Sex differences in gray matter, white matter, and regional brain perfusion in young, healthy adults.

Cerebrovascular and neurological diseases exhibit sex-specific patterns in prevalence, severity, and regional specificity, some of which are associated with altered cerebral blood flow (CBF). Females often exhibit higher resting CBF, but understanding the impact of sex per se on CBF is hampered by study variability in age, comorbidities, medications, and control for menstrual cycle or hormone therapies. A majority of studies report whole brain CBF without differentiating between gray and white matter or without assessing regional CBF. Thus fundamental sex differences in regional or whole brain CBF remain unclarified. While controlling for the above confounders, we tested the hypothesis that females will exhibit higher total gray and white matter perfusion as well as regional gray matter perfusion. Adults 18-30 yr old (females = 22 and males = 26) were studied using arterial spin labeling (ASL) magnetic resonance imaging (MRI) scans followed by computational anatomy toolbox (CAT12) analysis in statistical parametric mapping (SPM12) to quantify CBF relative to brain volume. Females displayed 40% higher perfusion globally (females = 62 ± 9 and males = 45 ± 10 mL/100 g/min, P < 0.001), gray matter (females = 75 ± 11 and males = 54 ± 12 mL/100 g/min, P < 0.001), and white matter (females = 44 ± 6 and males = 32 ± 7 mL/100 g/min, P < 0.001). Females exhibited greater perfusion than males in 67 of the 68 regions tested, ranging from 14% to 66% higher. A second MRI approach (4-dimensional flow) focused on large arteries confirmed the sex difference in global CBF. These data indicate strikingly higher basal CBF in females at global, gray, and white matter levels and across dozens of brain regions and offer new clarity into fundamental sex differences in global and regional CBF regulation before aging or pathology.NEW & NOTEWORTHY MRI used to measure cerebral blood flow (CBF) in gray matter, white matter, and 68 regions in healthy men and women. This study demonstrated that CBF is 40% higher in women, the highest sex difference reported, when controlling for numerous important clinical confounders like age, smoking, menstrual cycle, comorbidities, and medications.

Cerebral blood flow dependency on systemic arterial circulation in progressive multiple sclerosis.

OBJECTIVES: To determine the relationship between systemic arterial blood flow (SABF) and cerebral perfusion measures in multiple sclerosis (MS) patients. METHODS: Cerebral perfusion and SABF were assessed in 118 patients (75 clinically isolated syndrome (CIS)/relapsing-remitting MS and 43 progressive MS) through MRI examination with dynamic susceptibility contrast perfusion-weighted imaging (DSC-PWI) and Doppler ultrasound, respectively. Measures of mean transit time (MTT) and time-to-peak (TTP), measured in seconds, of the normal-appearing whole brain (NAWB) and gray matter (GM) were calculated. Blood flow through the bilateral common carotid and vertebral arteries (in mL/min) represents the SABF. Whole brain volume (WBV) and body mass index (BMI) were used as additional covariates. RESULTS: Higher systolic blood pressure was associated with lower SABF (-0.256, p = 0.006). In the total MS sample, higher SABF was associated with shorter MTT and TTP of the NAWB (r = -0.256, p = 0.007 and r = -0.307, p = 0.001) and GM (r = -0.239, p = 0.012 and r = -0.3, p = 0.001). The SABF and TTP associations were driven by the PMS patients (r = -0.451, p = 0.004 and r = -0.451, p = 0.011). Only in PMS, SABF remained a significant predictor of NAWB (standardized ß = -0.394, p = 0.022) and GM TTP (standardized ß = -0.351, p = 0.037). MTT and TTP were significantly lower in patients within lower SABF quartiles when compared to the higher quartiles (age-, sex-, BMI-, and WBV-adjusted ANCOVA p < 0.025). CONCLUSIONS: The direct relationship between systemic and cerebral blood flow seen in PMS patients may suggest failure in cerebrovascular reactivity mechanisms and insufficient perfusion control. Cerebral blood flow in PMS may be increasingly dependent on the SABF. KEY POINTS: • In progressive multiple sclerosis (MS) patients, the systemic arterial blood flow (SABF) is associated with perfusion-based measure of time-to-peak (TTP) of the normal-appearing whole brain (r = -0.451, p = 0.004) and gray matter (r = -0.451, p = 0.004). • Cerebral blood flow in progressive MS is directly dependent on systemic arterial blood flow and may be influenced by blood pressure changes. • Neurovascular unit impairment may play an important role in MS pathophysiology and contribute towards greater clinical disability.

