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Moral judgment in patients with idiopathic generalized epilepsy
Accepted Manuscript Title: Moral judgment in patients with idiopathic generalized epilepsy Author: YuBao Jiang YiMing Zhu JiaoNan Wu Nong Zhou PanPan Hu Kai Wang PII: DOI: Reference:
S1059-1311(16)30128-5 http://dx.doi.org/doi:10.1016/j.seizure.2016.08.002 YSEIZ 2775
To appear in:
Seizure
Received date: Revised date: Accepted date:
15-5-2016 25-7-2016 4-8-2016
Please cite this article as: Jiang YuBao, Zhu YiMing, Wu JiaoNan, Zhou Nong, Hu PanPan, Wang Kai.Moral judgment in patients with idiopathic generalized epilepsy.SEIZURE: European Journal of Epilepsy http://dx.doi.org/10.1016/j.seizure.2016.08.002 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Moral judgment in patients with idiopathic generalized epilepsy YuBao Jiang, YiMing Zhu, JiaoNan Wu, Nong Zhou, PanPan Hu, Kai Wang※ Department of Neurology, the First Affiliated Hospital of Anhui Medical University No.218, Jixi Road, Hefei, Anhui, China ※Corresponding Author: [email protected], Tel & Fax: 86+551-62923704
Abstract Purpose: The aim of the current study was to investigate morality while also investigating frontal lobe function with the goal of studying the relationship between frontal lobe and morality in patients with idiopathic generalized epilepsy. Method: A total of 23 right-handed patients with IGE and 25 right-handed healthy participants agreed to participate. Participants made judgments on a series of 50 hypothetical scenarios, which were adapted from a previously published set. The Stroop test, verbal fluency, digit span tests and Wisconsin Card-Sorting test were used to assess the frontal lobe function. Results: IGE patients with impaired frontal lobe function choosed more utilitarian options than healthy controls in impersonal dilemmas but not in personal dilemmas. The performance of impersonal judgments were correlated positively with total errors positively and correlated negatively with categories completed. Conclusions: IGE patients with impaired frontal lobe function possessed unusual impersonal moral decision-making and those decisions may be caused more by cognitive impairment than by social-emotional impairment. Correlation analysis indicated that the unusual moral decisions correlated with frontal lobe dysfunction in patients with IGE. Keywords: epilepsy, idiopathic generalized epilepsy, frontal lobe function, moral judgment, moral dilemma
Highlights 1. We describe the moral decisions in patients with IGE; 2. We found the dissociation of impersonal and personal moral judgment in patients with IGE; 3. We found that the moral decisions were corelated with the performance of frontal lobe functions.
Moral judgment in patients with idiopathic generalized epilepsy 1 Introduction: Epilepsy is a common brain disease characterized by recurrent and spontaneous seizures that result from abnormal and excessive synchronization of neuronal activity. The comorbidity of psychiatric disturbance and epilepsy has long been recognized; the most common psychiatric disorders observed alongside of epilepsy are depression, anxiety disorder and psychosis [1, 2]. Aggressive behaviour is a frequent comorbid psychiatric disorders observed in patients with epilepsy [3]. Recurrent episodes of interictal affective aggression are well recognized and reported problem in patients with temporal lobe epilepsy (TLE)[4] and ventromedial prefrontal lobe epilepsy[5]. Patients with epilepsy also have deficits in frontal lobe function, particularly executive function [6-8]. In our previous study, we suggested that empathy and theory of mind ability were impaired in patients with idiopathic generalized epilepsy (IGE) and that impairment may be caused by deficits in frontal lobe function [6, 9]. Empathy and morality have a complex relationship [10], but it is unclear whether patients with IGE have moral abnormality compared with healthy people. In addition, the relationship between frontal lobe dysfunction and morality for individuals with IGE is also unknown. Morality has traditionally been regarded as a code of values guiding the choices and actions that determine the purpose and course of our lives. Judging the morality of behaviour is critical for a well-functioning social group. An individual who behaves immorally may violate ethical rules and civil rights and may threaten others‟ individual liberty, sometimes by becoming violent and aggressive[11]. The frontal lobe plays an important role in our morality. Evidence from previous studies showed that the frontal lobe drives moral behaviour, and the role of the various frontal areas likely differs during moral decision processing; whereas, the orbital and ventromedial prefrontal cortices emotionally drive moral decisions, the dorsolateral prefrontal cortex acts primarily as a rational „filter‟. This dual opposite processing involving the
ventromedial prefrontal cortex and the dorsolateral prefrontal cortex seems to be mediated by the anterior cingulate cortex[11]. From a behavioural point of view, the primary consequence of moral abnormality is violence[11]. Aggression becomes violence when it is exaggerated and unjustifiable, leading to violation of social norms and to destruction[12]. Moral dilemmas are both useful and interesting because they evoke competing, incompatible judgments, revealing the fault lines in moral cognition [13]. In this study, we use moral dilemmas to investigate morality while also investigating frontal lobe function with the goal of studying the relationship between frontal lobe and morality in patients with IGE. 2 Materials and Methods: 2.1 Participants All patients admitted to the clinic for epilepsy of the First Affiliated Hospital of Anhui Medical University in 2015 were considered for participation in the present study. A total of 23 right-handed patients (13 male and 10 female) with IGE met the study criteria and agreed to participate. All patients received detailed clinical and neurological examinations, continuous ambulatory EEG monitoring and high resolution MRI. To be included in the study, patients were required to: (a) have been diagnosed with IGE as defined by the Commission on Classification and Terminology of the International League against Epilepsy[14]; (b) have a normal cognitive ability, as determined by Montreal cognitive assessment (MoCA); (c) have more than 5 years of education; (d) have normal or corrected vision; and (e) have the ability to understand the procedures of the experiment. Excluded were those with evidence of other neurological or psychiatric disorder, as determined by medical history, physical examination, or neuroimaging. All patients were being treated with antiepileptic drugs (AEDs); valproic acid (15 patients) and lamotrigine (7 patients) were the most frequently used AEDs among the patients with IGE, with only two patients using Phenobarbital. None of the patients experienced a seizure in the 24 h period that proceeded the experimental session. Patients with MoCA scores below 26 were excluded.
