NeuroImage

An almost sinusoidal, large amplitude ~0.1 Hz oscillation in cortical hemodynamics has been repeatedly observed in species ranging from mice to humans. However, the occurrence of 'slow sinusoidal hemodynamic oscillations' (SSHOs) in human functional magnetic resonance imaging (fMRI) studies is rarely noted or considered. As a result, little investigation into the cause of SSHOs has been undertaken, and their potential to confound fMRI analysis, as well as their possible value as a functional biomarker has been largely overlooked. Here, we report direct observation of large-amplitude, sinusoidal ~0.1 Hz hemodynamic oscillations in the cortex of an awake human undergoing surgical resection of a brain tumor. Intraoperative multispectral optical intrinsic signal imaging (MS-OISI) revealed that SSHOs were spatially localized to distinct regions of the cortex, exhibited wave-like propagation, and involved oscillations in the diameter of specific pial arterioles, confirming that the effect was not the result of systemic blood pressure oscillations. fMRI data collected from the same subject 4 days prior to surgery demonstrates that ~0.1 Hz oscillations in the BOLD signal can be detected around the same region. Intraoperative optical imaging data from a patient undergoing epilepsy surgery, in whom sinusoidal oscillations were not observed, is shown for comparison. This direct observation of the '0.1 Hz wave' in the awake human brain, using both intraoperative imaging and pre-operative fMRI, confirms that SSHOs occur in the human brain, and can be detected by fMRI. We discuss the possible physiological basis of this oscillation and its potential link to brain pathologies, highlighting its relevance to resting-state fMRI and its potential as a novel target for functional diagnosis and delineation of neurological disease.

Blood oxygen level dependent (BOLD) spontaneous signals from resting-state (RS) brains have typically been characterized by low-pass filtered timeseries at frequencies≤0.1Hz, and studies of these low-frequency fluctuations have contributed exceptional understanding of the baseline functions of our brain. Very recently, emerging evidence has demonstrated that spontaneous activities may persist in higher frequency bands (even up to 0.8Hz), while presenting less variable network patterns across the scan duration. However, as an indirect measure of neuronal activity, BOLD signal results from an inherently slow hemodynamic process, which in fact might be too slow to accommodate the observed high-frequency functional connectivity (FC). To examine whether the observed high-frequency spontaneous FC originates from BOLD contrast, we collected RS data as a function of echo time (TE). Here we focus on two specific resting state networks - the default-mode network (DMN) and executive control network (ECN), and the major findings are fourfold: (1) we observed BOLD-like linear TE-dependence in the spontaneous activity at frequency bands up to 0.5Hz (the maximum frequency that can be resolved with TR=1s), supporting neural relevance of the RSFC at higher frequency range; (2) Conventional models of hemodynamic response functions must be modified to support resting state BOLD contrast, especially at higher frequencies; (3) there are increased fractions of non-BOLD-like contributions to the RSFC above the conventional 0.1Hz (non-BOLD/BOLD contrast at 0.4~0.5Hz is~4 times that at <0.1Hz); and (4) the spatial patterns of RSFC are frequency-dependent. Possible mechanisms underlying the present findings and technical concerns regarding RSFC above 0.1Hz are discussed. Copyright © 2014. Published by Elsevier Inc.

Proton-density-weighted fMRI at low field (0.2 T) was carried out in the cervical spinal cord of healthy volunteers in this study to examine the feasibility of detecting proton density alteration accompanying activation in the spinal cord. Subjects were asked to grip both hands simultaneously, providing sensorimotor simulation for spinal fMRI. Over 70% subjects recruited had activation localized at C6-C7 spinal levels with discrete activation detected in both the anterior and posterior horns of the cervical spinal cord, and the average fractional signal change was 4.06%. The 0.2 T low magnetic field and the 24 ms short TE used in this study diminished the BOLD effect to a negligible level, thus the observed signal change was believed to be mainly attributable to proton density increase during neuronal stimulation. Our results suggested the existence of task-driven proton density change in the cervical spinal cord.