Age-related normative changes in cerebral perfusion: Data from The Irish Longitudinal Study on Ageing (TILDA).

OBJECTIVE: To establish normative reference values for total grey matter cerebral blood flow (CBFGM) measured using pseudo-continuous arterial spin labelling (pCASL) MRI in a large cohort of community-dwelling adults aged 54 years and older. BACKGROUND: Quantitative assessment of CBFGM may provide an imaging biomarker for the early detection of those at risk of neurodegenerative diseases, such as Alzheimer's and dementia. However, the use of this method to differentiate normal age-related decline in CBFGM from pathological reduction has been hampered by the lack of reference values for cerebral perfusion. METHODS: The study cohort comprised a subset of wave 3 (2014-2015) participants from The Irish Longitudinal Study on Ageing (TILDA), a large-scale prospective cohort study of individuals aged 50 and over. Of 4309 participants attending for health centre assessment, 578 individuals returned for 3T multi-parametric MRI brain examinations. In total, CBFGM data acquired from 468 subjects using pCASL-MRI were included in this analysis. Normative values were estimated using Generalised Additive Models for Location Shape and Scale (GAMLSS) and are presented as percentiles, means and standard deviations. RESULTS: The mean age of the cohort was 68.2 ± 6.9 years and 51.7% were female. Mean CBFGM for the cohort was 36.5 ± 8.2 ml/100 g/min. CBFGM decreased by 0.2 ml/100 g/min for each year increase in age (95% CI = -0.3, -0.1; p ≤ 0.001) and was 3.1 ml/100 g/min higher in females (95% CI = 1.6, 4.5; p ≤ 0.001). CONCLUSIONS: This study is by far the largest single-site study focused on an elderly community-dwelling cohort to present normative reference values for CBFGM measured at 3T using pCASL-MRI. Significant age- and sex-related differences exist in CBFGM.

Hippocampal vascular reserve associated with cognitive performance and hippocampal volume.

Medial temporal lobe dependent cognitive functions are highly vulnerable to hypoxia in the hippocampal region, yet little is known about the relationship between the richness of hippocampal vascular supply and cognition. Hippocampal vascularization patterns have been categorized into a mixed supply from both the posterior cerebral artery and the anterior choroidal artery or a single supply by the posterior cerebral artery only. Hippocampal arteries are small and affected by pathological changes when cerebral small vessel disease is present. We hypothesized, that hippocampal vascularization patterns may be important trait markers for vascular reserve and modulate (i) cognitive performance; (ii) structural hippocampal integrity; and (iii) the effect of cerebral small vessel disease on cognition. Using high-resolution 7 T time-of-flight angiography we manually classified hippocampal vascularization patterns in older adults with and without cerebral small vessel disease in vivo. The presence of a mixed supplied hippocampus was an advantage in several cognitive domains, including verbal list learning and global cognition. A mixed supplied hippocampus also was an advantage for verbal memory performance in cerebral small vessel disease. Voxel-based morphometry showed higher anterior hippocampal grey matter volume in mixed, compared to single supply. We discuss that a mixed hippocampal supply, as opposed to a single one, may increase the reliability of hippocampal blood supply and thereby provide a hippocampal vascular reserve that protects against cognitive impairment.

Hippocampal Blood Flow Is Increased After 20 min of Moderate-Intensity Exercise.