An additional control group included 25 right-handed healthy participants (14 male and 11 female) who were matched to the patient group for age, gender and education. This study was approved by the ethics committee of Anhui medical university, and all participants provided written informed consent to participate in the study. 2.2 Background test All patients completed the Beijing version of the Montreal cognitive assessment (MoCA). The Beck Depression Inventory (BDI, translated into Chinese) was administered to obtain the measure of depression, and the Hamilton Anxiety Scale (HAMA, translated into Chinese too) was administered to obtain the measure of anxiety for the IGE patients and the healthy controls. 2.3 Frontal lobe function investigation Frontal lobe function was assessed with the Stroop Test, Verbal Fluency Test (using animal, fruit, and word categories), Digit Span (forward and backward) tests and Wisconsin Card-Sorting Test. The Stroop Test evaluates the ease with which a person can maintain a goal in mind and suppress a habitual response in favour of a less familiar one. It also assesses selective attention, susceptibility to interference and cognitive flexibility. The difference (in seconds) between the execution time of the third (words) and the first (colours) tasks was evaluated. The Verbal Fluency Test (using semantic categories of animals and fruits and phonemic categories) evaluates the spontaneous production of words under restricted search conditions. The generation of words belonging to a certain category within one minute is used to assess verbal association fluency and mental retrieval from long-term memory. In the Digit Span Test (forward and backward), a string of digital numbers is presented beginning with length of 3 digits forward or 2 digits backward. In the DS forward test, the participant must listen to a digit span at a speed of one digit per second and repeat it forward. The DS backward test follows the same procedure as the DS forward except the participant must repeat the span backward. Two trials were
performed for each length. The test was halted when the participant failed to recall both sequences at a single sequence length. The Wisconsin Card-Sorting Test (WCST) requires participants to match cards to one of four target cards. The examinee was not told how to match the cards but was informed if their particular match on each response was correct or incorrect. The sorting principles include colour, shape and number. The sorting principles are changed during the course of the test, and the examinee must use examiner feedback to arrive at a correct solution. The 124-card, hand-administered version of WCST was used. Scores used for analysis were the number of categories completed, correct responses, total errors, preservative responses and preservative errors. 2.4 Moral judgment task Participants made judgments on a series of 50 hypothetical scenarios (translated into Chinese) that were adapted from a previously published set [15]. See the Supplementary Information for the full text of the actual scenarios used. Participants read the scenarios, which were printed on paper, and were told to make a choice between „yes‟ and „no‟. We used three classes of stimuli: non-moral scenarios (n=18) and two classes of moral scenarios subdivided according to the emotional reaction elicited by the proposed action („personal‟ (n=21) or „impersonal‟ (n=11), as described previously [15, 16]). A moral violation was considered to be personal if it met three criteria. First, the violation must be likely to cause serious bodily harm. Second, this harm must befall a particular person or set of persons. Third, the harm must not result from the deflection of an existing threat onto a different party[15]. One can think of these three criteria in terms of “ME HURT YOU”. The “HURT” criterion picks out the most primitive types of harmful violations (for example, assault rather than insider trading), while the “YOU” criterion ensures that the victim be vividly represented as an individual. Finally, the “ME” condition captures the notion of “agency”, requiring that the action spring in a direct way from the agent‟s will and that it be “authored” rather than merely “edited” by the agent [15]. Moral violations that fail to meet these three criteria are classified as “impersonal”.
