Adam E. Hansen

Evidence for a vascular factor in migraine

It has been suggested that migraine is caused by neural dysfunction without involvement of vasodilatation. Because dismissal of vascular mechanisms seemed premature, we examined diameter of extra‐ and intracranial vessels in migraine without aura patients.

Magnetic resonance angiography of intracranial and extracranial arteries in patients with spontaneous migraine without aura: a cross-sectional study

BACKGROUND Extracranial arterial dilatation has been hypothesised to be the cause of pain in patients who have migraine without aura. To test that hypothesis, we aimed to measure extracranial and intracranial arteries during attacks of migraine without aura. METHODS In this cross-sectional study, we recruited patients aged 18-60 years from the Danish Headache Centre and via announcements on a Danish website. We did magnetic resonance angiography during spontaneous unilateral migraine attacks. Primary endpoints were difference in circumference of extracranial and intracranial arterial segments comparing attack and attack-free days and the pain and the non-pain side. The extracranial arterial segments measured were the external carotid (ECA), the superficial temporal (STA), the middle meningeal (MMA), and the cervical part of the internal carotid (ICAcervical) arteries. The intracranial arterial segments were the cavernous (ICAcavernous) and cerebral (ICAcerebral) parts of the internal carotid, the middle cerebral (MCA), and the basilar (BA) arteries. This study is registered at Clinicaltrials.gov, number NCT01471314. FINDINGS Between Oct 12, 2010, and Feb 8, 2012, we recruited 78 patients, of whom 19 women had a scan during migraine and were included in the final analysis. On migraine compared with non-migraine days, we detected no statistically significant dilatation of the extracranial arteries on the pain side (ECA, mean difference 1·2% [95% CI -5·7 to 8·2] p=0·985, STA 3·6% [-3·7 to 11·0] p=0·532, MMA 1·7% [-1·7 to 5·2] p=0·341, and ICAcervical 2·3% [-0·3 to 4·9] p=0·093); the intracranial arteries were more dilated during attacks (MCA, 13·0% [6·4 to 19·6] p=0·001, ICAcerebral 11·5% [5·6 to 17·3] p=0·0004, and ICAcavernous 11·4% [5·3 to 17·5] p=0·001), except for the BA (1·6% [-2·7 to 5·9] p=0·621). Compared with the non-pain side, during attacks we detected dilatation on the pain side of the intracranial arteries (MCA, mean difference 10·5% [0·7-20·3] p=0·044, ICAcerebral (14·4% [4·6-24·1] p=0·013), and ICAcavernous (9·1% [3·9-14·4] p=0·003) but not of the extracranial arteries (ECA, 2·1% [-3·8 to 9·2] p=0·238, STA, 3·6% [-3·7 to 10·8] p=0·525, MMA, 2·7% [-1·3 to 5·6] p=0·531, and ICAcervical, 5·0% [-0·5 to 10·4] p=0·119). INTERPRETATION Migraine pain was not accompanied by extracranial arterial dilatation, and by only slight intracranial dilatation. Future migraine research should focus on the peripheral and central pain pathways rather than simple arterial dilatation. FUNDING University of Copenhagen, the Lundbeck Foundation, the Research Foundation of the Capital Region of Denmark, Danish Council for Independent Research-Medical Sciences, and the Novo Nordisk Foundation.

Measurement of brain perfusion, blood volume, and blood-brain barrier permeability, using dynamic contrast-enhanced T1-weighted MRI at 3 tesla

Assessment of vascular properties is essential to diagnosis and follow‐up and basic understanding of pathogenesis in brain tumors. In this study, a procedure is presented that allows concurrent estimation of cerebral perfusion, blood volume, and blood‐brain permeability from dynamic T1‐weighted imaging of a bolus of a paramagnetic contrast agent passing through the brain. The methods are applied in patients with brain tumors and in healthy subjects. Perfusion was estimated by model‐free deconvolution using Tikhonovs method (gray matter/white matter/tumor: 72 ± 16/30 ± 8/56 ± 45 mL/100 g/min); blood volume (6 ± 2/4 ± 1/7 ± 6 mL/100 g) and permeability (0.9 ± 0.4/0.8 ± 0.3/3 ± 5 mL/100 g/min) were estimated by using Patlaks method and a two‐compartment model. A corroboration of these results was achieved by using model simulation. In addition, it was possible to generate maps on a pixel‐by‐pixel basis of cerebral perfusion, cerebral blood volume, and blood‐brain barrier permeability. Magn Reson Med, 2009.

