Narcolepsy and emotions

J Sleep Res. (2014) 23, 432–440

Facing emotions in narcolepsy with cataplexy: haemodynamic and behavioural responses during emotional stimulation MASSIMILIANO DE ZAMBOTTI1,2, FABIO PIZZA3,4, NAIMA COVASSIN2, S T E F A N O V A N D I 3 , 4 , N I C O L A C E L L I N I 2 , L U C I A N O S T E G A G N O 2 and GIUSEPPE PLAZZI3,4 1

Center for Health Sciences, SRI International, Menlo Park, CA, USA, 2Department of General Psychology, University of Padua, Padua, Italy, Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy and 4IRCCS Istituto delle Scienze Neurologiche, ASL di Bologna, Bologna, Italy 3

Keywords cataplectic attack, hypocretinergic, limbic system, orexin Correspondence Massimiliano de Zambotti, PhD, SRI International, 333 Ravenswood Avenue, Menlo Park, CA-94025, USA. Tel.: +1 (650) 859-2714; fax: +1 (650) 859-2743; e-mail: [email protected] Accepted in revised form 5 January 2014; received 8 July 2013 DOI: 10.1111/jsr.12133

SUMMARY

Narcolepsy with cataplexy is a complex sleep disorder that affects the modulation of emotions: cataplexy, the key symptom of narcolepsy, is indeed strongly linked with emotions that usually trigger the episodes. Our study aimed to investigate haemodynamic and behavioural responses during emotional stimulation in narco-cataplexy. Twelve adult drug-naive narcoleptic patients (five males; age: 33.3  9.4 years) and 12 healthy controls (five males; age: 30.9  9.5 years) were exposed to emotional stimuli (pleasant, unpleasant and neutral pictures). Heart rate, arterial blood pressure and mean cerebral blood flow velocity of the middle cerebral arteries were continuously recorded using photoplethysmography and Doppler ultrasound. Ratings of valence and arousal and coping strategies were scored by the Self-Assessment Manikin and by questionnaires, respectively. Narcoleptic patients’ haemodynamic responses to pictures overlapped with the data obtained from controls: decrease of heart rate and increase of mean cerebral blood flow velocity regardless of pictures’ content, increase of systolic blood pressure during the pleasant condition, and relative reduction of heart rate during pleasant and unpleasant conditions. However, when compared with controls, narcoleptic patients reported lower arousal scores during the pleasant and neutral stimulation, and lower valence scores during the pleasant condition, respectively, and also a lower score at the ‘focus on and venting of emotions’ dimensions of coping. Our results suggested that adult narcoleptic patients, compared with healthy controls, inhibited their emotion-expressive behaviour to emotional stimulation, and that may be related to the development of adaptive cognitive strategies to face emotions avoiding cataplexy.

INTRODUCTION Narcolepsy with cataplexy (NC) is a rare disorder characterized by excessive daytime sleepiness, cataplexy (i.e. sudden loss of muscle tone evoked by strong emotions, the pathognomonic symptom of NC) and other dissociated rapid eye movement (REM) sleep symptoms, such as hypnagogic hallucinations and sleep paralysis (American Academy of Sleep Medicine, 2005). A deficient hypocretinergic neurotransmission underlies NC, as documented by low-absent

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cerebrospinal hypocretin-1 and reduced hypocretin cells in the posterolateral hypothalamus of patients (Peyron et al., 2000). In addition to sleep and wakefulness regulation, hypocretinergic neurotransmission influences feeding and reward functions by interacting with systems regulating emotions, reward and energy homeostasis (Tsujino and Sakurai, 2009). In NC, emotions play a key role by acting as a trigger for cataplectic attacks (Overeem et al., 2011). Increasing direct and indirect evidence, from functional magnetic resonance imaging (fMRI) studies in patients (Ponz ª 2014 European Sleep Research Society