An example of impersonal moral scenario is as follows: You are at the wheel of a runaway trolley quickly approaching a fork in the tracks. On the tracks extending to the left is a group of five railway workmen. On the tracks extending to the right is a single railway workman. If you do nothing, the trolley will proceed to the left, causing the deaths of the five workmen. The only way to avoid the deaths of these workmen is to hit a switch on your dashboard that will cause the trolley to proceed to the right, causing the death of the single workman. Would you hit the switch in order to avoid the deaths of the five workmen? An example of personal moral scenario is as follows: A runaway trolley is heading down the tracks toward five workmen who will be killed if the trolley proceeds on its present course. You are on a footbridge over the tracks, in between the approaching trolley and the five workmen. Next to you on this footbridge is a stranger who happens to be very large. The only way to save the lives of the five workmen is to push this stranger off the bridge and onto the tracks below where his large body will stop the trolley. The stranger will die if you do this, but the five workmen will be saved. Would you push the stranger on to the tracks in order to save the five workmen? An example of non-moral scenario is as follows: You are a farm worker driving a turnip-harvesting machine. You are approaching two diverging paths. By choosing the path on the left you will harvest ten bushels of turnips. By choosing the path on the right you will harvest twenty bushels of turnips. If you do nothing, your turnip-harvesting machine will turn to the left. Would you turn your turnip-picking machine to the right in order to harvest twenty bushels of turnips instead of ten? 2.5 Statistical analysis All statistical procedures were performed using the Statistical Package for the Social Sciences version 20. Between-group differences in performance of background tests, frontal lobe function, and moral judgments were assessed with nonparametric tests for two independent samples (Mann–Whitney tests). Gender differences between the two groups were assessed with Chi-square tests. Probability values below 0.01 were considered to be significant. Spearman correlations were used to determine the
strengths of the relationships between scores of frontal lobe function and the performance of moral judgments. 3 Results: 3.1 Performance of background tests There were no significant differences in age, education level, MoCA, BDI and HAMA between the two groups. The details are shown in Table 1. 3.2 Performance of frontal lobe function The patients with IGE performed worse than the healthy controls in the Stroop, digit span, verbal fluency tests and WCST (P<0.01). The details are shown in Table 2. 3.3 Performance of moral judgments Participants from the two groups made the same choices in the non-moral judgments. The patients with IGE chose more utilitarian options than healthy controls in the impersonal moral judgments, and the differences between the two groups were significant (P<0.01) (meaning that the frequency of endorsing „yes‟ responses was significantly greater in the patients with IGE than in healthy controls), but there were no significant difference between the two groups with regard to performance of personal moral judgments. The details are shown in Table 3 and Fig1. 3.4 The correlation between the performance of moral judgments and frontal lobe function We conducted correlation analyses between the scores of moral judgments and the performance of frontal lobe function. The performance of impersonal judgments were correlated positively with total errors positively and correlated negatively with Categories Completed (Table 4 & Fig2). 4 Discussion: In this exploratory study, we used 50 hypothetical scenarios including personal, impersonal and non-moral dilemmas to investigate moral decision-making in patients with IGE, and found that IGE patients choose more utilitarian options than healthy controls in impersonal moral dilemmas but not for personal moral dilemmas. Also, we used the Stroop test, verbal fluency, digit span tests and Wisconsin Card-Sorting test to assess frontal lobe function, and found that the frontal lobe function was impaired
in IGE patients. Moral decision-making performance was correlated positively with total errors and correlated negatively with categories completed. Morality is among the most sophisticated features of human judgment, behaviour and, ultimately, minds. Moral judgments are driven not only by intuitive/emotional processes but also by conscious reasoning processes [17]. These two processes underlie different types of moral judgment: “deontological judgments, judgments that are naturally regarded as reflecting concerns for rights and duties, are driven primarily by intuitive emotional responses”, whereas “consequentialist judgments, judgments aimed at promoting the greater good, are supported by controlled cognitive processes that look more like moral reasoning” [18]. Brain regions associated with emotional processing exhibited greater activation for personal than for impersonal dilemmas, whereas regions associated with working memory showed greater activation for impersonal than for personal dilemmas [16]. The frequency and speed of deontological judgments were unchanged by cognitive load; consequentialist judgments occurred more slowly with cognitive load than without [19]. Cognitive load selectively weakened consequentialist (but not deontological) judgments [20]. These results indicated that personal moral dilemmas are driven largely by social-emotional responses, while impersonal moral dilemmas are driven less by social-emotional responses and more by cognitive processes[15]. The anatomical structures implicated in morality include the frontal lobe, temporal lobe, cingulate gyrus, amygdala, hippocampus, and basal ganglia [21, 22]. Recent evidence showed that the amygdala provides an effective assessment of moral dilemmas, whereas the ventromedial prefrontal cortex (vmPFC) integrates that signal with a utilitarian assessment of expected outcomes to yield “all things considered” moral judgments [23]. When participants had to judge dilemma situations, personal moral dilemmas in contrast to non-moral and impersonal moral dilemmas were associated with greater activations of the frontal cortex - in particular BA 9 and 10, representing parts of the dorsolateral and medial prefrontal cortex, the posterior cingulated gyrus and the angular gyrus [16]. The role of the various frontal areas likely differs during moral decision-making processes. Whereas the orbital and
