Associations between regional blood-brain barrier permeability, aging, and Alzheimer's disease biomarkers in cognitively normal older adults.

BACKGROUND: Increased blood-brain barrier permeability (BBBp) has been hypothesized as a feature of aging that may lead to the development of Alzheimer's disease (AD). We sought to identify the brain regions most vulnerable to greater BBBp during aging and examine their regional relationship with neuroimaging biomarkers of AD. METHODS: We studied 31 cognitively normal older adults (OA) and 10 young adults (YA) from the Berkeley Aging Cohort Study (BACS). Both OA and YA received dynamic contrast-enhanced MRI (DCE-MRI) to quantify Ktrans values, as a measure of BBBp, in 37 brain regions across the cortex. The OA also received Pittsburgh compound B (PiB)-PET to create distribution volume ratios (DVR) images and flortaucipir (FTP)- PET to create partial volume corrected standardized uptake volume ratios (SUVR) images. Repeated measures ANOVA assessed the brain regions where OA showed greater BBBp than YA. In OA, Ktrans values were compared based on sex, Aß positivity status, and APOE4 carrier status within a composite region across the areas susceptible to aging. We used linear models and sparse canonical correlation analysis (SCCA) to examine the relationship between Ktrans and AD biomarkers. RESULTS: OA showed greater BBBp than YA predominately in the temporal lobe, with some involvement of parietal, occipital and frontal lobes. Within an averaged ROI of affected regions, there was no difference in Ktrans values based on sex or Aß positivity, but OA who were APOE4 carriers had significantly higher Ktrans values. There was no direct relationship between averaged Ktrans and global Aß pathology, but there was a trend for an Ab status by tau interaction on Ktrans in this region. SCCA showed increased Ktrans was associated with increased PiB DVR, mainly in temporal and parietal brain regions. There was not a significant relationship between Ktrans and FTP SUVR. DISCUSSION: Our findings indicate that the BBB shows regional vulnerability during normal aging that overlaps considerably with the pattern of AD pathology. Greater BBBp in brain regions affected in aging is related to APOE genotype and may also be related to the pathological accumulation of Aß.

Cerebral perfusion in post-stroke aphasia and its relationship to residual language abilities.

Stroke alters blood flow to the brain resulting in damaged tissue and cell death. Moreover, the disruption of cerebral blood flow (perfusion) can be observed in areas surrounding and distal to the lesion. These structurally preserved but suboptimally perfused regions may also affect recovery. Thus, to better understand aphasia recovery, the relationship between cerebral perfusion and language needs to be systematically examined. In the current study, we aimed to evaluate (i) how stroke affects perfusion outside of lesioned areas in chronic aphasia and (ii) how perfusion in specific cortical areas and perilesional tissue relates to language outcomes in aphasia. We analysed perfusion data from a large sample of participants with chronic aphasia due to left hemisphere stroke (n = 43) and age-matched healthy controls (n = 25). We used anatomically defined regions of interest that covered the frontal, parietal, and temporal areas of the perisylvian cortex in both hemispheres, areas typically known to support language, along with several control regions not implicated in language processing. For the aphasia group, we also looked at three regions of interest in the perilesional tissue. We compared perfusion levels between the two groups and investigated the relationship between perfusion levels and language subtest scores while controlling for demographic and lesion variables. First, we observed that perfusion levels outside the lesioned areas were significantly reduced in frontal and parietal regions in the left hemisphere in people with aphasia compared to the control group, while no differences were observed for the right hemisphere regions. Second, we found that perfusion in the left temporal lobe (and most strongly in the posterior part of both superior and middle temporal gyri) and inferior parietal areas (supramarginal gyrus) was significantly related to residual expressive and receptive language abilities. In contrast, perfusion in the frontal regions did not show such a relationship; no relationship with language was also observed for perfusion levels in control areas and all right hemisphere regions. Third, perilesional perfusion was only marginally related to language production abilities. Cumulatively, the current findings demonstrate that blood flow is reduced beyond the lesion site in chronic aphasia and that hypoperfused neural tissue in critical temporoparietal language areas has a negative impact on behavioural outcomes. These results, using perfusion imaging, underscore the critical and general role that left hemisphere posterior temporal regions play in various expressive and receptive language abilities. Overall, the study highlights the importance of exploring perfusion measures in stroke.

