Parkinsonism and Related Disorders 21 (2015) 709e716
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Ethical safety of deep brain stimulation: A study on moral decision-making in Parkinson's disease Manuela Fumagalli a, Sara Marceglia a, Filippo Cogiamanian b, Gianluca Ardolino b, Marta Picascia c, Sergio Barbieri b, Gabriella Pravettoni d, e, Claudio Pacchetti b, Alberto Priori a, f, * a
Centro Clinico per la Neurostimolazione, le Neurotecnologie ed i Disordini del Movimento, Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico, Via Francesco Sforza 35, Milan, Italy U.O. Neurofisiopatologia, Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico, Via Francesco Sforza 35, Milan, Italy c Operativa Parkinson e Disordini del Movimento, IRCCS Istituto Neurologico Mondino, Via Mondino 2, Pavia, Italy Unita d degli Studi di Milano, Via Festa del Perdono 7, Milan, Italy Dipartimento di Economia, Management e Metodi Quantitativi, Universita e Applied Research Unit for Cognitive and Psychological Science, Istituto Europeo di Oncologia, Via Giuseppe Ripamonti 435, Milan, Italy f degli Studi di Milano, Via Francesco Sforza 35, Milan, Italy Dipartimento di Fisiopatologia Medico-Chirurgica e dei Trapianti, Universita b
a r t i c l e i n f o
a b s t r a c t
Article history: Received 6 October 2014 Received in revised form 3 March 2015 Accepted 13 April 2015
Introduction: The possibility that deep brain stimulation (DBS) in Parkinson's disease (PD) alters patients' decisions and actions, even temporarily, raises important clinical, ethical and legal questions. Abnormal moral decision-making can lead to ethical rules violations. Previous experiments demonstrated the subthalamic (STN) activation during moral decision-making. Here we aim to study whether STN DBS can affect moral decision-making in PD patients. Methods: Eleven patients with PD and bilateral STN DBS implant performed a computerized moral task in ON and OFF stimulation conditions. A control group of PD patients without DBS implant performed the same experimental protocol. All patients underwent motor, cognitive and psychological assessments. Results: STN stimulation was not able to modify neither reaction times nor responses to moral task both when we compared the ON and the OFF state in the same patient (reaction times, p ¼ .416) and when we compared DBS patients with those treated only with the best medical treatment (reaction times: p ¼ .408, responses: p ¼ .776). Conclusions: Moral judgment is the result of a complex process, requiring cognitive executive functions, problem-solving, anticipations of consequences of an action, conflict processing, emotional evaluation of context and of possible outcomes, and involving different brain areas and neural circuits. Our data show that STN DBS leaves unaffected moral decisions thus implying relevant clinical and ethical implications for DBS consequences on patients' behavior, on decision-making and on judgment ability. In conclusion, the technique can be considered safe on moral behavior. © 2015 Elsevier Ltd. All rights reserved.
Keywords: Parkinson's disease Deep brain stimulation Subthalamus Moral decision Ethics
1. Introduction Despite its beneficial effects on motor symptoms and quality of life [1], subthalamic deep brain stimulation (STN DBS) in patients with Parkinson's disease (PD) can alter decision-making and
* Corresponding author. Centro Clinico per la Neurostimolazione, le Neurotecnologie ed i Disordini del Movimento, Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico, Via Francesco Sforza 35, 20122 Milan, Italy. Tel.: þ39 02 5503 3621; fax: þ39 02 5503 3855. E-mail address: [email protected] (A. Priori). http://dx.doi.org/10.1016/j.parkreldis.2015.04.011 1353-8020/© 2015 Elsevier Ltd. All rights reserved.
behavior, becoming an ethical and social challenge for personality, morality and action responsibility [2e4]. The STN has a role in premature and impulsive response selection [5,6] and its stimulation increases impulsivity during conflictual decisions [7]. However, the experimental results are heterogeneous. In some experiments, errors in high-conflict decision tasks were higher during STN-DBS [7e12], and impulse control disorders were shown to occur [13e15] or worsen with DBS [13,16]. Conversely, others found no DBS effects on behavior [13,16] or showed that impulse control disorders can even improve after DBS [14,16e20].
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Although impulsive decision-making and changes in behavior are reversible decreasing or turning off DBS, as well as appropriately managing drug treatment [21], the possibility that DBS can alter patients' competence of decision and action, even temporarily, raises important clinical, ethical and legal questions. An altered competence of decision and action can in turn alter moral decision-making, and even induce ethical rules violations [22]. We have previously shown that the modulation of STN neurophysiological activity is specifically involved in moral decisions in PD patients [23]. However, the modulation of STN activity does not imply a direct effect of STN DBS on moral decisions, since this can be mediated by other brain structures. Here we aim to study whether STN DBS can affect moral decision-making by comparing PD patients in ON and OFF DBS conditions to those of PD patients without DBS implant during a moral task [23]. 2. Materials and methods 2.1. Patients We recruited eleven patients with idiopathic PD (5 men and 6 women; mean ± standard deviation: age 63 ± 4.8 years, disease duration 11.9 ± 4.3 years, education 8.7 ± 4.2 years) implanted with bilateral STN DBS no less than 6 months before the experiment and with optimal stimulation parameters (experimental group). The control group included eleven patients with idiopathic PD and without DBS implant (6 men and 5 women; mean ± standard deviation: age 65 ± 9.2 years, disease duration 7.5 ± 3.7 years, education 10.9 ± 3.6 years) who were treated with the best medical treatment. All participants spoke native Italian and did not present behavioral or psychiatric disorders (Table 1). Patients were recruited at the Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan and at the Neurological Institute C. Mondino, Pavia. All patients gave written informed consent. The study was conducted in accordance with the Declaration of Helsinki and approved by the institutional review board.
2.2. Neuropsychological assessment To exclude cognitive impairment, all patients underwent a complete neuropsychological evaluation that included the Mini Mental State Examination (MMSE) [24], short and long term memory tests (the Digit Span [25], the Corsi Block-Tapping test [25], the Babcock Story Recall Test [26]), a logical deductive reasoning test (Raven Colored Progressive Matrices [27]), executive functions tests (the Frontal Assessment Battery e FAB [28]), the Phonological and Semantic Verbal Fluency tests [29], an attention test (Attentional Matrices [30]) and a constructional apraxia test (the Costructional Apraxia Test [30]) (Table 2). The neuropsychological battery was performed twice by the experimental group: before DBS surgery and 6 months after DBS surgery.
3. Statistical analyses 3.1. Neuropsychological assessment In the experimental group, corrected scores obtained by all tests performed before DBS surgery and 6 months after DBS surgery were compared by paired t-tests for dependent samples. To compare neuropsychological performances of the experimental group before and after DBS surgery and the control group, two paired t-tests for independent sample were run respectively (Table 2). 3.2. RTs Normality test was performed on RTs with the one-sample KolmogoroveSmirnov Test. To evaluate whether RTs obtained at the moral task by the experimental group differed in ON and OFF stimulation, a two-way ANOVA was run with sentence type (moral conflictual, moral non conflictual, and neutral) and DBS stimulation (ON, OFF) as within factors. To evaluate the role of gender, a three-way mixed-model ANOVA was applied with sentence type (moral conflictual, moral non conflictual, and neutral) and DBS stimulation (ON, OFF) as within factors and gender as between factor (man, woman). The role of education was investigated using a three-way mixedmodel ANOVA with sentence type (moral conflictual, moral non conflictual, and neutral) and DBS stimulation (ON, OFF) as within factors and education as between factor (5, 8, 13, 17 years of education). The same analyses were performed on the control group RTs comparing the two sessions in place of the DBS conditions (session 1, session 2). To assess whether the experimental and the control group were comparable, paired t-tests were calculated for the following variables: age, disease duration, education, levodopa equivalent dose, UPDRS III score, MMSE score, VASs scores (in ON stimulation for the experimental group, in the session 1 for the control group). A chisquare test was run to evaluate whether the experimental and the control groups differed for gender. To compare RTs obtained in the experimental and control groups, a three-way ANOVA was run with group (experimental, control group), condition (ON/OFF, session 1/session 2) and sentence type (moral conflictual, moral non conflictual, and neutral) as within factors.
