1 This is a preprint version of the final version of the manuscript published in Neuroscience Letters 475 (2010) 44–47 https://doi.org/10.1016/j.neulet.2010.03.043
Emotional electrodermal response in coma and other low-responsive patients. Jérôme Daltrozzo,1,2,5 Norma Wioland,1,2 Véronique Mutschler,1,2 Philippe Lutun,3 Bartholomeus Calon,4 Alain Meyer,4 Albert Jaeger,3 Thierry Pottecher,4 Boris Kotchoubey 5 1
CNRS UPS 858, Louis Pasteur University, Strasbourg, France
2
Department of Neurology, Strasbourg University Hospital, France
3
Intensive Care Unit, U.F. 6250, Strasbourg University Hospital, France
4
Intensive Care Unit, U.F. 6365, Strasbourg University Hospital, France
5
Institute of Medical Psychology and Behavioral Neurobiology, Tuebingen University,
Germany
Corresponding author: Jérôme Daltrozzo, CNRS UMR 5020, Université Claude Bernard Lyon I, 50 Avenue Tony Garnier, 69366 Lyon cedex 07, France. Phone +33 437 287 490, Fax +33 437 287 601, Email:
[email protected]
Acknowledgements
2 This study was supported by the Deutsche Forschungsgemeinshaft (SFB 550 to B.K.) and the French Ministry of Health (PHRC 2004 R-03-03).
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Abstract Emotional processing in coma remains an open question. Skin conductance responses to emotional and neutral auditory stimuli were recorded in thirteen low-responsive patients (12 of whom were in coma). A differential response between emotional and neutral stimuli was found, which significantly correlated with the Glasgow Coma Scale and the Cook and Palma score. These correlations indicate that emotional processing can occur in coma patients with relatively high clinical scores of reactivity.
Keywords: Coma, Consciousness, Emotion, Electrodermal, Skin Conductance, Galvanic Skin Response.
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Introduction Coma is a state of behavioral unresponsiveness that is thought to be caused by a dysfunction of the ascending reticular activating system [1]. The lack of behavioral responses implies that information about the patient’s cognition and emotion should be investigated with tools, such as neuroimaging techniques, that do not rely on overt responses. Thus, event-related potentials (ERPs) have been used to explore several cognitive aspects of consciousness disorders [2]. ERPs also allow the recording of a “late positive potential” component related to emotional arousal/attention [3]. However, this emotional response is likely to reflect only cognitive processes. Because the emotional responses may be better expressed in peripheral as compared to central physiological reactions, we measured electrodermal activity (EDA) in this study. The technique is known to be sensitive not only to cognitive but also to autonomic aspects of the emotional response [4].
There are only a few EDA studies of coma or low-responsive patients; these demonstrate spontaneous EDA fluctuations [5-7] as well as responses to electric stimuli [8, 9], to familiar voices [10] and to one’s own name [11]. Some of these studies indicated a positive correlation between the EDA and the level of consciousness according to clinical scores: a binary index (i.e., “normal” versus “impaired” consciousness) [8], the Glasgow Coma Scale (GCS, [12]) [5], and the Munich Coma Scale [11]. However, none of these studies were explicitly designed to test emotional responses.
Therefore, the aim of the present study was to test emotional responses in coma and other low-responsive patients using the EDA. Based on the above-mentioned studies, we predicted that some of these patients would show an emotional EDA response that would correlate with clinical scores of consciousness.
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Materials and methods Participants Written informed consent was obtained from healthy participants and patients’ families before participation in this study. The study was performed in accordance with the Declaration of Helsinki, and the procedure was approved by the ethics committee of the University Hospital of Strasbourg. Twenty right-handed healthy volunteers (21 years (SD = 2.6), range: 18-26; 10 males), without reported auditory or neurological deficits, were included for protocol validation. Participants were paid for their participation (Table 1). The patients were clinically evaluated on the day of EDA recording according to the Glasgow Coma Scale (GCS), Cook and Palma score [13], and the Ramsay score [14]. Sedated and restless patients were excluded from the study. The patients’ evolution was assessed three months after coma onset according to the Glasgow Outcome Score [15]. Fifteen patients were examined. The data from 2 patients were rejected due to artifacts; only 13 patients (Table 1) were included in the final analyses (Mean SD): 63.6 11.6) years, range 43-81; 8 males; GCS = 5.08 2.14), Ramsay = 5.38 0.77), Cook and Palma = 7.62 2.47); recorded 3.92 1.71) days after coma onset). The integrity of the patients’ auditory channels and primary auditory cortices were tested with ERPs [16]. We assumed integrity if at least one distinct ERP component was found for each patient. Note that, due to the sensitivity of these protocols, the lack of an ERP component does not imply the absence of cortical stimulus processing.