Emotions in narcolepsy et al., 2010a,b; Reiss et al., 2008; Schwartz et al., 2008), and from the recent results using orexin knockout mice models (Burgess et al., 2013), suggest altered cerebral emotion processing in NC (directly associating hypocretinergic function to the limbic system; Tucci and Plazzi, 2009). Schwartz et al. (2008) exposed patients with NC to neutral and humorous pictures to identify the areas activated by humour. While no group differences were found in behavioural humour appreciation, patients with NC exhibited a lack of hypothalamic response with reduced medial prefrontal activation and increased amygdala activity compared with controls. Reiss et al. (2008) ran a similar study on humour processing in NC, and showed enhanced activity in the nucleus accumbens, hypothalamus and right inferior frontal gyrus (an area considered to be involved in the inhibitory control) in comparison with controls. Ponz et al. (2010a) addressed the human reward system in NC using a gamelike task assessing expectancy and experience of monetary gains and losses. Authors suggested an abnormal rewardrelated brain response in patients with NC, as indicated by the lack of ventral midbrain activation during high-incentive condition (high potential reward) as well as reduced response in the ventral striatum during successful trials, and abnormally increased activity in the amygdala and dorsal striatum for positive outcomes. The International Affective Picture System (IAPS; Bradley and Lang, 2007) is a consolidated paradigm to study emotions consisting of a large standardized dataset of pictures classified in terms of the extent of pleasure (ranging from positive to negative states) and arousal (ranging from states of maximum relaxation to states of high activation or excitement) evoked during viewing. Two ‘appetitive’ and ‘defensive’ motive systems in the brain account for these two dimensions of the emotional expression in mediating individuals’ behaviour. The emotional engagement results in the activation of neural circuits with a subsequent autonomic and somatic response to the emotional situation (Bradley and Lang, 2007). Few studies have investigated psychophysiological responses to emotional stimulation using the IAPS paradigm in NC (Khatami et al., 2007; Tucci et al., 2003). Tucci et al. (2003) investigated cerebral, muscular, autonomic, cognitive and subjective activations by presenting 54 pictures illustrating unpleasant, pleasant and neutral scenarios. Results indicated an overall short-term attenuated response to visual stimuli, most evident with unpleasant pictures. NC compared with controls showed reduced amplitude and prolonged latency to event-related potentials components, lower reduction in mean blood pressure (MBP) and heart rate (HR), lower dominance rates, and smaller muscular and skin conductance increases, suggesting a temporal disadvantage in short-term input processing. Khatami et al. (2007) found an absence of acoustic startle reflex (ASR) in NC during unpleasant stimuli despite normal subjective ratings of valence and arousal in all three conditions when compared with controls, suggesting an ª 2014 European Sleep Research Society

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amygdala dysfunction in NC, given the role played by limbic structures and, in particular, by the amygdala in modulating the ASR. We aimed to further investigate the haemodynamic midterm (min) response during the presentation of the IAPS’s pleasant, unpleasant and neutral images in patients with NC compared with healthy individuals. Valence and arousal ratings associated with affective reactions to images were also assessed together with subjective coping strategies to face emotions. MATERIALS AND METHODS Participants Twelve drug-na€ıve patients with NC (five males; age range: 21–51 years), and 12 age- and sex-matched healthy controls (five males; age range: 19–50 years) participated in the study. Patients met the clinical and neurophysiological criteria of The International Classification of Sleep Disorders, 2nd edn (ICSD-2) for NC (American Academy of Sleep Medicine, 2005), and were free of comorbidities (e.g. arterial hypertension, diabetes, obstructive sleep apnea) interfering with the cardiovascular system. Additionally, all patients carried the HLA DQB1*06:02 allele, and 8/8 subjects who underwent lumbar puncture had reduced to absent levels of cerebrospinal hypocretin-1. The average age at NC onset was 32.3 years (9.3 years), with a mean disease duration of 8.7 years (5.9 years). Cataplexy (legs) was reported more than two-four times a week in all patients with NC. The study was approved by the Institutional Review Board. All participants gave written informed consent prior to the participation. Emotional stimulation Ninety pictures were selected based on their normative arousal and valence ratings from the standardized IAPS (Lang et al., 1999), and were organized in three blocks: 30 pleasant (erotic scenes and images of extreme sports; mean normative ratings: arousal 6.50  0.36, valence 6.89  0.47); 30 unpleasant (images of threat, injuries and mutilations and war scenes; mean normative ratings: arousal 6.56  0.48, valence 2.40  0.67); and 30 neutral stimuli (household objects, faces and urban landscapes; mean normative ratings: arousal 2.99  0.41, valence 5.08  0.30) (see Appendix). Pictures were randomly presented for 6 s each within each of the three blocks. Each block lasted 3 min and was preceded by 1 min of baseline recording (grey screen). The sequence of the blocks’ presentation was counterbalanced using a Latinsquare design. Participants evaluated their emotional status (referred to the whole block of pictures) in the domains of arousal (state of activation provoked by viewing the images), valence (state of pleasantness provoked by viewing the images) and dominance (how individuals were able to

