Electroencephalogram (EEG) is widely available as a powerful mean to non-invasively study
brain connectivity features in migraine patients. High density EEG, by means of a minimum of
64 up to 256 electrodes, enables to record electrical brain activity with high spatial
resolution. Through the analysis of brain oscillations across different frequency bands (from
alpha to delta), it can evaluate sensory, pain processing and information integration,
contributing to a better definition of baseline features and to detect potential markers or
predictors for therapeutic interventions in an era addressed to precision medicine.
Previous neurophysiological studies focused on EEG and to assess functional connectivity or
spectral analysis in migraine patients. Conventional studies found higher slow wave activity
(predominantly theta) in the interictal phase and higher excitability in the visual cortex
during visual aura.
In 2016 a resting state study showed a predominance of low frequency bands in the ictal
phase. The interictal and ictal phases patients also presented a diffuse lower coherence,
suggesting low functional connectivity. Furthermore, an altered spatial connectivity for
lower alpha-band activities was found in the interictal phases during sensory stimulation by
means of HD-EEG, suggesting a thalamocortical dysrhythmia.
Nowadays, targeted preventive migraine therapies are available, namely monoclonal antibodies
directed against the Calcitonin Gene Related Peptide (CGRP) pathway (mAbs). They demonstrated
high efficacy and tolerability in both chronic and episodic migraine. Despite their
peripheral site of action (outside of the blood brain barrier), the resulting action may take
place at central level or determine clinical modifications leading to a functional modulation
of several brain areas.
The primary aim of the study is to evaluate changes in functional connectivity in patients
undergoing preventive mAbs treatment using HD- EEG and eventual connectivity differences
between Responders and Non-Responders.
Study design:
Patients will undergo visits planned at baseline (T0) and quarterly (T3-T6) during which
clinical data is collected and an HD-EEG is performed. Healthy controls will undergo EEG
registration once.
HD-EEG registration:
The investigators will randomly acquire 4 recordings (6 minutes each) in resting-state
condition, 2 with opened eyes, and 2 with closed eyes.
Resting state FC will be analyzed among six resting state networks (Default mode network,
Dorsal attention network, Ventral attention network, Language network , Somatomotor network
and Visual network) in the following frequency bands: alfa 8-12 Hz, beta 13-30 Hz, gamma
31-80 Hz, theta 4-7 Hz. delta 1-3 Hz.
Acquisition parameters will be: High-Pass: 0.5 Hz; Low-Pass: 100 Hz; Notch: 50 Hz. For
analysis of HD-EEG data, the investigators will use a tailored analysis pipe-line that was
previously developed and validated to reconstruct neural sources from cortical/subcortical
gray matter. EEG signals will be band-pass filtered (1-80 Hz) and down-sampled at 250 Hz.
Biological artifacts will be rejected using Independent Component Analysis (ICA). EEG signals
will be referenced with a customized version of the Reference Electrode Standardization
Technique (REST). A matrix will estimate the relationship between the measured scalp
potentials and the dipoles corresponding to brain sources. Sources reconstruction will be
performed with the exact low-resolution brain electromagnetic tomography (eLORETA) algorithm
Statistical plan:
The sample size was computed with the freeware online platform www.openepi.com. As few
studies focused on functional connectivity evaluation in migraine, with no studies analyzing
longitudinal changes during a specific treatment, the sample size analysis was based on the
work of Bjork. The investigators thus considered as clinically meaningful a difference
between groups in the theta relative power band equal to 0.04 (±0.04). Considering a
two-tailed t-test for the comparison with confidence interval 95%; power: 80%, the minimum
suggested sample size was 20 subjects for CM group and 20 subjects for HFEM group.
A preliminary normality analysis will be performed to decide whether to use parametric or
non-parametric methods, through Shapiro Wilk test.
Numerical variables will be described as mean and standard deviation (or median and quartiles
if appropriate), categorical variables as raw numbers and percentages.
Functional connectivity analyses will be conducted for separate bands and eyes closed
registration.