Background
Migraine is a common and disabling neurological disorder which leads to reduced quality of life and significant functional impairments [
1]. In South Korea, a study investigating the prevalence of migraine over the course of 1 year reported that approximately 9.2% of women and 2.9% of men suffer from the disease [
2]. The burden of migraine is compounded by other co-occurring disorders, including psychiatric disorders, sleep problems, epilepsy, and stroke [
3]. Thus, it is important to identify manageable comorbidities for effective treatment of migraine.
There is contradictory evidence of the association between migraine and cognitive impairment. Some case-control studies reported that patients with migraine exhibit poor psychomotor speed [
4], attention [
5], and verbal memory [
6] performance compared to non-migraineurs, even during postictal periods. Conversely, several longitudinal and cross-sectional studies have shown that migraine is not associated with cognitive dysfunction or decline and may even associate with better function or less decline [
7‐
9]. Despite such inconsistent research findings on objective cognitive impairment, it is common that patients with migraine complain cognitive impairment in clinical practice. The perceptions of cognitive abilities are driven by comorbid symptoms rather than actual cognitive decline in patients with chronic pain. Therefore, cognitive problems in migraineurs is worthy to be approached from the assessment of complaints and its association with other comorbidities [
10,
11].
Subjective cognitive decline (SCD), also known as “subjective memory impairment” in early studies, refers to any self-perceived or subjectively experienced worsening of cognitive function in the absence of impaired performance on cognitive tests [
12]. SCD may represent the earliest symptoms of cognitive decline or preclinical Alzheimer’s disease (AD) and is also associated with psychological factors such as depression and anxiety in cognitively healthy elders [
13] and cerebrovascular disease [
14‐
19]. Multiple factors seem to contribute to the development of SCD; however, most studies on SCD are on the elderly population. Some investigations on healthy adults report that memory complaints are common, regardless of age, and seem to be related to negative affect [
20,
21]. However, these studies focused only on “memory complaints” while difficulties in other cognitive domains, such as attention or executive function are also common in patients with migraine.
There is strong evidence indicating an association between migraine and several psychiatric conditions, such as mood and anxiety disorders [
22,
23]. In a study using cluster analysis for patients with chronic migraine, patients with high levels of affective temperamental dysregulation showed a higher risk of suicidal behavior [
24]. Recent studies also supported genome wide association between migraine and bipolar disorder, therefore, it is important to identify manageable psychiatric comorbidities for effective treatment and improving life quality among migraineurs [
25,
26]. However, an association between SCD and comorbid symptoms or pain severity has not yet been investigated with relevant cognitive tests among patients with migraine.
We hypothesized that the migraineurs with SCD would complain of more severe pain and exhibit greater psychiatric comorbidities than individuals with migraine without SCD. Thus, the aim of the present study was to investigate the presence and frequency of SCD in patients with migraine, as well as to analyze the association of SCD with clinical features and headache impact, anxiety, depression and quality of sleep.
Results
Among a total of 669 first-visit patients for headache between January to November 2016, 481 patients were excluded due to following criteria (Fig.
1): having primary or secondary headache disorders other than migraine (
N = 199), age criteria (
N = 60), experiencing severe pain (
N = 68), and refuse to perform questionnaire or cognitive testing (
N = 154). Among migraineurs, none was excluded due to abnormal range of performance on both screening tests. Amongst the total of 470 migraine patients, the age of included patients (
N = 188, mean age = 38.09 ± 9.92) were significantly younger than the excluded patients (
N = 282, mean age = 40.68 ± 14.43,
p = 0.032), because those who were aged <19 or >65 were excluded. However, the percentage of gender did not differ between excluded versus included migraine patients (
p = 0.610).
A total of 188 participants with migraine, aged 38.1 ± 9.9 years, were included. The mean SCD-Q score was 6.5 (SD = 5.5), with 84 patients (44.7%) scoring higher than 7. Thus, 44.7% of participants were diagnosed as SCD in this study. Among the 188 participants, 106 (56.4%) scored higher than the cutoff on the GAD-7, 98 (52.1%) scored higher than the cutoff on the PHQ-9, and 154 (81.9%) scored higher than the cutoff on the PSQI.
Demographic and headache-related clinical data are shown in Table
1. An
independent-sample t-test and
Pearson’s Chi-square test did not reveal differences between groups in terms of age, sex, migraine type, pain duration, and medication. However, significant differences were found for pain intensity on the VAS and headache impact on the HIT-6. There were no significant differences between groups on both cognitive screening tests─the K-MMSE and K-MoCA (Table
1). Moreover, no group differences were found in any sub-items of both tests.
