Background
Migraine is one of the most common pain disorders with a prevalence of 5-20 % in the general population [
1], higher in women than in men (with an average prevalence of 20.2 % versus 9.4 %) [
2]. Until now, the relationship between migraine and cognitive deficits has been investigated by several cross-sectional studies providing divergent results (for a review see 3). Indeed, some studies did not find any cognitive difference between migraine patients and non-migraine subjects [
4‐
7]. Conversely, other studies revealed that migraine patients are characterized by a poorer cognitive performance [
8‐
15] during both interictal [
11‐
13] or ictal [
16,
17] phases when compared to HCs. In particular, it has been suggested that migraine patients might show selective defects in executive/attention and visuospatial domains [
9,
11,
13‐
15].
The discrepancies among studies assessing cognitive functions in migraine may be ascribed to several reasons, possibly related to differences in patients’ characteristics (some studies enrolled both patients with or without aura), sample sizes or neuropsychological assessments [
3]. Moreover, some studies did not control the possible influence of clinical variables, such as frequency of attacks, or relationship with pharmacological treatment. In fact, no neuropsychological study specified the role of pharmacological treatment even though some treatments for migraine (e.g., topiramate, amytriptiline) have been associated with cognitive dysfunctions [
18,
19]. Last, only a few studies took into account the possible relationships between cognitive performances and associated psychological symptoms or behavioural disturbances, which may often occur in migraine patients [
20]. Migraine patients may also present affective temperamental dysregulation, with high hopelessness that may be considered a significant risk factor for negative outcome [
21]. Among behavioural disturbances, apathy appears not only as a symptom of depression but as a specific behavioural disturbance [
22], with its neural (i.e. abnormalities of prefrontal cortex) and cognitive correlates (i.e. impaired executive/attention and visuospatial abilities) [
23,
24]. Since previous neuroimaging studies revealed reduced functional connectivity in the fronto-parietal network in MwoA patients [
25], and apathy is associated mainly with abnormalities of prefrontal cortex, it is possible that apathy in itself, not associated with clinically relevant depression, can occur in MwoA. Nonetheless, until now no study specifically assessed apathy, i.e. a loss of interest and motivation [
22], in MwoA.
On the basis of the above considerations, the present study aimed at investigating the cognitive profile in a homogeneous sample of drug-naïve migraine without aura (MwoA) patients, using the Montreal Cognitive Assessment (MoCA) [
26], a widely available screening tool, easy to use in clinical practice. Due to its sensitivity to executive/attention and visuospatial impairments, MoCA seems particularly suitable as a neuropsychological assessment tool in migraine patients, who might show selective defects in such cognitive domains [
9,
11,
13‐
15]. Moreover, we investigated possible relationships between cognitive performances and psychological symptoms such as depression, anxiety and apathy. Finally, we compared neuropsychological and psychological pattern in these patients with those of a group of healthy controls (HCs) matched for age and educational level to patients.
Discussion
The present study revealed that MwoA patients had significantly lower scores than HCs on the total MoCA scale and in 4 out of 6 cognitive subdomains in all subscores (i.e., executive function, attention, visuospatial and memory domains). However, no MwoA patients achieved scores below the available cut-off values, thus suggesting that the reduced efficiency in selected cognitive domains did not correspond to a clinically relevant cognitive deterioration.
As for the psychological profile, MwoA patients and HCs reported similar scores for depression (BDI-II), trait and state anxiety (STAI-Y-1 and STAI-Y-2), and apathy (AES-S). Cognitive scores in MwoA patients were not found to be associated with severity of psychological disturbances, whereas depression, trait and state anxiety and apathy were associated among them.
Our first main finding demonstrated the occurrence of cognitive dysfunctions in MwoA patients who had never taken anti-migraine preventive drugs in the course of their life with respect to HCs. In particular, our results revealed lower scores in the subscales assessing verbal memory, attention, frontal and visuospatial functions, in line with several previous studies [
8‐
15]. The low score on the memory scale (i.e., poor retrieval abilities) might be ascribed to defective strategic and organizational aspects of learning [
9], also in consideration of the lower attentional and executive function scores in MwoA patients compared to HCs. However, previous studies evaluating migraine patients in the community did not find differences between MwoA patients and HCs [
4‐
6]. The divergence between those studies and ours might be ascribed to the different patient selection procedures: in those studies MwoA patients were selected from a cohort of subjects (i.e., population-based register) on the basis of self-report measures. This procedure might have led to a misclassification of the non-migraine subjects, as suggested by Elkind and Scher [
34], and to the enrolment of individuals with very mild migraine, in terms of frequency and intensity of attacks. Instead, we performed a study in a clinical setting where MwoA patients, identified by expert neurologists according to established clinical criteria, required medical intervention due to migraine and related disability. However, our results underlined that MwoA patients’ scores were not lower than the cut-off value reported in normative studies [
25,
35]. We can, thus, suggest that MwoA patients with migraine symptoms needing medical consultations show “sub-clinical” neuropsychological impairments mainly affecting executive functions, i.e. a reduced efficiency of cognitive processes in the lack of clinically relevant cognitive deterioration.
Such cognitive results would be compatible with recent findings showing reduced functional connectivity in the fronto-parietal network even in migraineurs without overt executive dysfunctions, i.e. with scores on executive tests above the normal cut-off values [
25]. It is also worth mentioning that in MwoA patients reduced connectivity in prefrontal and temporal regions of the default mode network [
35], in the absence of structural abnormalities, thus suggesting that brain areas involved in executive control may show signs of dysfunction even before development of clinically detectable cognitive impairments.
