Our findings show that a mindset towards anxiety, poor sleeping and catastrophizing is more commonly recognized in individuals with migraine than in healthy subjects. While each of these three conditions are associated to both EM and CM, the association with CM is undoubtedly more evident. In fact, scores of EM participants were in between those recognized in the healthy condition and in CM, thus suggesting a gradient distribution across the explored groups. It is important to highlight that the subjects included in our study were selected based on the lack of concomitant well-known psychiatric comorbidities according to the DSM (Diagnostic and Statistical Manual of Mental Disorders)-V [24]. This choice aimed at identifying a vulnerable psychological profile of individuals with migraine, even in the lack of diagnosed mental health disorders. In fact, while the association of migraine with specific major psychiatric diseases is well-recognized, less is known about the influence of individual psychosocial factors on the migraine brain of otherwise healthy subjects with a lower mental health resilience. Our study makes a step forward in identifying which behavioral and psychological factors may increase migraine vulnerability in individuals not showing any mental health issues. The domains explored in this study included the sleeping behavior, the affective dimension, the tendency to experience unknown outcomes as unacceptably threatening, the decision-making style and the tendency to pain catastrophizing. The finding that poor sleeping, anxiety feelings and catastrophizing thinking are more likely to be found in association with migraine prompts reflections on the connotation of migraine as a vulnerable brain state, that can be influenced by daily behavioral and psychosocial stressors. In the same venue, another study in a sample of patients with chronic migraine and affective temperamental dysregulation interestingly found a relationship between the degree of temperamental dysregulation and the presence of suicidal ideation, feelings of hopelessness and negative attitudes about the future, albeit in the absence of previous diagnosed psychiatric disorders [25]. This suggests a possible predictive value of affective temperamental dysregulation for migraine chronicization and patient’s clinical outcomes.

Although the influence of behavioral factors on migraine is not fully understood, a growing body of evidence suggests that the interaction of biological, sociocultural and psychological elements can influence the migraine’s characteristics. Migraine is a biological entity with underlying mechanisms targeted by symptomatic and preventive treatments that are constantly evolving and provide patients with ever better opportunities to manage the disease. However, for a significant minority of patients there is a limited benefit with pharmacotherapy alone [26]. A possible reason for this is the presence of specific psychological traits that, even in the absence of major psychiatric diseases, contribute to a vicious cycle where maladaptive behavior and migraine feed off each other [26]. This is in line with recent data suggesting that, although monoclonal antibodies targeting calcitonin gene-related peptide (CGRP) pathway are usually effective in difficult-to-treat patients, the presence of “anxious-fearful” personality together with current stressors and anxiety represent negative predictors of treatment outcome [27]. All these observations suggest that a purely biomedical model of migraine is not fully appropriate to understand the various aspects of the disease and to improve the quality of life of patients. A biopsychosocial model of migraine could pave the way for an alternative management approach, by guiding clinicians to combine pharmacological treatments, behavioral interventions, and stress management strategies to reduce migraine-related disability. Within this framework, non-pharmacological interventions have not to be considered alternative to standard headache care, but as an additional treatment option for all the patients.

Indeed, whether migraine precedes psychological changes or it is triggered and exacerbated by them is still debated: the two conditions certainly feed each other in a vicious circle that reduce the patient’s well-being, with a growing demand for drugs acting both at pain and at behavioral level. Moreover, the tendency of patients with migraine to experience poor sleep quality, greater anxiety sensitivity and pain catastrophizing, associated with feelings of hopelessness and rumination behaviors, suggests a reciprocal influence between migraine and behavioral changes.

