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Metacognitive impairment in patients with episodic and chronic migraine
Journal of Clinical Neuroscience xxx (xxxx) xxx
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Clinical study
Metacognitive impairment in patients with episodic and chronic migraine Milena Zucca a,⇑, Elisa Rubino b, Alessandro Vacca a, Paola De Martino a, Fausto Roveta a, Flora Govone a, Annalisa Gai a, Marcella Caglio a, Salvatore Gentile a,b, Maria T. Giordana a,b, Innocenzo Rainero a,b a b
Neurology I – Headache Center, ‘‘Rita Levi Montalcini” Department of Neuroscience, University of Torino, Italy Department of Neuroscience and Mental Health, A.O.U. Città della Salute e della Scienza, Torino, Italy
a r t i c l e
i n f o
Article history: Received 11 September 2019 Accepted 20 December 2019 Available online xxxx Keywords: Metacognition Executive functions Migraine Medication-overuse headache Wisconsin card sorting test
a b s t r a c t Migraine is one of the most common medical disorder in the world. Metacognition is the ability to monitor one’s own cognitive functioning and consequently direct one’s behavior. In adult migraine patients, the neuropsychological profile has been poorly investigated, and metacognitive functions have never been assessed. The aim of the present study was therefore to evaluate executive metacognitive abilities in patients with episodic and chronic migraine. Sixty-four migraine patients (male/female = 18/46; mean age = 45.65 ± 11.61 years): 27 patients with episodic migraine without aura (male/female = 9/18; mean age ± SD = 45.11 ± 12.18 years) and 37 patients with chronic migraine and medication-overuse headache (male/female = 9/28; mean age ± SD = 46.05 ± 11.32 years) were selected for the study. Twenty-nine controls (male/female = 12/17; mean age ± SD = 42.86 ± 14.78 years) were also enrolled in the research. Metacognitive and executive skills were assessed using the metacognitive version of Wisconsin Card Sorting Test. Migraine patients exhibited a lower performance in metacognitive tasks in respect to controls in term of worse outcomes in accuracy score (p = 0.012), global monitoring (p = 0.015), monetary gains (p = 0.022), and control sensitivity (p = 0.027). A reduction in accuracy score (p = 0.001), freechoice improvement (p = 0.002), global monitoring (p = 0.003), monetary gains (p = 0.009), and control sensitivity (p < 0.001) was also found in patients with chronic migraine and medication-overuse headache in respect to patients with episodic migraine. Our study supports the hypothesis that migraine patients show metacognitive dysfunctions that become worse with the chronicization of the disease and the increase of medication use. Ó 2019 Elsevier Ltd. All rights reserved.
1. Introduction Migraine is a neurovascular disorder characterized by recurrent attacks of moderate to severe headache associated with autonomic nervous system dysfunctions and, in about one third of patients, visual, sensory, motor, or other, neurologic symptoms known as aura. Migraine is a highly prevalent headache disorder affecting approximately 10–12% of adult population in Western Countries, with a substantial impact on individuals, families and society [1]. Each year approximately 2% of migraineurs show a progressive worsening of headache in terms of an increasing in frequency and severity of attacks [2].
⇑ Corresponding author at: Neurology I – Headache Center, ‘‘Rita Levi Montalcini” Department of Neuroscience, University of Torino, Via Cherasco 15 – 10126 Torino, Italy. E-mail address: [email protected] (M. Zucca).
Chronic migraine (CM) is a disabling condition characterized by headache occurring for at least 15 days per month for >3 months [3]. Thence, CM patients can start overusing symptomatic drugs for migraine, thus causing the onset of a secondary headache with variable clinical features, called ‘‘medication-overuse headache” (MOH) [4]. In literature, migraineurs have been reported to show low cognitive performances, more frequently in terms of memory impairment, attention reduction and executive dysfunctions in respect to controls [5,6]. In migraine sufferers, cognitive impairment appears to be closely related with the frequency of migraine attacks [7,8]. Nevertheless, it was also reported that cognitive difficulties could persist in the inter-attacks period between migraine attacks, causing a reduction of cognitive performance in migraine patients [6]. Intriguingly, the presence of an executive impairment in terms of a poor decision making process, associated to a fronto-striatal circuit dysfunction, has also been also described in chronic migraine patients with or without medication overuse [9,10,11].
https://doi.org/10.1016/j.jocn.2019.12.048 0967-5868/Ó 2019 Elsevier Ltd. All rights reserved.
Please cite this article as: M. Zucca, E. Rubino, A. Vacca et al., Metacognitive impairment in patients with episodic and chronic migraine, Journal of Clinical Neuroscience, https://doi.org/10.1016/j.jocn.2019.12.048
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M. Zucca et al. / Journal of Clinical Neuroscience xxx (xxxx) xxx
Some authors, suggested that executive functions are inevitably coupled with a higher-order cognitive ability known as metacognition [12,13]. Metacognition is a dynamical neurocognitive process often described as knowledge and ability to understand, control, and manipulate one’s own cognitive processes [13,14]. Two important components of metacognitive functions are (1) monitoring, i.e. the subjective evaluation about one’s on-going cognitive activities and their functioning (knowledge about cognition) and (2) control i.e. the ability to use metacognitive knowledge to regulate an ongoing cognitive activity (strategy regulation of cognition) [13,15]. The presence of metacognitive dysfunctions in adult migraine patients has not been investigated yet. Therefore, the main aim of the present study was to explore the presence of executive metacognitive dysfunctions in adult patients with migraine.