Interactive effects of locus coeruleus structure and catecholamine synthesis capacity on cognitive function.

Background: The locus coeruleus (LC) produces catecholamines (norepinephrine and dopamine) and is implicated in a broad range of cognitive functions including attention and executive function. Recent advancements in magnetic resonance imaging (MRI) approaches allow for the visualization and quantification of LC structure. Human research focused on the LC has since exploded given the LC's role in cognition and relevance to current models of psychopathology and neurodegenerative disease. However, it is unclear to what extent LC structure reflects underlying catecholamine function, and how LC structure and neurochemical function are collectively associated with cognitive performance. Methods: A partial least squares correlation (PLSC) analysis was applied to 19 participants' LC structural MRI measures and catecholamine synthesis capacity measures assessed using [18F]Fluoro-m-tyrosine ([18F]FMT) positron emission tomography (PET). Results: We found no direct association between LC-MRI and LC-[18F]FMT measures for rostral, middle, or caudal portions of the LC. We found significant associations between LC neuroimaging measures and neuropsychological performance that were driven by rostral and middle portions of the LC, which is in line with LC cortical projection patterns. Specifically, associations with executive function and processing speed arose from contributions of both LC structure and interactions between LC structure and catecholamine synthesis capacity. Conclusion: These findings leave open the possibility that LC MRI and PET measures contribute unique information and suggest that their conjoint use may increase sensitivity to brain-behavior associations in small samples.

Xenotransplantation of porcine progenitor cells in an epileptic California sea lion (Zalophus californianus): illustrative case.

BACKGROUND: Domoic acid (DA) is a naturally occurring neurotoxin harmful to marine animals and humans. California sea lions exposed to DA in prey during algal blooms along the Pacific coast exhibit significant neurological symptoms, including epilepsy with hippocampal atrophy. OBSERVATIONS: Here the authors describe a xenotransplantation procedure to deliver interneuron progenitor cells into the damaged hippocampus of an epileptic sea lion with suspected DA toxicosis. The sea lion has had no evidence of seizures after the procedure, and clinical measures of well-being, including weight and feeding habits, have stabilized. LESSONS: These preliminary results suggest xenotransplantation has improved the quality of life for this animal and holds tremendous therapeutic promise.

Human CSF movement influenced by vascular low frequency oscillations and respiration.

Cerebrospinal fluid (CSF) movement through the pathways within the central nervous system is of high significance for maintaining normal brain health and function. Low frequency hemodynamics and respiration have been shown to drive CSF in humans independently. Here, we hypothesize that CSF movement may be driven simultaneously (and in synchrony) by both mechanisms and study their independent and coupled effects on CSF movement using novel neck fMRI scans. Caudad CSF movement at the fourth ventricle and hemodynamics of the major neck blood vessels (internal carotid arteries and internal jugular veins) was measured from 11 young, healthy volunteers using novel neck fMRI scans with simultaneous measurement of respiration. Two distinct models of CSF movement (1. Low-frequency hemodynamics and 2. Respiration) and possible coupling between them were investigated. We show that the dynamics of brain fluids can be assessed from the neck by studying the interrelationships between major neck blood vessels and the CSF movement in the fourth ventricle. We also demonstrate that there exists a cross-frequency coupling between these two separable mechanisms. The human CSF system can respond to multiple coupled physiological forces at the same time. This information may help inform the pathological mechanisms behind CSF movement-related disorders.

Coupling between cerebrovascular oscillations and CSF flow fluctuations during wakefulness: An fMRI study.

