End-to-end volumetric segmentation of white matter hyperintensities using deep learning.

BACKGROUND AND OBJECTIVES: Reliable detection of white matter hyperintensities (WMH) is crucial for studying the impact of diffuse white-matter pathology on brain health and monitoring changes in WMH load over time. However, manual annotation of 3D high-dimensional neuroimages is laborious and can be prone to biases and errors in the annotation procedure. In this study, we evaluate the performance of deep learning (DL) segmentation tools and propose a novel volumetric segmentation model incorporating self-attention via a transformer-based architecture. Ultimately, we aim to evaluate diverse factors that influence WMH segmentation, aiming for a comprehensive analysis of the state-of-the-art algorithms in a broader context. METHODS: We trained state-of-the-art DL algorithms, and incorporated advanced attention mechanisms, using structural fluid-attenuated inversion recovery (FLAIR) image acquisitions. The anatomical MRI data utilized for model training was obtained from healthy individuals aged 62-70 years in the Live active Successful Aging (LISA) project. Given the potential sparsity of lesion volume among healthy aging individuals, we explored the impact of incorporating a weighted loss function and ensemble models. To assess the generalizability of the studied DL models, we applied the trained algorithm to an independent subset of data sourced from the MICCAI WMH challenge (MWSC). Notably, this subset had vastly different acquisition parameters compared to the LISA dataset used for training. RESULTS: Consistently, DL approaches exhibited commendable segmentation performance, achieving the level of inter-rater agreement comparable to expert performance, ensuring superior quality segmentation outcomes. On the out of sample dataset, the ensemble models exhibited the most outstanding performance. CONCLUSIONS: DL methods generally surpassed conventional approaches in our study. While all DL methods performed comparably, incorporating attention mechanisms could prove advantageous in future applications with a wider availability of training data. As expected, our experiments indicate that the use of ensemble-based models enables the superior generalization in out-of-distribution settings. We believe that introducing DL methods in the WHM annotation workflow in heathy aging cohorts is promising, not only for reducing the annotation time required, but also for eventually improving accuracy and robustness via incorporating the automatic segmentations in the evaluation procedure.

X-linked creatine transporter (SLC6A8) deficiency in females: Difficult to recognize, but a potentially treatable disease.

Creatine transporter deficiency (CTD), caused by pathogenic variants in SLC6A8, is the second most common cause of X-linked intellectual disability. Symptoms include intellectual disability, epilepsy, and behavioral disorders and are caused by reduced cerebral creatine levels. Targeted treatment with oral supplementation is available, however the treatment efficacy is still being investigated. There are clinical and theoretical indications that heterozygous females with CTD respond better to supplementation treatment than hemizygous males. Unfortunately, heterozygous females with CTD often have more subtle and uncharacteristic clinical and biochemical phenotypes, rendering diagnosis more difficult. We report a new female case who presented with learning disabilities and seizures. After determining the diagnosis with molecular genetic testing confirmed by proton magnetic resonance spectroscopy (1H-MRS), the patient was treated with supplementation treatment including creatine, arginine, and glycine. After 28 months of treatment, the patient showed prominent clinical improvement and increased creatine levels in the brain. Furthermore, we provide a review of the 32 female cases reported in the current literature including a description of phenotypes, genotypes, diagnostic approaches, and effects of supplementation treatment. Based on this, we find that supplementation treatment should be tested in heterozygous female patients with CTD, and a prospective treatment underlines the importance of diagnosing these patients. The diagnosis should be suspected in a broad clinical spectrum of female patients and can only be made by molecular genetic testing. 1H-MRS of cerebral creatine levels is essential for establishing the diagnosis in females, and especially valuable when assessing variants of unknown significance.

