Chronic migraine is a disabling neurovascular disorder and one of the leading causes of years lived with disability worldwide. Population-based studies report a worrying level of resistance to currently available treatments in clinical practice. For this reason, the clinical and scientific community is increasingly investigating new therapeutic approaches aimed at reducing the burden of symptoms and improving patients' quality of life.

Among the alternative therapeutic approaches explored in migraine research, the placebo effect has emerged as a potentially important mechanism. However, the duration and intensity of its beneficial effects on migraine symptoms are still poorly understood. In particular, there is a need to identify biological and clinical markers that may predict which patients are more likely to benefit from placebo-related mechanisms.

One of the most promising factors is suggestibility, namely the tendency of an individual to respond to suggestions, expectations, or contextual influences. It is possible that patients with non-responsive chronic migraine may show different levels of suggestibility, which could influence the effectiveness of placebo-related responses.

To investigate this hypothesis, it is first necessary to better understand the psychobiological characteristics of patients with non-responsive chronic migraine (NRCM). Therefore, the primary aim of this monocentric observational study is to characterize the neurobiological and psychological profile of individuals affected by NRCM through advanced magnetic resonance imaging techniques (connectomics) and a comprehensive battery of psychodiagnostic assessments, including the evaluation of suggestibility.

The study plans to recruit at least 100 patients with NRCM and 100 healthy control subjects matched for age and sex. By comparing participants with high and low levels of suggestibility, the study aims to identify new neurobiological profiles (bio-phenotypes) associated with these characteristics. These findings may contribute to future research on the placebo effect and help develop more personalized treatment strategies for patients with chronic migraine who do not respond to conventional therapies.

Inclusion Criteria for Non-Responsive Chronic Migraine subjects:

• adults aged ≥ 18 years and ≤ 75 years;
• diagnosis of non-responsive chronic migraine (NRCM) according to ICHD-3 beta criteria;
• presence of at least 8 migraine days per month associated with disability (MIDAS ≥ 11), and insufficient response after 6 weeks or inability to tolerate at least three previously prescribed migraine preventive agents, i.e., resistance to standard therapy for at least 6 weeks;
• signed informed consent.

Inclusion Criteria for healthy subjects are:

• adults aged ≥ 18 years and not older than 75 years;
• absence of a diagnosis of NRCM according to ICHD3beta or other relevant -neurological disorders as assessed during the medical history taken at the headache center;
• signed informed consent.

Exclusion Criteria:

• older than 75 years;
• children
• pregnant or breastfeeding women;
• history of alcohol or substance abuse;
• affected by concomitant neurological, cardiovascular, or cerebrovascular diseases;
• liver disease or kidney disease;
• psychiatric disorders (psychosis, major depression, bipolar disorder).
• diagnosis or history of migraine (for healthy subjects).

The study population consists of patients with non-responsive chronic migraine ( NRCM ) attending the Headache Centre of the "Pugliese-Ciaccio" Hospital in Catanzaro, Italy. In parallel, healthy control subjects matched for age and sex will be recruited from the general population, residing in or domiciled in the Calabria region, through institutional advertisements and communications from the Headache and Adaptive Disorders Centre of the same hospital. All participants will undergo clinical screening and, if eligible, will be further assessed at the clinical and neuroimaging facilities involved in the study, including the neuroimaging unit of the IBSBC-CNR located at the "Mater Domini" Hospital in Catanzaro, Italy.