2.3. Moral task The moral task is described in Fumagalli et al., 2011 [23]. Patients were tested during the best ON medication condition. The experimental group performed the task in the STN DBS ON condition and in the STN DBS OFF condition in random order. For the STN DBS OFF condition, the DBS device was turned off by the physician 30 min prior to the session. Two parallel versions of the moral task were used and the versions of the task were randomized and counterbalanced (Fig. 1A). The control group similarly performed the moral task twice with the same time intervals, without the STN DBS manipulation. RTs and types of response (agree, disagree) were stored for further analysis (Fig. 1A).
2.4. Motor, cognitive and psychological assessment Patients underwent a motor, cognitive and psychological assessment by using the Unified Parkinson's Disease Rating Scale part III (UPDRS III, motor part), the MMSE [24], and five 100 mm Visual Analogue Scales (VASs) [31]: a mood VAS (0 corresponding to good mood), a happiness VAS (0 corresponding to happiness), an anxiety VAS (0 corresponding to anxiety), a movement difficulty VAS (0 corresponding to absence of motor difficulty) and a motor fatigue VAS (0 corresponding to maximum motor fatigue). VASs were performed twice: in STN DBS ON and OFF conditions for experimental group, and in the first and the second experimental session for the control group. UPDRS III and MMSE were evaluated when patients from the experimental group were in STN DBS ON condition (Fig. 1B) and when control patients were in the first session.
3.3. Type of response Normality test was performed on type of response with onesample KolmogoroveSmirnov Test. Because responses to moral sentences cannot be defined as correct or incorrect, to analyze the type of response, the most frequent response given by the control group for each moral conflictual and moral non conflictual sentence was considered as the reference response. The percentage of reference-like responses was calculated as the percentage of responses given at each sentence by the experimental group in ON and in OFF stimulation that agrees with the reference response. For example, to the sentence Abortion is a murder the majority of patients from the control group responded “I agree” (reference response). The percentage of patients from the experimental group tested in ON stimulation that agreed with the sentence was 45% (percentage of reference-like response in ON), and the percentage of patients from the experimental group and in OFF stimulation that agreed with the sentence was 36% (percentage of reference-like response in OFF). To assess whether DBS stimulation affects the type of response, paired t-tests
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Table 1 Patients' clinical details. Predominant Patient Age Disease Gender MMSE corrected symptoms (years) duration score (years)
Levodopa UPDRS Left stimulation Months III scores equivalent after DBS parameters ON drugs dose (mg/day)a implant
Experimental group 1 63 15 2 52 13 3 65 11
F F F
28.53 26.99 28.27
3 35 29
250 1210 1060
32 11 23
4 5 6 7 8 9 10 11
70 9 62 8 62 10 67 12 68 16 64 9 59 20 61 5 Control group 1c 68 8
F M M F F M M M
30 24.27 28.53 28.27 29.53 28.46 26.31 29.49
Tremor, dyskinesias Tremor, dyskinesias Motor fluctuations, dyskinesias Rigidity, dyskinesias Freezing, rigidity Freezing, dyskinesias Tremor Dyskinesias Rigidity, dyskinesias Rigidity Rigidity, dyskinesias
37 13 6 6 5 4 21 2
760 1200 800 950 460 510 510 500
28 22 21 31 58 13 132 6
M
27.27
5
1060
2c
76
16
F
27.86
18
1854
3c 4c 5c 6c 7c
50 67 69 70 65
2 6 4 8 10
M M M M M
27.97 28.49 27.53 28.20 29.49
4 15 18 10 16
730 905 870 535 1150
8c 9c 10c 11c
71 46 72 69
8 4 7 10
F F F F
28.85 28.89 29.86 27.49
Rigidity, dyskinesias, motor fluctuations Rigidity, dyskinesias, motor fluctuations Rigidity Tremor, rigidity Rigidity, bradykinesia Rigidity, bradykinesia Rigidity, dyskinesias, motor fluctuations Rigidity Tremor Tremor Rigidity
10 2 6 14
715 310 452 600
Right stimulation parameters
7þ/135 Hz/60 ms/3.3 V 11þ/80 Hz/60 ms/3.5 V 7þ/80 Hz/60 ms/2.5 V
3þ/135 Hz/60 ms/3.3 V 3þ/80 Hz/60 ms/4.0 V 3þ/80 Hz/60 ms/2.0 V
6þ 7-/130 Hz/90 ms/þ3.3 V 4þ/130 Hz/90 ms/3.5 V 6þ/130 Hz/60 ms/2.8 V 6þ-7-/110 Hz/60 ms/þ3.0 V 1þ/130 Hz/60 ms/4.4 V 2- Cþ/130 Hz/60 ms/þ2.6 V Cþ 2-/160 Hz/60 ms/þ3.6 V Cþ 10-/130 Hz/60 ms/þ2.2 V
3þ/130 Hz/60 ms/2.5 V 1þ/130 Hz/60 ms/2.8 V 1þ/130 Hz/60 ms/2.5 V 3þ/110 Hz/60 ms/þ3.0 V 6þ/130 Hz/60 ms/3.2 V 8- Cþ/130 Hz/60 ms/þ2.2 V Cþ 6-/160 Hz/60 ms/þ3.3 V 1þ 2-/130 Hz/60 ms/þ1.7 V
a Preoperative levodopa equivalent dose expressed in mg/day represented the sum of levodopa and dopamine agonist. Dopamine agonist equivalent doses were calculated with the following equivalences: 100 mg levodopa ¼ 2 mg apomorphine ¼ 1 mg pergolide ¼ 1.5e2 mg cabergoline ¼ 1 mg pramipexole ¼ 10 mg bromocriptine ¼ 5 mg ropinirole (LIMPE, 2002). MMSE, Mini Mental State Examination; UPDRS III, third part of the Unified Parkinson's Disease Rating Scale.
Table 2 Neuropsychological evaluations obtained from the experimental group and the control group. For each test, the mean score ± standard deviation of the experimental group pre and 6 months post DBS surgery and of the control group is reported. In the experimental group, corrected scores obtained by each test performed pre and post DBS surgery were compared by paired t-tests for dependent sample. To compare neuropsychological performances of the experimental group pre and post DBS surgery and the control group, respectively two paired t-tests for independent sample were run. *significant result. SD, standard deviation; MMSE, Mini Mental State Examination; FAB, Frontal assessment battery.
MMSE Digit Span Corsi Block-Tapping test Babcock Story Recall Test Raven Colored Progressive Matrices FAB Attentional Matrices Phonological Verbal Fluency test (F, A, S) Semantic Verbal Fluency test Costructional Apraxia Test
Experimental group PRE DBS
Experimental group POST DBS
Mean ± S.D.
Mean ± S.D.