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dominate the situation in viewing the images) using a computerized version of the Self-Assessment Manikin (Lang et al., 1999), on a nine-point graphic scale (minimum = 1; maximum = 9) presented at the end of each block. The task was programmed using E-Prime 1.1 software (Psychology Software Tools). Physiological assessment Polysomnographic recordings, including six electroencephalographic channels (F3-A2, F4-A1, C3-A2, C4-A1, O1-A2, O2-A1), left and right electrooculogram and mylohyoideus muscle electromyogram, were performed to ensure the maintenance of wakefulness throughout the task. Blood pressure was manually measured three times before the start of the procedure to exclude undiagnosed arterial hypertension. Beat-to-beat systolic (SBP; mmHg), diastolic (DBP; mmHg), MBP (mmHg) and HR (bpm) were noninvasively and continuously recorded during the task by way of a photoplethysmographic cuff placed on the individual’s middle finger using a Finapres 2300 device (Ohmeda, Englewood, CO, USA). The mean cerebral blood flow velocity (MFV; cm s 1) was assessed from both middle cerebral arteries by means of transcranial Doppler sonography (TCD; Multidop 94 system; DWL Elektronische Systeme). Signals were beatto-beat recorded by two dual 2-MHz probes (fixed by an elastic headband) insonating from the right and left temporal regions above the zygomatic arch through the transtemporal window. The depth of the insonation ranged from 48 to 56 mm. MFV was computed off-line by ensemble averaging 2-s signals obtained from the two sides. Measures of depression, anxiety, somnolence and coping strategies Trait levels of depression and anxiety were assessed by the Beck Depression Inventory (BDI-II; Beck et al., 1996) and the State Trait Anxiety Inventory (STAI-Y2; Spielberger et al., 1983). In patients with NC, trait levels of somnolence were measured by the Epworth Sleepiness Scale (ESS; Johns, 1991). Daytime sleep propensity and the numbers of sleeponset REM periods were assessed by the multiple sleep latency test (MSLT; Littner et al., 2005). Pre-task state anxiety and somnolence were assessed by the STAI-Y1 (Spielberger et al., 1983) and the Stanford Sleepiness Scale (SSS; Hoddes et al., 1973). To assess coping strategies, we administered the new Italian version of the Coping Orientation to Problems Experienced (COPE-NVI; Sica et al., 2008) that evaluates four independent dimensions of coping: social support; avoidance strategies; positive attitude; and transcendent orientation. In addition, we measured the factor ‘focus on and venting of emotions’, which consists of the tendency to focus on

whatever emotions an individual is experiencing and to express those feelings (i.e. laugh/scream when feeling happy/angry; Carver et al., 1989). Procedure Participants were requested not to eat or drink alcohol or beverages containing caffeine during the day of the experiment. Before the experimental session, all participants were allowed to take a brief nap if they felt sleepy. The experiment was conducted with the participant sitting in a semi-dark and sound-attenuated laboratory, while continuously monitored by a closed-circuit video system for the entire duration of the task. The task lasted about 30 min, and the recordings were performed in the late morning ranging from 10:30 to 13:30 hours. Statistical analysis Group demographic and self-report measures were compared by independent t-tests. A 2 Group (narcoleptics and controls) 9 3 Emotion (pleasant, unpleasant and neutral) mixed-design ANOVA was applied to the behavioural responses of arousal, valence and dominance. All physiological values were 1-min ensemble averaged across baseline, and the first, second and third minute of the task within each block. A 2 Group (narcoleptics and controls) 9 3 Emotion (pleasant, unpleasant and neutral blocks) 9 4 Time (baseline, first, second and third minute of the task) mixed-design ANOVA was applied to the mean values of SBP, DBP, MBP, HR and MFV. Given the skewed distribution of the physiological values, they were logarithmically transformed before statistical analyses. In order to explore potential group differences in laterality during emotional conditions compared with the neutral stimulation, we calculated the percentage changes in MFV from the baseline resting values separately for right and left hemispheres. A 2 Group (narcoleptics and controls) 9 2 Side (left and right) 9 2 Condition (pleasant minus neutral and unpleasant minus neutral) mixed-design ANOVA was applied. To investigate the relationships among the duration of NC, the levels of somnolence (as measured by the ESS and the MSLT), the self-report measures of ‘focus on and venting of emotions’ and the arousal and valence scores, we used the non-parametric Spearman’s correlations. Finally, in order to assess potential differences in behavioural and haemodynamic measures due to the severity of cataplexy, we compared two subgroups of patients with NC according to the number of cataplectic attacks experienced per week [i.e. 2–3 cataplectic attacks per week (N = 5) versus more than four attacks per week (N = 7)] using a Mann–Whitney U-test. Newman–Keuls post hoc comparisons were used on the significant effects. For all statistical analyses, the probability level was set at P < 0.05 for significance. ª 2014 European Sleep Research Society

Emotions in narcolepsy RESULTS Demographic and self-reported trait and state measures Demographic and self-report trait and state data are provided in Table 1. Patients with NC and controls did not differ regarding sex, age, body mass index, state anxiety, trait depression, state sleepiness, SBP and DBP values. However, the groups differed in coping strategies, as patients with NC had lower scores than controls in the ‘social support’ dimension and ‘focus on and venting of emotions’ factor. Given that ‘focus on and venting of emotions’ is a subscale of ‘social support’, we controlled how differences in ‘social support’ were due to the ‘focus on and venting of emotions’. An independent t-test was run on the social support dimension after subtracting the scores of the venting of emotions items. The results showed no group differences (t22 = 0.026, P = 0.98), indicating that the difference in the social support dimension was due to the venting subscale.