It is commonly believed that cerebrospinal fluid (CSF) movement is facilitated by blood vessel wall movements (i.e., hemodynamic oscillations) in the brain. A coherent pattern of low frequency hemodynamic oscillations and CSF movement was recently found during non-rapid eye movement (NREM) sleep via functional MRI. This finding raises other fundamental questions: 1) the explanation of coupling between hemodynamic oscillations and CSF movement from fMRI signals; 2) the existence of the coupling during wakefulness; 3) the direction of CSF movement. In this resting state fMRI study, we proposed a mechanical model to explain the coupling between hemodynamics and CSF movement through the lens of fMRI. Time delays between CSF movement and global hemodynamics were calculated. The observed delays between hemodynamics and CSF movement match those predicted by the model. Moreover, by conducting separate fMRI scans of the brain and neck, we confirmed the low frequency CSF movement at the fourth ventricle is bidirectional. Our finding also demonstrates that CSF movement is facilitated by changes in cerebral blood volume mainly in the low frequency range, even when the individual is awake.

Broadband selective excitation radiofrequency pulses for optimized localization in vivo.

PURPOSE: The aim of the study is to optimize the performance of localized 1 H MRS sequences at 3T, using the entire spin system of N-acetyl aspartate (NAA) as an example of the large chemical shift spread of all the metabolites routinely detected in vivo, including the amide region. We specifically focus on the design of the suitable broadband excitation radiofrequency (RF) pulses to minimize chemical shift artifacts. METHODS: The performance of the excitation and refocusing pulse shapes is evaluated with respect to NAA localization. Two new excitation RF pulses are developed to achieve optimized performance in the brain using single-voxel 1 H MRS at 3T. Numerical simulations and in vivo experiments are carried out to demonstrate the performance of the RF pulses. RESULTS: New excitation RF pulses with the same B1 requirements but larger excitation bandwidth (up to a factor of 2) are shown to significantly reduce localization artifacts. The large frequency spread of the entire NAA spin system necessitates the use of broadband excitation and refocusing pulses for MRS at 3T. CONCLUSION: To minimize chemical shift artifacts of metabolic compounds with spins in the amide area (>5 ppm) at 3T it is important to use broadband excitation and refocusing pulses.

A guide for concurrent TMS-fMRI to investigate functional brain networks.

Transcranial Magnetic Stimulation (TMS) allows for the direct activation of neurons in the human neocortex and has proven to be fundamental for causal hypothesis testing in cognitive neuroscience. By administering TMS concurrently with functional Magnetic Resonance Imaging (fMRI), the effect of cortical TMS on activity in distant cortical and subcortical structures can be quantified by varying the levels of TMS output intensity. However, TMS generates significant fluctuations in the fMRI time series, and their complex interaction warrants caution before interpreting findings. We present the methodological challenges of concurrent TMS-fMRI and a guide to minimize induced artifacts in experimental design and post-processing. Our study targeted two frontal-striatal circuits: primary motor cortex (M1) projections to the putamen and lateral prefrontal cortex (PFC) projections to the caudate in healthy human participants. We found that TMS parametrically increased the BOLD signal in the targeted region and subcortical projections as a function of stimulation intensity. Together, this work provides practical steps to overcome common challenges with concurrent TMS-fMRI and demonstrates how TMS-fMRI can be used to investigate functional brain networks.

An MRI protocol for anatomical and functional evaluation of the California sea lion brain.

BACKGROUND: Domoic acid (DOM) is a neurotoxin produced by some harmful algae blooms in coastal waters. California sea lions (Zalophus californianus) exposed to DOM often strand on beaches where they exhibit a variety of symptoms, including seizures. These animals typically show hippocampal atrophy on MRI scans. NEW METHOD: We describe an MRI protocol for comprehensive evaluation of DOM toxicosis in the sea lion brain. We intend to study brain development in pups exposed in utero. The protocol depicts the hippocampal formation as the primary region of interest. We include scans for quantitative morphometry, functional and structural connectivity, and a cerebral blood flow map. RESULTS: High-resolution 3D anatomical scans facilitate post hoc slicing in arbitrary planes and accurate morphometry. We demonstrate the first cerebral blood flow map using MRI, and the first structural tractography from a live sea lion brain. COMPARISON WITH EXISTING METHODS: Scans were compared to prior anatomical and functional studies in live sea lions, and structural connectivity in post mortem specimens. Hippocampal volumes were broadly in line with prior studies, with differences likely attributable to the 3D approach used here. Functional connectivity of the dorsal left hippocampus matched that found in a prior study conducted at a lower magnetic field, while structural connectivity in the live brain agreed with findings observed in post mortem studies. CONCLUSIONS: Our protocol provides a comprehensive, longitudinal view of the functional and anatomical changes expected to result from DOM toxicosis. It can also screen for other common neurological pathologies and is suitable for any pinniped that can fit inside an MRI scanner.