28.06 4.62 3.96 12.40 28.26
± ± ± ± ±
2.18 1.09 1.12 2.19 4.49
26.91 4.83 4.33 9.43 28.58
± ± ± ± ±
1.59 0.78 0.84 3.51 6.36
Control group
Experimental group PRE DBS vs. POST DBS
Mean ± S.D. 28.48 6.12 4.7 12.9 32.12
± ± ± ± ±
1.17 1.05 1.37 6.62 3.06
t t t t t
¼ ¼ ¼ ¼ ¼
1.33; p ¼ 0.24 1.27; p ¼ 0.26 1.06; p ¼ 0.34 1.70; p ¼ 0.15 0.15; p ¼ 0.88
Experimental group PRE DBS vs. Control group t t t t t
¼ ¼ ¼ ¼ ¼
0.16; p ¼ 0.88 2.5; p ¼ 0.03* 0.87; p ¼ 0.4 0.29; p ¼ 0.78 1.73; p ¼ 0.12
Experimental group POST DBS vs. Control group t t t t t
¼ ¼ ¼ ¼ ¼
2.28; 2.23; 0.54; 1.11; 1.02;
p p p p p
¼ ¼ ¼ ¼ ¼
0.04* 0.055 0.6 0.29 0.34
16.27 ± 1.13 45.29 ± 6.15 34.48 ± 11.50
13.87 ± 3.46 44.08 ± 9.21 29.38 ± 11.76
16.85 ± 0.78 52.1 ± 4.66 34.3 ± 13.97
t ¼ 1.93; p ¼ 0.15 t ¼ 0.82; p ¼ 0.45 t ¼ 1.56; p ¼ 0.18
t ¼ 0.24; p ¼ 0.82 t ¼ 1.97; p ¼ 0.07 t ¼ 0.45; p ¼ 0.66
t ¼ 1.13; p ¼ 0.32 t ¼ 1.75; p ¼ 0.11 t ¼ 0.63; p ¼ 0.54
22.16 ± 16.86 12.66 ± 1.59
23.37 ± 14.13 12.45 ± 2.68
e 12.95 ± 1.06
t ¼ 0.34; p ¼ 0.74 t ¼ 0.21; p ¼ 0.84
t ¼ 0.07; p ¼ 0.95
t ¼ 0.38; p ¼ 0.71
between percentage of reference-like response in ON and OFF stimulation in moral conflictual and moral non conflictual sentences were performed.
4. Results
3.4. Motor and psychological variables
In the experimental group, no significant differences were found between neuropsychological tests performed before DBS surgery and 6 months after DBS surgery. The comparison between neuropsychological performances obtained by the experimental group before DBS surgery and the control group revealed a significant difference only in the short-term verbal memory test (Digit Span) that was better performed by the control group. However, both groups (in average) performed this task normally.
Normality test was performed for mood VAS, happiness VAS, anxiety VAS, movement difficulty VAS, movement fatigue VAS with one-sample KolmogoroveSmirnov Test. In the experimental group, the effect of DBS stimulation was assessed with paired t-test for each variable. Differences were considered significant at p < .05.
4.1. Neuropsychological assessment
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Fig. 1. Moral task and experimental protocol. (A) Examples of moral conflictual, moral non conflictual and neutral statements. During the task, participants read the sentence on the PC screen: if they agreed/disagreed with the statement they pressed the “A”/“L” key. A black screen was displayed (1 s) before the next statement appeared on the screen. (B) Timeline for the experimental protocol.
Fig. 2. Moral task RTs. Histograms represent mean RTs (ms) for moral conflictual, moral non conflictual and neutral sentences in the experimental group in ON and OFF STN DBS conditions and in the control group in the session 1 and 2. Y-axis: mean RTs (ms). Error bars are standard error of the mean.
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Table 3 Statistical analysis and results for RTs (experimental group, control group, experimental group vs. control group), Percentage of reference-like responses (experimental group), VASs (experimental group, control group). *significant result. RTs, reaction times; ANOVA, analysis of variance; VAS, visual analogue scale. Statistics RTs Experimental group Two-way ANOVA Sentence Type Stimulation Sentence Type Stimulation Three-way mixed model ANOVA Sentence Type Stimulation Gender Gender Sentence Type Gender Stimulation Gender Sentence Type Stimulation Three-way mixed model ANOVA Sentence Type Stimulation Education Education Sentence Type Education Stimulation Education Sentence Type Stimulation Control group Two-way ANOVA Sentence Type Session Sentence Type Session Three-way mixed model ANOVA Sentence Type Session Gender Gender Sentence Type Gender Session Gender Sentence Type Session Three-way mixed model ANOVA Sentence Type Session Education Education Sentence Type Education Session Education Sentence Type Session Experimental group vs. Control group Three way ANOVA Group Condition Sentence Type Group Sentence Type Condition Sentence Type Group Condition Sentence Type Paired t-tests Group Age Group Disease duration Group Education Group Levodopa equivalent dose Group UPDRS III Group MMSE Group Mood VAS Group Happiness VAS Group Anxiety VAS Group Movement difficulty VAS Group Movement fatigue VAS Chi-Square Gender Percentage of reference-like responses Experimental group Paired t-tests Stimulation Moral Conflictual Sentences Stimulation Moral Non Conflictual Sentences VASs
F(2, 20) ¼ 8.071; p ¼ .002* F(1, 10) ¼ .721; p ¼ .416 F(2, 20) ¼ .166; p ¼ .848 F(2, 18) ¼ 7.92; p ¼ .003* F(1,9) ¼ .738; p ¼ .412 F(1, 9) ¼ .311; p ¼ .590 F(2, 18) ¼ 1.702; p ¼ .210 F(1, 9) ¼ .256; p ¼ .625 F(2, 18) ¼ .920; p ¼ .416 F(2, F(1, F(3, F(6, F(3, F(6,
14) ¼ 5.21; p ¼ .020* 7) ¼ .406; p ¼ .544 7) ¼ 3.89; p ¼ .063 14) ¼ 1.735; p ¼ .185 7) ¼ .108; p ¼ .953 14) ¼ .387; p ¼ .875
F(2, 20) ¼ 11.005; p ¼ .0005* F(1, 10) ¼ 1.857; p ¼ .203 F(2, 20) ¼ .480; p ¼ .625 F(2, F(1, F(1, F(2, F(1, F(2,
18) ¼ 11.831; p ¼ .0005* 9) ¼ 1.715; p ¼ .223 9) ¼ 2.335; p ¼ .161 18) ¼ 2.551; p ¼ .106 9) ¼ 2.440; p ¼ .153 18) ¼ .693; p ¼ .513
F(2, 10) ¼ 14.667; p ¼ .001* F(1, 5) ¼ .923; p ¼ .381 F(5, 5) ¼ 2.214; p ¼ .201 F(10,10) ¼ 2.976; p ¼ .0501 F(5, 5) ¼ .936; p ¼ .528 F(10, 10) ¼ 1.758; p ¼ .194
F(1, 10) ¼ 3.00; p ¼ .114 F(1, 10) ¼ 2.02; p ¼ .185 F (2, 20) ¼ 12.363; p ¼ .0003* F (2, 20) ¼ 2.791 p ¼ .085 F(2, 20) ¼ .161; p ¼ .852 F(2, 20) ¼ .256; p ¼ .776 t ¼ .755; p ¼ .468 t ¼ 2.173; p ¼ .055 t ¼ 1.299; p ¼ .223 t ¼ .548; p ¼ .589 t ¼ 1.468; p ¼ .280 t ¼ .944; p ¼ .367 Experimental group in Experimental group in Experimental group in Experimental group in Experimental group in Experimental group in Experimental group in Experimental group in Experimental group in Experimental group in
ON ON ON ON ON ON ON ON ON ON
stimulation stimulation stimulation stimulation stimulation stimulation stimulation stimulation stimulation stimulation
vs. vs. vs. vs. vs. vs. vs. vs. vs. vs.