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than controls. Both groups scored lower on the neutral block compared with the pleasant (narcoleptics: P < 0.05; controls: P < 0.001) and unpleasant (both groups P < 0.001) ones. In addition, patients with NC scored higher on the unpleasant versus pleasant blocks (P < 0.05). ANOVA applied on valence scores showed a significant Emotion main effect as well as a significant Group 9 Emotion interaction. Post hoc tests on the interaction indicated that patients with NC scored lower than controls on the pleasant block (P < 0.05). Both groups scored lower on the unpleasant block compared with the neutral (P < 0.001) and pleasant (P < 0.001) blocks. Valence scores were lower on the neutral block compared with the pleasant block in both narcoleptics (P < 0.05) and controls (P < 0.001). No group differences were found in dominance. However, there was a significant Emotion main effect, and post hoc tests indicated that dominance was reduced in unpleasant compared with the pleasant block (P < 0.05). Haemodynamic responses to emotional stimulation

Behavioural responses to emotional stimulation Significant ANOVA results are provided in Table 2. Arousal and valence mean scores are displayed in Fig. 1. ANOVA applied on arousal scores showed significant Group and Emotion main effects explained by a significant Group 9 Emotion interaction. Post hoc tests on the interaction indicated that patients with NC rated the pleasant (P < 0.01) and neutral (P < 0.05) pictures as less arousing

Significant ANOVA results are provided in Table 2. ANOVA applied on HR showed Emotion and Time main effects (Fig. 2). As revealed by post hoc tests, HR was reduced during pleasant and unpleasant blocks compared with the neutral block in both groups (P < 0.05). Post hoc tests applied on the Time main effect indicated that HR was lower during the first, second and third minutes of the picture presentation compared with baseline (P < 0.05) in both

Table 1 Demographic and self-report trait and state measures

N Age (years) Body mass index (kg m 2) BDI-II STAI-Y2 SBP (mmHg) DBP (mmHg) ESS MSLT-mean sleep latency (min) MSLT-number of sleep-onset REM periods Coping strategies Avoidance strategies Positive attitude Problem orientation Transcendent orientation Social support Focus on and venting of emotions Pre-task anxiety and sleepiness STAI-Y1 SSS

Patients with NC

Controls

t-Value

P-value

12 33.3 24.9 9.7 41.7 110.0 70.7 20 3.16 3.90

(5 males) (9.4) (4.2) (9.2) (8.6) (14.9) (6.3) (2.67) (1.88) (11.4)

12 30.9 22.7 6.5 43.1 108.1 68.3 – – –

(5 males) (9.5) (3.4) (4.0) (9.9) (9.2) (6.4)



– 0.539 0.178 0.272 0.712 0.693 0.348 – – –

22.92 31.25 31.25 17.25 26.08 14.67

(4.54) (6.48) (8.37) (6.17) (6.79) (8.34)

27.00 30.75 31.25 13.50 34.17 22.67

(9.29) (3.86) (2.93) (4.05) (7.67) (6.31)

31.7 (7.9) 2.7 (1.3)

0.62 1.39 1.13 0.37 0.40 0.96 – – –

32.5 (6.2) 2.0 (0.6)

1.37 0.22 0.00 1.76 2.73 2.65

0.185 0.820 1.00 0.092 0.012 0.014

0.26 1.61

0.798 0.122

BDI, Beck Depression Inventory; DBP, diastolic blood pressure; ESS, Epworth Sleepiness Scale; MSLT, multiple sleep latency test; NC, narcolepsy with cataplexy; REM, rapid eye movement; SBP, systolic blood pressure; SSS, Stanford Sleepiness Scale; STAI, State Trait Anxiety Inventory.

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Table 2 Significant ANOVA results for behavioural and haemodynamic data of patients with NC and controls during the emotional task

(P < 0.001) and third minutes (P < 0.01) of the task compared with baseline. In addition, MFV was reduced in the second (P < 0.05) and third minutes (P < 0.001) compared with the first minute of the emotional task.