N (males/females) Age, mean (±SD) years Education, mean (±SD) years Years with migraine
2.1. Participants and procedures Sixty-four migraine patients (male/female = 18/46; mean age ± SD = 45.65 ± 11.61 years) were recruited at the Headache Center, Department of Neuroscience ‘‘Rita Levi Montalcini”, University of Torino, Italy. According to ICHD-III criteria [16], migraine patients were divided in two subgroups: 27 patients with episodic migraine (EM) without aura (male/female = 9/18; mean age ± SD = 45.11 ± 12.18 years) and 37 patients with chronic migraine (male/female = 9/28; mean age ± SD = 46.05 ± 11.32 yea rs). All the involved CM patients also fulfilled the criteria for medication-overuse headache (CM-MOH). Twenty-nine healthy controls (HC) matched for age and gender, without headache or any other neurological or psychiatric disease, were also enrolled in the study (male/female = 12/17; mean age ± SD = 42.86 ± 14.7 8 years). The demographic and clinical characteristics are summarized in Tables 1 and 2. All subjects underwent a neuropsychological evaluation. Patients in CM-MOH group were evaluated at the end of a 5-day detoxification period from overuse medication, that was performed in an outpatient hospital regimen. Preventive medication was prescribed only in case of need. All patients were assessed during a pain-free period. Migraine patients were excluded from the study if they had a history of neurological diseases different from migraine, a diagnosis of chronic pain conditions, present or past alcohol and substance use disorders or pathological gambling as diagnosed by DSM-V [17]. Written informed consent was obtained from all participants, and the study was approved by the Hospital Ethics Committee. 2.2. Assessment of executive and metacognitive functions Metacognitive functions have been assessed using the metacognitive version of the Wisconsin Card Sorting Test (WCST) [18]. This
Table 1 Synopsis of the demographic and clinic characteristics of migraine patients and healthy controls. Migraine patients
Healthy controls
p-value
64 (18/46) 45.65 (±11.61) 13 (±4.07) <5 years (12) 5–15 years (24) >15 years (28)
29 (12/17) 42.86 (±14.78) 15.10 (±4.25) –
0.188 0.374 0.034 –
CM- MOH
EM
pvalue
37 (9/28) 46.05 (±11.32)
27 (9/18) 45.11 (±12.19)
0.063 0.748
12.65 (±3.41)
13.75 (±4.80)
0.308
< 5 years (5) 5–15 years (14) > 15 years (18)
< 5 years (7) 5–15 years (10) >15 years (10) 33.62 (±16.04)
–
MDQ-H
93.86 (±20.53)
Medication overuse
NSAIDs (4); triptans (11); combination (22) Combination (12); amitriptyline (1); topiramate (5); SSRI/SNRI (5); beta-blockers (2), valproic acid (2); no treatment (10)
Preventive medication
2. Materials and methods
N(males/females) Age, mean (±SD) years Education, mean (±SD) years Years with migraine
Table 2 Synopsis of the demographic and clinic characteristics of EM patients and CM-MOH patients.
– No treatment (19); amitriptyline (4); flunarizine (2); SSRI (2)
< 0.001 – –
Legend: NSAID’s: Non-steroidal anti-inflammatory drugs, SSRI: selective serotonin reuptake inhibitors, SNRI: serotonin–norepinephrine reuptake inhibitors.
version was selected because it allows to obtain a distinguished and contemporary evaluation of both executive functions and metacognitive abilities of the examined subjects. Furthermore, in addition to the standard ‘‘forced response’’ commonly adopted to test metacognition, this instrument used measures of ‘‘free response’’ performance, straightly related to the patient’s metacognitive abilities [19]. In respect to the original version of WCST, this test includes two additional requests: I) the subjective level of confidence (range 0– 100) about the correctness of one’s own response, and, II) the subject’s decision to gamble including the response in the final score test. A monetary gain or penalty was attributed according to a correct/incorrect sort. Six metacognitive variables have been achieved from the free-response outputs: (1) accuracy score (AS), which represents the percentage of ventured answers that were correct; (2) free-choice improvement (FCI), the difference between the accuracy score previously obtained and the percentage of correct answers calculated on the total pairings made; (3) global monitoring (GM), the difference between correct sorts and the total number of sorts, in order to know the veridicality of one’s own response; (4) monitoring resolution (MR), the extent to which the confidence judgments distinguish between the correct and incorrect sorts, in order to assess one’s own ability to monitor the quality of his/her performance; (5) control sensitivity (CS), which results from the relationship between one’s confidence about the match made and the decision or not to bet, to know the subject’s ability to regulate the quality of his/her performance on the basis of the previous assessments; (6) monetary gains (MG), which evaluates the monetary reward achieved by the subject, calculated as the difference between the correct and wrong pairings for which the patient decided to bet.
2.3. Neuropsychiatric assessment Each group underwent specific questionnaires on behavioral and mood changes. Depression was evaluated using the Beck
Please cite this article as: M. Zucca, E. Rubino, A. Vacca et al., Metacognitive impairment in patients with episodic and chronic migraine, Journal of Clinical Neuroscience, https://doi.org/10.1016/j.jocn.2019.12.048
M. Zucca et al. / Journal of Clinical Neuroscience xxx (xxxx) xxx
Depression Inventory (BDI) [20], while anxiety was examined with the Beck Anxiety Inventory (BAI) [21].
2.4. Assessment of medication overuse To evaluate the degree of medication overuse, the Medication Dependence Questionnaire for Headache sufferers (MDQ-H) [22], a self-administered questionnaire comprising twenty-one items, was used.