control control control control control control control control control control
group group group group group group group group group group
session session session session session session session session session session
1: 2: 1: 2: 1: 2: 1: 2: 1: 2:
t t t t t t t t t t
¼ ¼ ¼ ¼ ¼ ¼ ¼ ¼ ¼ ¼
1.654; p ¼ .113 .823; p ¼ .420 1.389; p ¼ .180 1.969; p ¼ .063 .646; p ¼ .526 1.477; p ¼ .155 .440; p ¼ .665 .161; p ¼ .873 .041; p ¼ .312 1.552; p ¼ .138
Chi-Square ¼ .18; p ¼ .669
t ¼ .847; p ¼ .408 t ¼ .000; p ¼ .99 (continued on next page)
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Table 3 (continued ) Statistics Experimental group Paired t-test Mood VAS Stimulation Happiness VAS Stimulation Anxiety VAS Stimulation Movement Difficulty VAS Stimulation Movement Fatigue VAS Stimulation Control group Paired t-test Mood VAS Session Happiness VAS Session Anxiety VAS Session Movement Difficulty VAS Session Movement Fatigue VAS Session
t t t t t
¼ ¼ ¼ ¼ ¼
.779; p ¼ .453 .618; p ¼ .550 .159; p ¼ .877 1.553; p ¼ .164 2.187; p ¼ .065
t t t t t
¼ ¼ ¼ ¼ ¼
.723; p ¼ .485 2.167; p ¼ .055 1.844; p ¼ .095 .529; p ¼ .608 1.080; p ¼ .306
By comparing neuropsychological performances obtained by the experimental group 6 months after DBS surgery and the control group, we found only a significant different performance at the MMSE score, that was higher in the control group, but in both groups indicated a non pathological performance (Table 2). 4.2. RTs The one-sample KolmogoroveSmirnov Test on RTs for moral conflictual, moral non conflictual, and neutral sentences collected from both experimental and control groups were normally distributed (p > .05 for all variables). In the experimental group, RTs significantly differed between sentence types (moral conflictual, moral non conflictual, and neutral) whereas they were not affected nor by DBS stimulation, nor by gender nor by education. Results in the control group resembled those in the experimental group: RTs were significantly different between the three sentence types, but did not differ considering the session, gender and education. Comparing the experimental and control group, cognitive, psychological, and motor variables revealed that groups did not differ for age, disease duration, years of education, levodopa equivalent dose, MMSE score, VASs scores, UPDRS III score, and gender. Comparing the two groups (Fig. 2), data revealed that RTs were similar in DBS and control patients (Table 3). 4.3. Response type
5. Discussion This study aimed to investigate whether electrical STN stimulation can affect moral decisions. Our findings revealed that STN DBS does not modify reaction times and type of response in a moral task in PD patients. A strength of our work is that there was no change both comparing the ON and the OFF DBS state in the same patient, and comparing patients treated with DBS versus those receiving only the best medical treatment. The negative findings in these two comparisons suggested that both stimulation and the surgical procedure per se have no effect on moral decision. We have previously shown in PD patients in the ON dopaminergic therapy that STN activity, recorded by local field potentials (LFPs), during the same moral task used here is specifically modulated by sentence type: the low frequency LFP oscillation (5e13 Hz) significantly increased during moral conflictual sentences, but not during moral non conflictual and neutral sentences [23]. These results sustained the STN involvement in moral decision-making and confirmed that this moral task is an appropriate tool to study the relationship between morality and STN. In the present study we showed that DBS interference on STN activity does not result in moral decision alterations. We hypothesized that STN, although implicated in moral decisions, is not the core moral structure, and that a specific brain structure for morality does not exist. Indeed, the ‘moral brain’ consists of a large functional network including both cortical and subcortical anatomical structures. This anatomically pervasive moral system reflects the complexity of moral functions, that involves other emotional,
The one-sample KolmogoroveSmirnov Test for moral conflictual, moral non conflictual and neutral responses obtained by patients from the experimental group in ON and OFF stimulation and by patients from the control group in the session 1 and 2 showed a normal distribution (p > .05 for all variables). The percentage of reference-like responses for moral conflictual sentences did not differ in the ON and OFF stimulation condition, nor it did the percentage of reference-like responses for moral non conflictual sentences (Table 3) (Fig. 3). 4.4. Motor and psychological variables The one-sample KolmogoroveSmirnov Tests for mood VAS, happiness VAS, anxiety VAS, movement difficulty VAS, movement fatigue VAS for both experimental (ON and OFF stimulation) and control groups (session 1, session 2) revealed that all variables were normally distributed (p > .05 for all variables). In the experimental group, VASs were not influenced by DBS condition. The same was observed in the control group, considering the effect of session (Table 3).
Fig. 3. Moral task percentage of reference-like responses. Histograms represent the percentage of reference-like responses in the experimental group in moral conflictual and moral non conflictual sentences in ON and OFF stimulation. Y-axis: reference-like responses expresses as percentage. Error bars are standard error of the mean.
M. Fumagalli et al. / Parkinsonism and Related Disorders 21 (2015) 709e716
behavioral and cognitive processes, such as theory of mind, problem-solving, anticipations of consequences of an action, conflict processing, emotional evaluation of context and of possible outcomes [22]. To argue that STN DBS is not able to interfere with moral decisions, we showed that all patients did not present cognitive deficits and that neuropsychological performance remains stable and unaffected by DBS: an efficient moral decision processing implies an undamaged cognitive system. From an evolutive point of view, the complexity of moral decision-making associated to a normal cognition ensures that a focal brain damage or a brain alteration through electrical stimulation cannot disrupt morality, preserving human being from pervasive abnormal morality. Assuming that moral judgments are produced by general, notspecific mechanisms of evaluation and decision [32], we should compare our findings with studies about STN and (non moral) conflictual decision-making. Our results disagree with studies demonstrating that STN DBS has a negative impact on executive control during attention-demanding tasks or in situations of conflict when habitual or prepotent responses have to be inhibited [10,12,33,34]. An explanation for this discrepancy could be that moral conflictual decisions are processed in a different way than economic and other conflictual decisions. Hence, not all the decisions are affected by STN DBS in PD, thus confirming the multifaceted nature of decisional processes. Because moral decision-making reflects the competence of decision and action [22], these findings suggest relevant clinical and ethical implications for DBS consequences on patients' behavior, on decision-making and on judgment ability. We have also shown that patients with PD maintain their ability to decide and to judge in moral and ethical fields independently of STN stimulation. This suggests that DBS is a safe procedure and seems to guarantee an unaltered moral thinking and ability to judge good and bad. Limitations of the study are the small patients sample and the absence of evaluation of mood changes with standard tests: further confirmations of our findings are therefore needed. Despite these drawbacks, our findings suggest that patients with STN DBS maintain their ability to decide in various domains, such as in choosing medical treatment or financial arrangements [35], or in relevant professional choices, especially for those patients whose social position makes them responsible for others (eg, physicians, company leaders and politicians). Conflict of interest No conflicts of interest. Acknowledgments The experiments reported in this manuscript are part of the PhD thesis of Manuela Fumagalli. This work was supported by Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, (Milan, Italy) (R.C. 2013 e Tema n. 107). References [1] G. Deuschl, S. Paschen, K. Witt, Clinical outcome of deep brain stimulation for Parkinson's disease, Handb Clin Neurol 116 (2013) 107e128. [2] E. Bell, G. Mathieu, E. Racine, Preparing the ethical future of deep brain stimulation, Surg Neurol 72 (2009) 577e586 discussion 86. [3] L. Klaming, P. Haselager, Did my brain implant make me do it? Questions raised by DBS regarding psychological continuity, responsibility for action and mental competence, Neuroethics 6 (2013) 527e539. [4] M. Schermer, Ethical issues in deep brain stimulation, Front Integr Neurosci 5 (2011) 17.