ventromedial prefrontal cortices emotionally drive moral decision-making, the dorsolateral prefrontal cortex acts mainly as a rational „filter‟. This dual opposite processing involving the ventromedial prefrontal cortex and the dorsolateral prefrontal cortex seems to be mediated by the anterior cingulate cortex [11]. As for our study, IGE patients chose more utilitarian options than healthy controls for impersonal moral judgments but not for personal moral judgments. This indicated that personal and impersonal moral judgments may be processed in two different ways, and IGE patients showed more cognitive impairment than social-emotional impairment in their moral judgments. Frontal lobe dysfunction is known to be associated with impairment in social behaviour. Damage to the prefrontal cortex could increase utilitarian moral judgment making [24], and transcranial direct current stimulation (tDCS) of the left dorsolateral prefrontal cortex can shift the preference of moral judgments [25]. In particular, damage to the orbitofrontal or vmPFC are likely to cause problems in impulsive control, which may lead to antisocial and less moral behaviours [21]. The theoretical basis for an association between the frontal lobe and aggressive behaviour is much stronger. Influential case reports, such as that for Phineas Gage [26], and case-control studies of war veterans who experienced frontal lobe damage [27] have provided support for this association. Patients with IGE also showed impaired frontal lobe functions[28]. O‟ Muircheartaigh reported subtle dysfunctions in verbal fluency, comprehension and expression, mental flexibility, and response inhibition in a cohort of 28 JME patients [29]. Devinsky assessed executive functions in 15 patients with JME and 15 with TLE, and significant differences were found between the JME and TLE groups with regard to tests requiring mental flexibility and concept formation-abstract reasoning; those findings were supportive of frontal lobe dysfunction, which may lead to maladaptive behaviour with social consequences[30]. Early studies report subtle gray and white matter abnormalities [31]. Quantitative analysis of high resolution magnetic resonance imaging (MRI) identified changes to the medial prefrontal cortex [29] and to the thalamus [32], with molecular imaging studies reporting abnormalities of the
dorsolateral prefrontal cortex in patients with IGE [33], which is indicative of an underlying thalamofrontocortical network dysfunction in patients with IGE. Morality and empathy are fundamental components of human nature across cultures. The brain regions underpinning morality share resources with circuits controlling other capacities, such as emotional saliency, mental state understanding, and decision-making, and involve the posterior superior temporal sulcus, amygdala, insula, vmPFC, dlPFC, and medial prefrontal cortex [34]. Support for a link between empathy and moral cognition is provided by studies demonstrating that low dispositional empathic concern predicts utilitarian moral judgment [35]. In a functional neuroimaging study examining the neural basis of indifference to harm, participants engaged in moral dilemmas, which uncovered a tendency toward counterintuitive impersonal utilitarian judgment that was associated positively both with „psychoticism‟ (or psychopathy) and psychoticism but was correlated negatively with vmPFC activation [36]. Lesions of this region have consistently been associated with increased utilitarian choices in moral dilemmas, opting to sacrifice one person‟s life to save several other individuals [37]. In our previous study, we suggested that empathy was impaired in patients with IGE [6]. In this study, we also found unusual moral decision-making in patients with IGE, and the results of this study are consistent with previous findings. In conclusion, we observed that IGE patients with impaired frontal lobe function possessed unusual impersonal moral decision-making compared with healthy controls, and those decisions may be caused more by cognitive impairment than by social-emotional impairment. Correlation analysis indicated that the unusual moral decisions correlated with frontal lobe dysfunction in patients with IGE. Acknowledgements: This work was supported by a grant from the National Natural Science Foundation of China (NSFC, NO. 31300925) Disclosure of Conflicts of Interest None of the authors have any conflict of interest to disclose.
Conflict of Interest None of the authors has any conflict of interest to disclose. We confirm that we have read the Journal‟s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.
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Fig 1 Performance of Moral judgements in patients with IGE and healthy controls
Fig 2 Scatter plots：correlation between impersonal moral judgments and frontal lobe functions
Table 1 Demographic variables and performance of Background Tests IGE
HC
P-Valve
N (M/F)
23(13/10)
25(14/11)
χ2=0.001, P=0.601
Age
18.0(15.0-20.0)
16.0(13.0-19.5)
U=236.50, P=0.291
Education
10.0(6.0-13.0)
9.0(6.5-11.5)
U=257.00, P=0.527
MoCA
28.0(26.0-28.0)
28.0(27.0-29.0)
U=219.50, P=0.150
BDI
3.0(1.0-6.0)
3.0(1.0-6.0)
U=272.50, P=0.755
HAMA
5.0(1.0-7.0)
2.0(1.5-5.5)
U=257.00, P=0.525
Age at seizure onset
13.0(11.0-15.0)
Disease duration(years)
3.0(2.0-6.0)
Seizure Free(years)
2.0(1.5-4.0)
MoCA= Montreal cognitive assessment; BDI= Beck Depression Inventory; HAMA= Hamilton Anxiety Scale; DSF= Digit Span (Forward); DSB= Digit Span (Backward); VFT= Verbal Fluency Test
Table 2 Performance of Frontal lobe function IGE
HC
P-Valve
Stroop*
12.56(8.55-18.48)
8.59(4.31-11.63)
U=147.00,P=0.004
DSF*
8.00(7.00-8.00)
8.00(8.00-9.00)
U=159.00, P=0.002
DSB*
5.00(4.00-6.00)
6.00(5.00-8.00)
U=166.00, P=0.010
VFT*
9.00(7.67-10.00)
18.00(15.00-21.00)
U=2.00, P=0.000
Categories Completed*
6.00(3.00-7.00)
9.00(8.00-9.00)
U=90.50, P=0.000
Correct Response*
92.00(79.00-97.00) 101.00(95.50-105.50)
U=123.00, P=0.001
Total Errors*
36.00(27.00-49.00)
21.00(19.00-24.50)
U=73.00, P=0.000
Preservative Responses
48.00(39.00-56.00)
39.00(36.50-45.00)
U=172.00, P=0.017
Preservative Errors*
20.00(16.00-33.00)
14.00(11.00-16.00)
U=114.50, P=0.000
DSF= Digit Span (Forward); DSB= Digit Span (Backward); VFT= Verbal Fluency Test
* p＜0.01
Table 3 Performance of Moral judgments P-Valve IGE
HC (Mann-Whitney U)
N (M/F)
23(13/10)
25(14/11)
χ2=0.001, P=0.601
Personal
10.0(5.0-14.0)
8.0(6.5-9.5)
U=233.50, P=0.263
Impersonal*
6.0(5.0-7.0)
5.0(4.0-6.0)
U=156.00, P=0.005
Non-Moral
10.0(8.0-11.0)
10.0(9.0-11.0)
U=246.00, P=0.384
* p＜0.01
Table 4 The correlation between frontal lobe function and impersonal moral decisions Impersonal P-Valve
r
Stroop
0.158
0.207
DSF
0.639
-0.069
DSB
0.017
-0.343
VFT
0.050
-0.285
Categories Completed*
0.001
-0.471
Correct Response
0.017
-0.342
Total Errors*
0.001
0.456
Preservative Responses
0.183
0.196
Preservative Errors
0.023
