in bvFTD, (suggesting a common basis for both deficits, possibly related to diminished subjective awareness of) emotional sensations. Abnormal moral cognition was neuro-anatomically related to structural integrity of areas of the default mode network (vmPFC) and baseline activation of areas of the salience network (anterior insula). Future research should address the causal and consequential socio-cognitive deficits, as well as more recent taxonomies of moral dilemmas (Rosas & Koenigs, 2014).