Functional magnetic resonance imaging of healthy human volunteers was carried out at 0.2 T, using proton-density weighted (TE = 24 ms) spin-echo imaging, in order to eliminate any contribution from the blood oxygenation-level dependent (BOLD) effect. The purpose of the study was to verify the existence of a proton-density change contribution to spin-echo functional magnetic resonance imaging (fMRI) data. Results demonstrated signal intensity changes in motor and sensory areas of the brain during performance of a motor task and cold sensory stimulation of the hand, with signal changes ranging from 1.7 to 2.3%. These values are consistent with 1.9% signal changes observed previously under similar conditions at 3 T. These findings confirm the proton-density change contribution to spin-echo fMRI data and support the theory of signal enhancement by extravascular water protons (SEEP) as a non-BOLD fMRI contrast mechanism. This study also demonstrates that fMRI based on the SEEP contrast mechanism can be carried out at low fields where the BOLD effect is expected to be negligible.

Antagonism of the central opioid receptor like-1 receptor (ORL1) has been implicated in cognition, and has been a focus of drug discovery efforts to ameliorate the cognitive deficits that remain during the stable treatment of schizophrenia with current antipsychotics. In order to facilitate dose selection for phase II clinical testing an ORL1-specific PET tracer was developed to determine drug plasma concentration versus occupancy relationships in order to ensure that the doses selected and the degree of target engagement were sufficient to ensure adequate proof of concept testing. MK-0911 is a selective, high affinity antagonist for the ORL1 receptor radiolabeled with high specific activity (18)F for positron emission tomography (PET) studies. Evaluation of [(18)F]MK-0911 in rhesus monkey PET studies showed a pattern of brain uptake which was consistent with the known distribution of ORL1. In vitro autoradiography with [(18)F]MK-0911 in rhesus monkey and human brain tissue slices showed a regional distribution that was consistent with in vivo imaging results in monkey. Pre-treatment of rhesus monkeys with high doses of structurally diverse ORL1 antagonists MK-0584, MK-0337, or MK-5757 achieved blockade of [(18)F]MK-0911 in all grey matter regions. Baseline PET studies with [(18)F]MK-0911 in healthy human subjects showed tracer distribution and kinetics similar to that observed in rhesus monkey. Quantification of [(18)F]MK-0911 uptake in repeat human baseline PET studies showed a test-retest variability in volume of distribution (V(T)) averaging 3% across brain regions. Humans dosed orally with MK-5757 showed reduced [(18)F]MK-0911 tracer concentration in brain proportional with MK-5757 dose and plasma level. [(18)F]MK-0911 was useful for determining MK-5757-induced receptor occupancy of ORL1 to guide MK-5757 dose-selection for clinical proof-of-concept studies. Additionally, [(18)F]MK-0911 may be a useful tool for studying the pharmacology of ORL1 in various human populations and disease states.

Long-term potentiation (LTP), a model of activity-dependent synaptic plasticity, involves the persistent enhancement of excitatory neurotransmission. Several recent studies have suggested a critical role for nitric oxide (NO) production in hippocampal LTP. However, increase in NO production in living tissue has not yet been directly demonstrated. We used 1,2-diaminoanthraquinone (DAQ) to demonstrate NO production in rat brain slices in relation to induction of LTP. DAQ was found to be without neurotoxic effects and it neither influenced normal evoked field potential amplitudes nor did it affect induction of LTP in comparison to controls. We found that DAQ-induced fluorescence is elevated within a limited area of about 40,000 microm(2) during LTP induction in the hippocampal area CA1. Furthermore, we could demonstrate that application of the NO-synthetase inhibitor l-NAME inhibits the induction of LTP in area CA1 and causes a strong reduction of DAQ induced fluorescence. Our results are consistent with the hypothesis that NO can serve as a retrograde messenger during induction of LTP in the hippocampus.

