Moral Motivation and the Basal Forebrain

Journal Pre-proof Moral Motivation and the Basal Forebrain Roland Zahn, Ricardo de Oliveira-Souza, Jorge Moll

PII:

S0149-7634(19)30077-6

DOI:

https://doi.org/10.1016/j.neubiorev.2019.10.022

Reference:

NBR 3587

To appear in:

Neuroscience and Biobehavioral Reviews

Received Date:

28 January 2019

Revised Date:

24 October 2019

Accepted Date:

28 October 2019

Please cite this article as: Zahn R, de Oliveira-Souza R, Moll J, Moral Motivation and the Basal Forebrain, Neuroscience and Biobehavioral Reviews (2019), doi: https://doi.org/10.1016/j.neubiorev.2019.10.022

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Moral Motivation and the Basal Forebrain Roland Zahn a,b , Ricardo de Oliveira-Souza a,c *, Jorge Moll a

a

Cognitive and Behavioral Neuroscience Unit, D’Or Institute for Research

& Education (IDOR), Rio de Janeiro, Brazil. b

Centre for Affective Disorders, Department of Psychological Medicine,

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Division of Academic Psychiatry, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, United Kingdom. c

The Federal University of the State of Rio de Janeiro, Rio de Janeiro,

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* Corresponding author

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Brazil.

Dr Jorge Moll, MD PhD

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Cognitive and Behavioral Neuroscience Unit D’Or Institute for Research & Education (IDOR) Rua Diniz Cordeiro, 30

22281-100 Rio de Janeiro, Brazil

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e-mail: [email protected].

Highlights  Moral motivations drive humans to serve the needs of others and society.

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The basal forebrain is important for enabling moral motivation.

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This includes the septo-hypothalamic region, implicated in kinship bonding.

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And also includes the connected subgenual frontal cortex.

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Implications for prosocial behaviour and mental health are discussed.

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Abstract

Moral motivations drive humans to sacrifice selfish needs to serve the needs of others and internalized sociocultural norms. Over the past two decades,

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several brain regions have been associated with different aspects of moral

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cognition and behaviour. Only more recently, however, investigations have highlighted the importance of the basal forebrain for moral motivation. This

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includes the septo-hypothalamic region, implicated in kinship bonding across mammal species, and the closely connected subgenual frontal cortex.

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Understanding the neuroanatomy of moral motivation and its impairments will be fundamental for future research aiming to promote prosocial behaviour and mental health.

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Keywords:

moral emotions; Brodmann’s area 25; social cognition; septal area; attachment; hypothalamus; subgenual cingulate cortex; anterior cingulate cortex

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1. Introduction In a time of complex and rapidly changing social identities, there is an urgent need to understand the roots of the sheer altruism of voluntary acts, as well as the ordinary manifestations of moral behaviour in everyday life. Significant advances have been made in identifying the key neural systems

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responsible for moral cognition and behaviour in humans in general since our review over a decade ago(Moll et al., 2005). Despite the rapidly

expanding field of moral cognitive neuroscience(Fumagalli and Priori,

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2012), only recently new research has started to unveil the brain systems underpinning moral motivations (being motivated to e.g. “help an orphan

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child”), that are important for driving moral behaviour (e.g. “donating to a

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charity that benefits orphan children”, Box 1). In keeping with our view of moral cognition and emotion as inextricably linked psychologically and anatomically(Moll et al., 2005), we will argue below that moral motivations

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require both cognitive components which specify the goal of one’s action (e.g. “alleviating a child’s hunger”) as well as basic emotional elements (e.g. “a caring/attached emotional state”) which provide the motivational force

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allowing us to overcome competing selfish motivations (e.g. “buying something for oneself”). This is in keeping with psychological models of motivation that postulate closely connected, but distinct roles of (1) goal representations and (2) the magnitude (i.e. force) of their subjective emotional value(Wigfield, 1994). Moral motivations promote both costly helping behaviours and moral punishment. These motivations are fundamental for driving moral

4 behaviour in the absence of external punishment and reward contingencies, such as norm enforcement, reputation and reciprocity concerns(Gintis et al., 2008; Nowak and Sigmund, 2005). Impaired moral motivations are typically illustrated by the behaviour of psychopathic individuals, who can play the moral rules when self-interest is at stake but fail to do so otherwise (Cleckley, 1976) , a similar pattern of behaviour is observed in healthy people with psychopathic traits (Lockwood et al., 2017).

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Over the last decade, novel evidence on the neural basis of moral motivations has emerged, and as we will show in this review, has

consistently implicated a set of basal forebrain structures – namely the

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septo-hypothalamic and subgenual frontal areas. These structures are closely connected anatomically (Box 2). In this review, we will integrate this recent

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evidence for the first time to elucidate the role of these regions in moral motivation, for which we only had scarce evidence in our review over a

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decade ago(Moll et al., 2008). We will discuss the contribution of the subcortical septo-hypothalamic area to kinship bonding across species (Moll

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et al., 2012; Preston, 2013; Stack et al., 2002) and the role of the subgenual area in more complex aspects of moral motivation such as social agency, and the value of social outcomes (Moll et al., 2008; Moll et al., 2006). Crucially, these brain regions are functionally and anatomically interlocked

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with those responsible for general reinforcement and social cognition (Moll et al., 2005; Preston, 2013). Moreover, recent studies addressing moral emotions and motivation bear direct relevance for a better understanding of neuropsychiatric disorders, with potential clinical applications (Decety et al., 2013; Green et al., 2012; Harrison et al., 2012).

5 After defining moral motivation, we will review the evidence for impaired moral behaviour as observed in patient lesion studies. This is because, in contrast to functional neuroimaging in healthy individuals, lesion studies are able to identify brain regions that are necessary for a specific function(Price et al., 1999). We will then review functional neuroimaging studies in healthy individuals with direct relevance for the understanding of the role of the basal forebrain in moral motivations.

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Finally, we will discuss implications for the fields of neuropsychiatry and psychological wellbeing research.

