Neurogenetic And Hemodynamic Of Migraine Aura And Pfo (PFOCUS)

February 9, 2026 updated by: Azienda Usl di Bologna

Association Between PFO and Migraine With Aura: A Case-Control Observational Study With Genetic and Neurosonological Analysis

The PFOCUS Study aims to clarify the relationship between patent foramen ovale (PFO) and migraine with aura (MA). Patients diagnosed with MA according to ICHD-3 criteria will be classified as cases (PFO+) or controls (PFO-) based on the presence or absence of a right-to-left shunt detected by transcranial Doppler or a previously documented PFO. The study will enroll 240 adult participants over 36 months.

The primary objective is to determine whether genetic variants differ significantly between patients with MA with and without PFO. Secondary objectives include assessing cerebral blood flow regulation and platelet function in patients with MA with and without PFO.

Participants will undergo a single study visit including the collection of demographic and clinical data and a comprehensive neurosonological assessment. This will include microembolic signal counts, cerebrovascular reactivity testing, and a contrast-enhanced transcranial Doppler study for shunt detection. Blood samples will be collected for whole-exome sequencing (with a focus on NOTCH3 and an expanded gene panel) and for platelet aggregometry.

The study is expected to provide new insights into the biological mechanisms linking PFO and MA-potentially involving endothelial dysfunction, altered vascular smooth muscle responses, or platelet activation-thereby informing prevention strategies and guiding future research.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

The PFOCUS study is a prospective, case-control observational investigation designed to explore the biological, vascular, and genetic factors associated with the coexistence of migraine with aura (MA) and patent foramen ovale (PFO). Epidemiological evidence indicates that individuals with MA have an increased risk of ischemic stroke even in the absence of traditional vascular risk factors. In parallel, a higher prevalence of PFO has been consistently reported in patients with MA, suggesting a potential role of PFO as a modifier of cerebrovascular risk. The mechanisms underlying this association are not fully understood and may involve factors beyond paradoxical embolism, including vascular dysfunction, altered cerebral hemodynamics, platelet activation, and genetic susceptibility.

The primary objective of the study is to compare the distribution of NOTCH3 gene variants and single nucleotide polymorphisms (SNPs) between patients with MA and PFO (PFO+) and patients with MA without PFO (PFO-). NOTCH3 encodes a receptor involved in vascular smooth muscle cell differentiation and small-vessel integrity, and pathogenic variants are known to cause cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Variants in this gene have also been associated with migraine phenotypes and alterations in cerebral small-vessel function. Given the role of NOTCH signaling pathways in cardiac septation and closure of the fetal foramen ovale, genetic variation in this pathway may contribute to both MA susceptibility and persistence of PFO.

Secondary objectives include: (1) assessing variants and SNPs in additional genes involved in NOTCH signaling, cardiac development, vascular regulation, and PFO heritability; (2) evaluating the relationship between genetic variants and the degree of right-to-left shunt; (3) comparing microembolic signals (MES) between PFO+ and PFO- participants using automated transcranial Doppler detection; (4) assessing cerebrovascular reactivity (CVR) and dynamic cerebral autoregulation (dCA) using standardized neurosonological protocols; and (5) comparing platelet function profiles between groups.

Each participant will undergo a single study visit. Data collection will include a structured clinical and demographic assessment, detailed characterization of migraine phenotype (including aura characteristics, attack frequency, and coexistence of migraine without aura), and review of available brain magnetic resonance imaging (MRI) findings when available. The neurosonological assessment will include continuous transcranial Doppler monitoring for MES detection, evaluation of CVR using breath-hold and hyperventilation maneuvers, and assessment of cerebral autoregulation using transfer function analysis, as well as contrast-enhanced detection of right-to-left shunt using agitated saline. Peripheral blood samples will be collected for genetic analysis and platelet function testing. Whole-exome sequencing will be performed, with subsequent analyses focused on a predefined panel of genes, including but not limited to NOTCH3, NOTCH1, JAG1, and HTRA1. Platelet aggregation studies will be conducted using standardized laboratory methods.