ANOVA

Behavioural data Arousal scores

Valence scores

Dominance scores Haemodynamic data HR (log bpm) SBP (log mmHg)

MBP (log mmHg) MFV (log cm s 1)

Group: F1,22 = 6.27, P = 0.020 Emotion: F2,44 = 30.70, P < 0.001 Emotion 9 Group: F2,44 = 4.05, P = 0.024 Emotion: F2,44 = 65.76, P < 0.001 Emotion 9 Group: F2,44 = 3.25, P = 0.048 Emotion: F2,44 = 3.68, P = 0.033 Emotion: F2,44 = 5.06, P = 0.010 Time: F3,66 = 11.59, P < 0.001 Group: F1,22 = 7.22, P = 0.013 Emotion 9 Time: F6,132 = 2.27, P = 0.041 Group: F1,22 = 5.39, P = 0.030 Time: F3,66 = 19.74, P < 0.001

HR, heart rate; MBP, mean blood pressure; MFV, mean cerebral blood flow velocity; SBP, systolic blood pressure.

patients with NC and controls, regardless of the emotion presented. ANOVA performed on SBP revealed a significant Group main effect and an Emotion 9 Time interaction (Fig. 2). Regardless of emotion and time, patients with NC exhibited a lower SBP than controls (Group main effect). Post hoc tests run on Emotion 9 Time showed that SBP was significantly higher during the second (P < 0.05) and third (P < 0.01) minute of the pleasant block compared with the corresponding minutes of the unpleasant block in both narcoleptics and controls. ANOVA applied on MBP showed a significant Group main effect, with narcoleptics having a lower MBP than controls irrespective of emotion and time. No significant results were found for DBP. ANOVA applied on MFV showed a significant Time main effect (Fig. 2). Post hoc tests indicated that in both groups and independently from the type of emotional stimulation MFV was elevated in the first (P < 0.001), second

Exploratory analyses: role of laterality, disease duration, cataplexy severity and sleep propensity at MSLT on haemodynamic and behavioural responses to emotional stimulation ANOVAs results on laterality showed a significant Side main effect (F1,22 = 4.50, P < 0.05), indicating greater increases in right- compared with left-MFV during pleasant and unpleasant stimulation in both patients with NC and controls. No significant group differences were found. Correlations between the disease duration and somnolence with the self-report measures of ‘focus on and venting of emotions’ and arousal and valence scores to each emotional block suggested that patients with NC with prolonged duration of NC tended to rate the pleasant and neutral images as less arousing and pleasant (correlation significant only in the neutral block; Table 3). No significant correlations have been found for subjective trait sleepiness (ESS) and objective sleep propensity (sleep latency and number of sleep-onset REM periods at the MSLT). Mann–Whitney U-tests failed to show group differences between patients with NC reporting 2–3 attacks per week versus those reporting more than four attacks per week in any of the parameters analysed.

DISCUSSION In the present work, we aimed to evaluate haemodynamic and behavioural responses to pleasant, neutral and unpleasant emotional visual stimulation in NC. Our results depicted a similar haemodynamic pattern in NC and in healthy age- and sex-matched individuals. Both groups showed a reduced HR coupled with increased MFV in response to the emotional stimulation, irrespective of the content. SBP increased only during the pleasant condition in both NC and controls. In addition, HR was globally reduced during the presentation of pleasant and unpleasant stimuli compared with neutral

Figure 1. Mean and standard errors of the arousal and valence self-report ratings for pleasant, unpleasant and neutral blocks in NC and controls. Group differences are marked on the graph. NC, narcolepsy with cataplexy. ª 2014 European Sleep Research Society

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Figure 2. Means and standard errors of heart rate (HR), systolic blood pressure (SBP) and mean cerebral blood flow velocity (MFV) responses to pleasant, unpleasant and neutral blocks in NC and controls. NC, narcolepsy with cataplexy.

Table 3 Spearman rank correlation coefficients between duration of NC and the cognitive responses to pleasant, unpleasant and neutral emotional stimuli in patients with NC Neutral Spearman R Arousal Valence