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2. What are moral motivations?

Morality can be operationally defined as the sets of customs and values

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that are embraced by a sociocultural group to guide social behaviour(Moll et

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al., 2005). This definition, however, does not specify the motivations that drive these actions(Moll et al., 2008). Only when considering the motivations behind an action, are we able to delineate the cognitive and

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emotional components that are specific for moral behaviour as compared with social behaviour in general. Thus, moral motivation can be more sharply defined as being driven by the needs of other people, including kin,

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or society(Zahn et al., 2011b). This definition allows for individual and cultural variability but excludes other adaptive types of social motivations (e.g., abiding by social norms to avoid reputation loss, helping others to obtain social recognition or to uphold any form of self-regarding preferences). We will use the term “prosocial” behaviour as an umbrella term to describe socially adaptive behaviours when their true motivation cannot be determined.

6 The term “moral motivation” was given prominence by eighteenth century philosophers of the Scottish Enlightenment (see Box 1, (Zahn et al., 2011b)). They highlighted the central importance of moral sentiments for providing moral motivation. Modern psychologists speak of “moral emotions” rather than sentiments and generally agree on the importance of guilt and compassion/sympathy (Eisenberg, 2000; Tangney et al., 2007). Stressing the subjective and complex nature of moral sentiments which

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include cognitive ingredients such as causal attributions, we will refer to them as feelings. We may also use the term emotions synonymously with feelings or sentiments.

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As mentioned above, we conceive of moral motivation as consisting of both the motivational force and the associated goal. This definition

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highlights two key components of moral motivation: the motivational force driving behaviour and the social knowledge about the needs of others and

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about sociocultural norms(Moll et al., 2008; Zahn et al., 2007), which

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defines the goals entailed in moral motivations.

3. The neural architecture of moral motivations In this section, we will first review studies of patients with brain lesions and impaired moral behaviour before summarising evidence from fMRI in

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healthy volunteers and in psychiatric conditions. We will focus on the involvement of basal forebrain and the partly overlapping ventromedial frontal cortex (FC) subregions, in particular on the septal, hypothalamic, and subgenual regions, which have been more consistently implicated in studies of moral decisions and feelings. We emphasize, however, that it is beyond the scope of this review to systematically report all the brain regions

7 implicated in studies relevant to moral motivation and kinship bonding, or to appraise all the studies reporting activations in the basal forebrain. Among others, two isocortical brain regions that have been implicated in abstract conceptual and sequential/prospective aspects of moral goals – the superior anterior temporal cortex (ATL) and the medial frontopolar cortex, respectively – will also be briefly discussed due to converging evidence from

3.1. Brain lesions and impaired moral behaviour

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lesion and fMRI studies for their importance in moral motivations.

By demonstrating which brain regions are necessary for moral and

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prosocial behaviour, lesion studies provide important insights, even if they

relate to less confined anatomical territories such as the ventral frontal areas

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which contain but are not limited to the subgenual region. The 19 th century physician Leonore Welt provided the first review of patients who exhibited

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changes in moral behaviour as a result of a focal brain injury(Welt, 1888),(Zahn et al., 2011a). In her article, she presented the case of a furrier

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who underwent a drastic change in character after a head injury with predominant damage to the right frontal lobe. Based on the location of the injury found at autopsy in her case as well as in 12 others that she collected from the literature with similar changes in moral character, Welt concluded

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that damage to the right medial orbital region was the common denominator in all cases(Zahn et al., 2015). In the 1980s, Eslinger & Damasio stimulated new interest in the neuroanatomy of impaired prosocial and moral conduct by describing EVR, a patient with a ventromedial FC injury resulting from a tumour resection(Eslinger and Damasio, 1985). A few years later, a neurodegenerative disease originally described by Pick in

8 the late 19th century became recognised as a form of early-onset dementia (frontotemporal dementia, FTD) that could reliably be diagnosed before death based on its clinical features alone(Snowden et al., 2001). Patients with FTD consistently displayed impaired prosocial behaviour(Bozeat et al., 2000), which was independently associated with atrophy of right ATL and ventromedial FC, including the subgenual region(Liu et al., 2004). Atrophy of the subgenual region was later shown to be associated with loss of

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empathy(Rankin et al., 2006), affiliative feelings and interpersonal warmth(Sollberger et al., 2009). More recent studies have provided evidence that empathic concern is primarily impaired in FTD(Baez et al., 2014) and

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associated with posterior medial orbitofrontal atrophy (Baez et al., 2016)

close to the subgenual cortex. Loss of guilt was also reported by caregivers

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(Koenigs et al., 2007), and associated with decreased prosocial decisions in economic games(Krajbich et al., 2009) in patients with ventromedial FC

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lesions that included subgenual sectors of the orbitofrontal cortex. Converging evidence from fMRI and patients with FTD linked the

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ventromedial FC to the anticipation of negative consequences of social behaviour(Grossman et al., 2010). Less evidence is available on the behavioural effects of the subcortical parts of the basal forebrain in humans, but hypothalamic lesions were associated with aggressive

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behaviour(Haugh and Markesbery, 1983; Weissenberger et al., 2001), although endocrine disturbances may have played a role. Further studies have begun to probe moral motivations experimentally

in FTD whilst controlling for social conceptual knowledge and viceversa(Zahn et al., 2009b),(Moll et al., 2011). These studies indicate that loss of simple interpersonal moral motivations and loss of abstract conceptual

9 social knowledge (e.g., what it means to act “tactfully”) are partly dissociable (Box 3). Septal damage in FTD was associated with diminished guilt and pity, but not embarrassment in an experimental task, whilst frontopolar damage was associated with impaired embarrassment in addition to guilt and pity(Moll et al., 2011). This showed that septal damage was associated with impairments of those moral feelings that entail empathic concern for other people, whilst frontopolar cortical damage was

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associated with prosocial feelings more generally, including embarrassment which is primarily related to upholding one’s social reputation rather than

concern for others(Eisenberg, 2000). The experimental task controlled for

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other negative emotions such as anger and disgust, whose impairment was associated with amygdala and dorsomedial FC damage(Moll et al., 2011),