Perceived stress has received particular attention as a trigger factor for headache both in episodic and chronic forms [28, 29]. Stress can be defined as an organism’s perception of and response to a perceived stressor [28, 29]. This includes how the body responds to perceived threats, challenges, or physical or psychological barriers, by activating the autonomic nervous system, especially through the hypothalamic-pituitary- adrenal (HPA) axis [29]. The individual response becomes dysfunctional when the stress pressure exceeds one’s perceived ability to cope with stress itself: this occurs when subjects have dysfunctional thoughts that feed a vicious feedback cycle potentially amplifying the pain related disability [29]. In physiologic conditions, when individuals experience a stressful event, the mechanism of allostasis usually induces self-limiting responses that revert to a normal baseline status when the individual withdraws from the external stress or challenge. When an hyperactivation of the allostatic system occurs, due to chronic stressors or underlying dysfunctional thoughts, a pathophysiologic response, named allostatic load or overload, interferes with the neuroendocrine, cardiovascular, immune, and metabolic homeostasis and results in pathophysiologic conditions associated with chronic diseases [29]. While allostasis contributes, together with other homeostatic mechanisms, to stress adaptation, the allostatic load represents the cumulative effect of chronic physiologic stress, which may be generated by internal processes or external factors. Internal processes include the tendency to develop anxiety feelings and catastrophizing thinking, while external factors are represented by chronic stressors or lifestyle habits such as poor sleep hygiene. Many studies suggest that an unfavorable allostatic load may contribute to the new onset of migraine, although a direct causal relationship with stress is still debated [28, 29]. Moreover, major stressful events, especially in vulnerable individuals, can be associated with migraine chronification, in a view of reciprocal influences between pain and behavioral dysfunctional states. Indeed, although stress is the most reported self-identified trigger for migraine, the sudden decline of perceived stress has also been reported as a precipitating factor for the onset of migraine attacks, especially with respect to “weekend”, “honey-moon” and “let-down” migraines [30,31,32]. These observations are in line with data from studies investigating the co-occurrence of migraine and psychopathological symptoms from young age onwards: children with primary headaches, especially with migraine, often have an association with sleep and behavioral disorders and about the half of adolescents with chronic daily headache presents with at least one psychiatric comorbidity, mostly major depression and panic disorder [33, 34]. Adolescents with migraine are more likely to develop a specific psychiatric disorder later in life as compared to adolescents without headache: therefore, specific attention is paid to the period of transition from adolescence to adulthood when a greater tendency to experience anxiety, sleep disorders and catastrophizing feelings can predispose to develop later psychiatric diseases [33, 34]. Non pharmacological interventions may be particularly useful at this age, when resilience‐training programs are more effective. In the adult age, anxiety, depression, post-traumatic stress disorder and sleep disorders are the most frequent comorbidities in subjects with primary headaches, acting as trigger for headache or as risk factors for chronicity [3, 35]. Specifically, anxiety in association with sleep-related disturbances may be a driver for migraine development and transformation due to shared pathophysiological pathways: a polymorphism in the 5-HT transporter gene and a specific dopamine D2 receptor genotype, an imbalance of serotonin neurotransmitters as well as a disproportion between pro-inflammatory and anti-inflammatory cytokines in the hypothalamic-pituitary adrenal axis may account for the simultaneous presence of these comorbidities [3, 35]. Moreover, neurofunctional data from 18 F-fluorodeoxyglucose positron emission tomography recently confirmed that CM patients have a decreased metabolism in prefrontal areas including frontal pole, superior and inferior frontal cortex as well as orbitofrontal areas, that are all structures associated with cognitive, affective, and sensory processing functions [36]. Prefrontal cortex is connected to limbic regions, which can regulate pain modulation in humans, especially in chronic pain conditions. This further endorses the possible bidirectional association between psychiatric disorders and migraine and the need of optimizing the pharmacological and non-pharmacological treatment of both [36].

Strengths of our study include the large sample, the rigorous selection of patients based on predefined criteria, and the comprehensive neuropsychological battery used for assessment. To limit the effect of confounders we included a highly selected sample. The choice to include women only was moved from the assumption that behavioral and psychological factors may operate differently in men and women, so analyzing them separately by gender is advisable. Moreover, we excluded patients beyond 65 years, as cognitive related issues in more advanced ages could have interfered with the proper compilation of the self-report neuropsychological battery. Finally, we excluded patients with medication overuse as commonly showing a more complex behavioral profile which requires separate assessment and analysis as objective for future research.

Limits of the study include the reduced generalizability of our findings to the whole population of migraineurs: in fact, while the use of rigorous criteria for enrolment represents for certain aspects a point of strength, the findings are not transferable to a broader group of people or situations, for instance men or older patients. The other limit is the adoption of a cross-sectional design which does not allow drawing conclusions about a causative relationship between the presence of specific behavioral traits and the development of migraine or its chronification: further longitudinal studies could allow investigating whether the presence of specific psychological traits and maladaptive behaviors really influences migraine progression and chronifications in a causal way. Moreover, self-reported measures may have some limits in evaluating psychosocial dimensions: once self-reported questionnaires have identified a vulnerable mindset for migraine, in-person interviews with the patient would be of help in orientating the overall management.

With these limits, our results suggest that behavioral and psychological factors, even in individuals without psychiatric comorbidities, are associated with the presence of migraine in general and of CM in particular. Further research is needed to address how behavioral and psychosocial issues “get under the skin” and trigger the vicious cycle potentially underlying migraine development and chronification.

Research in this area may have direct implications in clinical practice by providing patients with an integrated therapeutical approach characterized by a high degree of collaboration among different health professionals, also including psychologists. Pharmacotherapy alone is improbable to be paramount in managing migraine in a context of concomitant behavioral dysfunctions. Non-pharmacological treatments, such as acupuncture, electromyographical biofeedback, relaxation training, cognitive behavioral therapy or mindfulness-based approaches, would be essential to provide complementary treatment options enhancing the efficacy of ongoing pharmacologic interventions. Therefore, evidence on the role of psychological and behavioral factors on migraine clinical course needs to be integrated into innovative conceptual frameworks to better organize education and evidence-based clinical practices, in the view of a unified biopsychosocial approach to migraine care. This approach encompasses education and behavioral treatments as well as pharmacologic therapy and may contribute to improve the partnership with the patients and to reduce the burden of migraine, as well as the risk for medication overuse.