0.74 0.07

Pleasant P 0.006 0.827

Spearman R 0.44 0.41

pictures, in accordance with the literature (for an overview, see Kreibig, 2010). In agreement with previous investigations (Duschek and Schandry, 2003; Stegagno et al., 2007), increases in MFV were more pronounced in the right middle cerebral artery during pleasant and unpleasant stimulations, compared with the neutral condition, in both groups. Behavioural scores revealed significant between-group differences. As expected, both groups were more aroused by pleasant and unpleasant stimuli compared with neutral stimuli, and reported that the pleasant stimulation provoked more pleasantness compared with the neutral and unpleasant stimulation. However, patients with NC were less aroused by pleasant and neutral stimuli than controls, and also reported a status of less pleasantness induced by pleasant stimulation. According to the appraisal theories (Smith and Ellsworth, 1987), emotions are the result of the personal evaluation of an event rather than the consequence of the event itself. Appraisal can determine different emotional reactions and modulate the emotional intensity toward a particular event (Siemer et al., 2007). In our results, the subjective evaluation of images as less arousing and pleasant in patients with NC compared with controls together with the similar physiological pattern could be regarded as the result of a cognitive approach to minimize the impact of emotion itself in NC. On the other hand, the COPE results revealed that patients with ª 2014 European Sleep Research Society

Unpleasant P 0.157 0.186

Spearman R 0.01 0.08

P 0.986 0.807

NC focused less and had a reduced expression (venting) of their own emotions. This strategy could reduce or suppress emotion-related behaviours (e.g. laughing, crying) that are the usual triggers for cataplexy. Indeed in the general population, a diminished venting of emotions has been related to the concept of suppression, which is the attempt to decrease or inhibit ongoing emotion-expressive behaviour (Gross, 1998). Based on these results, we hypothesize that unconscious adaptive strategies to face emotions are developed by patients with NC who frequently report ‘tricks’ to prevent cataplexy (Overeem et al., 2011): they may influence and regulate their own emotions through both appraisal (i.e. evaluating stimuli as less arousing and pleasant) and behavioural coping strategies (i.e. inhibiting emotion expression). Despite the limited number of patients, our interpretation is further supported by the relation between disease duration and cognitive responses to the emotional stimuli. Overall, disease duration seemed to be associated with cognitive suppression (longer disease, lower arousal scores). In line with this hypothesis, our group (Pizza et al., 2013) recently showed for the first time a reduction of cataplexy severity over time by prospectively investigating the spontaneous evolution of NC in 21 children (at the diagnosis and after about 3 years after the symptom onset). Notwithstanding, in the current study the between-group comparisons between patients with NC with different cataplexy frequency

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failed to show significant differences in cognitive responses to the emotional stimuli. This may be related to a ceiling effect, given the absence of patients with rare cataplexy in our study population. Further investigations should be directed to the cognitive aspect of NC in a larger and more heterogeneous population to assess the relation between disease duration and cataplexy frequency (possibly with a repeated-measure design following the development of NC over time). Emotional processing influences perception, assigns significance to sensory information and elicits adaptive responses (Vuilleumier, 2005). Bilateral amygdala, posterior hippocampus, ventromedial prefrontal cortex and visual cortex are activated during passive view of facial expressions and evocative pictures (e.g. IAPS) paradigms (Britton et al., 2006). Among the brain circuits involved in the emotional processing, the amygdala plays a key role in mediating the sensory processing and the representation of emotional events (Vuilleumier, 2005). Functional and structural studies support an impairment of emotional processing in NC. A single-photon emissioncomputed tomography (SPECT) study (Hong et al., 2006) documented a hyper-activation of the right amygdala during cataplexy (triggered by emotions) in patients with narcolepsy, suggesting that the activation of the amygdalo-cortico-basal ganglia–brainstem circuit is involved during cataplexy. Nevertheless, a similar SPECT study (Chabas et al., 2007), failed to find evidence of hyper-activation of limbic structures. Schwartz et al. (2008) found a reduced hypothalamic response together with enhanced amygdala activation in NC, and Reiss et al. (2008) using a similar paradigm confirmed abnormal cerebral activation in NC. Interestingly, authors found that patients with NC rated the stimuli (cartoons) as being less funny than did controls, and suggested that patients with NC trained themselves to suppress the behavioural emotional expression. They speculated that the activation of some components of the inhibition network may modulate their physiological reaction to emotions by acting as a compensatory mechanism to prevent cataplexy. Using a proton resonance spectroscopy (¹H-MRS; Poryazova et al., 2009), authors found a significantly lower myo-inositol (mI/Cr) ratio in the right amygdala in patients with NC compared with controls, indicating a persistent metabolic dysfunction in narcolepsy. Ponz and colleagues showed amygdala dysfunction during aversive learning (Ponz et al., 2010b) and abnormal activity in reward brain circuits in NC (Ponz et al., 2010a) using fMRI technique. These results, together with the findings of a positive correlation between the disease duration and both the activity in the nucleus accumbens and in the ventralmedial prefrontal cortex, support the hypothesis of an alternative compensatory neural circuit. Ponz et al. (2010a) suggested that this adaptive mechanism could be developed in NC over time to control emotional responses and possibly compensate for the lack of modulation arising from ventral midbrain areas. Recent data by Blouin et al. (2013) provide