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although it is outside of the scope of this review to consider studies of disgust and anger. These selective patterns occurred despite comparable

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degrees of social knowledge being required to understand the stimuli used in the task. In contrast to these associations of different moral feelings with

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different frontal-subcortical lesion patterns, another study showed that FTD patients with right ATL damage displayed selective impairments of abstract conceptual social relative to non-social conceptual knowledge(Zahn et al., 2009b). These lesion studies confirmed earlier fMRI evidence of

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partly dissociable representations of abstract conceptual social knowledge in the right superior ATL(Zahn et al., 2007) and different moral feelings in frontal-subcortical regions(Zahn et al., 2009c), which can independently contribute to impaired prosocial behaviour(Krajbich et al., 2009; Liu et al., 2004). These results are further consistent with the hypothesis that frontal and subcortical basal forebrain regions are necessary for core aspects of

10 moral motivations, whereas ATL regions are relevant for representing conceptual aspects of abstract moral values which can serve as goals of complex societal value-based moral motivations (Box 3). This interpretation is based on the hypothesis that moral motivations in direct interpersonal interactions such as those driven by the perception of a sad facial expression of someone in need(Moll et al., 2005) for example, do not necessarily require more complex moral goal representations such as

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abstract conceptual goals (ATL). Taken together, lesions in the hypothalamus, the septal region and ventromedial parts of the frontal cortex, especially those including the

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subgenual cortex (BA25) and the more anterior subgenual cingulate and subgenual orbitofrontal areas, led to changes in moral behaviour which

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would be compatible with their proposed critical role for moral motivation. Lesions to other cortical brain regions which were shown to represent goals

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of socio-moral behaviour, such as the long-term consequences (frontopolar cortex, (Wood and Grafman, 2003; Zahn et al., 2017)) and conceptual

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quality of social behaviour (right superior ATL, (Zahn et al., 2009b)) led to changes in moral behaviour as well (Zahn et al., 2017) in keeping with the notion that motivations rely both on the motivational force as well as the goal representation (for further lesion evidence on the role of isocortical

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frontal regions in moral motivation, see Box 4). In contrast, lesions to the occipital and parietal cortices, posterior

inferior temporal, as well as posterior left dorsolateral, posterior dorsomedial frontal and dorsal anterior cingulate cortices are usually not clearly associated with observable inappropriate social behaviour(Moll et al., 2005). This does not preclude an important role of these regions in socio-

11 emotional functions more generally which is beyond the scope of this review. For example, the dorsal anterior cingulate region is activated for empathic simulation (Lockwood, 2016), such as sharing others’ pain(Lamm et al., 2011), with evidence for gyral versus sulcal functional subdivisions(Apps et al., 2016). Patients with anterior cerebral artery stroke regularly including the more posterior portions of the dorsal anterior cingulate develop the syndrome of “akinetic mutism” with a general lack of

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spontaneous activity and speech(Nagaratnam et al., 2004), but little evidence of selective social impairments. It is also important to note that

most ventromedial frontal subregions are necessary for prosocial behaviour,

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such as strategic cooperation, more generally (Melloni et al., 2016) rather than selective for moral motivation.

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Schadenfreude and envy were outside of the scope of this review as they are usually considered as social rather than moral feelings (Jankowski and Takahashi,

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2014). A recent study in patients with neurodegenerative disorders, however, specifically examined these emotions in moral situations (Santamaria-Garcia et al.,

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2017). Interestingly, Schadenfreude in moral situations was higher in patients with frontopolar and angular gyrus atrophy and envy in moral situations was more pronounced in patients with precuneus atrophy. Whilst interesting, it is difficult to ascertain which cognitive components of these experiences led to the described

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associations.

3.2. Moral vs. self-interested choices It is well established that patients showing impaired prosocial behaviour are often able to serve their own immediate self-interests (Eslinger and Damasio, 1985). This indicates the existence of at least partly

12 separable neural correlates of moral and selfish motivations. The studies discussed so far, however, have not made this direct comparison, which is necessary to draw conclusions about selectivity. Studies of human cooperation in economic games have paved the way for investigating the neural basis of complex altruistic behaviour (Figure 2). Using an economic game format, a charity donation paradigm was employed to determine areas of selective activation for altruistic decisions, compared

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with decisions associated with pure monetary gain for oneself(Moll et al., 2006). The septal and subgenual cortex and the anterior medial

orbitofrontal/frontopolar cortex showed selectivity for altruistic decisions,

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the latter area being more active during costly choices. Moreover, septal activations were also detected when pairs of participants relied on

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unconditional trust in their decisions to cooperate, in contrast to ventral tegmental area activity during strategic cooperation (i.e., expectancy of

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mutual gains from cooperation)(Krueger et al., 2007a). The engagement of the septal area in donation behaviour has also been confirmed in more

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recent studies(Harbaugh et al., 2007; Hsu et al., 2008). Importantly, septal activity was observed when healthy subjects observed sad faces when taking a compassionate perspective(Kim et al., 2009), and septal responses specifically predicted daily helping in another fMRI study(Morelli et al.,

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2014).