Previous studies in patients with multiple sclerosis (MS) revealed increased lesion count and volume on 3 T compared to 1.5 T. Morphological and spatial lesion characteristics between 1.5 T and 3 T have not been examined. The aim of this study was to investigate the effect of changing from a 1.5 T to a 3 T MRI scanner on the number, volume and spatial distribution of signal abnormalities (SA) on brain MRI in a sample of MS patients and normal controls (NC), using pair- and voxel-wise comparison procedures. Forty-one (41) MS patients (32 relapsing-remitting and 9 secondary-progressive) and 38 NC were examined on both 1.5 T and 3 T within one week in random order. T2-weighted hyperintensities (T2H) and T1-weighted hypointensities (T1H) were outlined semiautomatically by two operators in a blinded fashion on 1.5 T and 3 T images. Spatial lesion distribution was assessed using T2 and T1 voxel-wise SA probability maps (SAPM). Pair-wise analysis examined the proportion of SA not simultaneously outlined on 1.5 T and 3 T. A posteriori unblinded analysis was conducted to examine the non-overlapping identifications of SA between the 1.5 T and 3 T. For pair-wise T2- and T1-analyses, a higher number and individual volume of SA were detected on 3 T compared to 1.5 T (p<0.0001) in both MS and NC. Logistic regression analysis showed that the likelihood of missing SA on 1.5 T was significantly higher for smaller SA in both MS and NC groups. SA probability map (SAPM) analysis revealed significantly more regionally distinct spatial SA differences on 3 T compared to 1.5 T in both groups (p<0.05); these were most pronounced in the occipital, periventricular and cortical regions for T2H. This study provides important information regarding morphological and spatial differences between data acquired using 1.5 T and 3 T protocols at the two scanner field strengths.

Caffeine lowers the blood oxygenation level-dependent (BOLD) signal by acting as an adenosine antagonist, thus decreasing the cerebral blood flow (CBF). The aims of this study were to demonstrate the sensitivity of susceptibility-weighted imaging (SWI) to caffeine-induced changes in CBF and to investigate the time course and magnitude of signal change in caffeine-habituated and -abstinent volunteers. High-resolution susceptibility-weighted images were acquired with both groups at 1.5 T using a fully velocity compensated 3D gradient echo sequence. Following a native scan, subjects were given a tablet containing 200 mg of caffeine. Scans were repeated for about 1 h and the acquired 3D data sets were co-registered to each other. BOLD signal changes of several venous vessels were analyzed in dedicated ROIs. Maps of relative signal change clearly visualized the caffeine-induced signal response of veins. Only very weak signal changes of about -2+/-1% were found in both, grey and white matter and -1+/-2% in the ventricles. Maximum signal decrease of veins occurred 40-50 min after caffeine ingestion. The signal decrease was -16.5+/-6.5% and -22.7+/-8.3% for the caffeine users group and abstainers, respectively. The signal difference of both groups was statistically significant (Student's t-test, t=2.16, p=0.021). Data acquired at 1.5, 3 and 7 T with echo times scaled to the respective field strength display very similar temporal signal behavior.

The ability to acquire MRI data with consistent tissue contrast at multiple time points, and/or across different imaging centres has become increasingly important as the number of large longitudinal and multicentre studies has grown. Here, the use of quantitative magnetic resonance relaxation times measurement, or, voxel-wise determination of the intrinsic longitudinal and transverse relaxation times, T1 and T2 respectively, for standardizing the structural imaging component of such studies is reported. To demonstrate the ability to standardize across multiple time-points and imaging centres, T1 and T2 maps of seven healthy volunteers were acquired using the rapid DESPOT1 and DESPOT2 (driven equilibrium single pulse observation of T1 and T2) mapping techniques at three centres across the United Kingdom (each centre utilizing scanners from competing manufacturers and/or with varying gradient performance). An average coefficient of variation of the estimates of T1 and T2 was found to be approximately 6.5% and 8%, respectively, across the three centres and comparable to that achieved between repeated imaging sessions performed at the same centre. With a total combined imaging time of less than 12 min for whole-brain approximately 1.2 mm isotropic voxel T1 and T2 maps, quantitative voxel-wise T1 and T2 mapping represents an attractive and easy-to-implement approach for signal intensity standardization and normalization. Further, as T1 and T2 are related to tissue microstructure and biochemistry, quantitative images provide additional diagnostic information that can be compared between patient and control populations, for example through voxel-based analysis techniques.