illuminating results on interactions between hypocretin-1 concentration in the amygdala during different emotional states and across the sleep–wake cycle in humans: hypocretin-1 levels were found to be higher during social interactions and positive emotions (e.g. laughter or excitement) compared with waking periods with negative experiences (e.g. sadness or pain), thus suggesting a link between neurochemical changes and species-specific emotions that induce cataplexy in human NC. Other reports investigating emotions in NC with the standardized IAPS paradigm (Khatami et al., 2007; Tucci et al., 2003) failed to find group differences in ratings of arousal and valence in response to emotional stimuli. These contrasting results, however, could be ascribed to the sample size, to discrepancies to the stimuli presentation and, importantly, to the fact that only our study was performed on drug-na€ıve patients who were also carefully monitored for their state levels of somnolence at the time of task execution. In our study, TCD failed to discover group differences probably due to the low spatial resolution of this technique in comparison with other methods adopted to investigate cerebral structure activation (e.g. fMRI, SPECT, positron emission tomography). Indeed, TCD assesses cerebral blood flow velocity in the middle cerebral arteries, thus providing information about the activation of the brain areas supplied by the anterior circulation, whereas the activation of smaller areas would be detectable by measuring flow velocity in small and multiple arteries. In addition, given that the amygdala is mainly involved in emotional processing of negative emotion (Aldhafeeri et al., 2012), it may be possible that if the main group differences in emotional processing are mainly due to an abnormal amygdala activation, the combined insonation of the anterior cerebral artery (which supplies medial regions of both hemispheres) together with the middle cerebral artery may be a better approach in showing abnormal blood flow responses in NC, particularly in the unpleasant condition. Finally, given that flow velocity increases with the complexity of the visual stimuli (see Duschek and Schandry, 2003), it is possible that a different complexity of the images presented masked potential Group and/or Group 9 Emotion effects in the MFV response. It is worth noting that, as we expected, none of the patients with NC exhibited cataplectic attacks during the task (only one patient exhibited a cataplectic attack after the unpleasant block, see below), suggesting that the paradigm we adopted (IAPS) induced emotional responses not able/intense enough to evoke cataplexy. An fMRI study suggested that facial expressions yield a more intense activation in the amygdala than do IAPS stimuli (Hariri et al., 2002). Thus, our failure in finding a different autonomic reactivity to emotions in patients with NC versus controls could be due to insufficient emotional stimulation to activate the pathway involved in the cataplectic response. On the other hand, the cognitive strategy adopted by patients with NC over the task could prevent cataplexy and lead to a normal physiological activation. Another explanation could lie in the experimental ª 2014 European Sleep Research Society

Emotions in narcolepsy design: the prolonged emotional exposure with a 1-min temporal resolution could have masked a more transient change in physiological reactivity. Indeed, the study of cerebrovascular reactivity by means of TCD precludes any insight on short-term haemodynamic responses mediated by the neurovascular coupling. However, interestingly a single patient (who had personal war experiences) exhibited a cataplectic attack as soon as she completed the unpleasant block, telling us that ‘the stimuli were so sad […]’. Exploring the individual haemodynamic reactivity to that block, we found that she was the only patient who exhibited a different trend for physiological indices (drop of MFV and SBP) exclusively in response to the unpleasant block (Fig. 3), while following the group trend in the behavioural response. Indeed, the autonomic response for this participant did not follow the typical autonomic pattern during the cataplectic attack. The physiology of a cataplectic attack is characterized by autonomic cardiac deceleration, increases in BP and muscular sympathetic nerve activity (Donadio et al., 2008). Further studies are warranted to investigate the pattern and time course of the haemodynamic response to emotional stimuli with different levels of efficacy in provoking cataplexy. In summary, in the current study patients with NC exhibited a different approach, and self-reported evaluation of emotions compared with healthy controls that may affect the modulation of emotions at different levels. We suggest that patients with NC may develop cognitive adaptive strategies to face emotion in order to avoid cataplexy. However, based on our results and on the above-mentioned studies showing abnormal brain activation during emotional processing in NC, it is intriguing the possibility that the reduced arousability in NC is not the final outcome of cognitive adaptive mechanisms adopted by patients with NC to face emotions, but it may induce adaptive processes per se. Further studies aimed to clarify this issue are warranted.