Another neuroeconomic fMRI study demonstrated that activity in septal and anterior subgenual orbitofrontal areas tracked the levels of reported guilt associated with dishonouring trust(Chang et al., 2011). The anterior subgenual orbitofrontal region was also shown to respond to voluntary contributions in a public goods game more strongly when identical

13 outcomes were interpreted as emerging from a generous intent than when they were not (Cooper et al., 2010). Furthermore, activation in the subgenual orbitofrontal region was shown for upholding a principle of social equality in costly decisions(Zaki and Mitchell, 2011). The selectivity of subgenual areas for altruistic compared with selfish decisions was further corroborated in that individuals with higher empathic concern displayed stronger subgenual cingulate activation when deciding to

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sacrifice their money to prevent others from receiving an electric shock(FeldmanHall et al., 2012) (FeldmanHall et al., 2015). Moreover,

anterior subgenual cingulate activity tracked the amounts donated in a

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charitable donation task(Hare et al., 2010) and correlated with individual differences in aversion to third-party harm(Wiech et al., 2013). A meta-

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analysis comparing selfish and vicarious reward fMRI studies found, however, that right anterior subgenual cingulate activations (BA24) were

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both found consistently in selfish and vicarious reward studies vs. low level baseline conditions(Morelli et al., 2015). This meta-analysis did not identify

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more posterior subgenual, septal or hypothalamic activations consistently for vicarious rewards as one might have expected on the basis of our review of the literature. This is not surprising, however, given that quantitative imaging meta-analyses rely on peak coordinates reported to be significant in

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the cited studies and this will bias the results against basal forebrain areas which are only reliably detected using optimized fMRI parameters to improve the otherwise high rate of signal dropout due to the vicinity of the skull and sinuses(Wastling and Barker, 2015) and by including specific a priori regions of interest to improve the statistical power of detecting activations in small brain regions. This could explain why a more recent

14 meta-analysis, which modelled signal dropout, was able to detect selective activations in the subgenual cortex (BA25) for altruistic vs. selfish decisions (Cutler and Campbell-Meiklejohn, 2019). Another difference between both meta-analyses is that Morelli et al. included vicarious rewards in a nonmoral context, whereas Cutler and Campbell-Meiklejohn specifically investigated differences between moral and selfish motivations. More recent studies have investigated moral motivation-related brain

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responses using computational models. Prosocial prediction errors were specifically encoded within the posterior subgenual cortex and adjacent septal area employing reinforcement learning models(Lockwood et al.,

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2016). In contrast, non-overlapping responses in the ventral striatum

tracked both selfish and prosocial reward prediction errors(Lockwood et al.,

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2016). Interestingly, individuals prone to empathise had a higher learning rate in the prosocial condition and higher subgenual activity for prosocial

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vs. self-reward prediction errors. Another computational modelling study measured care and distress levels to narratives of human suffering (Ashar et

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al., 2017), which predicted subsequent charitable donation. Empathic care was preferentially associated with septal activity. Whilst these computational modelling-based studies are in agreement with the proposed role of basal forebrain areas in moral motivation, a

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recent study failed to show selective brain activations for altruistic choices to lessen others’ pain by sacrificing monetary reward vs. selfish choices (Crockett et al., 2017). Instead a large cluster of ventromedial frontal activation, strongest in the pregenual area, was common to selfish and altruistic choices; the cluster spread into the subgenual frontal area. This lack of selective activation, however, may well be due to using cluster-based

15 inference at the whole brain level, thus decreasing the likelihood of detecting activations in small basal forebrain and subgenual subregions. Another recent study failing to support the selective importance of ventromedial frontal areas for altruistic choices was conducted in Vietnam Veterans with penetrating head injuries(Moll et al., 2018). The study, however, had limited value in assessing these regions, because the number of veterans with such lesions was very low. Further limitations of this study

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were that MRI scans could not be carried out due to metal injuries, and so reliance on CT scans limited the precision of lesion mapping. In addition, time post-lesion of around 40 years was exceptionally long, which meant

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that compensation as well as ageing-related and neurodegenerative changes were likely to have added variability to CT-detectable lesion-function

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associations.

16 3.3. Imaging the experience of moral feelings The investigation of the neural correlates of subjective experiences of moral feelings is important for our understanding of moral motivation. This is because, the previous section showed that while neuroeconomic paradigms can be used to infer neural correlates of moral motivations as long as appropriate control conditions are used, they usually fail to reveal the qualities of underlying emotional experience. For example, one may

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decide to sacrifice money to benefit a social cause based on either guilt avoidance or on the positive feelings derived from such action (e.g. “warm glow”; (Andreoni, 1990)).

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In this section, we review research on moral feelings with a focus on

guilt and pity/compassion, given their consistent associations with altruistic

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behaviour. We conceive of moral feelings as the subjective experience of moral motivations. Experimentally, however, fMRI studies of moral feelings

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often suffer from not being able to directly show which of the activated brain regions are related to motivating moral behaviour and which regions

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are correlates of the experience without being relevant for motivating behaviour. This is why fMRI studies of moral feelings can only be interpreted in conjunction with the evidence provided in the previous sections.

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The anticipation of guilt is important in preventing us from immoral

actions and to motivate reparative action(Eisenberg, 2000; Tangney et al., 2007). Empathic concern—a core component of empathy—is closely related to pity, compassion and sympathy, which promote altruistic helping(Weng et al., 2015). Such feelings extend beyond perceiving, sharing or simulating other's emotions, requiring an extra step of feeling for the other

17 person(Decety et al., 2012). Frontopolar activations emerge as most reproducible for both guilt(Moll et al., 2007; Zahn et al., 2009c),(Basile et al., 2011; Kedia et al., 2008; Morey et al., 2012; Seara-Cardoso et al., 2016; Takahashi et al., 2004) and compassion(Immordino-Yang et al., 2009),(Moll et al., 2007),(Fehse et al., 2015; Kedia et al., 2008) compared against equally unpleasant and complex emotions, such as indignation towards others. In addition, guilt was reproducibly associated with activations of the subgenual

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cingulate cortex (extending posteriorly to the adjacent septal area and the more anterior pregenual cingulate area in several studies) when compared with other complex negative emotions(Zahn et al., 2009a),(Green et al.,

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2012; Zahn et al., 2009c),(Basile et al., 2011; Morey et al., 2012). Septal and/or subgenual cingulate activations for guilt were found in several

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studies, however, only when modelling individual differences in guilt proneness and empathic concern(Zahn et al., 2009a),(Green et al., 2012;

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Zahn et al., 2009c). Interestingly, a study on counterintuitive utilitarian judgments found that reduced anterior subgenual cingulate cortex activity

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undergirded an increased inclination to accept harmful actions towards a third party, suggesting reduced empathic concern instead of increased explicit moral deliberation(Wiech et al., 2013). Despite these reproducible associations of subgenual cingulate and

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septal activations with individual differences in guilt-proneness and empathic concern, two recent systematic reviews of fMRI studies probing guilt(Gifuni et al., 2016) (Bastin et al., 2016) have failed to detect these regions. Because these reviews did not base their conclusions on studies controlling for individual differences in the experience of guilt-evoking stimuli, and on those studies using optimised fMRI sequences for ventral

18 frontal regions, it is not surprising that subgenual cingulate/septal activations were not given prominence and this will be important in future systematic reviews.