Long-term exercise interventions have been shown to be a potent trigger for both neurogenesis and vascular plasticity. However, little is known about the underlying temporal dynamics and specifically when exercise-induced vascular adaptations first occur, which is vital for therapeutic applications. In this study, we investigated whether a single session of moderate-intensity exercise was sufficient to induce changes in the cerebral vasculature. We employed arterial spin labeling magnetic resonance imaging to measure global and regional cerebral blood flow (CBF) before and after 20 min of cycling. The blood vessels' ability to dilate, measured by cerebrovascular reactivity (CVR) to CO2 inhalation, was measured at baseline and 25-min postexercise. Our data showed that CBF was selectively increased by 10-12% in the hippocampus 15, 40, and 60 min after exercise cessation, whereas CVR to CO2 was unchanged in all regions. The absence of a corresponding change in hippocampal CVR suggests that the immediate and transient hippocampal adaptations observed after exercise are not driven by a mechanical vascular change and more likely represents an adaptive metabolic change, providing a framework for exploring the therapeutic potential of exercise-induced plasticity (neural, vascular, or both) in clinical and aged populations.

Effect of intravoxel incoherent motion on diffusion parameters in normal brain.

At very low diffusion weighting the diffusion MRI signal is affected by intravoxel incoherent motion (IVIM) caused by dephasing of magnetization due to incoherent blood flow in capillaries or other sources of microcirculation. While IVIM measurements at low diffusion weightings have been frequently used to investigate perfusion in the body as well as in malignant tissue, the effect and origin of IVIM in normal brain tissue is not completely established. We investigated the IVIM effect on the brain diffusion MRI signal in a cohort of 137 radiologically-normal patients (62 male; mean age = 50.2 ±â€¯17.8, range = 18 to 94). We compared the diffusion tensor parameters estimated from a mono-exponential fit at b = 0 and 1000 s/mm2 versus at b = 250 and 1000 s/mm2. The asymptotic fitting method allowed for quantitative assessment of the IVIM signal fraction f* in specific brain tissue and regions. Our results show a mean (median) percent difference in the mean diffusivity of about 4.5 (4.9)% in white matter (WM), about 7.8 (8.7)% in cortical gray matter (GM), and 4.3 (4.2)% in thalamus. Corresponding perfusion fraction f* was estimated to be 0.033 (0.032) in WM, 0.066 (0.065) in cortical GM, and 0.033 (0.030) in the thalamus. The effect of f* with respect to age was found to be significant in cortical GM (Pearson correlation ρ â€‹= â€‹0.35, p â€‹= â€‹3*10-5) and the thalamus (Pearson correlation ρ = 0.20, p = 0.022) with an average increase in f* of 5.17*10-4/year and 3.61*10-4/year, respectively. Significant correlations between f* and age were not observed for WM, and corollary analysis revealed no effect of gender on f*. Possible origins of the IVIM effect in normal brain tissue are discussed.

The costs and benefits of estimating T1 of tissue alongside cerebral blood flow and arterial transit time in pseudo-continuous arterial spin labeling.

Multi-post-labeling-delay pseudo-continuous arterial spin labeling (multi-PLD PCASL) allows for absolute quantification of the cerebral blood flow (CBF) as well as the arterial transit time (ATT). Estimating these perfusion parameters from multi-PLD PCASL data is a non-linear inverse problem, which is commonly tackled by fitting the single-compartment model (SCM) for PCASL, with CBF and ATT as free parameters. The longitudinal relaxation time of tissue T1t is an important parameter in this model, as it governs the decay of the perfusion signal entirely upon entry in the imaging voxel. Conventionally, T1t is fixed to a population average. This approach can cause CBF quantification errors, as T1t can vary significantly inter- and intra-subject. This study compares the impact on CBF quantification, in terms of accuracy and precision, of either fixing T1t , the conventional approach, or estimating it alongside CBF and ATT. It is shown that the conventional approach can cause a significant bias in CBF. Indeed, simulation experiments reveal that if T1t is fixed to a value that is 10% off its true value, this may already result in a bias of 15% in CBF. On the other hand, as is shown by both simulation and real data experiments, estimating T1t along with CBF and ATT results in a loss of CBF precision of the same order, even if the experiment design is optimized for the latter estimation problem. Simulation experiments suggest that an optimal balance between accuracy and precision of CBF estimation from multi-PLD PCASL data can be expected when using the two-parameter estimator with a fixed T1t value between population averages of T1t and the longitudinal relaxation time of blood T1b .