Figure 3. Physiological reactivity scores to the unpleasant block in patients with NC (the patient with NC who exhibited a cataplectic attack after the presentation of the unpleasant stimuli is highlighted in the graph). ª 2014 European Sleep Research Society

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AUTHOR CONTRIBUTORSHIP MdZ, GP and LS designed the study and wrote the protocol. SV and FP recruited and run the participants. MdZ, NC, NC and FP performed the data reduction and analysis. All authors contributed in writing the paper and in understanding the results. CONFLICTS OF INTEREST AND SOURCE OF FUNDING GP has consulted for UCB Pharma and Jazz. For the remaining authors, none was declared. REFERENCES Aldhafeeri, F., Mackenzie, I., Kay, T., Alghamdi, J. and Sluming, V. Regional brain responses to pleasant and unpleasant IAPS pictures: different networks. Neurosci. Lett., 2012, 512: 94–98. American Academy of Sleep Medicine. ICSD – The International Classification of Sleep Disorders: Diagnostic and Coding Manual, 2nd edn. American Academy of Sleep Medicine, Westchester, IL, 2005. Beck, A., Steer, R. and Brown, G. Beck Depression Inventory-II (BDIII). Psychological Corporation, San Antonio, TX, 1996. Blouin, A., Fried, I., Wilson, C. et al. Human hypocretin and melaninconcentrating hormone levels are linked to emotion and social interaction. Nat. Commun., 2013, 4: 1547. Bradley, M. and Lang, P. The International Affective Picture System (IAPS) in the study of emotion and attention. In: J. Coan and J. Allen (Eds) Handbook of Emotion Elicitation and Assessment. Oxford University Press, New York, NY, 2007: pp. 29–46. Britton, J., Taylor, S., Sudheimer, K. and Liberzon, I. Facial expressions and complex IAPS pictures: common and differential networks. Neuroimage, 2006, 31: 906–919. Burgess, C. R., Oishi, Y., Mochizuki, T., Peever, J. H. and Scammell, T. E. Amygdala lesions reduce cataplexy in orexin knock-out mice. J. Neurosci., 2013, 33: 9734–9742. Carver, C., Scheier, M. and Weintraub, J. Assessing coping strategies: a theoretically based approach. J. Pers. Soc. Psychol., 1989, 56: 267–283. Chabas, D., Habert, M., Maksud, P. et al. Functional imaging of cataplexy during status cataplecticus. Sleep, 2007, 30: 153–156. Donadio, V., Plazzi, G., Vandi, S. et al. Sympathetic and cardiovascular activity during cataplexy in narcolepsy. J. Sleep Res., 2008, 17: 458–463. Duschek, S. and Schandry, R. Functional transcranial Doppler sonography as a tool in psychophysiological research. Psychophysiology, 2003, 40: 436–454. Gross, J. Antecedent- and response-focused emotion regulation: divergent consequences for experience, expression, and physiology. J. Pers. Soc. Psychol., 1998, 74: 224–237. Hariri, A., Tessitore, A., Mattay, V., Fera, F. and Weinberger, D. The amygdala response to emotional stimuli: a comparison of faces and scenes. Neuroimage, 2002, 17: 317–323. Hoddes, E., Zarcone, V., Smythe, H., Phillips, R. and Dement, W. Quantification of sleepiness: a new approach. Psychophysiology, 1973, 10: 431–436. Hong, S., Tae, W. and Joo, E. Cerebral perfusion changes during cataplexy in narcolepsy patients. Neurology, 2006, 66: 1747–1749. Johns, M. A new method for measuring daytime sleepiness: the Epworth sleepiness scale. Sleep, 1991, 14: 540–545.

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APPENDIX IAPS pictures used in this study. Pleasant (4608, 4611, 4643, 4647, 4651, 4652, 4658, 4659, 4664, 4670, 4672, 4676, 4680, 4687, 4694, 4695, 4800, 5470, 5621, 5626, 5629, 8030, 8080, 8179, 8186, 8300, 8341, 8370, 8490, 8499); unpleasant (1050, 1120, 1300, 1932, 2683, 2703, 2730, 2811, 3010, 3015, 3030, 3051, 3060, 3064, 3550, 3400, 6022, 6212, 6230, 6313, 6315, 6350, 6550, 6821, 8480, 8485, 9254, 9410, 9600, 9921); neutral (2102, 2104, 2190, 2393, 2396, 2445, 2446, 2499, 2880, 5390, 5510, 7009, 7036, 7041, 7052, 7055, 7100, 7140, 7161, 7179, 7185, 7205, 7217, 7490, 7491, 7500, 7546, 7547, 7595, 7950).

ª 2014 European Sleep Research Society

Facing emotions in narcolepsy with cataplexy: haemodynamic and behavioural responses during emotional stimulation.

Narcolepsy with cataplexy is a complex sleep disorder that affects the modulation of emotions: cataplexy, the key symptom of narcolepsy, is indeed str...
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