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3.2. Results of executive functions assessment The overall group of migraineurs was characterized by the presence of lower number of categories completed (p = 0.017), a reduction of correct responses (p = 0.031) and a higher percentage of errors (p = 0.033) in comparison with controls. In addition, patients with CM-MOH exhibited worse executive performances at metacognitive version of WCST test, in terms of less number of categories completed (p = 0.014), lower percentage of correct responses (p = 0.003) and an increase of errors (p = 0.003), in respect to EM patients.
2.5. Statistical analysis Statistical analysis was performed using SPSS-version 20. Demographic and clinical variables were compared using T-test and v2. Metacognitive aspects were compared between groups using ANOVA test followed by Bonferroni correction for multiple comparisons. To assess relationships between medication dependence and metacognitive variables, a multiple linear regression was conducted. The level of statistical significance was taken at p < 0.05.
3. Results 3.1. Clinical characteristics No difference was found between patients and controls in demographic characteristics, except for lower education in migraineurs, in comparison with controls (p = 0.03). In the subgroup analysis of migraine patients, no significant differences in demographic characteristics were found between EM and CM-MOH. Patients in the CM-MOH group were abuser of a) triptans: Rizatriptan (4 pts), Frovatriptan (3 pts), Eletriptan (4 pts), b) nonsteroidal anti-inflammatory drugs (NSAIDs): Indometacin (1pt), Naproxen (1pt), Indomethacin/ Caffeine/Proclorperazine (2 pts), and most often a combination of the above (22). Twenty-seven CM-MOH patients were on preventive medication at enrollment: topiramate (5 pts), antidepressants (SSRI/SNRI; amitriptyline) (6 pts), beta-blockers (2 pts), valproic acid (2 pts), and 12 underwent a combined prophylaxis, due to severity of intensity and frequency of attacks. Four EM used amitriptyline, two flunarizine and two SSRI as migraine prophylaxis. No differences were found between the type of drugs overused in CM-MOH patients and their metacognitive executive performances. Demographic and clinic characteristics of EM and CM-MOH patients are summarized in Table 2.
3.3. Results of metacognitive functions assessment Patients with migraine presented worse performances when compared to controls in accuracy score (p = 0.012), global monitoring (p = 0.015), monetary gains (p = 0.022), and control sensitivity (p = 0.027) (Fig. 1). We also found statistically significant lower scores in most metacognitive indices of WCST test in CM-MOH in comparison to EM: accuracy score (p < 0.001), free-choice improvement (p = 0.004), global monitoring (p = 0.001), monetary gains (p = 0.001), and control sensitivity (p < 0.001) (Fig. 2).
3.4. Results of neuropsychiatric assessment Migraine patients exhibited higher levels of depression (p = 0.001) and anxiety (p < 0.001) in respect to healthy subjects. Higher scores of BDI (p = 0.013) and BAI (p = 0.017) were strongly related with worsening of CS scores obtained by subjects at metacognitive version of WCST test.
3.5. Results of medication overuse assessment In EM and CM-MOH subgroup, we found a high correlation between MDQ-H scores and level of metacognitive performances. Specifically, an increasing of medication overuse degree appeared to be straight correlated with low metacognitive performances in term of a reduction in accuracy score (p = 0.001), free-choice improvement (p = 0.002), global monitoring (p = 0.003), monetary gains (p = 0.009) and control sensitivity (p < 0.001) outcomes.
Fig. 1. Mean scores ± SD of metacognitive indexes in which migraine patients exhibited performance significantly worse in comparison to healthy controls. Abbreviations: AS: Accuracy score, GM: Global monitoring, CS: Control sensitivity, MG: Monetary gains.
Please cite this article as: M. Zucca, E. Rubino, A. Vacca et al., Metacognitive impairment in patients with episodic and chronic migraine, Journal of Clinical Neuroscience, https://doi.org/10.1016/j.jocn.2019.12.048
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M. Zucca et al. / Journal of Clinical Neuroscience xxx (xxxx) xxx
Fig. 2. Mean scores ± SD of metacognitive indexes in which chronic migraine patients with medication overuse headache (CM-MOH) exhibited performance significantly worse in comparison to episodic migraine (EM) patients. Abbreviations: AS: Accuracy score, GM: Global monitoring, CS: Control sensitivity, MG: Monetary gains, FCI: Freechoice improvement.