Most functional magnetic resonance imaging (fMRI) studies record the blood oxygen level-dependent (BOLD) signal using fast gradient-echo echo-planar imaging (GE EPI). However, GE EPI can suffer from substantial signal dropout caused by inhomogeneities in the static magnetic field. These field inhomogeneities occur near air/tissue interfaces, because they are generated by variations in magnetic susceptibilities. Thus, fMRI studies are often limited by a reduced BOLD sensitivity (BS) in inferior brain regions. Recently, a method has been developed which allows for optimizing the BS in dropout regions by specifically adjusting the slice tilt, the direction of the phase-encoding (PE), and the z-shim moment. However, optimal imaging parameters were only reported for the orbitofrontal cortex (OFC) and inferior temporal lobes. The present study determines the optimal slice tilt, PE direction, and z-shim moment at 3 T and 1.5 T, otherwise using standard fMRI acquisition parameters. Results are reported for all brain regions, yielding a whole-brain atlas of optimal parameters. At both field strengths, optimal parameters increase the BS by more than 60% in many voxels in the OFC and by at least 30% in the other dropout regions. BS gains are shown to be more widespread at 3 T, suggesting an increased benefit from the dropout compensation at higher fields. Even the mean BS of a large brain region, e.g., encompassing the medial OFC, can be increased by more than 15%. The maps of optimal parameters allow for assessing the feasibility and improving fMRI of brain regions affected by susceptibility-induced BS losses.

Patient outcome in minimally invasive stereotactic neurosurgical procedures depends on the ability to accurately locate the desired functional region within the deep brain while avoiding the surrounding anatomy. Due to the lack of sufficient contrast within this region in pre-operatively acquired MR images, electrophysiological exploration and histological atlases are currently required to define the surgical target within the thalamus in the treatment of many motor-control disorders. In this paper we introduce a method for segmenting the individual thalamic nuclei based on high-resolution quantitative magnetic resonance images, providing improved target visualization. The method was tested using whole-brain T1 and T2 data acquired from four healthy individuals. Accuracy of the segmentation results was assessed by comparing the center-of-mass coordinates of the segmented nuclei, with coordinates obtained from a classic histological atlas registered to these images. Strong agreement was found, with an average Euclidean distance difference of less than 4.5 mm averaged across all nuclei and all individuals. Reproducibility of the method, determined by calculating the percent similarity of segmentation results derived from data acquired from repeated scan sessions, was greater than 85%. These results illustrate the ability to accurately and reliably segment the primary nuclei of the thalamus and suggest that the method may have utility in the study of individual nuclear regions in disease state as well as for planning deep-brain surgical procedures.