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Priori, Functional and clinical neuroanatomy of morality, Brain 135 (2012) 2006e2021. [23] M. Fumagalli, G. Giannicola, M. Rosa, S. Marceglia, C. Lucchiari, S. MrakicSposta, et al., Conflict-dependent dynamic of subthalamic nucleus oscillations during moral decisions, Soc Neurosci 6 (2011) 243e256. [24] M.F. Folstein, S.E. Folstein, P.R. McHugh, “Mini-mental state”. A practical method for grading the cognitive state of patients for the clinician, J Psychiatr Res 12 (1975) 189e198. [25] A. Orsini, D. Grossi, E. Capitani, M. Laiacona, C. Papagno, G. Vallar, Verbal and spatial immediate memory span: normative data from 1355 adults and 1112 children, Ital J Neurol Sci 8 (1987) 539e548. [26] G. Novelli, C. Papagno, E. Capitani, M. Laiacona, S. Cappa, G. Vallar, Tre test clinici di memoria verbale a lungo termine. Taratura su soggetti normali, Arch Psicol Neurol Psichiatr 2 (1986) 278e296. [27] A. Basso, E. Capitani, M. 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Contents lists available at ScienceDirect
Parkinsonism and Related Disorders journal homepage: www.elsevier.com/locate/parkreldis
Ethical safety of deep brain stimulation: A study on moral decision-making in Parkinson's disease Manuela Fumagalli a, Sara Marceglia a, Filippo Cogiamanian b, Gianluca Ardolino b, Marta Picascia c, Sergio Barbieri b, Gabriella Pravettoni d, e, Claudio Pacchetti b, Alberto Priori a, f, * a
Centro Clinico per la Neurostimolazione, le Neurotecnologie ed i Disordini del Movimento, Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico, Via Francesco Sforza 35, Milan, Italy U.O. Neurofisiopatologia, Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico, Via Francesco Sforza 35, Milan, Italy c Operativa Parkinson e Disordini del Movimento, IRCCS Istituto Neurologico Mondino, Via Mondino 2, Pavia, Italy Unita d degli Studi di Milano, Via Festa del Perdono 7, Milan, Italy Dipartimento di Economia, Management e Metodi Quantitativi, Universita e Applied Research Unit for Cognitive and Psychological Science, Istituto Europeo di Oncologia, Via Giuseppe Ripamonti 435, Milan, Italy f degli Studi di Milano, Via Francesco Sforza 35, Milan, Italy Dipartimento di Fisiopatologia Medico-Chirurgica e dei Trapianti, Universita b
a r t i c l e i n f o
a b s t r a c t
Article history: Received 6 October 2014 Received in revised form 3 March 2015 Accepted 13 April 2015
Introduction: The possibility that deep brain stimulation (DBS) in Parkinson's disease (PD) alters patients' decisions and actions, even temporarily, raises important clinical, ethical and legal questions. Abnormal moral decision-making can lead to ethical rules violations. Previous experiments demonstrated the subthalamic (STN) activation during moral decision-making. Here we aim to study whether STN DBS can affect moral decision-making in PD patients. Methods: Eleven patients with PD and bilateral STN DBS implant performed a computerized moral task in ON and OFF stimulation conditions. A control group of PD patients without DBS implant performed the same experimental protocol. All patients underwent motor, cognitive and psychological assessments. Results: STN stimulation was not able to modify neither reaction times nor responses to moral task both when we compared the ON and the OFF state in the same patient (reaction times, p ¼ .416) and when we compared DBS patients with those treated only with the best medical treatment (reaction times: p ¼ .408, responses: p ¼ .776). Conclusions: Moral judgment is the result of a complex process, requiring cognitive executive functions, problem-solving, anticipations of consequences of an action, conflict processing, emotional evaluation of context and of possible outcomes, and involving different brain areas and neural circuits. Our data show that STN DBS leaves unaffected moral decisions thus implying relevant clinical and ethical implications for DBS consequences on patients' behavior, on decision-making and on judgment ability. In conclusion, the technique can be considered safe on moral behavior. © 2015 Elsevier Ltd. All rights reserved.
Keywords: Parkinson's disease Deep brain stimulation Subthalamus Moral decision Ethics
1. Introduction Despite its beneficial effects on motor symptoms and quality of life [1], subthalamic deep brain stimulation (STN DBS) in patients with Parkinson's disease (PD) can alter decision-making and
* Corresponding author. Centro Clinico per la Neurostimolazione, le Neurotecnologie ed i Disordini del Movimento, Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico, Via Francesco Sforza 35, 20122 Milan, Italy. Tel.: þ39 02 5503 3621; fax: þ39 02 5503 3855. E-mail address: [email protected] (A. Priori). http://dx.doi.org/10.1016/j.parkreldis.2015.04.011 1353-8020/© 2015 Elsevier Ltd. All rights reserved.
behavior, becoming an ethical and social challenge for personality, morality and action responsibility [2e4]. The STN has a role in premature and impulsive response selection [5,6] and its stimulation increases impulsivity during conflictual decisions [7]. However, the experimental results are heterogeneous. In some experiments, errors in high-conflict decision tasks were higher during STN-DBS [7e12], and impulse control disorders were shown to occur [13e15] or worsen with DBS [13,16]. Conversely, others found no DBS effects on behavior [13,16] or showed that impulse control disorders can even improve after DBS [14,16e20].
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Although impulsive decision-making and changes in behavior are reversible decreasing or turning off DBS, as well as appropriately managing drug treatment [21], the possibility that DBS can alter patients' competence of decision and action, even temporarily, raises important clinical, ethical and legal questions. An altered competence of decision and action can in turn alter moral decision-making, and even induce ethical rules violations [22]. We have previously shown that the modulation of STN neurophysiological activity is specifically involved in moral decisions in PD patients [23]. However, the modulation of STN activity does not imply a direct effect of STN DBS on moral decisions, since this can be mediated by other brain structures. Here we aim to study whether STN DBS can affect moral decision-making by comparing PD patients in ON and OFF DBS conditions to those of PD patients without DBS implant during a moral task [23]. 2. Materials and methods 2.1. Patients We recruited eleven patients with idiopathic PD (5 men and 6 women; mean ± standard deviation: age 63 ± 4.8 years, disease duration 11.9 ± 4.3 years, education 8.7 ± 4.2 years) implanted with bilateral STN DBS no less than 6 months before the experiment and with optimal stimulation parameters (experimental group). The control group included eleven patients with idiopathic PD and without DBS implant (6 men and 5 women; mean ± standard deviation: age 65 ± 9.2 years, disease duration 7.5 ± 3.7 years, education 10.9 ± 3.6 years) who were treated with the best medical treatment. All participants spoke native Italian and did not present behavioral or psychiatric disorders (Table 1). Patients were recruited at the Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan and at the Neurological Institute C. Mondino, Pavia. All patients gave written informed consent. The study was conducted in accordance with the Declaration of Helsinki and approved by the institutional review board.
2.2. Neuropsychological assessment To exclude cognitive impairment, all patients underwent a complete neuropsychological evaluation that included the Mini Mental State Examination (MMSE) [24], short and long term memory tests (the Digit Span [25], the Corsi Block-Tapping test [25], the Babcock Story Recall Test [26]), a logical deductive reasoning test (Raven Colored Progressive Matrices [27]), executive functions tests (the Frontal Assessment Battery e FAB [28]), the Phonological and Semantic Verbal Fluency tests [29], an attention test (Attentional Matrices [30]) and a constructional apraxia test (the Costructional Apraxia Test [30]) (Table 2). The neuropsychological battery was performed twice by the experimental group: before DBS surgery and 6 months after DBS surgery.
