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.