0.328
* p＜0.01
S1059-1311(16)30128-5 http://dx.doi.org/doi:10.1016/j.seizure.2016.08.002 YSEIZ 2775
To appear in:
Seizure
Received date: Revised date: Accepted date:
15-5-2016 25-7-2016 4-8-2016
Please cite this article as: Jiang YuBao, Zhu YiMing, Wu JiaoNan, Zhou Nong, Hu PanPan, Wang Kai.Moral judgment in patients with idiopathic generalized epilepsy.SEIZURE: European Journal of Epilepsy http://dx.doi.org/10.1016/j.seizure.2016.08.002 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Moral judgment in patients with idiopathic generalized epilepsy YuBao Jiang, YiMing Zhu, JiaoNan Wu, Nong Zhou, PanPan Hu, Kai Wang※ Department of Neurology, the First Affiliated Hospital of Anhui Medical University No.218, Jixi Road, Hefei, Anhui, China ※Corresponding Author: [email protected], Tel & Fax: 86+551-62923704
Abstract Purpose: The aim of the current study was to investigate morality while also investigating frontal lobe function with the goal of studying the relationship between frontal lobe and morality in patients with idiopathic generalized epilepsy. Method: A total of 23 right-handed patients with IGE and 25 right-handed healthy participants agreed to participate. Participants made judgments on a series of 50 hypothetical scenarios, which were adapted from a previously published set. The Stroop test, verbal fluency, digit span tests and Wisconsin Card-Sorting test were used to assess the frontal lobe function. Results: IGE patients with impaired frontal lobe function choosed more utilitarian options than healthy controls in impersonal dilemmas but not in personal dilemmas. The performance of impersonal judgments were correlated positively with total errors positively and correlated negatively with categories completed. Conclusions: IGE patients with impaired frontal lobe function possessed unusual impersonal moral decision-making and those decisions may be caused more by cognitive impairment than by social-emotional impairment. Correlation analysis indicated that the unusual moral decisions correlated with frontal lobe dysfunction in patients with IGE. Keywords: epilepsy, idiopathic generalized epilepsy, frontal lobe function, moral judgment, moral dilemma
Highlights 1. We describe the moral decisions in patients with IGE; 2. We found the dissociation of impersonal and personal moral judgment in patients with IGE; 3. We found that the moral decisions were corelated with the performance of frontal lobe functions.
Moral judgment in patients with idiopathic generalized epilepsy 1 Introduction: Epilepsy is a common brain disease characterized by recurrent and spontaneous seizures that result from abnormal and excessive synchronization of neuronal activity. The comorbidity of psychiatric disturbance and epilepsy has long been recognized; the most common psychiatric disorders observed alongside of epilepsy are depression, anxiety disorder and psychosis [1, 2]. Aggressive behaviour is a frequent comorbid psychiatric disorders observed in patients with epilepsy [3]. Recurrent episodes of interictal affective aggression are well recognized and reported problem in patients with temporal lobe epilepsy (TLE)[4] and ventromedial prefrontal lobe epilepsy[5]. Patients with epilepsy also have deficits in frontal lobe function, particularly executive function [6-8]. In our previous study, we suggested that empathy and theory of mind ability were impaired in patients with idiopathic generalized epilepsy (IGE) and that impairment may be caused by deficits in frontal lobe function [6, 9]. Empathy and morality have a complex relationship [10], but it is unclear whether patients with IGE have moral abnormality compared with healthy people. In addition, the relationship between frontal lobe dysfunction and morality for individuals with IGE is also unknown. Morality has traditionally been regarded as a code of values guiding the choices and actions that determine the purpose and course of our lives. Judging the morality of behaviour is critical for a well-functioning social group. An individual who behaves immorally may violate ethical rules and civil rights and may threaten others‟ individual liberty, sometimes by becoming violent and aggressive[11]. The frontal lobe plays an important role in our morality. Evidence from previous studies showed that the frontal lobe drives moral behaviour, and the role of the various frontal areas likely differs during moral decision processing; whereas, the orbital and ventromedial prefrontal cortices emotionally drive moral decisions, the dorsolateral prefrontal cortex acts primarily as a rational „filter‟. This dual opposite processing involving the
ventromedial prefrontal cortex and the dorsolateral prefrontal cortex seems to be mediated by the anterior cingulate cortex[11]. From a behavioural point of view, the primary consequence of moral abnormality is violence[11]. Aggression becomes violence when it is exaggerated and unjustifiable, leading to violation of social norms and to destruction[12]. Moral dilemmas are both useful and interesting because they evoke competing, incompatible judgments, revealing the fault lines in moral cognition [13]. In this study, we use moral dilemmas to investigate morality while also investigating frontal lobe function with the goal of studying the relationship between frontal lobe and morality in patients with IGE. 2 Materials and Methods: 2.1 Participants All patients admitted to the clinic for epilepsy of the First Affiliated Hospital of Anhui Medical University in 2015 were considered for participation in the present study. A total of 23 right-handed patients (13 male and 10 female) with IGE met the study criteria and agreed to participate. All patients received detailed clinical and neurological examinations, continuous ambulatory EEG monitoring and high resolution MRI. To be included in the study, patients were required to: (a) have been diagnosed with IGE as defined by the Commission on Classification and Terminology of the International League against Epilepsy[14]; (b) have a normal cognitive ability, as determined by Montreal cognitive assessment (MoCA); (c) have more than 5 years of education; (d) have normal or corrected vision; and (e) have the ability to understand the procedures of the experiment. Excluded were those with evidence of other neurological or psychiatric disorder, as determined by medical history, physical examination, or neuroimaging. All patients were being treated with antiepileptic drugs (AEDs); valproic acid (15 patients) and lamotrigine (7 patients) were the most frequently used AEDs among the patients with IGE, with only two patients using Phenobarbital. None of the patients experienced a seizure in the 24 h period that proceeded the experimental session. Patients with MoCA scores below 26 were excluded.