4. Discussion To the best of our knowledge, this is the first study that evaluated metacognitive abilities in adult patients with migraine using the metacognitive version of WCST. In our study migraine patients showed lower performances in executive frontal tasks, especially in terms of strategic planning deficits and set-shifting problems, in respect to control subjects. These results are in accord with other researches, which proposed that patients with migraine usually presented lower cognitive and executive abilities, in terms of a moderate or marked impairment in mental flexibility, set shifting abilities, problem solving domains and decision making skills [5,6,7,8,23]. Furthermore, our findings showed that CM-MOH patients exhibited worse performances also in strategic planning and setshifting tasks in respect to EM subjects. The presence of executive disturbances concerning a poor decision making process, associated to a fronto-striatal circuit dysfunction, has also been described in chronic migraine patients with medication overuse, compared with healthy subjects [9,24]. In literature, executive functions skills and metacognitive abilities are often considered mutually interacting [13]. In details, it was reported that set-shifting abilities tend to influence metacognitive control processes allowing the translation of information from monitoring processes into control actions [13]. Moreover, a previous study suggested that metacognition, with reference to monitoring and control, represents a crucial aspect for the implementation of an adaptive decision making process [25]. These two metacognitive subsystems separately influence the decision-making process, shaping a closed-loop network to control our coping strategies and adapt our behavior towards required goals [25]. In this sense it is not surprising that, focusing on the evaluation of metacognitive skills in our study, we found that patients with migraine exhibited a worse performance in metacognitive ability in respect to controls. Specifically, migraineurs tend to include the response in the final score test although they are more frequently insecure about its correctness in respect to healthy subjects. Besides, considering the metacognitive evaluation in the migraine patients, our data showed that a greater metacognitive impairment was also present in patients with CM-MOH in respect to EM patients. In details, patients with CM-MOH exhibited worst performances in metacognitive indexes, assessing patients’ control abil-
ity, although they performed monitoring process task as well as EM patients. In our study we also found that higher MDQ-H scores in connection with an increase of overuse of symptomatic medications were related with lower outcome in metacognitive performances in CM patients. According to recent studies [26,27], our findings confirm that subjects with substance abuse disorders present metacognitive executive dysfunctions, especially in term of a poor capacity to control and regulate their metacognitive knowledge to perform adaptive behaviors. These metacognitive disorders result associated to a selective impairment of prefrontal cortex (PFC) areas [26,27]. Intriguingly, both in subjects with chronic exposure to addictive drugs and in patients with CM-MOH was reported an alteration of PFC areas connectivity and their projections to the ventral striatum [28,29]. Finally, considering the neuropsychiatric profile, we observed a strong correlation between BDI and BAI scores and control metacognitive processes. In detail, high level of anxiety and depression appear to be straight related with a worse performance in control sensitivity index outcomes. In accord with our results, it was reported that anxiety and depression are usually related with dysfunctional metacognitive processes, which predispose patients to an increase in negative thoughts rumination [30,31]. Excessive attention to distressing thoughts could affect brain networks and induce to a maladaptive pain perception and modulation [32]. Intriguingly, it was also suggested that different areas of PFC, such as, anterior insular cortex, anterior cingulate cortex, ventrolateral prefrontal cortex, dorsolateral prefrontal cortex and the parietal gyrus, are commonly involved in affective-motivational and cognitive components of pain [32,33]. All these regions have direct mutual connections between each other, and are correlated with brain regions involved in sensory pain process components [32]. We acknowledge that our study has some limitations that deserve to be mentioned. First, the study population was relatively small. Future larger studies will be helpful in order to better understand the role of metacognitive executive dysfunctions in the onset and progression of migraine disease. Secondly, ten CM-MOH patients were not taking any preventive medication because all drugs had failed, while other patients were taking a combination of preventive medications. Therefore, we have performed a sub analysis to exclude the presence of a correlation between the type
Please cite this article as: M. Zucca, E. Rubino, A. Vacca et al., Metacognitive impairment in patients with episodic and chronic migraine, Journal of Clinical Neuroscience, https://doi.org/10.1016/j.jocn.2019.12.048
M. Zucca et al. / Journal of Clinical Neuroscience xxx (xxxx) xxx
of drugs used in CM-MOH patients and their metacognitive executive performances. Finally, five CM-MOH patients also had a previous diagnosis of Mixed Anxiety and Depressive Disorder (MADD), and three of Major Depressive Disorder (MDD) as diagnosed by DSM-V [17]. It is well known that neuropsychiatric diseases, in term of anxiety and depression, are most common in CM-MOH patients [34,35]. However, the presence of anxiety and depression, it was evaluated and analyzed for all subjects enrolled for the study. 5. Conclusions We can conclude that migraine patients present metacognitive dysfunctions, especially in term of a lower ability to control the cognitive process appointed to the implementation of a controlled behavior, in comparison to health subjects. Metacognitive control processes reduction can be due to setshifting problems that negatively influence translation of information from monitoring processes into adaptive actions. Deficits in metacognition can be involved in the increase of mood disorders such as depression and anxiety, that represent the most common psychiatric comorbidities in patients with episodic and chronic migraine [36]. Finally, metacognitive problems appear to get worse with the presence of medication overuse in CM subjects. This result link CM-MOH patients to people suffering with substance abuse disorders and can be explained by an alteration of PFC areas activity due to a ventral striatum dysfunction that could produce an unbalanced dopaminergic stimulation of these areas. In conclusion our data suggest that metacognitive deficits may become a possible new therapeutic target in migraine patients and especially in CM-MOH subjects. Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Acknowledgement The authors thank the subjects and patients who participated in this research. Source of funding This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. References [1] Lipton RB, Bigal ME, Diamond M, Freitag F, Reed ML, Stewart WF, et al. Migraine prevalence, disease burden and the need for preventive therapy. Neurology 2007;68:343–9. [2] Katsarava Z, Buse DC, Manack AN, Lipton RB. Defining the differences between episodic migraine and chronic migraine. Curr Pain Headache Rep 2012;16:86–92. [3] Lipton RB. Chronic migraine, classification, differential diagnosis, and epidemiology. Headache 2011;51:77–83. [4] Evers S, Marziniak M. Clinical features, pathophysiology and treatment of medication-overuse headache. Lancet Neurol 2010;9:391–401. [5] Le Pira F, Reggio E, Quattrocchi G, Sanfilippo C, Maci T, Cavallaro T, et al. Executive dysfunctions in migraine with and without aura: what is the role of white matter lesions?. Headache 2014;54(1):125–30. [6] Vuralli D, Ayata C, Bolay H. Cognitive dysfunction and migraine. J Headache Pain 2018;19(1):109.