Methylsulfonylmethane (MSM): A chemical shift reference for 1 H MRS of human brain.

PURPOSE: We investigate the potential of a common dietary supplement, methylsulfonylmethane (MSM), to act as a chemical shift reference for in vivo 1 H MR spectroscopy (MRS). The scope of the investigation is 2-fold: (1) We use high-resolution nuclear MR (NMR) measurements of the chemical shift values of MSM to establish the stability of MSM resonance across the ranges of pH and temperature, and (2) we demonstrate MR properties of MSM in the healthy human brain. METHODS: The relationship of chemical shift with temperature and pH is examined using high-resolution 1 H NMR (14.1T) spectra of MSM in aqueous solution. MSM concentration in human brain tissue was measured as a function of time, together with the relaxation properties in the brain using 1 H MRS at 3T. RESULTS: The chemical shift of MSM remains stable in the range of the biologically relevant temperatures and pH values. The chemical shift at pH = 7.2 and 37°C was measured to be 3.142 ppm (relative to DSS, a common water-soluble NMR reference compound). Time course in the brain tissue in vivo confirmed an observable MSM signal 10 minutes after oral intake and a stable signal intensity within a ~3-hour window. CONCLUSION: The chemical and biological properties of MSM-rapid crossing of the blood-brain barrier, water solubility, a singlet resonance resolved from metabolite resonances, chemical shift stability with respect to pH/temperature, and stable temporal presence in the brain-lead us to propose its use as a frequency reference for MRS.

Locus coeruleus imaging as a biomarker for noradrenergic dysfunction in neurodegenerative diseases.

Pathological alterations to the locus coeruleus, the major source of noradrenaline in the brain, are histologically evident in early stages of neurodegenerative diseases. Novel MRI approaches now provide an opportunity to quantify structural features of the locus coeruleus in vivo during disease progression. In combination with neuropathological biomarkers, in vivo locus coeruleus imaging could help to understand the contribution of locus coeruleus neurodegeneration to clinical and pathological manifestations in Alzheimer's disease, atypical neurodegenerative dementias and Parkinson's disease. Moreover, as the functional sensitivity of the noradrenergic system is likely to change with disease progression, in vivo measures of locus coeruleus integrity could provide new pathophysiological insights into cognitive and behavioural symptoms. Locus coeruleus imaging also holds the promise to stratify patients into clinical trials according to noradrenergic dysfunction. In this article, we present a consensus on how non-invasive in vivo assessment of locus coeruleus integrity can be used for clinical research in neurodegenerative diseases. We outline the next steps for in vivo, post-mortem and clinical studies that can lay the groundwork to evaluate the potential of locus coeruleus imaging as a biomarker for neurodegenerative diseases.

Alzheimer's pathology targets distinct memory networks in the ageing brain.