An additional control group included 25 right-handed healthy participants (14 male and 11 female) who were matched to the patient group for age, gender and education. This study was approved by the ethics committee of Anhui medical university, and all participants provided written informed consent to participate in the study. 2.2 Background test All patients completed the Beijing version of the Montreal cognitive assessment (MoCA). The Beck Depression Inventory (BDI, translated into Chinese) was administered to obtain the measure of depression, and the Hamilton Anxiety Scale (HAMA, translated into Chinese too) was administered to obtain the measure of anxiety for the IGE patients and the healthy controls. 2.3 Frontal lobe function investigation Frontal lobe function was assessed with the Stroop Test, Verbal Fluency Test (using animal, fruit, and word categories), Digit Span (forward and backward) tests and Wisconsin Card-Sorting Test. The Stroop Test evaluates the ease with which a person can maintain a goal in mind and suppress a habitual response in favour of a less familiar one. It also assesses selective attention, susceptibility to interference and cognitive flexibility. The difference (in seconds) between the execution time of the third (words) and the first (colours) tasks was evaluated. The Verbal Fluency Test (using semantic categories of animals and fruits and phonemic categories) evaluates the spontaneous production of words under restricted search conditions. The generation of words belonging to a certain category within one minute is used to assess verbal association fluency and mental retrieval from long-term memory. In the Digit Span Test (forward and backward), a string of digital numbers is presented beginning with length of 3 digits forward or 2 digits backward. In the DS forward test, the participant must listen to a digit span at a speed of one digit per second and repeat it forward. The DS backward test follows the same procedure as the DS forward except the participant must repeat the span backward. Two trials were
performed for each length. The test was halted when the participant failed to recall both sequences at a single sequence length. The Wisconsin Card-Sorting Test (WCST) requires participants to match cards to one of four target cards. The examinee was not told how to match the cards but was informed if their particular match on each response was correct or incorrect. The sorting principles include colour, shape and number. The sorting principles are changed during the course of the test, and the examinee must use examiner feedback to arrive at a correct solution. The 124-card, hand-administered version of WCST was used. Scores used for analysis were the number of categories completed, correct responses, total errors, preservative responses and preservative errors. 2.4 Moral judgment task Participants made judgments on a series of 50 hypothetical scenarios (translated into Chinese) that were adapted from a previously published set [15]. See the Supplementary Information for the full text of the actual scenarios used. Participants read the scenarios, which were printed on paper, and were told to make a choice between „yes‟ and „no‟. We used three classes of stimuli: non-moral scenarios (n=18) and two classes of moral scenarios subdivided according to the emotional reaction elicited by the proposed action („personal‟ (n=21) or „impersonal‟ (n=11), as described previously [15, 16]). A moral violation was considered to be personal if it met three criteria. First, the violation must be likely to cause serious bodily harm. Second, this harm must befall a particular person or set of persons. Third, the harm must not result from the deflection of an existing threat onto a different party[15]. One can think of these three criteria in terms of “ME HURT YOU”. The “HURT” criterion picks out the most primitive types of harmful violations (for example, assault rather than insider trading), while the “YOU” criterion ensures that the victim be vividly represented as an individual. Finally, the “ME” condition captures the notion of “agency”, requiring that the action spring in a direct way from the agent‟s will and that it be “authored” rather than merely “edited” by the agent [15]. Moral violations that fail to meet these three criteria are classified as “impersonal”.