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Please cite this article as: M. Zucca, E. Rubino, A. Vacca et al., Metacognitive impairment in patients with episodic and chronic migraine, Journal of Clinical Neuroscience, https://doi.org/10.1016/j.jocn.2019.12.048
Contents lists available at ScienceDirect
Journal of Clinical Neuroscience journal homepage: www.elsevier.com/locate/jocn
Clinical study
Metacognitive impairment in patients with episodic and chronic migraine Milena Zucca a,⇑, Elisa Rubino b, Alessandro Vacca a, Paola De Martino a, Fausto Roveta a, Flora Govone a, Annalisa Gai a, Marcella Caglio a, Salvatore Gentile a,b, Maria T. Giordana a,b, Innocenzo Rainero a,b a b
Neurology I – Headache Center, ‘‘Rita Levi Montalcini” Department of Neuroscience, University of Torino, Italy Department of Neuroscience and Mental Health, A.O.U. Città della Salute e della Scienza, Torino, Italy
a r t i c l e
i n f o
Article history: Received 11 September 2019 Accepted 20 December 2019 Available online xxxx Keywords: Metacognition Executive functions Migraine Medication-overuse headache Wisconsin card sorting test
a b s t r a c t Migraine is one of the most common medical disorder in the world. Metacognition is the ability to monitor one’s own cognitive functioning and consequently direct one’s behavior. In adult migraine patients, the neuropsychological profile has been poorly investigated, and metacognitive functions have never been assessed. The aim of the present study was therefore to evaluate executive metacognitive abilities in patients with episodic and chronic migraine. Sixty-four migraine patients (male/female = 18/46; mean age = 45.65 ± 11.61 years): 27 patients with episodic migraine without aura (male/female = 9/18; mean age ± SD = 45.11 ± 12.18 years) and 37 patients with chronic migraine and medication-overuse headache (male/female = 9/28; mean age ± SD = 46.05 ± 11.32 years) were selected for the study. Twenty-nine controls (male/female = 12/17; mean age ± SD = 42.86 ± 14.78 years) were also enrolled in the research. Metacognitive and executive skills were assessed using the metacognitive version of Wisconsin Card Sorting Test. Migraine patients exhibited a lower performance in metacognitive tasks in respect to controls in term of worse outcomes in accuracy score (p = 0.012), global monitoring (p = 0.015), monetary gains (p = 0.022), and control sensitivity (p = 0.027). A reduction in accuracy score (p = 0.001), freechoice improvement (p = 0.002), global monitoring (p = 0.003), monetary gains (p = 0.009), and control sensitivity (p < 0.001) was also found in patients with chronic migraine and medication-overuse headache in respect to patients with episodic migraine. Our study supports the hypothesis that migraine patients show metacognitive dysfunctions that become worse with the chronicization of the disease and the increase of medication use. Ó 2019 Elsevier Ltd. All rights reserved.
1. Introduction Migraine is a neurovascular disorder characterized by recurrent attacks of moderate to severe headache associated with autonomic nervous system dysfunctions and, in about one third of patients, visual, sensory, motor, or other, neurologic symptoms known as aura. Migraine is a highly prevalent headache disorder affecting approximately 10–12% of adult population in Western Countries, with a substantial impact on individuals, families and society [1]. Each year approximately 2% of migraineurs show a progressive worsening of headache in terms of an increasing in frequency and severity of attacks [2].
⇑ Corresponding author at: Neurology I – Headache Center, ‘‘Rita Levi Montalcini” Department of Neuroscience, University of Torino, Via Cherasco 15 – 10126 Torino, Italy. E-mail address: [email protected] (M. Zucca).
Chronic migraine (CM) is a disabling condition characterized by headache occurring for at least 15 days per month for >3 months [3]. Thence, CM patients can start overusing symptomatic drugs for migraine, thus causing the onset of a secondary headache with variable clinical features, called ‘‘medication-overuse headache” (MOH) [4]. In literature, migraineurs have been reported to show low cognitive performances, more frequently in terms of memory impairment, attention reduction and executive dysfunctions in respect to controls [5,6]. In migraine sufferers, cognitive impairment appears to be closely related with the frequency of migraine attacks [7,8]. Nevertheless, it was also reported that cognitive difficulties could persist in the inter-attacks period between migraine attacks, causing a reduction of cognitive performance in migraine patients [6]. Intriguingly, the presence of an executive impairment in terms of a poor decision making process, associated to a fronto-striatal circuit dysfunction, has also been also described in chronic migraine patients with or without medication overuse [9,10,11].
https://doi.org/10.1016/j.jocn.2019.12.048 0967-5868/Ó 2019 Elsevier Ltd. All rights reserved.
Please cite this article as: M. Zucca, E. Rubino, A. Vacca et al., Metacognitive impairment in patients with episodic and chronic migraine, Journal of Clinical Neuroscience, https://doi.org/10.1016/j.jocn.2019.12.048
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Some authors, suggested that executive functions are inevitably coupled with a higher-order cognitive ability known as metacognition [12,13]. Metacognition is a dynamical neurocognitive process often described as knowledge and ability to understand, control, and manipulate one’s own cognitive processes [13,14]. Two important components of metacognitive functions are (1) monitoring, i.e. the subjective evaluation about one’s on-going cognitive activities and their functioning (knowledge about cognition) and (2) control i.e. the ability to use metacognitive knowledge to regulate an ongoing cognitive activity (strategy regulation of cognition) [13,15]. The presence of metacognitive dysfunctions in adult migraine patients has not been investigated yet. Therefore, the main aim of the present study was to explore the presence of executive metacognitive dysfunctions in adult patients with migraine.