Hepatic Fibrosis Evaluated in Patients with Type 2 Diabetes with and without Chronic Kidney Disease.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD), and particularly liver fibrosis, has been suggested as a risk factor of chronic kidney disease (CKD). Given that NAFLD affects every fourth person globally, better insight is needed. Our aim was to investigate the association between hepatic fibrosis and CKD in patients with type 2 diabetes and to compare different methods for diagnosing liver fibrosis in this study population. METHODS: Cross-sectional study including patients with type 2 diabetes with CKD stages 3-5 (N = 50) or without CKD (N = 50). CKD was defined as estimated glomerular filtration rate <60 mL/min/1.73 m2 with or without proteinuria. Three methods were used to detect significant liver fibrosis defined as either ≥8 kilopascal measured by transient elastography (FibroScan®), fibrosis-4 (FIB-4) score ≥2.67, or NAFLD fibrosis score (NFS) >0.675. RESULTS: Significant liver fibrosis was found in 38% and 28% of the patients with and without CKD, respectively, using at least one of the three methods. Both FIB-4 score and NFS were significantly higher in patients with CKD (p < 0.0009 and p < 0.0001, respectively), although insignificant after adjustments for age, sex, body mass index, and duration of diabetes. In patients without CKD, a significant association between steatosis and fibrosis was observed (p = 0.0007). CONCLUSION: Our data do not support any strong independent association between liver fibrosis and established CKD as assessed by FibroScan, FIB-4 score, and NFS, respectively.

Nonalcoholic Fatty Liver Disease in Patients with Type 2 Diabetes and Chronic Kidney Disease.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is suggested as a risk factor for chronic kidney disease (CKD). The incidence of NAFLD is rising globally in parallel to the increasing incidences of obesity and type 2 diabetes. Diabetes remains the leading cause of CKD, but the co-existence of NAFLD, CKD, and type 2 diabetes is not well elucidated. Here, we evaluated the prevalence of NAFLD in patients with type 2 diabetes with and without CKD. METHODS: This was a cross-sectional study including 50 patients with type 2 diabetes and CKD stages 3-5 (no dialysis), and 50 patients with type 2 diabetes without CKD. Liver fat content was estimated by proton magnetic resonance spectroscopy and magnetic resonance imaging proton density fat fraction. NAFLD was defined as liver fat fraction ≥5.6% according to guidelines. RESULTS: Mean age was 72 ± 4.9 years in patients with CKD and 65.9 ± 7.8 years in patients without CKD (p < 0.0001). Three out of four participants were men. BMI was 28.6 ± 3.5 kg/m2 and 27 ± 4.0 kg/m2 in patients with and without CKD, respectively (p = 0.0087). NAFLD was identified in 22 (44%) patients with CKD and 19 (38%) patients without CKD (p = 0.6845). Median (IQR) liver fat fraction was 4.7% (3.0-8.5) and 4.1% (2.9-7.7) in patients with and without CKD, respectively (difference in geometric means 5.3%, 95% CI -23; 45, p = 0.7463). CONCLUSION: These findings do not support any association between NAFLD and CKD (stages 3-5) in patients with type 2 diabetes.

Neurovascular Coupling in Type 2 Diabetes With Cognitive Decline. A Narrative Review of Neuroimaging Findings and Their Pathophysiological Implications.

Type 2 diabetes causes substantial long-term damage in several organs including the brain. Cognitive decline is receiving increased attention as diabetes has been established as an independent risk factor along with the identification of several other pathophysiological mechanisms. Early detection of detrimental changes in cerebral blood flow regulation may represent a useful clinical marker for development of cognitive decline for at-risk persons. Technically, reliable evaluation of neurovascular coupling is possible with several caveats but needs further development before it is clinically convenient. Different modalities including ultrasound, positron emission tomography and magnetic resonance are used preclinically to shed light on the many influences on vascular supply to the brain. In this narrative review, we focus on the complex link between type 2 diabetes, cognition, and neurovascular coupling and discuss how the disease-related pathology changes neurovascular coupling in the brain from the organ to the cellular level. Different modalities and their respective pitfalls are covered, and future directions suggested.

Short periods of bipolar anodal TDCS induce no instantaneous dose-dependent increase in cerebral blood flow in the targeted human motor cortex.