An example of impersonal moral scenario is as follows: You are at the wheel of a runaway trolley quickly approaching a fork in the tracks. On the tracks extending to the left is a group of five railway workmen. On the tracks extending to the right is a single railway workman. If you do nothing, the trolley will proceed to the left, causing the deaths of the five workmen. The only way to avoid the deaths of these workmen is to hit a switch on your dashboard that will cause the trolley to proceed to the right, causing the death of the single workman. Would you hit the switch in order to avoid the deaths of the five workmen? An example of personal moral scenario is as follows: A runaway trolley is heading down the tracks toward five workmen who will be killed if the trolley proceeds on its present course. You are on a footbridge over the tracks, in between the approaching trolley and the five workmen. Next to you on this footbridge is a stranger who happens to be very large. The only way to save the lives of the five workmen is to push this stranger off the bridge and onto the tracks below where his large body will stop the trolley. The stranger will die if you do this, but the five workmen will be saved. Would you push the stranger on to the tracks in order to save the five workmen? An example of non-moral scenario is as follows: You are a farm worker driving a turnip-harvesting machine. You are approaching two diverging paths. By choosing the path on the left you will harvest ten bushels of turnips. By choosing the path on the right you will harvest twenty bushels of turnips. If you do nothing, your turnip-harvesting machine will turn to the left. Would you turn your turnip-picking machine to the right in order to harvest twenty bushels of turnips instead of ten? 2.5 Statistical analysis All statistical procedures were performed using the Statistical Package for the Social Sciences version 20. Between-group differences in performance of background tests, frontal lobe function, and moral judgments were assessed with nonparametric tests for two independent samples (Mann–Whitney tests). Gender differences between the two groups were assessed with Chi-square tests. Probability values below 0.01 were considered to be significant. Spearman correlations were used to determine the
strengths of the relationships between scores of frontal lobe function and the performance of moral judgments. 3 Results: 3.1 Performance of background tests There were no significant differences in age, education level, MoCA, BDI and HAMA between the two groups. The details are shown in Table 1. 3.2 Performance of frontal lobe function The patients with IGE performed worse than the healthy controls in the Stroop, digit span, verbal fluency tests and WCST (P<0.01). The details are shown in Table 2. 3.3 Performance of moral judgments Participants from the two groups made the same choices in the non-moral judgments. The patients with IGE chose more utilitarian options than healthy controls in the impersonal moral judgments, and the differences between the two groups were significant (P<0.01) (meaning that the frequency of endorsing „yes‟ responses was significantly greater in the patients with IGE than in healthy controls), but there were no significant difference between the two groups with regard to performance of personal moral judgments. The details are shown in Table 3 and Fig1. 3.4 The correlation between the performance of moral judgments and frontal lobe function We conducted correlation analyses between the scores of moral judgments and the performance of frontal lobe function. The performance of impersonal judgments were correlated positively with total errors positively and correlated negatively with Categories Completed (Table 4 & Fig2). 4 Discussion: In this exploratory study, we used 50 hypothetical scenarios including personal, impersonal and non-moral dilemmas to investigate moral decision-making in patients with IGE, and found that IGE patients choose more utilitarian options than healthy controls in impersonal moral dilemmas but not for personal moral dilemmas. Also, we used the Stroop test, verbal fluency, digit span tests and Wisconsin Card-Sorting test to assess frontal lobe function, and found that the frontal lobe function was impaired
in IGE patients. Moral decision-making performance was correlated positively with total errors and correlated negatively with categories completed. Morality is among the most sophisticated features of human judgment, behaviour and, ultimately, minds. Moral judgments are driven not only by intuitive/emotional processes but also by conscious reasoning processes [17]. These two processes underlie different types of moral judgment: “deontological judgments, judgments that are naturally regarded as reflecting concerns for rights and duties, are driven primarily by intuitive emotional responses”, whereas “consequentialist judgments, judgments aimed at promoting the greater good, are supported by controlled cognitive processes that look more like moral reasoning” [18]. Brain regions associated with emotional processing exhibited greater activation for personal than for impersonal dilemmas, whereas regions associated with working memory showed greater activation for impersonal than for personal dilemmas [16]. The frequency and speed of deontological judgments were unchanged by cognitive load; consequentialist judgments occurred more slowly with cognitive load than without [19]. Cognitive load selectively weakened consequentialist (but not deontological) judgments [20]. These results indicated that personal moral dilemmas are driven largely by social-emotional responses, while impersonal moral dilemmas are driven less by social-emotional responses and more by cognitive processes[15]. The anatomical structures implicated in morality include the frontal lobe, temporal lobe, cingulate gyrus, amygdala, hippocampus, and basal ganglia [21, 22]. Recent evidence showed that the amygdala provides an effective assessment of moral dilemmas, whereas the ventromedial prefrontal cortex (vmPFC) integrates that signal with a utilitarian assessment of expected outcomes to yield “all things considered” moral judgments [23]. When participants had to judge dilemma situations, personal moral dilemmas in contrast to non-moral and impersonal moral dilemmas were associated with greater activations of the frontal cortex - in particular BA 9 and 10, representing parts of the dorsolateral and medial prefrontal cortex, the posterior cingulated gyrus and the angular gyrus [16]. The role of the various frontal areas likely differs during moral decision-making processes. Whereas the orbital and