N (males/females) Age, mean (±SD) years Education, mean (±SD) years Years with migraine
2.1. Participants and procedures Sixty-four migraine patients (male/female = 18/46; mean age ± SD = 45.65 ± 11.61 years) were recruited at the Headache Center, Department of Neuroscience ‘‘Rita Levi Montalcini”, University of Torino, Italy. According to ICHD-III criteria [16], migraine patients were divided in two subgroups: 27 patients with episodic migraine (EM) without aura (male/female = 9/18; mean age ± SD = 45.11 ± 12.18 years) and 37 patients with chronic migraine (male/female = 9/28; mean age ± SD = 46.05 ± 11.32 yea rs). All the involved CM patients also fulfilled the criteria for medication-overuse headache (CM-MOH). Twenty-nine healthy controls (HC) matched for age and gender, without headache or any other neurological or psychiatric disease, were also enrolled in the study (male/female = 12/17; mean age ± SD = 42.86 ± 14.7 8 years). The demographic and clinical characteristics are summarized in Tables 1 and 2. All subjects underwent a neuropsychological evaluation. Patients in CM-MOH group were evaluated at the end of a 5-day detoxification period from overuse medication, that was performed in an outpatient hospital regimen. Preventive medication was prescribed only in case of need. All patients were assessed during a pain-free period. Migraine patients were excluded from the study if they had a history of neurological diseases different from migraine, a diagnosis of chronic pain conditions, present or past alcohol and substance use disorders or pathological gambling as diagnosed by DSM-V [17]. Written informed consent was obtained from all participants, and the study was approved by the Hospital Ethics Committee. 2.2. Assessment of executive and metacognitive functions Metacognitive functions have been assessed using the metacognitive version of the Wisconsin Card Sorting Test (WCST) [18]. This
Table 1 Synopsis of the demographic and clinic characteristics of migraine patients and healthy controls. Migraine patients
Healthy controls
p-value
64 (18/46) 45.65 (±11.61) 13 (±4.07) <5 years (12) 5–15 years (24) >15 years (28)
29 (12/17) 42.86 (±14.78) 15.10 (±4.25) –
0.188 0.374 0.034 –
CM- MOH
EM
pvalue
37 (9/28) 46.05 (±11.32)
27 (9/18) 45.11 (±12.19)
0.063 0.748
12.65 (±3.41)
13.75 (±4.80)
0.308
< 5 years (5) 5–15 years (14) > 15 years (18)
< 5 years (7) 5–15 years (10) >15 years (10) 33.62 (±16.04)
–
MDQ-H
93.86 (±20.53)
Medication overuse
NSAIDs (4); triptans (11); combination (22) Combination (12); amitriptyline (1); topiramate (5); SSRI/SNRI (5); beta-blockers (2), valproic acid (2); no treatment (10)
Preventive medication
2. Materials and methods
N(males/females) Age, mean (±SD) years Education, mean (±SD) years Years with migraine
Table 2 Synopsis of the demographic and clinic characteristics of EM patients and CM-MOH patients.
– No treatment (19); amitriptyline (4); flunarizine (2); SSRI (2)
< 0.001 – –
Legend: NSAID’s: Non-steroidal anti-inflammatory drugs, SSRI: selective serotonin reuptake inhibitors, SNRI: serotonin–norepinephrine reuptake inhibitors.
version was selected because it allows to obtain a distinguished and contemporary evaluation of both executive functions and metacognitive abilities of the examined subjects. Furthermore, in addition to the standard ‘‘forced response’’ commonly adopted to test metacognition, this instrument used measures of ‘‘free response’’ performance, straightly related to the patient’s metacognitive abilities [19]. In respect to the original version of WCST, this test includes two additional requests: I) the subjective level of confidence (range 0– 100) about the correctness of one’s own response, and, II) the subject’s decision to gamble including the response in the final score test. A monetary gain or penalty was attributed according to a correct/incorrect sort. Six metacognitive variables have been achieved from the free-response outputs: (1) accuracy score (AS), which represents the percentage of ventured answers that were correct; (2) free-choice improvement (FCI), the difference between the accuracy score previously obtained and the percentage of correct answers calculated on the total pairings made; (3) global monitoring (GM), the difference between correct sorts and the total number of sorts, in order to know the veridicality of one’s own response; (4) monitoring resolution (MR), the extent to which the confidence judgments distinguish between the correct and incorrect sorts, in order to assess one’s own ability to monitor the quality of his/her performance; (5) control sensitivity (CS), which results from the relationship between one’s confidence about the match made and the decision or not to bet, to know the subject’s ability to regulate the quality of his/her performance on the basis of the previous assessments; (6) monetary gains (MG), which evaluates the monetary reward achieved by the subject, calculated as the difference between the correct and wrong pairings for which the patient decided to bet.
2.3. Neuropsychiatric assessment Each group underwent specific questionnaires on behavioral and mood changes. Depression was evaluated using the Beck
Please cite this article as: M. Zucca, E. Rubino, A. Vacca et al., Metacognitive impairment in patients with episodic and chronic migraine, Journal of Clinical Neuroscience, https://doi.org/10.1016/j.jocn.2019.12.048
M. Zucca et al. / Journal of Clinical Neuroscience xxx (xxxx) xxx
Depression Inventory (BDI) [20], while anxiety was examined with the Beck Anxiety Inventory (BAI) [21].
2.4. Assessment of medication overuse To evaluate the degree of medication overuse, the Medication Dependence Questionnaire for Headache sufferers (MDQ-H) [22], a self-administered questionnaire comprising twenty-one items, was used.
