Ultra-high field MR angiography in human migraine models: a 3.0 T/7.0 T comparison study

We recruited healthy volunteers through a Danish recruitment website (www.​forsoegsperson.​dk). Participants were offered enrollment in this 7.0 T continuation study upon completion of the prior 3.0 T study, results of which have been published elsewhere [7]. Both men and women were eligible for inclusion if they were between 18 and 50 years of age, weighed 50 to 100 kg and had successfully completed the 3.0 T part of the parent study. Exclusion criteria were a history of somatic and/or psychiatric disease any primary headache disorder, other than infrequent episodes of tension type headache (less than 2 days/month), having first-degree relatives with migraine, being pregnant or breastfeeding, use of daily medication, other than oral contraceptives and not using safe contraceptive methods. Furthermore, volunteers were excluded if there were contraindications for MRI scans (i.e. ferromagnetic implants, recent surgical procedures, claustrophobia, etc.) or any other condition deemed by the investigator to be incompatible with participation. Participants provided written informed consent in accordance with the declaration of Helsinki and the study was approved by the Ethics committee of the Capital Region of Denmark (H-15019063) along with the Danish Medicines Agency (CIV-16-12-017964). The study is part of a parent study, which is registered at ClinicalTrials.​gov (NCT03143465) and other parts of the study have been or will be published elsewhere.

Participants were allocated to receive CGRP, sildenafil and placebo in random order on three separate study days. Drug administration was preceded by a 7.0 T MRA and succeeded by two additional scans at 30 min and 120 min post-administration. On each day, participants would receive an i.v. infusion of isotonic saline or CGRP as well as an oral administration of 100 mg sildenafil or placebo, where the combination was dependent on randomization (placebo+CGRP/sildenafil+placebo/placebo+placebo). This design was a replica of the previous 3.0 T study which all participants had previously completed at Rigshospitalet Glostrup, resulting in paired observations between 3.0 T and 7.0 T.

Participants arrived at the Danish Research Centre for Magnetic Resonance headache-free on the morning of each study day. They were required to avoid intake of any medication (other than oral contraceptives), coffee, tea, cocoa, other caffeinated beverages and methylxanthine-containing food 12 h before the first scan and to fast 4 h before commencing the experiment. After arrival, a peripheral venous catheter was placed in a cubital vein and participants were placed in the scanner. They were instructed to stay awake during the recordings.

MR angiography scans were obtained at baseline (T_Baseline) followed by drug administration at T₀ and two additional MRI scans at T₃₀ and T₁₂₀. Participants were monitored with an Expression In Vivo monitor (Philips Medical, Orlando, FL, USA) continuously, regarding blood pressure, heart rate, end-tidal CO₂, respiratory rate and pulse oximetry every 10 min following drug administration. A standardized headache questionnaire was used to evaluate any headache-related symptoms for the duration of the study where pain was scored on a numerical rating scale (NRS) from 0 (no pain) to 10 (maximum imaginable pain).

The acquisition of the 3.0 T scans used for comparisons in this study are described in detail elsewhere [7]. The 3.0 T MRI scans were performed on a Philips Achieva dStream Scanner (Philips Medical Systems, Netherlands) using a 32-channel phased-array head coil. A three-dimensional time-of-flight (TOF) MRA was conducted with the following parameters:

Field of view 200 × 200 × 36.75 mm³, acquired matrix size 800 × 570, acquired voxel resolution 0.25 × 0.35 × 0.70 mm³, reconstructed voxel resolution 0.20 × 0.20 × 0.35 mm³, TR 23 milliseconds, TE 3.5 milliseconds, flip angle 18°, SENSE p reduction 2.5, 3 chunks, duration 13 min 06 s.

The 7.0 T MRI scans were performed on a 7.0 T Philips Achieva Scanner (Philips Medical Systems, Netherlands) using a two-channel volume transmit head coil with 32-channel receiver array (Nova Medical, Inc., Burlington, MA, US). Again, a three-dimensional TOF MRA sequence was used with the following parameters:

Field of view 200 × 190.4 × 32.4 mm³, acquired matrix size 668 × 636, acquired voxel resolution 0.3 × 0.3 × 0.3 mm³, reconstructed voxel resolution 0.15 × 0.15 × 0.15 mm³, TR 19 milliseconds, TE 2.6 milliseconds, flip angle 30°, SENSE p reduction 4.5, 3 chunks, duration 9 min 58 s.

High-dielectric permittivity pads were placed over the temporomandibular joint to improve image quality at the base of the skull, where intradural segments of the MMA is located [9].

MR angiography data was transferred to a separate work station in the DICOM format and analyzed using LKEB QMra, and the updated LKEB LAVA vessel contour detection software [10, 11]. The software allows the user to pinpoint start- and endpoint of vessels for contour analysis, propagates a center line through the vessel and provides circumference slices perpendicular to this line along the chosen segment. If slices were distorted, noisy or otherwise immeasurable, they were discarded. The user made sure to select the same segments within each subject between scans to provide reliable measurements of change over time. We analyzed the intradural segment of MMA, identified as the innermost part covered by the field of view, approximately 20 mm after MMA enters the skull through the foramen spinosum. Ultimately, a 5 mm segment is chosen comprising up to 34 slices and the mean and standard deviation is computed for that segment at that time point. 7.0 T MRA resolution required us to use updated contour detection software (LAVA), which was not used in the original study, causing us to reanalyze the previous data using the new software post hoc. To further explore the potential effect of the resolution on 7.0 T, we resampled the 7.0 T data, decreasing the resolution, to mimic the original 3.0 T scans. Both QMra and LAVA analyses are reported, and the software change was factored into analyses (see below). All analyses of 3.0 T and 7.0 T scans were performed on the same workstation by CEC.

Our primary endpoint was difference in SDs of vessel segment measurements in intradural MMA at 3.0 T vs. 7.0 T within subject, within drug, within time point providing us with a maximum of 5_subjects x 3_days x 3_times x 2_sides = 90 paired observations. Vessel segment standard deviation was analyzed with a linear mixed effects model with scanner and contour detection software as fixed effects and subject, drug and time point as random effects. Secondary analyses on drug effect on circumference over time were performed descriptively as percentage change from baseline and using Bland-Altman agreement statistics between scanners [12].

We tested standard deviations along vessel segments in randomized, double-blind, placebo-controlled fashion using the same subjects on the two different systems resulting in quite strong paired comparisons. Furthermore, contour detection is a semi-automated procedure with minimal operator influence [15]. A central limitation is the time between 3.0 T and 7.0 T scans with a median of 476 days between them.