Table 1
Demographical and clinical characteristics of no-SCD versus SCD groups
Age | 37.3 ± 9.8 | 39.1 ± 10.0 | 0.228 |
Sex (male/female) | 24/80 | 24/60 | 0.390 |
Episodic/chronic headache | 84/20 | 65/19 | 0.569 |
Migraine types (with aura/without aura/chronic/probable) | 5/75/20/4 | 8/58/18/0 | 0.179 |
Frequency of attacks per month | 8.9 ± 8.1 | 10.2 ± 7.2 | 0.236 |
Maximum pain duration in hours | 35.3 ± 54.0 | 31.3 ± 31.3 | 0.542 |
Number of tablets per month | 4.3 ± 5.9 | 5.6 ± 6.7 | 0.169 |
Pain intensity on VAS | 6.6 ± 1.8 | 7.2 ± 1.5 | 0.024 |
HIT-6 | 59.2 ± 7.6 | 62.3 ± 7.0 | 0.005 |
K-MMSE | 29.0 ± 1.5 | 28.9 ± 1.6 | 0.566 |
K-MoCA | 27.5 ± 1.9 | 27.5 ± 2.0 | 0.966 |
Of the 84 migraineurs with SCD, 56 (66.7%) scored higher than the cutoff on the GAD-7, 59 (70.2%) scored higher than the cutoff on the PHQ-9, and 73 (86.9%) scored higher than the cutoff on the PSQI. Group differences between SCD and no-SCD groups in terms of anxiety, depression, and sleep quality are shown in Table
2. Significant differences were found in anxiety (GAD-7), depression (PHQ-9), sleep quality (PSQI), and average sleep (in hours) during weekdays. However, there was no significant group difference in terms of the average amount of sleep achieved during weekends.
Table 2
Anxiety, depression, sleep quality, and average sleeping hours during weekdays and weekends of no-SCD versus SCD groups
GAD-7 | 5.0 ± 3.9 | 8.2 ± 5.5 | < 0.001 |
PHQ-9 | 5.7 ± 4.0 | 10.4 ± 5.6 | < 0.001 |
PSQI | 8.5 ± 3.8 | 10.6 ± 4.3 | < 0.001 |
Average Sleeping hours during weekdays | 6.5 ± 1.1 | 6.0 ± 1.3 | 0.008 |
Average Sleeping hours during weekends | 7.6 ± 1.5 | 7.3 ± 2.0 | 0.335 |
SCD-Q scores were correlated with the depression on the PHQ-9 (r
s
= 0.49, p < 0.001), anxiety on the GAD-7 (r
s
= 0.34, p < 0.001), sleep quality on the PSQI (r
s
= 0.33, p < 0.001), sleep duration during weekdays (r
s
= −0.20, p = 0.007), VAS (r
s
= 0.17, p = 0.017), and the frequency of headache attacks per month (r
s
= 0.15, p = 0.047). However, SCD-Q scores were not significantly correlated with the HIT-6, age, maximum pain duration, medication, sleep duration during weekends, nor cognitive screening test scores (data not shown).
Upon multivariate logistic analysis adjusted for age, sex, headache characteristics, and psychological variables, depression was associated with increased risk of SCD (Odds ratio 1.31, 95% confidence interval 1.16–1.49) and sleep duration during weekdays was associated with decreased risk of SCD (Odds ratio 0.66, 95% confidence interval 0.44–0.97) (Table
3). As the level of depression on PHQ-9 increases by 1 unit, the likelihood of migraineurs with SCD increases by 0.272 times (b = 0.27, Wald χ
2(1) = 17.50,
p < 0.001). As the sleep duration during weekdays increases by 1 unit, the likelihood of migraineurs with SCD lower by 0.423 times (b = −0.423, Wald χ
2(1) = 4.39,
p = 0.036).
Table 3
Association of SCD with demographical and clinical variables: Multivariate logistic regression analyses
Age | 1.03 (0.99–1.08) | 0.131 |
Sex (male/female) | 0.88 (0.40–1.95) | 0.749 |
Episodic/chronic headache | 0.97 (0.17–5.43) | 0.968 |
Migraine types (with aura/without aura/chronic/probable) | 0.73 (0.35–1.51) | 0.392 |
Frequency of attacks per month | 1.02 (0.95–1.09) | 0.568 |
Maximum pain duration in hours | 0.994 (0.983–1.006) | 0.331 |
Number of tablets per month | 1.02 (0.95–1.09) | 0.590 |
Pain intensity on VAS | 1.14 (0.90–1.45) | 0.268 |
HIT-6 | 1.00 (0.94–1.07) | 0.887 |
K-MMSE | 1.02 (0.75–1.37) | 0.919 |
K-MoCA | 1.09 (0.85–1.38) | 0.507 |
GAD-7 | 0.96 (0.86–1.07) | 0.492 |
PHQ-9 | 1.31 (1.16–1.49) | <0.001 |
PSQI | 0.92 (0.82–1.03) | 0.161 |
Average Sleeping hours during weekdays | 0.66 (0.44–0.97) | 0.036 |
Average Sleeping hours during weekends | 1.02 (0.77–1.34) | 0.913 |
Discussion
We investigated SCD amongst the patients with migraine using a standard questionnaire with relevant cognitive testing. The main findings of this study were 1) SCD is relatively common in adult patients with migraine, 2) migraineurs with SCD reported severe headache pain severity and headache impact, 3) migraineurs with SCD were more depressed and anxious, while experiencing lowered sleep quality and sleep duration during weekdays were shorter, 4) depression on the PHQ-9 and sleep duration during weekdays were associated with SCD after adjusting demographic variables, headache related variables and psychological variables.