3. Statistical analyses 3.1. Neuropsychological assessment In the experimental group, corrected scores obtained by all tests performed before DBS surgery and 6 months after DBS surgery were compared by paired t-tests for dependent samples. To compare neuropsychological performances of the experimental group before and after DBS surgery and the control group, two paired t-tests for independent sample were run respectively (Table 2). 3.2. RTs Normality test was performed on RTs with the one-sample KolmogoroveSmirnov Test. To evaluate whether RTs obtained at the moral task by the experimental group differed in ON and OFF stimulation, a two-way ANOVA was run with sentence type (moral conflictual, moral non conflictual, and neutral) and DBS stimulation (ON, OFF) as within factors. To evaluate the role of gender, a three-way mixed-model ANOVA was applied with sentence type (moral conflictual, moral non conflictual, and neutral) and DBS stimulation (ON, OFF) as within factors and gender as between factor (man, woman). The role of education was investigated using a three-way mixedmodel ANOVA with sentence type (moral conflictual, moral non conflictual, and neutral) and DBS stimulation (ON, OFF) as within factors and education as between factor (5, 8, 13, 17 years of education). The same analyses were performed on the control group RTs comparing the two sessions in place of the DBS conditions (session 1, session 2). To assess whether the experimental and the control group were comparable, paired t-tests were calculated for the following variables: age, disease duration, education, levodopa equivalent dose, UPDRS III score, MMSE score, VASs scores (in ON stimulation for the experimental group, in the session 1 for the control group). A chisquare test was run to evaluate whether the experimental and the control groups differed for gender. To compare RTs obtained in the experimental and control groups, a three-way ANOVA was run with group (experimental, control group), condition (ON/OFF, session 1/session 2) and sentence type (moral conflictual, moral non conflictual, and neutral) as within factors.
2.3. Moral task The moral task is described in Fumagalli et al., 2011 [23]. Patients were tested during the best ON medication condition. The experimental group performed the task in the STN DBS ON condition and in the STN DBS OFF condition in random order. For the STN DBS OFF condition, the DBS device was turned off by the physician 30 min prior to the session. Two parallel versions of the moral task were used and the versions of the task were randomized and counterbalanced (Fig. 1A). The control group similarly performed the moral task twice with the same time intervals, without the STN DBS manipulation. RTs and types of response (agree, disagree) were stored for further analysis (Fig. 1A).
2.4. Motor, cognitive and psychological assessment Patients underwent a motor, cognitive and psychological assessment by using the Unified Parkinson's Disease Rating Scale part III (UPDRS III, motor part), the MMSE [24], and five 100 mm Visual Analogue Scales (VASs) [31]: a mood VAS (0 corresponding to good mood), a happiness VAS (0 corresponding to happiness), an anxiety VAS (0 corresponding to anxiety), a movement difficulty VAS (0 corresponding to absence of motor difficulty) and a motor fatigue VAS (0 corresponding to maximum motor fatigue). VASs were performed twice: in STN DBS ON and OFF conditions for experimental group, and in the first and the second experimental session for the control group. UPDRS III and MMSE were evaluated when patients from the experimental group were in STN DBS ON condition (Fig. 1B) and when control patients were in the first session.
3.3. Type of response Normality test was performed on type of response with onesample KolmogoroveSmirnov Test. Because responses to moral sentences cannot be defined as correct or incorrect, to analyze the type of response, the most frequent response given by the control group for each moral conflictual and moral non conflictual sentence was considered as the reference response. The percentage of reference-like responses was calculated as the percentage of responses given at each sentence by the experimental group in ON and in OFF stimulation that agrees with the reference response. For example, to the sentence Abortion is a murder the majority of patients from the control group responded “I agree” (reference response). The percentage of patients from the experimental group tested in ON stimulation that agreed with the sentence was 45% (percentage of reference-like response in ON), and the percentage of patients from the experimental group and in OFF stimulation that agreed with the sentence was 36% (percentage of reference-like response in OFF). To assess whether DBS stimulation affects the type of response, paired t-tests
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Table 1 Patients' clinical details. Predominant Patient Age Disease Gender MMSE corrected symptoms (years) duration score (years)
Levodopa UPDRS Left stimulation Months III scores equivalent after DBS parameters ON drugs dose (mg/day)a implant
Experimental group 1 63 15 2 52 13 3 65 11
F F F
28.53 26.99 28.27
3 35 29
250 1210 1060
32 11 23
4 5 6 7 8 9 10 11
70 9 62 8 62 10 67 12 68 16 64 9 59 20 61 5 Control group 1c 68 8
F M M F F M M M
30 24.27 28.53 28.27 29.53 28.46 26.31 29.49
Tremor, dyskinesias Tremor, dyskinesias Motor fluctuations, dyskinesias Rigidity, dyskinesias Freezing, rigidity Freezing, dyskinesias Tremor Dyskinesias Rigidity, dyskinesias Rigidity Rigidity, dyskinesias
37 13 6 6 5 4 21 2
760 1200 800 950 460 510 510 500
28 22 21 31 58 13 132 6
M
27.27
5
1060
2c
76
16
F
27.86
18
1854
3c 4c 5c 6c 7c
50 67 69 70 65
2 6 4 8 10
M M M M M
27.97 28.49 27.53 28.20 29.49
4 15 18 10 16
730 905 870 535 1150
8c 9c 10c 11c
71 46 72 69
8 4 7 10
F F F F
28.85 28.89 29.86 27.49
Rigidity, dyskinesias, motor fluctuations Rigidity, dyskinesias, motor fluctuations Rigidity Tremor, rigidity Rigidity, bradykinesia Rigidity, bradykinesia Rigidity, dyskinesias, motor fluctuations Rigidity Tremor Tremor Rigidity
10 2 6 14
715 310 452 600
Right stimulation parameters
7þ/135 Hz/60 ms/3.3 V 11þ/80 Hz/60 ms/3.5 V 7þ/80 Hz/60 ms/2.5 V
3þ/135 Hz/60 ms/3.3 V 3þ/80 Hz/60 ms/4.0 V 3þ/80 Hz/60 ms/2.0 V
6þ 7-/130 Hz/90 ms/þ3.3 V 4þ/130 Hz/90 ms/3.5 V 6þ/130 Hz/60 ms/2.8 V 6þ-7-/110 Hz/60 ms/þ3.0 V 1þ/130 Hz/60 ms/4.4 V 2- Cþ/130 Hz/60 ms/þ2.6 V Cþ 2-/160 Hz/60 ms/þ3.6 V Cþ 10-/130 Hz/60 ms/þ2.2 V
3þ/130 Hz/60 ms/2.5 V 1þ/130 Hz/60 ms/2.8 V 1þ/130 Hz/60 ms/2.5 V 3þ/110 Hz/60 ms/þ3.0 V 6þ/130 Hz/60 ms/3.2 V 8- Cþ/130 Hz/60 ms/þ2.2 V Cþ 6-/160 Hz/60 ms/þ3.3 V 1þ 2-/130 Hz/60 ms/þ1.7 V
a Preoperative levodopa equivalent dose expressed in mg/day represented the sum of levodopa and dopamine agonist. Dopamine agonist equivalent doses were calculated with the following equivalences: 100 mg levodopa ¼ 2 mg apomorphine ¼ 1 mg pergolide ¼ 1.5e2 mg cabergoline ¼ 1 mg pramipexole ¼ 10 mg bromocriptine ¼ 5 mg ropinirole (LIMPE, 2002). MMSE, Mini Mental State Examination; UPDRS III, third part of the Unified Parkinson's Disease Rating Scale.
Table 2 Neuropsychological evaluations obtained from the experimental group and the control group. For each test, the mean score ± standard deviation of the experimental group pre and 6 months post DBS surgery and of the control group is reported. In the experimental group, corrected scores obtained by each test performed pre and post DBS surgery were compared by paired t-tests for dependent sample. To compare neuropsychological performances of the experimental group pre and post DBS surgery and the control group, respectively two paired t-tests for independent sample were run. *significant result. SD, standard deviation; MMSE, Mini Mental State Examination; FAB, Frontal assessment battery.
MMSE Digit Span Corsi Block-Tapping test Babcock Story Recall Test Raven Colored Progressive Matrices FAB Attentional Matrices Phonological Verbal Fluency test (F, A, S) Semantic Verbal Fluency test Costructional Apraxia Test
Experimental group PRE DBS
Experimental group POST DBS
Mean ± S.D.
Mean ± S.D.
