Pulsed arterial spin labeling perfusion imaging at 3 T: estimating the number of subjects required in common designs of clinical trials

Pulsed arterial spin labeling (PASL) is an increasingly common technique for noninvasively measuring cerebral blood flow (CBF) and has previously been shown to have good repeatability. It is likely to find a place in clinical trials and in particular the investigation of pharmaceutical agents active in the central nervous system. We aimed to estimate the sample sizes necessary to detect regional changes in CBF in common types of clinical trial design including (a) between groups, (b) a two-period crossover and (3) within-session single dosing. Whole brain CBF data were acquired at 3 T in two independent groups of healthy volunteers at rest; one of the groups underwent a repeat scan. Using these data, we were able to estimate between-groups, between-session and within-session variability along with regional mean estimates of CBF. We assessed the number of PASL tag-control image pairs that was needed to provide stable regional estimates of CBF and variability of regional CBF across groups. Forty tag-control image pairs, which take approximately 3 min to acquire using a single inversion label delay time, were adequate for providing stable CBF estimates at the group level. Power calculations based on the variance estimates of regional CBF measurements suggest that comparatively small cohorts are adequate. For example, detecting a 15% change in CBF, depending on the region of interest, requires from 7-15 subjects per group in a crossover design, 6-10 subjects in a within-session design and 20-41 subjects in a between-groups design. Such sample sizes make feasible the use of such CBF measurements in clinical trials of drugs.     

Coupling of simultaneously acquired electrophysiological and haemodynamic responses during visual stimulation

We investigate the relationship between the temporal variation in the magnitude of occipital visual evoked potentials (VEPs) and of haemodynamic measures of brain activity obtained using both blood oxygenation level dependent (BOLD) and perfusion sensitive (ASL) functional magnetic resonance imaging (fMRI). Volunteers underwent a continuous BOLD fMRI scan and/or a continuous perfusion-sensitive (gradient and spin echo readout) ASL scan, during which 30 second blocks of contrast reversing visual stimuli (at 4 Hz) were interleaved with 30 second blocks of rest (visual fixation). Electroencephalography (EEG) and fMRI were simultaneously recorded and following EEG artefact cleaning, VEPs were averaged across the whole stimulation block (120 reversals, VEP₁₂₀) and at a finer timescale (15 reversals, VEP₁₅). Both BOLD and ASL time-series were linearly modelled to establish: (1) the mean response to visual stimulation, (2) transient responses at the start and end of each stimulation block, (3) the linear decrease between blocks, (4) the nonlinear between-block variation (covariation with VEP₁₂₀), (5) the linear decrease within block and (6) the nonlinear variation within block (covariation with VEP₁₅).     

Fine-scale functional connectivity in somatosensory cortex revealed by high-resolution fMRI

High-resolution functional magnetic resonance imaging (fMRI) at high field (9.4 T) has been used to measure functional connectivity between subregions within the primary somatosensory (SI) cortex of the squirrel monkey brain. The hand-face region within the SI cortex of the squirrel monkey has been previously well mapped with functional imaging and electrophysiological and anatomical methods, and the orderly topographic map of the hand region is characterized by a lateral to medial representation of individual digits in four subregions of areas 3a, 3b, 1 and 2. With submillimeter resolution, we are able to detect not only the separate islands of activation corresponding to vibrotactile stimulations of single digits but also, in subsequent acquisitions, the degree of correlation between voxels within the SI cortex in the resting state. The results suggest that connectivity patterns are very similar to stimulus-driven distributions of activity and that connectivity varies on the scale of millimeters within the same primary region. Connectivity strength is not a reflection of global larger-scale changes in blood flow and is not directly dependent on distance between regions. Preliminary electrophysiological recordings agree well with the fMRI data. In human studies at 7 T, high-resolution fMRI may also be used to identify the same subregions and assess responses to sensory as well as painful stimuli, and to measure connectivity dynamically before and after such stimulations.     

Unfolding the long-term pathophysiological processes following an acute inflammatory demyelinating lesion of multiple sclerosis

Background

Acute symptomatic inflammation is a main feature of multiple sclerosis but pathophysiological processes underlying total or partial recovery are poorly understood.

Objective

To characterize in vivo these processes at molecular, structural and functional levels using multimodal MR methods.

Methods

A neuroimaging 3-year follow-up (Weeks 0, 3, 11, 29, 59 and 169) was conducted on a 41-year-old woman presenting at baseline with a large acute demyelinating lesion of multiple sclerosis. Conventional magnetic resonance imaging (MRI), magnetization transfer imaging, diffusion-weighted imaging, functional MRI and magnetic resonance spectroscopy were conducted at 1.5 T.

Results

Patient presenting with subacute left hemiplegia recovered progressively (expended disability status scale 7 to 5.5). The MR exploration demonstrated structural functional and metabolic impairments at baseline. Despite restoration of the blood brain barrier integrity, high lactate levels persisted for several weeks concomitant with glial activation. Slow and progressive structural and metabolic restorations occurred from baseline to W169 (lesion volume −64%; apparent diffusion coefficient −14.7%, magnetization transfer ratio +14%, choline −51%, lipids −78%, N-acetylaspartate +77%) while functionality of the motor system recovered.

Conclusions

Multimodal MRI/MRS evidenced long-term dynamics recovery processes involving tissue repair, glial activation, recovery of neuronal function and functional systems. This may impact on customized rehabilitation strategies generally focused on the first months following the onset of symptoms.     

Temporal Dynamics of Brain Activity in Human Memory Processes

We propose a line of study by which Functional Magnetic Resonance Imaging (FMRI) can be used together with nonlinear dynamics concepts as a medium for the study of brain organization. The concentration is on (a) the complex behavior of elementary neural circuits, and how they interact over brief spans of time to produce cognition and memory; and (b) the change in circuit patterns associated with aging. The method of orbital decomposition appears to be ideally suited for these objectives and for determining how they integrate into hierarchical processes. The adapted procedure begins with a 3-D FMRI matrix of metabolic activity. Recurring patterns within a matrix row are identified and matched across rows and across depth slices. These hierarchical patterns are then compared over time for further recurrences. The computational procedure identifies the optimal pattern length over time, the patterns, and the largest Lyapunov for the system of patterns. Computations are assisted by statistical tests for the extent to which the isolated patterns represent the underlying data.