Previous studies found that patients with migraine showed normal range of performance on both the MMSE [
39] and MoCA [
40]. Similarly, none were excluded due to abnormal performance on screening tests among migraineurs in this study. Considering the mean SCD-Q scores of 3.2 (SD = 3.7) in normal controls in the previous study, the mean SCD-Q score of 6.5 (SD = 5.5) in migraineurs was relatively high [
32]. Not negligible number of young adult migraineurs seemed to complaint cognitive decline and, to our knowledge, this is the first report to identify SCD in adult patients with migraines. Moreover, the proportion of SCD (44.2%) is comparable to common comorbidities of migraine such as poor quality of sleep (81.6%), anxiety (55.8%) and depression (52.1%).
SCD in preclinical AD received particular interest on aging studies since longitudinal data support SCD as a risk factor for future cognitive decline as well as AD dementia [
14,
17,
41]. A review study on SCD suggested that the proposed age of onset in studies of preclinical AD is 60 years or older despite the age at SCD onset was not defined as a core criterion [
42]. Unlikely to SCD in elderly, there is no conclusive evidence for that SCD or perceived forgetfulness in young adult is a risk factor for future cognitive impairment or dementia [
43]. In studies of healthy adults, memory complaints are frequent regardless of age; however, the type of complaint varies and may be related to negative affect throughout adulthood [
20,
21]. This study also suggested that SCD among migraineurs require more attention to psychological or sleep problem rather than close follow-up of cognitive decline.
Subjective pain is a common symptom in patients suffering from depression and in turn, chronic pain may trigger a depressive state [
44,
45]. Interestingly, migraineurs with SCD complained of more severe difficulties in subjectively reported measures, such as pain intensity and headache impact, compared to migraineurs without SCD, but this association was not persistent on logistic analysis. This implies such sensitivity to perceived pain or subjective difficulties may be related to psychological impairments and/or sleep problem among migraineurs with SCD.
In line with previous studies, our data also revealed high levels of anxiety and depression in patients with migraine [
46]. Not surprisingly, depression was significantly associated with SCD among migraineurs in this study. It is possible that SCD among migraineurs may either independently or conjointly account for the high levels of depression and anxiety. Moreover, biased perceptions of cognitive function may relate more to emotional state than objective ability, causing individuals to misinterpret or exaggerate problems by overestimating minor cognitive disruptions. According to Beck’s cognitive theory of depression, depression is associated with a negative view of oneself, environment, and future [
47]. Increasing the awareness patients with migraine have of possible misperceptions could help them understand their neurological and psychological state more objectively.
Similar to a previous study, more than half of the total patients with migraine that were evaluated in the current study complained of poor sleep quality [
48]; this percentage was even higher (86.9%) in migraineurs with SCD. This relationship may be explained by the high correlation between SCD-Q and PSQI scores. Indeed, a previous study revealed an association between perception of poor sleep quality and worse cognitive performance in healthy elderly individuals [
49]. In the current study, the average amount of sleep achieved during weekdays for migraineurs with SCD was less than 6 h. This value is less than the recommended duration of 7 to 8 h for adults [
50]. It has been reported that migraineurs who routinely sleep 6 h per night exhibit more severe headache patterns and sleep complaints than migraineurs who slept longer [
51]. Thus, short sleep duration during weekdays may account for the poor perception of cognitive function and sleep quality observed in the current study.
Several limitations to this study should be addressed. The main limitations of the study would be that it is based on retrospective review of headache registry records. Therefore, this study may be biased in its sampling procedure and we cannot rule out the possibility that individuals who perceived SCD were more inclined to agree to cognitive testing. However, variables in this study were collected prospectively according to the registry and the difference between excluded and included patients was not significant in demographical characteristics such as gender. In addition, we used brief screening tests (i.e., K-MMSE and K-MoCA) as cognitive measures. These were employed as it is difficult to recruit a substantial number of patients willing to undergo comprehensive neuropsychological tests in clinical settings. Although there were no group differences in any sub-items of both tests, more detailed cognitive tests may help reveal subtle cognitive characteristics that might not yet exceed age-, sex-, and education-adjusted normal ranges in migraineurs with SCD. Lastly, future studies should include a healthy control group to provide better standards for understanding migraineurs with SCD.