Regional impairment of cortical and deep gray matter perfusion in preterm neonates with low-grade germinal matrix-intraventricular hemorrhage: an ASL study.

PURPOSE: The long-term impact of low-grade germinal matrix-intraventricular hemorrhage (GMH-IVH) on brain perfusion has not been fully investigated. We aimed to compare cortical and deep gray matter (GM) cerebral blood flow (CBF) obtained with pseudo-continuous arterial spin labeling (pCASL), among preterm neonates with and without low-grade GMH-IVH and full-term controls. METHODS: 3T-pCASL examinations of 9 healthy full-term neonates (mean gestational age 38.5 weeks, range 38-39) and 28 preterm neonates studied at term-equivalent age were analyzed. Eighteen preterm neonates presented normal brain MRI (mean gestational age 30.50 weeks, range 29-31) and 10 low-grade GMH-IVH according to Volpe's grading system (mean gestational age 32 weeks, range 28-34). A ROI-based mean CBF quantification was performed in 5 cortical (frontal, parietal, temporal, insula, occipital), and 4 subcortical GM regions (caudate, putamen, pallidum, thalamus) for each cerebral hemisphere. CBF differences were explored using a nonparametric analysis of covariance. RESULTS: Low-grade GMH-IVH hemispheres showed consistently lower CBF in all GM regions when compared with healthy preterm neonates, after controlling the confounding effect of gestational age, postmenstrual age, and birth weight P < .001, η2 = .394. No significant differences were observed between neonates with low-grade GMH and full-term controls. Healthy preterm neonates showed significantly higher CBF than full-term controls in parietal (P = .032), temporal (P = .016), and occipital cortex (P = .024), and at level of thalamus (P = .023) and caudate nucleus (P = .014). CONCLUSION: Low-grade GMH-IVH is associated with lower CBF in posterior cortical and subcortical gray matter regions in preterm neonates, suggesting regional vulnerability of these developing brain structures.

Acute Spinal Cord Infarction with Preferential Involvement of Ventral Gray Matter: An Autopsy Report.

Herein, we report abdominal aortic thrombosis as a rare cause of acute spinal cord infarction. A 78-year-old man with multiple vascular risk factors developed acute paraplegia with sensory and urinary disturbances and signs of ischemia in both lower limbs. The post-mortem study done 3 days after the onset of symptoms revealed a large coagulum in the abdominal aorta, distal to the renal arteries and extending to bilateral common iliac arteries; in addition, marked atherosclerosis was present in most large blood vessels. Premature incomplete necrotic foci were seen in the ventral gray matter of the spinal cord from T6 through S5; the surrounding white matter and dorsal gray matter were spared. Considering our autopsy case, spinal cord gray matter may be more vulnerable to ischemia than the white matter.

Cerebellar Microbleed Distribution Patterns and Cerebral Amyloid Angiopathy.

Background and Purpose- Hematoma location within the cerebellum may help identify the dominant small vessel disease type (cerebral amyloid angiopathy [CAA] versus nonamyloid small vessel disease). However, it is unknown whether this holds true for cerebral microbleeds (CMBs) within the cerebellum. We tested the hypothesis that cerebellar CMBs restricted to the cortex and vermis (defined as superficial regions) are associated with clinically diagnosed and pathology-verified CAA. Methods- Three hundred and seven consecutive spontaneous intracerebral hemorrhage (ICH) patients with a baseline magnetic resonance imaging that included susceptibility-weighted imaging or angiography were enrolled. Using a topographical template, cerebellar CMB patterns were defined as strictly superficial versus deep (cerebellar gray nuclei and white matter) or mixed (both regions involved). Thirty-six ICH patients with cerebellar CMBs and neuropathology data available were evaluated for the presence of CAA. Results- One hundred and thirty-five (44%) ICH patients had CMBs in the cerebellum. In the patient group with cerebellar CMBs, 85 (63%) showed a superficial pattern, and 50 (37%) had a deep/mixed pattern. Strictly superficial cerebellar CMBs were independently associated with a supratentorial pattern of probable CAA-ICH according to the Boston criteria (odds ratio, 1.6; CI, 1.03-2.5) and deep/mixed cerebellar CMBs with a pattern of deep/mixed ICH (odds ratio, 1.8; CI, 1.2-2.7). Pathologically verified CAA was present in 23 of 24 (96%) patients with superficial cerebellar CMBs versus 3 of 12 (25%) patients with deep/mixed cerebellar CMBs ( P<0.001). Conclusions- In ICH patients, cerebellar CMBs are relatively common and often restricted to superficial regions. A strictly superficial distribution of cerebellar CMBs is associated with clinically diagnosed and pathologically verified CAA.