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3.2. Results of executive functions assessment The overall group of migraineurs was characterized by the presence of lower number of categories completed (p = 0.017), a reduction of correct responses (p = 0.031) and a higher percentage of errors (p = 0.033) in comparison with controls. In addition, patients with CM-MOH exhibited worse executive performances at metacognitive version of WCST test, in terms of less number of categories completed (p = 0.014), lower percentage of correct responses (p = 0.003) and an increase of errors (p = 0.003), in respect to EM patients.
2.5. Statistical analysis Statistical analysis was performed using SPSS-version 20. Demographic and clinical variables were compared using T-test and v2. Metacognitive aspects were compared between groups using ANOVA test followed by Bonferroni correction for multiple comparisons. To assess relationships between medication dependence and metacognitive variables, a multiple linear regression was conducted. The level of statistical significance was taken at p < 0.05.
3. Results 3.1. Clinical characteristics No difference was found between patients and controls in demographic characteristics, except for lower education in migraineurs, in comparison with controls (p = 0.03). In the subgroup analysis of migraine patients, no significant differences in demographic characteristics were found between EM and CM-MOH. Patients in the CM-MOH group were abuser of a) triptans: Rizatriptan (4 pts), Frovatriptan (3 pts), Eletriptan (4 pts), b) nonsteroidal anti-inflammatory drugs (NSAIDs): Indometacin (1pt), Naproxen (1pt), Indomethacin/ Caffeine/Proclorperazine (2 pts), and most often a combination of the above (22). Twenty-seven CM-MOH patients were on preventive medication at enrollment: topiramate (5 pts), antidepressants (SSRI/SNRI; amitriptyline) (6 pts), beta-blockers (2 pts), valproic acid (2 pts), and 12 underwent a combined prophylaxis, due to severity of intensity and frequency of attacks. Four EM used amitriptyline, two flunarizine and two SSRI as migraine prophylaxis. No differences were found between the type of drugs overused in CM-MOH patients and their metacognitive executive performances. Demographic and clinic characteristics of EM and CM-MOH patients are summarized in Table 2.
3.3. Results of metacognitive functions assessment Patients with migraine presented worse performances when compared to controls in accuracy score (p = 0.012), global monitoring (p = 0.015), monetary gains (p = 0.022), and control sensitivity (p = 0.027) (Fig. 1). We also found statistically significant lower scores in most metacognitive indices of WCST test in CM-MOH in comparison to EM: accuracy score (p < 0.001), free-choice improvement (p = 0.004), global monitoring (p = 0.001), monetary gains (p = 0.001), and control sensitivity (p < 0.001) (Fig. 2).
3.4. Results of neuropsychiatric assessment Migraine patients exhibited higher levels of depression (p = 0.001) and anxiety (p < 0.001) in respect to healthy subjects. Higher scores of BDI (p = 0.013) and BAI (p = 0.017) were strongly related with worsening of CS scores obtained by subjects at metacognitive version of WCST test.
3.5. Results of medication overuse assessment In EM and CM-MOH subgroup, we found a high correlation between MDQ-H scores and level of metacognitive performances. Specifically, an increasing of medication overuse degree appeared to be straight correlated with low metacognitive performances in term of a reduction in accuracy score (p = 0.001), free-choice improvement (p = 0.002), global monitoring (p = 0.003), monetary gains (p = 0.009) and control sensitivity (p < 0.001) outcomes.
Fig. 1. Mean scores ± SD of metacognitive indexes in which migraine patients exhibited performance significantly worse in comparison to healthy controls. Abbreviations: AS: Accuracy score, GM: Global monitoring, CS: Control sensitivity, MG: Monetary gains.
Please cite this article as: M. Zucca, E. Rubino, A. Vacca et al., Metacognitive impairment in patients with episodic and chronic migraine, Journal of Clinical Neuroscience, https://doi.org/10.1016/j.jocn.2019.12.048
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Fig. 2. Mean scores ± SD of metacognitive indexes in which chronic migraine patients with medication overuse headache (CM-MOH) exhibited performance significantly worse in comparison to episodic migraine (EM) patients. Abbreviations: AS: Accuracy score, GM: Global monitoring, CS: Control sensitivity, MG: Monetary gains, FCI: Freechoice improvement.