Anodal transcranial direct current stimulation (aTDCS) of primary motor hand area (M1-HAND) can enhance corticomotor excitability, but it is still unknown which current intensity produces the strongest effect on intrinsic neural firing rates and synaptic activity. Magnetic resonance imaging (MRI) combined with pseudo-continuous Arterial Spin Labeling (pcASL MRI) can map regional cortical blood flow (rCBF). The measured rCBF signal is sensitive to regional changes in neuronal activity due to neurovascular coupling. Therefore, concurrent TDCS and pcASL MRI may reveal the relationship between current intensity and TDCS-induced changes in overall firing rates and synaptic activity in the cortical target. Here we employed pcASL MRI to map acute rCBF changes during short-duration aTDCS of left M1-HAND. Using the rCBF response as a proxy for regional neuronal activity, we investigated if short-duration aTDCS produces an instantaneous dose-dependent rCBF increase in the targeted M1-HAND that may be useful for individual dosing. Nine healthy right-handed participants received 30 s of aTDCS at 0.5, 1.0, 1.5, and 2.0 mA with the anode placed over left M1-HAND and cathode over the right supraorbital region. Concurrent pcASL MRI at 3 T probed TDCS-related rCBF changes in the targeted M1-HAND. Movement-induced rCBF changes were also assessed. Apart from a subtle increase in rCBF at 0.5 mA, short-duration aTDCS did not modulate rCBF in the M1-HAND relative to no-stimulation periods. None of the participants showed a dose-dependent increase in rCBF during aTDCS, even after accounting for individual differences in TDCS-induced electrical field strength. In contrast, finger movements led to robust activation of left M1-HAND before and after aTDCS. Short-duration bipolar aTDCS does not produce consistant instantaneous dose-dependent rCBF increases in the targeted M1-HAND at conventional intensity ranges. Therefore, the regional hemodynamic response profile to short-duration aTDCS may not be suited to inform individual dosing of TDCS intensity.

Improving brain B0 shimming using an easy and accessible multi-coil shim array at ultra-high field.

OBJECT: Improve shimming capabilities of ultra-high field systems, with addition of an accessible low-complexity B0 shim array for head MRI at 7 T. MATERIALS AND METHODS: An eight channel B0 shim coil array was designed as a tradeoff between shimming improvement and construction complexity, to provide an easy to use shim array that can be employed with the standard 7 T head coil. The array was interfaced using an open-source eight-channel shim amplifier rack. Improvements in field homogeneity for whole-brain and slice-based shimming were compared to standard second-order shimming, and to more complex higher order dynamic shimming and shim arrays with 32 and 48 channels. RESULTS: The eight-channel shim array provided 12% improvement in whole brain static shimming and provided 33% improvement when using slice-based shimming. With this, the eight-channel array performed similar to third-order dynamic shimming (without the need for higher order eddy current compensation). More complex shim arrays with 32 and 48 channels performed better, but require a dedicated RF coil. DISCUSSION: The designed eight-channel shim array provides a low-complexity and low-cost approach for improving B0 field shimming on an ultra-high field system. In both static and dynamic shimming, it provides improved B0 homogeneity over standard shimming.

Do glia provide the link between low-grade systemic inflammation and normal cognitive ageing? A 1 H magnetic resonance spectroscopy study at 7 tesla.

Low-grade systemic inflammation contributes to ageing-related cognitive decline, possibly by triggering a neuroinflammatory response through glial activation. Using proton magnetic resonance spectroscopy (1 H-MRS) at 7T in normal human individuals from 18 to 79 years in a cross-sectional study, we previously observed higher regional levels of myo-inositol (mIns), total creatine (tCr) and total choline (tCho) in older than younger age groups. Moreover, visuo-spatial working memory (vsWM) correlated negatively with tCr and tCho in anterior cingulate cortex (ACC) and mIns in hippocampus and thalamus. As mIns, tCr and tCho are higher in glia than neurons, this suggest a potential in vivo connection between cognitive ageing and higher regional levels of glia-related metabolites. In the present study, we tested whether these metabolic differences may be related to low-grade systemic inflammation. In the same individuals, plasma concentrations of the proinflammatory markers C-reactive protein (CRP), interleukin 8 (IL-8), and tumour necrosis factor α (TNF-α) were measured on the same day as 1 H-MRS assessments. We tested whether CRP, IL-8, and TNF-α concentrations correlated with the levels of glia-related metabolites. CRP and IL-8, but not TNF-α, were higher in older (69-79 years) than younger (18-26 years) individuals. CRP correlated positively with thalamic mIns and negatively with vsWM. IL-8 correlated positively with ACC tCho and hippocampal mIns, but not with vsWM. Mediation analysis revealed an indirect effect of IL-8 on vsWM via ACC tCho. Together, these findings corroborate the role of glial cells, perhaps via their role in neuroinflammation, as part of the neurobiological link between systemic inflammation and cognitive ageing.