Dependence of resting-state fMRI fluctuation amplitudes on cerebral cortical orientation relative to the direction of B0 and anatomical axes.

Functional magnetic resonance imaging (fMRI) is now capable of sub-millimetre scale measurements over the entire human brain, however with such high resolutions each voxel is influenced by the local fine-scale details of the cerebral cortical vascular anatomy. The cortical vasculature is structured with the pial vessels lying tangentially along the grey matter surface, intracortical diving arterioles and ascending venules running perpendicularly to the surface, and a randomly oriented capillary network within the parenchyma. It is well-known that the amplitude of the blood-oxygenation level dependent (BOLD) signal emanating from a vessel depends on its orientation relative to the B0-field. Thus the vascular geometric hierarchy will impart an orientation dependence to the BOLD signal amplitudes and amplitude differences due to orientation differences constitute a bias for interpreting neuronal activity. Here, we demonstrate a clear effect of cortical orientation to B0 in the resting-state BOLD-fMRI amplitude (quantified as the coefficient of temporal signal variation) for 1.1 mm isotropic data at 7T and 2 mm isotropic at 3T. The maximum bias, i.e. the fluctuation amplitude difference between regions where cortex is perpendicular to vs. parallel to B0, is about +70% at the pial surface at 7T and +11% at 3T. The B0 orientation bias declines with cortical depth, becomes progressively smaller closer to the white matter surface, but then increases again to a local maximum within the white matter just beneath the cortical grey matter, suggesting a distinct tangential network of white matter vessels that also generate a BOLD orientation effect. We further found significant (negative) biases with the cortex orientation to the anterior-posterior anatomical axis of the head: a maximum negative bias of about -30% at the pial surface at 7T and about -13% at 3T. The amount of signal variance explained by the low frequency drift, motion and the respiratory cycle also showed a cortical orientation dependence; only the cardiac cycle induced signal variance was independent of cortical orientation, suggesting that the cardiac induced component of the image time-series fluctuations is not related to a significant change in susceptibility. Although these orientation effects represent a signal bias, and are likely to be a nuisance in high-resolution analyses, they may help characterize the vascular influences on candidate fMRI acquisitions and, thereby, may be exploited to improve the neuronal specificity of fMRI.

Abnormal venous postural control: multiple sclerosis-specific change related to gray matter pathology or age-related neurodegenerative phenomena?

BACKGROUND: Autonomic nervous system dysfunction has been previously observed in multiple sclerosis (MS) patients. OBJECTIVE: To assess associations between magnetic resonance imaging-detected neuroinflammatory and neurodegenerative pathology and postural venous flow changes indicative of autonomic nervous system function. METHODS: We used a standardized 3T magnetic resonance imaging protocol to scan 138 patients with MS and 49 healthy controls. Lesion volume and brain volumes were assessed. The cerebral venous flow (CVF) was examined by color-Doppler sonography in supine and upright positions and the difference was calculated as ΔCVF. Based on ΔCVF, subjects were split into absolute or quartile groups. Student's t test, χ2-test, and analysis of covariance adjusted for age and sex were used accordingly. Benjamini-Hochberg procedure corrected the p-values for multiple comparisons. RESULTS: No differences were found between healthy controls and patients with MS in both supine and upright Doppler-derived CVF, nor in prevalence of abnormal postural venous control. Patients with absolute negative ΔCVF had higher disability scores (p = 0.013), lower gray matter (p = 0.039) and cortical (p = 0.044) volumes. The negative ΔCVF MS group also showed numerically worse bladder/bowel function when compared to the positive ΔCVF (2.3 vs. 1.5, p = 0.052). Similarly, the lowest quartile ΔCVF MS group had higher T1-lesion volumes (p = 0.033), T2-lesion volumes (p = 0.032), and lower deep gray matter (p = 0.043) and thalamus (p = 0.033) volumes when compared to those with higher ΔCVF quartiles. CONCLUSION: No difference in postural venous outflow between patients with MS and healthy controls was found. However, when the abnormal ΔCVF is present within the MS population, it may be associated with more inflammatory and neurodegenerative pathology. Further studies should explore whether the orthostatic venous changes are an aging or an MS-related phenomenon and if the etiology is due to impaired autonomic nervous system functioning.