3.4. Social attachment and moral motivation Being able to feel attached to others is a basic ingredient for moral feelings such as compassion and guilt (Moll and Schulkin, 2009; Moll et al.,

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2011) (Preston, 2013). Specific brain structures have been critically implicated in social attachment mechanisms in non-human animals,

including pair bonding and bonding between mother and offspring(Insel

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and Young, 2001; Stack et al., 2002; Swain et al., 2012). These brain

structures include the preoptic-anterior hypothalamic area, septal nuclei and

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associated basal forebrain regions (Stack et al., 2002). These areas host abundant receptors for neuropeptides (oxytocin, vasopressin), monoamines

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(dopamine) and opioids that have been shown to influence attachmentrelated behaviours (Depue and Morrone-Strupinsky, 2005; Insel and Young,

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2001; Stack et al., 2002). Septal damage in rodents disrupts maternal caregiving (Febo et al., 2005).

Human fMRI investigations of maternal and romantic love reported

remarkably overlapping activations in these regions(Aron et al., 2005;

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Bartels and Zeki, 2004; Swain et al., 2007), and oxytocin receptor polymorphisms and prosocial temperament were shown to be associated with individual differences in hypothalamic volume and function(Tost et al., 2010). Until recently, an open question was whether brain activation associated with attachment-related experiences could be dissociated from that associated with general positive or negative emotions. A recent study

19 employed passive presentation of social narratives involving kin (i.e., associated with affiliative states) or not involving kinship(Moll et al., 2012). The results confirmed the prediction that the septo-hypothalamic region was selectively activated for affiliative emotional states, while controlling for positive or negative emotional valence and for the context of agency. Interestingly, subgenual cingulate cortex activation was only detected when modelling individual differences in how strongly participants perceived their

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own families as a distinctive social group in affiliative social scenarios(Rusch et al., 2014). A recent study confirmed the role of

subgenual frontal areas in distinguishing between in- and outgroups by

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showing that the subgenual cortex was selectively activated for efforts

benefitting anonymous fellow fans of one’s soccer club compared with

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playing to benefit non-fans(Bortolini et al., 2017).

Basal forebrain regions were also found to be activated by witnessing the

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delivery of rewards to similar others (“vicarious rewards”(Mobbs et al., 2009)). In this study, watching another player, that one could identify with,

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receive rewards led to activation of the ventral striatum and adjoining septo-hypothalamic area. Interestingly, when correlating with the perceived degree of similarity of shared values (a more complex construct), higher

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activity was observed in the subgenual frontal cortex.

3.5. Summary of evidence on the basal forebrain’s role Taken together, this body of evidence suggests a specific neural basis

for moral motivations and associated feelings, which drive altruistic choices towards other individuals or groups including kin. The emerging picture indicates that the septo-hypothalamic and subgenual frontal areas may play

20 distinct but interlocking roles in moral motivation. 

The septo-hypothalamic region, given its anatomical organisation as well as the evidence discussed above, appears to be more relevant for representing basic components of moral motivation such as interpersonal affiliation and social bonding.

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In contrast, the subgenual frontal areas are likely to represent more dynamic and complex aspects of moral motivation, such as

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social agency, and the value of social outcomes, as well as perceived group belongingness (see also Figure 1).

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4. Moral motivation in psychiatry: emerging applications

The application of insights on the neural architecture of moral

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motivation to the study of psychiatric disorders is still in its infancy(Zahn et al., 2015). These insights are likely to become increasingly important in

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understanding individual differences in vulnerability to specific psychiatric disorders. Here, our focus is on psychopathy and major depressive disorder

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(MDD) as two examples of conditions associated with moral motivation disturbances.

Psychopathy has classically been described as a disorder of moral motivation, being specifically associated with an inability to experience guilt

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and pity, with a spared ability to understand and manipulate others for selfish purposes(Cleckley, 1976). Callousness in patients with psychopathy(Hare, 2003) correlates with diminished grey matter volume in the frontopolar and subgenual orbitofrontal areas(de Oliveira-Souza et al., 2008). Another study revealed that psychopaths show diminished subgenual cingulate activation to moral violation-depicting pictures(Harenski and

21 Hamann, 2006) and during empathy for pain(Decety et al., 2013). An association of neurodevelopmental changes in the septum pellucidum with antisocial behaviour and psychopathy was reported(Raine et al., 2010), in keeping with a purported role of the septal nuclei for moral behaviour. Psychopathy has also been reproducibly associated with abnormal fMRI activation (Harenski and Hamann, 2006; Kiehl et al., 2004) and structure of the right ATL(Gregory S and et al., 2012; Muller et al., 2008) and

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frontopolar cortex(Gregory S and et al., 2012), as well as the right uncinate fasciculus(Craig et al., 2009) connecting anterior temporal and subgenual areas. This suggests, that psychopathy is not only associated with basal

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forebrain dysfunction, but also with isocortical representations of more complex moral goals.