28.06 4.62 3.96 12.40 28.26
± ± ± ± ±
2.18 1.09 1.12 2.19 4.49
26.91 4.83 4.33 9.43 28.58
± ± ± ± ±
1.59 0.78 0.84 3.51 6.36
Control group
Experimental group PRE DBS vs. POST DBS
Mean ± S.D. 28.48 6.12 4.7 12.9 32.12
± ± ± ± ±
1.17 1.05 1.37 6.62 3.06
t t t t t
¼ ¼ ¼ ¼ ¼
1.33; p ¼ 0.24 1.27; p ¼ 0.26 1.06; p ¼ 0.34 1.70; p ¼ 0.15 0.15; p ¼ 0.88
Experimental group PRE DBS vs. Control group t t t t t
¼ ¼ ¼ ¼ ¼
0.16; p ¼ 0.88 2.5; p ¼ 0.03* 0.87; p ¼ 0.4 0.29; p ¼ 0.78 1.73; p ¼ 0.12
Experimental group POST DBS vs. Control group t t t t t
¼ ¼ ¼ ¼ ¼
2.28; 2.23; 0.54; 1.11; 1.02;
p p p p p
¼ ¼ ¼ ¼ ¼
0.04* 0.055 0.6 0.29 0.34
16.27 ± 1.13 45.29 ± 6.15 34.48 ± 11.50
13.87 ± 3.46 44.08 ± 9.21 29.38 ± 11.76
16.85 ± 0.78 52.1 ± 4.66 34.3 ± 13.97
t ¼ 1.93; p ¼ 0.15 t ¼ 0.82; p ¼ 0.45 t ¼ 1.56; p ¼ 0.18
t ¼ 0.24; p ¼ 0.82 t ¼ 1.97; p ¼ 0.07 t ¼ 0.45; p ¼ 0.66
t ¼ 1.13; p ¼ 0.32 t ¼ 1.75; p ¼ 0.11 t ¼ 0.63; p ¼ 0.54
22.16 ± 16.86 12.66 ± 1.59
23.37 ± 14.13 12.45 ± 2.68
e 12.95 ± 1.06
t ¼ 0.34; p ¼ 0.74 t ¼ 0.21; p ¼ 0.84
t ¼ 0.07; p ¼ 0.95
t ¼ 0.38; p ¼ 0.71
between percentage of reference-like response in ON and OFF stimulation in moral conflictual and moral non conflictual sentences were performed.
4. Results
3.4. Motor and psychological variables
In the experimental group, no significant differences were found between neuropsychological tests performed before DBS surgery and 6 months after DBS surgery. The comparison between neuropsychological performances obtained by the experimental group before DBS surgery and the control group revealed a significant difference only in the short-term verbal memory test (Digit Span) that was better performed by the control group. However, both groups (in average) performed this task normally.
Normality test was performed for mood VAS, happiness VAS, anxiety VAS, movement difficulty VAS, movement fatigue VAS with one-sample KolmogoroveSmirnov Test. In the experimental group, the effect of DBS stimulation was assessed with paired t-test for each variable. Differences were considered significant at p < .05.
4.1. Neuropsychological assessment
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Fig. 1. Moral task and experimental protocol. (A) Examples of moral conflictual, moral non conflictual and neutral statements. During the task, participants read the sentence on the PC screen: if they agreed/disagreed with the statement they pressed the “A”/“L” key. A black screen was displayed (1 s) before the next statement appeared on the screen. (B) Timeline for the experimental protocol.
Fig. 2. Moral task RTs. Histograms represent mean RTs (ms) for moral conflictual, moral non conflictual and neutral sentences in the experimental group in ON and OFF STN DBS conditions and in the control group in the session 1 and 2. Y-axis: mean RTs (ms). Error bars are standard error of the mean.
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713
Table 3 Statistical analysis and results for RTs (experimental group, control group, experimental group vs. control group), Percentage of reference-like responses (experimental group), VASs (experimental group, control group). *significant result. RTs, reaction times; ANOVA, analysis of variance; VAS, visual analogue scale. Statistics RTs Experimental group Two-way ANOVA Sentence Type Stimulation Sentence Type Stimulation Three-way mixed model ANOVA Sentence Type Stimulation Gender Gender Sentence Type Gender Stimulation Gender Sentence Type Stimulation Three-way mixed model ANOVA Sentence Type Stimulation Education Education Sentence Type Education Stimulation Education Sentence Type Stimulation Control group Two-way ANOVA Sentence Type Session Sentence Type Session Three-way mixed model ANOVA Sentence Type Session Gender Gender Sentence Type Gender Session Gender Sentence Type Session Three-way mixed model ANOVA Sentence Type Session Education Education Sentence Type Education Session Education Sentence Type Session Experimental group vs. Control group Three way ANOVA Group Condition Sentence Type Group Sentence Type Condition Sentence Type Group Condition Sentence Type Paired t-tests Group Age Group Disease duration Group Education Group Levodopa equivalent dose Group UPDRS III Group MMSE Group Mood VAS Group Happiness VAS Group Anxiety VAS Group Movement difficulty VAS Group Movement fatigue VAS Chi-Square Gender Percentage of reference-like responses Experimental group Paired t-tests Stimulation Moral Conflictual Sentences Stimulation Moral Non Conflictual Sentences VASs
F(2, 20) ¼ 8.071; p ¼ .002* F(1, 10) ¼ .721; p ¼ .416 F(2, 20) ¼ .166; p ¼ .848 F(2, 18) ¼ 7.92; p ¼ .003* F(1,9) ¼ .738; p ¼ .412 F(1, 9) ¼ .311; p ¼ .590 F(2, 18) ¼ 1.702; p ¼ .210 F(1, 9) ¼ .256; p ¼ .625 F(2, 18) ¼ .920; p ¼ .416 F(2, F(1, F(3, F(6, F(3, F(6,
14) ¼ 5.21; p ¼ .020* 7) ¼ .406; p ¼ .544 7) ¼ 3.89; p ¼ .063 14) ¼ 1.735; p ¼ .185 7) ¼ .108; p ¼ .953 14) ¼ .387; p ¼ .875
F(2, 20) ¼ 11.005; p ¼ .0005* F(1, 10) ¼ 1.857; p ¼ .203 F(2, 20) ¼ .480; p ¼ .625 F(2, F(1, F(1, F(2, F(1, F(2,
18) ¼ 11.831; p ¼ .0005* 9) ¼ 1.715; p ¼ .223 9) ¼ 2.335; p ¼ .161 18) ¼ 2.551; p ¼ .106 9) ¼ 2.440; p ¼ .153 18) ¼ .693; p ¼ .513
F(2, 10) ¼ 14.667; p ¼ .001* F(1, 5) ¼ .923; p ¼ .381 F(5, 5) ¼ 2.214; p ¼ .201 F(10,10) ¼ 2.976; p ¼ .0501 F(5, 5) ¼ .936; p ¼ .528 F(10, 10) ¼ 1.758; p ¼ .194
F(1, 10) ¼ 3.00; p ¼ .114 F(1, 10) ¼ 2.02; p ¼ .185 F (2, 20) ¼ 12.363; p ¼ .0003* F (2, 20) ¼ 2.791 p ¼ .085 F(2, 20) ¼ .161; p ¼ .852 F(2, 20) ¼ .256; p ¼ .776 t ¼ .755; p ¼ .468 t ¼ 2.173; p ¼ .055 t ¼ 1.299; p ¼ .223 t ¼ .548; p ¼ .589 t ¼ 1.468; p ¼ .280 t ¼ .944; p ¼ .367 Experimental group in Experimental group in Experimental group in Experimental group in Experimental group in Experimental group in Experimental group in Experimental group in Experimental group in Experimental group in
ON ON ON ON ON ON ON ON ON ON
stimulation stimulation stimulation stimulation stimulation stimulation stimulation stimulation stimulation stimulation
vs. vs. vs. vs. vs. vs. vs. vs. vs. vs.