Combined PET/MR imaging in neurology: MR-based attenuation correction implies a strong spatial bias when ignoring bone☆

AIM Combined PET/MR systems have now become available for clinical use. Given the lack of integrated standard transmission (TX) sources in these systems, attenuation and scatter correction (AC) must be performed using the available MR-images. Since bone tissue cannot easily be accounted for during MR-AC, PET quantification can be biased, in particular, in the vicinity of the skull. Here, we assess PET quantification in PET/MR imaging of patients using phantoms and patient data. MATERIALS AND METHODS Nineteen patients referred to our clinic for a PET/CT exam as part of the diagnostic evaluation of suspected dementia were included in our study. The patients were injected with 200MBq [(18)F]FDG and imaged with PET/CT and PET/MR in random sequence within 1h. Both, PET/CT and PET/MR were performed as single-bed acquisitions without contrast administration. PET/CT and PET/MR data were reconstructed following CT-based and MR-based AC, respectively. MR-AC was performed based on: (A) standard Dixon-Water-Fat segmentation (DWFS), (B) DWFS with co-registered and segmented CT bone values superimposed, and (C) with co-registered full CT-based attenuation image. All PET images were reconstructed using AW-OSEM, with neither resolution recovery nor time-of-flight option employed. PET/CT (D) or PET/MR (A-C) images were decay-corrected to the start time of the first examination. PET images following AC were evaluated visually and quantitatively using 10 homeomorphic regions of interest drawn on a transaxial T1w-MR image traversing the central basal ganglia. We report the relative difference (%) of the mean ROI values for (A)-(C) in reference to PET/CT (D). In a separate phantom experiment a 2L plastic bottle was layered with approximately 12mm of Gypsum plaster to mimic skull bone. The phantom was imaged on PET/CT only and standard MR-AC was performed by replacing hyperdense CT attenuation values corresponding to bone (plaster) with attenuation values of water. PET image reconstruction was performed with CT-AC (D) and CT-AC using the modified CT images corresponding to MR-AC using DWFS (A). RESULTS PET activity values in patients following MR-AC (A) showed a substantial radial dependency when compared to PET/CT. In all patients cortical PET activity was lower than the activity in the central region of the brain (10-15%). When adding bone attenuation values to standard MR-AC (B and C) the radial gradient of PET activity values was removed. Further evaluation of PET/MR activity following MR-AC (A) relative to MR-AC (C) using the full CT for attenuation correction showed an underestimation of 25% in the cortical regions and 5-10% in the central regions of the brain. Observations in patients were replicated by observations from the phantom study. CONCLUSION Our phantom and patient data demonstrate a spatially varying bias of the PET activity in PET/MR images of the brain when bone tissue is not accounted for during attenuation correction. This has immediate implications for PET/MR imaging of the brain. Therefore, refinements to existing MR-AC methods or alternative strategies need to be found prior to adopting PET/MR imaging of the brain in clinical routine and research.

Bias and temperature dependence of the 0.7 conductance anomaly in quantum point contacts

The 0.7 (2e^2/h) conductance anomaly is studied in strongly confined, etched GaAs/GaAlAs quantum point contacts, by measuring the differential conductance as a function of source-drain and gate bias as well as a function of temperature. We investigate in detail how, for a given gate voltage, the differential conductance depends on the finite bias voltage and find a so-called self-gating effect, which we correct for. The 0.7 anomaly at zero bias is found to evolve smoothly into a conductance plateau at 0.85 (2e^2/h) at finite bias. Varying the gate voltage the transition between the 1.0 and the 0.85 (2e^2/h) plateaus occurs for definite bias voltages, which defines a gate voltage dependent energy difference

Dilation by CGRP of middle meningeal artery and reversal by sumatriptan in normal volunteers

\Delta

An SPM8-Based Approach for Attenuation Correction Combining Segmentation and Nonrigid Template Formation: Application to Simultaneous PET/MR Brain Imaging

. This energy difference is compared with the activation temperature T_a extracted from the experimentally observed activated behavior of the 0.7 anomaly at low bias. We find \Delta = k_B T_a which lends support to the idea that the conductance anomaly is due to transmission through two conduction channels, of which the one with its subband edge \Delta below the chemical potential becomes thermally depopulated as the temperature is increased.