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MDD is associated with overgeneralised forms of empathy-based interpersonal guilt(O'Connor et al., 2002) and self-contempt/disgust(Green

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et al., 2013), which remain detectable on remission of symptoms(Green et al., 2013). This indicates that self-blaming emotional biases are a trait

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vulnerability factor for MDD as postulated by cognitive models(Abramson et al., 1978). The importance of subgenual FC dysfunction in MDD has been well established(Price and Drevets, 2010; Ressler and Mayberg, 2007). Accordingly, overgeneralization of guilt (i.e. feeling guilty for everything

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and thus hating oneself as a result) correlated with functional connectivity changes between a subgenual cingulate region and the right superior ATL whilst patients with remitted MDD experienced self-blame in the scanner(Green et al., 2012), and predicted risk of subsequent recurrence(Lythe et al., 2015). Another study of moral motivations in MDD employed a charity donation paradigm in remitted patients during fMRI to

22 show that subgenual cingulate activation was higher whilst sacrificing money to donate compared with control participants(Pulcu et al., 2014), despite no overall increase in donations made during the experiment. Further studies of the neural correlates of moral feelings and altruistic behaviour in psychopathy and MDD are needed to confirm and extend these findings. Promoting prosocial behaviours is a topic of wide interest and concern.

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There is some initial evidence pointing to ways on how to boost moral motivation and its neural underpinnings using psychological and

neurotechnological approaches. For example, a recent controlled study

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using mindfulness meditation demonstrated that activity in the septal area was selectively associated with increased cooperation in the Ultimatum

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game. Increased cooperation was also associated with increased functional connectivity between the septal area and insula (Kirk et al., 2016).

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Technological advances in real-time fMRI-based neurofeedback also promise exciting opportunities for testing neuroscience-informed models

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and for translating them into novel treatments(Kim and Birbaumer, 2014; Sulzer et al., 2013). fMRI neurofeedback provides individuals access to information about their current brain activity that is usually outside of their awareness. A recent study has demonstrated that healthy participants can

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voluntarily modulate neural correlates of complex moral feelings by increasing activation of septo-hypothalamic and frontopolar areas whilst experiencing affection(Moll et al., 2014). The possibility of enhancing human capacities has become a hot topic of debate within the scientific, educational and social policy communities during the last two decades(Hyman, 2011).

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5. Future perspectives and conclusion Research on moral cognitive neuroscience during the last decade has led to a striking advance in our understanding of human social behaviour, bringing to the neurobiological arena a topic that belonged exclusively to the humanities and the psychological sciences. We have discussed evidence indicating that the subgenual frontal and septo-hypothalamic area are

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currently the best candidates for hosting subregions with selective involvement in moral vs. selfish motivations. Future studies are needed to

address the question of a plausible anterior-posterior gradient in complexity

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within the septal and subgenual frontal continuum analogous to a similar proposal for hedonic reward value representations in the medial

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orbitofrontal cortex (Kringelbach and Rolls, 2004). It also remains to be investigated whether the anterior subgenual cingulate regions code for

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causal social agency due to their closer connection with pregenual anterior cingulate representations shown to correlate with subjective feelings of

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motor agency (Marchesotti et al., 2017) and emerging evidence for functional subdivisions between pregenual and subgenual areas in social learning(Lockwood and Wittmann, 2018). A primate pharmacological inactivation study further supports functional subdivisions between the

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subgenual cortex (BA25) and more anterior subgenual cingulate areas (BA32) as measured by autonomic nervous system responses to aversive stimuli (Wallis et al., 2017). Inactivation of BA25 reduced autonomic nervous system correlates of aversive stimuli, whereas BA32 inactivation led to overgeneralised responses. This would be compatible with more complex and contextualised information being represented in anterior subgenual

24 cingulate areas which guard against overgeneralisation. Future studies are needed to probe whether subregions within the subgenual cortex (BA25) represent attachment-related values of social outcomes analogous to the proposed role of the medial orbitofrontal cortex in representing hedonic reward value (Kringelbach and Rolls, 2004). An exciting future of applying novel neuroscience insights to an improved pathophysiological understanding and treatment of psychiatric disorders and societal

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functioning lies ahead.

Acknowledgements

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RZ was partly funded by the UK MRC (G09023042) and US Brain & Behavior

Research Foundation (24715). ROS and JM were funded by IDOR. The authors

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are thankful for discussions with Ivanei Bramati, Fernanda Tovar-Moll, Leonardo

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Fontenelle, Yotam Heineberg and João Ascenso.

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Boxes Box 1| The history of the idea of moral motivations

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Following the Aristotelian tradition, the perspective of virtue ethics highlighted the importance of attaining virtues by training oneself to act according to their

prescriptions(Casebeer, 2003). In the 18th century, philosophers of the Scottish Enlightenment – Francis Hutcheson, his successor Adam Smith, and David

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Hume(Zahn et al., 2011b) – highlighted the central importance of moral sentiments

for moral behaviour. “Sympathy”, defined as “man's capacity for fellow feeling with

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others”, was considered the primary moral sentiment by Adam Smith(Lamb, 1974).

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Hutcheson postulated that “benevolence” motivates virtuous actions and thereby provides “moral motivations”(Bishop, 1996). Modern psychologists speak of “moral emotions” rather than “moral sentiments” with some variation as to which

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emotions are considered moral(Eisenberg, 2000; Tangney et al., 2007). The German philosopher Immanuel Kant, who was a contemporary of Hume, distinguished the ability to judge what is morally right and wrong (“principium diiudicationis”) from the motivation (“principium motivationis”) to act accordingly(Kant, 1786) , He

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opposed the view that moral actions could be defined by the experienced moral sentiments, which were thought to originate from the external senses. He claimed instead that true moral actions are motivated directly by respect (“Achtung”) for the moral law, which is self-generated and an act of free will(Kant, 1786). Kant further pointed out that respect for the moral law is the impression of a moral value that opposes our selfishness. Moral actions are those guided by a principle

36 that the individual wants to become a general law. Thus, moral motivations as defined by the opposing schools of moral philosophy are either the respect for moral rules (Kant) or moral sentiments (Hutcheson and Smith). As previously pointed out(Zahn et al., 2011a), there is an often overlooked agreement across schools in that those motivations that enable us to overcome self-interest are key to understanding moral behaviour. Neuroscience and psychology can produce evidence and theories about the structure and dynamics of subjective experiences and behavioural expressions of moral motivations, such as “respect for moral

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principles” or “feelings of guilt”, and their neural underpinnings. Beyond the realm of pure empirical science, however, lies the contemporary philosophical debate

among supporters of versions of deontology, sentimentalism, consequentialism and

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virtue theory and their implications for free will, moral realism and moral

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philosophy in general (Casebeer, 2003),(Harris, 2011; Kahane, 2012; Walter, 2001).