Stimuli
6 We selected stimuli from the International Affective Digital Sounds (IADS) database [17]: 10 emotional (IADS arousal: 7.41; IADS valence: 7.29 or 2.87), 10 neutral environmental sounds (IADS arousal: 4.36; 5.04 < IADS valence < 6.05), and 20 fillers (i.e., sounds that were included in the sequence of stimulation to reduce the probability of occurrence or predictability of emotional stimuli). IADS valence and arousal differ as a function of gender. Thus, different emotional and neutral sounds were selected for males and females. The maximum root mean square power did not differ between emotional and neutral sounds (for males: Mean SD) = -5.98 (2.33) dB for emotional sounds, -4.38 (2.11) dB for neutral sounds, t(18) = -1.62, p = 0.12; for females: -6.63 (2.32) dB for emotional sounds, -5.10 (2.81) dB for neutral sounds, t(18) = -1.33, p = 0.20). These stimuli lasted 6 sec and were randomly presented with an onset-to-onset time interval of 16-25 seconds [18].
Recording and Analyses
The Skin Conductance Response (SCR) was recorded with Ag-Ag/Cl electrodes (Model FEGSR from Grass, Bionic), which were placed on the middle phalanges of the index and middle fingers [19] and connected to a Wheastone Bridge [20]. A NeuroScan, Inc. unit was used for stimulus presentation and recordings. The signal was band-pass filtered (0.05-30 Hz) and digitized at 100 Hz. The epoch windows started 3 s before and ended 16 s after stimulus onset. Single trials with an absolute SCR < 0.01 µS [18] or > 3 µS [4] were considered as artifacts and thus rejected. This procedure removed 6 % of the healthy participants’ trials and 13 % of the patients’ trials. Individual SCR averages were time-locked to the onset of the stimulus.
7 The “peak analysis” was performed on single-trial SCR epochs analyzed between 2 and 16 s for healthy participants and between 8 and 16 s for patients (time windows based on grand averages). The largest SCRs in those time windows, referred to below as “SCR peaks”, were measured for each trial [18]. For individual assessments, the difference between conditions was tested with the one-tailed Mann-Whitney test. The group assessment test employed Fisher's combined probability test, which tests the deviation of the distribution of the individual p-values against a uniform distribution [21]. The “waveform analysis” was performed on single-trial SCR waveforms (same time windows as in the peak analysis). For individual assessments, the difference between conditions was tested with a one-tailed permutation test (see “t-CWT” in [22]). The group assessment test employed Fisher’s method [21]. The Hotteling T 2 computed for the permutation test is a squared normalized Euclidian distance between two matrices of extracted features, calculated for each experimental condition. Thus, an Effect Size (ES) measure can be estimated as the square root of T2 [16]. ES can be roughly considered as a measure of waveform shape difference between the two experimental conditions (i.e., emotional versus neutral).
The median single-trial SCR peak of each healthy participant was defined as the response threshold. The number of true positives was the number of trials in which the SCR peak to emotional stimuli was larger than this threshold. True negatives were the trials in which SCR peaks to neutral stimuli were lower than the threshold. False positive were the trials in which SCR peaks to neutral stimuli were larger than the threshold, and false negative were the trials in which SCR peaks to emotional stimuli were lower than the threshold. The sensitivity, specificity, positive and negative predictive values were estimated based on these data. The exact 95 % Confidence Intervals (CIs) were estimated using the binomial distribution [23]. Reliability was defined as the correlation between the SCR peaks to 50 % randomly chosen
8 stimuli with the SCR peaks to the other 50 % for each participant and each experimental condition. All correlation analyses were performed with the two-tailed Spearman test.
Results Healthy participants demonstrated an SCR emotional effect, i.e., a larger SCR when listening to emotional as compared to neutral stimuli (Figure 1). The effect started about 2 s poststimulus and was largest at approximately 9 s. The SCR emotional effect was confirmed statistically with peak analysis (2 = 81.7, d.f. = 40, p < 0.001) and waveform analysis (2 = 75.9, d.f. = 40, p < 0.001). Individual assessments resulted in significant between-condition differences in three participants (as determined by peak analysis) and in five participants (as determined by waveform analysis) (Table 1). The sensitivity, specificity, positive and negative predictive values, and reliability of the SCR protocol were estimated at 60 % (95 % CI: 52-67), 57 % (95 % CI: 49-65), 58 % (95 % CI: 51-66), 59 % (95 % CI: 51-66), and 48 % ( = 0.479, p < 0.001), respectively.
The patients also showed an SCR emotional effect starting about 8 s post-stimulus onset, reaching a maximum at the end of the recorded epoch. Statistically, the SCR emotional effect was confirmed with waveform analysis ( 2 = 40.9, d.f. = 26, p = 0.03). Individual assessment resulted in significant between-condition differences in two patients in the peak analysis and in one patient in the waveform analysis (Table 1). The peak SCR emotional effect (i.e., largest SCR within the 8-16-sec analysis window to emotional minus neutral sounds) was positively correlated with the GCS ( = 0.562, p = 0.046, N=13) and the Cook and Palma score ( = 0.732, p = 0.004, N=13) (Figure 1). Furthermore, the peak SCR to emotional sounds correlated with the Cook and Palma score ( = 0.790, p = 0.001, N=13).