Headache and prolonged dilatation of the middle meningeal artery by PACAP38 in healthy volunteers

Background: Calcitonin gene–related peptide (CGRP) plays a fundamental role in the pathophysiology of neurovascular headaches. CGRP infusion causes headache and dilation of cranial vessels. However, it is unknown to what extent CGRP-induced vasodilation contributes to immediate head pain and whether the migraine-specific abortive drug sumatriptan, a 5-hydroxytryptamine 1B/1D agonist, inhibits CGRP-induced immediate vasodilation and headache. Methods: We performed a double-blind, randomized, placebo-controlled, crossover study in 18 healthy volunteers. We recorded circumference changes of the middle meningeal artery (MMA) and middle cerebral artery (MCA) using magnetic resonance angiography before and after infusion (20 minutes) of 1.5 μg/min human αCGRP or placebo (isotonic saline) as well as after a 6-mg sumatriptan subcutaneous injection. Results: Compared with placebo, CGRP caused significant dilation of MMA (p = 0.006) and no dilation of MCA (p = 0.69). Sumatriptan caused a marked contraction of MMA (15%–25.2%) and marginal contraction of MCA (3.9% to 5.3%). Explorative analysis revealed that sumatriptan had a more selective action on MMA compared with MCA on the CGRP day (p < 0.0001) and on the placebo day (p = 0.007). Conclusion: These data suggest that exogenous CGRP dilates extracranial vessels and not intracranial, and that sumatriptan exerts part of its antinociceptive action by constricting MMA and not MCA. Classification of evidence: This study provides Class I evidence that IV GCRP causes dilation of the MMA but not the MCA in healthy volunteers, and that sumatriptan reverses the dilation of the MMA caused by CGRP.

Dynamic contrast-enhanced quantitative perfusion measurement of the brain using T1-weighted MRI at 3T.

We present an approach for head MR-based attenuation correction (AC) based on the Statistical Parametric Mapping 8 (SPM8) software, which combines segmentation- and atlas-based features to provide a robust technique to generate attenuation maps (μ maps) from MR data in integrated PET/MR scanners. Methods: Coregistered anatomic MR and CT images of 15 glioblastoma subjects were used to generate the templates. The MR images from these subjects were first segmented into 6 tissue classes (gray matter, white matter, cerebrospinal fluid, bone, soft tissue, and air), which were then nonrigidly coregistered using a diffeomorphic approach. A similar procedure was used to coregister the anatomic MR data for a new subject to the template. Finally, the CT-like images obtained by applying the inverse transformations were converted to linear attenuation coefficients to be used for AC of PET data. The method was validated on 16 new subjects with brain tumors (n = 12) or mild cognitive impairment (n = 4) who underwent CT and PET/MR scans. The μ maps and corresponding reconstructed PET images were compared with those obtained using the gold standard CT-based approach and the Dixon-based method available on the Biograph mMR scanner. Relative change (RC) images were generated in each case, and voxel- and region-of-interest–based analyses were performed. Results: The leave-one-out cross-validation analysis of the data from the 15 atlas-generation subjects showed small errors in brain linear attenuation coefficients (RC, 1.38% ± 4.52%) compared with the gold standard. Similar results (RC, 1.86% ± 4.06%) were obtained from the analysis of the atlas-validation datasets. The voxel- and region-of-interest–based analysis of the corresponding reconstructed PET images revealed quantification errors of 3.87% ± 5.0% and 2.74% ± 2.28%, respectively. The Dixon-based method performed substantially worse (the mean RC values were 13.0% ± 10.25% and 9.38% ± 4.97%, respectively). Areas closer to the skull showed the largest improvement. Conclusion: We have presented an SPM8-based approach for deriving the head μ map from MR data to be used for PET AC in integrated PET/MR scanners. Its implementation is straightforward and requires only the morphologic data acquired with a single MR sequence. The method is accurate and robust, combining the strengths of both segmentation- and atlas-based approaches while minimizing their drawbacks.

Cortical surface-based analysis reduces bias and variance in kinetic modeling of brain PET data.

Aim: To explore a possible relationship between vasodilatation and delayed headache we examined the effect of pituitary adenylate cyclase-activating polypeptide-38 (PACAP38) on the middle meningeal artery (MMA) and middle cerebral artery (MCA) using high resolution magnetic resonance angiography (MRA). Methods: In a double-blind, randomized, placebo-controlled study 14 healthy volunteers were scanned repeatedly after infusion (20 min) of 10 pmol/kg/min PACAP38 or placebo. In addition, four participants were scanned following subcutaneous sumatriptan (6 mg). Results: We found significant dilatation of the MMA (p = 0.00001), but not of the MCA (p = 0.50) after PACAP38. There was no change after placebo (p > 0.40). Vasodilatation (range 16–23%) lasted more than 5 h. Sumatriptan selectively contracted the MMA by 12.3% (p = 0.043). Conclusion: PACAP38-induced headache is associated with prolonged dilatation of the MMA but not of the MCA. Sumatriptan relieves headache in parallel with contraction of the MMA but not of the MCA.