Previous studies comparing fMRI data acquired at 1.5 T and higher field strengths have focused on examining signal increases in the visual and motor cortices. No information is, however, available on the relative gain, or the comparability of data, obtained at higher field strengths for other brain regions such as the prefrontal and other association cortices. In the present study, we investigated fMRI activation at 1.5 and 3 T during visual perception, visuospatial working memory, and affect-processing tasks. A 23% increase in striate and extrastriate activation volume was observed at 3 T compared with that for 1.5 T during the visual perception task. During the working memory task significant increases in activation volume were observed in frontal and parietal association cortices as well as subcortical structures, including the caudate, globus pallidus, putamen, and thalamus. Increases in working memory-related activation volume of 82, 73, 83, and 36% were observed in the left frontal, right frontal, left parietal, and right parietal lobes, respectively, for 3 T compared with 1.5 T. These increases were characterized by increased activation at 3 T in several prefrontal and parietal cortex regions that showed activation at 1.5 T. More importantly, at 3 T, activation was detected in several regions, such as the ventral aspects of the inferior frontal gyrus, orbitofrontal gyrus, and lingual gyrus, which did not show significant activation at 1.5 T. No difference in height or extent of activation was detected between the two scanners in the amygdala during affect processing. Signal dropout in the amygdala from susceptibility artifact was greater at 3 T, with a 12% dropout at 3 T compared with a 9% dropout at 1.5 T. The spatial smoothness of T2* images was greater at 3 T by less than 1 mm, suggesting that the greater extent of activation at 3 T beyond these spatial scales was not due primarily to increased intrinsic spatial correlations at 3 T. Rather, the increase in percentage of voxels activated reflects increased sensitivity for detection of brain activation at higher field strength. In summary, our findings suggest that functional imaging of prefrontal and other association cortices can benefit significantly from higher magnetic field strength.

Functional magnetic resonance imaging (fMRI) based on arterial spin labeling (ASL) perfusion contrast is an emergent methodology for visualizing brain function both at rest and during task performance. Because of the typical pairwise subtraction approach in generating perfusion images, ASL contrast manifests different noise properties and offers potential advantages for some experimental designs as compared with blood oxygenation-level-dependent (BOLD) contrast. We studied the noise properties and statistical power of ASL contrast, with a focus on temporal autocorrelation and spatial coherence, at both 1.5- and 4.0-T field strengths. Perfusion fMRI time series were found to be roughly independent in time, and voxelwise statistical analysis assuming independence of observations yielded false-positive rates compatible with theoretical values using appropriate analysis methods. Unlike BOLD fMRI data, perfusion data were not found to have spatial coherence that varied across temporal frequency. This finding has implications for the application of spatial smoothing to perfusion data. It was also found that the spatial coherence of the ASL data is greater at high magnetic field than low field, and including the global signal as a covariate in the general linear model improves the central tendency of test statistic as well as reduces the noise level in perfusion fMRI, especially at high magnetic field.

Previous studies have shown that under some conditions, noise fluctuations in an fMRI time-course are dominated by physiological modulations of the image intensity with secondary contributions from thermal image noise and that these two sources scale differently with signal intensity, susceptibility weighting (TE) and field strength. The SNR of the fMRI time-course was found to be near its asymptotic limit for moderate spatial resolution measurements at 3 T with only marginal gains expected from acquisition at higher field strengths. In this study, we investigate the amplitude of image intensity fluctuations in the fMRI time-course at magnetic field strengths of 1.5 T, 3 T, and 7 T as a function of image resolution, flip angle and TE. The time-course SNR was a similar function of the image SNR regardless of whether the image SNR was modulated by flip angle, image resolution, or field strength. For spatial resolutions typical of those currently used in fMRI (e.g., 3 x 3 x 3 mm(3)), increases in image SNR obtained from 7 T acquisition produced only modest increases in time-course SNR. At this spatial resolution, the ratio of physiological noise to thermal image noise was 0.61, 0.89, and 2.23 for 1.5 T, 3 T, and 7 T. At a resolution of 1 x 1 x 3 mm(3), however, the physiological to thermal noise ratio was 0.34, 0.57, and 0.91 for 1.5 T, 3 T and 7 T for TE near T2*. Thus, by reducing the signal strength using higher image resolution, the ratio of physiologic to image noise could be reduced to a regime where increased sensitivity afforded by higher field strength still translated to improved SNR in the fMRI time-series.