Prospective frequency and motion correction for edited 1H magnetic resonance spectroscopy.

The major inhibitory neurotransmitter gamma-aminobutyric acid (GABA) and the dominant antioxidant glutathione (GSH) both play a crucial role in brain functioning and are involved in several neurodegenerative and psychiatric diseases. Magnetic resonance spectroscopy (MRS) is a unique way to measure these neurometabolites non-invasively, but the measurement is highly sensitive to head movements, and especially in specific patient groups, motion stabilization in MRS could be valuable. Conventional MRS is acquired at relatively short echo times (TE), however, for unambiguous detection of GABA and GSH, spectral editing techniques are typically used. These depend on longer TEs and use frequency selective spectral editing pulses to separate the low-intensity peaks of GABA and GSH from overlapping resonances, but results in further increased motion sensitivity. Low-intensity metabolite peaks are usually edited one-by-one, however, simultaneous editing of multiple metabolites can be achieved using a Hadamard scheme, resulting in a substantial reduction in scan time. To investigate and correct for motion sensitivity in both conventional short-TE MRS (PRESS) and edited MRS (HERMES), we implemented a navigator-based prospective motion correction strategy including reacquisition of corrupted data. PRESS and HERMES spectra were acquired without motion, with motion with correction (repeated twice), and with motion without correction. Results indicate that when sufficient retrospective outlier removal is used, no significant differences in concentration and spectral quality were observed between motion conditions, even without prospective correction. HERMES spectral editing data showed to be more sensitive to motion, as significant differences in metabolite estimates and variability of spectral quality measures were observed for tCr, GABA+ and GSH when only retrospective outlier removal was applied. When using both prospective and retrospective correction, spectral quality was improved to almost the level of the no-motion acquisition. No differences in metabolite ratios for GABA and GSH could be observed when using motion correction. In conclusion, edited MRS showed to be more prone to motion artifacts, and prospective motion correction can restore most of the spectral quality in both conventional and edited MRS.

Regional Myo-Inositol, Creatine, and Choline Levels Are Higher at Older Age and Scale Negatively with Visuospatial Working Memory: A Cross-Sectional Proton MR Spectroscopy Study at 7 Tesla on Normal Cognitive Ageing.

Proton MR spectroscopy (1H-MRS) has been used to assess regional neurochemical brain changes during normal ageing, but results have varied. Exploiting the increased sensitivity at ultra-high field, we performed 1H-MRS in 60 healthy human volunteers to asses age-related differences in metabolite levels and their relation to cognitive ageing. Sex was balanced, and participants were assigned to a younger, middle, and older group according to their age, ranging from 18 to 79 years. They underwent 7T 1H-MRS of the ACC, DLPFC, hippocampus, and thalamus and performed a visuospatial working memory task outside the scanner. A multivariate ANCOVA revealed a significant overall effect of age group on metabolite levels in all regions. Higher levels in the middle than the younger group were observed for myo-inositol (mIns) in DLPFC and hippocampus and total choline (tCho) in ACC. Higher levels in the older than the younger group were observed for mIns in hippocampus and thalamus, total creatine (tCr) and tCho in ACC and hippocampus; lower levels of glutamate (Glu) were observed in DLPFC. Higher levels in the older than the middle group were observed for mIns in hippocampus, tCr in ACC and hippocampus, tCho in hippocampus, and total N-acetyl aspartate (tNAA) in hippocampus. Working memory performance correlated negatively with tCr and tCho levels in ACC and mIns levels in hippocampus and thalamus, but not with tNAA or glutamate levels. As NAA and Glu are commonly regarded to reflect neuronal health and function and concentrations of mIns, tCr, and tCho are higher in glia than neurons, the findings of this study suggest a potential in vivo connection between cognitive ageing and higher regional levels of glia-related metabolites.SIGNIFICANCE STATEMENT Neurochemical ageing is an integral component of age-related cognitive decline. Proton MR spectroscopy (1H-MRS) studies of in vivo neurochemical changes across the lifespan have, however, yielded inconclusive results. 1H-MRS at ultra-high field strength can potentially improve the consistency of findings. Using 7T 1H-MRS, we assessed levels of mIns, tCr, and tCho (glia-related metabolites) and tNAA and Glu (neuron-related metabolites) in ACC, DLPFC, hippocampus, and thalamus. We found higher levels of glia-related metabolites in all brain regions in older individuals. Working memory performance correlated negatively with regional levels of glia-related metabolites. This study is the first to investigate normal ageing in these brain regions using 7T 1H-MRS and findings indicate that glia-related metabolites could be valuable in cognitive ageing studies.