control control control control control control control control control control
group group group group group group group group group group
session session session session session session session session session session
1: 2: 1: 2: 1: 2: 1: 2: 1: 2:
t t t t t t t t t t
¼ ¼ ¼ ¼ ¼ ¼ ¼ ¼ ¼ ¼
1.654; p ¼ .113 .823; p ¼ .420 1.389; p ¼ .180 1.969; p ¼ .063 .646; p ¼ .526 1.477; p ¼ .155 .440; p ¼ .665 .161; p ¼ .873 .041; p ¼ .312 1.552; p ¼ .138
Chi-Square ¼ .18; p ¼ .669
t ¼ .847; p ¼ .408 t ¼ .000; p ¼ .99 (continued on next page)
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Table 3 (continued ) Statistics Experimental group Paired t-test Mood VAS Stimulation Happiness VAS Stimulation Anxiety VAS Stimulation Movement Difficulty VAS Stimulation Movement Fatigue VAS Stimulation Control group Paired t-test Mood VAS Session Happiness VAS Session Anxiety VAS Session Movement Difficulty VAS Session Movement Fatigue VAS Session
t t t t t
¼ ¼ ¼ ¼ ¼
.779; p ¼ .453 .618; p ¼ .550 .159; p ¼ .877 1.553; p ¼ .164 2.187; p ¼ .065
t t t t t
¼ ¼ ¼ ¼ ¼
.723; p ¼ .485 2.167; p ¼ .055 1.844; p ¼ .095 .529; p ¼ .608 1.080; p ¼ .306
By comparing neuropsychological performances obtained by the experimental group 6 months after DBS surgery and the control group, we found only a significant different performance at the MMSE score, that was higher in the control group, but in both groups indicated a non pathological performance (Table 2). 4.2. RTs The one-sample KolmogoroveSmirnov Test on RTs for moral conflictual, moral non conflictual, and neutral sentences collected from both experimental and control groups were normally distributed (p > .05 for all variables). In the experimental group, RTs significantly differed between sentence types (moral conflictual, moral non conflictual, and neutral) whereas they were not affected nor by DBS stimulation, nor by gender nor by education. Results in the control group resembled those in the experimental group: RTs were significantly different between the three sentence types, but did not differ considering the session, gender and education. Comparing the experimental and control group, cognitive, psychological, and motor variables revealed that groups did not differ for age, disease duration, years of education, levodopa equivalent dose, MMSE score, VASs scores, UPDRS III score, and gender. Comparing the two groups (Fig. 2), data revealed that RTs were similar in DBS and control patients (Table 3). 4.3. Response type
5. Discussion This study aimed to investigate whether electrical STN stimulation can affect moral decisions. Our findings revealed that STN DBS does not modify reaction times and type of response in a moral task in PD patients. A strength of our work is that there was no change both comparing the ON and the OFF DBS state in the same patient, and comparing patients treated with DBS versus those receiving only the best medical treatment. The negative findings in these two comparisons suggested that both stimulation and the surgical procedure per se have no effect on moral decision. We have previously shown in PD patients in the ON dopaminergic therapy that STN activity, recorded by local field potentials (LFPs), during the same moral task used here is specifically modulated by sentence type: the low frequency LFP oscillation (5e13 Hz) significantly increased during moral conflictual sentences, but not during moral non conflictual and neutral sentences [23]. These results sustained the STN involvement in moral decision-making and confirmed that this moral task is an appropriate tool to study the relationship between morality and STN. In the present study we showed that DBS interference on STN activity does not result in moral decision alterations. We hypothesized that STN, although implicated in moral decisions, is not the core moral structure, and that a specific brain structure for morality does not exist. Indeed, the ‘moral brain’ consists of a large functional network including both cortical and subcortical anatomical structures. This anatomically pervasive moral system reflects the complexity of moral functions, that involves other emotional,
The one-sample KolmogoroveSmirnov Test for moral conflictual, moral non conflictual and neutral responses obtained by patients from the experimental group in ON and OFF stimulation and by patients from the control group in the session 1 and 2 showed a normal distribution (p > .05 for all variables). The percentage of reference-like responses for moral conflictual sentences did not differ in the ON and OFF stimulation condition, nor it did the percentage of reference-like responses for moral non conflictual sentences (Table 3) (Fig. 3). 4.4. Motor and psychological variables The one-sample KolmogoroveSmirnov Tests for mood VAS, happiness VAS, anxiety VAS, movement difficulty VAS, movement fatigue VAS for both experimental (ON and OFF stimulation) and control groups (session 1, session 2) revealed that all variables were normally distributed (p > .05 for all variables). In the experimental group, VASs were not influenced by DBS condition. The same was observed in the control group, considering the effect of session (Table 3).
Fig. 3. Moral task percentage of reference-like responses. Histograms represent the percentage of reference-like responses in the experimental group in moral conflictual and moral non conflictual sentences in ON and OFF stimulation. Y-axis: reference-like responses expresses as percentage. Error bars are standard error of the mean.
M. Fumagalli et al. / Parkinsonism and Related Disorders 21 (2015) 709e716
behavioral and cognitive processes, such as theory of mind, problem-solving, anticipations of consequences of an action, conflict processing, emotional evaluation of context and of possible outcomes [22]. To argue that STN DBS is not able to interfere with moral decisions, we showed that all patients did not present cognitive deficits and that neuropsychological performance remains stable and unaffected by DBS: an efficient moral decision processing implies an undamaged cognitive system. From an evolutive point of view, the complexity of moral decision-making associated to a normal cognition ensures that a focal brain damage or a brain alteration through electrical stimulation cannot disrupt morality, preserving human being from pervasive abnormal morality. Assuming that moral judgments are produced by general, notspecific mechanisms of evaluation and decision [32], we should compare our findings with studies about STN and (non moral) conflictual decision-making. Our results disagree with studies demonstrating that STN DBS has a negative impact on executive control during attention-demanding tasks or in situations of conflict when habitual or prepotent responses have to be inhibited [10,12,33,34]. An explanation for this discrepancy could be that moral conflictual decisions are processed in a different way than economic and other conflictual decisions. Hence, not all the decisions are affected by STN DBS in PD, thus confirming the multifaceted nature of decisional processes. Because moral decision-making reflects the competence of decision and action [22], these findings suggest relevant clinical and ethical implications for DBS consequences on patients' behavior, on decision-making and on judgment ability. We have also shown that patients with PD maintain their ability to decide and to judge in moral and ethical fields independently of STN stimulation. This suggests that DBS is a safe procedure and seems to guarantee an unaltered moral thinking and ability to judge good and bad. Limitations of the study are the small patients sample and the absence of evaluation of mood changes with standard tests: further confirmations of our findings are therefore needed. Despite these drawbacks, our findings suggest that patients with STN DBS maintain their ability to decide in various domains, such as in choosing medical treatment or financial arrangements [35], or in relevant professional choices, especially for those patients whose social position makes them responsible for others (eg, physicians, company leaders and politicians). Conflict of interest No conflicts of interest. Acknowledgments The experiments reported in this manuscript are part of the PhD thesis of Manuela Fumagalli. This work was supported by Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, (Milan, Italy) (R.C. 2013 e Tema n. 107). References [1] G. Deuschl, S. Paschen, K. Witt, Clinical outcome of deep brain stimulation for Parkinson's disease, Handb Clin Neurol 116 (2013) 107e128. [2] E. Bell, G. Mathieu, E. Racine, Preparing the ethical future of deep brain stimulation, Surg Neurol 72 (2009) 577e586 discussion 86. [3] L. Klaming, P. Haselager, Did my brain implant make me do it? Questions raised by DBS regarding psychological continuity, responsibility for action and mental competence, Neuroethics 6 (2013) 527e539. [4] M. Schermer, Ethical issues in deep brain stimulation, Front Integr Neurosci 5 (2011) 17.
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