Gas-free calibrated fMRI with a correction for vessel-size sensitivity.

Calibrated functional magnetic resonance imaging (fMRI) is a method to independently measure the metabolic and hemodynamic contributions to the blood oxygenation level dependent (BOLD) signal. This technique typically requires the use of a respiratory challenge, such as hypercapnia or hyperoxia, to estimate the calibration constant, M. There has been a recent push to eliminate the gas challenge from the calibration procedure using asymmetric spin echo (ASE) based techniques. This study uses simulations to better understand spin echo (SE) and ASE signals, analytical modelling to characterize the signal evolution, and in vivo imaging to validate the modelling. Using simulations, it is shown how ASE imaging generally underestimates M and how this depends on several parameters of the acquisition, including echo time and ASE offset, as well as the vessel size. This underestimation is the result of imperfect SE refocusing due to diffusion of water through the extravascular environment surrounding the microvasculature. By empirically characterizing this SE attenuation as an exponential decay that increases with echo time, we have proposed a quadratic ASE biophysical signal model. This model allows for the characterization and compensation of the SE attenuation if SE and ASE signals are acquired at multiple echo times. This was tested in healthy subjects and was found to significantly increase the estimates of M across grey matter. These findings show promise for improved gas-free calibration and can be extended to other relaxation-based imaging studies of brain physiology.

Epileptic networks in action: Synchrony between distant hemodynamic responses.

OBJECTIVE: Structural and functional imaging studies in focal epilepsy often reveal distributed regions of abnormality. These are interpreted as representing the existence of epileptic networks, but the presence of actual neuronal interactions between these regions has not been demonstrated. We sought to determine whether the distributed hemodynamic responses often seen in functional magnetic resonance imaging (fMRI) studies of scalp interictal epileptic discharges (IEDs) actually correspond to synchronized neuronal activities when examining the intracerebral electroencephalogram (iEEG) at distant nodes of the network. METHODS: We studied 28 patients who underwent first EEG-fMRI and then iEEG, and had significant hemodynamic responses in the gray matter. We coregistered the hemodynamic responses to the iEEG electrode contact positions and analyzed synchrony, measured by correlation, between IEDs recorded by iEEG in regions with and without hemodynamic responses. RESULTS: The synchrony of intracerebral IED activity between pairs of regions showing a hemodynamic response was higher compared to that between pairs of regions without (p < 0.0001) and between pairs of regions, one with and one without hemodynamic response (p < 0.0001). These differences were found during the interictal periods with IEDs but were absent during the interictal periods without IEDs. Higher synchrony was also observed between regions involved at seizure onset (p < 0.0001). INTERPRETATION: EEG-fMRI studies are unique in their ability to reveal hemodynamic concomitants of IEDs anywhere in the brain. This study proves that iEEG activity is synchronized between these regions of hemodynamic response, thus demonstrating the existence of an actual neuronally based interictal epileptic network. This also validates the EEG-fMRI approach to reveal this network noninvasively. Ann Neurol 2017;82:57-66.

Observer variability of reference tissue selection for relativecerebral blood volume measurements in glioma patients.