Alzheimer's disease researchers have been intrigued by the selective regional vulnerability of the brain to amyloid-ß plaques and tau neurofibrillary tangles. Post-mortem studies indicate that in ageing and Alzheimer's disease tau tangles deposit early in the transentorhinal cortex, a region located in the anterior-temporal lobe that is critical for object memory. In contrast, amyloid-ß pathology seems to target a posterior-medial network that subserves spatial memory. In the current study, we tested whether anterior-temporal and posterior-medial brain regions are selectively vulnerable to tau and amyloid-ß deposition in the progression from ageing to Alzheimer's disease and whether this is reflected in domain-specific behavioural deficits and neural dysfunction. 11C-PiB PET and 18F-flortaucipir uptake was quantified in a sample of 131 cognitively normal adults (age: 20-93 years; 47 amyloid-ß-positive) and 20 amyloid-ß-positive patients with mild cognitive impairment or Alzheimer's disease dementia (65-95 years). Tau burden was relatively higher in anterior-temporal regions in normal ageing and this difference was further pronounced in the presence of amyloid-ß and cognitive impairment, indicating exacerbation of ageing-related processes in Alzheimer's disease. In contrast, amyloid-ß deposition dominated in posterior-medial regions. A subsample of 50 cognitively normal older (26 amyloid-ß-positive) and 25 young adults performed an object and scene memory task while functional MRI data were acquired. Group comparisons showed that tau-positive (n = 18) compared to tau-negative (n = 32) older adults showed lower mnemonic discrimination of object relative to scene images [t(48) = -3.2, P = 0.002]. In a multiple regression model including regional measures of both pathologies, higher anterior-temporal flortaucipir (tau) was related to relatively worse object performance (P = 0.010, r = -0.376), whereas higher posterior-medial PiB (amyloid-ß) was related to worse scene performance (P = 0.037, r = 0.309). The functional MRI data revealed that tau burden (but not amyloid-ß) was associated with increased task activation in both systems and a loss of functional specificity, or dedifferentiation, in posterior-medial regions. The loss of functional specificity was related to worse memory. Our study shows a regional dissociation of Alzheimer's disease pathologies to distinct memory networks. While our data are cross-sectional, they indicate that with ageing, tau deposits mainly in the anterior-temporal system, which results in deficits in mnemonic object discrimination. As Alzheimer's disease develops, amyloid-ß deposits preferentially in posterior-medial regions additionally compromising scene discrimination and anterior-temporal tau deposition worsens further. Finally, our findings propose that the progression of tau pathology is linked to aberrant activation and dedifferentiation of specialized memory networks that is detrimental to memory function.

Feasibility of functional MRI at ultralow magnetic field via changes in cerebral blood volume.

We investigate the feasibility of performing functional MRI (fMRI) at ultralow field (ULF) with a Superconducting QUantum Interference Device (SQUID), as used for detecting magnetoencephalography (MEG) signals from the human head. While there is negligible magnetic susceptibility variation to produce blood oxygenation level-dependent (BOLD) contrast at ULF, changes in cerebral blood volume (CBV) may be a sensitive mechanism for fMRI given the five-fold spread in spin-lattice relaxation time (T1) values across the constituents of the human brain. We undertook simulations of functional signal strength for a simplified brain model involving activation of a primary cortical region in a manner consistent with a blocked task experiment. Our simulations involve measured values of T1 at ULF and experimental parameters for the performance of an upgraded ULFMRI scanner. Under ideal experimental conditions we predict a functional signal-to-noise ratio of between 3.1 and 7.1 for an imaging time of 30 min, or between 1.5 and 3.5 for a blocked task experiment lasting 7.5 min. Our simulations suggest it may be feasible to perform fMRI using a ULFMRI system designed to perform MRI and MEG in situ.

Ultralow-field and spin-locking relaxation dispersion in postmortem pig brain.