37 Box 2 | Anatomy of the basal forebrain The basal forebrain (BF) is a heterogeneous collection of structures and pathways lying underneath the intercommissural plane(Klingler and Gloor, 1960). We here briefly review and summarise the complex anatomy of this region. The medial BF comprises the more anteriorly located subgenual cingulate cortex (subgenual parts of areas 24, 32 and, 33), the posterior subgenual cortex (area 25), Broca’s paraolfactory area, preoptic area, and ventromedial hypothalamus. These areas contain the highest concentrations of receptors for the “affiliative neuropeptides”

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oxytocin and vasopressin in the human brain(Loup et al., 1991) and comprise a core node of the human “default mode” network(Bado et al., 2014). Laterally, the BF encompasses the nucleus accumbens and ventral pallidum, the amygdala and the

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basal nucleus of Meynert(Nauta and Domesick, 1981/1993). The medial and lateral BF structures are heavily interconnected by the medial forebrain bundle, Broca’s

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diagonal band (ventral amygdalofugal pathway), stria terminalis (dorsal amygdalofugal pathway), and stria medullaris(Ribas, 2007). Together with the

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median-paramedian structures of the upper brainstem tegmentum, they provide massive direct extrathalamic projections to the entire cerebral cortex(Saper, 2011).

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The orbitofrontal, subgenual, and paraolfactory areas, anterior insula and temporal pole (TP) are given anatomic unity by the uncinate fascicle, representing endpoints of massive ascending extrathalamic and thalamic projections. Figure Box 2. Parasagittal and coronal sections to illustrate the BF structures related to the visceroendocrine representation of the internal milieu and motivational

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states. (A) Subgenual: structures underneath the genu (“knee”) of the corpus callosum at this level are represented by the posterior subgenual cortex (area 25), originally referred to as “subgenual area” by Brodmann, and the more anterior subgenual cingulate cortex (subgenual parts of areas 24, 32, and 33). The subgenual cingulate cortex is bordered ventrally by the subgenual sectors of the orbitofrontal cortex ( [OFC], area 11) including the subgenual sector of the paracingulate cortex

38 which some atlases consider to be part of area 32 (B) Precommissural: the medial septal nuclei, which make up the surface of the ventromedial wall of the cerebral hemisphere at this level, are represented by the paraterminal and paraolfactory gyri (Broca’s paraolfactory area). Note that area 25 has also been described as extending more posteriorly(Price and Drevets, 2010) into the region here identified as paraolfactory area. (C) Commissural: the anterior commissure [AC] pierces the basal ganglia creating a subcommissural sector (nucleus accumbens [NAcc] and ventral pallidum [VP]), which is laterally coextensive with the basal nucleus of Meynert and

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the ansa peduncularis [AP]; the AP connects the amygdala [Amyg] with the

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ventromedial hypothalamus (not shown).

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Box 3 | The neural basis of socio-moral values Abstract social concepts such as “honour” and “honesty” are used to describe social and moral values which operate at a higher level of abstraction than simple social attitudes towards a person or specific action(Rohan, 2000). Social psychologists have defined social values as trans-situational goals which motivate and guide our behaviour(Schwartz and Bilsky, 1987). FMRI studies have shown that

40 the ATLs, especially within their right superior sectors(Skipper et al., 2011),(Zahn et al., 2007), are selectively more activated when considering social concepts than they are for non-social concepts(Ross and Olson, 2010; Zahn et al., 2015; Zahn et al., 2007),(Simmons et al., 2009),(Skipper et al., 2011). Furthermore, right superior ATL activation increased with the richness of detail with which social concepts describe social behaviour(Zahn et al., 2007) in keeping with the role of the ATLs in representing differentiated conceptual knowledge(Lambon Ralph and Patterson, 2008),(Patterson et al., 2007). Activation in the right superior ATL was reproduced

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when making emotional rather than semantic judgments about social values(Zahn et al., 2009c). Interestingly, activation in this region was independent of the emotional (valence: positive vs. negative(Zahn et al., 2007),(Zahn et al., 2011a; Zahn et al.,

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2009c), moral sentiment: guilt vs. pride vs. gratitude vs. indignation(Zahn et al.,

2009c)) and agency (self vs. other) context, supporting the hypothesis that the ATL

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represents the context-independent (i.e. trans-situational) meaning of social values and thus goals entailed in moral motivations, whereas fronto-subcortical regions

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represent cognitive and emotional ingredients specific for particular moral

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sentiments(Moll et al., 2005).

41 Box 4 | Lesions of frontal lobe subregions and moral motivation Altruistic giving is a prototypic behaviour involving moral motivation. Recent studies using non-invasive “virtual lesion” methods that employ brain stimulation techniques (transcranial direct current stimulation (tDCS) and transcranial magnetic stimulation (TMS)) and lesion mapping have provided important hints on the brain regions that are necessary for moral behaviours and choices(Tassy et al., 2012). TMS or tDCS studies using two-person economic games show that the right dorsolateral prefrontal cortex (DLPFC) is necessary for making choices that maximise one’s

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reputation(Knoch et al., 2009) and for social norm compliance under punishment

threats(Ruff et al., 2013), findings that are consistent with the suggested role of this region in reducing subjective values associated with the pursuit of immediate self-

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interest(Hare et al., 2009). Decisions to uphold social norms in these experiments

do not necessarily rely on moral motivation, because these decisions could also be

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driven by self-regarding motivations, such as avoidance of punishment, preserving one’s social reputation and anger resulting from one’s self-interest being

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challenged. By contrast, interference with medial frontopolar cortex function using tDCS reduced guilt and increased deceitful behaviour, facilitating lying in mock