Cerebral oxygen metabolism in adults with sickle cell disease.

In sickle cell disease (SCD), oxygen delivery is impaired due to anemia, especially during times of increased metabolic demand, and cerebral blood flow (CBF) must increase to meet changing physiologic needs. But hyperemia limits cerebrovascular reserve (CVR) and ischemic risk prevails despite elevated CBF. The cerebral metabolic rate of oxygen (CMRO2 ) directly reflects oxygen supply and consumption and may therefore be more insightful than flow-based CVR measures for ischemic risk in SCD. We hypothesized that adults with SCD have impaired CMRO2 at rest and that a vasodilatory challenge with acetazolamide would improve CMRO2 . CMRO2 was calculated from CBF and oxygen extraction fraction (OEF), measured with arterial spin labeling and T2 -prepared tissue relaxation with inversion recovery (T2 -TRIR) MRI. We studied 36 adults with SCD without a clinical history of overt stroke, and nine healthy controls. As expected, CBF was higher in patients with SCD versus controls (mean ± SD: 74 ± 16 versus 46 ± 5 mL/100 g/min, P < .001), resulting in similar oxygen delivery (SCD: 377 ± 67 versus controls: 368 ± 42 µmol O2 /100g/min, P = .69). OEF was lower in patients versus controls (27 ± 4 versus 35 ± 4%, P < .001), resulting in lower CMRO2 in patients versus controls (102 ± 24 versus 127 ± 20 µmol O2 /100g/min, P = .002). After acetazolamide, CMRO2 declined further in patients (P < .01) and did not decline significantly in controls (P = .78), indicating that forcing higher CBF worsened oxygen utilization in SCD patients. This lower CMRO2 could reflect variation between healthy and unhealthy vascular beds in terms of dilatory capacity and resistance whereby dysfunctional vessels become more oxygen-deprived, hence increasing the risk of localized ischemia.

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

After publication of the original article [1], the authors have notified us that an updated version of Figures 1, 2 and 3 should have been published. The incorrect and revised figures can be found below.

Improvement in diagnostic quality of structural and angiographic MRI of the brain using motion correction with interleaved, volumetric navigators.

INTRODUCTION: Subject movements lead to severe artifacts in magnetic resonance (MR) brain imaging. In this study we evaluate the diagnostic image quality in T1-weighted, T2-weighted, and time-of-flight angiographic MR sequences when using a flexible, navigator-based prospective motion correction system (iMOCO). METHODS: Five healthy volunteers were scanned during different movement scenarios with and without (+/-) iMOCO activated. An experienced neuroradiologist graded images for image quality criteria (grey-white-matter discrimination, basal ganglia, and small structure and vessel delineation), and general image quality on a four-grade scale. RESULTS: In scans with deliberate motion, there was a significant improvement in the image quality with iMOCO compared to the scans without iMOCO in both general image impression (T1 p<0.01, T2 p<0.01, TOF p = 0.03) and in anatomical grading (T1 p<0.01, T2 p<0.01, TOF p = 0.01). Subjective image quality was considered non-diagnostic in 91% of the scans with motion -iMOCO, but only in 4% of the scans with motion +iMOCO. iMOCO performed best in the T1-weighted sequence and least well in the angiography sequence. iMOCO was not shown to have any negative effect on diagnostic image quality, as no significant difference in diagnostic quality was seen between scans -iMOCO and +iMOCO with no deliberate movement. CONCLUSION: The evaluation showed that iMOCO enables substantial improvements in image quality in scans affected by subject movement, recovering important diagnostic information in an otherwise unusable scan.