PURPOSE: To investigate tissue-specific differences, a quantitative comparison was made between relaxation dispersion in postmortem pig brain measured at ultralow fields (ULF) and spin locking at 7 tesla (T). The goal was to determine whether ULF-MRI has potential advantages for in vivo human brain imaging. METHODS: Separate specimens of gray matter and white matter were investigated using an ULF-MRI system with superconducting quantum interference device (SQUID) signal detection to measure T1ULF at fields from 58.7 to 235.0 µT and using a commercial MRI scanner to measure T1ρ7T at spin-locking fields from 5.0 to 235.0 µT. RESULTS: At matched field strengths, T1ρ7T is 50 to 100% longer than T1ULF. Furthermore, dispersion in T1ULF is close to linear between 58.7 and 235 µT, whereas dispersion in T1ρ7T is highly nonlinear over the same range. A subtle elbow in the T1ULF dispersion at approximately 140 µT is tentatively attributed to the local dipolar field of macromolecules. It is suggested that different relaxation mechanisms dominate each method and that ULF-MRI has a fundamentally different sensitivity to the macromolecular structure of neural tissue. CONCLUSIONS: Ultralow-field MRI may offer distinct, quantitative advantages for human brain imaging, while simultaneously avoiding the severe heating limitation imposed on high-field spin locking. Magn Reson Med 78:2342-2351, 2017. © 2016 International Society for Magnetic Resonance in Medicine.

Comparison of non-invasive MRI measurements of cerebral blood flow in a large multisite cohort.

UNLABELLED: Arterial spin labeling and phase contrast magnetic resonance imaging provide independent non-invasive methods for measuring cerebral blood flow. We compared global cerebral blood flow measurements obtained using pseudo-continuous arterial spin labeling and phase contrast in 436 middle-aged subjects acquired at two sites in the NHLBI CARDIA multisite study. Cerebral blood flow measured by phase contrast (CBFPC: 55.76 ± 12.05 ml/100 g/min) was systematically higher (p < 0.001) and more variable than cerebral blood flow measured by pseudo-continuous arterial spin labeling (CBFPCASL: 47.70 ± 9.75). The correlation between global cerebral blood flow values obtained from the two modalities was 0.59 (p < 0.001), explaining less than half of the observed variance in cerebral blood flow estimates. Well-established correlations of global cerebral blood flow with age and sex were similarly observed in both CBFPCASL and CBFPC CBFPC also demonstrated statistically significant site differences, whereas no such differences were observed in CBFPCASL No consistent velocity-dependent effects on pseudo-continuous arterial spin labeling were observed, suggesting that pseudo-continuous labeling efficiency does not vary substantially across typical adult carotid and vertebral velocities, as has previously been suggested. CONCLUSIONS: Although CBFPCASL and CBFPC values show substantial similarity across the entire cohort, these data do not support calibration of CBFPCASL using CBFPC in individual subjects. The wide-ranging cerebral blood flow values obtained by both methods suggest that cerebral blood flow values are highly variable in the general population.

MRI of the human brain at 130 microtesla.

We present in vivo images of the human brain acquired with an ultralow field MRI (ULFMRI) system operating at a magnetic field B0 ~ 130 µT. The system features prepolarization of the proton spins at Bp ~ 80 mT and detection of the NMR signals with a superconducting, second-derivative gradiometer inductively coupled to a superconducting quantum interference device (SQUID). We report measurements of the longitudinal relaxation time T1 of brain tissue, blood, and scalp fat at B0 and Bp, and cerebrospinal fluid at B0. We use these T1 values to construct inversion recovery sequences that we combine with Carr-Purcell-Meiboom-Gill echo trains to obtain images in which one species can be nulled and another species emphasized. In particular, we show an image in which only blood is visible. Such techniques greatly enhance the already high intrinsic T1 contrast obtainable at ULF. We further present 2D images of T1 and the transverse relaxation time T2 of the brain and show that, as expected at ULF, they exhibit similar contrast. Applications of brain ULFMRI include integration with systems for magnetoencephalography. More generally, these techniques may be applicable, for example, to the imaging of tumors without the need for a contrast agent and to modalities recently demonstrated with T1ρ contrast imaging (T1 in the rotating frame) at fields of 1.5 T and above.

Pyrolytic graphite foam: a passive magnetic susceptibility matching material.