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crime interrogations(Karim et al., 2010). A recent study(Zhu et al., 2014) showed that damage to the (mostly left) DLPFC, but not to the orbitofrontal cortex, impaired honesty concerns. The economic decision task enabled teasing apart honesty concerns from altruistic preferences per se. Whereas all groups were equally altruistic in sharing money with anonymous participants in a dictator-type task,

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DLPFC lesion patients were less concerned about honesty and thus indulged more in sending “false messages”. These results highlight the roles of the DLPFC and medial orbitofrontal cortex in prosocial behaviour―i.e., abiding to the value of honesty, and are corroborated by their functional interplay in self-control(Hare et al., 2009; Hayashi et al., 2013) and value computations(Prevost et al., 2010). In patients with FTD, reduced resting glucose metabolism in the septal region and

42 frontopolar cortex predicted impairments of guilt and compassion on a moral sentiment task. Impairment of “other-critical” feelings (anger/indignation and disgust), in contrast, was associated with abnormal amygdala and dorsomedial prefrontal (DMPFC) metabolism(Moll et al., 2011). Taken together, these studies point to the importance of frontopolar and ventromedial frontal regions (subgenual cingulate and adjacent medial orbitofrontal cortex) in motivating positive prosocial behaviours, and indicate that the DLPFC and lateral orbitofrontal cortices are key for responses that enforce honesty, self-reputation concerns, self-control and third-

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party punishment(Coricelli et al., 2005; Delgado et al., 2005). The frontopolar

contribution to moral motivation is most likely related to its representation of longterm consequences of social behaviour (Wood and Grafman, 2003; Zahn et al.,

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2017) and thus its importance for representing goals of moral motivations.

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Figure legends Figure 1 The neural architecture of human moral motivation Panel a| Brain regions underpinning moral cognition and general motivation. Neural structures important to moral motivation include the septal/preoptic hypothalamic area (Septal/hypoth) and subgenual frontal cortex (SGC). The frontopolar and anterior superior temporal cortices enable more complex moral

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goals. These are closely integrated with reward and behavioural reinforcement systems, including the ventral tegmental area (VTA), ventral striatum (VStr), medial forebrain bundle (MFB), raphe nuclei and the amygdalae (Amyg). These regions are further integrated with the anterior and posterior medial (ant and post mOFC) and

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lateral (lat OFC) sectors of the orbitofrontal and dorsolateral (DLPFC) prefrontal cortices, pregenual anterior cingulate cortex (ACC), superior anterior temporal

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cortex (Sup ATL) and posterior superior temporal sulcus (pSTS) and temporoparietal junction (TPJ).

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b| The event-feature-emotion complex (EFEC) model(Moll et al., 2005) postulates that moral cognition, emotion and motivation emerge from network integration via

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temporal binding. Neural components having core roles for moral motivation: (1) basal forebrain, especially the septal/hypothalamic area, implicated in basic (i.e. context-independent) affiliative states(Moll et al., 2012; Moll et al., 2005; Stellar, 1954/1994), and subgenual frontal cortex [SGC], involved in more complex

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context-dependent aspects such as social agency and responsibility attribution(Moll et al., 2008),(Rusch et al., 2014); (2) anterior prefrontal / frontopolar cortex [FPC], which stores event and action sequences(Krueger et al., 2007b; Shima et al., 2007; Wood and Grafman, 2003; Zahn et al., 2017) enabling long-term goal representations; (3) anterior temporal cortex (especially the right Sup ATL), representing abstract social conceptual knowledge(Zahn et al., 2007), e.g. “generous” or “rude” qualities of behaviour(Zahn et al., 2009b)); and (4) the

44 pSTS/TPJ, encoding perceptual social features such as emotional face and body posture(Allison et al., 2000) and mental models of socially-relevant

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perspectives(Decety and Grezes, 2006).

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Figure 2

Functional imaging the basal forebrain in moral motivation

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Recent fMRI studies have implicated basal forebrain regions in social decisionmaking, altruistic choices and prosocial emotions. a| Septo-hypothalamic activity

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(arrow) during fMRI neurofeedback-training of affectionate/tender feelings(Moll et al., 2014). b| Cooperation increased septo-hypothalamic activity (circled), as trust developed in a repeated interaction economic task(Krueger et al., 2007a). c| Septal area fMRI responses evoked when seeing empathy-eliciting pictures depicting other’s pain, anxiety or happiness. Activation predicted self-reported scores of real-

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life helping behaviours, as illustrated by the scatterplot (pain vs. neutral contrast)(Morelli et al., 2014). d| Subgenual cingulate cortex fMRI responses to kinship-associated narratives tracked individual differences in “family entitativity”, i.e., perceiving own family as a cohesive social group(Rusch et al., 2014). e| Individuals higher in empathic concern showed increased subgenual cingulate responses to guilt/compassion-evoking scenarios(Zahn et al., 2009a). f| Functional

45 MRI responses of the subgenual cingulate cortex / septal area during charitable donations (altruistic decisions) (Moll et al., 2006) . g|Subgenual cortex fMRI activation selective for prosocial vs. selfish prediction errors which was higher in empathic individuals(Lockwood et al., 2016). h| Increased insula, SMA, and right DLPFC activity (yellow) when matching monetary expectations of the partner in a trust game. Activity in subgenual cortex (not shown) and in septal area / nucleus accumbens (NAcc, in blue), when participants returned less than expected, generating feelings of guilt(Chang et al., 2011). i| Scatterplot shows the relationship

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between counterfactual guilt sensitivity and septal area / NAcc responses(Chang et al., 2011).

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Panel a|, adapted from (Moll et al., 2014), panel b| adapted from (Krueger et al.,

2007a), panel c| adapted from (Morelli et al., 2014), panel d| adapted from (Rusch

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et al., 2014), panel e| adapted from (Zahn et al., 2009a), panel (f) adapted from

(Moll et al., 2006) , all with permission. Panel g| reproduced from (Smith et al.,

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permission.

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2010), with permission. Panels (h) and (i) adapted from (Chang et al., 2011), with

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