4. Discussion To the best of our knowledge, this is the first study that evaluated metacognitive abilities in adult patients with migraine using the metacognitive version of WCST. In our study migraine patients showed lower performances in executive frontal tasks, especially in terms of strategic planning deficits and set-shifting problems, in respect to control subjects. These results are in accord with other researches, which proposed that patients with migraine usually presented lower cognitive and executive abilities, in terms of a moderate or marked impairment in mental flexibility, set shifting abilities, problem solving domains and decision making skills [5,6,7,8,23]. Furthermore, our findings showed that CM-MOH patients exhibited worse performances also in strategic planning and setshifting tasks in respect to EM subjects. The presence of executive disturbances concerning a poor decision making process, associated to a fronto-striatal circuit dysfunction, has also been described in chronic migraine patients with medication overuse, compared with healthy subjects [9,24]. In literature, executive functions skills and metacognitive abilities are often considered mutually interacting [13]. In details, it was reported that set-shifting abilities tend to influence metacognitive control processes allowing the translation of information from monitoring processes into control actions [13]. Moreover, a previous study suggested that metacognition, with reference to monitoring and control, represents a crucial aspect for the implementation of an adaptive decision making process [25]. These two metacognitive subsystems separately influence the decision-making process, shaping a closed-loop network to control our coping strategies and adapt our behavior towards required goals [25]. In this sense it is not surprising that, focusing on the evaluation of metacognitive skills in our study, we found that patients with migraine exhibited a worse performance in metacognitive ability in respect to controls. Specifically, migraineurs tend to include the response in the final score test although they are more frequently insecure about its correctness in respect to healthy subjects. Besides, considering the metacognitive evaluation in the migraine patients, our data showed that a greater metacognitive impairment was also present in patients with CM-MOH in respect to EM patients. In details, patients with CM-MOH exhibited worst performances in metacognitive indexes, assessing patients’ control abil-
ity, although they performed monitoring process task as well as EM patients. In our study we also found that higher MDQ-H scores in connection with an increase of overuse of symptomatic medications were related with lower outcome in metacognitive performances in CM patients. According to recent studies [26,27], our findings confirm that subjects with substance abuse disorders present metacognitive executive dysfunctions, especially in term of a poor capacity to control and regulate their metacognitive knowledge to perform adaptive behaviors. These metacognitive disorders result associated to a selective impairment of prefrontal cortex (PFC) areas [26,27]. Intriguingly, both in subjects with chronic exposure to addictive drugs and in patients with CM-MOH was reported an alteration of PFC areas connectivity and their projections to the ventral striatum [28,29]. Finally, considering the neuropsychiatric profile, we observed a strong correlation between BDI and BAI scores and control metacognitive processes. In detail, high level of anxiety and depression appear to be straight related with a worse performance in control sensitivity index outcomes. In accord with our results, it was reported that anxiety and depression are usually related with dysfunctional metacognitive processes, which predispose patients to an increase in negative thoughts rumination [30,31]. Excessive attention to distressing thoughts could affect brain networks and induce to a maladaptive pain perception and modulation [32]. Intriguingly, it was also suggested that different areas of PFC, such as, anterior insular cortex, anterior cingulate cortex, ventrolateral prefrontal cortex, dorsolateral prefrontal cortex and the parietal gyrus, are commonly involved in affective-motivational and cognitive components of pain [32,33]. All these regions have direct mutual connections between each other, and are correlated with brain regions involved in sensory pain process components [32]. We acknowledge that our study has some limitations that deserve to be mentioned. First, the study population was relatively small. Future larger studies will be helpful in order to better understand the role of metacognitive executive dysfunctions in the onset and progression of migraine disease. Secondly, ten CM-MOH patients were not taking any preventive medication because all drugs had failed, while other patients were taking a combination of preventive medications. Therefore, we have performed a sub analysis to exclude the presence of a correlation between the type
Please cite this article as: M. Zucca, E. Rubino, A. Vacca et al., Metacognitive impairment in patients with episodic and chronic migraine, Journal of Clinical Neuroscience, https://doi.org/10.1016/j.jocn.2019.12.048
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of drugs used in CM-MOH patients and their metacognitive executive performances. Finally, five CM-MOH patients also had a previous diagnosis of Mixed Anxiety and Depressive Disorder (MADD), and three of Major Depressive Disorder (MDD) as diagnosed by DSM-V [17]. It is well known that neuropsychiatric diseases, in term of anxiety and depression, are most common in CM-MOH patients [34,35]. However, the presence of anxiety and depression, it was evaluated and analyzed for all subjects enrolled for the study. 5. Conclusions We can conclude that migraine patients present metacognitive dysfunctions, especially in term of a lower ability to control the cognitive process appointed to the implementation of a controlled behavior, in comparison to health subjects. Metacognitive control processes reduction can be due to setshifting problems that negatively influence translation of information from monitoring processes into adaptive actions. Deficits in metacognition can be involved in the increase of mood disorders such as depression and anxiety, that represent the most common psychiatric comorbidities in patients with episodic and chronic migraine [36]. Finally, metacognitive problems appear to get worse with the presence of medication overuse in CM subjects. This result link CM-MOH patients to people suffering with substance abuse disorders and can be explained by an alteration of PFC areas activity due to a ventral striatum dysfunction that could produce an unbalanced dopaminergic stimulation of these areas. In conclusion our data suggest that metacognitive deficits may become a possible new therapeutic target in migraine patients and especially in CM-MOH subjects. Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Acknowledgement The authors thank the subjects and patients who participated in this research. Source of funding This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. References [1] Lipton RB, Bigal ME, Diamond M, Freitag F, Reed ML, Stewart WF, et al. Migraine prevalence, disease burden and the need for preventive therapy. Neurology 2007;68:343–9. [2] Katsarava Z, Buse DC, Manack AN, Lipton RB. Defining the differences between episodic migraine and chronic migraine. Curr Pain Headache Rep 2012;16:86–92. [3] Lipton RB. Chronic migraine, classification, differential diagnosis, and epidemiology. Headache 2011;51:77–83. [4] Evers S, Marziniak M. Clinical features, pathophysiology and treatment of medication-overuse headache. Lancet Neurol 2010;9:391–401. [5] Le Pira F, Reggio E, Quattrocchi G, Sanfilippo C, Maci T, Cavallaro T, et al. Executive dysfunctions in migraine with and without aura: what is the role of white matter lesions?. Headache 2014;54(1):125–30. [6] Vuralli D, Ayata C, Bolay H. Cognitive dysfunction and migraine. J Headache Pain 2018;19(1):109.
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Please cite this article as: M. Zucca, E. Rubino, A. Vacca et al., Metacognitive impairment in patients with episodic and chronic migraine, Journal of Clinical Neuroscience, https://doi.org/10.1016/j.jocn.2019.12.048