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

BACKGROUND: Sildenafil and calcitonin gene-related peptide both dilate the intradural segments of the middle meningeal artery measured with 3.0 tesla (T) MR angiography. Here we hypothesized that an increase in field strength to 7.0 T and concomitant enhanced voxel resolution would lower variance in measurements of dilation in the intradural middle meningeal artery. METHODS: Five subjects completed two sessions at respectively 3.0 T and 7.0 T. Each session comprised MR angiography scans once before and twice after administration of sildenafil, calcitonin gene-related peptide or placebo in a three-way, crossover, double-blind, placebo-controlled design. RESULTS: Standard deviations of arterial circumference revealed no difference between 3.0 T and 7.0 T measurements (p = 0.379). We found a decrease in standard deviation from our original angiography analysis software (QMra) to a newer (LAVA) software package (p < 0.001). Furthermore, we found that the dilation after sildenafil and calcitonin gene-related peptide were comparable between 3.0 T and 7.0 T. CONCLUSIONS: Our findings suggest no gain from the increase in voxel resolution but cemented dilatory findings from earlier. The implemented software update improved variance in circumference measurements in the intradural middle meningeal artery, which should be exploited in future studies. TRIAL REGISTRATION: The study is part of a parent study, which is registered at ClinicalTrials.gov ( NCT03143465 ).

Hemodynamic provocation with acetazolamide shows impaired cerebrovascular reserve in adults with sickle cell disease.

Sickle cell disease is characterized by chronic hemolytic anemia and vascular inflammation, which can diminish the vasodilatory capacity of the small resistance arteries, making them less adept at regulating cerebral blood flow. Autoregulation maintains adequate oxygen delivery, but when vasodilation is maximized, the low arterial oxygen content can lead to ischemia and silent cerebral infarcts. We used magnetic resonance imaging of cerebral blood flow to quantify whole-brain cerebrovascular reserve in 36 adult patients with sickle cell disease (mean age, 31.9±11.3 years) and 11 healthy controls (mean age, 37.4±15.4 years), and we used high-resolution 3D FLAIR magnetic resonance imaging to determine the prevalence of silent cerebral infarcts. Cerebrovascular reserve was calculated as the percentage change in cerebral blood flow after a hemodynamic challenge with acetazolamide. Co-registered lesion maps were used to demonstrate prevalent locations for silent cerebral infarcts. Cerebral blood flow was elevated in patients with sickle cell disease compared to controls (median [interquartile range]: 82.8 [20.1] vs 51.3 [4.8] mL/100g/min, P<0.001). Cerebral blood flow was inversely associated with age, hemoglobin, and fetal hemoglobin, and correlated positively with bilirubin, and LDH, indicating that cerebral blood flow may reflect surrogates of hemolytic rate. Cerebrovascular reserve in sickle cell disease was decreased by half compared to controls (34.1 [33.4] vs 69.5 [32.4] %, P<0.001) and was associated with hemoglobin and erythrocyte count indicating anemia-induced hemodynamic adaptations. In total, 29/36 patients (81%) and 5/11 controls (45%) had silent cerebral infarcts (median volume of 0.34 vs 0.02 mL, P=0.03). Lesions were preferentially located in the borderzone. In conclusion, patients with sickle cell disease have a globally reduced cerebrovascular reserve as determined by arterial spin labeling with acetazolamide and reflects anemia-induced impaired vascular function in sickle cell disease. This study was registered at clinicaltrials.gov identifier 02824406.

Sildenafil and calcitonin gene-related peptide dilate intradural arteries: A 3T MR angiography study in healthy volunteers.

