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. In conventional arterial spin labeling (ASL) techniques, including both pulsed ASL (PASL) (1-5) and continuous ASL (CASL) (6 -8), arterial blood is tagged by magnetic inversion or saturation proximal to the region of interest (ROI). Tagged blood then flows into the ROI, and the inflow is detected as a modulation of the longitudinal magnetization. In these techniques there is necessarily a spatial gap between the tagging location and the ROI. This gap results in a transit delay (␦t) for the delivery of tagged blood to the ROI. The gap (and hence the delay) can be small for single-slice imaging, but is larger for multislice or volume acquisitions. The magnitude and variability of the transit delay in relation to the T 1 decay of the tag is one of the largest potential sources of errors in the quantitation of perfusion using ASL in the normal human brain (5,6,9). In stroke and other pathologies in which flow may be slow or may follow circuitous collateral routes of delivery, ␦t can be much larger than T 1 (10), which makes conventional ASL an impractical method for obtaining accurate measures of CBF.We recently introduced a new ASL method in which the tag pulse is purely velocity-selective (VS) and not spatially-selective. This allows for the tagging of all flowing spins within a specified velocity range, regardless of location, and can in principle eliminate the problem of transit delays. We refer to this technique as VSASL, and in this work we describe the implementation of VSASL, as well as some of the considerations involved in the design of VSASL pulse sequences and the quantitation of perfusion using this technique. VSASL was introduced in abstract form in Ref. 11, and some of the issues addressed herein were described in suggested the use of VS pulses in ASL, but did not present an implementation of VSASL. THEORYIn principle, the elements of a VSASL pulse sequence are similar to those of a conventional ASL experiment and include a tagging pulse that modifies the magnetization of inflowing arterial spins, followed by a delay (TI) to allow for inflow, and a rapid image...

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.

We use a novel balanced experimental design to specifically investigate brain mechanisms underlying the modulating effect of expected pain intensity on afferent nociceptive processing and pain perception. We used two visual cues, each conditioned to one of two noxious thermal stimuli [ϳ48°C (high) or 47°C (low)]. The visual cues were presented just before and during application of the noxious thermal stimulus. Subjects reported significantly higher pain when the noxious stimulus was preceded by the high-intensity visual cue. To control for expectancy effects, for one-half of the runs, the noxious thermal stimuli were accompanied by the cue conditioned to the other stimulus. Comparing functional magnetic resonance imaging blood oxygenation level-dependent activations produced by the high and low thermal stimulus intensities presented with the high-intensity visual cue showed significant activations in nociceptive regions of the thalamus, second somatosensory cortex, and insular cortex. To isolate the effect of expectancy, we compared activations produced by the two visual cues presented with the high-intensity noxious thermal stimulus; this showed significant differences in the ipsilateral caudal anterior cingulate cortex, the head of the caudate, cerebellum, and the contralateral nucleus cuneiformis (nCF). We propose that pain intensity expectancy modulates activations produced by noxious stimuli through a distinct modulatory network that converges with afferent nociceptive input in the nCF.

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 (∼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.

The magnitude and shape of Blood Oxygen Level Dependent (BOLD) responses in functional Magnetic Resonance Imaging (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 breath holding 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.Handwerker, Daniel A 3

Alzheimer’s disease researchers have been intrigued by the selective regional vulnerability of the brain to amyloid-β 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-β 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-β 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-β-positive) and 20 amyloid-β-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-β and cognitive impairment, indicating exacerbation of ageing-related processes in Alzheimer’s disease. In contrast, amyloid-β deposition dominated in posterior-medial regions. A subsample of 50 cognitively normal older (26 amyloid-β-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-β) was related to worse scene performance (P = 0.037, r = 0.309). The functional MRI data revealed that tau burden (but not amyloid-β) 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-β 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.

The apparent diffusion tensor (ADT) imaging method was extended to account for multiple diffusion components. A biexponential ADT imaging experiment was used to obtain separate images of rapidly and slowly diffusing water fractions in excised rat spinal cord. The fast and slow component tensors were compared and found to exhibit similar gross features, such as fractional anisotropy, in both white and gray matter. However, there were also some important differences, which are consistent with the different structures occupying intracellular and extracellular spaces. Evidence supporting the assignment of the two tensor components to extracellular and intracellular water fractions is provided by an NMR spectroscopic investigation of homogeneous samples of brain tissue. An underlying assumption for the apparent diffusion tensor (ADT) imaging method, as implemented to date, is that tissue water can be represented by a single diffusing component within each image pixel. The ADT method of Basser et al. (1,2) is an extension of the monoexponential isotropic diffusion model of Stejskal and Tanner (3), which takes into account diffusion anisotropy. NMR imaging and spectroscopic studies have shown, however, that at high diffusion weighting (b Ͼ 1500 s/mm 2 ) cells and tissues exhibit signal decay that is not monoexponential and may reflect the extracellular and intracellular water compartments (4 -12). The consequences of multiexponentiality on apparent diffusion coefficient (ADC) and ADT imaging have been recognized (8), but separate images of distinct water compartments have not been reported.In this work the ADT formalism of Basser et al.(1,2) is extended to account specifically for biexponential diffusion (13). For monoexponential diffusion, a series of diffusion-weighted images may be used to compute a singlerate ADT image by fitting to:where b is the diffusion weighting factor, S is the b-dependent signal intensity, S 0 is the (T 2 -weighted) signal intensity in the absence of diffusion-weighting gradients, b ij is the matrix of diffusion-weighting terms (14), D ij is the i,j th element of the ADT, and i,j ϭ x,y,z. For a two-compartment model under the assumption of slow exchange (i.e., minimal water exchanges compartments between excitation and signal reception), Eq.[1] may be expanded to a linear combination of observable signal components (15):where S 0f and S 0s are the (T 2 -weighted) signal intensities in the absence of diffusion weighting gradients and the subscripts f and s denote fast and slow components of diffusion, respectively. The suitability of a biexponential ADT analysis was first tested using ADT spectroscopy on homogeneous samples of nervous tissue. Spectroscopic experiments simplified data acquisition and facilitated direct comparisons of volume fractions determined by biexponential ADT and biexponential T 2 methods. Similar compartments have also been observed using multiexponential analyses of T 2 (16 -18). Next, biexponential ADT imaging was applied to a sample of fixed normal rat spinal cord. T...

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.