Variance estimates can be used in conjunction with scientifically meaningful effect sizes to design experiments with type II error control. Here we present estimates of intra- and inter-subject variances for region of interest (ROI) from resting cerebral blood flow (CBF) maps obtained using whole brain, spin echo echoplanar (SE-EPI) continuous arterial spin labeling (CASL) imaging on 52 elderly subjects (age=70.5+/-7.9 years, 29 males). There was substantial intrasubject systematic variability in CBF of gray matter ROIs corresponding to a range of standard deviations=[39-168] (ml/(100 g min)). This variability was mainly due to two factors: (1) an expected inverse relationship between ROI volume and intrasubject variance and (2) an increased effective post-labeling delay for more superior slices acquired later in the sequence. For example, intrasubject variance in Brodmann area 4 (BA 4) was approximately 8 times larger than in hippocampus, despite their similar gray matter volumes. Estimated ROI-wise power was computed for various numbers of acquired CBF images, numbers of subjects, and CBF effect sizes for two experimental designs: independent sample t-test and paired t-test. The theoretical effects of pulse sequence and field strength on general applicability of these results are discussed.

This study investigates some of the issues involved in magnetization transfer ratio (MTR) acquisition, and in particular aims to determine whether high quality in vivo MTR measurements can be made at 3.0 T. The dependency of the MTR white-to-grey matter contrast to noise ratio (CNR) on MT pulse characteristics at 1.5 T and at 3.0 T was investigated using an established two-pool model for MT. The simulations showed that MT pulse parameters optimizing the CNR can be derived for both field strengths. Both the SNR and the CNR of MTR maps at 3.0 T were increased compared to 1.5 T. Images obtained using a safe in vivo MTR acquisition protocol based on results of simulations at 3.0 T are presented.

Blood oxygenation level dependent (BOLD) signal changes occurring during execution of a simple motor task were measured at field strengths of 1.5, 3 and 7 T using multi-slice, single-shot, gradient echo EPI at a resolution of 1x1x3 mm(3), to quantify the benefits offered by ultra-high magnetic field for functional MRI. Using four different echo times at each field strength allowed quantification of the relaxation rate, R(2)* and the change in relaxation rate on activation, DeltaR(2)*. This work adds to previous studies of the field strength dependence of BOLD signal characteristics, through its: (i) focus on motor rather than visual cortex; (ii) use of single-shot, multi-slice, gradient echo EPI for data acquisition; (iii) co-registration of images acquired at different field strengths to allow assessment of the BOLD signal changes in the same region at each field strength. DeltaR(2)* was found to increase linearly with field strength (0.51+/-0.06 s(-1) at 1.5 T; 0.98+/-0.08 s(-1) at 3 T; 2.55+/-0.22 s(-1) at 7 T), while the ratio of DeltaR(2)*/R(2), which dictates the accessible BOLD contrast was also found to increase (0.042+/-0.002 at 1.5 T; 0.054+/-0.002 at 3 T; 0.084+/-0.003 at 7 T). The number of pixels classified as active, the t-value calculated over a common region of interest and the percentage signal change in the same region were all found to peak at TE approximately T(2)* and increase significantly with field strength. An earlier onset of the haemodynamic response at higher field provides some evidence for a reduced venous contribution to the BOLD signal at 7 T.

Gas calibrated fMRI in its most common form uses hypercapnia in conjunction with the Davis model to quantify relative changes in the cerebral rate of oxygen consumption (CMRO2) in response to a functional stimulus. It is most commonly carried out at 3T but, as 7T research scanners are becoming more widespread and the majority of clinical scanners are still 1.5T systems, it is important to investigate whether the model used remains accurate across this range of field strengths. Ten subjects were scanned at 1.5, 3 and 7T whilst performing a bilateral finger-tapping task as part of a calibrated fMRI protocol, and the results were compared to a detailed signal model. Simulations predicted an increase in value and variation in the calibration parameter M with field strength. Two methods of defining experimental regions of interest (ROIs) were investigated, based on (a) BOLD only and (b) BOLD responses within grey matter only. M values from the latter ROI were in closer agreement with theoretical predictions; however, reassuringly, ROI choice had less impact on CMRO2 than on M estimates. Relative changes in CMRO2 during motor tasks at 3 and 7T were in good agreement but were over-estimated at 1.5T as a result of the lower signal to noise ratio. This result is encouraging for future studies at 7T, but also highlights the impact of imaging and analysis choices (such as ASL sequence and ROI definition) on the calibration parameter M and on the calculation of CMRO2. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