OBJECTIVES: To assess observer variability of different reference tissues used for relative CBV (rCBV) measurements in DSC-MRI of glioma patients. METHODS: In this retrospective study, three observers measured rCBV in DSC-MR images of 44 glioma patients on two occasions. rCBV is calculated by the CBV in the tumour hotspot/the CBV of a reference tissue at the contralateral side for normalization. One observer annotated the tumour hotspot that was kept constant for all measurements. All observers annotated eight reference tissues of normal white and grey matter. Observer variability was evaluated using the intraclass correlation coefficient (ICC), coefficient of variation (CV) and Bland-Altman analyses. RESULTS: For intra-observer, the ICC ranged from 0.50-0.97 (fair-excellent) for all reference tissues. The CV ranged from 5.1-22.1 % for all reference tissues and observers. For inter-observer, the ICC for all pairwise observer combinations ranged from 0.44-0.92 (poor-excellent). The CV ranged from 8.1-31.1 %. Centrum semiovale was the only reference tissue that showed excellent intra- and inter-observer agreement (ICC>0.85) and lowest CVs (<12.5 %). Bland-Altman analyses showed that mean differences for centrum semiovale were close to zero. CONCLUSION: Selecting contralateral centrum semiovale as reference tissue for rCBV provides the lowest observer variability. KEY POINTS: • Reference tissue selection for rCBV measurements adds variability to rCBV measurements. • rCBV measurements vary depending on the choice of reference tissue. • Observer variability of reference tissue selection varies between poor and excellent. • Centrum semiovale as reference tissue for rCBV provides the lowest observer variability.

Intravoxel Incoherent Motion Imaging in Small Vessel Disease: Microstructural Integrity and Microvascular Perfusion Related to Cognition.

BACKGROUND AND PURPOSE: Cerebral small vessel disease (SVD) is associated with cognitive impairment. This may be because of decreased microstructural integrity and microvascular perfusion, but data on these relationships are scarce. We determined the relationship between cognition and microvascular perfusion and microstructural integrity in SVD patients, using intravoxel incoherent motion imaging-a diffusion-weighted magnetic resonance imaging technique designed to determine microvascular perfusion and microstructural integrity simultaneously. METHODS: Seventy-three patients with SVD and 39 controls underwent intravoxel incoherent motion imaging and neuropsychological assessment. Parenchymal diffusivity D (a surrogate measure of microstructural integrity) and perfusion-related measure fD* were calculated for the normal appearing white matter, white matter hyperintensities, and cortical gray matter. The associations between cognitive performance and D and fD* were determined. RESULTS: In SVD patients, multivariable analysis showed that lower fD* in the normal appearing white matter and cortical gray matter was associated with lower overall cognition (P=0.03 and P=0.002, respectively), lower executive function (P=0.04 and P=0.01, respectively), and lower information-processing speed (P=0.04 and P=0.01, respectively). D was not associated with cognitive function. In controls, no association was found between D, fD*, and cognition. CONCLUSIONS: In SVD patients, lower cognitive performance is associated with lower microvascular perfusion in the normal appearing white matter and cortical gray matter. Our results support recent findings that both cortical gray matter and normal appearing white matter perfusion may play a role in the pathophysiology of cognitive dysfunction in SVD. CLINICAL TRIAL REGISTRATION: URL: http://www.trialregister.nl. Unique identifier: NTR3786.

The IVIM signal in the healthy cerebral gray matter: A play of spherical and non-spherical components.

The intra-voxel incoherent motion (IVIM) model assumes that blood flowing in isotropically distributed capillary segments induces a phase dispersion of the MR signal, which increases the signal attenuation in diffusion-weighted images. However, in most tissue types the capillary network has an anisotropic micro-architecture. In this study, we investigated the possibility to indirectly infer the anisotropy of the capillary network in the healthy cerebral gray matter by evaluating the dependence of the IVIM signal from the direction of the diffusion-encoding. Perfusion-related indices and self-diffusion were modelled as symmetric rank 2 tensors. The geometry of the tensors was quantified pixel-wise by decomposing the tensor in sphere-like, plane-like, and line-like components. Additionally, trace and fractional anisotropy of the tensors were computed. While the self-diffusion tensor is dominated by a spherical geometry with a residual contribution of the non-spherical components, both, fraction of perfusion and pseudo-diffusion, present a substantial (in the order of 30%) contribution of planar and linear components to the tensor metrics. This study shows that the IVIM perfusion estimates in the cerebral gray matter present a detectable deviation from the spherical model. These non-spherical components may reflect the direction-dependent morphology of the microcirculation. Therefore, the tensor generalization of the IVIM model may provide a tool for the non-invasive monitoring of cerebral capillary micro-architecture during development, aging or in pathologies.