BACKGROUND: Sildenafil and calcitonin gene-related peptide are vasoactive substances that induce migraine attacks in patients. The intradural arteries are thought to be involved, but these have never been examined in vivo. Sildenafil is the only migraine-inducing compound for which cephalic, extracranial artery dilation is not reported. Here, we investigate the effects of sildenafil and calcitonin gene-related peptide on the extracranial and intradural parts of the middle meningeal artery. METHODS: In a double-blind, randomized, three-way crossover, placebo-controlled head-to-head comparison study, MR-angiography was recorded in healthy volunteers at baseline and twice after study drug (sildenafil/ calcitonin gene-related peptide/saline) administration. Circumferences of extracranial and intradural middle meningeal artery segments were measured using semi-automated analysis software. The area under the curve for circumference change was compared using paired t-tests between study days. RESULTS: Twelve healthy volunteers completed the study. The area under the curveBaseline-120min was significantly larger on both the sildenafil and the calcitonin gene-related peptide day in the intradural middle meningeal artery (calcitonin gene-related peptide, p = 0.013; sildenafil, p = 0.027) and the extracranial middle meningeal artery (calcitonin gene-related peptide, p = 0.0003; sildenafil, p = 0.021), compared to placebo. Peak intradural middle meningeal artery dilation was 9.9% (95% CI [2.9-16.9]) after sildenafil (T30min) and 12.5% (95% CI [8.1-16.8]) after calcitonin gene-related peptide (T30min). Peak dilation of the extracranial middle meningeal artery after calcitonin gene-related peptide (T30min) was 15.7% (95% CI [11.2-20.1]) and 18.9% (95% CI [12.8-24.9]) after sildenafil (T120min). CONCLUSION: An important novel finding is that both sildenafil and calcitonin gene-related peptide dilate intradural arteries, supporting the notion that all known pharmacological migraine triggers dilate cephalic vessels. We suggest that intradural artery dilation is associated with headache induced by calcitonin gene-related peptide and sildenafil.

Effects of sildenafil and calcitonin gene-related peptide on brainstem glutamate levels: a pharmacological proton magnetic resonance spectroscopy study at 3.0 T.

BACKGROUND: Studies involving human pharmacological migraine models have predominantly focused on the vasoactive effects of headache-inducing drugs, including sildenafil and calcitonin gene-related peptide (CGRP). However, the role of possible glutamate level changes in the brainstem and thalamus is of emerging interest in the field of migraine research bringing forth the need for a novel, validated method to study the biochemical effects in these areas. METHODS: We applied an optimized in vivo human pharmacological proton (1H) magnetic resonance spectroscopy (MRS) protocol (PRESS, repetition time 3000 ms, echo time 37.6-38.3 ms) at 3.0 T in combination with sildenafil and CGRP in a double-blind, placebo-controlled, randomized, double-dummy, three-way cross-over design. Seventeen healthy participants were scanned with the 1H-MRS protocol at baseline and twice (at 40 min and 140 min) after drug administration to investigate the sildenafil- and CGRP-induced glutamate changes in both brainstem and thalamus. RESULTS: The glutamate levels increased transiently in the brainstem at 40-70 min after sildenafil administration compared to placebo (5.6%, P = 0.039). We found no sildenafil-induced glutamate changes in the thalamus, and no CGRP-induced glutamate changes in the brainstem or thalamus compared to placebo. Both sildenafil and CGRP induced headache in 53%-62% of participants. We found no interaction in the glutamate levels in the brainstem or thalamus between participants who developed sildenafil and/or CGRP-induced headache as compared to participants who did not. CONCLUSIONS: The transient sildenafil-induced glutamate change in the brainstem possibly reflects increased excitability of the brainstem neurons. CGRP did not induce brainstem or thalamic glutamate changes, suggesting that it rather exerts its headache-inducing effects on the peripheral trigeminal pain pathways.

Improved calculation of the equilibrium magnetization of arterial blood in arterial spin labeling.