A confound for functional magnetic resonance imaging (fMRI), especially for auditory studies, is the presence of imaging acoustic noise generated mainly as a byproduct of rapid gradient switching during volume acquisition and, to a lesser extent, the radiofrequency transmit. This work utilized a novel pulse sequence to present actual imaging acoustic noise for characterization of the induced hemodynamic responses and assessment of linearity in the primary auditory cortex with respect to noise duration. Results show that responses to brief duration (46 ms) imaging acoustic noise is highly nonlinear while responses to longer duration (>1 s) imaging acoustic noise becomes approximately linear, with the right primary auditory cortex exhibiting a higher degree of nonlinearity than the left for the investigated noise durations. This study also assessed the spatial extent of activation induced by imaging acoustic noise, showing that the use of modeled responses (specific to imaging acoustic noise) as the reference waveform revealed additional activations in the auditory cortex not observed with a canonical gamma variate reference waveform, suggesting an improvement in detection sensitivity for imaging acoustic noise-induced activity. Longer duration (1.5 s) imaging acoustic noise was observed to induce activity that expanded outwards from Heschl's gyrus to cover the superior temporal gyrus as well as parts of the middle temporal gyrus and insula, potentially affecting higher level acoustic processing.

Diffusion tensor imaging (DTI) is used to study tissue composition and architecture in vivo. To increase the signal to noise ratio (SNR) of DTI contrasts, studies typically use more than the minimum of 6 diffusion weighting (DW) directions or acquire repeated observations of the same set of DW directions. Simulation-based studies have sought to optimize DTI acquisitions and suggest that increasing the directional resolution of a DTI dataset (i.e., the number of distinct directions) is preferable to repeating observations, in an equal scan time comparison. However, it is not always clear how to translate these recommendations into practice when considering physiological noise and scanner stability. Furthermore, the effect of different DW schemes on in vivo DTI findings is not fully understood. This study characterizes how the makeup of a DW scheme, in terms of the number of directions, impacts the precision and accuracy of in vivo fractional anisotropy (FA), mean diffusivity (MD), and principal eigenvector (PEV) findings. Orientation dependence of DTI reliability is demonstrated in vivo and a principled theoretical framework is provided to support and interpret findings with simulation results. As long as sampling orientations are well balanced, differences in DTI contrasts due to different DW schemes are shown to be small relative to intra-session variability. These differences are accentuated at low SNR, while minimized at high SNR. This result suggests that typical clinical studies, which use similar protocols but different well-balanced DW schemes, are readily comparable within the experimental precision.

As population-based studies may obtain images from scanners with different field strengths, a method to normalize regional brain volumes according to intracranial volume (ICV) independent of field strength is needed. We found systematic differences in ICV estimation, tested in a cohort of healthy subjects (n=5) that had been imaged using 1.5T and 3T scanners, and confirmed in two independent cohorts. This was related to systematic differences in the intensity of cerebrospinal fluid (CSF), with higher intensities for CSF located in the ventricles compared with CSF in the cisterns, at 3T versus 1.5T, which could not be removed with three different applied bias correction algorithms. We developed a method based on tissue probability maps in MNI (Montreal Neurological Institute) space and reverse normalization (reverse brain mask, RBM) and validated it against manual ICV measurements. We also compared it with alternative automated ICV estimation methods based on Statistical Parametric Mapping (SPM5) and Brain Extraction Tool (FSL). The proposed RBM method was equivalent to manual ICV normalization with a high intraclass correlation coefficient (ICC=0.99) and reliable across different field strengths. RBM achieved the best combination of precision and reliability in a group of healthy subjects, a group of patients with Alzheimer's disease (AD) and mild cognitive impairment (MCI) and can be used as a common normalization framework.