Field strength dependence of grey matter R2* on venous oxygenation.

The relationship between venous blood oxygenation and change in transverse relaxation rate (ΔR2*) plays a key role in calibrated BOLD fMRI. This relationship, defined by the parameter ß, has previously been determined using theoretical simulations and experimental measures. However, these earlier studies have been confounded by the change in venous cerebral blood volume (CBV) in response to functional tasks. This study used a double-echo gradient echo EPI scheme in conjunction with a graded isocapnic hyperoxic sequence to assess quantitatively the relationship between the fractional venous blood oxygenation (1-Yv) and transverse relaxation rate of grey matter (ΔR2⁢GM*), without inducing a change in vCBV. The results demonstrate that the relationship between ΔR2* and fractional venous oxygenation at all magnet field strengths studied was adequately described by a linear relationship. The gradient of this relationship did not increase monotonically with field strength, which may be attributed to the relative contributions of intravascular and extravascular signals which will vary with both field strength and blood oxygenation.

Challenges in measuring individual differences in functional connectivity using fMRI: The case of healthy aging.

Many studies report individual differences in functional connectivity, such as those related to age. However, estimates of connectivity from fMRI are confounded by other factors, such as vascular health, head motion and changes in the location of functional regions. Here, we investigate the impact of these confounds, and pre-processing strategies that can mitigate them, using data from the Cambridge Centre for Ageing & Neuroscience (www.cam-can.com). This dataset contained two sessions of resting-state fMRI from 214 adults aged 18-88. Functional connectivity between all regions was strongly related to vascular health, most likely reflecting respiratory and cardiac signals. These variations in mean connectivity limit the validity of between-participant comparisons of connectivity estimates, and were best mitigated by regression of mean connectivity over participants. We also showed that high-pass filtering, instead of band-pass filtering, produced stronger and more reliable age-effects. Head motion was correlated with gray-matter volume in selected brain regions, and with various cognitive measures, suggesting that it has a biological (trait) component, and warning against regressing out motion over participants. Finally, we showed that the location of functional regions was more variable in older adults, which was alleviated by smoothing the data, or using a multivariate measure of connectivity. These results demonstrate that analysis choices have a dramatic impact on connectivity differences between individuals, ultimately affecting the associations found between connectivity and cognition. It is important that fMRI connectivity studies address these issues, and we suggest a number of ways to optimize analysis choices. Hum Brain Mapp 38:4125-4156, 2017. © 2017 Wiley Periodicals, Inc.

Analysis of vascular homogeneity and anisotropy on high-resolution primate brain imaging.

Using a systematic investigation of brain blood volume, in high-resolution synchrotron 3D images of microvascular structures within cortical regions of a primate brain, we challenge several basic questions regarding possible vascular bias in high-resolution functional neuroimaging. We present a bilateral comparison of cortical regions, where we analyze relative vascular volume in voxels from 150 to 1000 µm side lengths in the white and grey matter. We show that, if voxel size reaches a scale smaller than 300 µm, the vascular volume can no longer be considered homogeneous, either within one hemisphere or in bilateral comparison between samples. We demonstrate that voxel size influences the comparison between vessel-relative volume distributions depending on the scale considered (i.e., hemisphere, lobe, or sample). Furthermore, we also investigate how voxel anisotropy and orientation can affect the apparent vascular volume, in accordance with actual fMRI voxel sizes. These findings are discussed from the various perspectives of high-resolution brain functional imaging. Hum Brain Mapp 38:5756-5777, 2017. © 2017 Wiley Periodicals, Inc.