The planned sample size is 240 participants, equally distributed between the PFO+ and PFO- groups. This sample size is based on the expected prevalence of NOTCH3 SNPs and the anticipated between-group differences. Statistical analyses will include comparisons of allele and genotype frequencies, assessment of Hardy-Weinberg equilibrium, linkage disequilibrium analyses, and multivariable comparisons of neurosonological and platelet function parameters.

By integrating genetic, neurosonological, and hematological data, the PFOCUS study aims to characterize potential biological differences between patients with MA with and without PFO and to contribute to a better understanding of migraine-related vascular vulnerability.

Study Type

Observational

Enrollment (Estimated)

240

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Sampling Method

Non-Probability Sample

Study Population

primary care clinic

Description

Inclusion Criteria:

  • Diagnosis of migraine with aura (according to Chapter 1.2 of the International Classification of Headache Disorders, 3rd edition [ICHD-3])
  • Age ≥ 18 years
  • Both sexes
  • Obtained written informed consent to participate in the study

Exclusion Criteria:

  • History of congenital heart disease

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

Cohorts and Interventions

Group / Cohort
Intervention / Treatment
Arm 1
Patients with migraine with aura who have a patent foramen ovale (MAPFO+)
Other: Intervention
Neurosonological protocol with continuous Doppler monitoring for microemboli detection, cerebrovascular reactivity and dynamic cerebral autoregulation testing, and a contrast-enhanced shunt study using agitated saline; blood samples for whole-exome sequencing and platelet aggregation studies.
Arm 2
Patients with migraine with aura without patent foramen ovale (MAPFO-)
Other: Intervention
Neurosonological protocol with continuous Doppler monitoring for microemboli detection, cerebrovascular reactivity and dynamic cerebral autoregulation testing, and a contrast-enhanced shunt study using agitated saline; blood samples for whole-exome sequencing and platelet aggregation studies.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Comparison of number of NOTCH3 genetic variants
Time Frame: T0 (day 1)
To evaluate whether significant differences exist in the frequency of NOTCH3 genetic variants between patients with migraine with aura who have a patent foramen ovale (PFO+) and those without (PFO-). Min=0, max undefined.
T0 (day 1)

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Correlation of genetic variants with shunt size
Time Frame: T0 (day 1)
To assess whether the frequency of detected variants and SNPs correlates with the size of the right-to-left shunt in the PFO+ group (present vs absent).
T0 (day 1)
Comparison in number of spontaneous microeboli
Time Frame: T0 (day 1)
To evaluate differences in the number of cerebral microemboli between PFO+ and PFO- patients. Min=0, max undefined.
T0 (day 1)
Comparison in cerebrovascular reactivity between PFO+ and PFO- patients
Time Frame: T0 (day 1)
Evaluation of phase shift, gain and coherence for very low, low and high frequency obtained from Transfer function analysis (significant group difference: yes vs no)
T0 (day 1)
Differences in platelet function profiles between PFO+ and PFO- patients
Time Frame: T0 (day 1)
Evaluation of ASPI-test and ADP-test values obtained from Multiplate® analyzer (significant group difference: yes vs no)
T0 (day 1)
Comparison of number of genetic variants in other selected genes
Time Frame: T0 (day 1)
To evaluate whether significant differences exist in the frequency of genetic variants in other selected genes between patients with migraine with aura who have a patent foramen ovale (PFO+) and those without (PFO-). Min=0, max undefined.
T0 (day 1)

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Azienda Usl di Bologna

Investigators

  • Principal Investigator: Matteo Paolucci, IRCCS Istituto delle Scienze Neurologiche di Bologna

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

November 24, 2025

Primary Completion (Actual)

November 24, 2025

Study Completion (Estimated)

November 1, 2028

Study Registration Dates

First Submitted

January 9, 2026

First Submitted That Met QC Criteria

January 9, 2026

First Posted (Actual)

January 16, 2026

Study Record Updates

Last Update Posted (Actual)

February 11, 2026

Last Update Submitted That Met QC Criteria

February 9, 2026

Last Verified

February 1, 2026

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • PFOCUS

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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