In the present study we found no significant difference on severity of depression, apathy, and state and trait anxiety in MwoA patients compared to HCs. Prevalence of depression and anxiety was lower than that reported in previous studies in which depression, anxiety disorders and migraine were considered to be comorbid diseases [
20]. Moreover, where previous study revealed a relationship between depression and migraine [
36], we failed to find any association; the divergence among other studies and ours might depend on difference in inclusion and exclusion criterion and on employment of different tools to assess depression. However, our observation is in line with an epidemiological study supporting the idea that psychiatric comorbidity occurs less frequently in MwoA than in migraine with aura [
37] or probable medication-overuse headache [
38].
Clinically significant apathy occurred in 8 patients only (11 %), and we did not observe significant differences on apathy scale (AES-S) between patients and HCs. Although the finding of mild frontal/executive dysfunction in our patient sample might predict a higher frequency of apathy [
23], it must be considered that we enrolled relatively young individuals and that apathy is thought to increase with age [
39]. Since this is the first study assessing apathy in MwoA patients, we believe that this issue deserves further cross-sectional and longitudinal investigation in MwA and MwoA patients, who are both characterised by functional abnormalities in prefrontal cortex [
25,
35].
Moreover, future studies in large samples of controls and migraineurs should investigate whether psychological disturbance modify the effect of migraine on cognitive impairment.
In the present study, several clinical aspects of migraine (pain intensity, disease duration, and frequency of attack) did not influence cognitive performance on MoCA. The lack of significant relationships between frequency of migraine attacks and cognitive performance is in agreement with most previous studies [
10,
11], as is the lack of a significant correlation between disease duration and cognitive dysfunctions [
9,
11], thus supporting the hypothesis that subtle alterations in information processing mechanisms might be present also in the early stages of migraine [
11]. Finally, among clinical aspects of migraine, we found that high levels of attack related disability were associated with reduced executive functioning as assessed by the MoCA executive subscore. This result may lend support to the idea that some aspects of cognitive dysfunction are relevant contributors to migraine attack-related disability [
16].
Taken together, our findings suggest that MwoA is associated with cognitive dysfunctions and in particular, that altered executive functioning can be related to high migraine related disability. Thus, these results underscore the importance of a careful evaluation of cognitive function even with a screening tool, provided that sensitive to detect dysfunctions of attention, memory, visuospatial and executive domains, as the MoCA is. Moreover, no correlation between scales assessing neuropsychiatric symptoms and cognitive tests suggests that the poorer cognitive performance exhibited by MwoA patients was not conditioned by the emotional variables such as depression, apathy or anxiety, differently from what reported in other neurological diseases [
23,
40].
Our study had several strengths and limitations. The inclusion of a sample of patients homogeneous for type of migraine (all MwoA patients) and drug-naïve for preventive pharmacological therapies can be considered as strength of the study, suggesting that cognitive dysfunctions can occur in the natural history of MwoA, independently from preventive migraine therapies. As a consequence, these data could be considered important to better understand the MwoA clinical spectrum. However, the cross-sectional nature of our study did not allow us to ascertain whether the mild cognitive impairments we could detect here are amenable to changes related to pharmacological treatment, and can herald clinically relevant cognitive impairments. Our patient group was a convenience sample of treatment seeking migraine suffers and thus, may represent a limitation about generalizability of the findings. Furthermore, our sample was composed mainly of women as migraine is strongly related to gender, but this might also limit the generalizability of the results. Furthermore, we could not evaluate whether pain prevalence on either side of the head may be associated with different cognitive profiles, because most of our patients had no preferred side for pain. This issue deserved to be explored in further studies including balanced groups of patients with unilateral side of pain. Finally, in the present paper we only aimed at obtaining a screening of general cognitive functioning, and for this purpose we adopted a relatively recent tool, i.e. MoCA, which has been developed to obtain an estimation of several cognitive domains, including those (such as executive functions) that are often overlooked in more common screening tools. The MoCA cannot be used as a diagnostic instrument, but to screen cognitive status of patients attending a migraine ambulatory and to provide a baseline assessment, which could be compared to future assessments.
The cut-off score used in our study refers to age- and adjusted-scores and not to raw scores, and it is specifically foreseen by the available Italian normative study. The cut-off value is clearly lower than that reported in the original study based on a sample of 90 healthy Canadian controls (mean age 72.84 ± 7.03 years; mean education 13.33 ± 3.40), using a one-point correction for education (12 years). However, several factors likely contribute to this discrepancy such as: i) reference to age- and education-adjusted scores and not to raw scores; ii) use of population-based normative sample instead of convenience sample, as in the original study (note that even in English speaking countries population-based normative studies provided lower cut-off values than that proposed in the original study [
41]; iii) cultural and linguistic biases related to translations of the test in different languages (as in Portuguese [
42] and Japan language [
43]. For this reasons it has been clearly stated that appropriate MoCA normative data have to be employed when interpreting MoCA scores [
41]. It is also interesting to note that the cut-off value of 15.5 for age- and education-adjusted scores did not identify any control or migraineurs participant as affected by cognitive impairment, whereas applying the cut-off score of 26 cognitive impairment would be present in 68/72 (94.4 %) MwoA patients and in 44/72 (61.1 %) controls. Such percentages appear to be implausibly high in two samples of home-dwelling and active young adults, thus further reinforcing the need for cut-off points based upon country-specific normative data.