9 Table 1: Participants’ data. Healthy participants for protocol validation (N=20, upper panel) and patients (N=13, lower panel).
Note: n° = Participant number; Day = Days between the coma onset and the SCR recording; GCS, R, and CP = Glasgow Coma Scale, Ramsay, and Cook and Palma scores on the day of the SCR recording, respectively; GOS = Glasgow Outcome Score 3 months after the SCR recording; hem. = hemorrhage; enceph.= encephalopathy; IAP = Integrity of the Auditory Pathways; Lesion side = Lesion side on baseline admission CT scan performed in eight patients; B = Bilateral; R = Right; L = Left; N = No lesion evidenced; Lesion loc.: Lesion localization on baseline admission CT scan performed in 8 patients; V = Ventricular; Bg = Basal ganglia; F = Frontal; O = Occipital; B = Brainstem; Cb = Cerebellum; SCR_e = SCR peak to emotional stimuli in µS (Standard Error of Mean [SEM] in parentheses); SCR_n = SCR peak to neutral stimuli in µS (SEM in parentheses); Peak = peak analysis p-value; ES = Effect size (based on the waveform analysis); Waveform: waveform analysis p-value.
10 Figure 1: Grand averaged SCRs to “emotional” (thick line) and “neutral” (thin line) sounds in healthy participants for protocol validation (N=20, upper panel) and in patients (N=13, middle panel) (horizontal unit: time in seconds, vertical unit: MicroSiemens). The onset of the emotional or neutral sound presentation is at the origin of the time axis. The duration of stimulus presentation is displayed. The SCR emotional effect (i.e., the difference between SCR to emotional and neutral stimuli) is plotted against the GCS (lower left panel) and the Cook and Palma (lower right panel) scores.
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Discussion Consistent with the literature [4], emotional stimuli elicited larger SCRs than neutral stimuli in healthy participants. This emotional SCR effect was confirmed with the peak and waveform analyses, thus validating the protocol.
12 In agreement with our hypothesis, the patients showed a small and late emotional response, the size of which correlated positively with two clinical scores: the GCS and the Cook and Palma. These correlations suggest that small responses were not artifacts or random oscillations but rather effective emotional responses.
The emotional SCR is controlled by the sympathetic part of the autonomous nervous system and several areas of the central nervous system, such as the ventromedial frontal and right lower parietal cortex, the limbic system, the basal ganglia, and the amygdala [4, 18]. In emotional states, the hypothalamic-limbic connections most likely activate the postganglionic sympathetic neurons and then, via the peripheral cutaneous nerve, the sweat glands [4]. Thus, the emotional SCR effect in our patient sample suggests that these cognitive and autonomic systems were at least partly preserved. In addition, given that most of the emotional IADS (e.g., sounds of a car crash or a baby’s cry) used are likely to evoke emotions following a semantic analysis, some of our patients may have a partially preserved semantic processing network [16].
The partial integrity of the emotional processing system is further confirmed in our patients by correlations between their emotional responses and clinical scores for their level of consciousness, a result in line with the idea that emotional processing constitutes an essential, profound, dimension of consciousness [24 - 26]. A distinction has been drawn between affective and cognitive consciousness, the former emerging from "primary-process affective experiences [...] such as the pleasure of taste and the distress of homeostatic imbalances" and the latter from "high cognitive process[es] that allow us to think and talk about our internal experiences" [27]. In our patients showing emotional processing, this consciousness might be present, at least at the affective level. Furthermore, if a semantic analysis was performed on the emotional IADS that induced emotions, it cannot be excluded that the emotional SCR
13 effect also reflected a cognitive consciousness. Whether only affective or also cognitive, the presence of consciousness in low-responsive patients raises important ethical questions (for a review, see [27]).
None of our patients met the clinical criteria of a vegetative state, locked-in syndrome, akinetic mutism, or minimally conscious state [28-29]. In these states, the level of vigilance varies and a sleep-wakefulness cycle is preserved, which was not the case in our patients. Only one of the examined patients (No. 4, GCS = 10) might be regarded as low-responsive but not comatose. The other 12 patients were in severe coma [28]. Therefore, our conclusions are mostly relevant to the coma state.
Similarly to the ERP protocols, results at the individual level are likely to present more false negatives than false positives [16]. Therefore, the number of patients who show a significant response is underestimated. A higher sensitivity is needed to use this type of protocol in clinical practice. This might be achieved using a larger number of trials per experimental condition and by recording larger epochs. Because we were the first group to implement this paradigm in this type of patients, the optimal number of stimuli and the epoch duration could not be known a priori; however, ethical considerations clearly indicated the need to start with a relatively short procedure to minimize patient load.
Conclusion We tested whether coma and other low-responsive patients could have emotional responses, and whether these responses could be measured with SCR. Our data suggest that a small but significant SCR emotional response persists in some patients but drops as the level of consciousness decreases.
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