Background: [(11)C]MDL100,907 is a promising positron emission tomography (PET) ligand for 5-HT(2A) receptor quantification in vivo. Studies suggest that [(11)C]MDL100,907 PET may be quantified by non-invasive reference tissue analyses using cerebellum as reference region. We systematically investigated the validity of such analyses. Methods: Five healthy volunteers underwent [(11)C]MDL100,907 PET at baseline and after mirtazapine pre-treatment. Regional time-activity curves of 10 regions of interest (ROI) were analyzed for binding potential (BP(ND)) and mirtazapine receptor occupancy (Occ) using: simplified reference tissue model (SRTM), multi-linear reference tissue model (MRTM), their two-parameter versions (SRTM2/MRTM2), non-invasive graphical analysis (NIGA) and a tissue activity concentration ratio. NIGA was also applied voxel-wise to generate BP(ND) maps. These methods were compared with a two-tissue compartment model with arterial input function (2TCM) Results: SRTM and MRTM frequently failed to yield reliable results. SRTM2 and MRTM2 gave virtually identical estimates of BP(ND), which were highly correlated with 2TCM analyses (R(2)>or=0.86) although with negative bias (-29+/-27% at baseline across all ROI). NIGA was less biased (-19+/-16%) and better correlated with 2TCM (R(2)>or=0.93). Regarding Occ, NIGA and SRTM2/MRTM2 showed comparable mean biases (-11+/-27% vs. -7+/-47%) but correlation with 2TCM was higher for NIGA (R(2)=0.90 vs. 0.77). NIGA parametric maps (analysed using identical ROI) resulted in moderate bias in BP(ND) (-26+/-22%; R(2)>or=0.88) and Occ (-17+/-36%; R(2)=0.78). Estimates obtained from tissue ratios performed least favourably. Conclusions: NIGA is well suited for analysis of [(11)C]MDL100,907 PET studies, yielding estimates of 5-HT(2A) receptor availability and changes that are highly correlated with results from invasive 2TCM analyses. This should greatly enhance the applicability of 5-HT(2A) receptor PET studies.

As researchers increase their efforts to characterize variations in the functional connectome across studies and individuals, concerns about the many sources of nuisance variation present and their impact on resting state fMRI (R-fMRI) measures continue to grow. Although substantial within-site variation can exist, efforts to aggregate data across multiple sites such as the 1000 Functional Connectomes Project (FCP) and International Neuroimaging Data-sharing Initiative (INDI) datasets amplify these concerns. The present work draws upon standardization approaches commonly used in the microarray gene expression literature, and to a lesser extent recent imaging studies, and compares them with respect to their impact on relationships between common R-fMRI measures and nuisance variables (e.g., imaging site, motion), as well as phenotypic variables of interest (age, sex). Standardization approaches differed with regard to whether they were applied post-hoc vs. during pre-processing, and at the individual vs. group level; additionally they varied in whether they addressed additive effects vs. additive + multiplicative effects, and were parametric vs. non-parametric. While all standardization approaches were effective at reducing undesirable relationships with nuisance variables, post-hoc approaches were generally more effective than global signal regression (GSR). Across approaches, correction for additive effects (global mean) appeared to be more important than for multiplicative effects (global SD) for all R-fMRI measures, with the exception of amplitude of low frequency fluctuations (ALFF). Group-level post-hoc standardizations for mean-centering and variance-standardization were found to be advantageous in their ability to avoid the introduction of artifactual relationships with standardization parameters; though results between individual and group-level post-hoc approaches were highly similar overall. While post-hoc standardization procedures drastically increased test-retest (TRT) reliability for ALFF, modest reductions were observed for other measures after post-hoc standardizations - a phenomena likely attributable to the separation of voxel-wise from global differences among subjects (global mean and SD demonstrated moderate TRT reliability for these measures). Finally, the present work calls into question previous observations of increased anatomical specificity for GSR over mean centering, and draws attention to the near equivalence of global and grey matter signal regression.