PURPOSE: To propose and assess an improved method for calculating the equilibrium magnetization of arterial blood ( M0a), used for calibration of perfusion estimates in arterial spin labeling. METHODS: Whereas standard M0a calculation is based on dividing a proton density-weighted image by an average brain-blood partition coefficient, the proposed method exploits partial-volume data to adjust this ratio. The nominator is redefined as the magnetization of perfused tissue, and the denominator is redefined as a weighted sum of tissue-specific partition coefficients. Perfusion data were acquired with a pseudo-continuous arterial spin labeling sequence, and partial-volume data were acquired using a rapid saturation recovery sequence with the same readout module. Results from 7 healthy volunteers were analyzed and compared with the conventional method. RESULTS: The proposed method produced improved M0a homogeneity throughout the brain in all subjects. The mean gray matter perfusion was significantly higher with the proposed method compared with the conventional method: 61.2 versus 56.3 mL/100 g/minute (+8.7%). Although to a lesser degree, the corresponding white matter values were also significantly different: 20.8 versus 22.0 mL/100 g/minute (-5.4%). The spatial and quantitative differences between the 2 methods were similar in all subjects. CONCLUSION: Compared with the conventional approach, the proposed method produced more homogenous M0a maps, corresponding to a more accurate calibration. The proposed method also yielded significantly different perfusion values across the whole brain, and performed consistently in all subjects. The new M0a method improves quantitative perfusion estimation with arterial spin labeling, and can therefore be of considerable value in perfusion imaging applications.

Increased variability of watershed areas in patients with high-grade carotid stenosis.

PURPOSE: Watershed areas (WSAs) of the brain are most susceptible to acute hypoperfusion due to their peripheral location between vascular territories. Additionally, chronic WSA-related vascular processes underlie cognitive decline especially in patients with cerebral hemodynamic compromise. Despite of high relevance for both clinical diagnostics and research, individual in vivo WSA definition is fairly limited to date. Thus, this study proposes a standardized segmentation approach to delineate individual WSAs by use of time-to-peak (TTP) maps and investigates spatial variability of individual WSAs. METHODS: We defined individual watershed masks based on relative TTP increases in 30 healthy elderly persons and 28 patients with unilateral, high-grade carotid stenosis, being at risk for watershed-related hemodynamic impairment. Determined WSA location was confirmed by an arterial transit time atlas and individual super-selective arterial spin labeling. We compared spatial variability of WSA probability maps between groups and assessed TTP differences between hemispheres in individual and group-average watershed locations. RESULTS: Patients showed significantly higher spatial variability of WSAs than healthy controls. Perfusion on the side of the stenosis was delayed within individual watershed masks as compared to a watershed template derived from controls, being independent from the grade of the stenosis and collateralization status of the circle of Willis. CONCLUSION: Results demonstrate feasibility of individual WSA delineation by TTP maps in healthy elderly and carotid stenosis patients. Data indicate necessity of individual segmentation approaches especially in patients with hemodynamic compromise to detect critical regions of impaired hemodynamics.

Examining the regional and cerebral depth-dependent BOLD cerebrovascular reactivity response at 7T.

Changes in cerebral blood flow (CBF) in response to hypercapnia induced changes in vascular tone, known as cerebrovascular reactivity (CVR), can be measured using the Blood Oxygenation Level Dependent (BOLD) MR contrast. We examine regional differences in the BOLD-CVR response to a progressively increasing hypercapnic stimulus as well as regional BOLD characteristics for the return to baseline normocapnia. CVR across 9 subjects was highest in the cerebral lobes and deep gray matter. Peak CVR in these regions was measured at 3.6±1.6mmHg above baseline end-tidal CO2. White matter CVR was generally reduced compared to that of the gray matter (peak white matter CVR was ~48% lower). A positive relationship between the end-tidal CO2 value at which peak CVR was measured and white matter depth is observed. Furthermore, the time required for the BOLD signal to return to baseline after cessation of the hypercapnic stimulus, was also related to white matter depth; the return, expressed as a time constant, was ~25% longer in white matter. To explain the observed differences in regional CVR response, a model is proposed that takes into account the local architecture of the cerebrovascular, which can result in changes in regional blood flow distribution as a function of end-tidal CO2.