ventromedial prefrontal cortices emotionally drive moral decision-making, the dorsolateral prefrontal cortex acts mainly as a rational „filter‟. This dual opposite processing involving the ventromedial prefrontal cortex and the dorsolateral prefrontal cortex seems to be mediated by the anterior cingulate cortex [11]. As for our study, IGE patients chose more utilitarian options than healthy controls for impersonal moral judgments but not for personal moral judgments. This indicated that personal and impersonal moral judgments may be processed in two different ways, and IGE patients showed more cognitive impairment than social-emotional impairment in their moral judgments. Frontal lobe dysfunction is known to be associated with impairment in social behaviour. Damage to the prefrontal cortex could increase utilitarian moral judgment making [24], and transcranial direct current stimulation (tDCS) of the left dorsolateral prefrontal cortex can shift the preference of moral judgments [25]. In particular, damage to the orbitofrontal or vmPFC are likely to cause problems in impulsive control, which may lead to antisocial and less moral behaviours [21]. The theoretical basis for an association between the frontal lobe and aggressive behaviour is much stronger. Influential case reports, such as that for Phineas Gage [26], and case-control studies of war veterans who experienced frontal lobe damage [27] have provided support for this association. Patients with IGE also showed impaired frontal lobe functions[28]. O‟ Muircheartaigh reported subtle dysfunctions in verbal fluency, comprehension and expression, mental flexibility, and response inhibition in a cohort of 28 JME patients [29]. Devinsky assessed executive functions in 15 patients with JME and 15 with TLE, and significant differences were found between the JME and TLE groups with regard to tests requiring mental flexibility and concept formation-abstract reasoning; those findings were supportive of frontal lobe dysfunction, which may lead to maladaptive behaviour with social consequences[30]. Early studies report subtle gray and white matter abnormalities [31]. Quantitative analysis of high resolution magnetic resonance imaging (MRI) identified changes to the medial prefrontal cortex [29] and to the thalamus [32], with molecular imaging studies reporting abnormalities of the
dorsolateral prefrontal cortex in patients with IGE [33], which is indicative of an underlying thalamofrontocortical network dysfunction in patients with IGE. Morality and empathy are fundamental components of human nature across cultures. The brain regions underpinning morality share resources with circuits controlling other capacities, such as emotional saliency, mental state understanding, and decision-making, and involve the posterior superior temporal sulcus, amygdala, insula, vmPFC, dlPFC, and medial prefrontal cortex [34]. Support for a link between empathy and moral cognition is provided by studies demonstrating that low dispositional empathic concern predicts utilitarian moral judgment [35]. In a functional neuroimaging study examining the neural basis of indifference to harm, participants engaged in moral dilemmas, which uncovered a tendency toward counterintuitive impersonal utilitarian judgment that was associated positively both with „psychoticism‟ (or psychopathy) and psychoticism but was correlated negatively with vmPFC activation [36]. Lesions of this region have consistently been associated with increased utilitarian choices in moral dilemmas, opting to sacrifice one person‟s life to save several other individuals [37]. In our previous study, we suggested that empathy was impaired in patients with IGE [6]. In this study, we also found unusual moral decision-making in patients with IGE, and the results of this study are consistent with previous findings. In conclusion, we observed that IGE patients with impaired frontal lobe function possessed unusual impersonal moral decision-making compared with healthy controls, and those decisions may be caused more by cognitive impairment than by social-emotional impairment. Correlation analysis indicated that the unusual moral decisions correlated with frontal lobe dysfunction in patients with IGE. Acknowledgements: This work was supported by a grant from the National Natural Science Foundation of China (NSFC, NO. 31300925) Disclosure of Conflicts of Interest None of the authors have any conflict of interest to disclose.
Conflict of Interest None of the authors has any conflict of interest to disclose. We confirm that we have read the Journal‟s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.
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Fig 1 Performance of Moral judgements in patients with IGE and healthy controls
Fig 2 Scatter plots：correlation between impersonal moral judgments and frontal lobe functions
Table 1 Demographic variables and performance of Background Tests IGE
HC
P-Valve
N (M/F)
23(13/10)
25(14/11)
χ2=0.001, P=0.601
Age
18.0(15.0-20.0)
16.0(13.0-19.5)
U=236.50, P=0.291
Education
10.0(6.0-13.0)
9.0(6.5-11.5)
U=257.00, P=0.527
MoCA
28.0(26.0-28.0)
28.0(27.0-29.0)
U=219.50, P=0.150
BDI
3.0(1.0-6.0)
3.0(1.0-6.0)
U=272.50, P=0.755
HAMA
5.0(1.0-7.0)
2.0(1.5-5.5)
U=257.00, P=0.525
Age at seizure onset
13.0(11.0-15.0)
Disease duration(years)
3.0(2.0-6.0)
Seizure Free(years)
2.0(1.5-4.0)
MoCA= Montreal cognitive assessment; BDI= Beck Depression Inventory; HAMA= Hamilton Anxiety Scale; DSF= Digit Span (Forward); DSB= Digit Span (Backward); VFT= Verbal Fluency Test
Table 2 Performance of Frontal lobe function IGE
HC
P-Valve
Stroop*
12.56(8.55-18.48)
8.59(4.31-11.63)
U=147.00,P=0.004
DSF*
8.00(7.00-8.00)
8.00(8.00-9.00)
U=159.00, P=0.002
DSB*
5.00(4.00-6.00)
6.00(5.00-8.00)
U=166.00, P=0.010
VFT*
9.00(7.67-10.00)
18.00(15.00-21.00)
U=2.00, P=0.000
Categories Completed*
6.00(3.00-7.00)
9.00(8.00-9.00)
U=90.50, P=0.000
Correct Response*
92.00(79.00-97.00) 101.00(95.50-105.50)
U=123.00, P=0.001
Total Errors*
36.00(27.00-49.00)
21.00(19.00-24.50)
U=73.00, P=0.000
Preservative Responses
48.00(39.00-56.00)
39.00(36.50-45.00)
U=172.00, P=0.017
Preservative Errors*
20.00(16.00-33.00)
14.00(11.00-16.00)
U=114.50, P=0.000
DSF= Digit Span (Forward); DSB= Digit Span (Backward); VFT= Verbal Fluency Test
* p＜0.01
Table 3 Performance of Moral judgments P-Valve IGE
HC (Mann-Whitney U)
N (M/F)
23(13/10)
25(14/11)
χ2=0.001, P=0.601
Personal
10.0(5.0-14.0)
8.0(6.5-9.5)
U=233.50, P=0.263
Impersonal*
6.0(5.0-7.0)
5.0(4.0-6.0)
U=156.00, P=0.005
Non-Moral
10.0(8.0-11.0)
10.0(9.0-11.0)
U=246.00, P=0.384
* p＜0.01
Table 4 The correlation between frontal lobe function and impersonal moral decisions Impersonal P-Valve
r
Stroop
0.158
0.207
DSF
0.639
-0.069
DSB
0.017
-0.343
VFT
0.050
-0.285
Categories Completed*
0.001
-0.471
Correct Response
0.017
-0.342
Total Errors*
0.001
0.456
Preservative Responses
0.183
0.196
Preservative Errors
0.023
0.328
* p＜0.01