PURPOSE: To evaluate a novel soft, lightweight cushion that can match the magnetic susceptibility of human tissue. The magnetic susceptibility difference between air and tissue produces field inhomogeneities in the B(0) field, which leads to susceptibility artifacts in magnetic resonance imaging (MRI) studies. MATERIALS AND METHODS: Pyrolytic graphite (PG) microparticles were uniformly embedded into a foam cushion to reduce or eliminate field inhomogeneities at accessible air and tissue interfaces. 3T MR images and field maps of an air/water/PG foam phantom were acquired. Q measurements on a 4T tuned head coil and pulse sequence heating tests at 3T were also performed. RESULTS: The PG foam improved susceptibility matching, reduced the field perturbations in phantoms, does not heat, and is nonconductive. CONCLUSION: The susceptibility matched PG foam is lightweight, safe for patient use, adds no noise or MRI artifacts, is compatible with radiofrequency coil arrays, and improves B(0) homogeneity, which enables more robust MR studies.

Reducing vascular variability of fMRI data across aging populations using a breathholding task.

The magnitude and shape of blood oxygen level-dependent (BOLD) responses in functional MRI (fMRI) studies vary across brain regions, subjects, and populations. This variability may be secondary to neural activity or vasculature differences, thus complicating interpretations of BOLD signal changes in fMRI experiments. We compare the BOLD responses to neural activity and a vascular challenge and test a method to dissociate these influences in 26 younger subjects (ages 18-36) and 24 older subjects (ages 51-78). Each subject performed a visuomotor saccade task (a vascular response to neural activity) and a breathholding task (vascular dilation induced by hypercapnia) during separate runs in the same scanning session. For the saccade task, signal magnitude showed a significant decrease with aging in FEF, SEF, and V1, and a delayed time-to-peak with aging in V1. The signal magnitudes from the saccade and hypercapnia tasks showed significant linear regressions within subjects and across individuals and populations. These two tasks had weaker, but sometimes significant linear regressions for time-to-peak and coherence phase measures. The significant magnitude decrease with aging in V1 remained after dividing the saccade task magnitude by the hypercapnia task magnitude, implying that the signal decrease is neural in origin. These findings may lead to a method to identify vascular reactivity-induced differences in the BOLD response across populations and the development of methods to account for the influence of these vasculature differences in a simple, noninvasive manner.

Analysis of oxygen metabolism implies a neural origin for the negative BOLD response in human visual cortex.

The sustained negative blood oxygenation level-dependent (BOLD) response in functional MRI is observed universally, but its interpretation is controversial. The origin of the negative response is of fundamental importance because it could provide a measurement of neural deactivation. However, a substantial component of the negative response may be due to a non-neural hemodynamic artifact. To distinguish these possibilities, we have measured evoked BOLD, cerebral blood flow (CBF), and oxygen metabolism responses to a fixed visual stimulus from two different baseline conditions. One is a normal resting baseline, and the other is a lower baseline induced by a sustained negative response. For both baseline conditions, CBF and oxygen metabolism responses reach the same peak amplitude. Consequently, evoked responses from the negative baseline are larger than those from the resting baseline. The larger metabolic response from negative baseline presumably reflects a greater neural response that is required to reach the same peak amplitude as that from resting baseline. Furthermore, the ratio of CBF to oxygen metabolism remains approximately the same from both baseline states (approximately 2:1). This tight coupling between hemodynamic and metabolic components implies that the magnitude of any hemodynamic artifact is inconsequential. We conclude that the negative response is a functionally significant index of neural deactivation in early visual cortex.

Velocity-selective arterial spin labeling.

In pathologies in which slow or collateral flow conditions may exist, conventional arterial spin labeling (ASL) methods that apply magnetic tags based on the location of arterial spins may not provide robust measures of cerebral blood flow (CBF), as the transit delay for the delivery of blood to target tissues may far exceed the relaxation time of the tag. Here we describe current methods for ASL with velocity-selective (VS) tags (termed VSASL) that do not require spatial selectivity and can thus provide quantitative measures of CBF under slow and collateral flow conditions. The implementation of a robust multislice VSASL technique is described in detail, and data obtained with this technique are compared with those obtained with conventional pulsed ASL (PASL). The technical considerations described here include the design of VS pulses, background suppression, anisotropy with respect to velocity-encoding directions, and CBF quantitation issues.